Conditions: Cystic Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 121
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of elexacaftor (ELX) / tezacaftor (TEZ) / ivacaftor (IVA) triple combination (TC) in subjects 6 through 11 years of age with cystic fibrosis (CF) who are heterozygous for F508del and a minimal function (MF) mutation (F/MF genotypes).

Detailed description:

Arms:
arm 1: Participants received placebo matched to ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks. arm 2: Participants weighing less than (\<) 30 kilograms (kg) at screening received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) and participants weighing greater than equals to (\>=) 30 kg at screening 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 3: Placebo (matched to ELX/TEZ/IVA) intervention 4: Placebo (matched to IVA)
Intervention descriptions: intervention 1: Fixed-dose combination tablet for oral administration qd in the morning. intervention 2: Tablet for oral administration qd in the evening. intervention 3: Placebo matched to ELX/TEZ/IVA for oral administration once daily (qd) in the morning. intervention 4: Placebo matched to IVA for oral administration qd in the evening.

Protocol document:
Prot_000.pdf: 
Page 1 of 65 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 3b, Randomized, Placebo-controlled Study 
Evaluating the Efficacy and Safety of 
Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis 
Subjects 6 Through 11 Years of Age Who Are 
Heterozygous for the F508del Mutation and a Minimal 
Function Mutation (F/MF) 
Vertex Study Number: VX19-445-116 
EudraCT Number: 2019-003554-86 
Date of Protocol: 18 December 2019 (Version 1.0)  
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 


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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3b, Randomized, Placebo-controlled Study Evaluating the Efficacy and 
Safety of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Subjects 6 Through 
11 Years of Age Who Are Heterozygous for the F508del Mutation and a Minimal 
Function Mutation (F/MF) 
  
Brief Title 
A Study Evaluating Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in 
Subjects 6 through 11 Years of Age With Cystic Fibrosis and F/MF genotypes 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 3b, efficacy and safety 
 
 
Objectives 
Primary Objective 
To evaluate the efficacy of elexacaftor (VX-445; ELX)/tezacaftor (TEZ)/ivacaftor 
(IVA) in subjects 6 through 11 years of age with cystic fibrosis (CF), 
heterozygous for F508del and a minimal function (MF) mutation (F/MF) 
Secondary Objective 
• 
To evaluate the pharmacodynamics (PD) of ELX/TEZ/IVA  
• 
To evaluate the safety of ELX/TEZ/IVA 
 
 
Endpoints 
Primary Endpoint 
Absolute change in lung clearance index2.5 (LCI2.5) from baseline through 
Week 24 
Secondary Endpoints  
• 
Absolute change in sweat chloride (SwCl) from baseline through 
Week 24 
• 
Safety and tolerability assessments based on adverse events (AEs), 
clinical laboratory values, standard 12-lead electrocardiograms (ECGs), 
vital signs, pulse oximetry 
 
 
Number of Subjects 
Approximately 108 subjects will be randomized (1:1) to the ELX/TEZ/IVA group 
or the placebo group. 
 
 
Study Population 
Male and female subjects 6 through 11 years of age with CF who have F/MF 
genotypes. 
 
 
Investigational Drug 
Active substance: ELX (VX-445)/TEZ (VX-661)/IVA (VX-770) 
 
Activity: CFTR corrector, CFTR corrector, and CFTR potentiator 
 
Strength and route of administration: 
• 
50-mg ELX/25-mg TEZ/37.5-mg IVA fixed-dose combination (FDC) tablets 


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for oral administration 
• 
100-mg ELX/50-mg TEZ/75-mg IVA FDC tablets for oral administration  
 
 
 
Active substance: IVA (VX-770) 
 
Activity: CFTR potentiator 
 
Strength and route of administration: 
• 
75-mg IVA tablet for oral administration 
• 
150-mg IVA tablet for oral administration  
 
 
Study Duration 
Excluding the Screening Period, the total study duration is approximately 
28 weeks (24 weeks for the Treatment Period, and 4 weeks for the Safety 
Follow-up Period). 
 
 
Study Design 
This is a Phase 3b, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study in CF subjects 6 through 11 years of age with F/MF genotypes. 
Figure 2-1 
VX19-445-116 Study Design 
 
ELX: elexacaftor; IVA: ivacaftor; N: number of subjects; TEZ: tezacaftor 
Note: Subjects will be randomized 1:1 to receive ELX/TEZ/IVA or placebo 
a 
The Safety Follow-up Visit is scheduled to occur 28 days (± 7 days) after the last 
dose.  
b 
Subjects who complete the visits in the Treatment Period, regardless of whether 
they are on a treatment interruption, will be offered the opportunity to enroll in an 
optional open-label extension safety study evaluating ELX/TEZ/IVA. The Safety 
Follow-up Visit is not required for subjects who complete the Week 24 Visit and 
have enrolled in an open-label study within 28 days after the last dose of study 
drug. 
Subjects will receive ELX/TEZ/IVA or placebo at the doses in Table 2-1 based on 
their weight at the Screening Visit.  
Table 2-1 
Treatment Period Groups and Dosages 
Treatment Group 
Weight at Screening Visit 
ELX Dosage 
TEZ Dosage 
IVA Dosage 
ELX/TEZ/IVA 
 
 
 
   <30 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
   ≥30 kg 
200 mg qd 
100 mg qd 
150 mg q12h 
Placebo 
0 mg 
0 mg 
0 mg 
ELX: elexacaftor; IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TEZ: tezacaftor  
Randomization will be stratified by LCI2.5 determined at the Screening Visit (<10 
versus ≥10) and weight at the Screening Visit (<30 kg versus ≥30 kg). 


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Assessments 
Efficacy Assessments: 
Multiple-breath washout (MBW), 
 
PD Assessment: 
Sweat chloride 
Safety Assessments: 
AEs, clinical laboratory assessments, ECGs, vital signs, pulse oximetry, physical 
examinations, and ophthalmologic examinations 
Statistical Analyses 
The primary efficacy endpoint is the absolute change in LCI2.5 from baseline 
through Week 24. The primary null hypothesis to be tested is that the mean 
absolute change in LCI2.5 from baseline through Week 24 is the same for the 2 
treatment groups, ELX/TEZ/IVA and placebo. The null hypothesis will be tested 
at a 2-sided significance level of 0.05. 
Assuming a within-group standard deviation (SD) of 1.5 and a 10% dropout rate 
through Week 24, a sample size of 54 subjects in each treatment group (108 
subjects total) will have approximately 90% power to detect a difference of -1.0 
for the mean absolute change in LCI2.5 from baseline through Week 24 between 
the 2 treatment groups, based on a 2-sided 2-sample t-test at a significant level of 
0.05.  
The analysis of the primary efficacy endpoint, absolute change in LCI2.5, will be 
based on a mixed-effects model for repeated measures (MMRM). The primary 
result obtained from the model will be the estimated treatment difference through 
Week 24, with a 2-sided 95% CI and a 2-sided P value provided. The treatment 
difference at each post-baseline visit will also be estimated and provided.  
The safety endpoints include treatment-emergent AEs, clinical laboratory values, 
ECGs, vital signs, pulse oximetry. The safety analysis will be descriptive only.   
 
 
DMC Reviews 
A data monitoring committee (DMC) will conduct periodic safety review(s) of 
study data as outlined in the DMC charter. 


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are in Table 3-1 and Table 3-2. 
All visits are to be scheduled relative to the Day 1 visit (first dose of randomized study drug). 
For example, the Week 4 (± 5 days) Visit would occur after 4 weeks of study drug administration 
has been completed. 
Table 3-1 
Study VX19-445-116: Screening 
Event/Assessment 
Screening Visit 
Day -28 to Day -1 
 
Comments 
Informed consent (and assent, if 
applicable) 
X 
 
Demographics 
X 
Section 11.1 
Medical history 
X 
Section 11.1 
Height and weight 
X 
Measured with shoes off. 
Ophthalmologic examination 
X 
Conducted by an ophthalmologist or 
optometrist (Section 11.5.5) 
Complete physical examination 
X 
Section 11.5.3 
Vital signs and 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 subject has been at rest for 
at least 5 minutes (Section 11.5.4) 
Multiple-breath washout 
X 
Performed pre- or post-bronchodilator, in 
multiple replicates, and before the 
spirometry assessment (Section 11.3.1) 
Spirometry 
X 
Performed pre- or post-bronchodilator 
(Section 11.3.2) 
Sweat chloride 
X 
Section 11.2 
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 and whose screening genotype 
does not confirm eligibility must be 
discontinued from the study (Section 9.9). 
Serum pregnancy test (all female 
subjects) 
X 
Section 11.5.6 
Serum chemistry 
X 
Section 11.5.2 
Hematology 
X 
Section 11.5.2 
Coagulation 
X 
Section 11.5.2 
Urinalysis 
X 
Section 11.5.2 
Medication review 
X 
Information regarding medications taken 
within 56 days before the Screening Visit 
will be collected (Section 9.5)  
AEs and SAEs 
Continuous from signing of 
ICF (and Assent Form) 
through Completion of 
Study Participation 
Section 13.1; completion of study 
participation is defined in Section 9.1.6. 


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Table 3-1 
Study VX19-445-116: Screening 
Event/Assessment 
Screening Visit 
Day -28 to Day -1 
 
Comments 
AE: adverse event; CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator; 
ECG: electrocardiogram; ICF: informed consent form; SAE: serious adverse event 
 


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Table 3-2 
Study VX19-445-116: Treatment Period and Safety Follow-up Visit 
Event/ 
Assessmenta 
Day 1b 
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-upc 
28 (± 7) Days 
After Last 
Dose of 
Study Drug 
Comments 
Clinic Visit 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Telephone 
contact 
 
X 
 
 
 
X 
 
X 
 
 
 
Assess subject’s 
status, any AEs, 
concomitant 
medications, 
treatments, and 
procedures. 
Inclusion/ 
exclusion 
criteria review 
X 
 
 
 
 
 
 
 
 
 
 
Section 8 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
Randomization may 
occur on either Day -
1 or Day 1, after all 
eligibility criteria are 
confirmed. 
Safety and Efficacy Assessments 
Ophthalmologic 
examination 
 
 
 
 
 
 
 
 
X 
at or up 
to 
4 weeks 
before 
X 
 
Section 11.5.5 
Height and 
weight 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
Measured before 
study drug dosing 
with shoes off 
 
a 
All assessments will be performed before dosing unless noted otherwise. 
b  To enter the Treatment Period, conditions for entry must be satisfied. 
c  The Safety Follow-up Visit is not required for subjects who complete the Week 24 Visit and enroll in an optional open-label extension safety study within 28 
days after the last dose of study drug (Section 9.1.3). 


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Table 3-2 
Study VX19-445-116: Treatment Period and Safety Follow-up Visit 
Event/ 
Assessmenta 
Day 1b 
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-upc 
28 (± 7) Days 
After Last 
Dose of 
Study Drug 
Comments 
Vital signs and 
pulse oximetry 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
Performed after 
subject has been at 
rest for at least 5 
minutes 
(Section 11.5.3) 
Physical 
examination 
X 
 
 
 
 
 
 
 
X 
X 
 
Symptom directed 
physical 
examinations may be 
performed at any 
time if deemed 
necessary by the 
investigator 
(Section 11.5.3) 
Standard 12-lead 
ECG 
X 
 
 
  
X 
 
 
X 
 
X 
X 
X 
Performed prior to 
any procedure that 
may affect heart rate 
(e.g., blood draws) 
and after subject has 
been at rest for at 
least 5 minutes 
(Section 11.5.4)  


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Table 3-2 
Study VX19-445-116: Treatment Period and Safety Follow-up Visit 
Event/ 
Assessmenta 
Day 1b 
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-upc 
28 (± 7) Days 
After Last 
Dose of 
Study Drug 
Comments 
Sweat chloride 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
  
Multiple-breath 
washout 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
Performed in 
multiple replicates, 
pre-bronchodilator, 
before the AM 
dose, and before 
spirometry 
assessment 
(Section 11.3.1).   
Observation 
4 hours after the 
morning dose 
X 
 
 
 
 
 
 
 
 
 
 
Section 9.6.1 
Pregnancy test 
(all female 
subjects) 
urine 
 
serum 
serum 
serum 
urine 
serum 
urine 
serum 
serum 
serum 
At telephone 
contacts, a urine 
pregnancy test will 
be performed with a 
home kit provided 
by the study site. 
Results will be 
reported to the site 
by telephone 
(Section 11.5.6). 
Serum chemistry 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
Section 11.5.2 
Hematology  
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
Section 11.5.2 
Coagulation 
X 
 
 
 
 
 
 
 
X 
X 
 
Section 11.5.2 


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Table 3-2 
Study VX19-445-116: Treatment Period and Safety Follow-up Visit 
Event/ 
Assessmenta 
Day 1b 
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-upc 
28 (± 7) Days 
After Last 
Dose of 
Study Drug 
Comments 
Urinalysis 
X 
 
 
 
 
 
 
 
X 
X 
 
Section 11.5.2 
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. 
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 
treatment 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. 


