Clinical trial NCT04058353
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2019-08-28; Completion date: 2020-06-12
Enrollment: 271 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety and pharmacodynamics of elexacaftor (ELX, VX-445) in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are heterozygous for F508del and a gating or residual function mutation (F/G and F/RF genotypes).

Detailed description:

Arms: arm 1: Following an IVA or TEZ/IVA run-in period of 4 weeks, participants either received IVA 150 milligrams (mg) every 12 hours (q12h) or TEZ 100 mg once daily (qd)/IVA 150 mg q12h in the treatment period for 8 weeks. arm 2: Following an IVA or TEZ/IVA run-in period of 4 weeks, participants received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 8 weeks.
Interventions: intervention 1: ELX/TEZ/IVA intervention 2: IVA intervention 3: TEZ/IVA
Intervention descriptions: intervention 1: FDC tablet for oral administration. intervention 2: Mono-tablet for oral administration. intervention 3: Fixed-dose combination (FDC) tablet for oral administration.

Protocol documents:
Prot_000.pdf: 
Page 1 of 69 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 3, Randomized, Double-blind, Controlled 
Study Evaluating the Efficacy and Safety of VX-445 
Combination Therapy in Subjects With Cystic 
Fibrosis Who Are Heterozygous for the F508del 
Mutation and a Gating or Residual Function Mutation 
(F/G and F/RF Genotypes) 
Vertex Study Number: VX18-445-104 
 
EudraCT Number: 2018-002835-76 
Date of Protocol: 02 December 2019 (Version 2.0)  
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 
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Summary of Changes to the Protocol 
The previous version of this protocol (Version 1.0, 30 May 2019) was amended to create the 
current version (Version 2.0, 02 December 2019). The protocol history is provided below. 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 30 May 2019 
Original version 
Version 2.0, 02 December 2019 
Current version 
 
Key changes in the current version of the protocol are summarized below. 
Change and Rationale  
Affected Sections  
Absolute change in BMI from baseline at Week 8 was added as an exploratory 
endpoint to meet an FDA post-marketing commitment. 
Sections 2, 7.3, and 12.3.3.5 
 
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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of 
VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Heterozygous for the 
F508del Mutation and a Gating or Residual Function Mutation (F/G and F/RF Genotypes) 
  
Brief Title 
A Phase 3 Study of VX-445 Combination Therapy in Cystic Fibrosis (CF) Subjects 
Heterozygous for F508del and a Gating or Residual Function Mutation (F/G and F/RF 
Genotypes) 
 
 
Clinical Phase 
and Clinical 
Study Type  
Phase 3, efficacy and safety  
 
 
Objectives 
Primary Objective 
To evaluate the efficacy of VX-445/tezacaftor (TEZ)/ivacaftor (IVA) in CF subjects who are 
heterozygous for F508del and a gating or residual function mutation (F/G and F/RF genotypes) 
Secondary Objectives 
• To evaluate the safety of VX-445/TEZ/IVA  
• To evaluate the pharmacodynamics (PD) of VX-445/TEZ/IVA 
 
 
Endpoints 
Primary Endpoint 
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline through Week 8 for the VX-445/TEZ/IVA group 
Key Secondary Endpoints 
• Absolute change in sweat chloride (SwCl) from baseline through Week 8 for the 
VX-445/TEZ/IVA group  
• Absolute change in ppFEV1 from baseline through Week 8 for the VX-445/TEZ/IVA group 
compared to the control group 
• Absolute change in SwCl from baseline through Week 8 for the VX-445/TEZ/IVA group 
compared to the control group 
Other Secondary Endpoints  
• Absolute change in CF Questionnaire-Revised (CFQ-R) respiratory domain (RD) score from 
baseline through Week 8 for the VX-445/TEZ/IVA group 
• Absolute change in CFQ-R RD score from baseline through Week 8 for the 
VX-445/TEZ/IVA group compared to the control group 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
ECGs, vital signs, and pulse oximetry 
Exploratory Endpoints 
• 
Absolute change in CFQ-R non-RD scores from baseline through Week 8 
• 
Absolute change in body mass index (BMI) from baseline at Week 8 
• 
Inflammatory mediators 
• 
Blood biomarkers 
 
 
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Number of 
Subjects 
Approximately 250 subjects will be enrolled in the study: 
 Approximately 40% of total subjects will be in the IVA comparator group (approximately 
100 subjects) 
o In the IVA comparator group, up to 20% of subjects may be enrolled with an R117H 
mutation (approximately 20 subjects) 
 Up to 15% of total subjects may be enrolled with SwCl values <30 mmol/L at screening 
(approximately 40 subjects) 
Subjects will be randomized (1:1) to the VX-445/TEZ/IVA treatment arm or the control arm 
(IVA or TEZ/IVA).  
Study 
Population 
Male and female CF subjects 12 years of age or older with F/G and F/RF genotypes 
 
 
Investigational 
Drug 
During the Run-in Period, study drug refers to TEZ/IVA and IVA, as applicable. 
During the Treatment Period, study drug refers to VX-445/TEZ/IVA and matching placebo, 
TEZ/IVA and matching placebo, and IVA and matching placebo, as applicable. 
Active study drugs will be orally administered as fixed-dose combination (FDC) film-coated 
tablets of VX-445/TEZ/IVA or TEZ/IVA and film-coated IVA tablets. 
 
Active substance: VX-445/TEZ/IVA 
 
Activity: VX-445 is a CFTR corrector, TEZ is a CFTR corrector, and IVA is a CFTR potentiator 
(increased Clˉ secretion) 
 
Strength: 100 mg/50 mg/75 mg FDC tablet 
 
 
 
Active substance: TEZ/IVA 
 
Activity: CFTR corrector and CFTR potentiator (increased Clˉ secretion) 
 
Strength: 100 mg/150 mg FDC tablet 
 
 
 
Active substance: IVA 
 
Activity: CFTR potentiator (increased Clˉ secretion) 
 
Strength: 150 mg tablet 
 
 
Study Duration 
The total study duration is approximately 20 weeks (4 weeks for the Screening Period, 4 weeks 
for the Run-in Period, 8 weeks for the Treatment Period, and 4 weeks for the Safety Follow-up 
Period). 
 
 
Study Design 
This is a Phase 3, randomized, double-blind, active-controlled, parallel-group, multicenter study 
(Figure 2-1). 
In the Run-in Period, subjects will be assigned to the IVA or TEZ/IVA comparator group based 
on genotype. Subjects assigned to the IVA comparator group will receive IVA 150 mg every 
12 hours (q12h) and subjects assigned to the TEZ/IVA comparator group will receive 
TEZ 100 mg once daily (qd)/IVA 150 mg q12h (Table 2-1).  
In the Treatment Period, subjects will be randomized (1:1) to the VX-445/TEZ/IVA treatment 
arm or control arm under a single randomization scheme. Subjects in the control arm who 
received IVA in the Run-in Period will receive IVA in the Treatment Period; subjects in the 
control arm who received TEZ/IVA in the Run-in Period will receive TEZ/IVA in the Treatment 
Period. 
Randomization will be stratified based on comparator group (IVA comparator versus TEZ/IVA 
comparator), ppFEV1 as determined during the Run-in Period (Day -14 assessment; <70 versus 
≥70), and SwCl as determined during the Run-in Period (Day -14 assessment; <30 mmol/L 
versus ≥30 mmol/L). 
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Table 2-1 
Treatment Groups and Dosages 
Comparator 
Group 
Treatment Arm 
VX-445 
Dosage 
TEZ Dosage 
IVA Dosage 
IVA 
VX-445/TEZ/IVA 
200 mg qd 
100 mg qd 
150 mg q12h 
Control 
0 mg 
0 mg 
150 mg q12h 
TEZ/IVA 
VX-445/TEZ/IVA 
200 mg qd 
100 mg qd 
150 mg q12h 
Control 
0 mg 
100 mg qd 
150 mg q12h 
IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TEZ: tezacaftor 
 
Figure 2-1 
VX18-445-104 Study Design 
 
IVA: ivacaftor; ppFEV1: percent predicted forced expiratory volume in 1 second; SwCl: sweat 
chloride; TC: triple combination; TEZ: tezacaftor  
Note: The Safety Follow-up Visit is not required for subjects who complete the Week 8 Visit 
and enroll in an open-label study within 28 days after the last dose of study drug.  
a 
Subjects will be randomized 1:1 to the TC arm or the control arm. Randomization will be 
stratified based on comparator group (IVA comparator versus TEZ/IVA comparator), 
ppFEV1 as determined during the Run-in Period (Day -14 assessment; <70 versus ≥70), 
and SwCl as determined during the Run-in Period (Day -14 assessment; <30 mmol/L 
versus ≥30 mmol/L). 
 
 
Assessments 
Efficacy: Spirometry and CFQ-R 
PD: SwCl 
Safety: AEs, clinical laboratory assessments, ECGs, vital signs, pulse oximetry, physical 
examinations, and ophthalmologic exams (for subjects <18 years of age) 
Pharmacokinetics (PK): VX-445, TEZ, M1-TEZ, and IVA plasma concentrations 
Exploratory: DNA sample (optional), inflammatory mediators, blood biomarker samples, and 
sputum samples 
 
 
Statistical 
Analyses 
Approximately 250 subjects will be enrolled and randomized (1:1) to the VX-445/TEZ/IVA 
treatment arm or control arm (IVA or TEZ/IVA). 
The primary efficacy endpoint is the absolute change in ppFEV1 from baseline through Week 8 
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for the VX-445/TEZ/IVA group. The primary null hypothesis to be tested is that the mean 
absolute change in ppFEV1 from baseline through Week 8 is 0 for the VX-445/TEZ/IVA 
treatment group. The null hypothesis will be tested at a 2-sided significance level of 0.05.  
For the primary hypothesis, assuming a within-group SD of 7.0 percentage points and a 10% 
dropout rate at Week 8, a sample size of 125 subjects in the VX-445/TEZ/IVA arm will have 
>99% power to detect the within-group difference of 3.0 percentage points (1 sample t-test at a 
2-sided significance level of 0.05).   
The primary endpoint will be analyzed using a mixed-effects model for repeated measures 
(MMRM). The model will include the absolute change from baseline in ppFEV1 at Day 15, 
Week 4, and Week 8 as the dependent variable; treatment group, visit, and treatment by visit as 
fixed effects; with continuous baseline ppFEV1, continuous baseline SwCl, and comparator 
group (IVA comparator versus TEZ/IVA comparator) as covariates; and an unstructured 
covariance structure for the within-subject errors. 
For the primary endpoint, the results obtained from the model will be the estimated 
within-treatment difference through Week 8 (average of Week 4 and Week 8) for the 
VX-445/TEZ/IVA group. The same model will be used to estimate between group differences 
(difference between VX-445/TEZ/IVA and the control group) through Week 8. The adjusted 
mean with a 2-sided 95% CI and a 2-sided P value will be provided for the primary endpoint and 
second key secondary endpoints.  
The safety endpoints include AEs, clinical laboratory values, ECGs, vital signs, and pulse 
oximetry through completion of study participation. The safety analyses will be descriptive only. 
 
 
IDMC Reviews 
An independent data monitoring committee (IDMC) will conduct safety reviews of study data as 
outlined in the IDMC charter. 
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3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are in Table 3-1 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). For example, the Week 8 (± 5 days) Visit would occur after 8 weeks of study 
drug administration in the Treatment Period has been completed. 
The Cystic Fibrosis Questionnaire-Revised (CFQ-R) must be completed before any other 
assessment (except signing of the informed consent form [ICF]) at relevant clinic visits. 
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. 
 
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Table 3-1 
Study VX18-445-104: Screening 
Event/Assessment 
Screening Period 
Day -56 Through Day -29 
 
Comments 
ICF and assent (when applicable)  
X 
 
Inclusion and exclusion criteria 
review 
X 
Sections 8.1 and 8.2 
Demographics 
X 
Section 11.1 
Medical history 
X 
CFTR genotype 
X 
Performed for all subjects (Section 11.6.2). In 
subjects with an R117H mutation, linkage to 
poly-T tract polymorphisms will also be 
determined from a second specimen. 
A subject’s screening CFTR genotype must 
confirm eligibility before the subject enters the 
Run-in Period (Section 8.1). 
FSH 
X 
Performed for any suspected postmenopausal 
female with at least 12 months of continuous 
spontaneous amenorrhea (Section 11.6.2) 
Serum pregnancy test (all 
females) 
X 
Section 11.6.2 
Hematology 
X 
Coagulation 
X 
Serum chemistry 
X 
Urinalysis 
X 
Weight and height 
X 
Measured with shoes off (Section 11.1) 
OE 
X 
Conducted only for subjects who are <18 years 
of age on the date of informed consent 
(Section 11.6.6) 
Complete physical examination 
X 
Section 11.6.3 
Vital signs 
X 
Performed after subject has been at rest for at 
least 5 minutes (Sections 11.6.3, 11.6.4, and 
11.6.5) 
Pulse oximetry 
X 
Standard 12-lead ECG 
X 
Spirometry 
X 
May be performed pre- or post-bronchodilator 
(Section 11.5.1) 
Medications review 
X 
Section 9.5 
Sweat chloride 
X 
Section 11.3 
AEs and SAEs 
Continuous from signing 
of the ICF through 
completion of study 
participation 
Sections 9.1.7, 13.1.1.3, and 13.1.2.2 
AE: adverse events; FSH: follicle-stimulating hormone; ICF: informed consent form; OE: ophthalmologic examination; 
SAE: serious adverse event 
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Table 3-2 
VX18-445-104: Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessmenta 
Run-in Period 
(4 Weeks) 
Treatment Period (8 Weeks) 
ETT 
Visitb 
Safety Follow-up 
Visit 
28 (± 7) Days 
After the Last Dose 
of Study Drug (If 
Applicable)c 
Comments 
Day -28 
± 1 Day 
Day -14  
± 2 Days 
Day 1d 
Day 15 
± 3 Days 
Week 4 
± 5 Days 
Week 8 
± 5 Days 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
 
Inclusion and 
exclusion criteria 
confirmation 
X 
 
 
 
 
 
 
 
Section 8 
CFQ-R 
X 
 
X 
X 
X 
X 
X 
X 
Must be completed before any 
other assessments at relevant 
clinic visits (Section 11.5.2). 
Weight and height 
X 
 
X 
X 
X 
X 
X 
X 
Measured with shoes off. Height 
will only be collected for subjects 
≤21 years of age on the date of 
informed consent (Section 11.1). 
OE 
 
 
 
 
 
 
 
X 
For subjects <18 years of age on 
the date of informed consent, an 
OE is required during Safety 
Follow-up only if the subject 
completed study drug dosing 
through Week 8 of the Treatment 
Period (Section 11.6.6) 
Physical examination 
Abbrev 
  
Complete 
 
 
Complete 
Complete 
 
Section 11.6.3 
Pregnancy testing 
Urine 
 
Urine 
  
Urine 
Urine 
Serum 
Serum 
All female subjects 
(Section 11.6.2) 
Standard 12-lead 
ECG 
X 
 
X 
X 
X 
X 
X 
X 
After subject has rested for at 
least 5 minutes and before dosing, 
as applicable (Section 11.6.5) 
 
a 
All assessments will be performed before dosing unless noted otherwise. 
b  
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to discontinue 
treatment. Subjects who prematurely discontinue treatment during the Treatment Period will continue to complete all scheduled study visits for assessments 
following completion of the ETT Visit (Section 9.1.5). 
c 
The Safety Follow-Up Visit is required for all subjects, unless the subject completes the Week 8 Visit and has enrolled in an open-label study within 28 days 
after the last dose of study drug (Section 9.1.4). If an 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 (Section 9.1.5). 
d 
To enter the Treatment Period, conditions for entry (Section 9.1.3) must be satisfied. 
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Table 3-2 
VX18-445-104: Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessmenta 
Run-in Period 
(4 Weeks) 
Treatment Period (8 Weeks) 
ETT 
Visitb 
Safety Follow-up 
Visit 
28 (± 7) Days 
After the Last Dose 
of Study Drug (If 
Applicable)c 
Comments 
Day -28 
± 1 Day 
Day -14  
± 2 Days 
Day 1d 
Day 15 
± 3 Days 
Week 4 
± 5 Days 
Week 8 
± 5 Days 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
After subject has been at rest for 
at least 5 minutes and before 
dosing, as applicable 
(Sections 11.6.3 and 11.6.4) 
Pulse oximetry  
X 
 
X 
X 
X 
X 
X 
X 
Spirometry 
 
X 
X 
X 
X 
X 
X 
X 
Must be performed before dosing, 
and should be performed 
pre-bronchodilator 
(Section 11.5.1) at approximately 
the same time at each visit. 
SwCl 
 
X 
X 
X 
X 
X 
X 
 
Must occur before dosing. At each 
time point, 2 samples will be 
collected, 1 from each arm (left 
and right) (Section 11.3) 
Urinalysis 
X 
 
X 
 
 
X 
X 
X 
Section 11.6.2 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
Day -28 and Day 1: Blood 
samples will be collected before 
the first dose of study drug in each 
study period (Section 11.6.2) 
Coagulation 
X 
 
X 
 
 
X 
X 
X 
Serum chemistry 
X 
 
X 
X 
X 
X 
X 
X 
PK sampling 
 
 
X 
X 
X 
X 
X 
 
Day 1, Day 15, and Week 4: 
Predose PK within 60 minutes 
before dosing (Section 11.2.1) 
Week 8: Predose PK within 
60 minutes before dosing for 
subjects receiving their first dose 
of study drug in an open-label 
study. For other subjects, the 
blood sample should be collected 
approximately 12 hours after the 
evening dose of IVA before the 
Week 8 Visit (Section 11.2.1) 
DNA sample 
(optional) 
 
 
X 
 
 
 
 
 
Section 11.4.1 
Inflammatory 
mediator samples 
X 
 
X 
 
 
X 
X 
 
Section 11.4.2 
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Table 3-2 
VX18-445-104: Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessmenta 
Run-in Period 
(4 Weeks) 
Treatment Period (8 Weeks) 
ETT 
Visitb 
Safety Follow-up 
Visit 
28 (± 7) Days 
After the Last Dose 
of Study Drug (If 
Applicable)c 
Comments 
Day -28 
± 1 Day 
Day -14  
± 2 Days 
Day 1d 
Day 15 
± 3 Days 
Week 4 
± 5 Days 
Week 8 
± 5 Days 
Blood biomarker 
samples 
X 
 
X 
 
 
X 
X 
 
Section 11.4.3 
Blood sample for 
RNA 
X 
 
X 
 
 
X 
X 
 
Sputum sample 
X 
 
X 
 
 
X 
X 
 
Collected from subjects who can 
produce a sample spontaneously 
(Section 11.4.4) 
Run-in dosing 
Day -28 to evening on 
Day -1 
 
 
 
A subject’s screening CFTR 
genotype must confirm eligibility 
before the subject enters the 
Run-in Period (Section 9.1.2 and 
Section 11.6.2). Run-in dosing 
details for each comparator group 
are provided in Section 9.6.1. 
Run-in drug count 
X 
X 
X 
 
 
 
 
 
Section 10.6 
Randomization 
 
 
X 
 
 
 
 
 
Randomization may occur on 
either Day -1 or Day 1, after 
conditions for entry into the 
Treatment Period (Section 9.1.3) 
have been met. 
Randomized study 
drug dosing 
 
 
Day 1 through evening before the Week 8 
Visit 
 
 
Subjects will be randomized 1:1 
to the VX-445 200 mg qd/ 
TEZ 100 mg qd/IVA 150 mg 
q12h arm or the control arm 
(IVA 150 mg q12h or TEZ 
100 mg qd/IVA 150 mg q12h, 
depending on comparator group 
assignment) (Section 9.6.1). 
Randomized study 
drug count 
 
