Clinical trial NCT05274269
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2022-05-09; Completion date: 2023-07-05
Enrollment: 307 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluated the efficacy, pharmacodynamics (PD) and safety of ELX/TEZ/IVA in participants 6 years of age and older with a non-F508del ELX/TEZ/IVA-responsive cystic fibrosis transmembrane conductance regulator gene (CFTR) mutation.

Detailed description:

Arms: arm 1: Participants received placebo matched to ELX/TEZ/IVA FDC in the morning and placebo matched to IVA in the evening for 24 weeks. arm 2: Participants 6 to less than (\<) 12 years of age and weighing \<30 kilogram (kg) at Day 1 received ELX 100 milligram (mg)/TEZ 50 mg /IVA 75 mg as fixed dose combination (FDC) tablets in the morning and IVA as mono tablet in the evening and those weighing more than or equal to (≥) 30 kg at Day 1 received ELX 200 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA as mono tablet in the evening for 24 weeks. Participants ≥12 years age at Day 1 received ELX 200 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA as mono tablet in the evening 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 (FDC) tablets for oral administration. intervention 2: Tablet for oral administration. intervention 3: Placebo matched to ELX/TEZ/IVA for oral administration. intervention 4: Placebo matched to IVA for oral administration.

Protocol documents:
Prot_000.pdf: 


Protocol VX21-445-124, Version 3.0 
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Summary of Changes to the Protocol 
The previous version of this protocol (Version 2.0, 24 January 2022) was amended to create the 
current version (Version 3.0, 21 April 2022). The protocol history is provided below. 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 12 October 2021 
Original version 
Version 2.0, 24 January 2022 
Additional ELX/TEZ/IVA-responsive mutations were added to the list of 
qualifying CFTR mutations.  
Version 3.0, 21 April 2022 
Current version 
 
Key changes in the current version of the protocol are summarized below.  
Change and Rationale 
Affected Sections  
The range of qualifying ppFEV1 values was expanded to broaden the eligible 
population. Specifically, the maximum ppFEV1 value was increased from 90% to 
100%. 
Section 8.1, Inclusion 
Criterion 6 
Specified that up to 10% of subjects may be enrolled with a screening ppFEV1 value 
>90% and ≤100% (approximately 27 subjects). 
Sections 2 and 9.1 
For the exclusion criterion related to medical history, a history of hypersensitivity to 
any component of the investigational drug product or placebo was added to the list of 
clinical conditions that might confound the results of the study or pose an additional 
risk in administering study drug(s) to the subject. 
Section 8.2, Exclusion 
Criterion 1 
Blood sample volumes to be drawn at each study visit are presented in Appendix B 
Section 16 
 
Typographical and administrative changes were also made to improve the clarity of the 
document. 
 


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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3 Double-blind, Randomized, Placebo-controlled Study Evaluating the 
Efficacy and Safety of ELX/TEZ/IVA in Cystic Fibrosis Subjects 6 Years of Age 
and Older With a Non-F508del ELX/TEZ/IVA-responsive CFTR Mutation 
 
 
Brief Title 
Evaluation of Efficacy and Safety of ELX/TEZ/IVA in Subjects Without an 
F508del Mutation 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 3 efficacy and safety  
 
 
Objectives 
Primary Objective:  
To evaluate the efficacy and pharmacodynamics (PD) of ELX/TEZ/IVA  
 