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Table 3-2 
Study VX19-445-116: Treatment Period and Safety Follow-up Visit 
Event/ 
Assessmenta 
Day 1b 
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-upc 
28 (± 7) Days 
After Last 
Dose of 
Study Drug 
Comments 
Study Drug Administration 
ELX/TEZ/IVA 
or placebo  
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 
morning 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). 
AE: adverse event; CF: cystic fibrosis; 
; ECG: electrocardiogram; ELX: elexacaftor; ETT: early termination of 
treatment; ICF: informed consent form; IVA: ivacaftor; SAE: serious adverse event; TEZ: tezacaftor 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Protocol Synopsis ................................................................................................................... 2 
3 
Schedule of Assessments ........................................................................................................ 5 
4 
Table of Contents ................................................................................................................. 12 
List of Tables ........................................................................................................................... 16 
List of Figures .......................................................................................................................... 16 
List of Abbreviations ............................................................................................................... 17 
5 
Introduction .......................................................................................................................... 20 
5.1 
Background ..................................................................................................................... 20 
5.2 
Study Rationale .............................................................................................................. 21 
6 
Study Objectives .................................................................................................................. 21 
6.1 
Primary Objective ........................................................................................................... 21 
6.2 
Secondary Objectives ..................................................................................................... 21 
7 
Study Endpoints ................................................................................................................... 21 
7.1 
Primary Endpoint ............................................................................................................ 21 
7.2 
Secondary Endpoints ...................................................................................................... 21 
 
 
8 
Study Population .................................................................................................................. 21 
8.1 
Inclusion Criteria ............................................................................................................ 22 
8.2 
Exclusion Criteria ........................................................................................................... 22 
9 
Study Implementation ......................................................................................................... 24 
9.1 
Study Design .................................................................................................................. 24 
9.1.1 
Screening ................................................................................................................ 25 
9.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 25 
9.1.1.2 
Rescreening ...................................................................................................... 25 
9.1.1.3 
Extension of Screening Period Window .......................................................... 25 
9.1.2 
Treatment Period .................................................................................................... 25 
9.1.3 
Follow-up ................................................................................................................ 25 
9.1.4 
Early Termination of Treatment ............................................................................. 26 
9.1.5 
Lost to Follow-up ................................................................................................... 26 
9.1.6 
Completion of Study Participation ......................................................................... 26 
9.1.7 
Data Monitoring Committee ................................................................................... 27 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 27 
9.3 
Rationale for Study Elements ......................................................................................... 27 
9.3.1 
Study Design ........................................................................................................... 27 
9.3.2 
Study Population..................................................................................................... 27 
9.3.3 
Study Drug Dose and Duration .............................................................................. 27 
9.3.4 
Rationale for Study Assessments ........................................................................... 28 
9.4 
Study Restrictions ........................................................................................................... 28 
9.4.1 
Prohibited Medications ........................................................................................... 28 
9.5 
Prior and Concomitant Medications ............................................................................... 29 
9.6 
Administration ................................................................................................................ 30 
9.6.1 
Dosing ..................................................................................................................... 30 
9.6.2 
Missed Doses .......................................................................................................... 31 


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9.7 
Dose Modification for Toxicity ...................................................................................... 31 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 31 
9.8.1 
Liver Function Tests ............................................................................................... 31 
9.8.2 
Rash ........................................................................................................................ 32 
9.9 
Removal of Subjects ....................................................................................................... 32 
9.10 Replacement of Subjects ................................................................................................ 33 
10 Study Drug Information and Management ....................................................................... 33 
10.1 Preparation and Dispensing ............................................................................................ 33 
10.2 Packaging and Labeling ................................................................................................. 33 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 33 
10.4 Drug Accountability ....................................................................................................... 34 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 34 
10.6 Compliance ..................................................................................................................... 34 
10.7 Blinding and Unblinding ................................................................................................ 34 
10.7.1 
Blinding .................................................................................................................. 35 
10.7.2 
Unblinding .............................................................................................................. 35 
11 Assessments .......................................................................................................................... 36 
11.1 Subject and Disease Characteristics ............................................................................... 36 
11.2 Pharmacodynamics: Sweat Chloride .............................................................................. 37 
11.3 Efficacy ........................................................................................................................... 37 
11.3.1 
Multiple-breath Washout ........................................................................................ 37 
11.3.2 
Spirometry .............................................................................................................. 37 
11.5 Safety .............................................................................................................................. 39 
11.5.1 
Adverse Events ....................................................................................................... 39 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 39 
11.5.3 
Physical Examinations and Vital Signs .................................................................. 41 
11.5.4 
Electrocardiograms ................................................................................................. 41 
11.5.5 
Ophthalmologic Examination ................................................................................. 42 
11.5.6 
Contraception and Pregnancy ................................................................................. 42 
11.5.6.1 Contraception ................................................................................................... 42 
11.5.6.2 Pregnancy ......................................................................................................... 44 
12 Statistical and Analytical Plans .......................................................................................... 44 
12.1 Sample Size and Power .................................................................................................. 44 
12.2 Analysis Sets .................................................................................................................. 44 
12.3 Statistical Analysis ......................................................................................................... 45 
12.3.1 
General Considerations ........................................................................................... 45 
12.3.2 
Background Characteristics .................................................................................... 45 
12.3.2.1 Subject Disposition .......................................................................................... 45 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 45 
12.3.2.3 Prior and Concomitant Medications ................................................................ 45 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 46 
12.3.3 
Efficacy and Pharmacodynamic Analysis .............................................................. 46 
12.3.3.1 Analysis of Primary Endpoint .......................................................................... 46 


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12.3.3.2 Analysis of Secondary Endpoints .................................................................... 47 
 
12.3.4 
Safety Analysis ....................................................................................................... 47 
12.3.4.1 Adverse Events ................................................................................................ 47 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 48 
12.3.4.3 Electrocardiogram ............................................................................................ 48 
12.3.4.4 Vital Signs ........................................................................................................ 49 
12.3.4.5 Pulse Oximetry ................................................................................................. 49 
12.3.4.6 Ophthalmologic Examinations ......................................................................... 49 
12.3.4.7 Physical Examination ....................................................................................... 49 
12.3.5 
Interim and Data Monitoring Committee Analyses ............................................... 49 
12.3.5.1 Interim Analysis ............................................................................................... 49 
12.3.5.2 Data Monitoring Committee Analysis ............................................................. 49 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 50 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 50 
13.1.1 
Adverse Events ....................................................................................................... 50 
13.1.1.1 Definition of an Adverse Event........................................................................ 50 
13.1.1.2 Clinically Significant Assessments .................................................................. 50 
13.1.1.3 Documentation of Adverse Events................................................................... 50 
13.1.1.4 Adverse Event Severity .................................................................................... 51 
13.1.1.5 Adverse Event Causality .................................................................................. 51 
13.1.1.6 Study Drug Action Taken ................................................................................ 52 
13.1.1.7 Adverse Event Outcome .................................................................................. 52 
13.1.1.8 Treatment Given............................................................................................... 53 
13.1.2 
Serious Adverse Events .......................................................................................... 53 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 53 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 54 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 54 
13.2 Administrative Requirements ......................................................................................... 54 
13.2.1 
Ethical Considerations ............................................................................................ 54 
13.2.2 
Subject Information and Informed Consent ........................................................... 55 
13.2.3 
Investigator Compliance ......................................................................................... 55 
13.2.4 
Access to Records ................................................................................................... 55 
13.2.5 
Subject Privacy ....................................................................................................... 55 
13.2.6 
Record Retention .................................................................................................... 56 
13.2.7 
Study Termination .................................................................................................. 56 
13.2.8 
End of Study ........................................................................................................... 56 
13.3 Data Quality Assurance .................................................................................................. 56 
13.4 Monitoring ...................................................................................................................... 57 
13.5 Electronic Data Capture ................................................................................................. 57 
13.6 Confidentiality and Disclosure ....................................................................................... 57 
13.7 Publications and Clinical Study Report .......................................................................... 58 
 
 
13.7.2 
Clinical Study Report ............................................................................................. 58 
14 References ............................................................................................................................. 59 


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APPENDIX A Eligible MF CFTR Mutations ....................................................................... 61 
15 Protocol Signature Pages .................................................................................................... 64 
15.1 Sponsor Signature Page .................................................................................................. 64 
15.2 Investigator Signature Page ............................................................................................ 65 
 


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List of Tables 
Table 2-1 
Treatment Period Groups and Dosages................................................................... 3 
Table 3-1 
Study VX19-445-116: Screening ............................................................................ 5 
Table 3-2 
Study VX19-445-116: Treatment Period and Safety Follow-up Visit ................... 7 
Table 9-1 
Treatment Period Groups and Dosages................................................................. 24 
Table 9-2 
Prohibited Medications ......................................................................................... 28 
Table 9-3 
Study Drug Administration ................................................................................... 30 
Table 10-1 
Study Drug: Dosing Form/Route/Strength ........................................................... 34 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 40 
Table 11-2 
Acceptable Methods of Contraception .................................................................. 43 
Table 13-1 
Grading of AE Severity ........................................................................................ 51 
Table 13-2 
Classifications for AE Causality ........................................................................... 52 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 52 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 52 
List of Figures 
Figure 2-1 
VX19-445-116 Study Design ................................................................................. 3 
Figure 9-1 
VX19-445-116 Study Design ............................................................................... 24 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
β 
beta, apparent elimination rate constant 
BMI 
body mass index 
CF 
cystic fibrosis 
 
 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DMC 
data monitoring committee 
ECGs 
electrocardiograms 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ELX 
elexacaftor 
ETT 
Early Termination of Treatment 
EU 
European Union 
F/MF 
F508del Mutation and a Minimal Function Mutation 
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 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
FEF25%-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
GPP3 
Good Publication Practices 
GPS 
Global Patient Safety 
HBE 
human bronchial epithelial 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
IA 
interim analysis 


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Abbreviation 
Definition 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IRB 
institutional review board 
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 
LS 
least squares 
LUM 
lumacaftor 
max 
maximum value 
MBW 
multiple-breath washout 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
minimal function 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
N 
size of subsample 
N 
total sample size 
OATP1B1 
organic anion transporting polypeptide 1B1 
OATP1B3 
organic anion transporting polypeptide 1B3 
P 
probability 
PC 
publication committee 
PD 
pharmacodynamics 
PE 
physical examination 
PEx 
pulmonary exacerbations 
P-gp 
P-glycoprotein 
PIs 
principal investigators 
PK 
pharmacokinetics 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval, segment 
PT 
preferred term 
q12h 
every 12 hours 
qd 
once daily 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QT 
QT interval 
QTcF 
QT corrected for HR 
RD 
respiratory domain 
RNA 
ribonucleic acid 
RR 
interval from the onset of 1 QRS complex to the next; use R-R if using with 
“intervals”, i.e., “R-R interval” 
SAE 
serious adverse event 


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Abbreviation 
Definition 
SAP 
statistical analysis plan 
SC 
steering committee 
SD 
standard deviation 
SET 
Study Execution Team 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SUSARs 
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 31,000 in the US2 and 48,000 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. Approximately 85% have at least 
1 F508del allele.10, 11 
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®).   
Elexacaftor (VX-445; ELX) is a next-generation CFTR corrector. In vitro, the triple combination 
(TC) of ELX, TEZ, and IVA (ELX/TEZ/IVA) increased CFTR chloride transport more than any 
of the dual combinations (ELX/TEZ, ELX/IVA, and TEZ/IVA) or individual components (ELX, 
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). Pivotal Phase 3 studies in CF subjects aged 12 years 
and older with F/MF and F/F genotypes demonstrated that treatment with ELX/TEZ/IVA 
resulted in rapid, robust, clinically meaningful, and statistically significant improvements in all 
primary and key secondary efficacy and pharmacodynamic (PD) endpoints. ELX/TEZ/IVA was 
generally safe and well tolerated with a low rate of treatment discontinuation. Given the younger 
age group in this study, the effect of ELX/TEZ/IVA on endpoints 
 
 
n this population may be different compared to older 


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populations. An open-label Phase 3 study is ongoing to evaluate the pharmacokinetics (PK), 
safety, and tolerability of ELX/TEZ/IVA in CF subjects aged 6 through 11 years of age.  
Additional information about ELX/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 treating patients early in life. 
Vertex evaluated ELX/TEZ/IVA TC therapy in Phase 3 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. 
In the 24-week placebo-controlled study in CF subjects with an F/MF genotype, there were 
clinically meaningful and statistically significant improvements in lung function (ppFEV1), 
CFTR function (sweat chloride [SwCl]), respiratory symptoms (CFQ-R RD scores), and 
nutritional status (body mass index [BMI] and body weight), as well as a reduction in number of 
pulmonary exacerbations (PEx). The present study is designed to obtain placebo-controlled 
efficacy, safety, and PD information to expand the evaluation of ELX/TEZ/IVA in the pediatric 
population 6 through 11 years of age with F/MF genotypes.  
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the efficacy of ELX/TEZ/IVA in subjects 6 through 11 years of age with CF, 
heterozygous for F508del and a MF mutation (F/MF) 
6.2 
Secondary Objectives 
• To evaluate the PD of ELX/TEZ/IVA 
• To evaluate the safety of ELX/TEZ/IVA 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Absolute change in lung clearance index2.5 (LCI2.5) from baseline through Week 24 
7.2 
Secondary Endpoints 
• Absolute change in SwCl from baseline through Week 24 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
standard 12-lead electrocardiograms (ECGs), vital signs, pulse oximetry 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 