 
X 
X 
X 
X 
X 
 
Section 10.6 
Medications review 
Continuous from signing of ICF through completion of study participation 
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 
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Table 3-2 
VX18-445-104: Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessmenta 
Run-in Period 
(4 Weeks) 
Treatment Period (8 Weeks) 
ETT 
Visitb 
Safety Follow-up 
Visit 
28 (± 7) Days 
After the Last Dose 
of Study Drug (If 
Applicable)c 
Comments 
Day -28 
± 1 Day 
Day -14  
± 2 Days 
Day 1d 
Day 15 
± 3 Days 
Week 4 
± 5 Days 
Week 8 
± 5 Days 
AEs and SAEs  
Continuous from signing of ICF through completion of study participation 
Completion of study participation 
is defined in Section 9.1.7. Refer 
to Sections 13.1.1.3 and 13.1.2.2 
for reporting and documentation 
of AEs and SAEs. 
Abbrev: abbreviated; AE: adverse event; CFQ-R: CF Questionnaire-Revised; ETT: Early Termination of Treatment; ICF: informed consent form; IVA: ivacaftor; OE: 
ophthalmologic examination; PK: pharmacokinetic; SAE: serious adverse event; SwCl: sweat chloride; TEZ: tezacaftor 
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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
Summary of Changes to the Protocol......................................................................................... 2 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 7 
4 
Table of Contents ................................................................................................................. 13 
List of Tables............................................................................................................................ 16 
Table of Figures ....................................................................................................................... 16 
List of Abbreviations................................................................................................................ 17 
5 
Introduction.......................................................................................................................... 20 
5.1 
Background ..................................................................................................................... 20 
5.2 
Study Rationale .............................................................................................................. 20 
6 
Study Objectives .................................................................................................................. 21 
6.1 
Primary Objective ........................................................................................................... 21 
6.2 
Secondary Objectives ..................................................................................................... 21 
7 
Study Endpoints ................................................................................................................... 21 
7.1 
Primary Endpoint ............................................................................................................ 21 
7.2 
Secondary Endpoints ...................................................................................................... 21 
7.2.1 
Key Secondary Endpoints ...................................................................................... 21 
7.2.2 
Other Secondary Endpoints .................................................................................... 21 
7.3 
Exploratory Endpoints .................................................................................................... 21 
8 
Study Population .................................................................................................................. 22 
8.1 
Inclusion Criteria ............................................................................................................ 22 
8.2 
Exclusion Criteria ........................................................................................................... 22 
9 
Study Implementation ......................................................................................................... 24 
9.1 
Study Design .................................................................................................................. 24 
9.1.1 
Screening ................................................................................................................ 25 
9.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 26 
9.1.1.2 
Rescreening ...................................................................................................... 26 
9.1.1.3 
Extension of Screening Period Window .......................................................... 26 
9.1.2 
Run-in Period .......................................................................................................... 26 
9.1.3 
Treatment Period .................................................................................................... 27 
9.1.4 
Safety Follow-up .................................................................................................... 27 
9.1.5 
Early Termination of Treatment ............................................................................. 27 
9.1.5.1 
Discontinuation During the Run-in Period ...................................................... 27 
9.1.5.2 
Discontinuation During the Treatment Period ................................................. 28 
9.1.6 
Lost to Follow-up ................................................................................................... 28 
9.1.7 
Completion of Study Participation ......................................................................... 28 
9.1.8 
Independent Data Monitoring Committee .............................................................. 28 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 29 
9.3 
Rationale for Study Elements ......................................................................................... 29 
9.3.1 
Study Design........................................................................................................... 29 
9.3.2 
Study Population..................................................................................................... 29 
9.3.3 
Study Drug Dose .................................................................................................... 30 
9.3.4 
Rationale for Study Assessments ........................................................................... 30 
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9.4 
Study Restrictions ........................................................................................................... 30 
9.4.1 
Prohibited Medications ........................................................................................... 30 
9.5 
Prior and Concomitant Medications ............................................................................... 31 
9.6 
Administration ................................................................................................................ 32 
9.6.1 
Dosing ..................................................................................................................... 32 
9.6.2 
Missed Doses .......................................................................................................... 33 
9.7 
Dose Modification for Toxicity ...................................................................................... 33 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 33 
9.8.1 
Liver Function Tests ............................................................................................... 34 
9.8.2 
Rash ........................................................................................................................ 35 
9.9 
Removal of Subjects ....................................................................................................... 35 
9.10 Replacement of Subjects ................................................................................................ 35 
10 Study Drug Information and Management ....................................................................... 36 
10.1 Preparation and Dispensing ............................................................................................ 36 
10.2 Packaging and Labeling ................................................................................................. 36 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 36 
10.4 Drug Accountability ....................................................................................................... 37 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 37 
10.6 Compliance ..................................................................................................................... 37 
10.7 Blinding and Unblinding ................................................................................................ 37 
10.7.1 
Blinding .................................................................................................................. 37 
10.7.2 
Unblinding .............................................................................................................. 38 
11 Assessments .......................................................................................................................... 39 
11.1 Subject and Disease Characteristics ............................................................................... 39 
11.2 Pharmacokinetics ............................................................................................................ 39 
11.2.1 
Blood Sampling ...................................................................................................... 39 
11.2.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 40 
11.2.3 
Bioanalysis.............................................................................................................. 40 
11.3 Pharmacodynamics: Sweat Chloride .............................................................................. 40 
11.4 Exploratory Assessments ................................................................................................ 40 
11.4.1 
Pharmacogenomics ................................................................................................. 40 
11.4.2 
Inflammatory Mediators ......................................................................................... 40 
11.4.3 
Other Blood Biomarkers ......................................................................................... 40 
11.4.4 
Microbiology and Other Sputum Biomarkers ........................................................ 41 
11.5 Efficacy ........................................................................................................................... 41 
11.5.1 
Spirometry .............................................................................................................. 41 
11.5.2 
Cystic Fibrosis Questionnaire-Revised .................................................................. 42 
11.6 Safety .............................................................................................................................. 42 
11.6.1 
Adverse Events ....................................................................................................... 42 
11.6.2 
Clinical Laboratory Assessments ........................................................................... 42 
11.6.3 
Physical Examinations and Vital Signs .................................................................. 44 
11.6.4 
Pulse Oximetry ....................................................................................................... 44 
11.6.5 
Electrocardiograms ................................................................................................. 44 
11.6.6 
Ophthalmologic Examination ................................................................................. 45 
11.6.7 
Contraception and Pregnancy ................................................................................. 45 
11.6.7.1 Contraception ................................................................................................... 45 
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11.6.7.2 Pregnancy ......................................................................................................... 47 
12 Statistical and Analytical Plans .......................................................................................... 47 
12.1 Sample Size and Power .................................................................................................. 47 
12.2 Analysis Sets .................................................................................................................. 47 
12.3 Statistical Analysis ......................................................................................................... 48 
12.3.1 
General Considerations ........................................................................................... 48 
12.3.2 
Background Characteristics .................................................................................... 48 
12.3.2.1 Subject Disposition .......................................................................................... 48 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 49 
12.3.2.3 Prior and Concomitant Medications................................................................. 49 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 50 
12.3.2.5 Important Protocol Deviations ......................................................................... 50 
12.3.3 
Efficacy and Pharmacodynamic Analyses ............................................................. 50 
12.3.3.1 Analysis of Primary Efficacy Endpoint ........................................................... 50 
12.3.3.2 Analysis of Key Secondary Efficacy Endpoints .............................................. 51 
12.3.3.3 Analysis of Other Secondary Efficacy Endpoints ............................................ 51 
12.3.3.4 Multiplicity Adjustment ................................................................................... 52 
12.3.3.5 Analysis of Exploratory Efficacy Endpoints.................................................... 52 
12.3.4 
Safety Analysis ....................................................................................................... 52 
12.3.4.1 Adverse Events................................................................................................. 53 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 54 
12.3.4.3 Electrocardiogram ............................................................................................ 54 
12.3.4.4 Vital Signs ........................................................................................................ 54 
12.3.4.5 Pulse Oximetry ................................................................................................. 54 
12.3.4.6 Physical Examination ....................................................................................... 55 
12.3.4.7 Other Safety Analysis ...................................................................................... 55 
12.3.5 
Exploratory Endpoints ............................................................................................ 55 
12.3.5.1 Analysis of Exploratory Endpoints .................................................................. 55 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses ........................... 55 
12.3.6.1 Interim Analysis ............................................................................................... 55 
12.3.6.2 Independent Data Monitoring Committee Analysis ........................................ 55 
12.4 Clinical Pharmacology Analysis .................................................................................... 55 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 55 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 55 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 55 
13.1.1 
Adverse Events ....................................................................................................... 55 
13.1.1.1 Definition of an Adverse Event........................................................................ 55 
13.1.1.2 Clinically Significant Assessments .................................................................. 55 
13.1.1.3 Documentation of Adverse Events................................................................... 56 
13.1.1.4 Adverse Event Severity .................................................................................... 56 
13.1.1.5 Adverse Event Causality .................................................................................. 57 
13.1.1.6 Study Drug Action Taken ................................................................................ 57 
13.1.1.7 Adverse Event Outcome .................................................................................. 58 
13.1.1.8 Treatment Given............................................................................................... 58 
13.1.2 
Serious Adverse Events .......................................................................................... 58 
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13.1.2.1 Definition of a Serious Adverse Event............................................................. 58 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 59 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 60 
13.2 Administrative Requirements ......................................................................................... 60 
13.2.1 
Ethical Considerations ............................................................................................ 60 
13.2.2 
Subject Information and Informed Consent ........................................................... 60 
13.2.3 
Investigator Compliance ......................................................................................... 60 
13.2.4 
Access to Records ................................................................................................... 61 
13.2.5 
Subject Privacy ....................................................................................................... 61 
13.2.6 
Record Retention .................................................................................................... 61 
13.2.7 
Study Termination .................................................................................................. 61 
13.2.8 
End of Study ........................................................................................................... 62 
13.3 Data Quality Assurance .................................................................................................. 62 
13.4 Monitoring ...................................................................................................................... 62 
13.5 Electronic Data Capture ................................................................................................. 62 
13.6 Confidentiality and Disclosure ....................................................................................... 63 
13.7 Publications and Clinical Study Report .......................................................................... 63 
13.7.1 
Publication of Study Results ................................................................................... 63 
13.7.2 
Clinical Study Report ............................................................................................. 64 
14 References ............................................................................................................................. 65 
15 APPENDIX A: Eligible Mutations for Subjects Who Are Heterozygous for the 
F508del-CFTR Mutation and a Gating or Residual Function Mutation (F/G and F/RF 
Genotypes) ............................................................................................................................ 67 
16 Protocol Signature Pages .................................................................................................... 68 
16.1 Sponsor Signature Page .................................................................................................. 68 
16.2 Investigator Signature Page ............................................................................................ 69 
 
List of Tables 
Table 2-1 
Treatment Groups and Dosages .............................................................................. 5 
Table 3-1 
Study VX18-445-104: Screening ............................................................................ 8 
Table 3-2 
VX18-445-104: Run-in Period, Treatment Period, and Safety Follow-up Visit .... 9 
Table 9-1 
IVA and TEZ/IVA Comparator Group Mutations ................................................ 25 
Table 9-2 
Treatment Groups and Dosages ............................................................................ 25 
Table 9-3 
Prohibited Medications ......................................................................................... 31 
Table 10-1 
Study Drug: Dosing Form/Route/Strength ........................................................... 36 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 43 
Table 11-2 
Acceptable Methods of Contraception.................................................................. 46 
Table 13-1 
Grading of AE Severity ........................................................................................ 57 
Table 13-2 
Classifications for AE Causality ........................................................................... 57 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 57 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 58 
Table of Figures 
Figure 2-1 
VX18-445-104 Study Design ................................................................................. 5 
Figure 9-1 
VX18-445-104 Study Design ............................................................................... 24 
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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BMI 
body mass index 
bpm 
beats per minute 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator protein 
CFTR 
CF transmembrane conductance regulator gene 
Clˉ 
chloride ion 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ETT 
Early Termination of Treatment 
EU 
European Union 
F/F 
homozygous for F508del 
F/G 
heterozygous for F508del and a gating mutation 
F/MF 
heterozygous for F508del with a second CFTR allele carrying a minimal function mutation that is 
not responsive to TEZ, IVA, and TEZ/IVA 
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 
F508del 
CFTR protein lacking the phenylalanine normally found at position 508 of the wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
FEF25%-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
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 
HBE 
human bronchial epithelial (cells) 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
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Abbreviation 
Definition 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IND 
Investigational New Drug (application) (US) 
IPD 
important protocol deviation 
IRB 
institutional review board 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LUM 
lumacaftor 
M1-TEZ 
metabolite of TEZ 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
minimal function 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
n 
number of subjects 
OATP1B1 
organic anion transporting polypeptide 1B1 
OE 
ophthalmological examination 
P 
probability 
PD 
pharmacodynamic, pharmacodynamics 
PEx 
pulmonary exacerbation 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic, pharmacokinetics 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval, segment 
PT 
Preferred Term 
q12h 
every 12 hours 
qd 
once daily 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing ventricular 
depolarization 
QT 
QT interval 
QTcF 
QT interval corrected by Fridericia’s formula 
RD 
respiratory domain 
RF 
residual function 
RNA 
ribonucleic acid 
RR 
interval from the onset of 1 QRS complex to the next  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SUSAR 
suspected, unexpected, serious adverse reaction 
SwCl 
sweat chloride 
TC 
triple combination 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
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Abbreviation 
Definition 
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 
WHO-DD 
World Health Organization Drug-Dictionary 
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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive chronic disease with serious morbidities and 
frequent premature mortality. CF affects more than 70,000 individuals worldwide1 
(approximately 30,000 in the US2 and 45,000 in the EU3). Based on its prevalence, CF qualifies 
as an orphan disease.4, 5 
CF is caused by decreased quantity and/or function of the CFTR protein due to mutations in the 
CFTR gene.6 CFTR is an ion channel that regulates the flow of chloride and other ions across 
epithelia in various tissues, including the lungs, pancreas and other gastrointestinal organs, and 
sweat glands.7 Decreased CFTR quantity or function results in the failure to regulate chloride 
transport in these tissues leading to the multisystem pathology associated with CF.8 In the lungs, 
obstruction of airways with thick mucus, establishment of a chronic bacterial infection in the 
airways, and damaging inflammatory responses are all thought to play a role in causing 
irreversible structural changes in the lungs, leading to respiratory failure. Progressive loss of lung 
function is the leading cause of mortality.9  
The most common disease-causing CFTR mutation is F508del, which accounts for 
approximately 70% of the identified alleles in people with CF.10 Approximately 40% to 45% of 
people with CF are homozygous for F508del (F/F), and approximately 85% have at least 
1 F508del allele.2, 3  
Based on the understanding of the molecular defects caused by CFTR mutations, 
2 complementary approaches have been developed to address the decreased quantity and/or 
function of CFTR in order to enhance chloride transport in patients with CF. Correctors facilitate 
the cellular processing and trafficking to increase the quantity of CFTR at the cell surface. 
Potentiators increase the channel open probability (channel gating activity) of the CFTR protein 
delivered to the cell surface to enhance ion transport. With differing mechanisms of action, a 
combination of correctors and potentiators increases F508del CFTR-mediated chloride transport 
more than either type of modulator alone. 
The therapeutic activity of CFTR modulators has been established with products developed by 
Vertex and approved for the treatment of CF: ivacaftor (IVA) monotherapy (Kalydeco), 
lumacaftor (LUM)/IVA (Orkambi®), and tezacaftor (TEZ)/IVA (Symdeko/Symkevi®).   
VX-445 is a next-generation CFTR corrector. In vitro, the triple combination (TC) of VX-445, 
TEZ, and IVA (VX-445/TEZ/IVA) increased CFTR chloride transport more than any of the dual 
combinations (VX-445/TEZ, VX-445/IVA, and TEZ/IVA) or individual components (VX-445, 
TEZ, and IVA) when added to human bronchial epithelial (HBE) cells derived from 2 groups of 
CF patients: those heterozygous for F508del with a second CFTR allele carrying a minimal 
function (MF) mutation that is not responsive to TEZ, IVA, and TEZ/IVA (F/MF genotypes); 
and those homozygous for F508del (F/F genotypes). 
Additional information about VX-445/TEZ/IVA can be found in the Investigator’s Brochure. 
5.2 
Study Rationale 
This study will evaluate the efficacy and safety of VX-445/TEZ/IVA in CF subjects who are 
heterozygous for F508del and a second CFTR allele carrying either a gating mutation or a 
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residual function mutation (F/G and F/RF genotypes). Results from the Phase 1/2 study showed 
that treatment with VX-445/TEZ/IVA resulted in clinically meaningful improvements in percent 
predicted forced expiratory volume in 1 second (ppFEV1) and sweat chloride (SwCl) in CF 
subjects with 1 or 2 copies of the F508del mutation, namely those with F/MF and F/F genotypes 
(for the latter, as compared to their TEZ/IVA baseline). These results suggest that 
VX-445/TEZ/IVA treatment may result in clinical benefit beyond currently approved standard of 
care CFTR modulators for CF subjects who have F/G and F/RF genotypes. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the efficacy of VX-445/TEZ/IVA in CF subjects who are heterozygous for F508del 
and a gating or residual function mutation (F/G and F/RF genotypes) 
6.2 
Secondary Objectives 
 To evaluate the safety of VX-445/TEZ/IVA  
 To evaluate the pharmacodynamics (PD) of VX-445/TEZ/IVA 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Absolute change in ppFEV1 from baseline through Week 8 for the VX-445/TEZ/IVA group 
7.2 
Secondary Endpoints 
7.2.1 
Key Secondary Endpoints 
 Absolute change in SwCl from baseline through Week 8 for the VX-445/TEZ/IVA group  
 Absolute change in ppFEV1 from baseline through Week 8 for the VX-445/TEZ/IVA group 
compared to the control group 
 Absolute change in SwCl from baseline through Week 8 for the VX-445/TEZ/IVA group 
compared to the control group 
7.2.2 
Other Secondary Endpoints  
 Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain (RD) 
score from baseline through Week 8 for the VX-445/TEZ/IVA group 
 Absolute change in CFQ-R RD score from baseline through Week 8 for the 
VX-445/TEZ/IVA group compared to the control group 
 Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
ECGs, vital signs, and pulse oximetry 
7.3 
Exploratory Endpoints 
 Absolute change in CFQ-R non-RD scores from baseline through Week 8 
 Absolute change in body mass index (BMI) from baseline at Week 8 
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 Inflammatory mediators 
 Blood biomarkers 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects receive study drug on Day -28. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
8.1 
Inclusion Criteria 
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
informed consent form (ICF), and, when appropriate, an assent form.  
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Age 12 years or older, at the date of informed consent. 
4. Confirmed diagnosis of CF as determined by the investigator. 
5. Subject is heterozygous for F508del and either a gating or residual function mutation (F/G 
and F/RF genotypes) and is in a region where their genotype and age group are approved 
indications for treatment with IVA and/or TEZ/IVA (see Appendix A for qualifying 
mutations).  
6. Forced expiratory volume in 1 second (FEV1) value ≥40% and ≤90% of predicted mean for 
age, sex, race, and height (equations of the Global Lung Function Initiative [GLI])11 at the 
Screening Visit. Spirometry measurements must meet American Thoracic Society/European 
Respiratory Society criteria12 for acceptability and repeatability.  
7. Subjects must be able to produce a valid (quantity-sufficient) sweat sample at screening.  
8. Stable CF disease as judged by the investigator. 
9. Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) through 
completion of study participation. 
8.2 
Exclusion Criteria 
1. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study drug(s) to 
the subject. This includes, but is not limited to, the following: 
 Clinically significant cirrhosis with or without portal hypertension. 
 Solid organ or hematological transplantation. 
 Alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, 
and opiates, as deemed by the investigator. 
 Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical 
carcinoma in situ (each being disease-free for the last 5 years). 
2. Any of the following abnormal laboratory values at screening. 
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 Hemoglobin <10 g/dL 
 Total bilirubin ≥2 × upper limit of normal (ULN) 
 Aspartate transaminase (AST), alanine transaminase (ALT), or gamma-glutamyl 
transferase (GGT) ≥3 × ULN 
 Abnormal renal function defined as estimated glomerular filtration rate 
≤50 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease Study 
Equation)13,14 for subjects ≥18 years of age, or ≤45 mL/min/1.73 m2 (calculated by the 
Counahan-Barratt equation)15 for subjects 12 to 17 years of age (inclusive) 
3. An acute upper or lower respiratory infection, pulmonary exacerbation (PEx), or change in 
therapy (including antibiotics) for sinopulmonary disease within 28 days before the first dose 
of study drug in the Run-in Period (Day -28). 
4. Lung infection with a microbial pathogen that is 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 respiratory tract culture positive for these organisms within the 
12 months before the date of informed consent. 
 The subject has had at least 2 respiratory tract cultures negative for such organisms 
within the 12 months before the date of informed consent, with the first and last of these 
separated by at least 3 months, and the most recent one within the 6 months before the 
date of informed consent. 
5. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of 
study drug in the Run-in Period (Day -28). 
6. 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. The duration of the elapsed time may be longer if required by local regulations. 
7. Use of prohibited medications as defined in Table 9-3 within the specified window before the 
first dose of study drug in the Run-in Period (Day -28). 
8. Pregnant or breast-feeding females. All female subjects, regardless of childbearing potential 
status, must have negative pregnancy tests at the Screening Visit (Day -56) and at the 
Day -28 Visit, before the first dose of study drug in the Run-in Period.  
9. The subject or a close relative of the subject is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study at that site. However, an adult (aged 18 years or older) who is a relative of a study 
staff member may be 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. 
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9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3, randomized, double-blind, active-controlled, parallel-group, multicenter study 
(Figure 9-1).  
Figure 9-1 
VX18-445-104 Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IVA: ivacaftor; ppFEV1: percent predicted forced expiratory volume in 1 second; SwCl: sweat chloride; TC: triple 
combination; TEZ: tezacaftor 
Note: The Safety Follow-up Visit is not required for subjects who complete the Week 8 Visit and enroll in an 
open-label study within 28 days after the last dose of study drug.  
a 
Subjects will be randomized 1:1 to the TC arm or the control arm. Randomization will be stratified based on 
comparator group (IVA comparator versus TEZ/IVA comparator), ppFEV1 as determined during the Run-in 
Period (Day -14 assessment; <70 versus ≥70), and SwCl as determined during the Run-in Period (Day -14 
assessment; <30 mmol/L versus ≥30 mmol/L).  
Approximately 250 subjects will be enrolled in the study.  
 Approximately 40% of total subjects will be in the IVA comparator group (approximately 
100 subjects) 
o In the IVA comparator group, up to 20% of subjects may be enrolled with an R117H 
mutation (approximately 20 subjects) 
 Up to 15% of total subjects may be enrolled with SwCl values <30 mmol/L at screening 
(approximately 40 subjects) 
Study drug is defined in Section 10. 
In the Run-in Period, subjects will be assigned to the IVA or TEZ/IVA comparator group based 
on genotype per Table 9-1. Subjects assigned to the IVA comparator group will receive 
Treatment Perioda 
TC Arm: 
VX-445/TEZ/IVA 
Control Arm: 
IVA or TEZ/IVA** 
Run-in Period 
IVA or  
TEZ/IVA* 
Screening 
Period 
Safety Follow-up 
Day -56 to Day -29 Day -28 to Day -1 
Randomization 
(Day -1 or Day 1) 
8 Weeks  
(Day 1 to Week 8) 
Open-label Study 
28 days 
*In the Run-in Period, subjects will be assigned to the IVA or TEZ/IVA comparator 
group based on genotype; subjects in the IVA comparator group will receive IVA, 
and subjects in the TEZ/IVA comparator group will receive TEZ/IVA.  
**In the Treatment Period, subjects in the control arm who received IVA in the 
Run-in Period will receive IVA; subjects in the control arm who received TEZ/IVA in 
the Run-in Period will receive TEZ/IVA.  
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IVA 150 mg every 12 hours (q12h) and subjects assigned to the TEZ/IVA comparator group will 
receive TEZ 100 mg once daily (qd)/IVA 150 mg q12h.  
In the Treatment Period, subjects will be randomized (1:1) to the VX-445/TEZ/IVA treatment 
arm or control arm under a single randomization scheme. Subjects in the control arm who 
received IVA in the Run-in Period will receive IVA in the Treatment Period; subjects in the 
control arm who received TEZ/IVA in the Run-in Period will receive TEZ/IVA in the Treatment 
Period.  
Randomization will be stratified; details are provided in Section 9.2. 
The dosages for the Treatment Period are shown in Table 9-2.  
Table 9-1 
IVA and TEZ/IVA Comparator Group Mutations 
IVA Comparator Group Mutations 
R117H 
G551D 
G1244E 
G178R  
G551S 
S1251N 
S549N  
G1069R 
S1255P 
S549R  
R1070Q 
G1349D 
TEZ/IVA Comparator Group Mutations 
711+3A>G 
R117C 
S977F 
2789+5G>A 
E193K 
F1052V 
3272-26A>G 
L206W 
K1060T 
3849+10kbC>T 
R347H 
A1067T 
E56K 
R352Q 
R1070W 
P67L 
A455E 
F1074L 
R74W 
D579G 
D1152H 
D110E 
E831X 
D1270N 
D110H 
S945L 
 
