Clinical trial NCT03691779
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2018-10-02; Completion date: 2020-08-07
Enrollment: 71 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will evaluate the pharmacokinetics (PK), safety, tolerability, efficacy, and pharmacodynamic effect of VX-445, tezacaftor (TEZ), and ivacaftor (IVA) when dosed in triple combination (TC) in Cystic Fibrosis (CF) subjects 6 through 11 years of age with F/F and F/MF genotypes.

Detailed description:

Arms: arm 1: Participants in Part A received ELX 100 milligrams (mg) once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) in the treatment period for 15 days. arm 2: Participants in Part B weighing less than (\<) 30 kilograms (kg) at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing greater than equals to (\>=) 30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Interventions: intervention 1: ELX/TEZ/IVA intervention 2: IVA
Intervention descriptions: intervention 1: Fixed-dose combination tablet orally once daily in the morning. intervention 2: IVA tablet orally once daily in the evening.

Protocol documents:
Prot_000.pdf: 
Page 1 of 78
1
TITLE PAGE
VERTEX PHARMACEUTICALS INCORPORATED
Clinical Study Protocol
A Phase 3 Study Evaluating the Pharmacokinetics, Safety, 
and Tolerability of VX-445/TEZ/IVA Triple Combination 
Therapy in Cystic Fibrosis Subjects 6 Through 11 Years 
of Age
Vertex Study Number: VX18-445-106
EudraCT Number: 2018-001695-38
Date of Protocol: 18 December 2019 (Version 3.0) 
Replaces Version 2.0, dated 07 June 2019
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue
Boston, MA 02210-1862, USA
CONFIDENTIAL
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them.




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2
PROTOCOL SYNOPSIS
Title
A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of 
VX-445/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 Through 
11 Years of Age
Brief Title
Evaluation of VX-445/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years 
Clinical Phase 
and Clinical 
Study Type 
Phase 3, pharmacokinetics (PK), safety, and tolerability
Objectives
Part A
Primary Objective
To evaluate the PK of VX-445, tezacaftor (TEZ), and ivacaftor (IVA) when dosed in triple 
combination (TC)
Secondary Objectives
!
To evaluate the PK of VX-445, TEZ and IVA metabolites 
!
To evaluate the safety and tolerability of VX-445/TEZ/IVA 
Part B
Primary Objective
To evaluate the safety and tolerability of VX-445/TEZ/IVA through Week 24
Secondary Objectives
!
To evaluate the efficacy of VX-445/TEZ/IVA through Week 24
!
To evaluate the PK of VX-445, TEZ, and IVA 
!
To evaluate the PK of VX-445, TEZ and IVA metabolites 
Endpoints
Part A 
Primary Endpoint
PK parameters of VX-445, TEZ, and IVA, including Cmax, Ctrough, and AUC0-τ
Secondary Endpoints
!
PK parameters of VX-445, TEZ, and IVA metabolites, including Cmax, Ctrough, and AUC0-τ
!
Safety and tolerability as determined by adverse events (AEs), clinical laboratory values, 
standard 12-lead ECGs, vital signs, and pulse oximetry
Part B
Primary Endpoint
Safety and tolerability assessments based on AEs, clinical laboratory values, standard 12-lead 
ECGs, vital signs, pulse oximetry, and ophthalmologic examinations
Secondary Endpoints
!
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
from baseline through Week 24 
!
Absolute change in sweat chloride (SwCl) from baseline through Week 24
!
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain 
score from baseline through Week 24
!
Absolute change in body mass index (BMI) and BMI-for-age z-score from baseline at 
Week 24


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!
Absolute change in weight and weight-for-age z-score from baseline at Week 24
!
Absolute change in height and height-for-age z-score from baseline at Week 24
!
Drug acceptability assessment using Modified Facial Hedonic Scale 
!
Number of pulmonary exacerbations (PEx) and CF-related hospitalizations through 
Week 24
!
PK parameters of VX-445, TEZ, IVA, and relevant metabolites 
!
Absolute change in lung clearance index2.5 (LCI2.5) from baseline through Week 24
Number of 
Subjects
Part A
Approximately 12 subjects are planned for enrollment. Subjects who participate in Part A 
may participate in Part B. 
Part B
Approximately 56 subjects are planned for enrollment.
Study 
Population
Male and female cystic fibrosis (CF) subjects 6 through 11 years of age who are homozygous 
for F508del (F/F genotype) or heterozygous for F508del and a minimal function (MF) 
mutation that is not responsive to IVA and TEZ/IVA (F/MF genotypes). Approximately 25 
subjects with F/MF genotypes and approximately 20 subjects with F/F genotypes are targeted 
for enrollment in Part B.
Investigational 
Drug
Part A
Active substance: VX-445/TEZ/IVA 
Activity: CFTR correctors (VX-445 and TEZ) and CFTR potentiator (IVA) (increased 
chloride ion secretion)
Strength and route of administration: 100-mg VX-445/50-mg TEZ/75-mg IVA fixed-dose 
combination (FDC) tablet for oral administration AND 75-mg IVA tablet for oral 
administration
Dose administered:
!
VX-445 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h; 1 × VX-445/TEZ/IVA FDC tablet 
in the morning and 1 × IVA tablet in the evening
Part B
Active substance: VX-445/TEZ/IVA 
Activity: CFTR correctors (VX-445 and TEZ) and CFTR potentiator (IVA) (increased 
chloride ion secretion)
Strength and route of administration: 
!
Subjects <30 kg at Day 1: 50-mg VX-445/25-mg TEZ/37.5-mg IVA FDC tablets for oral 
administration AND 75-mg IVA tablet for oral administration
!
Subjects ≥30 kg at Day 1: 100-mg VX-445/50-mg TEZ/75-mg IVA FDC tablets for oral 
administration AND 150-mg IVA tablet for oral administration
Doses administered:
!
Subjects <30 kg at Day 1: VX-445 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h
!
Subjects ≥30 kg at Day 1: VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h


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Study Duration
Part A
Excluding the Screening Period, subjects will participate in the study for up to 6 weeks 
(± 7 days)
Part B
Excluding the Screening Period, subjects will participate in the study for up to 28 weeks 
(± 7 days)
Study Design
This is a Phase 3, 2-part (Parts A and B), multicenter study evaluating the PK, safety, and 
tolerability of VX-445/TEZ/IVA TC therapy in CF (F/F and F/MF genotypes) subjects 
6 through 11 years of age (inclusive). 
Part A
A schematic of the study design for Part A is provided below. Approximately 12 subjects (F/F 
or F/MF genotypes) are planned for enrollment. During the Treatment Period, subjects will be 
administered VX-445/TEZ/IVA for approximately 15 days. A review of safety, tolerability, 
and available PK data will be completed by an internal Vertex team after Part A to confirm or 
adjust the dose(s) chosen for Part B. Additional subjects may be enrolled as needed in Part A, 
based on emerging PK data, to confirm the dose(s) for Part B.
Part A Study Design 
Part B
A schematic of the study design for Part B is provided below. Part B will initiate after 
completion of the internal Vertex team’s review of available data in Part A that will confirm 
or adjust the dose(s) to be evaluated in Part B. Approximately 56 subjects (F/F or F/MF 
genotypes) are planned for enrollment to ensure approximately 45 subjects complete Part B. 
Approximately 25 subjects with F/MF genotypes and approximately 20 subjects with F/F 
genotypes are targeted for enrollment in Part B. During the Treatment Period, subjects will be 
administered VX-445/TEZ/IVA for approximately 24 weeks. 
Subjects who complete the Part B Treatment Period and have not permanently discontinued 
study drug will be offered the opportunity to enroll in an optional open-label extension safety 
study (enrollment will be based on the eligibility criteria specified within the Open-label 
Extension Safety Study protocol).


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Part B Study Design 
Parts A and B Doses
Subject Weight at 
Day 1
VX-445 Dose
TEZ Dose
IVA Dose
Part A
All weights
100 mg qd
50 mg qd
75 mg q12h
Part B
<30 kg
100 mg qd
50 mg qd
75 mg q12h
≥30 kg
200 mg qd
100 mg qd
150 mg q12h
IVA: ivacaftor; qd: once daily; q12h: every 12 hours; TEZ: tezacaftor
Assessments
Parts A and B
PK Assessments:
PK parameters for VX-445, M23-445, TEZ, M1-TEZ, IVA, M1-IVA 
Safety Assessments:
AEs, clinical laboratory assessments (serum chemistry, hematology, coagulation, and 
urinalysis), standard 12-lead ECGs, vital signs, pulse oximetry, ophthalmologic examinations, 
and physical examinations (PEs)
Efficacy Assessments:
Spirometry and sweat chloride 
Part B
Efficacy Assessments:
Weight, height, BMI, CFQ-R, multiple-breath washout (MBW), and other events related to 
outcome (e.g., PEx) 
Other Assessments:
!
Drug acceptability assessment using Modified Facial Hedonic Scale.


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Statistical 
Analyses
Data from Parts A and Part B will be analyzed separately.
Part A
Approximately 12 subjects will be enrolled in Part A. Sample size calculations were 
determined based on VX-445 PK using noncompartmental analysis-based parameters, such as 
clearance and volume of distribution. Based on the variability observed in adults, data from 
12 subjects will allow 80% power to target a 95% CI within 60% and 140% of the geometric 
mean estimate of clearance for VX-445. 
Part B
With 45 subjects expected to complete Part B, there is a 90% chance of observing an AE in at
least 1 subject if the true incidence rate is 5%, and a >95% chance of observing an AE in at 
least 1 subject if the true incidence rate is 10%. 
For the primary endpoint, summary statistics will be provided for treatment-emergent AEs, 
clinical laboratory assessments, standard 12-lead ECGs, vital signs, and pulse oximetry. 
IDMC Reviews
An independent data monitoring committee (IDMC) will conduct periodic safety review(s) of 
study data as outlined in the IDMC charter (Part B only).


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3
SCHEDULE OF ASSESSMENTS
The schedules of assessments are shown in Table 3-1 (Part A Screening Period), Table 3-2
(Part A Treatment Period and Safety Follow-up Visit), Table 3-3 (Part B Screening Period), and 
Table 3-4 (Part B Treatment Period and Safety Follow-up Visit).
Table 3-1
VX18-445-106, Part A Screening Period 
Assessment
Screening Visit
(Day -28 to Day -1)
Comments
Informed Consent (and Assent)
X
Demographics
X
Section 11.1 for details
Medical History
X
Section 11.1 for details
Ophthalmologic Examination
X
Conducted by an ophthalmologist or optometrist 
(Section 11.5.5)
Full Physical Examination
X
Section 11.5.3 for details
Weight, Height, and BMI
X
Weight and height will be measured with shoes off 
(Section 11.4.4)
Vital Signs
X
Collected after the subject has been at rest for at least
5 minutes (Section 11.5.3)
Pulse Oximetry
X
Collected after the subject has been at rest for at least
5 minutes (Section 11.5.3)
Standard 12-lead ECG
X
Performed after the subject has been at rest for at least
5 minutes (Section 11.5.4)
Spirometry
X
Performed pre- or post-bronchodilator (Section 11.4.1). 
Screening spirometry evaluation may be repeated, as 
specified in (Section 9.1.1.1).
Sweat chloride
X
Section 11.4.2 for details
CF Genotype (all subjects)
X
If the CFTR genotype result is not received before the first 
dose of study drug, a previous CFTR genotype laboratory 
report may be used to establish eligibility (Section 8.1). 
Subjects who have been enrolled whose screening genotype 
does not confirm study eligibility must be discontinued from 
the study (Section 9.9).
Serum Pregnancy Test 
(females of childbearing 
potential)
X
Females of childbearing potential is defined as females 
10 years of age and older (Section 11.5.6)
Serum Chemistry
X
Section 11.5.2 for details
Hematology
X
Section 11.5.2 for details
Coagulation Studies
X
Section 11.5.2 for details
G6PD Activity Test
X
Section 11.5.2 for details
Urinalysis
X
Section 11.5.2 for details
Drug Test (urine only) 
X
Section 11.5.2 for details
Alcohol Test (urine only) 
X
Section 11.5.2 for details
Inclusion/Exclusion Criteria 
Review
X
Section 8 for details
Medication Review
X
AEs and SAEs
X
Continuous, From Signing of ICF (and Assent Form)


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Table 3-2
VX18-445-106, Part A Treatment Period and Safety Follow-up Visit 
Assessmenta
Day 1
Day 2
Day 4 (± 1 Day)
Day 8 
(± 1 Day)
Day 15
(± 1 Day)
ETT Visit
Safety Follow-up Visit 
28 (± 7) Days After the 
Last Dose of Study Drug Comments
Clinic Visit
X
X
X
X
X
X
Telephone Contact
X
Inclusion and Exclusion Criteria 
Review
X
Section 8 for details
Safety Assessments
Full Physical Examination
X
X
X
X
Section 11.5.3 for details. 
Symptom-directed physical examinations 
will occur at any time during the study if 
deemed necessary by the investigator.
Weight, Height, and BMI
X
X
X
X
Weight and height will be measured 
before study drug dosing with shoes off 
(Section 11.4.4).
Vital Signs
X
X
X
X
X
X
Collected after the subject has been at rest 
for at least 5 minutes (Section 11.5.3)
Pulse Oximetry 
X
X
X
X
X
X
Collected after the subject has been at rest 
for at least 5 minutes (Section 11.5.3)
Standard 12-lead ECG
X
(triplicate)
X
X
X
X
Day 1 and 2: before the AM dose
Day 15: before the AM dose and 4 hours 
(+/- 30 min) after the AM dose
Performed after the subject has been at 
rest for at least 5 minutes (Section 11.5.4)
Spirometry
X
X
X
X
X
X
Should be performed pre-bronchodilator, 
before the AM dose, and at approximately 
the same time at each visit 
(Section 11.4.1). 
Sweat chloride
X
X
Collection will be done approximately at 
the same time as predose blood 
collections; however they may not be 
done at exactly the same time 
(Section 11.4.2).
Pregnancy Test 
(females of childbearing potential)
X 
(urine)
X 
(urine)
X 
(urine)
X
(urine)
Females of childbearing potential is 
defined as females 10 years of age and 
older (Section 11.5.6)
Serum Chemistry
X
X
X
X
X
Section 11.5.2 for details
Hematology
X
X
X
X
X
Section 11.5.2 for details.
Coagulation
X
X
Section 11.5.2 for details.
Drug Test (urine)
X
Section 11.5.2 for details.
Alcohol Test (urine)
X
Section 11.5.2 for details.
a
All assessments will be performed before study drug dosing (within 60 minutes) unless noted otherwise (Section 11).


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Table 3-2
VX18-445-106, Part A Treatment Period and Safety Follow-up Visit 
Assessmenta
Day 1
Day 2
Day 4 (± 1 Day)
Day 8 
(± 1 Day)
Day 15
(± 1 Day)
ETT Visit
Safety Follow-up Visit 
28 (± 7) Days After the 
Last Dose of Study Drug Comments
Observation 4 hours After the 
Morning Dose
X
Concomitant Medications
Continuous, From Signing of ICF (and Assent Form) Through Completion of Study Participation
Concomitant Treatments and 
Procedures
Continuous, From Signing of ICF (and Assent Form) Through Completion of Study Participation
AEs and SAEs
Continuous, From Signing of ICF (and Assent Form) Through Completion of Study Participation
Section 13.1
PK Assessments
PK Sampling
X
X
X
Day 1: before the AM dose, and at 1, 2, 4,
and 6 hours after the AM dose
Day 8: before the AM dose
Day 15: before the AM dose, and at 1, 2, 
4, and 6 hours after the AM dose
If study drug is not administered on the 
day of the visit (i.e., study drug 
interruption or permanent discontinuation 
of study drug), only 1 PK blood sample 
will be collected.
See Table 11-1 for details.
Study Drug Administration
Meal(s) or Snack(s) at Site
X
X
X
X
Fat-containing food such as a standard 
“CF” meal or snack will be provided at 
the site to subjects after all predose 
assessments have occurred. 
Section 9.6.1 for details.
VX-445/TEZ/IVA 
Day 1 Through Day 15 
(morning dose only on Day 15)
Administered within approximately 
30 minutes of consuming fat-containing 
food (e.g., standard “CF” meal or snack) 
(Section 9.6.1). On scheduled visits, the 
AM dose of study drug will be 
administered at the site after predose 
assessments have been completed (food 
to be provided by site on these days).


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Table 3-3
VX18-445-106, Part B Screening Period
Assessment
Screening Visit
(Day -28 to Day -1)
Comments
Informed Consent (and Assent)
X
Demographics
X
Section 11.1 for details
Medical History
X
Section 11.1 for details
Ophthalmologic Examination
X
Conducted by an ophthalmologist or optometrist 
(Section 11.5.5)
Full Physical Examination
X
Section 11.5.3 for details
Weight, Height, and BMI
X
Weight and height will be measured with shoes off 
(Section 11.4.4).
Vital Signs
X
Collected after the subject has been at rest for at least
5 minutes (Section 11.5.3)
Pulse Oximetry
X
Collected after the subject has been at rest for at least
5 minutes (Section 11.5.3)
Standard 12-lead ECG
X
Performed after the subject has been at rest for at least
5 minutes (Section 11.5.4)
Multiple-breath Washout
X
Performed in multiple replicates pre- or post-bronchodilator 
and before the spirometry assessment (Section 11.4.3)
Spirometry
X
Performed pre- or post-bronchodilator (Section 11.4.1). 
Screening spirometry evaluation may be repeated, as 
specified in (Section 9.1.1.1).
Sweat Chloride
X
Section 11.4.2 for details
CF Genotype (all subjects)
X
If the CFTR genotype result is not received before the first 
dose of study drug, a previous CFTR genotype laboratory 
report may be used to establish eligibility (Section 8.1).
Subjects who have been enrolled whose screening genotype 
does not confirm study eligibility must be discontinued from 
the study (Section 9.9).
Serum Pregnancy Test 
(all female subjects)
X
Section 11.5.2 for details
Serum Chemistry
X
Section 11.5.2 for details
Hematology
X
Section 11.5.2 for details
Coagulation
X
Section 11.5.2 for details
Urinalysis
X
Section 11.5.2 for details
Inclusion/Exclusion Criteria 
Review
X
Section 8 for details
Medication Review
X
Information regarding medications taken within 56 days 
before the Screening Visit will be collected (Section 9.5)
AEs and SAEs
X
Continuous, From Signing of ICF (and Assent Form)


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Table 3-4
VX18-445-106, Part B Treatment Period and Safety Follow-up Visit
Event/
Assessmenta
Day 1
Day 3
(± 1 day)
Day 15
(± 3 days)
Week 4
(± 5 days)
Week 8
(± 5 days)
Week 12
(± 5 days)
Week 16
(± 5 days)
Week 20
(± 5 days)
Week 24
(± 5 days)
ETT 
Visit
Safety 
Follow-up 
Visit 28 (± 7)
Days After the 
Last Dose of 
Study Drugb
Comments
Clinic Visit
X
X
X
X
X
X
X
X
X
Telephone 
Contact
X
X
Assess the subject's status, any 
AEs, concomitant 
medications, treatments, and 
procedures.
Inclusion and 
Exclusion Criteria 
Review
X
Section 8 for details
Safety and Efficacy 
Assessments
CFQ-R
X
X
X
X
X
X
X
X
Completed before the start of 
any other assessments 
(Section 11.4.5).
Modified Facial 
Hedonic Scale
X
X
X
X
X
X
X
X
X
Completed immediately after 
dosing with study drug 
(Section 11.3.1).
Ophthalmologic 
Examination
X
at or up to 
4 weeks
before 
X
Section 11.5.5
Full Physical 
Examination
X
X
X
X
Section 11.5.3 for details. 
Symptom-directed physical 
examinations will occur at any 
time during the study if 
deemed necessary by the 
investigator.
Weight, Height, 
and BMI
X
X
X
X
X
X
X
X
X
Weight and height will be 
measured before study drug 
dosing with shoes off 
(Section 11.4.4).
Vital Signs
X
X
X
X
X
X
X
X
X
Collected after the subject has 
been at rest for at least
5 minutes (Section 11.5.3)
a
All assessments will be performed before study drug dosing unless noted otherwise (Section 11). For any assessments with multiple time points for an individual visit, only 1 set of assessments 
will be collected if study drug is not administered on the day of the visit (i.e., study drug interruption or permanent discontinuation of study drug). 
b
The Safety Follow-up Visit is not required for subjects who complete the Week 24 Visit and enroll in the optional open-label extension safety study within 28 days after the last dose.