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8.1 
Inclusion Criteria 
1. Subject's legally appointed and authorized representative (e.g., parent or legal guardian) will 
sign and date informed consent form (ICF) and subject will sign an assent form (if 
applicable). 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures.  
3. Subjects (male and female) 6 through 11 years of age, inclusive, on the date of informed 
consent. 
4. Subjects who weigh ≥15 kg without shoes at the Screening Visit.  
5. Confirmed diagnosis of CF as determined by the investigator. 
6. Subjects heterozygous for F508del and an MF mutation that is not responsive to IVA and 
TEZ/IVA (F/MF genotypes, Appendix A).  
• Genotype should be confirmed at the Screening Visit.  
• 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). 
7. Subjects with forced expiratory volume in 1 second (FEV1) value ≥70% of predicted normal 
for age, sex, and height using equations of the Global Lung Function Initiative (GLI)12 as 
determined by spirometry at screening (Section 11.3.2. 
8. Subjects with a screening LCI2.5 result ≥ 7.5 (Section 11.3.1). 
9. Subjects with stable CF disease at the start of the Treatment Period as deemed by the 
investigator.  
10. Subjects who are willing to remain on a stable CF medication regimen (other than CFTR 
modulators) through Week 24 or, if applicable, through the Safety Follow-up Visit 
11. Subjects who are able to swallow tablets.  
12. As judged by the investigator, the parent or legal guardian must be able to understand 
protocol requirements, restrictions, and instructions and the parent or legal guardian should 
be able to ensure that the subject will comply with and is likely to complete the study as 
planned. 
8.2 
Exclusion Criteria 
1. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study drug(s) to 
the subject. This includes, but is not limited to, the following: 
• Clinically significant liver cirrhosis with or without portal hypertension 
• Solid organ or hematological transplantation 


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• Alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, 
and opiates, as deemed by the investigator 
• Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical 
carcinoma in situ (all 3 with no recurrence for the last 5 years) 
2. 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. 
• 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. 
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 ELX with or without coadministration of 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.  
8. Use of restricted medication within specified duration before the first dose of study drug as 
defined in Table 9-2. 


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9. Pregnant and breast-feeding females. All female subjects regardless of childbearing potential 
status (Section 11.5.6) must have a negative pregnancy test at the Screening Visit and the 
Day 1 Visit. 
10. The subject or a close relative of the subject is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study at that site. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3b, randomized, double-blind, placebo-controlled, parallel-group, multicenter 
study in CF subjects aged 6 through 11 years who are heterozygous for the F508del mutation and 
a minimal function mutation (F/MF) (Figure 9-1). 
Figure 9-1 
VX19-445-116 Study Design 
ELX: elexacaftor; IVA: ivacaftor; N: number of subjects; TEZ: tezacaftor  
a 
The Safety Follow-up Visit is scheduled to occur 28 days (± 7 days) after the last dose.  
b 
Subjects who complete the visits in the Treatment Period, regardless of whether they are on a treatment 
interruption, will be offered the opportunity to enroll in an optional open-label extension safety study 
evaluating ELX/TEZ/IVA. The Safety Follow-up Visit is not required for subjects who complete the Week 
24 Visit and have enrolled in an open-label study within 28 days after the last dose of study drug.  
Approximately 108 subjects will be randomized (1:1) to the ELX/TEZ/IVA group or the placebo 
group. The planned dosages to be evaluated are shown in Table 9-1. 
Table 9-1 
Treatment Period Groups and Dosages 
Treatment Group 
  Weight at Screening Visit 
ELX Dosage 
TEZ Dosage 
IVA Dosage 
ELX/TEZ/IVA 
 
 
 
   <30 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
   ≥30 kg 
200 mg qd 
100 mg qd 
150 mg q12h 
Placebo 
0 mg 
0 mg 
0 mg 
ELX: elexacaftor; IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TEZ: tezacaftor 
Note: Study drug administration is described in Section 9.6. 


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Randomization will be stratified by LCI2.5 determined at the Screening Visit (<10 versus ≥10) 
and weight at the Screening Visit (<30 kg versus ≥30 kg). 
9.1.1 
Screening 
Screening Visit assessments are listed in Table 3-1. 
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. 
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.4 and concomitant medications (Section 9.5). 
9.1.1.1 
Repetition of Screening Assessment(s) 
Screening assessments may be repeated once to establish study eligibility. If repeat values of the 
individual assessment(s) are within the eligibility criteria and completed within the screening 
window, then the subject is eligible for the study. 
9.1.1.2 
Rescreening 
Subjects may be rescreened once. If a subject is rescreened, the subject will provide re-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 
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 
The Treatment Period will last approximately 24 weeks. 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. 
9.1.3 
Follow-up 
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.  


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An 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 
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) 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. 
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 3-2. 
Subjects who prematurely discontinue treatment are not eligible to enroll in the optional 
open-label extension safety study. 
9.1.5 
Lost to Follow-up 
A subject will be considered lost to follow-up if both of the following occur: 
• The subject misses 2 consecutive study visits (telephone contact and/or clinic visit) and is 
subsequently unable to be contacted by telephone (3 documented attempts by telephone 
within 2 weeks following the second missed visit) 
• The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 
9.1.6 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as 1 of the following: 
• For subjects who complete the Treatment Period and enter an open-label 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) 


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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 subject had with the site.  
The end of study is defined in Section 13.2.8. 
9.1.7 
Data Monitoring Committee 
A data monitoring committee (DMC) will be formed. The DMC objectives and operational 
details will be defined in a separate document (DMC Charter), which will be finalized before the 
first subject is screened. The DMC will conduct regular planned reviews of study data as 
outlined in the DMC Charter. 
9.2 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized (1:1) to the ELX/TEZ/IVA or placebo group. Randomization will 
be stratified by LCI2.5 determined at the Screening Visit (<10 versus ≥10) and weight at the 
Screening Visit (<30 kg versus ≥30 kg).  
An interactive web response system (IWRS) will be used to assign subjects to treatment. The 
randomization code will be produced by Vertex Biostatistics or a qualified randomization 
vendor. The Vertex study biostatistician will review and approve the production of the final 
randomization list, which will be reviewed and approved by a designated unblinded 
biostatistician who is not a member of the study execution team (SET).  
9.3 
Rationale for Study Elements 
9.3.1 
Study Design 
A randomized, double-blind, placebo-controlled study design was selected to ascertain the 
effects of ELX/TEZ/IVA through between-group comparisons while avoiding observer bias. 
Placebo is considered the appropriate comparator because no CFTR modulator regimen has been 
approved for use in subjects 6 through 11 years of age who have F/MF genotypes.  
The rationale for including absolute change in LCI2.5 from baseline through Week 24 as the 
primary endpoint is discussed in Section 9.3.4. 
9.3.2 
Study Population 
This study will enroll CF subjects with F/MF genotypes, 6 through 11 years of age. 
ELX/TEZ/IVA is expected to provide clinical benefit to these patients based on the results of a 
Phase 3 study (Study VX17-445-102), which demonstrated the efficacy and safety of 
ELX/TEZ/IVA in CF subjects ≥12 years of age who have F/MF genotypes. 
Given the progressive nature of CF, there is a strong rationale for treating patients earlier in life. 
Experience with CFTR modulators, including TEZ/IVA, in pediatric subjects 6 to 11 years of 
age, suggests that the safety profile of ELX/TEZ/IVA will be similar in children and adults, 
which supports evaluation of ELX/TEZ/IVA in pediatric subjects in the present study. 
9.3.3 
Study Drug Dose and Duration 
Study Drug Dose 
The dose of ELX/TEZ/IVA evaluated in the pivotal Phase 3 study in subjects with F/MF 
genotypes ≥12 years of age (200 mg qd/100 mg qd/150 mg q12h) was generally safe and well 
tolerated and resulted in clinically meaningful improvements compared to placebo in endpoints 
including ppFEV1 (LS mean treatment difference of 14.3 percentage points [p<0.0001] for 


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absolute change from baseline) and SwCl (LS mean treatment difference of -41.8 mmol/L 
[p<0.0001] for absolute change from baseline) through 24 weeks.  
The doses of ELX/TEZ/IVA administered in this study (200 mg qd/100 mg qd/150 mg q12h for 
subjects ≥30 kg, 100 mg qd/50 mg qd/75 mg q12h for subjects <30 kg) have been selected 
through assessment of PK over approximately 2 weeks in Part A of a registrational Phase 3 study 
in 6 to 11 year of age CF subjects, and are the same doses being administered over 24 weeks in 
Part B of that registrational study.  
Treatment Duration 
This study will have a 24-week treatment duration to allow for placebo-controlled assessment of 
safety and efficacy over 24 weeks of treatment.   
9.3.4 
Rationale for Study Assessments 
Most of the 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. 
LCI 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 FEV1 in its ability to measure airway disease and 
can detect lung disease at an earlier stage than spirometry.16, 17  
9.4 
Study Restrictions 
9.4.1 
Prohibited Medications 
Table 9-2 lists prohibited medications. A non-exhaustive list of study prohibitions and cautions 
for medication will be provided in the Study Reference Manual. 
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 
ELX, 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 ELX, 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 
(investigational or 
approved), except for 
study drugs 
None allowed 
within 28 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
until after the 
last dose of 
study drug 
These agents may confound the results of this 
study. 


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Table 9-2 
Prohibited Medications 
Medication 
Timing of Restriction 
Rationale 
Start of 
Restriction 
End of 
Restriction 
CYP: cytochrome P450; ELX: elexacaftor; IVA: ivacaftor; TEZ: tezacaftor 
a 
Ciprofloxacin is not a moderate CYP3A inhibitor on the basis of results of a drug-drug interaction study 
conducted with IVA, a sensitive CYP3A substrate (Kalydeco [ivacaftor] US Package Insert). 
9.5 
Prior and Concomitant Medications 
Information regarding prior and concomitant medications, including CF medications, other 
medications, and herbal and naturopathic remedies, will be collected from each subject’s source 
documentation for medications taken within 56 days before the Screening Visit through 
completion of study participation, as defined in Section 9.1.6. 
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. 
• ELX may inhibit OATP1B1 and OATP1B3, which may increase the exposure of medicinal 
products that are substrates for these transporters. Substrates such as statins, glyburide, 
nateglinide, and repaglinide should be used with caution.  
• IVA is a weak inhibitor of P-glycoprotein (P-gp). Administration of IVA may increase 
systemic exposure of medicinal products that are sensitive substrates of P-gp, which may 
increase or prolong their therapeutic effect and adverse reactions. Digoxin or other substrates 
of P-gp with a narrow therapeutic index, such as cyclosporine, everolimus, sirolimus, and 
tacrolimus, should be used with caution and appropriate monitoring.  


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• 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 11.3.2. 
9.6 
Administration 
9.6.1 
Dosing 
Study drug tablets will be administered orally as shown in Table 9-3. Subjects in both treatment 
groups (ELX/TEZ/IVA and placebo) will receive the same number of tablets each day to 
maintain the blind. Additional information is provided in the Pharmacy Manual. 
Table 9-3 
Study Drug Administration 
Subject Weight 
at Screening 
Tablet Strength 
Time 
Number of Tablets Taken 
<30 kg 
50-mg ELX/25-mg TEZ/37.5-mg IVA 
AM 
2 tablets 
75-mg IVA 
PM 
1 tablet 
≥30 kg 
100-mg ELX/50-mg TEZ/75-mg IVA 
AM 
2 tablets 
150-mg IVA 
PM 
1 tablet 
ELX: elexacaftor; 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 approximately 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. On days of scheduled visits, the morning dose of study drug will be administered at the site 
after predose assessments have been completed. The meal or snack will be provided by the 
site for the morning dose of study drug.  
5. 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. 
6. 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. 