IVA: ivacaftor; TEZ: tezacaftor 
Note: This table represents all gating and residual function mutations that may qualify for enrollment in this study 
but is not intended to determine subject eligibility. Refer to Appendix A for a list of eligible mutations based on 
approved indications for treatment with IVA and/or TEZ/IVA. 
 
Table 9-2 
Treatment Groups and Dosages 
Comparator Group 
Treatment Arm 
VX-445 Dosage 
TEZ Dosage 
IVA Dosage 
IVA 
VX-445/TEZ/IVA 
200 mg qd 
100 mg qd 
150 mg q12h 
Control 
0 mg 
0 mg 
150 mg q12h 
TEZ/IVA 
VX-445/TEZ/IVA 
200 mg qd 
100 mg qd 
150 mg q12h 
Control 
0 mg 
100 mg qd 
150 mg q12h 
IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TEZ: tezacaftor 
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 
The Screening Period (Day -56 through Day -29) will occur within 28 days before the first dose 
of study drug in the Run-in Period. 
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Screening assessments will be used to confirm that subjects meet the eligibility criteria 
(Table 3-1). 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 who have not entered the Run-in Period may be rescreened once. If a subject is 
rescreened, all screening assessments will be repeated, except for the following assessments, 
which are not required to be repeated:  
 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 (OE) (if performed within 3 months of the date of informed 
consent, for subjects <18 years of age) 
If a subject is rescreened, a new screening window will begin when the first rescreening 
assessment has been initiated. 
9.1.1.3 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 2 weeks for the following 
reasons: 
 Repetition of the Screening Period assessments (Section 9.1.1.1) 
 Unexpected operational or logistic delays, or to meet the eligibility criteria 
 Scheduling of OE (for subjects <18 years of age on the date of informed consent, 
Section 11.6.6) 
9.1.2 
Run-in Period 
The Run-in Period has a 4-week duration and is designed to establish a reliable on-treatment 
(IVA for the IVA comparator group and TEZ/IVA for the TEZ/IVA comparator group) baseline 
for the Treatment Period. The first dose of open-label IVA or TEZ/IVA (as applicable) will be 
administered at the Day -28 Visit. The last dose of open-label IVA will be administered in the 
evening on Day -1 (1 day before the Day 1 Visit). 
A subject’s screening CFTR genotype must confirm eligibility before the subject enters the 
Run-in Period (Section 11.6.2).  
On Day -14, spirometry and SwCl will be assessed. The Day -14 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) and are not permitted to 
rescreen. 
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9.1.3 
Treatment Period 
The Treatment Period will be randomized, double-blind, and active-controlled (Table 3-2). It 
will last approximately 8 weeks (Day 1 to Week 8). 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, after the conditions below have been met. Randomization 
and stratification details are provided in Section 9.2. 
To randomize and 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 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 during the Run-in Period), the subject will be discontinued and will not 
be permitted to rescreen. 
Subjects who prematurely discontinue study drug treatment during the Treatment Period will 
remain in the study from the time of discontinuation of study drug treatment through the last 
scheduled study visit and complete the assessments for all study visits, as described in 
Section 9.1.5.2. 
9.1.4 
Safety Follow-up 
The Safety Follow-up Visit will occur approximately 28 days after the last dose of study drug for 
subjects who complete study drug dosing and for subjects who prematurely discontinue study 
drug dosing, as described in Section 9.1.5 (Table 3-2). 
An open-label study will be available for subjects who complete the Week 8 Visit and are 
eligible. The Safety Follow-up Visit is not required for subjects who complete the Week 8 Visit 
and enroll in an open-label study within 28 days after the last dose of study drug. 
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 days after their last dose of study drug. The assessments 
performed at the Safety Follow-up Visit are listed in Table 3-2. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
If a subject withdraws from the study and also withdraws consent or assent, no further 
assessments will be performed. Vertex may retain and continue to use any data and samples 
collected before such withdrawal of consent or assent. 
9.1.5.1 
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 (Section 9.1.3). These subjects will complete 
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an ETT Visit and Safety Follow-up Visit (as applicable; see Section 9.1.5).  The Safety 
Follow-up Visit will be their last visit in this study. 
9.1.5.2 
Discontinuation During the Treatment Period 
Subjects who prematurely discontinue study drug treatment during the Treatment Period will 
continue to complete all scheduled study visits for assessments following completion of the ETT 
Visit, as detailed in Table 3-2. These subjects will complete an ETT Visit and Safety Follow-up 
Visit (as applicable; see Section 9.1.5).  
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 1 of the following: 
 For subjects who complete the Treatment Period and enter an open-label study within 
28 days after the Week 8 Visit: the Week 8 Visit 
 For subjects who complete the Treatment Period and do not enter an open-label study within 
28 days after the Week 8 Visit: the Safety Follow-up Visit 
 For subjects who prematurely discontinue study drug treatment during the Treatment Period 
but do not withdraw consent (and assent, as applicable): the latest of the Week 8 Visit, ETT 
Visit, or Safety Follow-up Visit (if required) 
 For subjects who prematurely discontinue study drug treatment during the Run-in Period but 
do not withdraw consent (and assent, as applicable): the ETT 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 13.2.8. 
9.1.8 
Independent Data Monitoring Committee 
This study will be monitored by an independent data monitoring committee (IDMC), which will 
conduct periodic safety reviews of study data (Section 12.3.6.2). Procedural details of the 
IDMC’s structure and function, frequency of meetings, and data planned for review will be 
included in the IDMC charter. The IDMC charter will be finalized before the first subject is 
screened. 
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9.2 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized (1:1) to the VX-445/TEZ/IVA treatment arm or the control arm 
(IVA or TEZ/IVA). 
Randomization will be stratified based on comparator group (IVA comparator versus TEZ/IVA 
comparator), ppFEV1 as determined during the Run-in Period (Day -14 assessment; <70 versus 
≥70), and SwCl as determined during the Run-in Period (Day -14 assessment; <30 mmol/L 
versus ≥30 mmol/L). If the Day -14 ppFEV1 or SwCl value(s) are not valid or not available, the 
most recent available valid value(s) 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, PD, and safety of VX-445/TEZ/IVA therapy in CF 
subjects with F/G or F/RF genotypes.  
A randomized, double-blind, active-controlled study design has been selected to ascertain the 
effects of VX-445/TEZ/IVA while avoiding observer bias. IVA and TEZ/IVA are appropriate 
active controls because IVA is approved standard of care for treatment of patients with F/G 
genotypes and selected F/RF genotypes in some regions, and TEZ/IVA is approved for treatment 
of patients with selected F/RF genotypes in some regions. Subjects will be assigned to a 
comparator group per Table 9-1. 
To establish a reliable on-treatment (IVA or TEZ/IVA) baseline for comparison during the 
Treatment Period, a 4-week Run-in Period has been incorporated into the study design. 
The study has an 8-week treatment duration. Based on prior experience with approved CFTR 
modulators, 8 weeks is sufficient to assess the impact of TC on the endpoints being evaluated.  
Randomization will be stratified by comparator group (IVA comparator versus TEZ/IVA 
comparator) (Table 9-1) and the subject’s ppFEV1 (an index of disease severity) and SwCl 
values determined at the Day -14 Visit.  
9.3.2 
Study Population 
This study will enroll CF subjects with F/G or F/RF genotypes in regions where their genotype 
and age group are approved indications for treatment with IVA and/or TEZ/IVA. As described in 
Section 5.2, treatment with VX-445/TEZ/IVA offers the potential for additional clinical benefit 
in these subjects, as compared to the standard of care CFTR modulator regimens that are 
currently approved for these genotype groups. 
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 TEZ/IVA, suggests that the exposures and safety profile of VX-445/TEZ/IVA will be 
similar in adolescents and adults, which supports evaluation of VX-445/TEZ/IVA in adolescents 
in the present study. Adolescent subjects are currently being evaluated in ongoing Phase 3 
studies (Study VX17-445-102 [Study 102] for F/MF subjects, Study VX17- 445-103 [Study 103] 
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for F/F subjects, and open-label Study VX17-445-105 [Study 105] for both F/MF and F/F 
subjects). 
9.3.3 
Study Drug Dose  
VX-445 Dosage 
A VX-445 dose of 200 mg qd will be administered. This is the dosing regimen that was 
evaluated in the Phase 3 pivotal studies of VX-445/TEZ/IVA in CF subjects with F/MF and F/F 
genotypes.  
TEZ and IVA Dosages 
TEZ will be administered as 100 mg qd and IVA will be administered as 150 mg q12h. This is 
the approved dosing regimen for Symdeko, which is now approved in certain countries. IVA 
monotherapy will be administered as 150 mg q12h, which is the approved dosing regimen for 
Kalydeco. 
Dosage for Subjects Aged 12 to 17 Years  
Phase 3 studies with IVA and TEZ/IVA have demonstrated similar exposures between adults 
(≥18 years old) and adolescent subjects ≥12 to <18 years of age. In Studies 102 and 103, 
adolescent subjects in the F/MF and F/F genotype groups are being evaluated at the same dose as 
adult subjects because VX-445, TEZ, and IVA exposures are expected to be similar in adolescent 
subjects and adults. Therefore, in the current study, all subjects (both adolescents and adults) will 
receive the same dose of VX-445/TEZ/IVA.  
9.3.4 
Rationale for Study Assessments 
The safety, pharmacokinetic (PK), efficacy, and PD assessments are standard parameters for 
clinical studies in drug development and are generally recognized as reliable, accurate, and 
relevant to the study of CF subjects. Additional exploratory assessments will be obtained to 
explore inflammatory mediators and other biomarkers. 
9.4 
Study Restrictions 
9.4.1 
Prohibited Medications 
Table 9-3 lists prohibited medications. A non-exhaustive list of study prohibitions and cautions 
for medication will be provided in the Study Reference Manual. Guidance for concomitant 
medications is provided in Section 9.5. 
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Table 9-3 
Prohibited Medications 
Medication 
Timing of Restriction 
Rationale 
Start of 
Restriction 
End of 
Restriction 
Moderate and strong 
CYP3A inducers 
None allowed after 
the first dose of 
study drug on 
Day -28 
None allowed 
through 
completion of 
study 
participation 
VX-445, TEZ, and 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-445, TEZ, or IVA, will be 
prohibited. 
 
Moderate and strong 
CYP3A inhibitors 
(except 
ciprofloxacin)a 
None allowed after 
the first dose of 
study drug on 
Day -28 
None allowed 
through 
completion of 
study 
participation 
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 
study drug on 
Day -28 
None allowed 
until after the  
last dose of  
study drug 
 
These agents may confound the results of this 
study. 
IVA: ivacaftor; TEZ: tezacaftor 
a 
Ciprofloxacin is not a moderate CYP3A inhibitor on the basis of results of a drug-drug interaction study 
conducted with IVA, a sensitive CYP3A substrate (Kalydeco [ivacaftor] US Package Insert). 
9.5 
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. Medications will be categorized as 
defined in Section 12.3.2.3. 
For subjects who are screened but are not subsequently randomized, details of prior medication 
will be documented only in the subjects’ source documents. 
 Subjects should remain on a stable treatment regimen for their CF from 28 days before the 
Day -28 Visit through completion of study participation. Stable treatment regimen is defined 
as the current treatment regimen for CF that subjects have been following for at least 28 days 
before the Day -28 Visit. Subjects who are on Vertex CFTR modulators (investigational or 
approved) at the date of informed consent may remain on these during the Screening Period 
and should transition directly to study drug at the beginning of the Run-in Period on Day -28 
without a washout (Table 9-3). Subjects should not initiate long-term treatment with new 
medication from 28 days before the Day -28 Visit through completion of study participation. 
Guidelines for stable treatment regimens for CF are as follows: 
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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 study drug on the Day 1 Visit should be 
synchronized as closely as possible (e.g., not more than ± 3 days) to the first day in the 
cycle onto the inhaled antibiotic. 
o Subjects who alternate between 2 different inhaled antibiotics should remain on the same 
cycling schedule during the study. The timing of the first dose of study drug on the Day 1 
Visit should be synchronized as closely as possible (e.g., not more than ± 3 days) to the 
first day in the cycle onto 1 of the inhaled antibiotics. 
 Subjects may receive doses of prednisone or prednisolone of up to 10 mg/day chronically, or 
up to 60 mg daily for up to 5 days. 
 VX-445 may inhibit OATP1B1 and OATP1B3, which may increase the exposure of 
medicinal products that are substrates for these transporters. Substrates such as statins, 
glyburide, nateglinide, and repaglinide should be used with caution. 
 IVA is a weak inhibitor of P-glycoprotein (P-gp). Administration of 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 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. 
 Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments performed 
according to the guidelines provided in Section 11.5.1. 
9.6 
Administration 
9.6.1 
Dosing 
Study drug will be administered orally. All subjects will receive the same number of tablets each 
day during the Treatment Period to maintain the blind. Additional information is provided in the 
Pharmacy Manual. 
Study drug should 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. In the IVA comparator group, study drug in the Run-in Period will be administered as 1 IVA 
tablet in the morning and 1 IVA tablet in the evening. Study drug in the Treatment Period 
will be administered as 2 fixed-dose combination (FDC) TC tablets or matching placebo 
tablets and 1 IVA tablet or matching placebo tablet in the morning, and 1 IVA tablet in the 
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evening (Table 9-2). For each subject, doses of study drugs should be taken at approximately 
the same time (± 2 hours) each day. 
3. In the TEZ/IVA comparator group, study drug in the Run-in Period will be administered as 
1 TEZ/IVA FDC tablet in the morning and 1 IVA tablet in the evening. Study drug in the 
Treatment Period will be administered as 2 FDC TC tablets or matching placebo tablets and 
1 TEZ/IVA FDC tablet or matching placebo tablet in the morning, and 1 IVA tablet in the 
evening (Table 9-2). For each subject, doses of study drugs should be taken at approximately 
the same time (± 2 hours) each day. 
4. 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 (if applicable). 
5. 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. 
6. If a subject’s scheduled visit is to occur in the afternoon, the following guidelines should 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.  
7. 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 9.1.5). 
9.8 
Study Drug Interruption and Stopping Rules 
In subjects who have interrupted study drug for >72 hours for any reason, the investigator should 
resume study drug only after a thorough investigation of the cause for interruption. The 
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investigator will evaluate the subject’s clinical stability and should consider resumption of study 
drug only after the subject is clinically stable and there is no comorbidity or condition that, in the 
opinion of the investigator, might confound the results of the study or pose an additional risk in 
administering study drug to the subject. 
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. The medical monitor 
should be notified of any plan to discontinue study drug. 
9.8.1 
Liver Function Tests 
The central laboratory will notify the medical monitor of ALT or AST >3 × ULN and total 
bilirubin >2 × ULN that are derived from centrally submitted samples. 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, with or without 
total bilirubin >2 × ULN, must be followed closely, including confirmatory testing performed by 
the central laboratory within 48 to 72 hours of the initial finding and subsequent close 
monitoring of ALT, AST, and bilirubin levels, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results must be reported immediately to the medical monitor, and the subject 
must have the tests repeated and sent to the central laboratory as soon as possible (ideally within 
48 to 72 hours). 
Study drug administration must be interrupted immediately (prior to confirmatory testing) if 
any of the following criteria are met: 
 ALT or AST >8 × ULN 
 ALT or AST >5 × ULN for more than 2 weeks 
 ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical jaundice 
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 
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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 with differential, liver function test), photographs of the rash, and 
dermatology consultation. The investigator may consider resumption of study drug if 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 prematurely terminates study drug treatment will continue to be followed, unless the subject 
withdraws consent (or assent, when applicable). 
In addition, a subject must be discontinued from study drug treatment if the subject meets either 
of the following criteria, and should return for study assessments as noted in Section 9.1.5.2: 
 Meets any of the stopping (discontinuation) criteria (Section 9.8) 
 Becomes pregnant (Section 11.6.7.2) 
Other criteria that require subjects to be discontinued from study drug treatment are: 
 If a subject is identified after randomization as having been enrolled to the incorrect 
comparator group, the subject must be discontinued from the study. 
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 9.1.5), 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 compounds, 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 or her information from the study data. A subject 
may request destruction of the samples collected from him or her during the study as long as 
those samples can be identified as his or 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. 
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Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period(s) may be replaced at Vertex’s discretion. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
During the Run-in Period, study drug refers to IVA and TEZ/IVA.  
During the Treatment Period, study drug refers to VX-445/TEZ/IVA and matching placebo, 
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. 
10.2 
Packaging and Labeling 
Study drug tablets will be supplied in blister cards by Vertex. Study drug labeling will be in 
compliance with applicable local and national regulations. Additional details regarding 
packaging, labeling, and dispensing for study drug will be in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
VX-445/TEZ/IVA will be supplied as 2 FDC film-coated tablets (100 mg VX-445/50 mg 
TEZ/75 mg IVA). Matching VX-445/TEZ/IVA placebo tablets will be of similar size and 
appearance and contain 0 mg VX-445, 0 mg TEZ, and 0 mg IVA (Table 10-1). 
TEZ/IVA will be supplied as an FDC film-coated tablet (100 mg TEZ/150 mg IVA). A matching 
TEZ/IVA placebo tablet will be of similar size and appearance and contain 0 mg TEZ and 0 mg 
IVA (Table 10-1). 
IVA (150 mg) will be supplied as a film-coated 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: Dosing Form/Route/Strength 
Drug Name, Dosing Form, Route 
Tablet Strength 
VX-445/TEZ/IVA, FDC tablet, oral 
 
VX-445 
100 mg 
TEZ 
50 mg 
IVA 
75 mg 
VX-445/TEZ/IVA-matching placebo, tablet, oral 
0 mg 
TEZ/IVA, FDC tablet, oral 
 