Secondary Objective:  
To evaluate safety and tolerability of ELX/TEZ/IVA 
 
 
Endpoints 
Primary Endpoint: 
• 
Absolute change from baseline in percent predicted forced expiratory 
volume in 1 second (ppFEV1) through Week 24 
Secondary Endpoints: 
• 
Absolute change from baseline in sweat chloride (SwCl) through Week 24 
• 
Absolute change from baseline in Cystic Fibrosis Questionnaire - Revised 
(CFQ-R) respiratory domain (RD) score through Week 24 
• 
Absolute change from baseline in body mass index (BMI) at Week 24 
• 
Absolute change from baseline in weight at Week 24 
• 
Number of pulmonary exacerbations (PEx) through Week 24 
• 
Safety and tolerability assessments based on adverse events (AEs), clinical 
laboratory values, ECGs, vital signs, and pulse oximetry 
Other Endpoints: 
• 
Absolute change from baseline in BMI z-score (subjects ≤20 years of age) at 
Week 24 
• 
Absolute change from baseline in weight z-score (subjects ≤20 years of age) 
at Week 24 
• 
Plasma PK parameters including ELX, TEZ, IVA, and relevant metabolites 
 
 
Number of Subjects 
Approximately 270 subjects will be enrolled in the study with up to approximately 
30 subjects per CFTR mutation. Up to 10% of subjects may be enrolled with a 
screening ppFEV1 value >90% and ≤100% (approximately 27 subjects). 
 
 
Study Population 
Male and female CF subjects 6 years of age and older with at least 1 non-F508del, 
ELX/TEZ/IVA-responsive CFTR mutation 
 
 
Investigational Drug 
Active substance: ELX (VX-445)/TEZ (VX-661)/IVA (VX-770) 
 
Activity: ELX and TEZ are CFTR correctors; IVA is a CFTR potentiator 
 
Strength and route of administration: ELX/TEZ/IVA fixed-dose combination 
(FDC) tablets for oral administration at the following strengths: 
• 
ELX 100 mg/TEZ 50 mg/IVA 75 mg 
• 
ELX 50 mg/TEZ 25 mg/IVA 37.5 mg 
 
 


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Active substance: IVA (VX-770) 
 
Activity: CFTR potentiator 
 
Strength and route of administration: IVA tablets for oral administration at the 
following strengths: 
• 
IVA 150 mg 
• 
IVA 75 mg 
 
 
Study Duration 
The total study duration is approximately 32 weeks (4 weeks for the Screening 
Period, 24 weeks for the Treatment Period, and 4 weeks for the Safety Follow-up 
Period). 
 
 
Study Design 
This is a Phase 3, randomized, placebo-controlled, double-blind, parallel group 
study. Subjects 6 years of age and older with a qualifying non-F508del 
ELX/TEZ/IVA-responsive CFTR mutation and no exclusionary mutations may be 
eligible for enrollment. Qualifying ELX/TEZ/IVA-responsive mutations can be 
categorized as minimal function (MF)-like and residual function (RF)-like. 
MF-like mutations have a clinical phenotype without evidence of residual CFTR 
function. RF-like mutations result in residual CFTR function. Exclusionary 
mutations are indicated for IVA in the EU label regardless of the mutation on the 
second allele. 
Subjects will be randomized 2:1 (ELX/TEZ/IVA group: placebo group). 
Randomization will be stratified based on ppFEV1 determined during the 
Screening Period (<70 versus ≥70), age at the Screening Visit (<18 years old 
versus ≥18 years old) and CFTR genotype (contains ≥1 RF-like mutation versus 
does not contain an RF-like mutation).  
Figure 2-1 
Study VX21-445-124 Design 
 
 




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The safety endpoints include AEs, clinical laboratory values, ECGs, vital signs, 
and pulse oximetry through the Safety Follow-up Visit. The safety analysis will be 
descriptive only. 
 
 
Independent Data 
Monitoring Committee 
Safety and tolerability data will be reviewed by an independent data monitoring 
committee (IDMC) to ensure the safety of the subjects. Procedural details of the 
IDMC’s structure and function, frequency of meetings, and data planned for 
review will be in the IDMC charter. The IDMC charter will be finalized before the 
first subject is screened. 
 