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9.6.2 
Missed Doses 
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. 
9.7 
Dose Modification for Toxicity 
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 
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 study 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 
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 


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• ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical 
jaundice 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression. 
Study drug administration must be discontinued if the following criterion is met: 
• Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, 
alcohol ingestion) is identified, regardless of whether transaminase levels have improved. 
All subjects in whom treatment is discontinued for elevated transaminases (and bilirubin, as 
applicable) should have these levels monitored closely until levels normalize or return to 
baseline. 
If an alternative, reversible cause of transaminase elevation with or without increased bilirubin or 
clinical jaundice has been identified, subjects may receive study drug once transaminases return 
to baseline or are ≤2 × ULN, whichever is higher. Regardless of the duration of interruption, the 
medical monitor should be notified prior to resumption of study drug. Upon resumption of study 
drug, transaminases and bilirubin should be assessed weekly for 4 weeks. If a protocol-defined 
transaminase elevation interruption threshold recurs within 4 weeks of rechallenge with the study 
drug (with confirmation of the initial elevation by repeat testing within 48 to 72 hours), then the 
study drug must be permanently discontinued, regardless of the presumed etiology.  
9.8.2 
Rash 
Individuals who develop a generalized rash will be monitored closely. Study drug dosing should 
be interrupted if a subject develops a generalized rash of Grade 3 or higher (Section 13.1.1.4), 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, 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  
Subjects may withdraw from the study at any time at the request of the subject’s parent or legal 
guardian. 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) 


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• 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.  
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 ends, 
and may use the samples and information in the development of the study compounds, 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 or 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 or her samples. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study drug treatment period will not be 
replaced. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
Study drug refers to ELX/TEZ/IVA and matching placebo, and IVA and matching placebo.  
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
10.2 
Packaging and Labeling 
Study drug tablets will be supplied in blister cards by Vertex. Study drug labeling will be in 
compliance with applicable local and national regulations. Additional details regarding 
packaging, labeling, and dispensing for study drug will be in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
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. To ensure adequate records, all study drugs will be accounted for via the drug 
accountability forms as instructed by Vertex. 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 
Subjects <30 kg at 
Screening 
Subjects ≥30 kg at 
Screening 
ELX/TEZ/IVA, FDC tablet, oral 
 
 
ELX 
50 mg 
100 mg 
TEZ 
25 mg 
50 mg 
IVA 
37.5 mg 
75 mg 
ELX/TEZ/IVA-matching placebo, tablet, oral 
0 mg 
0 mg 
IVA, tablet, oral 
75 mg 
150 mg 
IVA-matching placebo, tablet, oral 
0 mg 
0 mg 
ELX: elexacaftor; FDC: fixed-dose combination; IVA: ivacaftor; TEZ: tezacaftor 
Note: See Table 9-3 for details on study drug administration. 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee. The study monitor will review study drug 
records and inventory throughout the study. 
If a site uses a site-specific drug accountability system and/or process, including processes 
associated with the destruction of returned materials, the process must be documented and 
approved by Vertex. The study monitor must review the drug accountability documentation on a 
regular basis. The study monitor will promptly communicate to Vertex any discrepancies he/she 
is unable to resolve with the site.  
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should consider discontinuing the subject from the study. 
10.7 
Blinding and Unblinding 
This will be a double-blind study. 


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10.7.1 
Blinding  
All subjects (and their parents/caregivers/companions), site personnel (including the investigator, 
the site monitor, and the study team), and members of the Vertex study team will be blinded to 
the treatment codes. 
Individuals who may be unblinded include only the following: 
• Any site personnel for whom this information is important to ensure the safety of the 
subject in the event of a life-threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of the 
subject and her fetus in the event of a pregnancy 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy SAE 
processing and reporting regulations 
• Vendor preparing the final (production) randomization list 
• Vertex IWRS Manager 
• Vertex Clinical Supply Chain 
• DMC 
• Vendor preparing the unblinded analysis for safety review by the DMC 
Access to MBW,
 and SwCl Results: 
During the conduct of the study, the Vertex study team will not have access to the MBW, 
 or SwCl results after the first dose of study drug in the Treatment Period.  
 
Shortly before any planned efficacy analysis is conducted, the MBW,
 and SwCl data 
will be reviewed for data cleaning purposes by a biostatistician who does not have access to the 
treatment codes. 
 
Individual SwCl test results will not be disclosed to the study sites with the exception of the 
screening values. Subjects and their parents/caregivers/companions should not be informed of 
study-related MBW 
 results until Vertex has determined that the study has 
completed (i.e., clinical study report [CSR] finalization), regardless of whether the subject has 
prematurely discontinued treatment. 
10.7.2 
Unblinding 
At the initiation of the study, study site personnel will be instructed on the method for breaking 
the blind. The unblinding method will be either manual or electronic. 
 
Unblinding of Individual Subject Treatment Assignments by Investigator for Medical 
Emergencies or Urgent Clinical Situations 
 
Unblinding of the individual subject’s treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject’s study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss unblinding. 


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If investigators deem it unnecessary to unblind immediately, they will first attempt to contact the 
medical monitor to discuss unblinding. If investigators have tried but are unable to reach the 
medical monitor, they will use their best judgment, based on the nature and urgency of the 
clinical situation, and may proceed with unblinding. 
 
Contact information for the medical monitor (or appropriate backup) will be in a separate 
document. 
 
If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding event. 
The reason and the date of the unblinding will be documented clearly in the subject’s study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with Vertex, the contract research 
organization, or any site personnel (other than the physician treating the subject). In addition, the 
investigator will consider whether the clinical event that prompted unblinding will be considered 
an SAE, according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE 
report to Vertex GPS or designee, per Section 13.1.2. 
 
Unblinding of Individual Subject Treatment Assignments by Vertex GPS or Designee for 
SAEs or Safety Concerns 
 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety, unblind individual 
subjects at any time. 
Unblinding: Interim Analysis 
A limited Vertex team may be unblinded if an IA is performed. Members of the limited Vertex 
unblinded team will not be involved in or influence the conduct of the remaining part of the 
study to protect the integrity of the study (Section 12.3.5.1) Subjects (and their 
parents/caregivers/companions), site personnel (including the investigator, the site monitor, and 
the study team), and members of the Vertex study team will remain blinded to subject-level data 
until the final database lock. 
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1 and Table 3-2. 
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 


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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 
Pharmacodynamics: Sweat Chloride 
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). 
See Section 10.7.1 for information about access to SwCl results. 
11.3 
Efficacy 
11.3.1 
Multiple-breath Washout 
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. 
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 11.3.2. The MBW test should be performed before the spirometry assessment 
(Section 11).  
Detailed MBW procedures will be supplied separately in a Study Manual. 
11.3.2 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines18 and according to the additional guidelines that follow. 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
• withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 
• withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the 
spirometry assessment; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilator.
 
 


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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. 
 
The measured spirometric values listed below will be converted to percent predicted values using 
the standard equations of GLI.12  
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 
• Forced expiratory flow, midexpiratory phase (FEF25%-75%) (L/s) 


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11.5 
Safety 
Safety evaluations will include reporting of AEs, clinical laboratory assessments, physical 
examination (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 
All AEs will be assessed, documented, and reported in accordance with ICH E6 GCP Guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE case report form 
(CRF) completion guidelines for investigators as well as training will be provided. 
11.5.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory with the exception of urine 
pregnancy tests. As described below, urine pregnancy tests will either be analyzed by the site or 
at home using a home kit. All blood samples will be collected while subjects are in a seated or 
supine position. Specific instructions for the collection, processing, and shipment of samples will 
be provided in a separate Laboratory Manual.  
Laboratory test results that are abnormal and considered clinically significant 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 and Table 3-2). 


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Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Total bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate transaminase 
Alanine transaminase 
Amylase  
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Thyroid-stimulating hormone 
Urate 
Cholesterol  
Triglycerides 
Low-density lipoprotein-direct  
High-density lipoprotein  
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 done, and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
b 
If blood urea nitrogen cannot be collected, urea may be substituted. 
Pregnancy (β-human chorionic gonadotropin) Tests for all Female Subjects: 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. Urine pregnancy tests will either be performed 
and analyzed at the site or, when there is no clinic visit scheduled, at home by using a home kit 
provided by the site. Results will be reported to the site by telephone. The urine pregnancy test 
on Day 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.  
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 


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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 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits (see Table 3-1 and Table 3-2). At other visits, symptom-directed 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 (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs. 
Symptom-directed PEs and symptom-directed vital signs assessment may be performed if 
appropriate. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed.  
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 
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. 
A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. Clinically significant ECG abnormalities occurring during the study 
through the Safety Follow-up Visit will be recorded as AEs.  
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. 


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11.5.5 
Ophthalmologic Examination 
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. 
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 3-2. 
Any clinically significant abnormal findings will be reported as AEs. 
11.5.6 
Contraception and Pregnancy 
The effects of ELX monotherapy or in combination with TEZ/IVA on conception, pregnancy, 
and lactation in humans are not known. ELX, 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 
ELX, TEZ, and IVA have not shown teratogenicity in rats and rabbits. 
11.5.6.1 
Contraception 
Contraception requirement 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 subject is male and 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 subject is female and 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 


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Note: All other females (including females with tubal ligations and pre-menarchal females) 
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. Methods of contraception must be in successful use from signing of consent, 
approximately 28 days before the first dose of study drug (unless otherwise noted), and until 
90 days following the last dose of study drug. Additional contraception requirements may need 
to be followed according to local regulations and/or requirements. Acceptable methods of 
contraception are listed in Table 11-2. 
Table 11-2 
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 
 
Hormone-releasing 
Yes 
Yes 
 
Non-hormone releasing 
Yes 
Yes 
Oral, implanted, injected, or vaginal hormonal 
contraceptives, if successfully used for at least 60 days 
before the first dose of study drug. 
Yes 
Yes 
a 
A female condom cannot be used with a male condom due to risk of tearing. 
Additional notes: 
• If over the course of the study the subject meets the criteria for waiving the contraception 
requirements, the subject does not need to follow the contraceptive methods listed in Table 
11-2.  
• If over the course of the study the subject’s status changes and the subject does not meet the 
criteria for waiving the contraception requirements, the subject must begin following the 
contraceptive methods listed in Table 11-2. 
• 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. 
• Female partners of male subjects should not plan to become pregnant during the study or 
within 90 days after the last dose of study drug, with the exception of those who plan to 


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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 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a subject, or the female partner of a male subject, becomes pregnant while participating in the 
study, the study drug will be permanently discontinued immediately. The investigator will 
1) notify the medical monitor and Vertex GPS within 24 hours of the site’s knowledge of the 
subject’s (or partner’s) pregnancy, and 2) send the Pregnancy Information Collection Form to 
Vertex GPS. 
If confirmed to be on active drug, the subject or partner will be followed until the end of the 
pregnancy and the infant will be followed for 1 year after the birth, provided informed consent 
(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 
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the statistical analysis plan (SAP), which will be finalized before the 
clinical data lock for the study and treatment unblinding. 
12.1 
Sample Size and Power 
Approximately 108 subjects will be enrolled and randomized (1:1) to the ELX/TEZ/IVA group 
or the placebo group.  
Power for Primary Efficacy Endpoint 
The primary efficacy endpoint is the absolute change in LCI2.5 from baseline through Week 24. 
The primary null hypothesis to be tested is that the mean absolute change in LCI2.5 from baseline 
through Week 24 is the same for the 2 treatment groups, ELX/TEZ/IVA and placebo. The null 
hypothesis will be tested at a 2-sided significance level of 0.05. 
Assuming a within-group SD of 1.5 and a treatment difference of -1.0 between ELX/TEZ/IVA 
and placebo, a sample size of 49 subjects completing the Treatment Period in each group for a 
total of 98 subjects will have approximately 90% power for the LCI2.5 hypothesis testing, based 
on a 2-sided 2-sample t-test at a significance level of 0.05. Assuming a 10% dropout rate, 
approximately 108 subjects will be enrolled. 
12.2 
Analysis Sets 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), and Safety 
Set. 
The All Subjects Set will include all subjects who were randomized or received at least 1 dose 
of study drug. This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified. 
The FAS will include all randomized subjects who carry the intended CFTR allele mutation and 
received at least 1 dose of study drug. The FAS will be used to summarize subject demographics 


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and baseline characteristics, and for analyses of all efficacy and PD endpoints in which subjects 
will be analyzed according to their randomized treatment group, unless otherwise specified. 
The Safety Set will include all subjects who received at least 1 dose of study drug. The Safety 
Set will be used for all safety analyses in which subjects will be analyzed according to the 
treatment they actually received, unless otherwise specified.  
12.3 
Statistical Analysis 
12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
number of subjects (n), mean, SD, median, minimum value (min), and maximum value (max).  
Categorical variables will be summarized using counts and percentages.  
Treatment-emergent (TE) period will include the time from the first dose of study drug in the 
Treatment Period (ELX/TEZ/IVA or placebo) through 28 days after the last dose or the 
completion of study participation date (as defined in Section 9.1.6), whichever occurs first. 
Baseline unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug. For ECG, 
baseline will be defined as the most recent pretreatment measurement, or the average of triplicate 
measurements if the most recent pretreatment measurement is obtained in triplicate, before the 
first dose of study drug.  
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
The number and percentage of subjects in each disposition category (e.g., randomized, included 
in the FAS, included in the Safety Set, completed Treatment Period, completed study, 
prematurely discontinued treatment or study with a breakdown of the reasons for 
discontinuation, and entered an open-label study) will be summarized by treatment group. 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographic, medical history, and baseline characteristics will be summarized using descriptive 
summary statistics. 
The following demographics and baseline characteristics will be summarized by treatment group 
for the FAS, and will include (but are not limited to): sex, race, age, weight, height, BMI, LCI2.5, 
ppFEV1, and SwCl. 
Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT).  
12.3.2.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug-Dictionary and 
categorized as follows: 


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• Prior medication: any medication that is administered during the 56 days before the first 
dose of study drug 
• 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 a prior medication, a concomitant medication, or a post-
treatment medication; both prior and concomitant; both concomitant and post-treatment; or prior, 
concomitant, and post-treatment. If a medication has a missing or partially missing start/end date 
or time and if it cannot be determined whether it was taken before the first dose of study drug, 
concomitantly during the TE Period, or after the TE Period, it will be considered in all 3 
categories of prior, concomitant, and post-treatment medication. 
 