TEZ 
100 mg 
IVA 
150 mg 
TEZ/IVA-matching placebo, tablet, oral 
0 mg 
IVA, tablet, oral 
150 mg 
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Table 10-1 
Study Drug: Dosing Form/Route/Strength 
Drug Name, Dosing Form, Route 
Tablet Strength 
IVA-matching placebo, tablet, oral 
0 mg 
FDC: fixed-dose combination; IVA: ivacaftor; TEZ: tezacaftor 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee. The study monitor will review study drug 
records and inventory throughout the study. 
If a site uses a site-specific drug accountability system and/or process, including processes 
associated with the destruction of returned materials, the process must be documented and 
approved by Vertex. The study monitor must review the drug accountability documentation on a 
regular basis. The study monitor will promptly communicate to Vertex any discrepancies he or 
she is unable to resolve with the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
10.6 
Compliance 
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should consider discontinuing the subject from the study. 
10.7 
Blinding and Unblinding 
This will be a double-blind study. 
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 
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 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 
 IDMC 
 Vendor preparing the unblinded analysis of data for safety review by the IDMC  
 Bioanalytical contract research organization (CRO) analyzing PK samples and the Vertex 
bioanalytical personnel who is not a member of the study team but reviews raw data from the 
bioanalytical CRO. The Vertex bioanalytical study team member will continue to be blinded. 
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 in the Treatment Period.  
Shortly before any planned efficacy analysis is conducted, the spirometry and SwCl data will be 
reviewed for data cleaning purposes by a biostatistician who does not have access to the 
treatment codes. 
Individual SwCl test results will not be disclosed to the study sites with the exception of the 
screening and Day -14 Visit 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 Individual Subject Treatment Assignments by Investigator for Medical 
Emergencies or Urgent Clinical Situations 
Unblinding of the individual subject’s treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject’s study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss 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. 
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If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding event. 
The reason and the date of the unblinding will be documented clearly in the subject’s study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with Vertex, the CRO, or any site 
personnel (other than the physician treating the subject). In addition, the investigator will 
consider whether the clinical event that prompted unblinding will be considered an SAE, 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to 
Vertex GPS or designee, per Section 13.1.2. 
Unblinding of Individual Subject Treatment Assignments by Vertex GPS or Designee for 
SAEs or Safety Concerns 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety, 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. 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-445, TEZ, M1-TEZ, 
and IVA. These samples may also be used to evaluate metabolites of VX-445 and IVA or 
additional metabolites of TEZ for further evaluation of the bioanalytical method, or for 
exploratory analyses that provide information on the metabolic pathways used by or affected by 
VX-445. 
The Day 1, Day 15, and Week 4 predose PK samples should be collected within 60 minutes 
before dosing. The Week 8 predose PK sample should be collected within 60 minutes before 
dosing for subjects who are receiving their first dose of study drug in an open-label study on the 
same day as the Week 8 Visit. For subjects who are not entering an open-label study within 
24 hours of the Week 8 Visit, the Week 8 sample should be collected approximately 12 hours 
after the evening dose of IVA before the Week 8 Visit.  
All efforts should be made to obtain the PK samples during this specified window. Samples 
collected outside of the window will be considered protocol deviations. 
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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. 
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 provided in the PK Sample Handling 
Guidelines. 
11.2.3 
Bioanalysis 
Samples will be analyzed using validated analytical methods in compliance with Vertex or 
designee standard operating procedures. A description of the assays and validation data will be 
provided in separate reports. 
11.3 
Pharmacodynamics: Sweat Chloride 
SwCl samples will be collected with an approved collection device. Each collection will occur 
before study drug dosing (Section 9.6.1). At each time point, 2 samples will be collected, 1 from 
each arm (left and right). Sweat samples will be sent to a central laboratory for testing and 
interpretation of results. Specific instructions for the collection, handling, processing, and 
shipping of SwCl samples to the central laboratory will be provided separately. 
See Section 10.7.1 for information about access to SwCl results. 
11.4 
Exploratory Assessments 
These data will be used for exploratory purposes. Detailed procedures for the collection, 
processing, storage, and shipment of samples for exploratory assessments 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 correlations between DNA markers with PK, PD, treatment response, AEs, and 
biomarkers related to health and disease, including CF, for subjects who choose to participate in 
this assessment. 
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 markers may include, but 
are not limited to, C-reactive protein, immunoglobulin G, white blood cell (leukocyte) count, and 
interleukin-8. 
11.4.3 
Other Blood Biomarkers 
Serum from an inflammatory mediator sample and an additional blood sample for plasma 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. 
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A blood sample for RNA isolation will be collected as indicated in Table 3-2 for potential 
exploratory evaluation of gene signatures associated with various disease manifestations of CF 
and/or treatment response. 
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, and each sample will be processed and frozen. This will 
establish a baseline for subjects who continue into an open-label study and allow for 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. 
11.5 
Efficacy 
11.5.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines12 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 or her dose of bronchodilator, spirometry 
should be performed post-bronchodilator, and all subsequent spirometric measurements 
(according to the schedule of assessments in Table 3-2) should be performed 
post-bronchodilator. 
 Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator. 
All sites will be provided with spirometers to be used for all study assessments. Spirometry data 
will be transmitted to a centralized spirometry service for quality review. The investigator’s 
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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.11 
 Forced expiratory volume in 1 second (FEV1) (L) 
 Forced vital capacity (FVC) (L) 
 FEV1/FVC (ratio) 
 Forced expiratory flow, midexpiratory phase (FEF25%-75%) (L/s) 
11.5.2 
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.16, 17 If there is no validated translation available in the subject’s native language, 
the subject will not complete the questionnaire. Copies of the CFQ-R used will be provided in 
the Study Reference Manual. Validated translations of the CFQ-R, if available, will be provided 
for participating centers in non-English-speaking countries.18, 19  
The CFQ-R will be completed before any other assessments are performed at that visit.  
Subjects who are 12 and 13 years of age at the date of informed consent will complete the 
CFQ-R Child version themselves, and their parents/caregivers will complete the CFQ-R Parent 
version, at all visits, regardless of whether the subject subsequently turns 14 years of age during 
the study. Subjects 14 years of age or older at the date of informed consent will complete the 
Adolescent/Adult version of the questionnaire themselves at all visits. 
11.6 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, physical examinations, and 
clinical evaluation of vital signs, ECGs and pulse oximetry. 
For subjects <18 years of age on the date of informed consent, OEs will also be performed at 
screening (if not done within the preceding 3 months). 
11.6.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP Guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF completion 
guidelines for investigators as well as training will be provided. 
11.6.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, with the exception of the urine 
pregnancy tests. On Day -28 and Day 1, blood samples will be collected before the first dose of 
study drug in each study period. 
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Laboratory test results that are abnormal and considered clinically significant will be reported as 
AEs (Section 13.1). 
The safety laboratory test panels are shown in Table 11-1. 
Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Inorganic phosphate  
Total and direct bilirubin  
Alkaline phosphatase  
Aspartate transaminase 
Alanine transaminase 
Amylase  
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Total cholesterol  
Lactate dehydrogenase  
Hemoglobin  
Erythrocytes 
Mean corpuscular volume 
Platelets  
Reticulocytes  
Leukocytes  
Differential (absolute and percent): 
Eosinophils 
Basophils  
Neutrophils 
Lymphocytes 
Monocytes  
Coagulation 
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. 
Pregnancy (β-human Chorionic Gonadotropin) Tests for Female Subjects: All female subjects, 
regardless of childbearing potential status, must have a serum pregnancy test at screening. Serum 
pregnancy tests will be performed at the study site and analyzed at the central laboratory. Urine 
pregnancy tests will be performed and analyzed at the site. The urine pregnancy test on Day -28 
and Day 1 must be negative before the first dose of study drug in each study period. Additional 
pregnancy tests may be required according to local regulations and/or requirements. 
FSH (Screening Period Only): Blood samples for FSH will be measured for any suspected 
postmenopausal female with at least 12 months of continuous spontaneous amenorrhea. Serum 
FSH levels must be in the postmenopausal range as determined by the laboratory performing the 
test.  
CFTR Genotype (Screening Period Only): CFTR genotyping will be performed for all subjects. 
A subject’s screening CFTR genotype must confirm eligibility before the subject enters the 
Run-in Period. In subjects with an R117H mutation, linkage to poly-T tract polymorphisms will 
also be determined from a second specimen. Specific instructions will be provided in the 
Laboratory Manual. 
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Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For the purposes of study conduct and unless noted otherwise, 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 physical examination of all body systems and vital signs assessment will be performed at 
screening and select study visits (see Table 3-1 and Table 3-2). At other visits, symptom-directed 
physical examinations and symptom-directed vital signs assessments can be performed at the 
discretion of the investigator or healthcare provider. 
A complete physical examination 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 physical examinations will be reported as AEs. 
The abbreviated physical examination will include an assessment of the following body systems: 
EENT, cardiovascular system, respiratory system, skin, and abdomen. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiratory rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed. 
11.6.4 
Pulse Oximetry 
Pulse oximetry is a noninvasive measure of oxygen delivery to the tissues and has been 
correlated with clinical status and lung function. Arterial oxygen saturation by pulse oximetry 
will be assessed following at least a 5-minute rest and before study drug dosing.  
11.6.5 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs may 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. 
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 the safety of the subjects, a qualified individual at the study site will make 
comparisons to baseline measurements. If the QTcF is increased by >60 msec from the baseline 
or an absolute QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be 
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performed approximately 2 to 4 minutes apart to confirm the original measurement. If either of 
the QTcF values from these repeated ECGs remains above the threshold value (>60 msec from 
baseline or ≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement. Further 
details pertaining to ECGs will be provided to sites in the ECG Manual. 
11.6.6 
Ophthalmologic Examination 
OEs will be conducted at screening only for subjects who are <18 years of age on the date of 
informed consent. OEs do 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.  
For subjects <18 years of age on the date of informed consent, an OE is required at the Safety 
Follow-up Visit only if they completed study drug dosing through Week 8 of the Treatment 
Period. This examination may be completed up to 28 days before the Safety Follow-up Visit, 
after the last dose of study drug in the Treatment Period.  
Any clinically significant abnormal findings will be reported as AEs. 
For subjects who subsequently enroll in an open-label study, follow-up OEs will be performed as 
per that study’s protocol. 
11.6.7 
Contraception and Pregnancy 
The effects of VX-445, TEZ, and IVA on conception, pregnancy, and lactation in humans are not 
known. VX-445, TEZ, and IVA did not show genotoxic potential in a standard battery of in vitro 
(Ames test, chromosomal aberration, or micronucleus in cultured mammalian cells) and in vivo 
(rodent micronucleus) studies. Reproductive toxicology studies of VX-445, TEZ, and IVA have 
not shown teratogenicity in rats and rabbits.  
11.6.7.1 
Contraception 
Contraception requirement for a couple is waived for the following: 
 True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception. True abstinence must 
be practiced from the date of informed consent through 90 days after the last dose of study 
drug. 
 If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the first 
dose of study drug (e.g., examination of a semen specimen or by demonstration of the 
absence of the vas deferens by ultrasound). 
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 If the female is of non-childbearing potential. To be considered of non-childbearing potential, 
the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH level 
within the laboratory’s reference range for postmenopausal females. 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy. 
Note: All other females (including females with tubal ligations) will be considered to be of 
childbearing potential. 
 Same-sex relationships 
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used as a couple. Methods of contraception must be in successful use from signing of consent (or 
assent, when applicable), approximately 28 days before the first dose of study drug (unless 
otherwise noted), and until 90 days following the last dose of study drug. Additional 
contraception requirements may need to be followed according to local regulations and/or 
requirements. Acceptable methods of contraception are listed in Table 11-2.  
Table 11-2 
Acceptable Methods of Contraception 
Method 
Male Subjects and Their 
Female (Non-study) 
Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy performed at least 6 months previously, 
with a documented negative postvasectomy semen 
analysis for sperm 
Yes 
Yes 
Bilateral tubal occlusion (e.g., ligation) performed at 
least 6 months previously 
Yes 
Yes 
Male or female condom with or without spermicidea 
Yes 
Yes 
Female barrier contraception (such as diaphragm, 
cervical cap, or sponge) with spermicide 
Yes 
Yes 
Continuous use of an intrauterine device for at least 
90 days before the first dose of study drug 
Yes 
Yes 
Oral, implanted, injected, or vaginal hormonal 
contraceptives, if successfully used for at least 
60 days before the first dose of study drug 
Yes 
Yes 
a 
A female condom cannot be used with a male condom due to risk of tearing.  
 
Additional notes: 
 If over the course of the study the subject meets the criteria for waiving the contraception 
requirements, the subject does not need to follow the contraceptive methods listed in 
Table 11-2. 
 If over the course of the study the subject’s status changes and the subject does not meet the 
criteria for waiving the contraception requirements, the subject must begin following the 
contraceptive methods listed in Table 11-2.  
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 Male subjects must not donate sperm during the period starting from the first dose of study 
drug until 90 days after the last dose of study drug. 
 Female subjects should not nurse a child during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
 For male subjects with a female partner of childbearing potential, the couple should not plan 
to become pregnant during the study or within 90 days after the last dose of study drug, with 
the exception of couples who plan to become pregnant by artificial insemination using sperm 
banked by the male subject before the first dose of study drug or sperm from another source. 
11.6.7.2 
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 female subject becomes pregnant during study participation, study drug will be permanently 
discontinued immediately. The investigator will notify the medical monitor and Vertex GPS 
within 24 hours of the site’s knowledge of the subject’s (or partner’s) pregnancy using the 
Pregnancy Information Collection Form. Male subjects with female partners who become 
pregnant during the study must use a male condom to avoid exposure of a potential embryo or 
fetus to study drug via the seminal fluid.  
The subject or partner will be followed until the end of the pregnancy and the infant will be 
followed for 1 year after the birth, provided informed consent is obtained. A separate ICF will be 
provided to explain these follow-up activities. Pregnancy itself does not constitute an AE. 
12 
STATISTICAL AND ANALYTICAL PLANS 
12.1 
Sample Size and Power  
Approximately 250 subjects will be enrolled and randomized (1:1) to the VX-445/TEZ/IVA 
treatment arm or control arm (IVA or TEZ/IVA).  
The primary efficacy endpoint is the absolute change in ppFEV1 from baseline through Week 8 
for the VX-445/TEZ/IVA group. The primary null hypothesis to be tested is that the mean 
absolute change in ppFEV1 from baseline through Week 8 is 0 for the VX-445/TEZ/IVA 
treatment group. The null hypothesis will be tested at a 2-sided significance level of 0.05.  
For the primary hypothesis, assuming a within-group SD of 7.0 percentage points and a 10% 
dropout rate at Week 8, a sample size of 125 subjects in the VX-445/TEZ/IVA arm will have 
>99% power to detect the within-group difference of 3.0 percentage points (1 sample t-test at a 
2-sided significance level of 0.05).    
12.2 
Analysis Sets 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), and Safety 
Set. Additional analysis sets related to the Run-in Period will be defined in the Statistical 
Analysis Plan (SAP), as appropriate. 
The All Subjects Set will include all subjects who were randomized or received at least 1 dose 
of study drug. This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified.  
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The FAS will include all randomized subjects who carry the intended CFTR allele mutation and 
have received at least 1 dose of study drug in the Treatment Period. The FAS will be used to 
summarize subject demographics and baseline characteristics, and for all efficacy analyses in 
which subjects will be analyzed according to their randomized treatment group, unless otherwise 
specified. 
The Safety Set will include all subjects who received at least 1 dose of study drug in the 
Treatment Period. The Safety Set will be used for all safety analyses in which subjects will be 
analyzed according to the treatment they received, unless otherwise specified. 
12.3 
Statistical Analysis 
12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). The precision of the measurement for each continuous variable will be specified in the 
SAP. Unless otherwise specified, min and max values will be reported with the same precision as 
the units of the raw data. The mean, median, and SD will be reported to 1 additional decimal 
place. Any values that require a transformation to standard units (metric or SI) will be converted 
with the appropriate precision. 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
The baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
Treatment Period (i.e., the Day 1 Visit). For ECGs, baseline will be defined as the most recent 
pretreatment measurement (or the average of triplicate measurements, if the most recent 
pretreatment measurement is obtained in triplicate) before the first dose of study drug in the 
Treatment Period (i.e., the Day 1 Visit). 
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, 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 of study drug 
in the Treatment Period (TC, placebo + TEZ/IVA, or placebo + IVA) to 28 days after the last 
dose of study drug or to the completion of study participation date (as defined in Section 9.1.7), 
whichever occurs first. 
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
The number and percentage of subjects in each disposition category (e.g., randomized, included 
in the FAS, included in the Safety Set, completed Treatment Period, completed study, 
prematurely discontinued treatment or study with a breakdown of the reasons for 
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discontinuation, and entered an open-label study) will be summarized overall and by treatment 
group. 
An additional subject disposition summary related to the Run-in Period will be defined in the 
SAP, as appropriate. 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographic, medical history, and baseline characteristics will be summarized using descriptive 
summary statistics. 
The following demographics and baseline characteristics will be summarized overall and by 
treatment group based on the FAS, and will include (but are not limited to): sex, race, ethnicity, 
baseline age, baseline weight, baseline height, baseline BMI, baseline ppFEV1, and baseline 
SwCl. 
Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT) for the FAS.  
No statistical tests will be performed to evaluate baseline imbalance between treatment groups. 
12.3.2.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug-Dictionary (WHO-DD) 
and categorized as follows: 
 Prior medication: any medication that was administered during the 56 days before the first 
dose of study drug in the Treatment Period but not 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 therefore does not occur, prior medication will be considered any medication that was 
administered during the 56 days before the last dose of study drug in the Run-in Period but 
before 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: 
o the TE Period for the Run-in Period if the subject did not receive study drug in the 
Treatment Period  
o the TE Period for the Treatment Period for subjects who received study drug in the 
Treatment Period 
A given medication may be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; or 
prior, concomitant, and post-treatment. If a medication has a missing or partially missing 
start/end date or time and if it cannot be determined whether it was taken before the first dose of 
study drug, concomitantly during the TE Period, or after the TE Period, it will be considered in 
all 3 categories of prior, concomitant, and post-treatment medication. 
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Prior medications and concomitant medications will be summarized descriptively by Preferred 
Name, overall, and by treatment group based on the FAS. Post-treatment medications will be 
provided separately in an individual subject data listing. 
12.3.2.4 
Study Drug Exposure and Compliance 
Study drug exposure and compliance will be summarized for the Treatment Period only. 
Study drug exposure will be summarized overall and by treatment group based on the Safety Set 
in terms of the duration of treatment a subject received (in days), defined as [(the last day of 
study drug administration – the first day of study drug administration) + 1 day], regardless of 
study drug interruption.  
Study drug compliance will be summarized overall and by treatment group based on the FAS, 
and will be derived as: 100 × [1 - (total number of days of study drug interruption) / (duration of 
study drug exposure in days)]. A study drug interruption on a given day is defined as an 
interruption of any study drug on that day.  
In addition, percentage of tablets taken will also be summarized overall and by treatment group 
based on the FAS, and will be calculated as 100 × [(total number of tablets dispensed for the 
Treatment Period) – (total number of tablets returned for the Treatment Period)] / (total number 
of tablets planned to be taken per day × duration of study drug exposure in days for the 
Treatment Period). 
12.3.2.5 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. The rules for identifying an IPD will be described in the SAP. 
All IPDs will be provided in an individual subject data listing and summarized, as appropriate. 
12.3.3 
Efficacy and Pharmacodynamic Analyses 
The primary objective of the study is the evaluation of the efficacy of VX-445/TEZ/IVA. The 
analysis in this section will be based on the FAS, unless otherwise specified. 
12.3.3.1 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is the absolute change in ppFEV1 from baseline through Week 8 
for the VX-445/TEZ/IVA group. The primary endpoint will be analyzed using a mixed-effects 
model for repeated measures (MMRM).The model will include the absolute change from 
baseline in ppFEV1 at Day 15, Week 4, and Week 8 as the dependent variable; treatment group, 
visit, and treatment by visit as fixed effects; with continuous baseline ppFEV1, continuous 
baseline SwCl, and comparator group (IVA comparator versus TEZ/IVA comparator) as 
covariates; and an unstructured covariance structure for the within-subject errors. The Day 15 
Visit will not be included in the estimation of the average treatment effect through Week 8. The 
model will be estimated using restricted maximum likelihood. Denominator degrees of freedom 
for the F test for fixed effects will be estimated using the Kenward-Roger approximation. An 
unstructured covariance structure will be used to model the within-subject errors. If the model 
estimation does not converge, a reduced compound symmetry covariance structure will be used 
instead. Conditional on the observed data and covariates, missing data due to treatment or study 
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discontinuation will be assumed to be missing at random; consequently, no imputation of 
missing data will be performed. 
The primary results obtained from the model will be the estimated within-treatment difference 
through Week 8 (average of Week 4 and Week 8) for the VX-445/TEZ/IVA group. The adjusted 
mean with a 2-sided 95% CI and a 2-sided P value will be provided. Furthermore, the treatment 
difference at each post-baseline visit will also be provided, obtained from the model. 
Sensitivity analyses for handling missing data will be described in the SAP.  
Supportive analyses and subgroup analyses by selected baseline characteristics will also be 
described in the SAP.    
12.3.3.2 
Analysis of Key Secondary Efficacy Endpoints 
The key secondary endpoints are: 
 Absolute change in SwCl from baseline through Week 8 for the VX-445/TEZ/IVA 
group: Analysis of this endpoint will be based on the same MMRM model as the analysis of 
the primary efficacy endpoint. Data obtained from the Day 15, Week 4, and Week 8 Visits 
will be included in the model.  
 Absolute change in ppFEV1 from baseline through Week 8 for the VX-445/TEZ/IVA 
group compared to the control group: Analysis of this endpoint will be based on the same 
MMRM model as the analysis of the primary efficacy endpoint. Data obtained from the 
Day 15, Week 4, and Week 8 Visits will be included in the model. However, the Day 15 
Visit will not be included in the estimation of the average treatment effect through Week 8. 
 