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Table 3-4
VX18-445-106, Part B Treatment Period and Safety Follow-up Visit
Event/
Assessmenta
Day 1
Day 3
(± 1 day)
Day 15
(± 3 days)
Week 4
(± 5 days)
Week 8
(± 5 days)
Week 12
(± 5 days)
Week 16
(± 5 days)
Week 20
(± 5 days)
Week 24
(± 5 days)
ETT 
Visit
Safety 
Follow-up 
Visit 28 (± 7)
Days After the 
Last Dose of 
Study Drugb
Comments
Pulse Oximetry
X
X
X
X
X
X
X
X
X
Collected after the subject has 
been at rest for at least
5 minutes (Section 11.5.3).
Standard 12-lead 
ECG
X
X
X
X 
X
X
X
Performed after the subject 
has been at rest for at least
5 minutes and before the AM 
dose (Section 11.5.4). 
Spirometry
X
X
X
X
X
X
X
X
X
Should be performed 
pre-bronchodilator, before the 
AM dose, and at 
approximately the same time 
at each visit (Section 11.4.1).
Sweat chloride
X
X
X
X
X
X
Section 11.4.2
Pregnancy Test 
(all female 
subjects)
X
(urine)
X
(serum)
X
(serum)
X
(serum)
X
(serum)
X
(serum)
X
(serum)
X
(serum)
X
(serum)
A local laboratory may be 
used for the Week 20 sample 
if a subject cannot return to 
the study site for the blood 
draw (Section 11.5.2).
Serum Chemistry
X
X
X
X
X
X
X
X
X
X
Section 11.5.2 for details.
Liver function testing (ALT, 
AST, GGT, ALP, and total 
bilirubin) must be performed 
at the scheduled visits and at 
Week 20 (a minimum of every 
4 weeks after Week 4). A 
local laboratory may be used 
for the Week 20 sample if a 
subject cannot return to the 
study site for the blood draw. 
Hematology
X
X
X
X
X
X
X
X
X
Section 11.5.2 for details.
Coagulation
X
X
X
X
Section 11.5.2 for details.
Urinalysis
X
X
X
Section 11.5.2 for details.


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Table 3-4
VX18-445-106, Part B Treatment Period and Safety Follow-up Visit
Event/
Assessmenta
Day 1
Day 3
(± 1 day)
Day 15
(± 3 days)
Week 4
(± 5 days)
Week 8
(± 5 days)
Week 12
(± 5 days)
Week 16
(± 5 days)
Week 20
(± 5 days)
Week 24
(± 5 days)
ETT 
Visit
Safety 
Follow-up 
Visit 28 (± 7)
Days After the 
Last Dose of 
Study Drugb
Comments
Multiple-breath 
Washout
X
X
X
X
X
X
Performed in multiple 
replicates pre-bronchodilator
and before the spirometry 
assessment (Section 11.4.3).
Observation 
4 Hours After the 
Morning Dose
X
Study Drug Count
X
X
X
X
X
X
X
Other Events 
Related to 
Outcome
Continuous, From Signing of ICF (and Assent Form) Through Completion of Study Participation
Includes PEx, administration 
of antibiotic therapy for 
sinopulmonary 
signs/symptoms, and 
hospitalizations for CF 
(Section 11.4.6). Completion 
of study participation is 
defined in Section 9.1.6.
Concomitant 
Medications
Continuous, From Signing of ICF (and Assent Form) Through Completion of Study Participation
Completion of study 
participation is defined in 
Section 9.1.6.
Concomitant 
Treatments and 
Procedures
Continuous, From Signing of ICF (and Assent Form) Through Completion of Study Participation
Completion of study 
participation is defined in 
Section 9.1.6.
AEs and SAEs
Continuous, From Signing of ICF (and Assent Form) Through Completion of Study Participation
Section 13.1; completion of 
study participation is defined 
in Section 9.1.6.


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Table 3-4
VX18-445-106, Part B Treatment Period and Safety Follow-up Visit
Event/
Assessmenta
Day 1
Day 3
(± 1 day)
Day 15
(± 3 days)
Week 4
(± 5 days)
Week 8
(± 5 days)
Week 12
(± 5 days)
Week 16
(± 5 days)
Week 20
(± 5 days)
Week 24
(± 5 days)
ETT 
Visit
Safety 
Follow-up 
Visit 28 (± 7)
Days After the 
Last Dose of 
Study Drugb
Comments
PK Assessments
Single PK 
Sampling
X
X
X
Blood samples collected 
before dosing must be 
collected within 60 minutes 
before dosing. See Table 11-1
for details.
Serial PK 
Sampling
X
X
Day 1: Blood samples 
collected at 2, 4, and 6 hours 
after the AM dose. 
Week 4: Blood samples 
collected before dosing 
(within 60 minutes before 
dosing) and 1, 2, 4, and 
6 hours after the AM dose. If 
study drug is not administered 
on the day of the visit 
(i.e., study drug interruption 
or permanent discontinuation 
of study drug), only 1 PK 
blood sample will be 
collected. See Table 11-1 for 
details.
Study Drug 
Administration
VX-445/TEZ/IVA
VX-445/TEZ/IVA
(Day 1 through evening before Week 24 Visit)
Administered within 
approximately 30 minutes of 
consuming fat-containing 
food (e.g., standard “CF” meal 
or snack) (Section 9.6.1). On 
scheduled visits, the AM dose 
of study drug will be 
administered at the site after 


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Table 3-4
VX18-445-106, Part B Treatment Period and Safety Follow-up Visit
Event/
Assessmenta
Day 1
Day 3
(± 1 day)
Day 15
(± 3 days)
Week 4
(± 5 days)
Week 8
(± 5 days)
Week 12
(± 5 days)
Week 16
(± 5 days)
Week 20
(± 5 days)
Week 24
(± 5 days)
ETT 
Visit
Safety 
Follow-up 
Visit 28 (± 7)
Days After the 
Last Dose of 
Study Drugb
Comments
predose assessments have 
been completed (food to be 
provided by site on these 
days).


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4
TABLE OF CONTENTS
1
Title Page............................................................................................................................1
2
Protocol Synopsis ...............................................................................................................3
3
Schedule of Assessments ....................................................................................................8
4
Table of Contents .............................................................................................................17
List of Tables .......................................................................................................................20
List of Figures ......................................................................................................................20
List of Abbreviations............................................................................................................21
5
Introduction......................................................................................................................24
5.1
Background.................................................................................................................24
5.2
Study Rationale...........................................................................................................24
6
Study Objectives...............................................................................................................25
6.1
Primary Objectives......................................................................................................25
6.2
Secondary Objectives..................................................................................................25
7
Study Endpoints...............................................................................................................25
7.1
Primary Endpoints.......................................................................................................25
7.2
Secondary Endpoints...................................................................................................25
8
Study Population..............................................................................................................26
8.1
Inclusion Criteria.........................................................................................................26
8.2
Exclusion Criteria........................................................................................................27
9
Study Implementation......................................................................................................29
9.1
Study Design...............................................................................................................29
9.1.1
Screening.............................................................................................................30
9.1.1.1
Repetition of Screening Assessments.............................................................31
9.1.1.2
Rescreening...................................................................................................31
9.1.1.3
Extension of Screening Period Window.........................................................31
9.1.2
Treatment Period .................................................................................................31
9.1.3
Follow-up............................................................................................................32
9.1.4
Early Termination of Treatment...........................................................................32
9.1.5
Lost to Follow-up ................................................................................................32
9.1.6
Completion of Study Participation .......................................................................33
9.1.7
Independent Data Monitoring Committee ............................................................33
9.2
Method of Assigning Subjects to Treatment Groups....................................................33
9.3
Rationale for Study Elements ......................................................................................33
9.3.1
Study Design .......................................................................................................33
9.3.2
Study Population .................................................................................................34
9.3.3
Study Drug Dose and Duration ............................................................................34
9.3.4
Rationale for Study Assessments .........................................................................35
9.4
Study Restrictions .......................................................................................................36
9.4.1
Prohibited Medications........................................................................................36
9.5
Prior and Concomitant Medications.............................................................................37
9.6
Administration ............................................................................................................38
9.6.1
Dosing.................................................................................................................38


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9.6.2
Missed Doses.......................................................................................................39
9.7
Dose Modification for Toxicity ...................................................................................40
9.8
Study Drug Interruption and Stopping Rules ...............................................................40
9.8.1
Liver Function Tests............................................................................................40
9.8.2
Rash ....................................................................................................................41
9.9
Removal of Subjects....................................................................................................41
9.10 Replacement of Subjects .............................................................................................42
10 Study Drug Information and Management.....................................................................42
10.1 Preparation and Dispensing .........................................................................................42
10.2 Packaging and Labeling ..............................................................................................42
10.3 Study Drug Supply, Storage, and Handling .................................................................42
10.4 Drug Accountability....................................................................................................43
10.5 Disposal, Return, or Retention of Unused Drug...........................................................43
10.6 Compliance.................................................................................................................43
10.7 Blinding and Unblinding .............................................................................................44
11
Assessments ......................................................................................................................44
11.1 Subject and Disease Characteristics.............................................................................44
11.2 Pharmacokinetics ........................................................................................................44
11.2.1
Blood Sampling...................................................................................................44
11.2.2
Processing and Handling of Pharmacokinetic Samples.........................................45
11.2.3
Bioanalysis ..........................................................................................................45
11.3 Other Assessments ......................................................................................................45
11.3.1
Modified Facial Hedonic Scale for Drug Acceptability Assessment.....................45
11.4 Efficacy and Pharmacodynamics.................................................................................46
11.4.1
Spirometry...........................................................................................................46
11.4.2
Sweat Chloride ....................................................................................................47
11.4.3
Multiple-breath Washout .....................................................................................47
11.4.4
Height and Weight...............................................................................................48
11.4.5
Cystic Fibrosis Questionnaire-Revised.................................................................48
11.4.6
Other Events Related to Outcome ........................................................................48
11.4.6.1
Antibiotic Therapy for Sinopulmonary Sign/Symptoms.................................48
11.4.6.2
Hospitalization for CF ...................................................................................49
11.5 Safety..........................................................................................................................49
11.5.1
Adverse Events....................................................................................................49
11.5.2
Clinical Laboratory Assessments .........................................................................49
11.5.3
Physical Examinations and Vital Signs ................................................................51
11.5.4
Electrocardiograms..............................................................................................52
11.5.5
Ophthalmologic Examination ..............................................................................52
11.5.6
Contraception and Pregnancy...............................................................................53
11.5.6.1
Contraception................................................................................................53
11.5.6.2
Pregnancy......................................................................................................54
12
Statistical and Analytical Plans .......................................................................................55
12.1 Sample Size and Power ...............................................................................................55


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12.2 Analysis Sets...............................................................................................................55
12.3 Statistical Analysis......................................................................................................56
12.3.1
General Considerations........................................................................................56
12.3.2
Background Characteristics .................................................................................57
12.3.2.1
Subject Disposition........................................................................................57
12.3.2.2
Demographics and Baseline Characteristics...................................................57
12.3.2.3
Prior and Concomitant Medications...............................................................57
12.3.2.4
Study Drug Exposure and Compliance ..........................................................57
12.3.3
Final Efficacy Analysis........................................................................................58
12.3.3.1
Analysis of Primary Efficacy Endpoints ........................................................58
12.3.3.2
Analysis of Secondary Efficacy and Pharmacodynamic Endpoints ................58
12.3.4
Safety Analysis....................................................................................................59
12.3.4.1
Adverse Events..............................................................................................60
12.3.4.2
Clinical Laboratory Assessments...................................................................61
12.3.4.3
Electrocardiogram.........................................................................................61
12.3.4.4
Vital Signs.....................................................................................................61
12.3.4.5
Pulse Oximetry..............................................................................................61
12.3.4.6
Ophthalmologic Examinations.......................................................................62
12.3.4.7
Physical Examination ....................................................................................62
12.3.5
Interim and IDMC Analyses................................................................................62
12.3.5.1
Interim Analysis............................................................................................62
12.3.5.2
IDMC Analysis .............................................................................................62
12.4 Clinical Pharmacology Analysis..................................................................................62
12.4.1
Pharmacokinetic Analysis....................................................................................62
12.4.2
Pharmacokinetic/Pharmacodynamic Analyses .....................................................62
13 Procedural, Ethical, Regulatory, and Administrative Considerations...........................63
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ....................................................................................................................63
13.1.1
Adverse Events....................................................................................................63
13.1.1.1
Definition of an Adverse Event......................................................................63
13.1.1.2
Clinically Significant Assessments................................................................63
13.1.1.3
Documentation of Adverse Events.................................................................63
13.1.1.4
Adverse Event Severity .................................................................................64
13.1.1.5
Adverse Event Causality................................................................................64
13.1.1.6
Study Drug Action Taken..............................................................................65
13.1.1.7
Adverse Event Outcome................................................................................65
13.1.1.8
Treatment Given............................................................................................66
13.1.2
Serious Adverse Events .......................................................................................66
13.1.2.1
Definition of a Serious Adverse Event...........................................................66
13.1.2.2
Documentation of Serious Adverse Events ....................................................67
13.1.2.3
Reporting Serious Adverse Events.................................................................67
13.1.2.4
Expedited Reporting and Investigator Safety Letters......................................67
13.2 Administrative Requirements ......................................................................................68
13.2.1
Ethical Considerations .........................................................................................68
13.2.2
Subject Information and Informed Consent and Assent........................................68
13.2.3
Investigator Compliance ......................................................................................68


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13.2.4
Access to Records................................................................................................68
13.2.5
Subject Privacy....................................................................................................68
13.2.6
Record Retention.................................................................................................69
13.2.7
Study Termination...............................................................................................69
13.2.8
End of Study........................................................................................................69
13.3 Data Quality Assurance...............................................................................................70
13.4 Monitoring ..................................................................................................................70
13.5 Electronic Data Capture ..............................................................................................70
13.6 Publications and Clinical Study Report........................................................................71
13.6.2
Clinical Study Report ..........................................................................................71
14 Reference ..........................................................................................................................72
APPENDIX A 
Eligible MF CFTR Mutations....................................................................74
15 Protocol Signature Pages .................................................................................................77
15.1 Sponsor Signature Page...............................................................................................77
15.2 Investigator Signature Page.........................................................................................78
List of Tables
Table 3-1
VX18-445-106, Part A Screening Period..............................................................8
Table 3-2
VX18-445-106, Part A Treatment Period and Safety Follow-up Visit...................9
Table 3-3
VX18-445-106, Part B Screening Period............................................................11
Table 3-4
VX18-445-106, Part B Treatment Period and Safety Follow-up Visit.................12
Table 9-1
Parts A and B Doses...........................................................................................30
Table 9-2
Prohibited Medications ......................................................................................36
Table 9-3
Study Drug Administration, Part B.....................................................................39
Table 10-1
Study Drug: Dosing Form/Route/Strength..........................................................43
Table 11-1
Acceptable Pharmacokinetic Sampling Windows...............................................45
Table 11-2
Safety Laboratory Test Panels............................................................................50
Table 11-3
Acceptable Methods of Contraception................................................................54
Table 12-1
Probability of Observing At Least 1 Subject With an AE in the Study if the AE 
Incidence (∀) is 5% and 10%..............................................................................55
Table 13-1
Grading of AE Severity......................................................................................64
Table 13-2
Classifications for AE Causality.........................................................................65
Table 13-3
Classifications for Study Drug Action Taken With Regard to an AE ..................65
Table 13-4
Classifications for Outcome of an AE ................................................................66
List of Figures
Figure 9-1
Part A Study Design...........................................................................................29
Figure 9-2
Part B Study Design...........................................................................................30


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List of Abbreviations
Abbreviation
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transaminase
AST
aspartate transaminase
AUC
area under the concentration versus time curve
BMI
body mass index
CF
cystic fibrosis
CFQ-R
Cystic Fibrosis Questionnaire - Revised
CFTR
CF transmembrane conductance regulator gene
CFTR
CF transmembrane conductance regulator protein
CI
confidence interval
Cl−
chloride ion
Cmax
maximum observed concentration
CPAP
clinical pharmacology analysis plan
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
predose concentration
CYP
cytochrome P450
ECG
electrocardiogram
EDC
electronic data capture
ETT
Early Termination of Treatment
EU
European Union
F508del
CFTR gene mutation with an in-frame deletion of a phenylalanine codon corresponding to 
position 508 of the wild-type protein
F/F
homozygous for F508del
F/MF
heterozygous for F508del and a CFTR minimal function mutation
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
G6PD
glucose-6-phosphate dehydrogenase
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLI
Global Lung Function Initiative
GPS
Global Patient Safety
HBE
human bronchial epithelial (cells)


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Abbreviation
Definition
HIPAA
Health Insurance Portability and Accountability Act 
HR
heart rate
IA
interim analysis
ICF
informed consent form
ICH
International Council for Harmonization
IDMC
independent data monitoring committee
IEC
independent ethics committee
IND
investigational new drug
IRB
institutional review board
IV
intravenous
IVA
ivacaftor
IWRS
interactive web response system
LCI
lung clearance index
LCI2.5
number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of 
its starting value
LCI5.0
number of lung turnovers required to reduce the end tidal inert gas concentration to 1/20th of 
its starting value
LUM
lumacaftor
M1-IVA
metabolite of IVA
M1-TEZ
metabolite of TEZ
M23-445
metabolite of VX-445
max
maximum value
MBW
multiple-breath washout
MedDRA
Medical Dictionary for Regulatory Activities
MF
CFTR minimal function mutation
min
minimum value
MMRM
mixed-effects model for repeated measures
N
number of subjects
NCA
noncompartmental analysis
NG
next generation
OATP1B1
organic anion transporting polypeptide 1B1
OE
ophthalmologic examination
P
probability
PD
pharmacodynamic, pharmacodynamics
PDCO
European Medicines Agency Pediatric Committee
PE
physical examination
PEx
pulmonary exacerbation
P-gp
P-glycoprotein
PK
pharmacokinetic, pharmacokinetics
ppFEV1
percent predicted forced expiratory volume in 1 second
PR
PR interval, segment
q12h
every 12 hours
qd
once daily


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Abbreviation
Definition
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
RR
interval from the onset of 1 QRS complex to the next
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SI
SI units (International System of Units)
SUSAR
suspected, unexpected, serious adverse reaction
SwCl
sweat chloride
TC
triple combination
TE
treatment-emergent
TEAE
treatment-emergent adverse event
TEZ
tezacaftor
ULN
upper limit of normal
US
United States


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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 Pharmaceuticals Incorporated 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 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
Given the progressive nature of CF, there is a strong rationale for preventing disease progression 
by treating patients earlier in life. Vertex is evaluating VX-445/TEZ/IVA TC therapy in Phase 3 