Prior medications and concomitant medications will be summarized descriptively by Preferred 
Name based on the FAS. Post-treatment medications will be provided separately in an individual 
subject data listing.  
12.3.2.4 
Study Drug Exposure and Compliance 
Study drug exposure will be summarized by treatment group, based on the Safety Set in terms of 
the duration of treatment a subject received (in days), defined as the last day – the first day of 
study drug plus 1, regardless of study drug interruption. 
 
Study drug compliance will be summarized by treatment group based on the FAS, and 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 on that day.  
12.3.3 
Efficacy and Pharmacodynamic Analysis 
The primary objective of the study is the evaluation of the efficacy of ELX/TEZ/IVA. The 
analysis in this section will be based on the FAS, unless otherwise specified. 
12.3.3.1 
Analysis of Primary Endpoint 
The primary efficacy endpoint is the absolute change in LCI2.5 from baseline through Week 
24. The analysis of this endpoint will be performed using a mixed-effects model for repeated 
measures (MMRM) with absolute change from baseline in LCI2.5 at each post-baseline visit as 
the dependent variable. The model will include treatment group, visit, and treatment-by-visit 
interaction as fixed effects, and will be adjusted for main covariates as appropriate. Details will 
be described in the SAP. The primary result obtained from the model will be the estimated 
treatment difference through Week 24 (defined as the average of Weeks 4, 8, 16, 24), with a 
2-sided 95% CI and a 2-sided P value provided. The treatment difference at each post-baseline 
visit, obtained from the mode, will also be provided.  
 


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12.3.3.2 
Analysis of Secondary Endpoints 
• Absolute change in SwCl from baseline through Week 24 
The analysis of this pharmacodynamic endpoint will be based on an MMRM model similar to 
the analysis of the primary endpoint above, with absolute change from baseline in SwCl at each 
post-baseline visit as the dependent variable.   
 
The primary result obtained from the model will be the estimated treatment difference through 
Week 24. The LS mean estimate with a 2-sided 95% CI and a 2-sided P value will be provided. 
The treatment difference at each post-baseline visit, obtained from the model, will also be 
provided. 
12.3.4 
Safety Analysis  
All safety analyses will be based on the data from the TE period for all subjects in the Safety Set. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability assessments:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis as 
applicable) 
• Standard 12-lead ECGs 
• Vital signs 
• Pulse oximetry 
• Ophthalmological examinations 
Safety assessments will be analyzed based on the Safety Set. Only a descriptive analysis of 
safety will be performed. 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
• Pretreatment AE: any AE that 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, by treatment group, and will include the 
following: 


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• Overview of TEAEs 
• TEAEs and related TEAEs 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Serious TEAEs and related serious TEAEs 
• 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. 
Listings containing individual subject level AE data will be provided separately for: 
• Serious TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• TEAEs leading to death 
In addition, all AEs, including pre- and post-treatment AEs, will be presented in individual 
subject data listings. 
12.3.4.2 
Clinical Laboratory Assessments 
For the 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, by treatment group at each scheduled visit. 
For threshold analysis, the number and percentage of subjects meeting threshold criteria during 
the TE Period will be summarized by treatment group. Shift analysis from baseline to 
post-baseline will also be conducted by treatment group for selected laboratory parameters. The 
threshold criteria and selected parameters 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 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided by treatment group, 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). 


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For threshold analysis, the number and percentage of subjects meeting threshold criteria during 
the TE Period will be summarized by treatment group. The threshold criteria will be provided in 
the SAP.  
12.3.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized by treatment group at each scheduled visit. The following 
vital signs parameters will be summarized: systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), pulse rate (heart rate, beats per minute), and respiratory rate (breaths per 
minute). 
For threshold analysis, the number and percentage of subjects meeting threshold criteria during 
the TE Period will be summarized by treatment group. The threshold criteria will be provided in 
the SAP.  
12.3.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided by treatment group at each scheduled visit for the 
percent of oxygen saturation by pulse oximetry. 
Shift analysis from baseline to the lowest value of the percent of oxygen saturation during the TE 
Period will be performed by treatment group. 
12.3.4.6 
Ophthalmologic Examinations 
The ophthalmologic examination results will be presented in individual subject data listings. 
12.3.4.7 
Physical Examination 
PE findings will be presented in individual subject data listings only. 
12.3.5 
Interim and Data Monitoring Committee Analyses 
12.3.5.1 
Interim Analysis 
An optional interim analysis (IA) may be conducted during the study at the discretion of the 
sponsor. In the event that an IA is performed, multiplicity adjustment will be applied to control 
for family-wise type I error rate, and the details will be provided in the SAP.  
12.3.5.2 
Data Monitoring Committee Analysis 
The DMC will conduct regularly planned safety reviews of study data. Details of the safety 
reviews will be described in the DMC charter. 


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


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• 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: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials, 
September 2007, Center for Biologics Evaluation and Research, 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInfor
mation/Guidances/Vaccines/UCM091977.pdf (Accessed September 2019). AEs of CTCAE 
Grades 4 and 5 will be documented as “life-threatening.” When considering the severity of an 
AE in a pediatric subject, the investigator will consider that reference ranges for pediatric clinical 
laboratory parameters may differ from those in the CTCAE. The severity of an AE described by 
a term that does not appear in the CTCAE will be determined according to the definitions in 
Table 13-1. 
Table 13-1 
Grading of AE Severity  
Classification 
Definition 
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 (Moderate) 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADLa 
Grade 3 (Severe)  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADLb 
Grade 4 
(Life-threatening) 
Life-threatening consequences; urgent intervention indicated  
Grade 5 (Death) 
Death related to adverse event 
Source: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed September 2019) 
ADL: activities of daily living; AE: adverse event 
a 
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
b 
Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories in Table 13-2. 


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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 subject’s medical record). 
AE: adverse event 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
AE: adverse event 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 


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Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
AE: adverse event 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation and is suspected of being a delayed toxicity due to administration of the study 
drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious”, which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  


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13.1.2.2 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, regardless of causality, will be reported by the investigator to Vertex 
GPS within 24 hours of identification. In addition, all SAEs that occur after the Safety 
Follow-up Visit and are considered related to study drug(s) will be reported to Vertex GPS 
within 24 hours of identification.  
For SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, the SAE Form will be completed for new/initial events as well as to 
report follow-up information on previously reported events. Investigators are asked to report 
follow-up information as soon as it becomes available to ensure timely reporting to health 
authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email: 
(preferred choice) 
Fax:
  
For technical issues related to submitting the form, contact telephone: 
 
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) will 
be recorded on the Vertex Clinical Trial Safety Information Collection Form (hereafter referred 
to as the “SAE Form”) using a recognized medical term or diagnosis that accurately reflects the 
event. SAEs will be assessed by the investigator for relationship to the investigational study 
drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be assessed 
only as related (includes possibly related) or not related (includes unlikely related), and severity 
assessment will not be required. For the purposes of study analysis, if the event has not resolved 
at the end of the study reporting period, it will be documented as ongoing. For purposes of 
regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report the outcome to Vertex using the SAE Form. 
13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IECs, and 
participating investigators in accordance with ICH Guidelines and/or local regulatory 
requirements, as applicable. In addition, Vertex, or authorized designee, will be responsible for 
the submission of safety letters to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/IEC of all 
unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH E6 GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will be 
conducted only at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 


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(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
current ICH E6 GCP Guidelines 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 
numbers will be limited to the site and the study physician and will not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE Forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 


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For sites participating in the US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will comply with all HIPAA 
requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to current ICH E6 GCP Guidelines 
and/or applicable local regulatory requirement(s), whichever is longest, as described in the 
Clinical Trial Agreement. If the investigator withdraws from the responsibility of keeping the 
study records, custody will be transferred to a person willing to accept the responsibility and 
Vertex will be notified. 
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 scheduled contact) of the last subject. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each subject. Study 
data for each enrolled subject will be entered into a CRF by study site personnel using a secure, 


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validated, web-based electronic data capture (EDC) application. Vertex will have read-only 
access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database.  
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP Guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc or other electronic media will be placed in the investigator’s 
study file.  
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator's employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 


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The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 
13.7.2 
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. 2018 Patient Registry Annual Data Report. Bethesda, MD: 
2019. 
3 
European Cystic Fibrosis Society. 2017 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: 2019. 
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 JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, et al. 
Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 
1989;245(4922):1059-65. 
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;10:88. 
10 
Cystic Fibrosis Foundation. 2017 Patient Registry Annual Data Report. Bethesda, MD: 
2018. 
11 
European Cystic Fibrosis Society. 2016 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: European Cystic Fibrosis Society; 2018. 
12 
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. 
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 
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. 
22 
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. 
23 
Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
publication practice for communicating company-sponsored medical research: GPP3. 
Ann Intern Med. 2015;163(6):461-4. 
24 
International Committee of Medical Journal Editors (ICMJE). December 2017. 
Recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals. Available at: http://www.icmje.org/recommendations/. Accessed 03 
August 2018. 


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APPENDIX A 
Eligible MF CFTR Mutations 
“MF” mutations are a subset of minimal function mutations that are non-responsive to 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 VX19-445-116 
 
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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Non-exhaustive List of Minimal Function CFTR Mutations Eligible for VX19-445-116 
 
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;  
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. 
a 
Also known as 2183delAA>G.  
 