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are in Table 3-1 and Table 3-2. 
Table 3-1 
Study VX21-445-124: Screening 
Event/Assessment 
Screening Visita 
Day -28 to Day -1 
 
Comments 
Informed consent (and assent, 
if applicable) 
X 
 
Demographics 
X 
Section 11.1 
Medical history 
X 
Section 11.1 
CFTR genotype 
X 
Performed for all subjects (Section 11.5.2). A 
subject’s screening CFTR genotype must 
confirm eligibility before the subject is 
randomized. 
Medications review 
X 
Information regarding medications taken 
within 56 days before the Screening Visit will 
be collected; Section 9.5. 
Height, weight, and BMI 
X 
Weight and height will be measured with 
shoes off; Sections 11.4.4 and 11.5.3 
Full 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 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 
Serum FSH  
X 
Suspected postmenopausal female subjects 
only; Section 11.5.2 
Serum pregnancy test  
X 
Female subjects 9 years of age and older, and 
female subjects who have undergone 
menarche (regardless of age), Section 11.5.2 
Serum chemistry 
X 
Section 11.5.2 
Hematology and coagulation 
X 
Urinalysis 
X 
Ophthalmological 
examination 
X 
Conducted by an ophthalmologist or 
optometrist for subjects <18 years of age on 
the date of initial informed consent; 
Section 11.5.5 
Sweat chloride 
X 
Section 11.4.2 
Spirometry 
X 
Performed pre- or post-bronchodilator; 
Section 11.4.1 
Adverse events 
Continuous from signing of 
informed consent form (ICF) 
through completion of study 
participation 
Section 11.5.1 
BMI: body mass index; CFTR: cystic fibrosis transmembrane conductance regulator gene; ECG: 
electrocardiogram; FSH: follicle-stimulating hormone 
a 
Visit must be performed in clinic (Section 9.1.7) 




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Table 3-2 
Study VX21-445-124: Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Day 
1b 
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 24b 
(± 5 Days) 
ETT 
Visitc  
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dose of 
Study Drugd 
Comments 
Physical examination 
Full 
 
 
 
 
 
 
Full 
Full 
 
Symptom-directed 
physical examinations 
may occur at any time 
if deemed necessary by 
the investigator; 
Section 11.5.3 
Ophthalmological 
examination 
 
 
 
 
 
 
 
X 
at or up to 
4 weeks 
before 
X 
 
Conducted by an 
ophthalmologist or 
optometrist for subjects 
<18 years of age on the 
date of informed 
consent; Section 11.5.5 
Pregnancy test (female 
subjects of 
childbearing potential) 
urine 
serum or 
urine 
serum or 
urine 
serum or 
urine 
urine 
 (at home) 
serum or 
urine 
urine  
(at home) 
serum or 
urine 
serum 
or 
urine 
serum or 
urine 
Female subjects of 
childbearing potential 
are defined in 
Section 11.5.6.1.   
Serum chemistry 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Collected before the 
first dose of study drug 
on Day 1; Section 
11.5.2 
Hematology  
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Coagulation 
X 
 
 
 
 
 
 
X 
X 
X 
PK sampling 
 X 
 
X 
 
 
 
 
X  
 
 
Collected within 
60 min before the AM 
dose; Section 11.2.1 
Urinalysis 
X 
 
 
 
 
 