Absolute change in SwCl from baseline through Week 8 for the VX-445/TEZ/IVA 
group compared to the control group: Analysis of this endpoint will be based on the same 
MMRM model as the analysis of the primary efficacy endpoint. Data obtained from the 
Day 15, Week 4, and Week 8 Visits will be included in the model.  
Details will be provided in the SAP.  
12.3.3.3 
Analysis of Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints include: 
 Absolute change in CFQ-R RD score from baseline through Week 8 for the 
VX-445/TEZ/IVA group: Analysis of this endpoint will be based on an MMRM model 
similar to the analysis of the primary efficacy endpoint. Data obtained from the Day 15, 
Week 4, and Week 8 Visits will be included in the model. However, the Day 15 Visit will not 
be included in the estimation of the average treatment effect through Week 8. 
 Absolute change in CFQ-R RD score from baseline through Week 8 for the 
VX-445/TEZ/IVA group compared to the control group: Analysis of this endpoint will be 
based on an MMRM model similar to the analysis of the primary efficacy endpoint. Data 
obtained from the Day 15, Week 4, and Week 8 Visits will be included in the model. 
However, the Day 15 Visit will not be included in the estimation of the average treatment 
effect through Week 8. 
Details will be provided in the SAP. 
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12.3.3.4 
Multiplicity Adjustment 
A hierarchical testing procedure will be used to control the overall type I error at an alpha of 0.05 
for the primary endpoint and the key secondary endpoints tested. The key secondary endpoints 
will only be tested at an alpha of 0.05 if the primary endpoint of absolute change in ppFEV1 from 
baseline through Week 8 for the VX-445/TEZ/IVA group is statistically significant. For a test at 
any step to be considered statistically significant within the testing hierarchy, it must be 
statistically significant, and all previous tests (if any) within the hierarchy must be statistically 
significant at the 0.05 level. The testing order of the key secondary endpoints is as follows: 
1. First key secondary endpoint: Absolute change in SwCl from baseline through Week 8 for 
the VX-445/TEZ/IVA group  
2. Second key secondary endpoint: Absolute change in ppFEV1 from baseline through Week 8 
for the VX-445/TEZ/IVA group compared to the control group 
3. Third key secondary endpoint: Absolute change in SwCl from baseline through Week 8 for 
the VX-445/TEZ/IVA group compared to the control group 
12.3.3.5 
Analysis of Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include: 
 Absolute change in CFQ-R non-RD scores from baseline through Week 8: Analysis of 
this endpoint will be based on an MMRM model similar to the analysis of the primary 
efficacy endpoint. Data obtained from the Day 15, Week 4, and Week 8 Visits will be 
included in the model. However, the Day 15 Visit will not be included in the estimation of 
the average treatment effect through Week 8. 
 Absolute change in BMI from baseline at Week 8: Analysis of this endpoint will be based 
on an MMRM model similar to the analysis of the primary efficacy endpoint. Data obtained 
from the Day 15, Week 4, and Week 8 Visits will be included in the model. 
Additional details will be specified in the SAP. 
12.3.4 
Safety Analysis 
All safety analyses will be based on data from the TE Period for all subjects in the Safety Set. 
The overall safety profile of study drug will be assessed based on the following safety and 
tolerability endpoints: 
 Treatment-emergent AEs (TEAEs) 
 Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis) 
 ECGs 
 Vital signs 
 Pulse oximetry 
All safety data from the TE Period will be summarized by treatment group and overall. 
All safety data will be presented in individual subject data listings, including safety data from the 
Run-in Period. 
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12.3.4.1 
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 started before the first dose of study drug (TEZ/IVA or IVA) 
during the Run-in Period 
 TEAE during the Run-in Period: any AE that worsened (either in severity or seriousness) 
or that was newly developed at or after the first dose date of study drug (TEZ/IVA or IVA) 
through the end of the TE Period for the Run-in Period 
 TEAE during the Treatment Period: any AE that worsened (either in severity or 
seriousness) or that was newly developed at or after the first dose of study drug (TC or 
placebo + TEZ/IVA or placebo + IVA) 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: 
o the TE Period for the Run-in Period if the subject did not receive treatment in the 
Treatment Period 
o the TE Period for the Treatment Period if the subject received treatment in the Treatment 
Period 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study drug treatment, then the AEs will be classified as TEAEs corresponding to 
the Treatment Period. Unless otherwise specified, TEAE refers to TEAE during the Treatment 
Period. 
AE summary tables will be presented for TEAEs, overall and by treatment group, and will 
include the following: 
 All TEAEs 
 TEAEs by strongest relationship  
 TEAEs by maximum severity 
 TEAEs leading to treatment discontinuation 
 TEAEs leading to treatment interruption 
 Grade 3 and Grade 4 TEAEs 
 Serious TEAEs 
 TEAEs leading to death 
 Frequently reported TEAEs 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same AE or a 
continuing AE will be counted once. Only the maximum severity level will be presented in the 
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severity summaries, and the strongest relationship level will be presented in the relationship 
summaries. In addition, a listing containing individual subject level AE data for all deaths and 
other serious and significant AEs will be provided separately. All AEs, including pre- and post-
treatment AEs, will be presented in individual subject data listings. 
12.3.4.2 
Clinical Laboratory Assessments 
For the TE laboratory measurements, the observed values and change from baseline values of the 
continuous hematology, serum chemistry, and coagulation results will be summarized in SI units 
overall and by treatment group at each scheduled visit. 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period will be summarized overall and by treatment group. The threshold analysis criterion 
shift from baseline will also be summarized for select laboratory parameters. The threshold 
analysis criteria and the parameter selection criteria will be provided in the SAP. 
Results of urinalysis and pregnancy tests will be listed in individual subject data listings only. In 
addition, a listing containing individual subject hematology, chemistry, and coagulation values 
will be provided. This listing will include data from scheduled and unscheduled visits. 
12.3.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided overall and by treatment group, at each scheduled visit and time 
point, as applicable, for the following standard 12-lead ECG interval measurements (in msec): 
RR, PR, QT, and QT corrected for HR (QTcF), QRS duration, and HR (beats per minute [bpm]). 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period will be summarized overall and by treatment group. The threshold analysis criteria 
will be provided in the SAP. 
Additional ECG analyses may be described in the SAP. 
12.3.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized overall and by treatment group at each scheduled visit. The 
following vital signs parameters will be summarized: systolic and diastolic blood pressure 
(mm Hg), temperature (C), pulse rate (bpm), and respiratory rate (breaths per minute). 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period will be summarized overall and by treatment group. The threshold analysis criteria 
will be provided in the SAP. 
Additional vital signs analyses may be described in the SAP. 
12.3.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided overall and by treatment group, at each scheduled 
visit for the percent of oxygen saturation by pulse oximetry. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the 
TE Period will be summarized overall and by treatment group. 
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12.3.4.6 
Physical Examination 
Physical examination findings will be presented in an individual subject data listing only. 
12.3.4.7 
Other Safety Analysis 
Not applicable 
12.3.5 
Exploratory Endpoints 
12.3.5.1 
Analysis of Exploratory Endpoints 
Details of other analyses, including inflammatory mediators and blood biomarkers analyses, will 
be provided in a separate document. 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses 
12.3.6.1 
Interim Analysis 
Not applicable 
12.3.6.2 
Independent Data Monitoring Committee Analysis 
The IDMC (Section 9.1.8) will conduct safety reviews of study data. Details will be described in 
the IDMC charter. 
12.4 
Clinical Pharmacology Analysis 
12.4.1 
Pharmacokinetic Analysis 
PK analysis of VX-445, TEZ, M1-TEZ, and IVA may be performed using nonlinear 
mixed-effects modeling, as data allow. Descriptive statistics will be used to summarize predose 
plasma concentrations for all analytes. 
A detailed description of the planned PK analysis will be presented in the clinical pharmacology 
analysis plan. 
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, physical examinations, 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 
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provided, rather than the abnormal test result alone (e.g., urinary tract infection, anemia). In the 
absence of a diagnosis, the abnormal study assessment itself will be listed as the AE 
(e.g., bacteria in urine or decreased hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
 Concomitant signs or symptoms related to the abnormal study assessment 
 Further diagnostic testing or medical/surgical intervention 
 A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the subject completes study 
participation, as defined in Section 9.1.7. 
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 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 2018). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” 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 
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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. 
Table 13-1 
Grading of AE Severity  
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
AE: adverse event 
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 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
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Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
AE: adverse event 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories 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 
 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 
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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 
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 Safety 
Follow-up Visit and are considered related to study drug(s) will be reported to Vertex GPS 
within 24 hours of identification.  
For SAEs that occur after obtaining informed consent and assent (where applicable) through 
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: 
 (preferred choice) 
Fax: 
  
For technical issues related to submitting the form, contact telephone: 
 
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) will 
be recorded on the Vertex 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 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. 
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13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IECs, and 
participating investigators in accordance with ICH Guidelines and/or local regulatory 
requirements, as applicable. In addition, Vertex, or authorized designee, will be responsible for 
the submission of safety letters to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/IEC of all 
unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will be 
conducted only at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
ICH GCP and all applicable laws and regulations and will be subject to approval by Vertex or its 
designee. When determining the age of the subject, other study eligibility criteria, and timing of 
collection applicable assessments, the informed consent will be used as the reference (e.g., age at 
time of informed consent, date of informed consent, timing of AE collection). 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
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13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers, and access to subject names linked to such 
numbers 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. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP Guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
 Subject or investigator noncompliance 
 Unsatisfactory subject enrollment 
 Lack of adherence to protocol procedures 
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 Lack of evaluable and/or complete data 
 Potentially unacceptable risk to study subjects 
 Decision to modify drug development plan 
 Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.2.8 
End of Study 
The end of study is defined as the last scheduled visit (or 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. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each subject. Study 
data for each enrolled subject will be entered into a CRF by study site personnel using a secure, 
validated, web-based electronic data capture (EDC) application. Vertex will have read-only 
access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP Guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
Protocol deviations will be monitored and identified throughout study conduct as outlined in the 
Protocol Deviation Plan. 
13.5 
Electronic Data Capture 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
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The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc or other electronic media 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.20 
Publication Planning: Vertex staff along with the lead principal investigators, 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 criteria21: 
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;  
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. 
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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 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 ICH E3 Guideline, will be submitted in accordance with 
local regulations. 
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14 
REFERENCES 
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 24 March 2019. 
2 
Cystic Fibrosis Foundation. Patient Registry: 2017 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2018. 
3 
European Cystic Fibrosis Society. 2016 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: European Cystic Fibrosis Society; 2018. 
4 
United States Department of Health and Human Services. Food and Drug Administration. 
Office of Orphan Products Development. Developing Products for Rare Diseases & 
Conditions. Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.
htm. Accessed 24 March 2019. 
5 
European Medicines Agency [Internet]. Committee for Orphan Medicinal Products 
(COMP). Available at: https://www.ema.europa.eu/en/committees/committee-orphan-
medicinal-products-comp. Accessed 24 March 2019. 
6 
Rommens J, Iannuzzi M, Kerem B, Drumm M, Melmer G, Dean M, et al. Identification 
of the cystic fibrosis gene: chromosome walking and jumping. Science. 
1989;245(4922):1059-65. 
7 
Kreindler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
8 
Sheppard MN, Nicholson AG. The pathology of cystic fibrosis. Curr Diagn Pathol. 
2002;8(1):50-59. 
9 
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
10 
CFTR2.org. Clinical and functional translation of CFTR. The Clinical and Functional 
TRanslation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins 
University, the Hospital for Sick Children. Available at: http://www.cftr2.org. Accessed 
24 March 2019. 
11 
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. 
12 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
13 
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. 
14 
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. 
15 
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. 
16 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 
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17 
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of 
the Cystic Fibrosis Questionnaire in the United States. Chest. 2005;128(4):2347-54. 
18 
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life 
Res. 2003;12(1):63-76. 
19 
Wenninger K, Aussage P, Wahn U, Staab D, German Cystic Fibrosis Questionnaire study 
group. The revised German Cystic Fibrosis Questionnaire: validation of a disease-
specific health-related quality of life instrument. Qual Life Res. 2003;12(1):77-85. 
20 
Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
publication practice for communicating company-sponsored medical research: GPP3. 
Ann Intern Med. 2015;163(6):461-4. 
21 
International Committee of Medical Journal Editors (ICMJE). Recommendations for 
conduct, reporting, editing, and publication of scholarly work in medical journals. 
Available at: http://www.icmje.org/recommendations/. Accessed April 9, 2018. 
 
 
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15 
APPENDIX A: ELIGIBLE MUTATIONS FOR SUBJECTS WHO ARE 
HETEROZYGOUS FOR THE F508DEL-CFTR MUTATION AND A 
GATING OR RESIDUAL FUNCTION MUTATION (F/G AND F/RF 
GENOTYPES)  
As described in Section 8.1, subjects heterozygous for the F508del mutation and a gating or 
residual function mutation (F/G and F/RF genotypes) and in regions where their genotype and 
age group are approved indications for treatment with IVA and/or TEZ/IVA qualify to be 
screened for the study.  
Qualifying gating and residual function mutations that met these conditions at the time of 
protocol finalization are presented below. Additional mutations may subsequently qualify under 
these conditions; investigators should contact the medical monitor with questions about such 
mutations. 
Eligible Mutations 
IVA Comparator Group Mutations 
R117H 
G551D 
G1244E 
G178R  
G551S 
S1251N 
S549N  
G1069R 
S1255P 
S549R  
R1070Q 
G1349D 
TEZ/IVA Comparator Group Mutations 
711+3A>G 
R117C 
S977F 
2789+5G>A 
E193K 
F1052V 
3272-26A>G 
L206W 
K1060T 
3849+10kbC>T 
R347H 
A1067T 
E56K 
R352Q 
R1070W 
P67L 
A455E 
F1074L 
R74W 
D579G 
D1152H 
D110E 
E831X 
D1270N 
D110H 
S945L 
 
IVA: ivacaftor; TEZ: tezacaftor 
 
 
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16.2 
Investigator Signature Page 
Protocol #:  
VX18-445-104 
Version #: 
2.0 
Version Date: 
02 December 2019 
Study Title: A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy 
and Safety of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are 
Heterozygous for the F508del Mutation and a Gating or Residual Function Mutation (F/G and 
F/RF Genotypes) 
 
 
I have read Protocol VX18-445-104, Version 2.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-445, tezacaftor, and ivacaftor and this 
protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
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Page 1 of 7 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol Addendum  
for Cystic Fibrosis  
Cystic Fibrosis Studies for the Following Programs 
 
 
 
Elexacaftor/Tezacaftor/Ivacaftor (VX-445/VX-661/VX-770) 
 
 
Version and Date of Protocol Addendum: Version 2.0, 15 May 2020 
Replaces Version 1.0, dated 24 April 2020  
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 
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Summary of Changes to Cystic Fibrosis Clinical Study Protocols 
Vertex is currently evaluating several CFTR modulators in clinical studies for the treatment of 
cystic fibrosis (CF), a serious and life-threatening disease. In completed studies, treatment with 
these CFTR modulators has generally resulted in rapid, robust, clinically meaningful, and 
statistically significant improvements in clinical measures, and are generally safe and well 
tolerated. Adverse events (AEs) seen with these treatments are mostly consistent with common 
manifestations of CF disease or with common illnesses in CF subjects.  
During this COVID-19 pandemic, the safety of the subjects, investigators, and site personnel 
participating in these clinical studies is Vertex’s first priority, thus it is important to minimize 
any unnecessary risk to COVID-19 exposure through travel to study sites. This addendum 
summarizes the measures taken for ongoing CF clinical studies. These operational adjustments 
were implemented to align with Health Authority guidance ensuring the protection of subjects, 
investigators, and site personnel while maintaining compliance with GCP and minimizing impact 
to the integrity of the studies. Overall, the benefit-risk of these studies remains favorable. 
Vertex recommends that subjects and sites refer to local guidance regarding travel restrictions. 
There are no operational changes to the study protocols for subjects who can travel to the study 
sites for their visits. However, to ensure continued safety of subjects who cannot travel to the 
study sites for their visits (for any reason due to COVID-19), specific alternative measures are 
being implemented to minimize the risk of exposure to COVID-19 (see table below). As the 
COVID-19 pandemic evolves, Vertex will continue to assess the need for additional actions to 
ensure the safety of all involved in these clinical studies. 
Addendum Version 2.0 summarizes additional measures taken for these ongoing CF clinical 
studies (see table below) to ensure continued safety. In addition, administrative changes were 
made to provide clarifications (e.g., changed Addendum 1 to Addendum Version 1.0) and to 
provide examples of qualified personnel (e.g., personnel from site or qualified health care 
agency) who may conduct safety assessments, as indicated per protocol, during in-home visits. 
 
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Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Rationale for Change 
Study Number 
Addendum Version 2.0, dated 15 May 2020 
Assessments 
 
Weight and height/length/stature may be assessed by subjects or their 
caregivers using medical grade scales and stadiometers, as indicated per 
protocol and per local regulation. Sites and subjects will receive training and 
guidance as needed on these devices.  
 
Subjects or caregivers will provide these measurements to site personnel by 
telephone or video call. Investigators will review results and contact subjects 
for follow-up as needed. All data will continue to be retained in the subject’s 
source files. 
To allow for collection of key data to assess safety and/or 
efficacy while maintaining study integrity and the safety 
of subjects and site personnel. 
 
Addendum 1 allowed for these assessments to be 
performed by qualified personnel conducting the in-home 
visits. Addendum 2 allows for these assessments to be 
performed by subjects or caregivers. 
 
 
 
 
 
 
 
 
VX18-445-104 
 
 
 
 
 
 
 
 
 
 
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Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Consenting of Subjects 
ICFs may be provided electronically or by post mail to subjects (and/or caregivers, as 
indicated per protocol). The subjects and/or caregivers will review the ICF with an 
appropriately qualified member of the investigator’s team via telephone contact or video call. 
After this review, subjects and/or caregivers will consent (or assent, if applicable), and/or 
reconsent verbally and by signing and dating the ICF and returning it to the site via post mail. 
The signed and dated ICF will then be signed and dated by the investigator.  
 
Subjects participating in select studies may have the opportunity to enroll in longterm 
extension studies. Informed consent (or assent, if applicable), and/or reconsent for subjects 
(and/or caregivers, as indicated per protocol) may be obtained per the same process described 
above, as applicable. 
To provide alternative methods of 
obtaining reconsent or consent, as 
applicable, while ensuring subject 
safety. 
 
 
 
 
 
 
 
 
 
VX18-445-104 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Shipping 
Study drug may be shipped directly from the site to the subject, as applicable, and if permitted 
by local regulations; subject protected health information will not be released to Vertex.  
 
Reconciliation, return, and destruction of study drug will continue to occur at the clinical site 
as indicated per protocol and in adherence to local regulations. 
To ensure subjects can continue 
treatment with study drug without 
interruption while ensuring their safety. 
 
To clarify that despite these alternative 
measures, reconciliation, return, and 
destruction of study drug will remain as 
indicated per protocol. 
In-home Visits and/or Telephone Contact 
Study visits may be conducted as in-home visits by qualified personnel as requested by 
participating sites on a per-subject basis. In addition, all subjects may be contacted by site 
personnel by telephone or video call, irrespective of in-home visits. 
To provide subjects the opportunity to 
continue participation in the clinical 
studies while ensuring their safety by 
minimizing the risk to COVID-19 
exposure through travel. 
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Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Safety Assessments and Reporting 
Safety assessments, as indicated per protocol, may be performed by qualified personnel 
conducting the in-home visits (e.g., personnel from site or qualified health care agency). These 
assessments may include the following, as indicated per protocol, and per local regulation:  
• vital signs 
• pulse oximetry 
• height/length/stature 
• weight 
• physical examination 
(complete or abbreviated) 
• pregnancy test  
(serum or urine) 
• urinalysis 
• blood draws for safety test panels 
(chemistry, LFT panel, lipid panel, 
hematology, coagulation).  
Blood and/or urine samples for safety assessments are analyzed as indicated per protocol for 
subjects who have in-home visits. 
Blood and/or urine samples for safety assessments may be collected and analyzed at local 
laboratories for subjects who do not have in-home visits, but do not complete the assessment 
at the site. 
In addition, safety assessents will be evaluated by telephone. These assessments may include 
the review of the following:  
• AEs 
• signs and symptoms/systems for CF 
• medications 
• planned or unplanned hospitalizations for CF 
• study drug administration 
• outcomes related to PEx  
• outcomes related to antibiotic treatment 
Investigators will review results (in-home and telephone) and contact subjects for follow-up as 
needed. 
All data will continue to be retained in the subject’s source files. 
Any clinically significant finding (e.g., AE, SAE, laboratory abnormalities) will continue to be 
reported as indicated per protocol. 
To assess the safety and tolerability of 
the CFTR modulator evaluated in the 
specific clinical study while ensuring 
subject safety. These safety 
assessments will continue to provide 
safety data while minimizing burden to 
subjects and site personnel.  
 