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studies in adult and adolescent CF subjects with 1 or 2 copies of the F508del mutation, namely 
those with F/MF and F/F genotypes. Given the clinical benefit seen in a Phase 2 study of adults 
with CF with VX-445/TEZ/IVA, the present study is designed to obtain pharmacokinetic (PK), 
safety, tolerability, and pharmacodynamic (PD) information to expand the evaluation of this 
study drug in the pediatric population 6 through 11 years of age with F/MF or F/F genotypes.
6
STUDY OBJECTIVES
6.1
Primary Objectives
Part A
To evaluate the PK of VX-445, TEZ, and IVA when dosed in TC
Part B
To evaluate the safety and tolerability of VX-445/TEZ/IVA through Week 24
6.2
Secondary Objectives
Part A
!
To evaluate the PK of VX-445, TEZ and IVA metabolites 
!
To evaluate the safety and tolerability of VX-445/TEZ/IVA 
Part B
!
To evaluate the efficacy of VX-445/TEZ/IVA through Week 24
!
To evaluate the PK of VX-445, TEZ, and IVA 
!
To evaluate the PK of VX-445, TEZ and IVA metabolites
7
STUDY ENDPOINTS
7.1
Primary Endpoints
Part A 
PK parameters of VX-445, TEZ, and IVA, including Cmax, Ctrough, and AUC0-τ
Part B
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
standard 12-lead ECGs, vital signs, pulse oximetry, and ophthalmologic examinations
7.2
Secondary Endpoints
Part A 
!
PK parameters of VX-445, TEZ and IVA metabolites, including Cmax, Ctrough, and AUC0-τ
!
Safety and tolerability as determined by AEs, clinical laboratory values, standard 12-lead 
ECGs, vital signs, and pulse oximetry


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Part B
!
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline through Week 24
!
Absolute change in sweat chloride (SwCl) from baseline through Week 24
!
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score 
from baseline through Week 24
!
Absolute change in body mass index (BMI) and BMI-for-age z-score from baseline at 
Week 24
!
Absolute change in weight and weight-for-age z-score from baseline at Week 24
!
Absolute change in height and height-for-age z-score from baseline at Week 24
!
Drug acceptability assessment using Modified Facial Hedonic Scale
!
Number of pulmonary exacerbations (PEx) and CF-related hospitalizations through Week 24
!
PK parameters of VX-445, TEZ, IVA, and relevant metabolites 
!
Absolute change in lung clearance index2.5 (LCI2.5) from baseline through Week 24
8
STUDY POPULATION
Eligibility will be reviewed and documented by a qualified member of the investigator’s team 
before enrollment.
8.1
Inclusion Criteria
Parts A and B
Subjects who meet all of the following inclusion criteria will be eligible for Part A and Part B.
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
informed consent form (ICF), and an assent form.
2. Subjects (males and/or females), 6 through 11 years of age, inclusive, on the date of informed 
consent.
3. Subjects who weigh ∃15 kg without shoes at the Screening Visit.
4. Confirmed diagnosis of CF as determined by the investigator.
5. Subjects who are homozygous for F508del (F/F genotype) or heterozygous for F508del and 
an MF mutation that is not responsive to IVA and TEZ/IVA (F/MF genotypes; Appendix A). 


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!
Genotype should be confirmed at the Screening Visit. This assessment does not need to 
be repeated for confirmed subjects in Part A who wish to participate in Part B.
!
If the screening CFTR genotype result is not received before the first dose of study drug, 
a previous CFTR genotype laboratory report may be used to establish eligibility. 
!
Subjects who have been enrolled and whose screening genotype does not confirm study 
eligibility must be discontinued from the study (Section 9.9).
6. Subjects with FEV1 ≥40% of predicted normal for age, sex, and height using equations of the 
Global Lung Function Initiative (GLI)11 at the Screening Visit (Section 11.4.1). Spirometry 
measurements used to confirm eligibility must meet American Thoracic Society/European 
Respiratory Society criteria12 for acceptability and repeatability, as judged by the 
investigator.
7. Subjects with stable CF disease at the start of the Treatment Period as deemed by the 
investigator.
8. Subjects who are willing to remain on a stable CF medication regimen (other than CFTR 
modulators) through Day 15 (Part A) or through Week 24 (Part B) or, if applicable, through 
the Safety Follow-up Visit.
9. Subjects who are able to swallow tablets. 
10. Female subjects must have a negative serum pregnancy test at the Screening Visit.
11. Subjects of childbearing potential and who are sexually active must meet the contraception 
requirements outlined in Section 11.5.6.1.
12. As deemed by the investigator, the subject’s legally appointed and authorized representative 
(e.g., parent or legal guardian) AND the subject must be able to understand protocol 
requirements, restrictions, and instructions. The subject’s legally appointed and authorized 
representative should be able to ensure that the subject will comply with and is likely to 
complete the study as planned.
8.2
Exclusion Criteria
Parts A and B
Subjects who meet any of the following exclusion criteria will not be eligible for Part A and 
Part B.
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 (all 3 with no recurrence for the last 5 years). 


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2. Any clinically significant laboratory abnormalities at the Screening Visit that would interfere 
with the study assessments or pose an undue risk for the subject (as deemed by the 
investigator).
3. Any of the following abnormal laboratory values at screening:
!
Hemoglobin <10 g/dL
!
Total bilirubin ≥2 × upper limit of normal (ULN)
!
Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase 
(GGT), or alkaline phosphatase (ALP) ≥3 × ULN
!
Abnormal renal function defined as glomerular filtration rate ≤45 mL/min/1.73 m2
(calculated by the Counahan-Barratt equation)13
4. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy 
(including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study 
drug).
5. Lung infection with organisms associated with a more rapid decline in pulmonary status 
(including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and 
Mycobacterium abscessus). For subjects who have had a history of a positive culture, the 
investigator will apply the following criteria to establish whether the subject is free of 
infection with such organisms: 
!
The subject has not had a respiratory tract culture positive for these organisms within the 
12 months before the date of informed consent and assent.
!
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 and assent.
6. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of 
study drug (Day 1).
7. Ongoing or prior participation in an investigational drug study (including studies 
investigating VX-445 with or without coadministration with other study drugs) within 
28 days of the Screening Visit. 
!
A washout period of 5 terminal half-lives of the previous investigational study drug, or
28 days, whichever is longer, must elapse before the Screening Visit. 
!
The duration of the elapsed time may be longer if required by local regulations. 
Note: Ongoing participation in a noninterventional study (including observational 
studies) is permitted.
8. Use of restricted medication within specified duration before the first dose of study drug as 
defined in Table 9-2.
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.


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9
STUDY IMPLEMENTATION
9.1
Study Design
This is a Phase 3, 2-part (Parts A and B), multicenter study evaluating the PK, safety, and 
tolerability of VX-445/TEZ/IVA TC therapy in CF (F/F and F/MF genotypes) subjects 6 through 
11 years of age (inclusive). 
Part A
A schematic of the study design for Part A is provided in Figure 9-1. Approximately 12 subjects 
(F/F or F/MF genotypes) are planned for enrollment. During the Treatment Period, subjects will 
be administered VX-445/TEZ/IVA for approximately 15 days. A review of safety, tolerability, 
and available PK data will be completed by an internal Vertex team after Part A to confirm or 
adjust the dose(s) chosen for Part B. Additional subjects may be enrolled as needed in Part A, 
based on emerging PK data, to confirm the dose(s) for Part B. Subjects who participate in Part A 
may participate in Part B. 
Figure 9-1
Part A Study Design 
Part B
A schematic of the study design for Part B is provided in Figure 9-2 Part B will initiate after 
completion of the internal Vertex team’s review of available data in Part A that will confirm or 
adjust the dose(s) to be evaluated in Part B. Approximately 56 subjects (F/F or F/MF genotypes) 
are planned for enrollment to ensure approximately 45 subjects complete Part B. Approximately 
25 subjects with F/MF genotypes and approximately 20 subjects with F/F genotypes are targeted 
for enrollment in Part B. During the Treatment Period, subjects will be administered 
VX-445/TEZ/IVA (Table 9-1) for approximately 24 weeks. An optional interim analysis (IA) 
may be conducted.
Subjects who complete the Part B Treatment Period and have not permanently discontinued 
study drug will be offered the opportunity to enroll in an optional open-label extension safety 
study (enrollment will be based on the eligibility criteria specified within the Open-label 
Extension Safety Study protocol).


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Figure 9-2
Part B Study Design 
Table 9-1
Parts A and B Doses
Subject Weight at Day 1
VX-445 Dose
TEZ Dose
IVA Dose
Part A
All subjects
100 mg qd
50 mg qd
75 mg q12h
Part B
<30 kg
100 mg qd
50 mg qd
75 mg q12h
≥30 kg
200 mg qd
100 mg qd
150 mg q12h
IVA: ivacaftor; qd: once daily; q12h: every 12 hours; TEZ: tezacaftor
9.1.1
Screening
Parts A and B
Screening will occur within 28 days before administration of study drug. The investigator (or an 
appropriate authorized designee) will obtain informed consent and assent, if applicable, for each 
subject before any study procedure takes place.
Subjects who participate in Part A may participate in Part B. Subjects from Part A will be 
screened for Part B and must be deemed eligible before enrolling in Part B. 
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.4) and concomitant medications (Section 9.5).


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Part A Only
Subjects previously screened for another Vertex study may participate in this study provided 
they meet the eligibility criteria (Section 8). Screening data from the previous study will be 
considered sufficient to satisfy the requirements of this study. Procedures required by this 
protocol will only be done if the procedures were not performed for the previous study. All 
screening data from these subjects must be obtained within 28 days before administration of 
study drug.
9.1.1.1
Repetition of Screening Assessments
Parts A and B
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
Parts A and B
Subjects may be rescreened once. If a subject is rescreened, the subject will provide informed 
consent and assent (as applicable), and all screening assessments will be repeated, except for: 
!
CFTR genotyping
!
Ophthalmologic examination (if performed within 3 months before the date of informed 
consent)
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
Parts A and B
A subject may have the Screening Period window extended by 2 weeks for the following 
reasons:
!
Repetition of the Screening Period assessments (Section 9.1.1.1)
!
Unexpected operational or logistic delays, or to meet the eligibility criteria
!
Scheduling of ophthalmologic examination (Section 11.5.5)
9.1.2
Treatment Period
Parts A and B
The Treatment Period will last approximately 15 days in Part A and 24 weeks in Part B. Study 
drug administration details are provided in Section 9.6.
Subjects who prematurely discontinue study drug treatment will remain in the study from the 
time of discontinuation of study drug treatment through the last scheduled study visit and 
complete the assessments for all study visits, as described in Section 9.1.4.


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9.1.3
Follow-up
Part A
Subjects will have a Safety Follow-up Visit 28 (± 7) days after the last dose of study drug. 
Part B
The Safety Follow-up Visit is scheduled to occur 28 (± 7) days after the last dose of study drug 
for subjects who complete study drug dosing and for subjects who prematurely discontinue study 
drug dosing, as described in Section 9.1.4. 
An optional open-label extension safety study will be available for subjects who complete the 
last treatment period visit and are eligible. The Safety Follow-up Visit is not required for subjects 
who complete the Week 24 Visit and enroll in the optional open-label extension safety study 
within 28 days after the last dose of study drug.
9.1.4
Early Termination of Treatment
Parts A and B
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 (Table 3-2 for Part A and Table 3-4 for Part B), if applicable (Section 9.1.3). 
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. 
Part B
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.
Subjects who prematurely discontinue study drug treatment will continue to complete all 
scheduled study visits for assessments following completion of the ETT Visit, as detailed in 
Table 3-4.
Subjects who prematurely discontinue treatment in Part B are not eligible to enroll in the 
optional open-label extension safety study. 
9.1.5
Lost to Follow-up
Part B
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.


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9.1.6
Completion of Study Participation
Completion of study participation for each individual subject is defined as 1 of the following:
Part A
!
For subjects who complete the Treatment Period: the Safety Follow-up Visit
!
For subjects who prematurely discontinue study drug treatment but do not withdraw consent 
(and assent, as applicable): the latest of the Day 15 Visit, ETT Visit, or Safety Follow-up 
Visit
!
For subjects who withdraw consent or assent: date of withdrawal of consent or assent, 
whichever is earlier (Section 9.9)
Part B
!
For subjects who complete the Treatment Period and enter an open-label extension safety 
study within 28 days of the Week 24 Visit: the Week 24 Visit 
!
For subjects who complete the Treatment Period and do not enter an open-label extension 
safety study within 28 days of the Week 24 Visit: the Safety Follow-up Visit
!
For subjects who prematurely discontinue study drug treatment but do not withdraw consent 
(and assent, as applicable): the latest of the Week 24 Visit, ETT Visit, or Safety Follow-up 
Visit (if required)
!
For subjects who withdraw consent or assent: date of withdrawal of consent or assent, 
whichever is earlier (Section 9.9)
If subjects are lost to follow-up (Section 9.1.5), 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.
9.1.7
Independent Data Monitoring Committee
Part B Only
An independent data monitoring committee (IDMC) will be formed using the Cystic Fibrosis 
Foundation Data Safety Monitoring Board. The IDMC objectives and operational details will be 
defined in a separate document (IDMC Charter), which will be finalized before the first subject 
is screened. The IDMC will conduct regular planned reviews of study data as outlined in the 
IDMC Charter.
9.2
Method of Assigning Subjects to Treatment Groups
This is an open-label study. Randomization is not required because all subjects will be treated 
identically. An interactive web response system (IWRS) will be used to dispense dosage based 
on subject weight at Day 1. 
9.3
Rationale for Study Elements
9.3.1
Study Design
The subjects studied are from the population that is expected to benefit from treatment with 
VX-445/TEZ/IVA.


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Part A
The open-label design is considered adequate to evaluate the PK and safety of VX-445/TEZ/IVA 
in this pediatric population. Evaluation of a single-dose level is sufficient for the assessment of 
VX-445/TEZ/IVA across subjects in different weight ranges to confirm the doses and 
appropriate weight cutoff for Part B.
Part B
Part B is designed to evaluate the long-term safety in the pediatric CF population. This design is 
in harmony with guidelines for the study of human subjects, especially children, and balances 
safety concerns with potential benefits for the individual.
9.3.2
Study Population
Parts A and B
Patients with an F/MF genotype (30% of all patients with CF) generally have severe disease and 
do not have approved CFTR modulator therapy available to them; clinical studies of LUM/IVA 
and TEZ/IVA did not show improvement in lung function in this patient population. Without an 
available CFTR modulator therapy, patients with F/MF genotypes must continue to rely on 
adjunctive treatments and symptomatic therapies to manage their severe CF disease. Patients 
with an F/F genotype also have continuing unmet need despite the availability of CFTR 
modulators for this population. Based on in vitro data and preliminary clinical data, 
VX-445/TEZ/IVA is expected to provide a clinically relevant advantage over currently available 
treatments for F/MF and F/F patients.
Given the progressive nature of CF, there is a strong rationale for treating patients earlier in life. 
Experience with CFTR modulators in pediatric subjects ≥6 to ≤11 years of age, including with 
TEZ/IVA, suggests that the safety profile of VX-445/TEZ/IVA will be similar in children and 
adults, which supports evaluation of VX-445/TEZ/IVA in pediatric subjects in the present study. 
9.3.3
Study Drug Dose and Duration
Parts A and B
VX-445 Dosage 
A VX-445 dose of 200 mg qd was evaluated in Phase 3 studies of adult and adolescent 
(≥12 years of age) CF subjects with F/MF and F/F genotypes. The 200-mg dose was selected 
based on an assessment of the benefit-risk profile from Phase 2 Study VX16-445-001 
(Study 445-001) which evaluated a range of VX-445 doses (50 mg qd, 100 mg qd, and 200 mg 
qd) in TC with TEZ/IVA in CF subjects with F/MF and F/F genotypes. In Study 445-001, the TC 
was generally safe and well tolerated in all VX-445 dose groups. Subjects with F/MF genotypes 
who received the VX-445 200 mg qd TC demonstrated a clinically meaningful improvement in 
ppFEV1 (within-group mean [SE] absolute change of 13.8 [1.4] percentage points from baseline 
[P<0.0001], compared with a mean absolute change of 0.0 [2.0] percentage points in subjects 
who received placebo [P = 0.9943]). A similar magnitude of change was observed in subjects 
with F/F genotypes compared with subjects who received the active comparator of TEZ/IVA.
Part A
The VX-445 dose of 100 mg qd selected for evaluation in Part A was determined based on 
population-PK modeling utilizing data from adults and simulating exposures over a range of 


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body weights typical for a population of 6- to <12-year-olds, ranging from 15 to 50 kg. The 
simulations indicate that a VX-445 dose of 100 mg qd is predicted to provide exposures that 
would not exceed the exposures observed in adults dosed with 200 mg qd. Hence, the VX-445 
100-mg qd dose was predicted to be safe and was selected to be evaluated in Part A for all 
subject weight groups. 
Part B
For Part B, subjects in the higher weight range will be administered VX-445 200 mg qd. The 
appropriate weight cutoff for the switch from 100 mg qd to 200 mg qd was determined based on 
population-PK modeling which was updated with preliminary PK data from Part A and data 
from studies conducted in adult and adolescent CF subjects. For Part B, a VX-445 dose of 100 
mg qd will be evaluated in subjects weighing <30 kg. In subjects weighing ≥30 kg, a VX-445 
dose of 200 mg qd will be evaluated. These doses are predicted to be safe based on PK data from 
Part A, data obtained from adults in the Phase 2 Study 445-001, and preliminary data obtained 
from adults and adolescents (12- to <18-year-olds) in Phase 3 Studies 445-102 and 445-103.
TEZ and IVA Dosages
TEZ will be administered as 50 mg qd and IVA will be administered as 75 mg every 12 hours 
(q12h) in all subjects in Part A and in subjects weighing <30 kg in Part B. In Part B, doses of 
TEZ 100 mg qd and IVA 150 mg q12h will be administered in subjects weighing ≥30 kg. The 
dosages and weight cutoff in Part B were selected based on an evaluation of PK and safety of 
TEZ/IVA in CF subjects 6 to 11 years of age in Part A of Study VX15-661-113 (Study 661-113). 
Part B of Study 661-113 assessed the safety and efficacy of TEZ/IVA at these doses in CF 
subjects 6 to 11 years of age. 
Part A 
Duration of Dosing
The 15-day duration of dosing was chosen to provide an adequate assessment PK, safety, and 
tolerability of VX-445/TEZ/IVA before exposing subjects to a longer duration of treatment in 
Part B.
Part B
Duration of Dosing
The 24-week duration of dosing was chosen to provide an adequate assessment of long-term 
safety.
9.3.4
Rationale for Study Assessments
Parts A and B
The PK, safety, 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 
subjects with CF. Baseline and follow-up ophthalmologic examinations are recommended for 
monitoring of pediatric patients treated with IVA-containing drug regimens, and have been 
added to the standard safety assessments.
 