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15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol #: VX19-445-116 Version #: 
1.0 
Version 
Date: 
18 December 2019 
Study Title: A Phase 3b, Randomized, Placebo-controlled Study Evaluating the Efficacy and 
Safety of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Subjects 6 Through 11 Years of 
Age Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation 
(F/MF) 
This clinical study protocol has been reviewed and approved by the sponsor. 
Printed Name 
 
Title 
Signature 
 
Date 


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15.2 
Investigator Signature Page 
Protocol #:  VX19-445-116 Version #: 
1.0 
Version 
Date: 
18 December 2019 
Study Title: A Phase 3b, Randomized, Placebo-controlled Study Evaluating the Efficacy and 
Safety of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Subjects 6 Through 11 Years of 
Age Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation 
(F/MF) 
 
 
I have read Protocol VX19-445-116, Version 1.0, and agree to conduct the study according to its 
terms. I understand that all information concerning elexacaftor (ELX), tezacaftor (TEZ), and 
ivacaftor (IVA) and this protocol supplied to me by Vertex Pharmaceuticals Incorporated 
(Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 
 
 
 


Page 1 of 8 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol Addendum  
for Cystic Fibrosis  
Cystic Fibrosis Studies for the Following Programs 
Ivacaftor (VX-770) 
 
 
Elexacaftor/Tezacaftor/Ivacaftor (VX-445/VX-661/VX-770) 
 
 
Version and Date of Protocol Addendum: Version 3.0, 29 July 2020 
Replaces Version 2.0, dated 15 May 2020  
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 2 of 8 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes to Cystic Fibrosis Clinical Study Protocols 
Vertex is currently evaluating several CFTR modulators in clinical studies for the treatment of 
cystic fibrosis (CF), a serious and life-threatening disease. In completed studies, treatment with 
these CFTR modulators has generally resulted in rapid, robust, clinically meaningful, and 
statistically significant improvements in clinical measures, and are generally safe and well 
tolerated. Adverse events (AEs) seen with these treatments are mostly consistent with common 
manifestations of CF disease or with common illnesses in CF subjects.  
During this COVID-19 pandemic, the safety of the subjects, investigators, and site personnel 
participating in these clinical studies is Vertex’s first priority, thus it is important to minimize 
any unnecessary risk to COVID-19 exposure through travel to study sites. This addendum 
summarizes the measures taken for ongoing CF clinical studies. These operational adjustments 
were implemented to align with Health Authority guidance ensuring the protection of subjects, 
investigators, and site personnel while maintaining compliance with GCP and minimizing impact 
to the integrity of the studies. Overall, the benefit-risk of these studies remains favorable. 
Vertex recommends that subjects and sites refer to local guidance regarding travel restrictions. 
There are no operational changes to the study protocols for subjects who can travel to the study 
sites for their visits. However, to ensure continued safety of subjects who cannot travel to the 
study sites for their visits (for any reason due to COVID-19), specific alternative measures are 
being implemented to minimize the risk of exposure to COVID-19 (see table below). As the 
COVID-19 pandemic evolves, Vertex will continue to assess the need for additional actions to 
ensure the safety of all involved in these clinical studies. 
Addendum Version 3.0 summarizes additional measures taken for these ongoing CF clinical 
studies (see table below) to ensure continued safety. 
 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
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Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Rationale for Change 
Study Number 
Addendum Version 3.0, dated 29 July 2020 
Assessments 
 
Unscheduled visit(s) will be permissible at the discretion of the investigator(s) 
or Vertex. The unscheduled visit(s) may be conducted at any time during the 
study (including after the protocol defined last study visit) in the event 
assessments specified to be collected at a scheduled visit were not collected 
due to COVID-19.  
 
To ensure subject safety and/or to facilitate evaluation of 
safety and/or efficacy if assessments are not performed 
per the schedule in the protocol due to COVID-19. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VX19-445-116 
 
 
 
Implementaion of measures described in addenda versions 1.0 and 2.0, as 
applicable. 
To ensure subject safety and/or to facilitate evaluation of 
safety and/or efficacy while maintaining study integrity 
and the safety of subjects and site personnel. 
 
 
 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
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Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Rationale for Change 
Study Number 
Addendum Version 2.0, dated 15 May 2020 
Assessments 
 
Weight and height/length/stature may be assessed by subjects or their 
caregivers using medical grade scales and stadiometers, as indicated per 
protocol and per local regulation. Sites and subjects will receive training and 
guidance as needed on these devices.  
 
Subjects or caregivers will provide these measurements to site personnel by 
telephone or video call. Investigators will review results and contact subjects 
for follow-up as needed. All data will continue to be retained in the subject’s 
source files. 
To allow for collection of key data to assess safety and/or 
efficacy while maintaining study integrity and the safety 
of subjects and site personnel. 
 
Addendum 1 allowed for these assessments to be 
performed by qualified personnel conducting the in-home 
visits. Addendum 2 allows for these assessments to be 
performed by subjects or caregivers. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VX19-445-116 
 
 
 
 


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Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Consenting of Subjects 
ICFs may be provided electronically or by post mail to subjects (and/or caregivers, as 
indicated per protocol). The subjects and/or caregivers will review the ICF with an 
appropriately qualified member of the investigator’s team via telephone contact or video call. 
After this review, subjects and/or caregivers will consent (or assent, if applicable), and/or 
reconsent verbally and by signing and dating the ICF and returning it to the site via post mail. 
The signed and dated ICF will then be signed and dated by the investigator.  
 
Subjects participating in select studies may have the opportunity to enroll in longterm 
extension studies. Informed consent (or assent, if applicable), and/or reconsent for subjects 
(and/or caregivers, as indicated per protocol) may be obtained per the same process described 
above, as applicable. 
To provide alternative methods of 
obtaining reconsent or consent, as 
applicable, while ensuring subject 
safety. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VX19-445-116 
 
 
 
 
for telephone 
contact only 
Study Drug Shipping 
Study drug may be shipped directly from the site to the subject, as applicable, and if permitted 
by local regulations; subject protected health information will not be released to Vertex.  
 
Reconciliation, return, and destruction of study drug will continue to occur at the clinical site 
as indicated per protocol and in adherence to local regulations. 
To ensure subjects can continue 
treatment with study drug without 
interruption while ensuring their safety. 
 
To clarify that despite these alternative 
measures, reconciliation, return, and 
destruction of study drug will remain as 
indicated per protocol. 
In-home Visits and/or Telephone Contact 
Study visits may be conducted as in-home visits by qualified personnel as requested by 
participating sites on a per-subject basis. In addition, all subjects may be contacted by site 
personnel by telephone or video call, irrespective of in-home visits. 
To provide subjects the opportunity to 
continue participation in the clinical 
studies while ensuring their safety by 
minimizing the risk to COVID-19 
exposure through travel. 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 6 of 8 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Safety Assessments and Reporting 
Safety assessments, as indicated per protocol, may be performed by qualified personnel 
conducting the in-home visits (e.g., personnel from site or qualified health care agency). These 
assessments may include the following, as indicated per protocol, and per local regulation:  
• vital signs 
• pulse oximetry 
• height/length/stature 
• weight 
• physical examination 
(complete or abbreviated) 
• pregnancy test  
(serum or urine) 
• urinalysis 
• blood draws for safety test panels 
(chemistry, LFT panel, lipid panel, 
hematology, coagulation).  
Blood and/or urine samples for safety assessments are analyzed as indicated per protocol for 
subjects who have in-home visits. 
Blood and/or urine samples for safety assessments may be collected and analyzed at local 
laboratories for subjects who do not have in-home visits, but do not complete the assessment 
at the site. 
In addition, safety assessents will be evaluated by telephone. These assessments may include 
the review of the following:  
• AEs 
• signs and symptoms/systems for CF 
• medications 
• planned or unplanned hospitalizations for CF 
• study drug administration 
• outcomes related to PEx  
• outcomes related to antibiotic treatment 
Investigators will review results (in-home and telephone) and contact subjects for follow-up as 
needed. 
All data will continue to be retained in the subject’s source files. 
Any clinically significant finding (e.g., AE, SAE, laboratory abnormalities) will continue to be 
reported as indicated per protocol. 
To assess the safety and tolerability of 
the CFTR modulator evaluated in the 
specific clinical study while ensuring 
subject safety. These safety 
assessments will continue to provide 
safety data while minimizing burden to 
subjects and site personnel.  
 
To clarify that despite these alternative 
measures, all adverse events and 
serious adverse events should be 
reported as indicated per protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VX19-445-116 
 
 
 
 
for telephone 
contact and blood 
samples collected 
and analyzed at 
local laboratories 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
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Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Efficacy and Other Assessments 
Efficacy and other assessments, as indicated per protocol, may be performed by qualified 
personnel conducting the in-home visits. These assessments may include the following, as 
indicated per protocol, and per local regulation. 
In-home Spirometry Assessment 
A spirometry device may be provided to subjects for in-home assessments of lung function as 
indicated per protocol. Sites and subjects will receive training and guidance as needed. 
Other Assessments  
• ECGs  
• sweat chloride 
• blood samples for CFTR genotype testing, 
 PK, FSH, 
 
  
 
 
To be able to assess safety, treatment 
effectiveness, and quality of life 
measures of the CFTR modulator 
evaluated in the specific clinical study 
while ensuring subject safety. 
 
All Efficacy and 
Other 
Assessments 
 
 
 
 
 
 
 
  
 
VX19-445-116 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
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Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Remote Monitoring 
Vertex has implemented remote monitoring visits where applicable, including remote source 
data verification, as allowed per local regulations. Remote monitoring will focus on collection 
of safety data, and data supporting primary and key secondary endpoints. 
To allow for review of key data to 
inform on the safety of subjects 
receiving treatment. 
 
To allow for review of other key data 
to inform on the objectives of the study 
while maintaining study integrity and 
the safety of subjects and site 
personnel. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VX19-445-116 
 
 
 
AE: adverse event; CF: cystic fibrosis; 
 ECG: electrocardiogram; 
 
FSH: follicle-stimulating hormone; GCP: Good Clinical Practice; ICF: informed consent form; 
; LFT: liver function test; 
PEx: pulmonary exacerbation; PK: pharmacokinetic; SAE: serious adverse event; 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 29 
Protocol Number: VX19-445-116 
 
 
Vertex Pharmaceuticals Incorporated 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX19-445-116 Version 1.0 
(Final Analysis) 
 
 
A Phase 3b, Randomized, Placebo-controlled Study Evaluating the 
Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Cystic 
Fibrosis Subjects 6 Through 11 Years of Age Who Are Heterozygous 
for the F508del Mutation and a Minimal Function Mutation (F/MF) 
 
Authors of SAP: 
 
 
Version: 1.0 
Version Date of SAP: 23 May 2021 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods) 
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Vertex Pharmaceuticals Incorporated 
 
2 
TABLE OF CONTENTS 
 
1 
Title Page ................................................................................................................................ 1 
2 
Table of Contents ................................................................................................................... 2 
4 
Introduction ............................................................................................................................ 5 
5 
Study Objectives .................................................................................................................... 5 
5.1 
Primary Objective ............................................................................................................. 5 
5.2 
Secondary Objectives ....................................................................................................... 5 
6 
Study Endpoints ..................................................................................................................... 5 
6.1 
Primary Endpoint .............................................................................................................. 5 
6.2 
Secondary Endpoints ........................................................................................................ 5 
 
 
7 
Study Design ........................................................................................................................... 6 
7.1 
Overall Design .................................................................................................................. 6 
7.2 
Sample Size and Power .................................................................................................... 6 
7.3 
Randomization .................................................................................................................. 7 
7.4 
Blinding and Unblinding .................................................................................................. 7 
8 
Analysis Sets ........................................................................................................................... 7 
8.1 
All Subjects Set ................................................................................................................ 7 
8.2 
Full Analysis Set ............................................................................................................... 7 
8.3 
Safety Set .......................................................................................................................... 7 
9 
Statistical Analysis ................................................................................................................. 7 
9.1 
General Considerations .................................................................................................... 7 
9.2 
Background Characteristics .............................................................................................. 8 
9.2.1 
Subject Disposition ................................................................................................... 8 
9.2.2 
Demographics and Baseline Characteristics ............................................................. 9 
9.2.3 
Medical History ...................................................................................................... 10 
9.2.4 
Prior and Concomitant Medications ....................................................................... 10 
9.2.5 
Study Drug Exposure .............................................................................................. 10 
9.2.6 
Study Drug Compliance ......................................................................................... 10 
9.2.7 
Important Protocol Deviations ................................................................................ 11 
9.3 
Efficacy Analysis ............................................................................................................ 11 
9.3.1 
Analysis of Primary Efficacy Endpoint .................................................................. 11 
9.3.2 
Analysis of Secondary Endpoint ............................................................................ 12 
 
 
9.4 
Safety Analysis ............................................................................................................... 14 
9.4.1 
Adverse Events ....................................................................................................... 14 
9.4.2 
Clinical Laboratory ................................................................................................. 16 
9.4.3 
Electrocardiogram .................................................................................................. 16 
9.4.4 
Vital Signs .............................................................................................................. 17 


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9.4.5 
Pulse Oximetry ....................................................................................................... 17 
9.4.6 
Ophthalmology Examination .................................................................................. 17 
9.4.7 
Physical Examination ............................................................................................. 17 
9.4.8 
COVID-19 Impacted Visits .................................................................................... 17 
10 Interim and DMC Analyses ................................................................................................ 17 
10.1 Interim Analysis ............................................................................................................. 17 
10.2 DMC analysis ................................................................................................................. 17 
11 References ............................................................................................................................. 18 
12 List of Appendices ................................................................................................................ 19 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessment ........................... 19 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 22 
 
Appendix D: Imputation Rules for Missing AE dates ............................................................. 24 
Appendix E: Criteria for Threshold Analysis .......................................................................... 25 
Appendix F: Adverse Events of Special Interest ..................................................................... 29 
 
 




Statistical Analysis Plan (Methods) 
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Vertex Pharmaceuticals Incorporated 
 
4 
INTRODUCTION 
This statistical analysis plan (SAP) is based on the most recent approved clinical study protocol 
(CSP), the most recent approved electronic case report form (eCRF), and the most recent 
approved eCRF completion guidelines.  
This SAP (Methods) documents the planned statistical analyses of efficacy and safety endpoints 
defined in the VX19-445-116 study protocol. 
 