To clarify that despite these alternative 
measures, all adverse events and 
serious adverse events should be 
reported as indicated per protocol. 
 
 
 
 
 
 
 
 
VX18-445-104 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Efficacy and Other Assessments 
Efficacy and other assessments, as indicated per protocol, may be performed by qualified 
personnel conducting the in-home visits. These assessments may include the following, as 
indicated per protocol, and per local regulation. 
In-home Spirometry Assessment 
A spirometry device may be provided to subjects for in-home assessments of lung function as 
indicated per protocol. Sites and subjects will receive training and guidance as needed. 
Patient Reported Outcome 
CFQ-R questionnaires may be provided to subjects (electronically or post mail) to be 
completed at home as indicated per protocol. Subjects will return these questionnaires to the 
site via post mail. 
Other Assessments  
• ECGs  
• sweat chloride 
• blood samples for CFTR genotype testing, 
, PK, FSH, inflammatory mediator, 
biomarkers, and 
  
• 
 
 
To be able to assess safety, treatment 
effectiveness, and quality of life 
measures of the CFTR modulator 
evaluated in the specific clinical study 
while ensuring subject safety. 
 
All Efficacy and 
Other 
Assessments 
 
 
 
VX18-445-104 
 
 
 
  
 
 
 
 
 
 
 
 
Other Outcomes 
Only 
 
 
 
 
 
 
 
Page 6 of 561


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 2.0 
Page 7 of 7 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Remote Monitoring 
Vertex has implemented remote monitoring visits where applicable, including remote source 
data verification, as allowed per local regulations. Remote monitoring will focus on collection 
of safety data, and data supporting primary and key secondary endpoints. 
To allow for review of key data to 
inform on the safety of subjects 
receiving treatment. 
 
To allow for review of other key data 
to inform on the objectives of the study 
while maintaining study integrity and 
the safety of subjects and site 
personnel. 
 
 
 
 
 
 
 
 
 
 
 
 
VX18-445-104 
 
 
 
 
 
 
 
 
 
AE: adverse event; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; ECG: electrocardiogram; 
 
FSH: follicle-stimulating hormone; GCP: Good Clinical Practice; ICF: informed consent form; 
; LFT: liver function test; 
PEx: pulmonary exacerbation; PK: pharmacokinetic; SAE: serious adverse event; 
 
 
 
Page 7 of 561

SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 38 
Protocol Number: VX18-445-104 
 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX18-445-104 Version 2.0 
(Final Analysis) 
 
 
A Phase 3, Randomized, Double-blind, Controlled Study Evaluating 
the Efficacy and Safety of VX-445 Combination Therapy in Subjects 
With Cystic Fibrosis Who Are Heterozygous for the F508del Mutation 
and a Gating or Residual Function Mutation (F/G and F/RF 
Genotypes) 
 
Authors of SAP: 
 
 
Version: 2.0 
Version Date of SAP: 22 JUNE 2020 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods) 
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Vertex Pharmaceuticals Incorporated 
2 
TABLE OF CONTENTS 
 
1 
Title Page ................................................................................................................................ 1 
2 
Table of Contents ................................................................................................................... 2 
3 
Modifications .......................................................................................................................... 4 
3.1 
Modifications to the Approved Clinical Study Protocol .................................................. 4 
3.2 
Modifications to the Approved Statistical Analysis Plan ................................................. 4 
3.3 
Modifications to the Approved DMC Charter .................................................................. 4 
4 
Introduction............................................................................................................................ 5 
5 
Study Objectives .................................................................................................................... 5 
5.1 
Primary Objective ............................................................................................................. 5 
5.2 
Secondary Objectives ....................................................................................................... 5 
6 
Study Endpoints ..................................................................................................................... 5 
6.1 
Efficacy and Pharmacodynamic Endpoints ...................................................................... 5 
6.1.1 
Primary Endpoint ...................................................................................................... 5 
6.1.2 
Key Secondary Endpoints ........................................................................................ 6 
6.1.3 
Other Secondary Endpoints ...................................................................................... 6 
6.2 
Safety Endpoints ............................................................................................................... 6 
7 
Study Design ........................................................................................................................... 6 
7.1 
Overall Design .................................................................................................................. 6 
7.2 
Sample Size and Power .................................................................................................... 8 
7.3 
Randomization .................................................................................................................. 8 
7.4 
Blinding and Unblinding .................................................................................................. 8 
8 
Analysis Sets ........................................................................................................................... 8 
8.1 
All Subjects Set ................................................................................................................ 8 
8.2 
Full Analysis Set ............................................................................................................... 8 
8.3 
Safety Set .......................................................................................................................... 8 
9 
Statistical Analysis ................................................................................................................. 9 
9.1 
General Considerations .................................................................................................... 9 
9.2 
Background Characteristics ............................................................................................ 10 
9.2.1 
Subject Disposition ................................................................................................. 10 
9.2.2 
Demographics and Baseline Characteristics ........................................................... 10 
9.2.3 
Medical History ...................................................................................................... 12 
9.2.4 
Prior and Concomitant Medications ....................................................................... 12 
9.2.5 
Study Drug Exposure.............................................................................................. 13 
9.2.6 
Study Drug Compliance ......................................................................................... 13 
9.2.7 
Important Protocol Deviations ................................................................................ 13 
9.3 
Efficacy Analysis ............................................................................................................ 14 
9.3.1 
Analysis of Primary Efficacy Variable ................................................................... 14 
9.3.2 
Analysis of Key Secondary Variables .................................................................... 16 
9.3.3 
Analysis of Other Secondary Efficacy Variables ................................................... 17 
9.3.4 
Analysis of Exploratory Variables ......................................................................... 18 
9.3.5 
Analysis of Additional Efficacy Variables ............................................................. 18 


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9.4 
Safety Analysis ............................................................................................................... 19 
9.4.1 
Adverse Events ....................................................................................................... 19 
9.4.2 
Clinical Laboratory ................................................................................................. 21 
9.4.3 
Electrocardiogram .................................................................................................. 22 
9.4.4 
Vital Signs .............................................................................................................. 22 
9.4.5 
Pulse Oximetry ....................................................................................................... 22 
9.4.6 
Physical Examination ............................................................................................. 22 
9.4.7 
Ophthalmology Examination .................................................................................. 23 
9.4.8 
COVID-19 Impacted Visits .................................................................................... 23 
9.4.9 
Supportive Safety Analysis .................................................................................... 23 
10 Interim and DMC Analyses ................................................................................................ 23 
10.1 Interim Analysis ............................................................................................................. 23 
10.2 DMC analysis ................................................................................................................. 23 
11 References ............................................................................................................................. 24 
12 List of Appendices................................................................................................................ 25 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessment ........................... 25 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 27 
Appendix C: Details of GLI Equations for Calculating ppFEV1 ............................................. 28 
Appendix D: Steps for Multiple Imputation ............................................................................ 29 
Appendix E: Imputation Rules for Missing AE dates .............................................................. 31 
Appendix F: Criteria for Threshold Analysis .......................................................................... 33 
Appendix G: Adverse Events of Special Interest ..................................................................... 38 
 
 


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3 
MODIFICATIONS  
3.1 
Modifications to the Approved Clinical Study Protocol 
Not Applicable. 
3.2 
Modifications to the Approved Statistical Analysis Plan 
This is the 2nd version of Statistical Analysis Plan.  
Change and Rationale 
Affected Sections 
The rationale to amend the SAP is included. 
SAP Version 1.0, Section 
4 
SAP Version 2.0, Section 
4 
Clarify that the primary analysis for ppFEV1 will be based on 
clinical spirometry only, and add potential additional analysis to 
include the Air Next Spirometry data. 
 
SAP Version 1.0, Section 
9.3.1.2 
SAP Version 2.0, Section 
9.3.1.2 
Clarify that the main analysis for CFQ-R RD score will include 
both clinic and home assessed CFQ-R data. Additional analyses 
may be performed to assess data consistency.  
 
SAP Version 1.0, Section 
9.3.3.2  
SAP Version 2.0, Section 
9.3.3.2  
An additional listing containing subjects’ visits impacted due to 
COVID-19 will be provided. This listing is to meet FDA, EMA, 
and other health agency issued guidance on clinical trials 
conducted during the COVID-19 pandemic. 
SAP Version 1.0, Section 
9.4.8 
SAP Version 2.0, Section 
9.4.8 
 
3.3 
Modifications to the Approved DMC Charter 
Not Applicable. 
 


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4 
INTRODUCTION 
This statistical analysis plan (SAP) is based on the most recent approved clinical study protocol 
(CSP), the most recent approved electronic case report form (eCRF), and the most recent 
approved eCRF completion guidelines.  
This SAP (Methods) documents the planned final statistical analyses of efficacy and safety 
endpoints defined in the VX18-445-104 study protocol. It also documents analyses for additional 
efficacy and safety variables not specified in the protocol, which will provide supportive 
information for the scientific understanding of the drug entity.  
The pharmacodynamic (PD) characteristics of (ELX, VX-445)/TEZ/IVA in CF subjects who are 
heterozygous for F508del and a gating or residual function mutation also will be evaluated in the 
study. Selected analyses related to sweat chloride will be documented in this SAP, other PK and 
PD analyses will be documented separately in the clinical pharmacology analysis plan (CPAP) 
for the study. 
The Vertex Biometrics Department will perform the statistical analyses on efficacy and safety 
endpoints, and selected analyses on sweat chloride; SAS (Version 9.4 or higher) will be used to 
generate all statistical outputs (tables, figures, listings, and datasets). The SAP will be finalized 
and approved prior to the clinical database lock and treatment unblinding for the study. Any 
revisions to the approved SAP will be documented and approved in an amendment to the SAP 
prior to the clinical database lock for the final analysis. Any changes made to the SAP (Methods) 
after the clinical database lock has occurred will be documented in the clinical study report for 
this study. 
Due to the outbreak of COVID-19, to ensure continued safety of subjects who cannot travel to 
the study sites for their visits (for any reason due to COVID-19), specific alternative measures 
are being implemented to minimize the risk of exposure to COVID-19. The SAP Version 2.0 
summarizes the additional statistical analyses that are related to these alternative measures.  
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
To evaluate the efficacy of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) in CF subjects 
who are heterozygous for F508del and a gating or residual function mutation (F/G and F/RF 
genotypes) 
5.2 
Secondary Objectives  
• To evaluate the safety of ELX/TEZ/IVA   
• To evaluate the pharmacodynamics (PD) of ELX /TEZ/IVA  
6 
STUDY ENDPOINTS 
6.1 
Efficacy and Pharmacodynamic Endpoints  
6.1.1 
Primary Endpoint 
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline through Week 8 for the ELX/TEZ/IVA group 


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6.1.2 
Key Secondary Endpoints 
The key secondary efficacy endpoints are as follows:  
• 
Absolute change in sweat chloride (SwCl) from baseline through Week 8 for the 
ELX/TEZ/IVA group  
• Absolute change in ppFEV1 from baseline through Week 8 for the ELX/TEZ/IVA group 
compared to the control group  
• 
Absolute change in SwCl from baseline through Week 8 for the ELX/TEZ/IVA group 
compared to the control group 
6.1.3 
Other Secondary Endpoints 
• Absolute change in CF Questionnaire-Revised (CFQ-R) respiratory domain (RD) score 
from baseline through Week 8 for the ELX/TEZ/IVA group 
• Absolute change in CFQ-R RD score from baseline through Week 8 for the 
ELX/TEZ/IVA group compared to the control group 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory 
values, ECGs, vital signs, and pulse oximetry 
6.2 
Safety Endpoints 
Safety and tolerability will be evaluated via the following endpoints: 
• Adverse events (AEs) 
• Clinical laboratory values 
• Standard 12-lead ECGs 
• Vital signs 
• Pulse oximetry 
7 
STUDY DESIGN  
7.1 
Overall Design  
This is a Phase 3, randomized, double-blind, active-controlled, parallel-group, multicenter study. 
A schematic of the study design is shown in Figure 7-1. 


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Figure 7-1 
Schematic of the Study Design 
 
IVA: ivacaftor; ppFEV1: percent predicted forced expiratory volume in 1 second; SwCl: sweat chloride; TC: triple 
combination; TEZ: tezacaftor  
Note: The Safety Follow-up Visit is not required for subjects who complete the Week 8 Visit and enroll in an open-
label study within 28 days after the last dose of study drug.  
a 
Subjects will be randomized 1:1 to the TC arm or the control arm. Randomization will be stratified based on 
comparator group (IVA comparator versus TEZ/IVA comparator), ppFEV1 as determined during the Run-in 
Period (Day -14 assessment; <70 versus ≥70), and SwCl as determined during the Run-in Period (Day -14 
assessment; <30 mmol/L versus ≥30 mmol/L). 
In the Run-in Period, subjects will be assigned to the IVA or TEZ/IVA comparator group based 
on genotype. Subjects assigned to the IVA comparator group will receive IVA 150 mg every 12 
hours (q12h) and subjects assigned to the TEZ/IVA comparator group will receive TEZ 100 mg 
once daily (qd)/IVA 150 mg q12h. The planned dosages for the Treatment Period are shown in 
Table 7-1.   
In the Treatment Period, subjects will be randomized (1:1) to the ELX/TEZ/IVA treatment arm 
or control arm under a single randomization scheme. Subjects in the control arm who received 
IVA in the Run-in Period will receive IVA in the Treatment Period; subjects in the control arm 
who received TEZ/IVA in the Run-in Period will receive TEZ/IVA in the Treatment Period. 
Table 7-1 
Treatment Period Arms and Planned Dosages 
Comparator 
Group 
Treatment Arm 
ELX Dosage 
TEZ Dosage 
IVA Dosage 
IVA 
ELX/TEZ/IVA 
200 mg qd 
100 mg qd 
150 mg q12h 
Control 
0 mg 
0 mg 
150 mg q12h 
TEZ/IVA 
ELX/TEZ/IVA 
200 mg qd 
100 mg qd 
150 mg q12h 
Control 
0 mg 
100 mg qd 
150 mg q12h 
IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TEZ: tezacaftor 
All visits will occur within the windows specified. Please refer to the Table 3-1 and Table 3-2 of 
the CSP for more details about study visits and assessments. 


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7.2 
Sample Size and Power 
The primary efficacy endpoint is the absolute change in ppFEV1 from baseline through Week 8 
for the ELX/TEZ/IVA group. The primary null hypothesis to be tested is that the mean absolute 
change in ppFEV1 from baseline through Week 8 is 0 for the ELX/TEZ/IVA treatment group. 
The null hypothesis will be tested at a 2-sided significance level of 0.05. 
For the primary hypothesis, assuming a within-group standard deviation (SD) of 7.0 percentage 
points and a 10% dropout rate at Week 8, a sample size of 125 subjects in the ELX/TEZ/IVA 
arm will have >99% power to detect the within group difference of 3.0 percentage points (1 
sample t test at a 2-sided significance level of 0.05). 
7.3 
Randomization 
Randomization will be stratified based on comparator group (IVA comparator versus TEZ/IVA 
comparator), ppFEV1 as determined during the Run-in Period (Day -14 assessment; <70 versus 
≥70), and SwCl as determined during the Run-in Period (Day -14 assessment; <30 mmol/L 
versus ≥30 mmol/L). 
7.4 
Blinding and Unblinding 
Refer to the CSP section 10.7 for details. 
8 
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), Safety Set for 
the Run-in Period and Safety Set for the Treatment Period.  
8.1 
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.  
8.2 
Full Analysis Set  
The Full Analysis Set (FAS) will include all randomized subjects who carry the intended CFTR 
allele mutation and have received at least 1 dose of study drug in the Treatment Period. The FAS 
will be used to summarize subject demographics and baseline characteristics, and for all efficacy 
analyses in which subjects will be analyzed according to their randomized treatment group, 
unless otherwise specified.  
8.3 
Safety Set 
The Safety Set for the Run-in Period will include all subjects who received at least 1 dose of 
TEZ/IVA or IVA in the Run-in Period. This safety set will be included in individual subject data 
listings, unless otherwise specified. 
The Safety Set for the Treatment Period will include all subjects who receive at least 1 dose of 
study drug in the Treatment Period. This safety set will be used for all safety analyses in which 
subjects will be analyzed according to the treatment they receive, unless otherwise specified. 


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9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of CSP. The precision standards for 
reporting safety and efficacy variables are provided in an internal Biometrics document that 
specifies the programming rules including the precision for derived variables. 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, standard deviation (SD), median, minimum value (min), and 
maximum value (max).  
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline value, unless otherwise specified, is defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
Treatment Period (i.e., the Day 1 Visit). For ECGs, baseline will be defined as the most recent 
pretreatment measurement before the first dose of study drug in the Treatment Period (i.e., the 
Day 1 Visit). 
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. 
The Treatment-emergent (TE) Period for the Run-in Period will be from the first dose of 
study drug in the Run-in Period to (1) the first dose 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 include the time from the first dose date of study 
drug in the Treatment Period (TC, placebo + TEZ/IVA, or placebo + IVA) to 28 days after the 
last dose of the study drug or to the completion of study participation date, whichever occurs 
first. 
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 
3) In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values during TE period for safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix A. 
Incomplete/missing data will not be imputed, unless otherwise specified.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless otherwise specified. 


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9.2 
Background Characteristics  
9.2.1 
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 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 Run-in Period and the reason for study discontinuation 
A separate disposition table will be provided for the Treatment Period with the following 
categories:  
• Full Analysis Set 
• Safety Set for the Treatment Period 
• Randomized 
• Randomized but not dosed in the Treatment Period 
• Randomized or dosed in the Treatment Period 
The number and percentage (based on Safety Set for the Treatment Period) of subjects in each of 
the following disposition categories will be summarized by treatment group and overall: 
• Completed study drug treatment 
• Prematurely discontinued treatment and the reason for discontinuation (i.e., discontinued all 
study drugs) 
• Completed study 
• Prematurely discontinued the study and the reason for discontinuation  
• Rollover to the open-label study 
A listing will be provided for subjects who discontinued treatment (including both the Run-in 
Period and Treatment Period) or who discontinued study with reasons for discontinuation. 
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the FAS, and presented 
by treatment group and overall, as applicable. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Sex (female and male) 


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• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, and not collected per local regulations) 
• Geographic region (North America, Europe [including Australia]) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• Age group at the Screening Visit (≥12 to <18, ≥18) 
Stratification categories will include the following: 
• Comparator group (TEZ/IVA, IVA) 
• ppFEV1 at Day -14 (<70, ≥70) 
• Sweat Chloride at Day -14 (<30 mmol/L, ≥30 mmol/L) 
Disease characteristics will include the following: 
• ppFEV1 category at baseline (<40, ≥ 40 to <70, ≥70 to ≤90, and >90) 
• ppFEV1 at baseline (continuous)  
• Sweat chloride at baseline (continuous) 
• CFQ-R respiratory domain score at baseline (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 bronchodilator before first dose of study drug in the Treatment Period (Yes, No)  
• Prior use of inhaled 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. 


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9.2.3 
Medical History 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). Medical history will be summarized descriptively by System Organ Class and 
Preferred Term based on the FAS. The corresponding data listing will also be provided. 
In addition, the number of subjects reported to have had positive cultures for respiratory 
pathogens within the 2 years prior to screening (i.e., answered yes on the respiratory 
microbiology form) will be summarized for the FAS. The corresponding data listing will be 
provided. 
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD) 
and categorized as follows: 
Prior medication: any medication that was administered during the 56 days before the first dose 
date of study drug in the Treatment Period but not in the Run-in Period. For subjects who 
discontinue during 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 
prior to the last dose date in the Run-in Period but before the first dose date 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 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 B. 
Prior medications and concomitant medications will be summarized descriptively based on the 
FAS using frequency tables by: 1) treatment group and overall, preferred name (PN); and 2) 
treatment group and overall, anatomic class (ATC) level 1, ATC level 2, and PN.  
Prior and concomitant medication during the Run-in Period will be summarized together in one 
summary table. Post-treatment medications will be listed in the all medication listing. 