 


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LCI (Part B only) is a measure of ventilation inhomogeneity assessed by multiple-breath 
washout (MBW) that is based on tidal breathing techniques that have been evaluated in patients 
as young as infants.14, 15 Studies have shown that LCI correlates with forced expiratory volume in 
1 second (FEV1) in its ability to measure airway disease and can detect lung disease at an earlier 
stage than spirometry.16, 17 Furthermore, data from Study VX10-770-106 in CF patients with an 
FEV1 >90% showed LCI to be a more sensitive outcome measure than FEV1. 
The Modified Facial Hedonic Scale questionnaire (Part B only) will evaluate the subject’s 
acceptance of the administered study drug dose. The convenience, ease of administration, and 
perception of the child’s acceptance of the study drug by the parent/caregiver will also be 
evaluated. All subjects will be observed for their facial expressions and the reaction will be 
scored using a visual analog scale; any spontaneous comments in regards to likes or dislikes will 
also be noted. Interviews will be conducted on a one-on-one basis in the clinic setting.
9.4
Study Restrictions
9.4.1
Prohibited Medications
Parts A and B
Table 9-2 lists prohibited medications. A non-exhaustive list of study prohibitions and cautions 
for medication will be provided in the Study Reference Manual. 
Table 9-2
Prohibited Medications
Medication
Timing of Restriction
Rationale
Start of 
Restriction
End of 
Restriction
Moderate and strong 
CYP3A inducers
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1
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 
within 14 days 
before the first 
dose of the study 
drug on Day 1
None allowed 
through 
completion of 
study 
participation
CFTR modulators 
None allowed 
None allowed 
These agents may confound the results of this 


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Table 9-2
Prohibited Medications
Medication
Timing of Restriction
Rationale
Start of 
Restriction
End of 
Restriction
(investigational or 
approved), except for 
study drugs
within 28 days 
before the first 
dose of the study 
drug on Day 1
until after the 
last dose of 
study drug
study.
CYP: cytochrome P450; 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
Parts A and B
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 9.1.6.
For subjects who are screened but are not subsequently enrolled, 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 1 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 1 Visit. Subjects should not initiate long-term treatment with new medication 
from 28 days before the Day 1 Visit through completion of study participation. Guidelines 
for stable treatment regimens for CF are as follows:
o
Subjects who are taking inhaled tobramycin or other chronically inhaled antibiotics 
should remain on that regimen throughout the study.
o
Subjects who cycle onto and off of an inhaled antibiotic should continue on their prior 
schedule. The timing of the first dose of 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. 


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!
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 should have their spirometry assessments performed 
according to the guidelines provided in Section 11.4.1.
9.6
Administration
9.6.1
Dosing
Part A 
On Day 1 through Day 15, VX-445/TEZ/IVA will be orally administered with water. On Day 15, 
only the morning dose of VX-445/TEZ/IVA will be administered.
Study drug should be administered within approximately 30 minutes of the start of a 
fat-containing snack or meal, such as a standard “CF” meal or snack according to the following 
guidelines: 
1. Morning dose of study drug will be administered at the site on Days 1, 2, 8, and 15.
2. Study drug will be administered after all predose assessments have been performed.
3. All doses of study drug (morning and evening, as applicable) should be administered at 
approximately every 12 hours (± 1 hour) on each dosing occasion (e.g., if the morning doses 
of study drug are administered at 08:00 hour on Day 1, all subsequent morning doses should 
be administered between 07:00 hour and 09:00 hour).
4. Study drug tablets will be administered within 5 minutes of each other.
5. Study drug will be administered with approximately 240 mL (approximately 1 cup, 8 ounces, 
or half a pint) of water. 
6. At the Day 1 Visit, all subjects will be observed for 4 hours after the morning dose of the 
study drug.
7. The date, amount taken, and time of study drug administration including whether food was 
taken with each dose, will be recorded for 2 days before PK sample collection and on the 
days of PK sample collection.
Part B
Study drug tablets will be administered orally as shown in Table 9-3. A review of 
safety, tolerability, and available PK data will be completed by an internal Vertex team after 
Part A and the dose chosen for Part B will be confirmed by this review.


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Table 9-3
Study Drug Administration, Part B
Subject Weight 
at Day 1
Tablet Strength
Time
Number of Tablets Taken
<30 kg
50-mg VX-445/25-mg TEZ/37.5-mg IVA
AM
2 tablets
75-mg IVA
PM
1 tablet
≥30 kg
100-mg VX-445/50-mg TEZ/75-mg IVA
AM
2 tablets
150-mg IVA
PM
1 tablet
IVA: ivacaftor; TEZ: tezacaftor
Study drug should be administered with a fat-containing meal or snack, such as a standard “CF”
meal or snack or a standard meal according to the following guidelines:
1. It is recommended that the dose be taken within 30 minutes of the start of the meal or snack.
2. All doses of study drug (morning and evening, as applicable) should be administered at 
approximately every 12 hours (± 2 hours) on each dosing occasion (e.g., if the morning doses 
of study drug are administered at 08:00 hour on Day 1, all subsequent morning doses should 
be administered between 06:00 hour and 10:00 hour).
3. At the Day 1 Visit, all subjects will be observed for 4 hours after the morning dose of the 
study drug.
4. The date, amount taken, and time of study drug administration including whether food was 
taken with each dose, will be recorded for 2 days before PK sample collection and on the 
days of PK sample collection.
5. On days of scheduled visits (Day 1, Day 15, Weeks 4, 8, 12, and 16), the morning dose of 
study drug will be administered at the site after predose assessments have been completed. 
The meal or snack will be provided by the site for the morning dose of study drug. 
6. For visits after the Day 1 Visit, subjects will be instructed to bring all used and unused study 
drug to the site; study drug will be dispensed at each visit, as appropriate.
7. At the Week 24 Visit, the morning dose of study drug will NOT be administered. The last 
dose of study drug will be the evening dose administered the day before the Week 24 Visit.
9.6.2
Missed Doses
Parts A and B
If 6 hours or less have passed since the missed morning or evening dose, the patient 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 patient 
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 patient 
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.


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9.7
Dose Modification for Toxicity
Parts A and B
Modifications of the study drug dose are prohibited. Should any unacceptable toxicity arise, 
individual subjects will be withdrawn from the study and dosing will cease.
9.8
Study Drug Interruption and Stopping Rules
Part B
In subjects who have interrupted study drug for >72 hours for any reason, the investigator should 
resume study drug only after a thorough investigation of the cause for interruption. The 
investigator 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. In subjects for whom 
study drug was previously interrupted, the medical monitor should be notified of any plan to 
discontinue study drug, before the discontinuation has occurred, if possible.
9.8.1
Liver Function Tests
Parts A and B
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 criteria are met:


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!
Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, 
alcohol ingestion) is identified, regardless of whether transaminase levels have improved
All subjects in whom treatment is discontinued for elevated transaminases (and bilirubin, as 
applicable) should have these levels monitored closely until levels normalize or return to 
baseline.
If an alternative, reversible cause of transaminase elevation with or without increased bilirubin or 
clinical jaundice has been identified, study drug administration may be resumed once 
transaminases return to baseline or are ≤2 × ULN, whichever is higher. Regardless of the 
duration of interruption, the medical monitor should be notified prior to resumption of study 
drug. Upon resumption of study drug, transaminases and bilirubin should be assessed weekly for 
4 weeks. If a protocol-defined transaminase elevation interruption threshold recurs within 
4 weeks of rechallenge with the study drug (with confirmation of the initial elevation by repeat 
testing within 48 to 72 hours), then the study drug must be permanently discontinued, regardless 
of the presumed etiology.
9.8.2
Rash
Parts A and B
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 tests), photographs of the rash, and 
dermatology consultation. The investigator may consider resumption of study drug if considered 
clinically appropriate.
9.9
Removal of Subjects 
Parts A and B
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. If a subject 
has been withdrawn from study drug treatment, the subject will continue to be followed, 
provided that the subject has not withdrawn consent (and assent, as applicable).
In addition, a subject must be discontinued from study drug treatment if the subject meets any of 
the following criteria:
!
Has a screening CFTR genotype that does not confirm study eligibility if a previous CFTR
genotype laboratory report was used to establish eligibility. These subjects must be 
discontinued from the study (Section 8.1)
!
Meets any of the stopping (discontinuation) criteria (Section 9.8)
!
Becomes pregnant (Section 11.5.6.2) 
Subjects who discontinue study drug treatment should return for study assessments, as noted in 
Section 9.1.4.


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If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for an ETT Visit and Safety 
Follow-up Visit, if applicable (see Section 9.1.4), and follow up with the subject regarding any 
unresolved AEs.
If the 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 is 
over, and may use the samples and information in the development of the study compound, and 
for other drugs and diagnostics, in publications and presentations, and for education purposes. If 
the subject withdraws from the study, the study data and samples collected will remain part of 
the study. A subject will not be able to request the withdrawal of his/her information from the 
study data. A subject may request destruction of the samples collected from him/her during the 
study as long as those samples can be identified as his/her samples.
9.10
Replacement of Subjects
Part A Only
Subjects who withdraw or are withdrawn for nonsafety reasons during the Treatment Period may 
be replaced as needed in Part A, based on emerging PK data, to confirm the dose(s) for Part B.
10
STUDY DRUG INFORMATION AND MANAGEMENT
Parts A and B
Study drug refers to VX-445/TEZ/IVA.
10.1
Preparation and Dispensing
Parts A and B
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
Parts A and B
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
Parts A and B
Table 10-1 provides the study drug information. 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. Detailed instructions regarding the storage, handling, and dispensation of the study 
drug will be provided in the Pharmacy Manual.


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Table 10-1
Study Drug: Dosing Form/Route/Strength
Drug Name, Dosing Form, Route
Tablet Strength
Part A: 
All Subjects
Part B: 
Subjects <30 kg at 
Day 1
Part B: 
Subjects ≥30 kg at 
Day 1
VX-445/TEZ/IVA, FDC tablet, oral
VX-445
100 mg 
50 mg
100 mg 
TEZ
50 mg
25 mg
50 mg
IVA
75 mg
37.5 mg
75 mg
IVA, tablet, oral
75 mg
75 mg
150 mg 
FDC: fixed-dose combination; IVA: ivacaftor; TEZ: tezacaftor
10.4
Drug Accountability
Parts A and B
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/she 
is unable to resolve with the site. 
10.5
Disposal, Return, or Retention of Unused Drug
Parts A and B
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 
Parts A and B
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.


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10.7
Blinding and Unblinding
Parts A and B
This will be an open-label study; however, subjects and their legally appointed and authorized 
representative (e.g., parent or legal guardian) should not be informed of their study-related 
spirometry and LCI, sweat chloride, 
 results during the Treatment Period, 
regardless if the subject permanently discontinues treatment.
11
ASSESSMENTS
The timing of assessments is shown in Table 3-1 through Table 3-4. 
The following assessments must be performed in the order specified below when more than 
1 assessment is required at a particular time point:
Parts A and B
1. Vital signs
2. Pulse oximetry 
3. Standard 12-lead ECG recordings
4. Safety laboratory assessments 
5. PK sampling and spirometry may be performed in either order when occurring at the same 
time point. PK blood samples collected before dosing must be collected within 60 minutes 
before dosing as described in Section 11.2.1.
Part B Only
1. The CFQ-R should be completed before the start of any other assessments (except signing of 
ICF or assent) scheduled at that visit. 
2. The MBW assessment should be performed before spirometry.
11.1
Subject and Disease Characteristics
Parts A and B
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.
11.2
Pharmacokinetics
11.2.1
Blood Sampling
Parts A and B
Blood samples will be collected to determine plasma concentrations of VX-445, M23-445, TEZ, 
M1-TEZ, IVA, and M1-IVA. 
 


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All efforts should be made to obtain the PK samples at the exact nominal time relative to dosing. 
Acceptable windows for sampling times are shown in Table 11-1. Samples collected outside of 
these acceptable windows will be considered protocol deviations. 
Table 11-1
Acceptable Pharmacokinetic Sampling Windows
Sampling Time
Time From Scheduled Sampling Allowed
predose (before morning dose)
within 60 minutes before dosing
>0.25 and <6 hours after morning dose
% 10 minutes
≥6 hours after morning dose
% 30 minutes
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
Parts A and B
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
Parts A and B
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.
11.3.1
Modified Facial Hedonic Scale for Drug Acceptability Assessment
Part B
The acceptability of study drug will be assessed by the investigator and authorized designee. All 
subjects will be observed for their facial expressions and the reaction will be scored using a 
visual analog scale; any spontaneous comments in regards to likes or dislikes will also be noted. 
Interviews will be conducted on a one-on-one basis in the clinic setting. The Modified Facial 


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Hedonic Scale questionnaire for drug acceptability will be completed immediately after dosing 
with study drug. 
11.4
Efficacy and Pharmacodynamics
11.4.1
Spirometry
Parts A and B
Spirometry will be performed according to the American Thoracic 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.


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During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilator. At all other visits, all spirometry assessments should be performed 
pre-bronchodilator. During the Treatment Period, spirometry assessments must be performed 
before study drug dosing (Section 9.6.1) at approximately the same time at each visit. In the 
event that a subject forgets to withhold bronchodilator(s), spirometry should be performed 
according to the following:
!
If a subject’s Day 1 spirometry assessment is pre-bronchodilator, but, on a subsequent visit, 
the subject forgets to withhold bronchodilator use, a post-bronchodilator spirometry 
assessment will be obtained for that visit only, and the visit will not be rescheduled.
!
If, on Day 1, the subject forgets to withhold his/her dose of bronchodilator, spirometry 
should be performed post-bronchodilator, and all subsequent spirometric measurements 
(according to the schedule of assessments) 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 
assessment of the spirometry results will be used for the screening assessment and determination 
of eligibility.
See Section 10.7 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
!
FEV1 (L)
!
Forced vital capacity (FVC) (L)
!
FEV1/FVC (ratio)
!
Forced expiratory flow, midexpiratory phase (FEF25%-75%) (L/s)
11.4.2
Sweat Chloride
Parts A and B
The sweat chloride test is a standard diagnostic tool for CF, serving as a biomarker of CFTR 
activity. Sweat samples will be sent to a central laboratory for testing and interpretation of 
results. Individual sweat chloride test results will not be disclosed to the study sites. Specific 
instructions for collection, handling, processing, and shipping of sweat chloride samples to the 
central laboratory will be provided separately. The sweat chloride test must be conducted 
predose relative to the morning dose of study drug during the Treatment Period. At each time 
point, 2 samples will be collected, 1 sample from each arm (left and right).
11.4.3
Multiple-breath Washout
Part B
The N2-MBW testing will be performed in multiple replicates for each visit and the final LCI 
value will be calculated from the technically acceptable washout replicates by a central reader. 


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The final LCI value at each visit will be the value provided by the LCI vendor based on the 
replicates.
During the Screening Period, the MBW test may be performed pre- or post-bronchodilator. At all 
other visits, all MBW tests should be performed “pre-bronchodilator” as described in 
Section 11.4.1. The MBW test should be performed before the spirometry assessment 
(Section 11). Subjects and parents/caregivers should not be informed of study-related LCI 
results.
Detailed MBW procedures will be supplied separately in a Study Manual.
11.4.4
Height and Weight
Parts A and B
Height and weight will be measured with shoes off and before the dose of the study drug during 
the Treatment Period.
11.4.5
Cystic Fibrosis Questionnaire-Revised
Part B
The questionnaires provide information about demographics; general quality of life, school, 
work, or daily activities; and symptom difficulties (pertaining to CF).
Subjects/caregivers will be asked to complete the CFQ-R in their native language, if validated 
translations are available.18, 19 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.20, 21
The CFQ-R will be completed before any other assessments are performed at that visit. 
11.4.6
Other Events Related to Outcome 
11.4.6.1
Antibiotic Therapy for Sinopulmonary Sign/Symptoms
New or changed antibiotic therapy (intravenous [IV], inhaled, or oral) for the following 
sinopulmonary signs/symptoms will be determined and documented at visits as indicated in 
Table 3-4:
!
Change in sputum
!
New or increased hemoptysis
!
Increased cough
!
Increased dyspnea
!
Malaise, fatigue, or lethargy
!
Temperature above 38°C (equivalent to approximately 100.4°F)
!
Anorexia or weight loss
!
Sinus pain or tenderness
!
Change in sinus discharge


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!
Change in physical examination (PE) of the chest
!
Decrease in pulmonary function by 10%
!
Radiographic changes indicative of pulmonary infection
For this study, PEx is defined as a new or change in antibiotic therapy (IV, inhaled, or oral) 
for any 4 or more of the above signs/symptoms. This definition is based on the definition of a 
PEx used in previous clinical studies, including IVA clinical studies.22, 23
It is recommended that the study drug not be interrupted during a PEx unless, in the opinion of 
the investigator, it would be in the best interest of the subject.
11.4.6.2
Hospitalization for CF
Subjects will be queried about planned and unplanned hospitalizations lasting ≥24 hours that 
occurred during the study. The dates of hospitalizations and the reasons for hospitalizations will 
be documented.
For any hospitalization (planned and unplanned), the procedures for safety reporting should also 
be followed.
11.5
Safety
Parts A and B
Safety evaluations will include reporting of AEs, clinical laboratory assessments, PEs, clinical 
evaluation of vital signs, pulse oximetry, standard 12-lead ECGs, and ophthalmologic 
examinations.
Medical history and PE information will be collected during the course of the study and will be 
captured in the source documentation. Physical examinations post-baseline will not be captured 
for inclusion into the study database. However, any untoward findings identified on PEs 
conducted after the administration of the first dose of study drug will be captured as an AE if 
those findings meet the definition of an AE. Demographic data collected at the Screening Visit 
will be included in the study database.
11.5.1
Adverse Events
Parts A and B
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. Electronic AE case report form (CRF) completion 
guidelines for investigators as well as training will be provided.
11.5.2
Clinical Laboratory Assessments
Parts A and B
Blood and urine samples will be analyzed at a central laboratory with the exception of urine 
pregnancy tests, which will be analyzed locally. A local laboratory may be used for the Week 20 
(Part B) assessments if the subject cannot return to the site for a blood draw. All blood samples 
will be collected while subjects are in a seated or supine position. Specific instructions for the 
collection, processing, and shipment for centrally drawn samples will be provided in a separate 


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Laboratory Manual. Laboratory test results that are abnormal and considered clinically 
significant must be reported as AEs (see Section 13.1.1.2). 
Blood and urine samples for clinical laboratory assessments will be collected according to the 
schedule of assessments (Table 3-1 through Table 3-4).
Table 11-2
Safety Laboratory Test Panels
Serum Chemistry
Hematology
Urinalysisa
Glucose
Blood urea nitrogenb
Creatinine
Sodium
Potassium
Calcium
Chloride
Magnesium
Bicarbonate
Inorganic phosphate 
Total 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 
Note: Haptoglobin may be analyzed if judged to be clinically appropriate by the investigator.
a
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be performed, and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and 
casts.
b
If blood urea nitrogen cannot be collected, urea may be substituted.
Clinical laboratory assessments from screening will have no clinically significant findings that 
preclude participation in the study, as deemed by the investigator, for a subject to receive study 
drug on Day 1. 
In Part B, liver function testing (ALT, AST, GGT, ALP, and total bilirubin) must be performed 
at the scheduled visits and at Week 20 (a minimum of every 4 weeks after Week 4). A local 
laboratory may be used for the Week 20 sample if a subject cannot return to the site for the blood 
draw; confirmatory testing by the central lab must be performed as soon as possible if liver 
function tests are determined to be abnormal.