  
The Vertex Biometrics Department will perform the statistical analysis of efficacy and safety 
data; SAS (Version 9.4 or higher) will be used to generate all statistical outputs (tables, figures, 
listings, and datasets). The SAP will be finalized and approved prior to the clinical database lock 
and treatment unblinding for the study. Any revisions to the approved SAP will be documented 
and approved in an amendment prior to the clinical database lock and treatment unblinding. Any 
changes made to the SAP (Methods) after the clinical database lock has occurred will be 
documented in the clinical study report for this study. 
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
To evaluate the efficacy of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) in subjects 6 
through 11 years of age with cystic fibrosis (CF), heterozygous for F508del and a minimal 
function (MF) mutation (F/MF). 
5.2 
Secondary Objectives  
• To evaluate the pharmacodynamics (PD) of ELX/TEZ/IVA 
• To evaluate the safety of ELX/TEZ/IVA 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
• Absolute change in lung clearance index2.5 (LCI2.5) from baseline through Week 24 
6.2 
Secondary Endpoints 
• Absolute change in sweat chloride (SwCl) from baseline through Week 24 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
standard 12-lead electrocardiograms (ECGs), vital signs, pulse oximetry 


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7 
STUDY DESIGN  
7.1 
Overall Design  
This is a Phase 3b, randomized, double-blind, placebo-controlled, parallel-group, multicenter 
study in CF subjects aged 6 through 11 years who are heterozygous for the F508del mutation and 
a minimal function mutation (F/MF genotypes), as shown in Figure 7-1. 
Figure 7-1 
VX19-445-116 Study Design 
ELX: elexacaftor; IVA: ivacaftor; N: number of subjects; TEZ: tezacaftor  
a 
The Safety Follow-up Visit is scheduled to occur 28 days (± 7 days) after the last dose.  
b 
Subjects who complete the visits in the Treatment Period, regardless of whether they are on a treatment 
interruption, will be offered the opportunity to enroll in an optional open-label extension safety study 
evaluating ELX/TEZ/IVA. The Safety Follow-up Visit is not required for subjects who complete the Week 
24 Visit and have enrolled in an open-label study within 28 days after the last dose of study drug.  
Approximately 108 subjects are planned to be randomized (1:1) to the ELX/TEZ/IVA group or 
the placebo group. Randomization will be stratified by LCI2.5 determined at the Screening Visit 
(<10 versus ≥10) and weight at the Screening Visit (<30 kg versus ≥30 kg). 
The planned dosages to be evaluated are shown in Table 7-1. 
Table 7-1 
Treatment Period Groups and Dosages 
Treatment Group 
  Weight at Screening Visit 
ELX Dosage 
TEZ Dosage 
IVA Dosage 
ELX/TEZ/IVA 
 
 
 
   <30 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
   ≥30 kg 
200 mg qd 
100 mg qd 
150 mg q12h 
Placebo 
0 mg 
0 mg 
0 mg 
ELX: elexacaftor; IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TEZ: tezacaftor 
7.2 
Sample Size and Power 


Statistical Analysis Plan (Methods) 
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Assuming a within-group SD of 1.5 and a treatment difference of -1.0 between ELX/TEZ/IVA 
and placebo, a sample size of 49 subjects completing the Treatment Period in each group for a 
total of 98 subjects will have approximately 90% power for the LCI2.5 hypothesis testing, based 
on a 2-sided 2-sample t-test at a significance level of 0.05. Assuming a 10% dropout rate, 
approximately 108 subjects will be enrolled. 
All power calculations were based on EAST software Version 6.4. 
7.3 
Randomization 
Randomization will be stratified by LCI2.5 determined at the Screening Visit (<10 versus ≥10) 
and weight at the Screening Visit (<30 kg versus ≥30 kg). 
Randomization will occur before the first dose of study drug during the Treatment Period and 
may occur on either Day 1 or Day -1. 
7.4 
Blinding and Unblinding 
Refer to the CSP Section 10.7 for details. 
8 
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), and Safety 
Set.  
8.1 
All Subjects Set 
The All Subjects Set will include all subjects who are randomized 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 
Full Analysis Set  
The FAS will include all randomized subjects who 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 all efficacy analyses in which subjects will be analyzed 
according to their randomized treatment group, unless otherwise specified. 
8.3 
Safety Set 
The Safety Set will include all subjects who receive at least 1 dose of study drug. This safety set 
will be used for all safety analyses in which subjects will be analyzed according to the treatment 
they receive, unless otherwise specified. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max).  
Categorical variables will be summarized using counts and percentages.  


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Baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
Treatment Period.  
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. 
Treatment-emergent (TE) Period will include the time from the first dose date of study drug to 
28 days after the last dose of the study drug or to the date of completion of study participation, 
whichever occurs first. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
1) In scheduled visit windows per specified visit windowing rules 
2) In the derivation of baseline and last on-treatment measurements 
3) In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values during TE period for safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: 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 
A disposition table will be provided with the number of subjects in:  
• All Subjects Set 
• Randomized 
• Randomized but not dosed 
• Full Analysis Set 
• Safety Set 
The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized by treatment group and overall: 
• Completed treatment 
• Prematurely discontinued treatment and the reason for discontinuation 
• Completed study 
• Prematurely discontinued the study and the reason for discontinuation  
• Rollover to the open-label study 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation.  


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9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the FAS and presented 
by treatment group and overall. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other, and not collected per local regulations) 
• Country 
Baseline characteristics will include the following: 
• Weight (kg) 
• Weight z-score 
• Height (cm) 
• Height z-score 
• BMI (kg/m2) 
• BMI z-score 
Stratification categories will include the following: 
• LCI2.5 at the Screening Visit (<10 versus ≥10) 
• Weight at the Screening Visit (<30 kg, and ≥30 kg) 
Disease characteristics will include the following: 
• LCI2.5 at baseline (continuous) 
• SwCl at baseline (continuous) 
• 
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) 
• Prior use of any inhaled corticosteroids (Yes, No) 
In addition, data listings will also be provided for: 
• Informed consent 


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• Inclusion/Exclusion criteria violation for subjects with any such violations 
9.2.3 
Medical History 
Medical history will be coded by 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. 
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD) 
and categorized as follows: 
Prior medication: any medication that was administered during the 56 days before the first dose 
of study drug.  
Concomitant medication: medication continued or newly received during the TE period. 
Post-treatment medication: medication continued or newly received after the TE period. 
A given medication may be classified as a prior medication, a concomitant medication, or a post-
treatment medication; both prior and concomitant; both concomitant and post treatment; or prior, 
concomitant, and post treatment.  
If a medication has a missing or partially missing start/end date or time and if it cannot be 
determined whether it was taken before the first dose of study drug, concomitantly during the TE 
Period, or after the TE Period, it will be classified as prior, concomitant, and post treatment 
medication. Details for imputing missing or partial start and/or stop dates of medication are 
described in Appendix B. 
For FAS, prior medications and concomitant medications will be summarized descriptively using 
frequency tables by: 1) treatment group and overall, preferred name (PN); and 2) treatment group 
and overall, anatomic class (ATC) level 1, ATC level 2, and PN. Post-treatment medications will 
be also included in the medication listing. 
9.2.5 
Study Drug Exposure  
Study drug exposure will be summarized based on the Safety Set and will be presented by 
treatment group. 
Duration of study drug exposure (in weeks) will be calculated as: (last dose date of study drug – 
first dose date of study drug + 1)/7, regardless of study drug interruption.  
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max. It will also be summarized by interval, using counts and 
percentages.  
9.2.6 
Study Drug Compliance 
Study drug compliance will be summarized based on the FAS and will be presented by treatment 
group and overall.   
Study drug compliance will be calculated as: 100 × [1 - (total number of days of study drug 
interruption) / (duration of study drug exposure in days)]. A study drug interruption on a given 
day is defined as an interruption of any study drugs on that day. A study drug interruption that 


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Vertex Pharmaceuticals Incorporated 
 
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. 
9.2.7 
Important Protocol Deviations  
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. IPD rules will be developed and finalized before database lock.  
The protocol deviations that should be considered as potential IPDs include, but are not limited 
to:  
• Subject was enrolled in the study despite the violation of inclusion/exclusion criteria  
• Subject was less than 80% compliant with study drug for non-safety reasons 
• Subject received prohibited concomitant medications  
• Subject received the wrong treatment or incorrect doses  
Occurrence of any of these events should be considered as potential IPDs, but a blinded team 
should categorize them as IPDs only if they have the potential to significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being.  
IPDs (from the clinical database or from the site deviation log) will be summarized descriptively 
based on the FAS and presented by treatment group and overall. Additionally, IPDs will be 
provided in an individual subject data listing.  
9.3 
Efficacy Analysis  
Unless otherwise defined, all efficacy analyses described in this section will be based on the 
FAS.  
9.3.1 
Analysis of Primary Efficacy Endpoint 
9.3.1.1 
Definition of Variable 
The primary efficacy endpoint is the absolute change in LCI2.5 from baseline through Week 24.  
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 valid LCI value at 
each visit based on the multiple attempt 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. 


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9.3.1.2 
Primary Analysis  
The primary analysis will be performed using a mixed-effects model for repeated measures 
(MMRM) with the absolute change from baseline at each post-baseline visit as the dependent 
variable. The model will include treatment group, visit, and treatment-by-visit interaction as 
fixed effects, with continuous baseline LCI2.5 and weight at Screening (<30 versus ≥30 kg) as 
covariates. The model will be estimated using restricted maximum likelihood. Denominator 
degrees of freedom for the F-test for fixed effects will be estimated using the Kenward-Roger 
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 and therefore will be handled by MMRM model.  
The primary result obtained from the model will be the estimated treatment difference through 
Week 24 (defined as the average of Weeks 4, 8, 16, 24). Data obtained from Day 15, Week 4, 
Week 8, Week 16, and Week 24 Visits will be included in the model, but the Day 15 Visit will 
not be included in the estimation of the average treatment effect through Week 24. The least 
squares (LS) mean estimate with a 2-sided 95% CI and a 2-sided P value will be provided. The 
treatment difference at each post-baseline visit, obtained from the model, will also be provided. 
The LS mean (with SE) obtained from the MMRM analysis at each post-baseline visit up to 
Week 24 will be plotted by treatment group. In addition, the post-baseline raw values and the 
absolute change from baseline at each post-baseline visit up to Week 24 will be summarized 
descriptively (n, mean, SD, median, minimum, and maximum). 
9.3.2 
Analysis of Secondary Endpoint  
9.3.2.1 
Definition of Variable 
Sweat chloride (SwCl): the SwCl value for a given visit will be calculated as the mean of the 
non-missing sweat chloride measurements obtained on the left and right arms at that visit.  If one 
of the two arm measurements at a time point is missing, the other will be used as the mean.  A 
volume ≥15 μL is required for an accurate determination of sweat chloride.  Any results reported 
as having volume <15 μL will be considered missing.  Any sweat chloride values reported as 
<10 mmol/L or >160 mmol/L will be considered missing. 
9.3.2.2 
Analysis Method 
Absolute change in SwCl from baseline through Week 24 will be analyzed based on an MMRM 
that is the same as the primary efficacy endpoint. Data obtained from Day 15, Week 4, Week 8, 
Week 16, and Week 24 Visits will be included in the model, but the Day 15 Visit will not be 
included in the estimation of the average treatment effect through Week 24. The primary result 
obtained from the model will be the estimated treatment difference through Week 24 (defined as 
the average of Weeks 4, 8, 16, 24). The LS mean estimate with a 2-sided 95% CI and a 2-sided 
nominal P value will be provided. The treatment difference at each post-baseline visit, obtained 
from the model, will also be provided. 
The LS mean (with SE) obtained from the MMRM analysis at each post-baseline visit up to 
Week 24 will be plotted by treatment group. In addition, the post-baseline raw values and the 
absolute change from baseline at each post-baseline visit up to Week 24 will be summarized 
descriptively (n, mean, SD, median, minimum, and maximum). 