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9.2.5 
Study Drug Exposure  
Study drug exposure will be summarized for the Treatment Period only based on the Safety Set 
for the Treatment Period, and will be presented by treatment group and overall. 
Duration of study drug exposure (in days) will be calculated as: last dose date of study drug in 
the Treatment Period – first dose date of study drug in the Treatment Period + 1, regardless of 
study drug interruption, and will be summarized descriptively.  
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max. It will also be summarized by interval: ≤2 weeks, >2- ≤4 
weeks, >4- ≤8 and >8 weeks, using counts and percentages. Additionally, the total study drug 
exposure, defined as the sum total of the study drug exposure across all subjects (in patient-
weeks), will be provided. 
9.2.6 
Study Drug Compliance 
Study drug compliance will be summarized for the Treatment Period only based on the FAS, and 
will be presented by treatment group and overall.   
Study drug compliance will be calculated as: 100 × [1 - (total number of days of study drug 
interruption 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 drugs on that day. A study drug interruption that continues through the end of the study 
participation (i.e., subject does not resume study drug before the end of the study participation) 
will not be included in the compliance calculation. 
Study drug compliance will be summarized descriptively by the number of subjects (n), mean, 
SD, median, min, and max.  It will also be summarized in categories: <80% and ≥80% using 
frequency tables. 
In addition, percentage of tablets taken will be calculated using the following formula: 
100  [(total number of tablets dispensed for the Treatment Period) – (total number of tablets 
returned for the Treatment Period)] / (total number of tablets planned to be taken per 
day  duration of study drug exposure in days for the Treatment Period).  Summary similar to 
those for the study drug compliance will be produced based on the FAS. 
9.2.7 
Important Protocol Deviations  
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. IPD rules will be developed and finalized before database lock.  
The protocol deviations that should be considered as potential IPDs include, but are not limited 
to:  
• Subject was enrolled in the study despite the violation of inclusion/exclusion criteria  
• Subject was less than 80% compliant with study drug for non-safety reasons 
• Subject received prohibited concomitant medications  
• Subject received the wrong treatment or incorrect doses  


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Occurrence of any of these events should be considered as potential IPDs, but a blinded team 
should categorize them as IPDs only if they have the potential to significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being.  
IPDs (from the site deviation log) will be summarized descriptively based on the FAS and 
presented by treatment group and overall. Additionally, IPDs will be provided in an individual 
subject data listing.  
9.3 
Efficacy Analysis  
Unless otherwise defined, all efficacy analyses described in this section will be based on the 
FAS.  
9.3.1 
Analysis of Primary Efficacy Variable 
9.3.1.1 
Definition of Variable 
The primary efficacy variable is absolute change in ppFEV1 from baseline through Week 8 for 
the ELX/TEZ/IVA group. Percent predicted FEV1 is the ratio of FEV1 (L) to the predicted FEV1 
(L), expressed as a percentage. The predicted FEV1 will be calculated using the Global Lung 
Function Initiative1 (GLI); details are in Appendix C.  
9.3.1.2 
Primary Analysis  
The primary analysis will be performed using a mixed-effects model for repeated measures 
(MMRM) with the absolute change from baseline at Day 15, Week 4 and Week 8 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, and 
comparator group (IVA comparator versus TEZ/IVA comparator) as covariates. The Day 15 
Visit will not be included in the estimation of the average treatment effect through Week 8. The 
model will be estimated using restricted maximum likelihood. Denominator degrees of freedom 
for the F-test for fixed effects will be estimated using the Kenward-Roger approximation2. An 
unstructured covariance structure will be used to model the within-subject errors. If the model 
estimation does not converge, a compound symmetry covariance structure will be used instead. 
Conditional on the observed data and covariates, missing data will be assumed to be missing at 
random; consequently, no imputation of missing data will be performed.  
The primary results obtained from the model will be the estimated within-group treatment 
difference through Week 8 (average of Week 4 and Week 8) for the ELX/TEZ/IVA group. The 
adjusted means with 2-sided 95% confidence intervals and 2-sided P values will be provided.  
Furthermore, the within-group treatment difference at each post-baseline visit will also be 
provided, obtained from the model. 
The adjusted mean (with SE) obtained from the MMRM analysis at each post-baseline visit up to 
Week 8 will be plotted by treatment group. 
The primary analysis will be conducted with the clinic spirometry data only. An additional 
analysis may also be performed to include pooled spirometry data obtained in clinic and by Air 
Next Spirometer, if the Air Next Spirometry data are assessed to be reasonably consistent with 
clinic spirometry data. 


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9.3.1.3 
Supportive Analysis  
There will be no supportive analysis for the primary efficacy endpoint. 
9.3.1.4 
Sensitivity Analysis  
MMRM based on Multiple Imputation (MI)  
An underlying assumption of the MMRM method is that data are missing at random. To 
minimize the amount of missing data, subjects who prematurely discontinue study drug 
treatment will continue to complete all scheduled study visits for spirometry and other efficacy 
assessments. 
To assess the impact of missing data and the assumption that data are missing at random, a 
multiple imputation algorithm will be used if at least 10% of the subjects have missing changes 
in ppFEV1 at Week 8 in any treatment group. Missing absolute change from baseline in ppFEV1 
assessments will be imputed starting from the first visit with missing values, for which all 
subsequent visits through Week 8 are also missing. For intermediate missing data, i.e., missing 
values that fall between two non-missing ones, it is reasonable to assume that they are missing at 
random and therefore will not be imputed. An MMRM analogous to that for the primary analysis 
of the primary endpoint will be applied to each imputed dataset and the relevant MI estimators 
will be reported. Details for the MI steps are presented in Appendix D. 
9.3.1.5 
Subgroup Analysis  
Subgroup analyses of the primary efficacy endpoint will be performed using a model similar to 
that of the primary analysis for each of the following subgroups. The primary result obtained 
from the model will be estimated within-treatment difference through Week 8 (average of Week 
4 and Week 8) for the ELX/TEZ/IVA group: 
• Age at Screening (<18, ≥18 years) 
• ppFEV1 at baseline (< 70, ≥ 70)  
• Comparator group (TEZ/IVA comparator, IVA comparator) 
• Sex (male, female)  
• Geographic region (North America, Europe) 
The MMRM used for the primary analysis will be used for the subgroup analysis, where the 
same model will be applied to each category of the subgroup. Note that for the subgroup analysis 
based on comparator group, the covariate of comparator group (TEZ/IVA comparator, IVA 
comparator) from the MMRM will be removed. The adjusted means with 2-sided 95% 
confidence intervals will be provided. Furthermore, estimated within-treatment difference 
through Week 8 (average of Week 4 and Week 8) for the ELX/TEZ/IVA group in different 
categories within a subgroup will also be presented in a forest plot. Note: The purpose of 
subgroup analysis is to assess trend consistency; not hypothesis testing with sufficient power. 
Due to potential small sample size, the results from above mentioned subgroup analysis, 
especially the comparison between two comparator groups, should be interpreted with caution. 


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9.3.2 
Analysis of Key Secondary Variables  
9.3.2.1 
Definition of Variables 
Sweat chloride (SwCl): the SwCl value for a given visit will be calculated as the mean of the 
non-missing sweat chloride measurements obtained on the left and right arms at that visit.  If one 
of the two arm measurements at a time point is missing, the other will be used as the mean.  A 
volume ≥15 μL is required for an accurate determination of sweat chloride.  Any results reported 
as having volume <15 μL will be considered missing.  Any sweat chloride values reported as 
>160 mmol/L will be considered missing. Any sweat chloride values reported as <10 mmol/L 
will be imputed as 10 mmol/L.  
9.3.2.2 
Analysis Method 
Absolute change in SwCl from baseline through Week 8 for the ELX/TEZ/IVA group:  
Analysis of this endpoint will be based on the same MMRM model as the analysis of the primary 
efficacy endpoint. Data obtained from the Day 15, Week 4, and Week 8 Visits will be included 
in the model. Absolute change in SwCl from baseline through Week 8 is defined as average of 
Day 15, Week 4, and Week 8. 
Absolute change in ppFEV1 from baseline through Week 8 for the ELX/TEZ/IVA group 
compared to the control group:  
Analysis of this endpoint will be based on the same MMRM model as the analysis of the primary 
efficacy endpoint. Data obtained from the Day 15, Week 4, and Week 8 Visits will be included 
in the model. However, the Day 15 Visit will not be included in the estimation of the average 
treatment effect through Week 8.  
Absolute change in SwCl from baseline through Week 8 for the ELX/TEZ/IVA group compared 
to the control group:  
Analysis of this endpoint will be based on the same MMRM model as the analysis of the primary 
efficacy endpoint. Data obtained from the Day 15, Week 4, and Week 8 Visits will be included 
in the model. Absolute change in SwCl from baseline through Week 8 is defined as average of 
Day 15, Week 4, and Week 8. 
The LS mean (SE) of the within-treatment group change from baseline at each post-baseline visit 
up to Week 8 along with the 95% CI will be estimated from the corresponding MMRM.  The LS 
mean (SE) of the treatment difference between ELX/TEZ/IVA and control at each post-baseline 
visit will be provided along with the corresponding 95% CI and P value.  The LS mean (SE) at 
each visit will also be plotted by treatment group.  In addition, the post-baseline raw values and 
the absolute change from baseline at each post-baseline visit up to Week 8 will be summarized 
descriptively (n, mean, SD, median, minimum, and maximum). 
9.3.2.3 
Multiplicity Adjustment 
A hierarchical testing procedure will be used to control the overall type I error at an alpha of 0.05 
for the primary endpoint and the key secondary endpoints tested. The key secondary endpoints 
will only be tested at an alpha of 0.05 if the primary endpoint of absolute change in ppFEV1 from 
baseline through Week 8 for the ELX/TEZ/IVA group is statistically significant. For a test at any 
step to be considered statistically significant within the testing hierarchy, it must be statistically 


Statistical A nal ysis Pla n ( Met h o ds)  
P a ge 1 7  of 3 8  
Pr ot oc ol N u m ber: V X 1 8 -4 4 5 -1 0 4  
 
Verte x P har mace uticals I nc or p orate d  
si g nifica nt, a n d all pre vi o us tests (if a n y) wit hi n t he hierarc h y m ust be statisticall y si g nifica nt at 
t he 0. 0 5 le vel. T he testi n g or der of t he ke y sec o n d ar y e n d p oi nts is as f oll o ws : 
•  First ke y sec o n dar y e n d p oi nt: A bs ol ute c ha n ge i n S w Cl fr o m baseli ne t hr o u g h Wee k 8 f or 
t he E L X / T E Z/I V A gr o u p  
•  Sec o n d ke y sec o n dar y e n d p oi nt: A bs ol ute c ha n ge i n p p F E V 1 fr o m baseli ne t hr o u g h Wee k 8 
f or t he E L X / T E Z/I V A gr o u p c om pare d t o t he c o ntr ol gr o u p   
•  T hir d ke y sec o n d ar y e n d p oi nt: A bs ol ute c ha n ge i n S w Cl fr o m baseli ne t hr o u g h Wee k 8 f or 
t he E L X / T E Z/I V A gr o u p c o m pare d t o t he c o ntr ol gr o u p 
9. 3. 2. 4  
S e n siti vit y A n al y si s  
T o assess t he i m pact of i ncl u di n g e xtre me s mall s weat c hl ori de val u es, a s e nsiti vit y a nal ysis will 
be c o n d ucte d i n w hi c h case a n y s weat c hl ori de val ues re p orte d as < 1 0 m m ol/ L will be 
c o nsi dere d as missi n g. T his se nsiti vit y a n al ysis o nl y a p plies t o  t he a bs ol ut e c ha n ge fr o m bas eli ne 
i n S w Cl. A n M M R M a nal o g o us t o  t he a nal ysis of S w Cl descri be d i n Secti o n 9. 3. 2. 2 will be 
c o n d ucte d a n d t h e rele v a nt esti mat ors will be re p orte d .   
9. 3. 3  
A n al y si s of Ot h er S e c o n d ar y Effi c a c y V ari a bl e s  
9. 3. 3. 1  
D efi niti o n of V ari a bl e s  
C ystic Fi br osis Q u esti o n naire -Re vise d ( C F Q -R) : T he C F Q-R 3, 4, 5 is a vali date d C F -s p ecific 
i nstr u me nt t hat meas ures q ualit y-of -life d o mai ns.  T his st u d y utilizes t hree differe nt v ersi o ns of 
C F Q -R:  
•  C F Q -R f or C hil dre n a ges 1 2 a n d 1 3  
•  C F Q -R f or A d ol esce nts a n d A d ults (s u bjects 1 4 ye ars a n d ol der)  
•  C F Q -R f or Pare nts/ Care gi vers (s u bjects 1 3 years a n d y o u n ger)  
I n all t hree v ersi o ns, s pecific q uesti o n bel o n gi n g t o a d o mai n is sc ore d 1, 2, 3, or 4.  T he C F Q-R 
d o mai n sc ore, e. g., p h ysi cal d o mai n sc ore or res pirat or y d o mai n sc ore, is defi ne d as a scale d 
sc ore as f oll o ws: 
Sc al e d  sc or e f or a  d o m ai n = 1 0 0   × (m e a n  (sc or es of  all  q u esti o ns  i n t h e d o m ai n ) −1 )/ 3 , 
w here t he s c ore fr o m a n e gati vel y p hras e d q uesti o n is first re verse d, i.e., re verse d sc ore = 5 –  
act ual sc ore, s o t hat 1 al wa ys re prese nts t he w orst c o n diti o n a n d 4 t he best c o n diti o n.  T he 
(scale d) d o m ai n sc ore ra n ges fr o m 0 ( w orst c o n diti o n) t o 1 0 0 ( best c o n diti o n).  T he scal e d sc ore 
f or a s pecific d o mai n will n ot be calc ulate d if m or e t ha n half of t h e q uesti o ns i n t he d o mai n ha ve 
missi n g sc ores.  
T he (scal e d) d o mai n sc ore fr o m t he C F Q -R f or  C hil dre n a ges 1 2 a n d 1 3 a n d f or A d olesce nt a n d 
A d ults will be p o ole d f or t he a nal ysis p ur p ose.  
9. 3. 3. 2  
A n al y si s M et h o d  
Ot her sec o n d ar y effic ac y e n d p oi nt s i ncl u de: 
A bs ol ute c ha n ge i n C F Q -R R D sc ore fr o m baseli ne t hr o u g h Wee k 8 f or t h e E L X/ T E Z/I V A 
gr o u p :  


Statistical A nal ysis Pla n ( Met h o ds)  
P a ge 1 8  of 3 8  
Pr ot oc ol N u m ber: V X 1 8 -4 4 5 -1 0 4  
 
Verte x P har mace uticals I nc or p orate d  
A bs ol ute c ha n ge i n C F Q -R R D sc ore fr o m baseli ne t hr o u g h Wee k 8 f or t h e E L X/ T E Z/I V A 
gr o u p c o m pare d t o t he c o ntr ol gr o u p : 
A nal ysis of b ot h e n d p oi nt s will be base d o n a n M M R M m o del si milar t o t he a nal ysis of t he 
pri mar y efficac y e n d p oi nt. Data o btai ne d fr o m t he Da y 1 5 , Wee k 4, a n d W ee k 8 Visits will be 
i ncl u de d i n t he m o del. H o we ver, t he Da y 1 5 Visit will n ot be i ncl u de d i n t he esti mati o n of t he 
a vera ge treat me nt effect t hr o u g h Wee k 8.  T he a n al ysis will i ncl u de p o ole d C F Q -R  R D sc ore  
assesse d at cli nic a n d at h o me.  A n a d diti o nal a nal ysis ma y  be p erf or me d t o i ncl u de o nl y t he 
cli nic assesse d C F Q -R  R D sc ore , if t he h o me assesse d data  are i nc o nsiste nt wit h  t he cli nic 
assesse d data .  
I n a d diti o n, si milar a nal yses ma y b e perf or me d , if t he C F Q-R R D sc ore c oll ecte d pri or t o t he 
o ut brea k of C O VI D -1 9 ( defi ne d as Marc h 2, 2 0 2 0) are i n c o nsiste nt wit h t he data c ollecte d 
d uri n g C O VI D -1 9 , f or t he c o h ort of s u bjects w h o c o m plete wee k 8 bef ore t he o ut brea k of 
C O VI D -1 9 . S uc h a n al ysis res ults s h o ul d be i nter prete d with ca uti o n d ue t o s mall sa m ple siz e.  
9. 3. 4  
A n al y si s of E x pl or at or y V ari a bl e s  
9. 3. 4. 1  
D efi niti o n of V ari a bl e s  
B o d y mass i n de x ( B MI): t he B MI at eac h visit is calc ulate d usi n g t he wei g ht a n d hei g ht at eac h 
visit as f oll o ws:  
���=
W ei g ht  (k g )
H ei g ht .  (m
) 
9. 3. 4. 2  
A n al y si s M et h o d  
A bs ol ute c ha n ge i n C F Q -R n o n -res pirat or y d o mai n sc ores fr o m baseli ne t hr o u g h Wee k 8: 
( P o ole d ' C hil dre n A ges 1 2 a n d 1 3' Versi o n a n d ' A d olesce nts a n d A d ults' Versi o n): A nal ysis of 
t his e n d p oi nt will be base d o n a n M M R M m o del si milar t o t he a nal ysis of t he pri mar y efficac y 
e n d p oi nt. Data o btai ne d fr o m t he Da y 1 5, Wee k 4, a n d Wee k 8 Visits will be i ncl u de d i n t he 
m o del. H o we ver, t he Da y 1 5 Visit will n ot be i ncl u de d i n t he esti mati o n of t he a vera ge tr eat me nt 
effect t hr o u g h Wee k 8 . 
A bs ol ute c ha n ge i n B MI fr o m baseli ne at Wee k 8:   
A nal ysis of t h ese e n d p oi nt s will be base d o n a n M M R M m o del si milar t o t he a nal ysis of t he 
pri mar y efficac y e n d p oi nt. Data o btai ne d fr o m t he Da y 1 5, Wee k 4, a n d W ee k 8 Visits will be 
i ncl u de d i n t he m o del. N o P -val ues will be pr o vi d e d f or e x pl orat or y varia bles.  
9. 3. 5  
A n al y si s of A d diti o n al Effi c a c y V ari a bl e s  
9. 3. 5. 1  
A n al y si s of A d diti o n al S pir o m etr y V ari a bl e s  
S u m mar y statistics f or t h e f oll o wi n g s pir o metr y meas ure m e nts will be pres e nte d b y treat me nt 
gr o u p at eac h visit u p t o Wee k 8:  
•  F E V 1:  
o  A bs ol ute c ha n ge fr o m baseli ne i n F E V 1 ( L)  
o  Relati ve c ha n ge fr o m baseli ne i n F E V 1 ( %) 
o  A bs ol ute c ha n ge fr o m baseli ne i n perce nt pre dicte d F E V 1 ( perce nta ge p oi nts) 
o  Relati ve c ha n ge fr o m baseli ne i n perce nt pre dicte d F E V 1 ( %) 
 


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• 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)  
o Relative change from baseline in percent predicted FVC (%)  
 
• FEF25-75%:  
o Absolute change from baseline in FEF25-75% (L/sec)  
o Relative change from baseline in FEF25-75% (%)  
o Absolute change from baseline in percent predicted FEF25-75% (percentage points)  
o Relative change from baseline in percent predicted FEF25-75% (%)  
 
• 
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 (percentage points) 
o Relative change from baseline in percent predicted FEV1/FVC (%)  
9.4 
Safety Analysis 
All safety analyses will be based on data from the TE period for the Treatment Period for all 
subjects in the corresponding Safety Set for the Treatment Period, unless otherwise specified. 
Subjects will be analyzed according to the treatment group (ELX/TEZ/IVA or control) they 
actually received in the Treatment Period. For listing purpose, both the treatment group 
(ELX/TEZ/IVA or control) and the treatment (ELX/TEZ/IVA or TEZ/IVA or IVA) a subject 
receives will be presented. For subjects receiving study drug from more than one treatment, the 
treatment allocation will be the higher treatment (ELX/TEZ/IVA > TEZ/IVA > IVA). 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values 
• ECGs 
• Vital signs 
• Pulse oximetry 
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. 
9.4.1 
Adverse Events  
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs during the Run-in 
Period, TEAEs during the Treatment Period, and post-treatment AEs, defined as follows:  
Pretreatment AE: any AE that occurred before the first dose date of study drug (TEZ/IVA or 
IVA) in the Run-in Period 


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TEAE during the Run-in Period: any AE that worsened (either in severity or seriousness) or 
that was newly developed at or after the first dose date of study drug (TEZ/IVA or IVA) through 
the end of the TE period for the Run-in Period 
TEAE during the Treatment Period: any AE that worsened (either in severity or seriousness) 
or that was newly developed at or after the first dose date of study drug (TC or 
placebo+TEZ/IVA or placebo+IVA) 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 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 are pre-treatment or TEAE during the Run-in Period or post-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 E. 
An overview of all TEAEs by treatment group and overall will be summarized in the following 
categories: 
• Number of TEAEs (total number of TEAEs only) 
• Subjects with any TEAEs  
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation (discontinuation of any study 
drugs) 
• Subjects with TEAEs leading to study drug interruption (interruption of any study drugs) 
• Subjects with Grade 3/4 TEAEs 
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAE leading to death  
The following summary tables of TEAEs will be presented by treatment group: 
• All TEAEs 
• Grade 3/4 TEAEs 
• TEAEs by strongest relationship 


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• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Related TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to death 
Summaries will be presented by MedDRA System Organ Class (SOC) and Preferred Term (PT) 
using frequency counts and percentages (i.e., number and percentage of subjects with an event). 
When summarizing the number and percentages of subjects, subjects with multiple occurrences 
of the same adverse event or a continuing adverse event will be counted once, and only the 
maximum severity level will be presented in the severity summaries, and the strongest 
relationship level in the relationship summaries.  
Additional summary tables will be presented by treatment group 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 adverse event data for TEAEs leading to treatment 
discontinuation, TEAEs leading to treatment interruption, Grade 3/4 TEAEs, SAEs and all 
deaths will be provided separately, with a flag indicating the TEAE status for SAEs and deaths. 
In addition, the following tables for the Run-in period will be presented by 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 
9.4.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments, the observed values and change from 
baseline values of the continuous hematology, coagulation and chemistry results will be 
summarized in SI units at each visit by treatment group.  
The number and percentage of subjects meeting at least 1 threshold analysis criterion event, 
during the TE period for Treatment Period, will be summarized by treatment group. The 
threshold analysis criterion shift from baseline will also be summarized for selected laboratory 
parameters. The threshold analysis criteria are provided in Appendix F.  
For selected LFT laboratory test (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase [ALP], and total bilirubin), a scatter plot of the maximum treatment-
emergent value versus the baseline value corresponding to ×ULN (upper limit of normal) will be 
presented. Further, a scatter plot of the maximum treatment-emergent value of ALT and AST, 


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


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9.4.7 
Ophthalmology Examination  
Ophthalmology examination results will be provided in a data listing.  
9.4.8 
COVID-19 Impacted Visits  
A listing containing subjects’ visits impacted due to COVID-19 will be provided. 
9.4.9 
Supportive Safety Analysis 
9.4.9.1 
Adverse Events of Special Interest 
For this study, elevated transaminase events and rash events, as determined by MedDRA 
preferred terms in Appendix G, are considered as adverse events of special interest. 
For treatment-emergent elevated transaminase events and rash events, 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 serious events 
• Subjects with related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event 
In addition, for treatment-emergent rash events, these categories will be summarized for the 
following subgroups: 
• Sex (male, female) 
• Female subjects with concomitant hormonal therapy (Yes, No) 
9.4.9.2 
Hormonal Therapy 
The number of subjects who used hormonal therapy concomitantly will be summarized by 
treatment group based on the Safety Set for the Treatment Period. 
10 
Interim and DMC Analyses 
10.1 
Interim Analysis 
No interim analysis is planned. 
10.2 
DMC analysis 
The DMC’s objectives and operational details are defined in a separate document (DMC 
Charter) which was finalized before the first subject was screened in the study. The DMC’s 
planned safety reviews of study data are outlined in the DMC Charter and DMC Statistical 
Analysis Plan.  