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Pregnancy (β-human chorionic gonadotropin) Tests for Female Subjects of Childbearing 
Potential (Part A) or all Female Subjects (Part B): In Part B, all female subjects must have a 
serum pregnancy test at screening. Serum pregnancy tests will be performed at the study site and 
analyzed at the central laboratory. A local laboratory may be used for the Week 20 sample if a 
subject cannot return to the site for the blood draw. The urine pregnancy test on Day 1 must be 
negative before the first dose of study drug is administered to the subject. Additional pregnancy 
tests may be required according to local regulations and/or requirements.
CF genotype (Screening Period only): CF genotyping will be performed on all subjects to 
confirm the genotype documented in the subject's medical record. This assessment does not need 
to be repeated in the case of rescreening or for confirmed subjects in Part A who wish to 
participate in Part B.
G6PD Activity Test (Part A Screening Period Only): A blood sample will be collected for a 
quantitative G6PD activity assay, which will be performed in an established laboratory that runs 
the assay routinely. The use of a local laboratory that routinely runs the assay is permissible 
following approval by the medical monitor.
Drug and Alcohol Screening (Screening Period [Part A Only] and Day 1 [Part A Only]): 
opiates, methadone, cannabinoids, cocaine, amphetamines/methamphetamines, barbiturates, 
benzodiazepines, cotinine, and alcohol will be assessed by a urine test. Subjects may undergo 
random urine drug screen and alcohol testing if deemed appropriate by the investigator. Drug 
screen result will be negative for all subjects to receive study drug. Drug and alcohol testing may 
be performed at the discretion of the investigator in Part B. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged by the investigator to be clinically appropriate. 
For the purposes of study conduct and unless noted otherwise (e.g., G6PD activity test), 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.
11.5.3
Physical Examinations and Vital Signs
Parts A and B
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits. At other visits, symptom-directed PEs and symptom-directed vital signs assessments 
can be performed at the discretion of the investigator or healthcare provider.
A PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, nose, and 
throat; respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs.
Symptom-directed PEs and symptom-directed vital signs assessment may be performed if 
appropriate.


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Weight, height, and BMI (derived) will also be assessed (Section 11.4.4).
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. These will be assessed following at least a 5-minute rest in the seated or supine 
position.
Arterial oxygen saturation by pulse oximetry will be assessed following at least a 5-minute rest 
and before study drug dosing. At visits when study drug is taken at the site, pulse oximetry will 
be collected before study drug dosing.
11.5.4
Electrocardiograms
Parts A and B
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines:
!
The ECG will be done before any other procedures that may affect heart rate, such as blood 
draws.
!
The subject will be instructed to rest for at least 5 minutes before having an ECG.
!
ECGs will be performed in triplicate at the Day 1 Visit (Part A only).
A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. Clinically significant ECG abnormalities occurring during the study 
through completion of study participation will be recorded as AEs.
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. 
11.5.5
Ophthalmologic Examination
Parts A and B
Ophthalmologic examinations 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.
Any clinically significant abnormal findings will be reported as AEs.


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Part B
In addition to the screening ophthalmologic examination, all subjects who have completed at 
least 12 weeks of study drug treatment will have a single follow-up ophthalmologic examination. 
This examination should be completed at or up to 4 weeks before the Week 24 Visit, unless the 
subject prematurely discontinues study drug, in which case this examination should occur by the 
Safety Follow-up Visit (or ETT Visit for subjects who do not complete a Safety Follow-up 
Visit), as described in Table 3-4.
11.5.6
Contraception and Pregnancy
Parts A and B
The effects of VX-445 monotherapy or in TC with 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.
11.5.6.1
Contraception
Parts A and B
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 Screening Visit through 90 days after the last dose of study drug.
!
If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the first 
dose of study drug (e.g., examination of a semen specimen or by demonstration of the 
absence of the vas deferens by ultrasound).
!
If the female is of non-childbearing potential. To be considered of non-childbearing potential, 
the female must meet at least 1 of the following criteria:
o
Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum 
follicle-stimulating hormone (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, 
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 


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to be followed according to local regulations and/or requirements. Acceptable methods of 
contraception are listed in Table 11-3.
Table 11-3
Acceptable Methods of Contraception
Male Subjects and Their 
Female (Non-study) 
Partners
Female Subjects and 
Their Male (Non-study) 
Partners
Vasectomy 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 11-3. 
!
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 11-3.
!
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.
11.5.6.2
Pregnancy
Parts A and B
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 Global 
Patient Safety (GPS) within 24 hours of the site’s knowledge of the subject’s (or partner’s) 


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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 (and assent, as applicable) 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
Parts A and B
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the statistical analysis plan (SAP), and clinical pharmacologic analysis 
details will be provided in the clinical pharmacology analysis plan (CPAP), both of which will be 
finalized before the clinical data lock for the study.
12.1
Sample Size and Power
Part A
Approximately 12 subjects will be enrolled in Part A. Sample size calculations were determined 
based on VX-445 PK, using noncompartmental analysis (NCA)-based parameters, such as 
clearance and volume of distribution. Based on the variability observed in adults, data from 12 
subjects will allow 80% power to target a 95% CI within 60% and 140% of the geometric mean 
estimate of clearance for VX-445. 
Part B 
The planned enrollment is approximately 56 subjects. Approximately 45 subjects are expected to 
complete Part B. Incidence of AEs is a safety endpoint. Table 12-1 presents estimates of the 
probability for observing at least 1 subject with an AE for the given incidence (θ) and sample 
size. The study will have at least 90% chance of observing an AE in at least 1 subject if the true 
incidence rate is 5%; and a >95% chance of observing an AE in at least 1 subject if the true 
incidence rate is 10%. The probabilities have been calculated by assuming a binomial 
distribution for the number of AEs using SAS®. 
Table 12-1
Probability of Observing At Least 1 Subject With an AE in the Study if the 
AE Incidence (∀) is 5% and 10%
Sample Size
∀= 5%
∀= 10%
45
90.0%
99.1%
50
92.3%
99.5%
AE: adverse event
12.2
Analysis Sets
Parts A and B
Assignment of subjects to analysis sets will be done before the clinical data lock for the study. 
The analysis set will be defined separately for Part A and Part B.


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Safety Set 
The Safety Set will include all subjects who received at least 1 dose of study drug. The Safety 
Set will be used for all safety analyses.
Full Analysis Set (FAS)
The FAS will include all subjects who are enrolled and carry the intended CFTR allele mutation 
and received at least 1 dose of study drug. The FAS will be used to summarize subject 
demographics and baseline characteristics, and for analyses of all efficacy and PD endpoints, 
unless otherwise specified.
All Subjects Set 
The All Subjects Set will include all subjects who are enrolled 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. 
12.3
Statistical Analysis
12.3.1
General Considerations
Parts A and B
Data from Part A and Part B will be analyzed separately.
Continuous variables will be summarized using the following descriptive summary statistics: 
number of subjects (n), mean, SD, median, minimum value (min), and maximum value (max). 
The precision of the measurement for each continuous variable will be specified in the SAP.
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place.
Treatment-emergent (TE) period for Parts A and B will include the time from the first dose of 
study drug in the respective Part through 28 days after the last dose, or the completion of study 
participation date, whichever is earlier.
Baseline for Part A, unless otherwise specified, is defined as the most recent nonmissing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in Part A. 
For ECGs, baseline will be defined as the most recent pretreatment measurement (or the average 
of replicate measurements, if the most recent pretreatment measurement is obtained in replicates) 
before the first dose of study drug. For sweat chloride, the baseline value will be the mean of 
assessment values on the left and the right arm at the most recent time point prior to the first dose 
of study drug. The measurement end time can be up to 30 minutes after dosing to be considered 
in the calculation for baseline sweat chloride. Baseline for Part B will be similarly defined.
Absolute change from baseline will be calculated as post-baseline value – baseline value.
Relative change from baseline will be calculated as (post-baseline value – baseline 
value)/baseline value.


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12.3.2
Background Characteristics
Parts A and B
Subject disposition, demographic and baseline characteristics, prior and concomitant 
medications, study drug exposure, and other background characteristics will be summarized for 
Part A and Part B, respectively. 
12.3.2.1
Subject Disposition
Parts A and B
The number of subjects in All Subjects Set and Safety Set will be summarized for Part A; and in 
All Subjects Set, FAS, and Safety Set will be summarized for Part B. In addition, the number and 
percentage of subjects in each disposition category (e.g., completed treatment, completed study; 
with a breakdown of the reason for study discontinuation or treatment discontinuation) will be 
summarized.
12.3.2.2
Demographics and Baseline Characteristics
Parts A and B
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized separately for Part A and Part B. 
The following demographics and baseline characteristics will be summarized: sex, race, 
ethnicity, age, weight, height, BMI, region, ppFEV1, and sweat chloride. 
12.3.2.3
Prior and Concomitant Medications
Parts A and B
Medications will be coded using the World Health Organization Drug-Dictionary and 
categorized as follows for Parts A and B separately:
!
Prior medication: any medication that is administered during the 56 days before the first 
dose of study drug in the corresponding Part
!
Concomitant medication: medication continued or newly received during the corresponding 
TE Period
!
Post-treatment medication: medication continued or newly received after the 
corresponding TE Period 
A given medication can 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 partial missing start/end date 
or time and it cannot be determined whether the medication was taken before first dose, 
concomitantly, or post-treatment, it will be considered as prior, concomitant, and post-treatment.
The concomitant medications will be summarized descriptively based on the FAS. 
12.3.2.4
Study Drug Exposure and Compliance
Parts A and B
Study drug compliance will be measured by the exposure ratio, which is calculated as: 
100 × [1 - (Total number of days study drug interruption) / (Duration of study drug exposure in 


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days)]. The total number of days of study drug interrupted is defined as the sum of (number of 
days of study drug interrupted in each interruption interval); where number of days of study drug 
interrupted in each interval is defined as the interruption end date - the corresponding 
interruption start date + 1.
Study drug exposure will be summarized based on the Safety Set in terms of the duration of 
treatment a subject received (in days), defined as the last day – the first day of study drug plus 1, 
regardless of study drug interruption.
In addition, percentage of tablets taken will also be summarized based on the FAS, and will be 
calculated as 100 × [(total number of tablets dispensed) – (total number of tablets returned)] / 
(total number of tablets planned to be taken per day × duration of study drug exposure in days).
Duration of treatment and exposure ratio will be summarized using descriptive statistics.
12.3.3
Final Efficacy Analysis
The secondary objective for Part B is to evaluate the efficacy of VX-445/TEZ/IVA. 
Further details of efficacy analysis will be presented in the SAP.
12.3.3.1
Analysis of Primary Efficacy Endpoints
Not applicable as efficacy is not a primary endpoint. 
12.3.3.2
Analysis of Secondary Efficacy and Pharmacodynamic Endpoints
Part B
A summary of observed values and change from baseline will be provided for all secondary 
efficacy endpoints based on the FAS in Part B. 
!
Absolute change in ppFEV1 from baseline through Week 24 
Absolute change from baseline in ppFEV1 will be analyzed using a mixed-effects model for 
repeated measures (MMRM) approach based on the FAS population. The MMRM will be 
used to estimate the within-group mean absolute change in ppFEV1 through Week 24. The 
model will include absolute change from baseline in ppFEV1 as the dependent variable, visit 
(as a class variable) as the fixed effect, with baseline ppFEV1 value and genotype group (F/F 
versus F/MF) as covariates. Data obtained from Day 15, Week 4, Week 8, Week 12, 
Week 16, and Week 24 Visits will be included in the model. An unstructured covariance 
structure will be used to model the within-subject errors.
The primary results obtained from the model will be the average treatment effect through 
Week 24. Note that the Day 15 Visit will not be included in the estimation of the average 
treatment effect through Week 24. The estimated mean change from baseline in ppFEV1
through Week 24, along with the corresponding 95% CI and 2-sided P value will be 
provided. The treatment effect at each post-baseline visit, obtained from the model, will be 
provided as well.
Summary statistics for change from baseline in ppFEV1 through Week 24 and at each visit 
will also be provided.


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!
Absolute change in SwCl from baseline through Week 24
Analysis of this endpoint will be based on an MMRM model that is similar to the analysis of 
absolute change from baseline in ppFEV1 through Week 24 with the baseline sweat chloride 
value included as a covariate instead of baseline ppFEV1. Data obtained from Day 15, 
Week 4, Week 12, and Week 24 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 24.
!
Absolute change in CFQ-R respiratory domain score from baseline through Week 24
Analysis of this endpoint will be based on an MMRM model that is similar to the analysis of 
absolute change from baseline in ppFEV1 through Week 24 with the baseline CFQ-R 
respiratory domain score included as a covariate instead of baseline ppFEV1. Data obtained 
from Week 4, Week 8, Week 12, Week 16, and Week 24 Visits will be included in the 
model. 
!
Absolute change in BMI and BMI-for-age z-score from baseline at Week 24 
!
Absolute change in weight and weight-for-age z-score from baseline at Week 24
!
Absolute change in height and height-for-age z-score from baseline at Week 24
Analysis of these endpoints will be based on an MMRM similar to the analysis of absolute 
change in ppFEV1 from baseline through Week 24 with the corresponding baseline value 
included as a covariate instead of baseline ppFEV1. Data obtained from Day 15, Week 4, 
Week 8, Week 12, Week 16, and Week 24 Visits will be included in the model.
!
Drug acceptability assessment using Modified Facial Hedonic Scale
Modified Facial Hedonic Scale for drug acceptability assessment will be summarized.
!
Number of PEx and CF-related hospitalizations through Week 24
Number of PEx and CF-related hospitalizations will be summarized.
!
Absolute change in LCI2.5 from baseline through Week 24
Analysis of this endpoint will be based on an MMRM model that is similar to the analysis of 
absolute change from baseline in ppFEV1 through Week 24 with the baseline LCI2.5 value 
included as a covariate instead of baseline ppFEV1. Data obtained from Day 15, Week 4, 
Week 12, and Week 24 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 24.
12.3.4
Safety Analysis
Parts A and B
Safety is a secondary objective of Part A, and the primary objective of Part B. All safety analyses 
will be conducted for Part A and Part B separately, based on data from the corresponding TE 
Period in the Safety Set. The overall safety profile of study drug will be assessed based on the 
following safety and tolerability endpoints:
!
Treatment-emergent adverse events (TEAEs)
!
Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis as 
applicable)


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!
Standard 12-lead ECGs
!
Vital signs
!
Pulse oximetry
!
Ophthalmological examinations
12.3.4.1
Adverse Events
Parts A and B
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows: 
!
Pretreatment AE: any AE that occurred before the first dose of study drug
!
TEAE: any AE that is worsened (either in severity or seriousness) or that was newly 
developed at or after the first dose of study drug through the end of the TE Period
!
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed after the TE Period
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study drug treatment, then the AEs will be classified as TEAEs.
AE summary tables will be presented for TEAEs only, 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
!
Serious TEAEs
!
TEAEs leading to death
!
Grade 3 and Grade 4 TEAEs
Summaries will be presented by MedDRA System Organ Class and Preferred Term using 
frequency counts and percentages (i.e., number and percentage of subjects with an event). When 
summarizing the number and percentage of subjects with an event, subjects with multiple 
occurrences of the same AE or a continuing AE will be counted once, only the maximum 
severity level will be presented in the severity summaries, and the strongest relationship level in 
the relationship summaries. An AE overview table will be provided. 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.


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12.3.4.2
Clinical Laboratory Assessments
Parts A and B
For the treatment-emergent 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 at each scheduled visit.
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized. 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 
outside the reference ranges will be provided. This listing will include data from scheduled and 
unscheduled visits.
12.3.4.3
Electrocardiogram
Parts A and B
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided, at each scheduled visit and time point, as applicable, for the 
following ECG interval measurements (in msec): RR, PR, QT, and QT corrected for HR (QTcF), 
QRS duration, and heart rate (HR) (beats per minute).
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized. The threshold analysis criteria will be provided in the SAP.
12.3.4.4
Vital Signs
Parts A and B
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each scheduled visit. The following vital signs parameters 
will be summarized: systolic and diastolic blood pressure (mm Hg), body temperature (&C), pulse 
rate (heart rate, beats per minute), and respiratory rate (breaths per minute).
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized. The threshold analysis criteria will be provided in the SAP.
12.3.4.5
Pulse Oximetry
Parts A and B
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each scheduled visit for the percent of oxygen 
saturation by 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.


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12.3.4.6
Ophthalmologic Examinations
Parts A and B
The ophthalmologic examination results will be presented in individual subject data listings.
12.3.4.7
Physical Examination
Parts A and B
Physical examination findings will be presented in an individual subject data listing only.
12.3.5
Interim and IDMC Analyses
12.3.5.1
Interim Analysis
Part B
An optional IA may be conducted. In the event that an IA is performed, details of the IA will be 
provided in the SAP.
12.3.5.2
IDMC Analysis
Part B
The IDMC will conduct regular planned safety reviews of study data. Details of the safety 
reviews will be described in the IDMC Charter
12.4
Clinical Pharmacology Analysis
12.4.1
Pharmacokinetic Analysis
Parts A and B
The PK analysis of VX-445, M23-445, TEZ, MI-TEZ, IVA, and M1-IVA may be performed 
using nonlinear mixed effects modeling and/or standard noncompartmental analysis, as data 
allow. Metabolites may be included in the analyses as supported by data. Descriptive statistics 
will be used to summarize PK parameter values for all analytes.
A detailed description of the planned PK analysis will be presented in the CPAP.
12.4.2
Pharmacokinetic/Pharmacodynamic Analyses
Parts A and B
PK/PD analyses may be performed on selected PD assessments, which include sweat chloride, 
ppFEV1, as well as other endpoints such as BMI, BMI z-score, or CFQ-R respiratory domain 
score.
A sequential approach will be used to perform the population PK/PD analysis. The Bayesian 
estimates of individual PK parameters from the final population PK model will be used to 
simulate PK profiles for each subject. The simulated VX-445, TEZ, IVA, or metabolite plasma 
concentrations will be used in the potential pharmacological response models to describe 
changes in each endpoint from baseline. Fixed- and random-effect parameter estimates and the 
associated asymptotic SEs will be estimated. Descriptive statistics will be used to summarize 
Bayesian estimates of individual PK/PD parameters obtained from the population PK/PD model.


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13
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS
All subsections below apply to Parts A and B.
13.1
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting
13.1.1
Adverse Events
13.1.1.1
Definition of an Adverse Event
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed. 
An AE is considered serious if it meets the definition in Section 13.1.2.1. 
13.1.1.2
Clinically Significant Assessments
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically-significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin).
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following:
!
Concomitant signs or symptoms related to the abnormal study assessment
!
Further diagnostic testing or medical/surgical intervention
!
A change in the dose of study drug or discontinuation from the study
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator.
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE.
13.1.1.3
Documentation of Adverse Events
All AEs will be collected from the time the ICF is signed until the subject completes study 
participation, as defined in Section 9.1.6.
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the study 
will be recorded only in the subject’s source documents. The following data will be documented 
for each AE:


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!
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 February 
2019). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” In considering 
the severity of an AE in a pediatric subject, the investigator will consider that reference ranges 
for pediatric clinical laboratory parameters may differ from those given in the CTCAE. The 
severity of an AE that does not appear in the CTCAE will be determined according to the 
definitions in Table 13-1. 
Table 13-1
Grading of AE Severity
Classification
Definition
Mild (Grade 1)
Mild level of discomfort and does not interfere with regular activities
Moderate (Grade 2)
Moderate level of discomfort and significantly interferes with regular activities
Severe (Grade 3)
Significant level of discomfort and prevents regular activities
Life-threatening 
(Grade 4)
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death 
13.1.1.5
Adverse Event Causality
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories presented in Table 13-2.


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Table 13-2
Classifications for AE Causality
Classification
Definition
Related
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug.
Possibly related
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease.
Unlikely related
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug. 
Not related
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject’s medical record).
13.1.1.6
Study Drug Action Taken
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories shown in Table 13-3.
Table 13-3
Classifications for Study Drug Action Taken With Regard to an AE
Classification
Definition
Dose not changed
Study drug dose not changed in response to an AE
Dose reduced
Study drug dose reduced in response to an AE
Drug interrupted
Study drug administration interrupted in response to an AE 
Drug withdrawn
Study drug administration permanently discontinued in response to an AE
Not applicable
Action taken regarding study drug administration does not apply. 
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible.
13.1.1.7
Adverse Event Outcome
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4.