Statistical Analysis Plan (Methods) 
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9.4 
Safety Analysis 
All safety analyses will be based on data from the TE period for all subjects in the Safety Set, 
unless otherwise specified. Subjects will be analyzed according to the treatment they actually 
received in the Treatment Period. For subjects receiving study drug from more than one 
treatment group, the treatment group allocation will be ELX/TEZ/IVA. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability assessments:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values 
• 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  
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  
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed at 
or after the first dose date of study drug through the end of the TE period 
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was newly 
developed after the TE period 
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs are pretreatment or post-treatment, the AEs will be classified as TEAEs.  
Details for imputing missing or partial start dates of adverse events are described in Appendix D. 
An overview of all TEAEs by treatment group and overall will be summarized in the following 
categories: 
• Number of TEAEs  


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• Subjects with any TEAEs  
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation  
• Subjects with TEAEs leading to study drug interruption 
• 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 by MedDRA System Organ Class 
(SOC) and Preferred Term (PT) using frequency counts and percentages (i.e., number and 
percentage of subjects with an event), and by treatment group:  
• All TEAEs 
• Grade 3/4 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Related TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to death 
When summarizing the number and percentages of subjects, subjects with multiple occurrences 
of the same adverse event or a continuing adverse event will be counted once, and only the 
maximum severity level will be presented in the severity summaries, and the strongest 
relationship level in the relationship summaries.  
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, listings containing 
individual subject adverse event data for TEAEs leading to treatment discontinuation, TEAEs 
leading to treatment interruption, Grade 3/4 TEAEs, SAEs and all deaths will be provided 
separately, with a flag indicating the TEAE status for SAEs and deaths. 
9.4.1.1 
Adverse Events of Special Interest 
For this study, elevated transaminase events and rash events, as determined by MedDRA 
preferred terms in Appendix F, are considered as adverse events of special interest. 
For treatment-emergent elevated transaminase events and rash events, the following categories 
will be summarized by treatment group: 
• Subjects with events 


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• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 
• Subjects with serious events 
• Subjects with related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event 
9.4.2 
Clinical Laboratory 
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 by treatment group at each visit. 
The number and percentage of subjects meeting at least 1 threshold analysis criterion, during the 
TE period, will be summarized by treatment group. The threshold analysis of shift from baseline 
will also be summarized for LFT laboratory parameters. The threshold analysis criteria are 
provided in Appendix E. 
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 by treatment group. 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 by treatment group.  
Results of urinalysis and positive urine/serum pregnancy test will be listed in individual subject 
data listings only. For positive serum pregnancy listing, subjects with serum HCG which are 
abnormally high will be selected. 
In addition, a listing containing individual subject hematology, chemistry, and coagulation values 
will be provided. This listing will include data from both scheduled and unscheduled visits.  
9.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided at each visit by treatment group for the following ECG interval 
measurements (in msec): RR interval, PR interval, QT interval, QTcF interval, QRS duration, 
and Heart Rate (beats per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period will be summarized by treatment group. 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.  


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9.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each visit by treatment group. The following vital signs 
parameters will be summarized: weight (kg), weight-for-age z-score, height (cm), height-for-age 
z-score, BMI (kg/m2), BMI-for-age z-score, systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), pulse rate (beats per minute), and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period will be summarized by treatment group. The threshold analysis criteria are provided in 
Appendix E. 
In addition, a listing containing individual subject vital signs values will be provided. This listing 
will include data from both scheduled and unscheduled visits.  
9.4.5 
Pulse Oximetry 
For the treatment-emergent oxygen saturation values by pulse oximetry, a summary of observed 
values and change from baseline values will be provided at each visit by treatment group. 
The number and percentage of subjects with shift from baseline category (classified as 
normal/missing and low according to the reference range) to the category at the lowest percent of 
oxygen saturation during the TE period will be summarized by treatment group. The reference 
range for normal oxygen saturation is specified as >95%, and <=95% for low oxygen saturation. 
9.4.6 
Ophthalmology Examination  
Ophthalmology examination results will be provided in an individual subject data listing.  
9.4.7 
Physical Examination  
Abnormal PE findings will be presented as an individual subject data listing only. 
9.4.8 
COVID-19 Impacted Visits  
A listing containing subjects’ visits impacted due to COVID-19 will be provided. 
10 
Interim and DMC Analyses 
10.1 
Interim Analysis 
No interim analysis is planned at this moment; otherwise, SAP will be amended. 
10.2 
DMC analysis 
The DMC’s objectives and operational details have been defined in a separate document (DMC 
Charter) which was finalized before the first subject was screened in the study. The DMC’s 
planned safety reviews of study data is outlined in the DMC Charter and DMC Statistical 
Analysis Plan.  


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11 
REFERENCES 
2  Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 
4 Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of life 
for children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45. 
5 Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life measure for 
children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32. 
6 Rubin, DB. and Schenker, N.. Interval estimation from multiply-imputed data: a case study 
using agriculture industry codes. Journal of the American Statistical Association. 1987; 81: 
366–374. 
7 O'Brien PC, Fleming TR. A Multiple Testing Procedure for Clinical Trials. Biometrics. 
1979;35(3):549-56. 
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 Assessment
 
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3, 4, 5 
Safety Assessment  
Serum Chemistry 
Hematology 
 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
113 
169 
Not applicable 
≤1 Pre-dose 
[1, 22] 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 183] 
Use nominal visit 
Standard 12-lead ECG 
Day 1 (Baseline)  
Week 8 
Week 16 
Week 24 
Safety Follow-up 
1 
57 
113 
169 
Not applicable 
≤1 Pre-dose 
[1, 85] 
(85, 141] 
(141, 183] 
Use nominal visit 
Vital signs (excluding BMI, 
Weight and Height, and their 
z-scores) and pulse oximetry  
 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
113 
169 
Not applicable 
≤1 
[1, 22] 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 183] 
Use nominal visit 
Coagulation 
 
Day 1 (Baseline)  
Week 24 
 
1 
169 
 
≤1 Pre-dose 
[1, 183] 
 
BMI, Weight, Height and the 
corresponding z-scores 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
Week 16 
Week 24 
Safety Follow-up 
1 
15 
29 
57 
113 
169 
Not applicable 
≤1 
(1, 22] 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 183] 
>183 
Efficacy Assessment and Pharmacodynamic Assessment  


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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3, 4, 5 
Sweat Chloride  
Lung Clearance Index (LCI) 
Day 1 (Baseline)  
Day 15 
Week 4 
Week 8 
Week 16 
Week 24 
1 
15 
29 
57 
113 
169 
≤1 Pre-dose 
(1, 22] 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 183]
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 
 
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 >183, then the ETT visit will be 
mapped into Safety Follow-up analysis visit. 
5 For efficacy assessments and nutrition variables (BMI, Weight, Height and their Z-scores), if there are multiple 
assessments >183, then nominal Safety Follow-up visit will be mapped to Safety Follow-up visit. If there is only 
ETT assessment > 183, the ETT visit will be mapped to the Safety Follow-up visit; else if there are multiple 
assessments with >183 then select the earliest record.   
 
Derived Variables: 
1. Age (in years) at first dose date and nominal visit (for demographics, listing and the calculation of [percent] 
predicted spirometry variables): 
Obtain the age at informed consent (in days) in “yy, mm” format (e.g., 24 years, 6 months) from the Vital Signs 
(VS) page at the Screening Visit, and add 0.5 month to convert to days. 
Obtain the informed consent date. 
Then age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed consent 
date) in days + age at informed consent (in days)]/365.25. 


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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3, 4, 5 
2. Age (in months) at nominal visit (for use in calculation of BMI, height and weight z-score): 
Obtain the age at informed consent (in months) in “yy, mm” format (e.g., 24 years, 6 months) from Vital Signs 
(VS) page at the Screening Visit. 
Obtain the informed consent date. 
Then age (in months) at nominal visit = integer part of {[(age at informed consent (in months) + 0.5 + diff(first 
dose date or nominal visit date, informed consent date) in months]} + 0.5. 
3. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date to impute. 
If the last dose date is missing or partial date is reported, the last dose date will be imputed based on, in 
descending order priority, the Early Treatment Termination (ETT) visit date, last visit date before the Safety 
Follow-up, or the last study drug administration date from EX SDTM domain, as appropriate.  The imputation 
algorithm will ensure the imputed last dose date does not exceed the study participation end date. 
4. Sweat Chloride: 
Non-missing sweat chloride concentrations from the left arm and right arm with assessment end date/time for a 
given arm up to 30 minutes after first dose time in treatment period will be considered for baseline. 
5. Electrocardiogram: 
Baseline is defined as the most recent pretreatment measurement before the first dose of study drug in the 
Treatment Period.  If multiple ECG measurements are obtained on the same calendar day during the TE period,  
o 
For summary purpose, the calculated average ECG will be used as the ECG value on that day; 
o 
For threshold analysis purpose, all reported ECG values will be used. 
 
 
 
 
 
 


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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 the inform consent date to impute). 
2. Missing or partial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month and year are all missing, assign ‘continuing’ status to stop date (in 
practical, use the end of study date to impute). 
In summary, the prior, concomitant, or post categorization of a medication is described below. 
Table 12-2 
Prior, Concomitant, and Post Categorization of a Medication  
Medication Start Date 
Medication Stop Date 
< First Dose Date of 
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. 
 
 




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


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Appendix E: Criteria for Threshold Analysis 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 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. 
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.  
 


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Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
(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 
>1x -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon 
CTCAE 
Creatinine 
>ULN - ≤ 1.5xULN 
>1.5x - ≤ 3xULN 
>3x - ≤ 6xULN 
>6xULN 
CTCAE grades 1-4 
Lipase 
>ULN -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon 
CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine kinase 
>ULN - ≤ 2.5xULN 
>2.5x - ≤ 5xULN 
>5x - ≤ 10xULN  
>10xULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L  
< 80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥ 75 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 
 


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Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Reticulocytes/Erythrocytes 
(%)    
<LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated partial 
thromboplastin time  (PTT)  
 
>ULN - ≤ 1.5xULN 
>1.5x – ≤ 2.5xULN 
>2.5xULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤ 1.5xULN 
>1.5x – ≤ 2.5xULN 
>2.5xULN 
CTCAE grade 1-3 
  
Table 12-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
≤50 bpm  
 
 
Tachycardia 
≥140 bpm 
 
PR 
≥200 ms and increase from baseline ≥20 ms 
 
QRS 
≥120 ms 
 
QTc 
 
Absolute values (ms) 
>450 ms (Male) or >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 12-5 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Pulse Rate 
Same as above in ECG category 
 
SBP 
 
>120 mmHg 
< 70 mmHg 
 
DBP  
>80 mmHg 
<50 mmHg 
 
Weight   
Weight gain  
≥5 % increase from baseline    
CTCAE grade 1-3 
 
 
Weight loss  
≥5 % decrease from baseline    
CTCAE grade 1-3 
 
 


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Table 12-6 
Threshold Analysis Criteria for Laboratory Tests  
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT or AST 
>3xULN 
>5xULN 
>8xULN 
 
 
 


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Appendix F: Adverse Events of Special Interest  
Table 12-3 
MedDRA Preferred Terms for Event of Special Interest 
Adverse event of special interest 
MedDRA preferred terms 
Elevated transaminases 
Alanine aminotransferase abnormal, Alanine aminotransferase 
increased, Aspartate aminotransferase abnormal, Aspartate 
aminotransferase increased, Transaminases abnormal, 
Transaminases increased, Liver function test abnormal, Liver 
function test increased, Hypertransaminasaemia, Hepatic 
enzyme abnormal, Hepatic enzyme increased 
Rash 
Rash, Rash erythematous, Rash macular, Rash maculo-papular, 
Rash maculovesicular, Rash vesicular, Rash pruritic, Rash 
follicular, Rash pustular, Nodular rash, Drug eruption, Fixed 
eruption, Urticaria, Urticaria papular, Urticaria vesiculosa, 
Urticarial dermatitis, Rash morbilliform, Rash papular, Rash 
papulosquamous, Rash rubelliform, Rash scarlatiniform , Drug 
hypersensitivity, Type IV hypersensitivity reaction, Dermatitis, 
Dermatitis atopic, Epidermolysis, Skin toxicity, Dermatitis 
allergic, Dermatitis exfoliative, Dermatitis exfoliative 
generalised, Erythema multiforme, Exfoliative rash, 
Mucocutaneous rash, Acute generalised exanthematous 
pustulosis, Cutaneous vasculitis, Urticarial vasculitis, Dermatitis 
bullous, Drug reaction with eosinophilia and systemic 
symptoms, Epidermal necrosis, Oculomucocutaneous syndrome, 
Skin exfoliation, Skin necrosis, Stevens-Johnson syndrome, 
Toxic epidermal necrolysis, Toxic skin eruption, Perioral 
dermatitis, Vasculitic rash, Immune-mediated dermatitis, Penile 
rash, SJS-TEN overlap, Erythrodermic atopic dermatitis, Scrotal 
dermatitis, Anal Rash, generalised bullous fixed drug eruption 
Note: the preferred terms listed in the table is based on the MedDRA version applicable at the time of 
finalization of the SAP.  If the MedDRA version is upgraded at the time of the analysis, the 
corresponding preferred terms based on the upgraded version, including adding, removing and 
renaming the preferred terms, will be used in the analysis of adverse events of special interest.