Statistical Analysis Plan (Methods) 
Page 24 of 38 
Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
11 
REFERENCES 
1 Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 
2  Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 
3 Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
4 Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of life 
for children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45. 
5 Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life measure for 
children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32. 
6 Rubin, DB. and Schenker, N.. Interval estimation from multiply-imputed data: a case study 
using agriculture industry codes. Journal of the American Statistical Association. 1987; 81: 
366–374. 
 
 


Statistical Analysis Plan (Methods) 
Page 25 of 38 
Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
12 
LIST OF APPENDICES 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessment
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3, 4 
(in study days) 
Safety Assessment 
Serum Chemistry 
Hematology 
Standard 12-lead ECG 
 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
Safety Follow-up 
1 
15 
29 
57 
Not applicable 
1 Pre-dose 
[1, 22] 
(22, 43] 
(43, 71] 
Use nominal visit 
Coagulation 
Day 1 (Baseline)  
Week 8 
Safety Follow-up 
1 
57 
Not applicable 
1 Pre-dose 
[1, 71] 
Use nominal visit 
Vital Signs (excluding BMI, 
Weight, Height) 
 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
Safety Follow-up 
1 
15 
29 
57 
Not applicable 
1  
[1,22] 
(22, 43] 
(43, 71] 
Use nominal visit 
Efficacy Assessment and Pharmacodynamic Assessment  
Spirometry5  
 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
Safety Follow-up 
1 
15 
29 
57 
Not applicable 
1 Pre-dose 
(1,22] 
(22, 43] 
(43, 71] 
>71 
Sweat Chloride 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
1 
15 
29 
57 
1 Pre-dose 
(1,22] 
(22, 43] 
(43, 71] 
CFQ-R  
Weight, Height and BMI5 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
Safety Follow-up 
1 
15 
29 
57 
Not applicable 
1 
(1,22] 
(22, 43] 
(43, 71] 
>71 
Notes: 
1Visit name for analysis purpose is used to report data in tables and figures. 
 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
b. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. If the latest measurement cannot be determined, then unscheduled visit will be selected. 
 
3 For measurement collected on the date of first dose of study drug in Treatment Period, if it cannot be determined 
whether the measurement is before or after the first dose:  
a. 
Scheduled measurement will be treated as pre-dose observation. 


Statistical Analysis Plan (Methods) 
Page 26 of 38 
Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3, 4 
(in study days) 
b. Unscheduled measurement will be treated as post-dose observation. 
 
4 For safety Assessment, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a 
subject doesn’t have a nominal Safety Follow-up visit but has an ETT visit with study day >71, then the ETT visit 
will be mapped into Safety Follow-up analysis visit.  
5 For efficacy analysis, if there are multiple assessments >71, then nominal Safety Follow-up visit will be mapped to 
Safety Follow-up visit. If there is only ETT assessment > 71, the ETT visit will be mapped to the Safety Follow-up 
visit;else if there are multiple assessments with >71 then select the earliest record.   
 
Derived Variables: 
1. Age (in years) at first dose date and nominal visit (for demographics, listing and the calculation of [percent] 
predicted spirometry variables): 
Obtain the age at informed consent (in days) in “yy, mm” format (e.g., 24 years, 6 months) from the Vital Signs 
(VS) page at the Screening Visit, and add 0.5 month to convert to days. 
Obtain the informed consent date. 
Then age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed consent 
date) in days + age at informed consent (in days)]/365.25. 
2. Age (in months) at nominal visit (for use in calculation of BMI and weight z-score, as applicable): 
Obtain the age at informed consent (in months) in “yy, mm” format (e.g., 24 years, 6 months) from Vital Signs 
(VS) page at the Screening Visit. 
Obtain the informed consent date. 
Then age (in months) at nominal visit = integer part of {[(age at informed consent (in months) + 0.5 + diff 
(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 Day 1 visit date to impute. 
If the last dose date is missing or partial date is reported, the last dose date will be imputed based on, in 
descending order priority, the Early Treatment Termination (ETT) visit date, last visit date before the Safety 
Follow-up, or the last study drug administration date from EX SDTM domain, as appropriate.  The imputation 
algorithm will ensure the imputed last dose date does not exceed the study participation end date. 
4. Sweat Chloride: 
Non-missing sweat chloride concentrations from the left arm and right arm with assessment end date/time for a 
given arm up to 30 minutes after first dose time in treatment period will be considered for baseline. 
5. Electrocardiogram: 
Baseline is defined as the most recent pretreatment measurement before the first dose of study drug in the 
Treatment Period.  If multiple ECG measurements are obtained on the same calendar day during the TE period,  
o 
For summary purpose, the calculated average ECG will be used as the ECG value on that day;  
o For threshold analysis purpose, all reported ECG values will be used. 
 
 


Statistical Analysis Plan (Methods) 
Page 27 of 38 
Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
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 (to 
impute in practical, use the informed consent date). 
2. Missing or partial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month and year are all missing, assign ‘continuing’ status to stop date (in 
practical, use the End of Study Date to impute). 
In summary, the prior, concomitant, or post categorization of a medication is described below. 
Table 12-2 
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 and < 
End Date of Run-in TE 
Period  
≥ First Dose Date and ≤ End 
Date of Treatment TE Period  
> End Date of 
Treatment TE 
Period  
< First dose date of Run-in 
TE period  
P 
PC1 
PC1C2 
PC1C2A 
≥ First dose date and  
< End date of Run-in  TE 
Period 
- 
C1 
C1C2 
C1C2A 
≥ First dose date and  
≤ End date of Treatment TE 
Period 
- 
- 
C2 
C2A 
> End date of Treatment TE 
Period 
- 
- 
- 
A 
P: Prior; C1: Concomitant during the Run-in Period; C2: Concomitant during the Treatment Period; A: Post 
Imputation rules for missing and/or partial dates of non-pharmacological treatment/procedure 
will follow the same imputation rule. 
 
 


Statistical Analysis Plan (Methods) 
Page 28 of 38 
Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
Appendix C: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 Regression 
Equation and Lookup Tables (Version 7 April 2013). Global Lung Function Initiative. [online] 
Available at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138978 
[Accessed  Jul. 9, 2019]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] Available 
at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138979 [Accessed  Jul. 
9, 2019].   
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: http://www.ers-education.org/home/browse-all-
content.aspx?idParent=138988 [Accessed  Jul. 9, 2019]. 
 Data handling rule for spirometry is as follows:  
• Input age with at least 2 decimal place 
• Use height at screening regardless if height is collected at other study visits for subjects 
whose age at informed consent is >21 years. For subjects with age <=21 years, height 
collected at the respective visit should be used.  
• For race, map CRF black or AA to black, all other races in CRF (except white) are 
mapped to 'other'; multiple checks for race in CRF are also mapped to 'other'; white is a 
reference race in the equations and assumes 0 values for all race coefficients in the       
GLI equations. 
 
 


Statistical A nal ysis Pla n ( Met h o ds)  
P a ge 2 9  of 3 8  
Pr ot oc ol N u m ber: V X 1 8 -4 4 5 -1 0 4  
 
Verte x P har mace uticals I nc or p orate d  
A p p e n di x D: St e p s f or M ulti pl e I m p ut ati o n  
F or t he m ulti ple i m p utati o n ( MI) t o be a p plie d t o t he M M R M m o del f or t he pri mar y efficac y 
e n d p oi nt, t he f oll o wi n g ste ps will be f ol l o we d: 
I m p ut ati o n distri b uti o n  
T he i m p utati o n distri b uti o n f or t he missi n g a bs ol ute c ha n ge fr o m baseli ne i n p p F E V 1 at visit t 
will be a n or mal distri b uti o n.  All ra n d o mize d s u bjects will be classifie d i nt o o ne of t hree 
cate g ories b ase d o n t he f oll o wi n g r ules:  
•  N o n -missi n g cate g or y: S u bjects w h o ha ve a p p F E V 1 assess me nt at Wee k 8 (i.e., s u bjects 
w h o ha ve a n o n -missi n g a bs ol ute c h a n ge fr o m bas eli ne i n p p F E V 1 at Wee k 8).  
•  Missi n g cate g or y 1: S u bjects wit h missi n g a bs ol ute c ha n ge fr o m bas eli ne i n p p F E V
1 at 
Wee k 8, w h o disc o nti n ue d treat me nt beca use of a d verse e v e nts, n o nc o m plia nce wit h 
st u d y dr u g, deat h, or p h ysicia n decisi o n, or beca us e t he s u bject r ef use d f urt her d osi n g or 
re q uire d pr o hi bite d me di cati o n.  
•  Missi n g cate g or y 2: S u bjects w h o disc o nti n ue d treat me nt f or a n y reas o n n ot liste d i n 
Cate g or y 1 a n d ha v e missi n g a bs ol ute c h a n ge fr o m baseli ne i n p p F E V 1 at Wee k 8, or 
s u bjects w h o ha ve c o m plete d 8 wee ks treat me nt d urati o n b ut are missi n g t h e a bs ol ute 
c ha n ge fr o m baseli ne i n p p F E V 1 at visit Wee k 8  
I m p ut ati o n al g orit h m 
We will use t he f oll o wi n g al g orit h m t hat relates t he mea n of t he missi n g a bs ol ute c ha n ge f r o m 
baseli ne i n p p F E V 1 at visit t t o t he missi n g cate g ories defi ne d a b o v e.  T he al g orit h m will be 
i m ple me nte d wit hi n eac h treat me nt gr o u p as f oll o ws: 
•  Missi n g cate g or y 1: ra n d o ml y dra w a sa m ple fr o m t he n or mal distri b uti o n (�
,�), 
w here  �
 is t he 2 5th perce ntile of t he n o n -missi n g a bs ol ute c ha n ges fr o m baseli ne i n 
p p F E V 1 at visit t a n d � is t he sa m ple vari a nce esti mate d usi n g t he n o n-missi n g a bs ol ute 
c ha n ges at visit t. 
•  Missi n g cate g or y 2: ra n d o ml y dra w a sa m ple fr o m t he n or mal distri b uti o n (�,�
), w here 
� is t he mea n of t he n o n-missi n g a bs ol ute c ha n ges fr o m baseli ne i n p p F E V 1 at visit t a n d 
�2 is t he sa m ple varia nce esti mate d usi n g t he n o n-missi n g a bs ol ute c ha n ges at visit t. 
A n al ysis m o del  
T he c o m plete MI met h o d is descri be d bel o w:  
•  F or m a n “i m p ute d dataset” b y i m p uti n g missi n g v al ues at eac h visit f or t h ose s u bjects 
w h o ha ve a missi n g val u e at t he visit a n d ha ve all s u bse q ue nt val ues missi n g. T he 
a p pr o priate n or mal distri b uti o n s pecifie d i n t he al g orit h m a b o ve will be use d f or eac h 
suc h s u bject, base d o n t h eir cate g or y.  
•  Re peat t his pr ocess K ( K = 2 0) ti mes t o f or m K i m p ute d datasets.  
•  Fit t he sa me M M R M m o del t o eac h i m p ute d datas et t o esti mate t he a bs ol ute c ha n ge at 
Wee k 8.  
•  C o m bi ne t he res ults fr o m t he K i m p ute d datasets usi n g t he S A S pr oce d ure MI A N A L Y Z E 
t o deri ve t he MI esti mat or.  


Statistical A nal ysis Pla n ( Met h o ds)  
P a ge 3 0  of 3 8  
Pr ot oc ol N u m ber: V X 1 8 -4 4 5 -1 0 4  
 
Verte x P har mace uticals I nc or p orate d  
Let θ b e t he tr ue tr eat me nt differe n ce. De n ote b y � t he esti mate of θ fr o m t h e �
 i m p ute d 
dataset, a n d t he c orres p o n di n g esti mate of t h e vari a nce is de n ote d b y �. T he MI esti mat or of θ, 
�
, is t he a vera ge of t he K i n di vi d ual esti mates.  
T he esti mate d vari a nce of �
 is a c o m bi nati o n of t he bet wee n- a n d wit hi n-i m p utati o n varia bilit y 
as f oll o ws: �
= �
+
1 +  
�, w here �
=
∑
� is t he wit hi n-i m p utati o n varia bilit y 
a n d is �=
∑
(�
−�
)  is t he bet wee n-i m p utati o n varia nce. T he st atistic 
 has a n 
a p pr o xi mate � distri b uti o n, w here �= (�−1 )(1 +
) . 


Statistical Analysis Plan (Methods) 
Page 31 of 38 
Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
Appendix E: Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date are defined below. If the imputed AE start 
date is before the informed consent date, the AE start date will be imputed using the study 
informed consent date. 
• If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year and month are equal to the month and year of first dose date 
of the Treatment Period, then impute the AE start day as the day of first dose 
date of the Treatment Period;  
 else if AE start year and month are equal to the month and year of first dose 
date of the Run-in Period, then impute the AE start day as the day of first dose 
date of the Run-in Period;  
 else impute the AE start day as 1.  
o else if the full (or partial) AE end date is NOT before the first dose date of the Run-in 
Period, then  
 if AE start year and month are equal to the month and year of first dose date 
of the Run-in Period, then impute the AE start day as the day of first dose date 
of the Run-in Period;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE 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 of the Treatment 
Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Treatment Period;  
 else if AE start year is equal to the year of first dose date of the Run-in Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Run-in Period;  
 else impute the AE start month as January and day as 1.  
o else if the full (or partial) AE end date is NOT before the first dose date of the Run-in 
Period, then  
 if AE start year is equal to the year of first dose date of the Run-in Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Run-in Period;  


Statistical Analysis Plan (Methods) 
Page 32 of 38 
Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
 else impute the AE start month as January and day as 1. 
o else impute the AE start month as January and day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE 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 is missing or AE start date is completely missing then query site and 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the date of first 
dose date of the Treatment Period.  
o else if the full (or partial) AE end date is NOT before the first dose date of the Run-in 
Period, then impute the AE start date as the date of first dose date of the Run-in 
Period. 
o else impute AE date as the informed consent date. 
 
The imputation should ensure the imputed AE start date is not before the informed consent date. 
 
Imputation rules for partial AE end date are defined below:  
If partial end date, then impute as min (the last day of the month, end of study participation) if 
day is missing, or min (Dec, end of study participation) if month is missing. 
 
 


Statistical Analysis Plan (Methods) 
Page 33 of 38 
Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
Appendix F: Criteria for Threshold Analysis 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤3xULN) or 
(AST>ULN - ≤3xULN) 
(ALT>3x - ≤5xULN) or (AST>3x - 
≤5xULN) 
(ALT>5x- ≤8xULN) or (AST>5x - ≤    
8xULN) 
(ALT>8x - ≤20xULN) or (AST>8x - ≤ 
20xULN) 
ALT>20xULN or AST> 20xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤1.5xULN 
>1.5x – ≤2.5xULN 
>2.5x – ≤5.0 x ULN 
>5.0x – ≤20.0 x ULN 
>20.0xULN 
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. 
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 34 of 38 
Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
GGT 
>ULN - ≤2.5xULN 
>2.5x – ≤5.0xULN 
>5.0x – ≤20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤ 1.5xULN 
>1.5x - ≤ 3.0xULN 
>3.0x - ≤ 6.0xULN 
>6.0xULN 
CTCAE grades 1-4 
Lipase 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine kinase 
>ULN - ≤2.5xULN 
>2.5x - ≤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 
 


Statistical Analysis Plan (Methods) 
Page 35 of 38 
Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Reticulocytes/Erythrocytes (%)    <LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated partial thromboplastin 
time  (PTT)  
 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
  
Table 12-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
Per HV grade 2, 3, plus shift change 
 
 
 
Tachycardia 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
Table 12-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
QTc 
 
>450 to <500ms (Male) or >470 to <500ms 
(Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction 
formula.  
 
 
 
 
 
Table 12-5 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Pulse Rate 
Same as above in ECG category 
 
SBP increased 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from 
baseline 
>140 mmHg & >20 mmHg increase from 
baseline 
>160 mmHg & >10 mmHg increase from 
baseline 
>160 mmHg & >20 mmHg increase from 
baseline 
809/770 analyses 
SBP decrease 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from 
baseline 
<90 mmHg and >20 mmHg decrease from 
baseline 
<80 mmHg and >10 mmHg decrease from 
baseline 
<80 mmHg and >20 mmHg decrease from 
baseline 
Per HV grade 1, 3, plus shift change 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
Table 12-5 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
DBP increased 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from 
baseline 
>90 mmHg and >10 mmHg increase from 
baseline 
>100 mmHg and >5 mmHg increase from 
baseline 
>100 mmHg and >10 mmHg increase from 
baseline 
 
DBP decreased 
 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from 
baseline 
<60 mmHg and >10 mmHg decrease from 
baseline 
<45 mmHg and >5 mmHg decrease from 
baseline 
<45 mmHg and >10 mmHg decrease from 
baseline 
 
Weight   
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
CTCAE grade 1-3 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
CTCAE grade 1-3 
 
 
Table 12-6 
Threshold Analysis Criteria for Laboratory Tests (for labeling purpose) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT or AST 
>3xULN 
>5xULN 
>8xULN 
For labeling purpose 
 
 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX18-445-104 
 
Vertex Pharmaceuticals Incorporated 
Appendix G: Adverse Events of Special Interest  
Notes: 
[1]: The preferred terms listed in the table is 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 preferred terms based on 
the upgraded version will be used in the analysis of adverse events of special interest. 
Table 12-7 MedDRA Preferred Terms for Event of Special Interest 
Adverse event of special interest 
MedDRA preferred terms [1] 
Elevated transaminase 
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 
Rash, Rash erythematous, Rash macular, Rash maculo-papular, Rash 
maculovesicular, Rash vesicular, Rash pruritic, Rash follicular, Rash 
pustular, Nodular rash, Drug eruption, Fixed eruption, Urticaria, Urticaria 
papular, Urticaria vesiculosa, Urticarial dermatitis, Rash morbilliform, 
Rash papular, Rash papulosquamous, Rash rubelliform, Rash 
scarlatiniform , Drug hypersensitivity, Type IV hypersensitivity reaction, 
Dermatitis, Dermatitis atopic, Epidermolysis, Skin toxicity, Dermatitis 
allergic, Dermatitis exfoliative, Dermatitis exfoliative generalised, 
Erythema multiforme, Exfoliative rash, Mucocutaneous rash, Acute 
generalised exanthematous pustulosis, Cutaneous vasculitis, Urticarial 
vasculitis, Dermatitis bullous, Drug reaction with eosinophilia and 
systemic symptoms, Epidermal necrosis, Oculomucocutaneous syndrome, 
Skin exfoliation, Skin necrosis, Stevens-Johnson syndrome, Toxic 
epidermal necrolysis, Toxic skin eruption, Perioral dermatitis, Vasculitic 
rash, Immune-mediated dermatitis, Penile rash, SJS-TEN overlap, 
Erythrodermic atopic dermatitis, Scrotal rash