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


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Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.
13.1.2.2
Documentation of Serious Adverse Events
All SAEs that occur after obtaining informed consent through completion of study participation, 
regardless of causality, will be reported by the investigator to Vertex GPS. In addition, all SAEs 
that occur after completion of study participation and are considered related to study drug(s) will 
be reported to Vertex GPS within 24 hours.
SAEs will be recorded on the Vertex Organized Safety Information Collection Form (hereafter 
referred to as the “SAE Form”) using a recognized medical term or diagnosis that accurately 
reflects the event. SAEs will be assessed by the investigator for relationship to the investigational 
study drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be 
assessed only as related (includes possibly related) or not related (includes unlikely related), and 
severity assessment will not be required. For the purposes of study analysis, if the event has not 
resolved at the end of the study reporting period, it will be documented as ongoing. For purposes 
of regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report to Vertex the outcome of the event using the SAE Form.
13.1.2.3
Reporting Serious Adverse Events
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. The SAE Form will be 
completed for new/initial events as well as to report follow-up information on previously 
reported events. Investigators are asked to report follow-up information as soon as it becomes 
available to ensure timely reporting to health authorities. 
Please send completed SAE Forms to Vertex GPS via:
Email: 
(preferred choice)
Fax: 
 
For questions, contact telephone: 
13.1.2.4
Expedited Reporting and Investigator Safety Letters
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IECs, and 
participating investigators in accordance with ICH Guidelines and/or local regulatory 
requirements, as applicable. In addition, Vertex, or authorized designee, will be responsible for 
the submission of safety letters to central IECs. 
It is the responsibility of the investigator or designee to promptly notify the local IRB/local IEC 
of all unexpected serious adverse drug reactions involving risk to human subjects.


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13.2
Administrative Requirements
13.2.1
Ethical Considerations
The study will be conducted in accordance with the current ICH GCP guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will only 
be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations.
13.2.2
Subject Information and Informed Consent and Assent
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. 
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 


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Vertex Pharmaceuticals Incorporated
numbers shall be limited to the site and the study physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE Forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection.
For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act (HIPAA) and associated regulations, an executed HIPAA 
authorization shall be obtained by the site from each subject (or the legal representative of the 
subject) before research activities may begin. Each HIPAA authorization shall comply with all 
HIPAA requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long.
13.2.6
Record Retention
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified.
13.2.7
Study Termination
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center.
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to:
!
Subject or investigator noncompliance
!
Unsatisfactory subject enrollment
!
Lack of adherence to protocol procedures
!
Lack of evaluable and/or complete data
!
Potentially unacceptable risk to study subjects
!
Decision to modify drug development plan
!
Decision by the FDA or other regulatory authority
Written notification that includes the reason for the clinical study termination is required.
13.2.8
End of Study
The end of study is defined as the last scheduled visit or, for subjects who have been lost to 
follow-up, the last contact, whichever occurs later, for the latest completing subject in the study.


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Vertex Pharmaceuticals Incorporated
13.3
Data Quality Assurance
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation.
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
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.
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected. 
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible. 
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc or other electronic media will be placed in the investigator’s 
study file.


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


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14
REFERENCES
1
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 22 March 2018.
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 19 September 2016.
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 07 December 2018.
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 
09 January 2018.
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
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51(11):875-78.
14
Horsley A. Lung clearance index in the assessment of airways disease. Respir Med. 
2009;103(6):793-99.
15
Sinhal S, Galati J, Baldwin DN, Stocks J, Pillow JJ. Reproducibility of multiple breath 
washout indices in the unsedated preterm neonate. Pediatr Pulmonol. 2010;45(1):62-70.
16
Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection 
of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. 
Thorax. 2007;62(4):341-47.
17
Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout 
and spirometry versus structural lung disease in cystic fibrosis. Thorax. 2008;63(2):129-
34.


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18
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86.
19
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.
20
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.
21
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.
22
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR 
potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 
2011;365(18):1663-72.
23
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 
1994;331(10):637-42.


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APPENDIX A 
Eligible MF CFTR Mutations
“MF” mutations are a subset of minimal function mutations that are non-responsive to IVA and 
TEZ/IVA. A mutation is considered an MF mutation if it meets at least 1 of the following 
2 criteria:
(1) No biological plausibility of translated protein (genetic sequence predicts the complete 
absence of CFTR protein), or
(2) in vitro testing that supports lack of responsiveness to IVA and TEZ/IVA.
Inclusion of MF Mutations Based on In Vitro Testing
Mutations that were considered to be MF mutations based on in vitro testing met the following 
criteria in in vitro experiments:
!
baseline chloride transport that was <10% of wildtype CFTR
!
an increase in chloride transport of <10% over baseline following the addition of IVA 
and TEZ/IVA in the assay
Eligible MF Mutations
The list below represents acceptable mutations, which are detectable by an FDA-cleared 
genotyping assay or other method (e.g., sequencing); however, this list may not include every 
eligible mutation, and investigators should contact the medical monitor regarding other 
mutations that may also meet study eligibility criteria.


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Non-exhaustive List of Minimal Function CFTR Mutations Eligible for VX18-445-106
Q2X
L218X
Q525X
R792X
E1104X
S4X
Q220X
G542X
E822X
W1145X
W19X
Y275X
G550X
W882X
R1158X
G27X
C276X
Q552X
W846X
R1162X
Q39X
Q290X
R553X
Y849X
S1196X
W57X
G330X
E585X
R851X
W1204X
E60X
W401X
G673X
Q890X
L1254X
R75X
Q414X
Q685X
S912X
S1255X
L88X
S434X
R709X
Y913X
W1282X
E92X
S466X
K710X
Q1042X
Q1313X
Q98X
S489X
Q715X
W1089X
Q1330X
Y122X
Q493X
L732X
Y1092X
E1371X
E193X
W496X
R764X
W1098X
Q1382X
W216X
C524X
R785X
R1102X
Q1411X
185+1G>T
711+5G>A
1717-8G>A
2622+1G>A
3121-1G>A
296+1G>A
712-1G>T
1717-1G>A
2790-1G>C
3500-2A>G
296+1G>T
1248+1G>A
1811+1G>C
3040G>C (G970R)
3600+2insT
405+1G>A
1249-1G>A
1811+1.6kbA>G
3850-1G>A
405+3A>C
1341+1G>A
1811+1643G>T
3120G>A
4005+1G>A
406-1G>A
1525-2A>G
1812-1G>A
3120+1G>A
4374+1G>T
621+1G>T
1525-1G>A
1898+1G>A
3121-2A>G
711+1G>T
1898+1G>C
182delT
1119delA
1782delA
2732insA
3791delC
306insA
1138insG
1824delA
2869insG
3821delT
365-366insT
1154insTC
1833delT
2896insAG
3876delA
394delTT
1161delC
2043delG
2942insT
3878delG
442delA
1213delT
2143delT
2957delT
3905insT
444delA
1259insA
2183AA>G a
3007delG
4016insT
457TAT>G
1288insTA
2184delA
3028delA
4021dupT
541delC
1343delG
2184insA
3171delC
4022insT
574delA
1471delA
2307insA
3171insC
4040delA
663delT
1497delGG
2347delG
3271delGG
4279insA
849delG
1548delG
2585delT
3349insT
4326delTC
935delA
1609del CA
2594delGT
3659delC
1078delT
1677delTA
2711delT
3737delA


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Vertex Pharmaceuticals Incorporated
Non-exhaustive List of Minimal Function CFTR Mutations Eligible for VX18-445-106
CFTRdele1
CFTRdele16-17b
991del5
CFTRdele2
CFTRdele17a,17b
1461ins4
CFTRdele2,3
CFTRdele17a-18
1924del7
CFTRdele2-4
CFTRdele19
2055del9>A
CFTRdele3-10,14b-16
CFTRdele19-21
2105-2117del13insAGAAA
CFTRdele4-7
CFTRdele21
2372del8
CFTRdele4-11
CFTRdele22-24
2721del11
CFTR50kbdel
CFTRdele22,23
2991del32
CFTRdup6b-10
124del23bp
3121-977_3499+248del2515
CFTRdele11
306delTAGA
3667ins4
CFTRdele13,14a
602del14
4010del4
CFTRdele14b-17b
852del22
4209TGTT>AA
A46D
V520F
Y569D
N1303K
G85E
A559T
L1065P
R347P
R560T
R1066C
L467P
R560S
L1077P
I507del
A561E
M1101K
CFTR: cystic fibrosis transmembrane conductance regulator; IVA: ivacaftor; SwCl: sweat chloride; TEZ: tezacaftor
Source: CFTR2.org [Internet]. Baltimore (MD): Clinical and functional translation of CFTR. The Clinical and 
Functional Translation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins University, the Hospital 
for Sick Children. Available at: http://www.cftr2.org/. Accessed 15 February 2016.
Notes: %PI: percentage of F508del-CFTR heterozygous patients in the CFTR2 patient registry who are pancreatic 
insufficient; SwCl: mean sweat chloride of F508del-CFTR heterozygous patients in the CFTR2 patient registry.
a
Also known as 2183delAA>G. 




Protocol VX18-445-106, Version 3.0
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Vertex Pharmaceuticals Incorporated
15.2
Investigator Signature Page
Protocol #: 
VX18-445-106
Version #:
3.0
Version Date:
18 December 2019
Study Title: A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of 
VX-445/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 Through 
11 Years of Age
I have read Protocol VX18-445-106, Version 3.0, 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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SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 46 
Protocol Number: VX18-445-106 
 
 
Vertex Pharmaceuticals Incorporated 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan  
(Methods) 
 
 
Protocol Number VX18-445-106, Version 3.0 
 
 
A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of 
VX-445/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 
Through 11 Years of Age 
 
 
Author of SAP: 
 
 
 
Version: 3.0 
Version Date of SAP: 11 August 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)  
Page 2 of 46 
Protocol Number: VX18-445-106 
Vertex Pharmaceuticals Incorporated 
 
1 
TABLE OF CONTENTS 
1 
Table of Contents ........................................................................................................................... 2 
2 
List of Abbreviations ..................................................................................................................... 4 
4 
Introduction.................................................................................................................................... 8 
5 
Study Objectives ............................................................................................................................ 8 
5.1 
Primary Objectives ................................................................................................................... 8 
5.2 
Secondary Objectives ............................................................................................................... 9 
6 
Study Endpoints ............................................................................................................................. 9 
6.1 
Primary Endpoint ...................................................................................................................... 9 
6.2 
Secondary Endpoints ................................................................................................................ 9 
 
 
7 
Study Design ................................................................................................................................. 10 
7.1 
Overall Design ........................................................................................................................ 10 
7.2 
Sample Size and Power .......................................................................................................... 11 
7.3 
Randomization ........................................................................................................................ 12 
7.4 
Blinding and Unblinding ........................................................................................................ 12 
8 
Analysis Sets ................................................................................................................................. 12 
8.1 
All Subjects Set ...................................................................................................................... 12 
8.2 
Safety Set ................................................................................................................................ 12 
8.3 
Full Analysis Set ..................................................................................................................... 13 
9 
Statistical Analysis ....................................................................................................................... 13 
9.1 
General Considerations .......................................................................................................... 13 
9.2 
Background Characteristics .................................................................................................... 14 
9.2.1 
Subject Disposition ......................................................................................................... 14 
9.2.2 
Demographics and Baseline Characteristics ................................................................... 14 
9.2.3 
Medical History .............................................................................................................. 16 
9.2.4 
Prior and Concomitant Medications ............................................................................... 16 
9.2.5 
Study Drug Exposure...................................................................................................... 16 
9.2.6 
Study Drug Compliance ................................................................................................. 17 
9.2.7 
Important Protocol Deviations ........................................................................................ 17 
9.3 
Efficacy Analysis .................................................................................................................... 18 
9.3.1 
Efficacy Summary for Part A ......................................................................................... 18 
9.3.1.1 
Spirometry ................................................................................................................ 18 
9.3.1.2 
Sweat Chloride ......................................................................................................... 18 
9.3.1.3 
Weight, Height, BMI and their Z-scores .................................................................. 18 
9.3.2 
Efficacy Analysis for Part B ........................................................................................... 18 
9.3.2.1 
Analysis of Primary Efficacy Variables ................................................................... 18 
9.3.2.2 
Analysis of Secondary Efficacy Variables ............................................................... 18 
 
 
 
 


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9.4 
Safety Analysis ....................................................................................................................... 24 
9.4.1 
Adverse Events ............................................................................................................... 24 
9.4.2 
Clinical Laboratory ......................................................................................................... 26 
9.4.3 
Electrocardiogram .......................................................................................................... 26 
9.4.4 
Vital Signs ...................................................................................................................... 27 
9.4.5 
Pulse Oximetry ............................................................................................................... 27 
9.4.6 
Ophthalmologic Examinations ....................................................................................... 27 
9.4.7 
Physical Examination ..................................................................................................... 27 
9.4.8 
COVID-19 Impacted Visits ............................................................................................ 28 
10 Interim and DMC Analyses ........................................................................................................ 29 
10.1 Interim Analysis ..................................................................................................................... 29 
10.2 IDMC Analysis ....................................................................................................................... 29 
11 References ..................................................................................................................................... 30 
12 List of Appendices........................................................................................................................ 31 
 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments ........................ 31 
 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ............... 35 
 
Appendix C: Details of GLI Equations for Calculating ppFEV1 ........................................... 36 
 
Appendix D: Imputation Rules for Missing AE Dates ........................................................... 37 
 
Appendix E: Criteria for Threshold Analysis ......................................................................... 38 


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2 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
bpm 
beats per minute 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire – Revised 
CFTR 
cystic fibrosis transmembrane conductance regulator protein or the gene 
encoding the protein. 
CI 
confidence interval 
CRF 
case report form 
CRO 
contract research organization 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ELX 
elexacaftor 
FAS 
full analysis set 
FDC 
fixed-dose combination 
FEF25-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
 
 
FVC 
forced vital capacity  
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
F/F 
homozygous for F508del 
F/MF 
heterozygous for F508del and a CFTR minimal function mutation 
IVA 
ivacaftor 
LS means 
Least squares means 
LFT 
liver function test 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
minimal function 
MFHS 
modified facial hedonic scale 
min 
minimum value 
MMRM 
mixed model repeated measure 
N 
number of subjects 
PD 
pharmacodynamic/pharmacodynamics  
PK 
pharmacokinetic/pharmacokinetics 
ppFEV1 
percent predicted FEV1 
PT 
preferred term 
q12h 
every 12 hours 
QRS 
Q, R, and S-wave define the QRS-complex in an ECG 


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Abbreviation 
Term 
QT 
QT interval: The duration of ventricular depolarization and subsequent 
repolarization; it is measured from the beginning of the QRS complex to the end 
of the T wave 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate with Fridericia’s correction  
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TC 
triple combination 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
ULN 
upper limit of normal 
WHODD 
World Health Organization Drug Dictionary Enhanced 
 
 






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4 
INTRODUCTION 
Study VX18-445-106 (Study 445-106) is a Phase 3, 2-part (Parts A and B), multicenter study 
evaluating the pharmacokinetics (PK), safety, and tolerability of elexacaftor (ELX, VX-445) in triple 
combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects 6 through 11 years of age 
(inclusive) with cystic fibrosis (CF) who are either homozygous for F508del mutation (F/F) or 
heterozygous for F508del and a minimal function mutation (F/MF). 
This statistical analysis plan (SAP) for Study 445-106 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 statistical analyses of safety and efficacy endpoints for 
the study. It also documents analyses for additional safety and efficacy variables not specified in the 
protocol. Selected analyses related to sweat chloride will be documented in this SAP. PK and PD (if 
applicable) analyses will be documented separately in the clinical pharmacology analysis plan 
(CPAP) for the 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. This SAP summarizes the additional 
statistical analyses that are related to these alternative measures including but not limited to 
spirometry assessments using the Air Next device and obtained in the home, home assessed Cystic 
Fibrosis Questionnaire – Revised (CFQ-R), home assessed Modified Facial Hedonic Scale (MFHS), 
and additional data collected during the unscheduled visits that occurred to perform assessments that 
had been missed at the time of the Week 24 visit. 
The Vertex Biometrics Department or designee will perform the statistical analysis of the safety and 
efficacy data; SAS (Version 9.4 or higher) will be used to generate all statistical outputs (tables, 
figures, listings, and datasets). The original SAP (version 1.0) was based on CSP Version 1.0 and 
finalized and approved prior to the data lock for Part A. The SAP amendment (version 2.0) was 
finalized and approved to incorporate changes in the CSP Version 3.0. This SAP amendment (version 
3.0) will be finalized and approved prior to the data lock for Part B. Any revisions to the approved 
SAP amendment, if applicable, will be documented and approved in an additional amendment to the 
SAP. 
5 
STUDY OBJECTIVES 
5.1 
Primary Objectives 
Part A 
To evaluate the PK of ELX, TEZ, and IVA when dosed in TC 
Part B 
To evaluate the safety and tolerability of ELX/TEZ/IVA through Week 24 


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5.2 
Secondary Objectives 
Part A 
• 
To evaluate the PK of ELX, TEZ and IVA metabolites 
• 
To evaluate the safety and tolerability of ELX/TEZ/IVA 
Part B 
• 
To evaluate the efficacy of ELX/TEZ/IVA through Week 24 
• 
To evaluate the PK of ELX, TEZ, and IVA 
• 
To evaluate the PK of ELX, TEZ and IVA metabolites 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
Part A 
PK parameters of ELX, TEZ, and IVA, including Cmax, Ctrough, and AUC0- 
Part B 
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
standard 12-lead ECGs, vital signs, pulse oximetry, and ophthalmologic examinations 
6.2 
Secondary Endpoints 
Part A 
• 
PK parameters of ELX, TEZ and IVA metabolites, including Cmax, Ctrough, and AUC0- 
• 
Safety and tolerability as determined by AEs, clinical laboratory values, standard 12-lead ECGs, 
vital signs and pulse oximetry 
Part B 
• 
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline through Week 24 
• 
Absolute change in sweat chloride (SwCl) from baseline through Week 24 
• 
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score 
from baseline through Week 24 
• 
Absolute change in body mass index (BMI) and BMI-for-age z-score from baseline at Week 24 
• 
Absolute change in weight and weight-for-age z-score from baseline at Week 24 
• 
Absolute change in height and height-for-age z-score from baseline at Week 24 
• 
Drug acceptability assessment using Modified Facial Hedonic Scale 
• 
Number of pulmonary exacerbations (PEx) and CF-related hospitalizations through Week 24 


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• 
PK parameters of ELX, TEZ, IVA, and relevant metabolites 
• 
Absolute change in lung clearance index2.5 (LCI2.5) from baseline through Week 24 
7 
STUDY DESIGN 
7.1 
Overall Design 
This is a Phase 3, 2-part (Parts A and B), multicenter study evaluating the PK, safety, and tolerability 
of ELX/TEZ/IVA TC therapy in CF (F/F and F/MF genotypes) subjects 6 through 11 years of age 
(inclusive). 
Part A 
A schematic of the study design for Part A is provided in Figure 7-1. Approximately 12 subjects (F/F 
or F/MF genotypes) are planned for enrollment. During the Treatment Period, subjects will be 
administered ELX/TEZ/IVA for approximately 15 days. A review of safety, tolerability, and available 
PK data will be completed by an internal Vertex team after Part A to confirm or adjust the dose(s) 
chosen for Part B. Additional subjects may be enrolled as needed in Part A, based on emerging PK 
data, to confirm the dose(s) for Part B. Subjects who participate in Part A may participate in Part B. 
Figure 7-1 
Part A Study Design 
 
Part B 
A schematic of the study design for Part B is provided in Figure 7-2. Part B will initiate after 
completion of the internal Vertex team’s review of available data in Part A that will confirm or adjust 
the dose(s) to be evaluated in Part B. Approximately 56 subjects (F/F or F/MF genotypes) are planned 
for enrollment to ensure approximately 45 subjects complete Part B. Approximately 25 subjects with 
F/MF genotypes and approximately 20 subjects with F/F genotypes are targeted for enrollment in Part 
B. During the Treatment Period, subjects will be administered ELX/TEZ/IVA for approximately 24 
weeks. 


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Subjects who complete the Part B Treatment Period and have not permanently discontinued study 
drug will be offered the opportunity to enroll in an optional open-label extension safety study 
(enrollment will be based on the eligibility criteria specified within the Open-label Extension Safety 
Study protocol). 
Figure 7-2 
Part B Study Design 
 
The planned dosages to be evaluated are shown in Table 7-1. 
Table 7-1 
Part A and Part B Doses 
Subjects Weight 
ELX Dose 
TEZ Dose 
IVA Dose 
Part A 
 
 
 
All subjects 
100 mg qd 
50 mg qd 
75 mg q12h 
Part B 
 
 
 
<30 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
≥30 kg 
200 mg qd 
100 mg qd 
150 mg q12h 
ELX: elexacaftor; IVA: ivacaftor; qd: daily; q12h: every 12 hours; TEZ: tezacaftor 
7.2 
Sample Size and Power 
Part A 
Approximately 12 subjects will be enrolled in Part A. Sample size calculations were determined based 
on ELX PK, using noncompartmental analysis (NCA)-based parameters, such as clearance and 
volume of distribution. Based on the variability observed in adults, data from 12 subjects will allow 


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80% power to target a 95% CI within 60% and 140% of the geometric mean estimate of clearance for 
ELX. 
Part B 
The planned enrollment is approximately 56 subjects. Approximately 45 subjects are expected to 
complete Part B. Incidence of AEs is a safety endpoint. Table 7-2 presents estimates of the probability 
for observing at least 1 subject with an AE for the given incidence (θ) and sample size. The study will 
have at least 90% chance of observing an AE in at least 1 subject if the true incidence rate is 5%; and 
a >95% chance of observing an AE in at least 1 subject if the true incidence rate is 10%. The 
probabilities have been calculated by assuming a binomial distribution for the number of AEs using 
SAS. 
Table 7-2 
Probability of Observing At Least 1 Subject with an AE in the Study if the AE 
Incidence (θ) is 5% and 10% 
 
7.3 
Randomization 
Part A and Part B 
Randomization is not relevant (open-label study). 
7.4 
Blinding and Unblinding 
Part A and Part B 
This is an open-label study. Refer to Section 10.7 of the CSP for details. 
8 
ANALYSIS SETS 
Part A and Part B 
The analysis set will be defined separately for Part A and Part B. 
8.1 
All Subjects Set 
The All Subjects Set will include all subjects who are enrolled or receive 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 
Safety Set 
The Safety Set will include all subjects who receive at least 1 dose of study drug. The Safety Set will 
be used for all safety analyses. 


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8.3 
Full Analysis Set 
The Full Analysis Set (FAS) will include all subjects who are enrolled and carry the intended CFTR 
allele mutation and receive at least 1 dose of study drug. The FAS will be used to summarize subject 
demographics and baseline characteristics, and for analyses of all efficacy and PD endpoints, unless 
otherwise specified. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
Part A and Part B 
Data from Part A and Part B will be analyzed separately. 
The Schedule of Assessments is provided in Section 3 of the 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 unless otherwise specified, is defined as the most recent non-missing measurement 
(scheduled or unscheduled) collected prior to the first dose of study drug in the corresponding Part. 
Note: for subjects who take Orkambi or Symdeko (branded as Symkevi in Europe) during the 28 days 
before the screening visit, the data collected at screening visit will not be used for baseline derivation 
for spirometry, sweat chloride and LCI. 
Absolute change from baseline will be calculated as Post-baseline value − Baseline value. 
Relative change from baseline will be calculated and expressed in percentage as 100% × (Post-
baseline value − Baseline value) / Baseline value. 
Treatment-emergent (TE) Period for Part A and Part B will include the time from the first dose of 
study drug in the corresponding Part through 28 days after the last dose or the completion of study 
participation date in the corresponding Part, whichever occurs first.  
Extended Treatment-emergent (TE) Period for Part B will include the time from the first dose of 
study drug in Part B through the completion of study participation. 
For subjects who do not have unscheduled visit after the Week 24 visit, refer to Section 9.1.6 of the 
CSP for the definition of completion of study participation. For subjects who have unscheduled visit 
after the Week 24 visit, the completion of study participation is defined as the date of the last 
unscheduled visit. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
• In scheduled visit windows per specified visit windowing rules 


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• In the derivation of baseline and last on-treatment measurements 
• In the derivation of maximum and minimum values during TE periods, and maximum and 
minimum change from baseline values during TE periods for safety analyses 
• In individual subject data listings as appropriate 
Visit windowing rules: For analysis specified in Sections 9.2, 9.3, and 9.4, the analysis visit windows 
for protocol-defined visits are provided in Appendix A.  
Incomplete/missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
Part A and Part B 
The number of subjects in the following categories will be summarized based on the All Subjects Set:  
• All Subjects Set 
• Safety Set 
• FAS 
The number and percentage (based on FAS) of subjects in each of the following disposition categories 
will be summarized: 
• Completed treatment 
• Prematurely discontinued treatment and the reason for discontinuation 
• Completed study  
• Prematurely discontinued the study and the reason for discontinuation 
• Rollover to open-label study (Part B only) 
A listing will be provided for subjects who discontinued treatment or who discontinued study with 
reasons for discontinuation. 
9.2.2 
Demographics and Baseline Characteristics 
Part A and Part B 
Demographics and baseline characteristics will be summarized based on the FAS. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Sex (male, female) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 


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• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Other, and not collected per local regulations) 
• Geographic region (North America for Part A; North America, Europe [including Australia] 
for Part B) 
Baseline characteristics will include the following: 
• CFTR genotype group (F/F, F/MF) 
• Weight group (<30 kg, and ≥30 kg) 
• Weight (kg) 
• Weight z-score 
• Height (cm) 
• Height z-score 
• BMI (kg/m2) 
• BMI z-score 
Disease characteristics will include the following: 
• ppFEV1 at baseline (<70, ≥70 to ≤90, and >90)  
• ppFEV1 at baseline (continuous) 
• Sweat chloride at baseline (continuous) 
For Part B, the following additional disease characteristics will also be provided:  
• CFQ-R respiratory domain score at baseline (child’s version; continuous) 
• LCI2.5 at baseline (continuous) 
• Prior use of CFTR modulator (Yes, No) 
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 
• Prior use of any bronchodilator (Yes, No) 
• Prior use of any inhaled bronchodilator (Yes, No) 
• Prior use of any inhaled hypertonic saline (Yes, No) 
• Infection with Pseudomonas aeruginosa within 2 years prior to screening (Positive, Negative) 
In addition, the following data listings will also be provided: 
• Informed consent/assent; 
• Inclusion/Exclusion criteria violation for subjects with any such violations. 


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9.2.3 
Medical History 
Part A and Part B 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). For 
the FAS, medical history will be summarized descriptively by system organ class (SOC) and 
preferred term (PT). 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 
Part A and Part B 
Medications will be coded using the World Health Organization Drug Dictionary (WHODD) and 
categorized as follows: 
• Prior medication: any medication that administered during the 56 days before the first dose 
of study drug in the corresponding Part. 
• Concomitant medication: medication continued or newly received during the corresponding 
TE period. 
• Post-treatment medication: medication continued or newly received after the corresponding 
TE period. 
A given medication may be classified as follows: prior, concomitant, post-treatment, both prior and 
concomitant, both concomitant and post-treatment, or prior, concomitant, and post-treatment.  
If a medication has a completely missing or partially missing start date or stop date and it cannot be 
determined whether it was taken before the first dose date, concomitantly, or after the TE period, it 
will be classified as prior, concomitant, and post-treatment. Details for imputing missing or partial 
start and/or stop dates of medication are described in Appendix B. 
Concomitant medications will be summarized descriptively for the FAS using frequency tables by: 1) 
preferred name (PN); and 2) anatomic class (ATC) level 1, ATC level 2, and PN. For Part B, prior 
medications will also be summarized the same way as concomitant medications. All medications will 
be listed for each subject. 
9.2.5 
Study Drug Exposure 
Part A and Part B 
Study drug exposure summaries will be based on the Safety Set. 
Duration of study drug exposure (in days) will be calculated as: last dose date – first dose date 
+ 1 day, regardless of study drug interruption. 
Study drug exposure (in days for Part A; in weeks for Part B) will be summarized descriptively by the 
number of subjects (n), mean, SD, median, min, and max. It will also be summarized using counts and 
percentages for Treatment Period categories. For Part A, categories are specified as: ≤2 days; >2 and 
≤4 days; >4 and ≤8 days; >8 and ≤15 days; >15 days. For Part B, they are specified as: ≤15 days; >15 
days and ≤4 weeks; >4 and ≤8 weeks; >8 and ≤12 weeks; >12 and ≤16 weeks; >16 and ≤20 weeks; 


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>20 and ≤24 weeks; >24 weeks. Additionally, the total study drug exposure, defined as the sum total 
of the study drug exposure across all subjects (in patient-weeks for Part A; in patient-weeks and 
patient-years for Part B), will be provided. 
9.2.6 
Study Drug Compliance 
Part A and Part B 
Study drug compliance will be summarized based on the FAS. 
Study drug compliance will be calculated as: 100 × [1 − (total number of days of study drug 
interruption) / (duration of study drug exposure in days)]. A study drug interruption on a given day is 
defined as an interruption of any study drug dose or component on that day. In addition, for Part B, 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) − (total number of tablets returned)] / (total number of tablets planned to 
be taken per day × duration of study drug exposure in days). A summary similar to that for study drug 
compliance will be produced based on the FAS. 
9.2.7 
Important Protocol Deviations 
Part A and Part B 
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 the data lock for Part A. 
Protocol deviations that should be considered as potential IPDs include, but are not limited to: 
• Subject was enrolled in the study despite not satisfying one or more inclusion/exclusion 
criterion 
• 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 
The occurrence of any of these events should be considered as a potential IPD, but the team should 
categorize such an event as an IPD only if it has the potential to affect the completeness, accuracy, or 
reliability of the study data or the subject’s rights, safety, or well-being. 
For Part A, IPDs will only be provided in an individual subject data listing. For Part B, besides the 
listing, a summary table of IPDs based on the FAS will also be provided. 


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9.3 
Efficacy Analysis 
9.3.1 
Efficacy Summary for Part A 
Only summary tables based on the FAS will be provided for efficacy assessments in Part A. 
9.3.1.1 
Spirometry 
For spirometry measurements, a summary of raw values, absolute and relative change from baseline 
values will be provided at each scheduled time point for the following parameters: FEV1 (L), forced 
vital capacity (FVC) (L), FEV1/FVC (ratio), forced expiratory flow (FEF25%-75%) (L/s), ppFEV1, 
percent predicted FVC, percent predicted FEF, and percent predicted FEV1/FVC. The predicted 
values from spirometry will be calculated using the Global Lung Initiative (GLI) equation. Details on 
GLI equation are described in Appendix C. 
9.3.1.2 
Sweat Chloride 
The raw values and change from baseline values of sweat chloride measurements will be summarized 
descriptively (n, mean, SD, median, min, and max) at baseline and post-baseline visits. 
9.3.1.3 
Weight, Height, BMI and their Z-scores 
The raw values and change from baseline values of weight, height, BMI and their z-scores will be 
summarized descriptively (n, mean, SD, median, min, and max) at baseline and post-baseline visits. 
9.3.2 
Efficacy Analysis for Part B 
There is no multiplicity adjustment; P-values provided for the secondary and other endpoints in Part 
B are considered nominal. 
All efficacy analyses described in this section will be based on the FAS, unless otherwise specified. 
The analysis will include all available measurements through the last scheduled visit, including 
measurements after treatment discontinuation. 
9.3.2.1 
Analysis of Primary Efficacy Variables 
Not applicable. 
9.3.2.2 
Analysis of Secondary Efficacy Variables 
9.3.2.2.1 
Definition of Variables 
Percent predicted FEV1 (ppFEV1): the ppFEV1 value is the ratio of FEV1 (L) and predicted FEV1 (L), 
expressed as a percentage. See Appendix C for more details. 
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 for analysis purposes. Any sweat chloride values reported as <10 
mmol/L or >160 mmol/L will be considered missing for analysis purposes. 
Cystic Fibrosis Questionnaire-Revised (CFQ-R): the CFQ-R1,4,6 is a validated CF-specific instrument 
that measures quality-of-life domains. This study utilizes two different versions of CFQ-R: 
• CFQ-R for Children ages 6 to 11 


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• CFQ-R for Parents/Caregivers 
In both versions, specific questions belonging to a domain is scored 1, 2, 3, or 4. The CFQ-R domain 
score, e.g., physical domain score or respiratory domain score, is defined as a scaled score as follows: 
Scaled score for a domain = 100 × (mean (scores of all questions in the domain) − 1) / 3, 
where the score from a negatively phrased question is first reversed, i.e., reversed score = 5 – actual 
score, so that 1 always represents the worst condition and 4 the best condition. The (scaled) domain 
score ranges from 0 (worst condition) to 100 (best condition). The scaled score for a specific domain 
will not be calculated if more than half of the questions in the domain have missing scores. 
Body mass index (BMI): the BMI at each visit is calculated using the weight and height at each visit 
as follows:  
BMI = Weight (kg) / [Height (m)]2 
BMI z-score: the BMI score, adjusted for age and sex, will be referred to as BMI-for-age z-score 
(BMI z-score). The BMI z-score will be calculated by using Centers for Disease Control and 
Prevention (CDC) growth charts8, with the age (in months) used for the calculation defined in 
Appendix A. 
Height z-score and Weight z-score: the height z-score and weight z-score, adjusted for age and sex, 
will be referred to as weight-for-age z-score (weight z-score) and height-for-age z-score (height z-
score). The weight z-score and height z-score will be calculated by using Centers for Disease Control 
and Prevention (CDC) growth charts8, with the age (in months) used for the calculation defined in 
Appendix A.  
Modified Facial Hedonic Scale: refer to Section 11.3.1 of the CSP for details. 
Pulmonary exacerbation (PEx): A PEx is defined as a new or changed antibiotic therapy (intravenous 
[IV], inhaled, or oral) for any 4 or more of the following signs/symptoms: 
•  Change in sputum 
• New or increased hemoptysis 
• Increased cough 
• Increased dyspnea 
• Malaise, fatigue, or lethargy 
• Temperature above 38°C (equivalent to approximately 100.4°F) 
• Anorexia or weight loss 
• Sinus pain or tenderness 
• Change in sinus discharge 
• Change in physical examination (PE) of the chest 
• Decrease in pulmonary function by 10% 
• Radiographic changes indicative of pulmonary infection 


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The PEx analysis period will include the time from the first dose date of study drug until the last 
efficacy assessment, which may be collected up to the Week 24 Visit or the earlier of Day 169 and the 
end of study participation if the subject does not have the Week 24 Visit. 
The number of PEx through Week 24 is then defined as the total number of PEx during the PEx 
analysis period. 
Lung clearance index (LCI): the LCI assessments are derived from N2-multiple-breath washout 
(MBW) testing. Each MBW will be performed in multiple replicates for each visit and the final LCI 
value will be calculated from the technically acceptable washout replicates as graded and determined 
by a central reader. The following algorithm is used to derive the LCI values at each visit based on the 
multiple replicates: 
• When there is only one acceptable replicate at the visit, the LCI values will not be calculated.  
The assessment for that subject at the corresponding visit will be missing. 
• When there are 2 or more acceptable replicates at the visit, the mean of the values for the 
acceptable replicates will be calculated as the LCI value at the corresponding visit. 
9.3.2.2.2 
Analysis Method 
Absolute change in ppFEV1 from baseline through Week 24: 
Absolute change from baseline in ppFEV1 will be analyzed using a mixed-effects model for repeated 
measures (MMRM) approach based on the FAS. The MMRM will be used to estimate the within-
group mean absolute change in ppFEV1 through Week 24. The model will include absolute change 
from baseline in ppFEV1 (including all measurements up to Week 24 [inclusive], both on-treatment 
measurements and measurements after treatment discontinuation) as the dependent variable, and visit 
as the fixed effect, with baseline ppFEV1 value and genotype group (F/F vs. F/MF) as covariates. The 
model will be estimated using restricted maximum likelihood. Denominator degrees of freedom for 
the F-test of 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 results obtained from the model will be the average treatment effect through Week 24. Note that 
the Day 15 Visit will not be included in the estimation of the average treatment effect through Week 
24 as the treatment effect is not expected to reach the steady state at Day 15. The estimated mean 
change from baseline in ppFEV1 through Week 24, along with the corresponding 2-sided 95% 
confidence interval (CI) and P-value will be provided. The treatment effect at each post-baseline visit 
with 95% CI, obtained from the model, will be provided as well. 
The 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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Absolute change in sweat chloride from baseline through Week 24: 
Analysis of this PD variable will be based on an MMRM similar to the analysis of the absolute 
change in ppFEV1 from baseline through Week 24 with the baseline sweat chloride included as a 
covariate instead of baseline ppFEV1. Data obtained from Day 15, Week 4, Week 12, and Week 24 
Visits will be included in the model. However, Day 15 Visit will not be included in the estimation of 
the average treatment effect through Week 24 as the treatment effect is not expected to reach the 
steady state at Day 15. 
Absolute change in the CFQ-R respiratory domain score from baseline through Week 24: 
Analysis of this domain (child’s version) will be based on an MMRM similar to the analysis of the 
absolute change in ppFEV1 from baseline through Week 24 with the baseline CFQ-R respiratory 
domain score (child’s version) included as a covariate instead of baseline ppFEV1. Data obtained 
from Week 4, Week 8, Week 12, Week 16, and Week 24 Visits will be included in the model and all 
of these visits will be included in the estimation of the average treatment effect through Week 24. The 
analysis will include only the clinic assessed CFQ-R RD score. An additional analysis may be 
performed to include CFQ-R RD score assessed at clinic and at home, if the home assessed data are 
consistent with the clinic assessed data.  
Absolute change in BMI and BMI-for-age z-score from baseline at Week 24; 
Absolute change in weight and weight-for-age z-score from baseline at Week 24; 
Absolute change in height and height-for-age z-score from baseline at Week 24: 
Analysis of these variables will be based on an MMRM similar to the analysis of the absolute change 
in ppFEV1 from baseline through Week 24 with the corresponding baseline included as a covariate 
instead of baseline ppFEV1. Data obtained from Day 15, Week 4, Week 8, Week 12, Week 16, and 
Week 24 Visits will be included in the model. 
Drug acceptability assessment using Modified Facial Hedonic Scale: 
Analysis of this variable will be based on descriptive statistics. The number and percentage (based on 
the FAS) of subjects in each category will be summarized for each question at all scheduled visit. The 
analysis will include only the data assessed at clinic. An additional analysis may be performed to 
include the data assessed at clinic and at home, if the home assessed data are consistent with the clinic 
assessed data. 
Number of PEx and CF-related hospitalizations through Week 24: 


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The analysis period for these variables will be the same as the PEx analysis period. 
PEx will be summarized as described below: 
• Number of events: 
o 
Number of PEx 
o 
Number of PEx requiring hospitalizations 
o 
Number of PEx requiring IV antibiotic therapy 
o 
Number of PEx requiring hospitalization or IV antibiotic therapy 
• Duration of events: 
o 
Number of days with PEx 
o 
Number of days with PEx requiring hospitalizations 
o 
Number of days with PEx requiring IV antibiotic therapy 
o 
Number of days with PEx requiring hospitalization or IV antibiotic therapy 
CF-related hospitalizations will be summarized as described below: 
• Number of events: 
o 
Number of planned hospitalizations for CF (i.e., antibiotic therapy) 
o 
Number of unplanned hospitalizations for reasons other than antibiotic therapy for 
sinopulmonary signs/symptoms 
• Duration of events: 
o 
Number of days of planned hospitalizations for CF (i.e., antibiotic therapy) 
o 
Number of days of unplanned hospitalizations for reasons other than antibiotic therapy for 
sinopulmonary signs/symptoms 
For number of events variables, subjects with multiple defined events during the PEx analysis period 
will be counted multiple times. The annualized duration of events for each subject will be the total 
number of days with the defined events times 48 weeks divided by the total number of weeks on 
study up to the end of the PEx analysis period. 
Absolute change in LCI2.5 from baseline through Week 24: 
Analysis of this variable will be based on an MMRM similar to the analysis of the absolute change in 
ppFEV1 from baseline through Week 24 with the baseline LCI2.5 included as a covariate instead of 
baseline ppFEV1. Data obtained from Day 15, Week 4, Week 12, and Week 24 Visits will be included 
in the model. However, Day 15 Visit will not be included in the estimation of the average treatment 
effect through Week 24 as the treatment effect is not expected to reach the steady state at Day 15. 
To better assess the longitudinal profile of the efficacy and pharmacodynamics assessments with 
repeated measures up to Week 24, the LS mean (SE) of the change from baseline at each post-
baseline visit along with the 95% CI will be estimated from the corresponding MMRM. The LS mean 
(SE) at each visit will also be plotted. In addition, the post-baseline raw values and the absolute 


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change from baseline at each post-baseline visit will be summarized descriptively (n, mean, SD, 
median, minimum, and maximum). 
9.3.2.2.3 
Sensitivity Analysis 
Not applicable because the primary endpoints are safety and tolerability assessments. 


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9.4 
Safety Analysis 
Part A and Part B 
Safety is a secondary objective of Part A, and the primary objective of Part B. All safety analyses will 
be conducted for Part A and Part B separately, based on data from the corresponding TE period in the 
Safety Set. 
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 
• Standard 12-lead ECGs 
• Vital signs  
• Pulse oximetry 
Only descriptive analysis of safety will be performed, and no statistical testing will be performed. 
9.4.1 
Adverse Events  
Part A and Part B 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment AEs, 
defined as follows: 
• Pretreatment AE: any AE that occurred before the first dose date of study drug in the 
corresponding Part. 


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• TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed 
at or after the first dose of study drug through the end of the TE period in the corresponding 
Part. 
• Extended TEAE: (Part B only) any AE that worsened (either in severity or seriousness) or 
that was newly developed at or after the first dose of study drug in Part B through the end of 
the Extended Treatment-emergent Period. 
• Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed after the TE period in the corresponding Part. 
For AEs with completely missing or partially missing start dates, if there is no clear evidence that the 
AEs were pretreatment or post-treatment, the AEs will be classified as TEAEs.  
Details for imputing missing or partial start dates of adverse events are defined in Appendix D. 
An overview of all TEAEs will be provided with 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 
drug) 
• Subjects with TEAEs leading to study drug interruption (interruption of any study drug) 
• Subjects with grade 3/4 TEAEs  
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAEs leading to death 
The following summary tables of TEAEs will be presented: 
• All TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Serious TEAEs 
• TEAEs leading to death 
• Grade 3/4 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 


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• Related TEAEs 
• Related serious TEAEs (Part B only) 
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, subjects with multiple occurrences of the same AE or a continuing AE will be 
counted once and only the maximum severity level will be presented in the severity summaries, and 
the strongest relationship level will be presented in the relationship summaries.  
Additional summary tables will be provided for TEAEs showing number and percentage of subjects 
• All TEAEs by PT 
All AEs, including pretreatment AEs, TEAEs, and post-treatment AEs, will be presented in an 
individual subject data listing based on the All Subjects Set. In addition, a listing 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. 
9.4.2 
Clinical Laboratory 
Part A and Part B 
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.  
The number and percentage of subjects meeting at least 1 threshold analysis criterion event for 
selected parameters during the TE period will be summarized. The threshold analysis criterion shift 
from baseline will also be summarized for selected laboratory parameters. The threshold analysis 
criteria are provided in Appendix E. 
Results of urinalysis and the 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 
abnormal will be selected. 
In addition, a listing containing individual subject hematology, chemistry, and coagulation values will 
be provided. This listing will include data from both scheduled and unscheduled visits. 
Part B Only 
For selected LFT laboratory tests (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase [ALP], and total bilirubin), a scatter plot of the maximum treatment-emergent 
value versus the baseline value corresponding to ×ULN (upper limit of normal) will be presented. 
Further, a scatter plot of the maximum treatment-emergent value of ALT and AST, separately, versus 
the maximum treatment-emergent value of total bilirubin corresponding to ×ULN will also be 
presented. 
9.4.3 
Electrocardiogram  
Part A and Part B 


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For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided at each visit for the following ECG 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 for selected 
parameters during the TE period will be summarized. The threshold analysis criteria are provided in 
Appendix E. 
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 
Part A and Part B 
For the treatment-emergent vital signs measurements, the observed values and change from baseline 
values will be summarized at each visit. The following vital signs parameters will be summarized: 
systolic and diastolic blood pressure (mm Hg), body temperature (°C), pulse rate (breaths per minute), 
and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion for selected 
parameters during the TE period will be summarized. The threshold analysis criteria are provided in 
Appendix E. 
In addition, a listing containing individual subject vital sign values will be provided. This listing will 
include data from both scheduled and unscheduled visits. 
Part B Only 
The number and percentage of subjects meeting at least 1 threshold analysis criterion at each visit will 
be summarized for blood pressure (systolic and diastolic). The threshold analysis criteria are provided 
in Appendix E. 
9.4.5 
Pulse Oximetry 
Part A and Part B 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and change 
from baseline values will be provided at each visit for the percent of oxygen saturation. 
The number and percentage of subjects with shift change 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. The reference range for normal oxygen saturation is specified as >95%, and <=95% 
for low oxygen saturation. 
9.4.6 
Ophthalmologic Examinations 
Part A and Part B 
The ophthalmologic examination results will be presented in individual subject data listings. 
9.4.7 
Physical Examination 
Part A and Part B 
Abnormal PE findings will be presented as an individual subject data listing only. 


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9.4.8 
COVID-19 Impacted Visits 
A listing containing subjects’ visits impacted due to COVID-19 will be provided.  


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10 
INTERIM AND DMC ANALYSES 
10.1 
Interim Analysis 
Part A 
No interim analysis is planned. 
Part B 
No interim analysis is planned at this moment; otherwise, SAP will be amended. 
10.2 
IDMC Analysis 
Part A 
No IDMC analysis is planned. 
Part B 
The DMC’s objectives and operational details will be defined in a separate document (DMC Charter) 
which will be finalized before the first subject is screened in Part B of the study. The DMC’s planned 
safety reviews of study data will be outlined in the DMC Charter and DMC Statistical Analysis Plan. 


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11 
REFERENCES 
1 Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 2007;4:1-9. 
2 Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 
3 Meyer, R. Daniel, et al. Statistical Issues and Recommendations for Clinical Trials Conducted 
During the COVID-19 Pandemic. Statistics in Biopharmaceutical Research just accepted (2020): 1-
22. 
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 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. 
6 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. 
7 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. 
8 Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
 


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12 
LIST OF APPENDICES 
 Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments in Part A 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3, 4 
Safety Assessment  
• Serum Chemistry 
• Hematology 
Day 1 (Baseline)  
Day 8 
Day 15 
Safety Follow-up 
1 
8 
15 
Not applicable 
1 Pre-dose 
[1, 12] 
(12, 29] 
Use nominal visit 
• Standard 12-lead ECG 
Day 1 (Baseline)  
Day 2 
1 
2 
1 Pre-dose 
[1, 9] 
Day 15 Pre-dose and 
Post-dose 
Not applicable 
Use nominal visit 
Safety Follow-up 
Not applicable 
Use nominal visit 
• Vital Signs 
 
Day 1 (Baseline)  
Day 2 
Day 8 
Day 15 
Safety Follow-up 
1 
2 
8 
15 
Not applicable 
1 
[1, 5] 
(5, 12] 
(12, 29] 
Use nominal visit 
• Coagulation 
 
Day 1 (Baseline)  
Day 15 
1 
15 
1 Pre-dose 
[1, 29] 
Efficacy Assessment and Pharmacodynamic Assessment  
• Spirometry  
 
Day 1 (Baseline)  
Day 2 
Day 8 
Day 15 
Safety Follow-up 
1 
2 
8 
15 
Not applicable 
1 Pre-dose 
(1, 5] 
(5, 12] 
(12, 29] 
>29 
• Sweat Chloride 
Day 1 (Baseline)  
Day 15 
1 
15 
1 Pre-dose 
(1, 29] 
• Weight, Height and BMI 
(and the corresponding z-
scores, as applicable) 
Day 1 (Baseline)  
Day 15 
Safety Follow-up 
1 
15 
Not applicable 
1 
(1, 29] 
>29 
 


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Table 12-2 
Analysis Visit Windows for Safety and Efficacy Assessments in Part B 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3, 4 
Safety Assessment  
• Serum Chemistry 
Day 1 (Baseline) 
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
85 
113 
141 
169 
Not applicable 
1 Pre-dose 
[1, 22] 
(22, 43] 
(43, 71] 
(71, 99] 
(99, 127] 
(127, 155] 
(155, 183] 
Use nominal visit 
• Hematology 
Day 1 (Baseline) 
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
85 
113 
169 
Not applicable 
1 Pre-dose 
[1, 22] 
(22, 43] 
(43, 71] 
(71, 99] 
(99, 141] 
(141, 183] 
Use nominal visit 
• Vital Signs (excluding weight, 
height, and BMI) 
Day 1 (Baseline) 
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
85 
113 
169 
Not applicable 
1 
[1, 22] 
(22, 43] 
(43, 71] 
(71, 99] 
(99, 141] 
(141, 183] 
Use nominal visit 
• Standard 12-lead ECG 
Day 1 (Baseline) 
Day 15 
Week 12 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
85 
113 
169 
Not applicable 
1 Pre-dose 
[1, 50] 
(50, 99] 
(99, 141] 
(141, 183] 
Use nominal visit 
• Coagulation 
Day 1 (Baseline) 
Week 24 
Safety Follow-up 
1 
169 
Not applicable 
1 Pre-dose 
[1, 183] 
Use nominal visit 
Efficacy Assessment and Pharmacodynamic Assessment  
• Spirometry 
Day 1 (Baseline) 
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
85 
113 
169 
Not applicable 
1 Pre-dose 
(1, 22] 
(22, 43] 
(43, 71] 
(71, 99] 
(99, 141] 
(141, 183] 
>183 


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Table 12-2 
Analysis Visit Windows for Safety and Efficacy Assessments in Part B 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3, 4 
• Weight, Height and BMI (and 
the corresponding z-scores) 
 
Day 1 (Baseline) 
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
85 
113 
169 
Not applicable 
1 
(1, 22] 
(22, 43] 
(43, 71] 
(71, 99] 
(99, 141] 
(141, 183] 
>183 
• Modified Facial Hedonic Scale 
Day 1 
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
85 
113 
169 
Not applicable 
1 
(1, 22] 
(22, 43] 
(43, 71] 
(71, 99] 
(99, 141] 
(141, 183] 
>183 
• CFQ-R 
Day 1 (Baseline) 
Week 4 
Week 8 
Week 12 
Week 16 
Week 24 
Safety Follow-up 
1 
29 
57 
85 
113 
169 
Not applicable 
1 
(1, 43] 
(43, 71] 
(71, 99] 
(99, 141] 
(141, 183] 
>183 
• Sweat Chloride 
• Lung Clearance Index 
 
Day 1 (Baseline) 
Day 15 
Week 4 
Week 12 
Week 24 
1 
15 
29 
85 
169 
1 Pre-dose 
(1, 22] 
(22, 57] 
(57, 127] 
(127, 183] 
 
Notes: 
1 Visit name for analysis purpose is used to report data in tables and figures. 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
b. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. 
The measurement closest to the target day will be used; or  
ii. 
If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. If the latest measurement cannot be determined, then unscheduled visit will be selected 
 


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3 For measurements collected on the date of first dose of study drug, if it cannot be determined whether the 
measurement is before or after the first dose: 
a. Scheduled measurement will be treated as pre-dose observation. 
b. Unscheduled measurement will be treated as post-dose observation. 
 
4 For safety assessment, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a subject 
doesn’t have a nominal Safety Follow-up visit but has an ETT visit with study day >29 for Part A and >183 for Part 
B, then the ETT visit will be mapped into Safety Follow-up analysis visit. 
 
5 For efficacy analysis of Part B, if there are assessments with study days > 183, the nominal Safety Follow-up visit 
will be mapped to the Safety Follow-up visit. If there is only ETT assessment with study day > 183, the ETT visit 
will be mapped to the Safety Follow-up visit. 
 
Derived Variables: 
1. Age (in years) at first dose date and nominal visit (for demographics, listing and the calculation of [percent] 
predicted spirometry variables): 
Obtain the age at informed consent/assent (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/assent date. 
Then age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed 
consent/assent date) in days + age at informed consent/assent (in days)]/365.25. 
2. Age (in months) at nominal visit (for use in calculation of BMI, weight z-score and height z-score, as applicable): 
Obtain the age at informed consent/assent (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/assent date. 
Then age (in months) at nominal visit = integer part of {[(age at informed consent/assent (in months) + 0.5 + diff 
(first dose date or nominal visit date, informed consent/assent 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 will be defined as the most recent non-missing measurement (or the average of triplicate measurements, 
if the most recent non-missing measurement is obtained in triplicate), before the first dose of study drug 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 (except for Day 
15 visit in Part A); 
o For threshold analysis purpose, all reported ECG values will be used. 


Statistical Analysis Plan (Methods)  
Page 35 of 46 
Protocol Number: VX18-445-106 
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 
(in practical, use Jan. 01, 2000 to impute). 
2. Missing or partial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month and year are all missing, assign ‘continuing’ status to stop 
date (in practical, use Dec. 31, 2050 to impute). 
In summary, the prior, concomitant, or post categorization of a medication is described 
below. 
Table 12-3 
Prior, Concomitant, and Post Categorization of a Medication  
Medication Start Date 
Medication Stop Date 
< First Dose Date of 
Study Drug 
≥ First Dose Date 
and  
≤ End Date of TE 
Period 
> End Date of TE 
Period 
< First dose date of study drug 
P 
PC 
PCA 
≥ First dose date and  
≤ End date of TE period 
- 
C 
CA 
> End date of TE period 
- 
- 
A 
P: Prior; C: Concomitant; A: Post 
 
Imputation rules for missing and/or partial dates of non-pharmacological treatment/procedure 
will follow the same imputation rule. 
 


Statistical Analysis Plan (Methods)  
Page 36 of 46 
Protocol Number: VX18-445-106 
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 Mar 26, 2018]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] 
Available at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138979 
[Accessed Mar 26, 2018].   
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: http://www.ers-education.org/home/browse-all-
content.aspx?idParent=138988 [Accessed  Mar 26, 2018]. 
Data handling rule for spirometry is as follows:  
 Input age and height with at least 2 decimal place 
 Height collected at the respective visit should be used; if the height at the respective visit is 
not available, the last non-missing record will be used. 
 For race, map the CRF reported Black or African American 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 Analysis Plan (Methods)  
Page 37 of 46 
Protocol Number: VX18-445-106 
Vertex Pharmaceuticals Incorporated 
 
 Appendix D: Imputation Rules for Missing AE Dates 
Imputation rules for missing or partial AE start date are defined below.  If the imputed AE 
start date is before the study informed consent/assent date, the AE start date will be imputed 
using the study informed consent/assent date. 
• If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the 
Treatment Period or AE end date is missing, then  
 if AE start year and month are equal to the month and year of first dose 
date of the Treatment Period, then impute the AE start day as the day of 
first dose date of the Treatment Period;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the 
Treatment Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment 
Period, then impute the AE start month and day as the month and day of 
first dose date of the Treatment Period;  
 else impute the AE start month as January and day as 1.  
o else impute the AE start month as January and day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site 
and  
o If the full (or partial) AE end date is NOT before the first dose date of the 
Treatment Period or AE end date is missing, then impute the AE start date as the 
first dose date of the Treatment Period;  
o else impute the AE start date as the informed consent/assent date. 
 
Imputation rules for partial AE end date are defined below:  
• Impute the AE end date as min (the last day of the month, end of study participation) if 
day is missing, or min (Dec, end of study participation) if month is missing. 


Statistical Analysis Plan (Methods)  
Page 38 of 46 
Protocol Number: VX18-445-106 
Vertex Pharmaceuticals Incorporated 
 
 Appendix E: Criteria for Threshold Analysis 
Table 12-4 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤ 3xULN) or (AST>ULN - 
≤3xULN) 
(ALT>3x - ≤5xULN) or (AST>3x - 
≤5xULN) 
(ALT>5x - ≤8xULN) or (AST>5x - 
≤8xULN) 
(ALT>8x - ≤20xULN) or (AST>8x - 
≤20xULN) 
ALT>20xULN or AST>20xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤1.5xULN 
>1.5x - ≤2.5xULN 
>2.5x - ≤5xULN 
>5x - ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤3xULN  
>3x - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤3xULN  
>3x - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Indirect Bilirubin 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤3xULN  
>3x - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 


Statistical Analysis Plan (Methods)  
Page 39 of 46 
Protocol Number: VX18-445-106 
Vertex Pharmaceuticals Incorporated 
 
Table 12-4 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
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. 
GGT 
>ULN - ≤2.5xULN 
>2.5x - ≤5xULN 
>5x - ≤20xULN  
>20xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN - ≥30 g/L 
<30 - ≥20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤1.5xULN 
>1.5x - ≤3xULN 
>3x - ≤6xULN 
>6xULN 
CTCAE grades 1-4 
Lipase 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine kinase 
>ULN - ≤2.5xULN 
>2.5x - ≤5xULN 
>5x - ≤10xULN  
>10xULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥100 g/L 
<100 - ≥80 g/L  
<80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤20 g/L above ULN 
>20 g/L above ULN - ≤40 g/L above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 


Statistical Analysis Plan (Methods)  
Page 40 of 46 
Protocol Number: VX18-445-106 
Vertex Pharmaceuticals Incorporated 
 
Table 12-4 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Platelets 
Platelet decreased 
<LLN - ≥75 x 10e9 /L 
<75 - ≥50 x 10e9 /L  
<50 - ≥25 x 10e9 /L  
<25 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 
Reticulocytes/Erythrocytes (%)    <LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated partial thromboplastin 
time  (PTT)  
 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5xULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5 x ULN 
CTCAE grade 1-3 
 
Table 12-5 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
≤50 bpm  
 
Tachycardia 
≥140 bpm 
 
PR 
≥220 ms and increase from baseline ≥20 ms 
 
QRS 
≥120 ms 
 
QTc 
Absolute values (ms) 
>450 ms (Male); >470 ms (Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline 30-60 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT 
correction formula.  
 
Table 12-6 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
SBP 
 
>120 mmHg 
 
<70 mmHg 
 
DBP 
 
>80 mmHg 
 
<50 mmHg 
 


Statistical Analysis Plan (Methods)  
Page 41 of 46 
Protocol Number: VX18-445-106 
Vertex Pharmaceuticals Incorporated 
 
Table 12-6 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Weight 
Weight gain 
≥5% increase from baseline 
 
Weight loss 
≥5% decrease from baseline