 
X 
X 
X 
Section 11.5.2 




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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 7 
4 
Table of Contents ................................................................................................................. 11 
List of Tables............................................................................................................................ 14 
List of Figures .......................................................................................................................... 14 
List of Appendices ................................................................................................................... 14 
List of Abbreviations................................................................................................................ 15 
5 
Introduction.......................................................................................................................... 17 
5.1 
Background ..................................................................................................................... 17 
5.2 
Study Rationale .............................................................................................................. 17 
5.3 
Risk Assessment ............................................................................................................. 18 
6 
Study Objectives .................................................................................................................. 18 
6.1 
Primary Objective ........................................................................................................... 18 
6.2 
Secondary Objective ....................................................................................................... 18 
7 
Study Endpoints ................................................................................................................... 18 
7.1 
Primary Endpoint ............................................................................................................ 18 
7.2 
Secondary Endpoints ...................................................................................................... 18 
7.3 
Other Endpoints .............................................................................................................. 19 
8 
Study Population .................................................................................................................. 19 
8.1 
Inclusion Criteria ............................................................................................................ 19 
8.2 
Exclusion Criteria ........................................................................................................... 19 
9 
Study Implementation ......................................................................................................... 21 
9.1 
Study Design .................................................................................................................. 21 
9.1.1 
Screening ................................................................................................................ 22 
9.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 22 
9.1.1.2 
Rescreening ...................................................................................................... 22 
9.1.1.3 
Extension of Screening Period Window .......................................................... 23 
9.1.2 
Treatment Period .................................................................................................... 23 
9.1.3 
Follow-up................................................................................................................ 23 
9.1.4 
Early Termination of Treatment ............................................................................. 23 
9.1.5 
Lost to Follow-up ................................................................................................... 24 
9.1.6 
Completion of Study Participation ......................................................................... 24 
9.1.7 
Use of Remote Measures in Extenuating Circumstances ....................................... 24 
9.1.8 
Independent Data Monitoring Committee .............................................................. 25 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 25 
9.3 
Rationale for Study Elements ......................................................................................... 25 
9.3.1 
Study Design........................................................................................................... 25 
9.3.2 
Study Population..................................................................................................... 25 
9.3.3 
Study Drug Dose .................................................................................................... 26 
9.3.4 
Rationale for Study Assessments ........................................................................... 26 
9.4 
Study Restrictions ........................................................................................................... 26 
9.5 
Prior and Concomitant Medications ............................................................................... 27 
9.6 
Administration ................................................................................................................ 28 


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9.7 
Missed Doses .................................................................................................................. 28 
9.8 
Dose Modification for Toxicity ...................................................................................... 29 
9.9 
Study Drug Interruption and Stopping Rules ................................................................. 29 
9.9.1 
Liver Function Tests ............................................................................................... 29 
9.9.2 
Rash ........................................................................................................................ 30 
9.10 Removal of Subjects ....................................................................................................... 30 
9.11 Replacement of Subjects ................................................................................................ 31 
10 Study Drug Information and Management ....................................................................... 31 
10.1 Preparation and Dispensing ............................................................................................ 31 
10.2 Packaging and Labeling ................................................................................................. 31 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 31 
10.4 Drug Accountability ....................................................................................................... 32 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 32 
10.6 Compliance ..................................................................................................................... 32 
10.7 Blinding and Unblinding ................................................................................................ 32 
10.7.1 
Blinding .................................................................................................................. 32 
10.7.2 
Unblinding .............................................................................................................. 33 
11 Assessments .......................................................................................................................... 34 
11.1 Subject and Disease Characteristics ............................................................................... 34 
11.2 Pharmacokinetics ............................................................................................................ 34 
11.2.1 
Blood Sampling ...................................................................................................... 34 
11.2.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 35 
11.2.3 
Bioanalysis.............................................................................................................. 35 
11.3 Exploratory Assessments ................................................................................................ 35 
11.4 Efficacy ........................................................................................................................... 35 
11.4.1 
Spirometry .............................................................................................................. 35 
11.4.2 
Sweat Chloride ....................................................................................................... 36 
11.4.3 
Cystic Fibrosis Questionnaire – Revised ................................................................ 36 
11.4.4 
Height and Weight .................................................................................................. 37 
11.4.5 
Other Events Related to Outcome .......................................................................... 37 
11.4.5.1 Antibiotic Therapy for Sinopulmonary Sign/Symptoms ................................. 37 
11.4.5.2 Hospitalization for CF ...................................................................................... 37 
11.5 Safety .............................................................................................................................. 38 
11.5.1 
Adverse Events ....................................................................................................... 38 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 38 
11.5.3 
Physical Examinations, Vital Signs, and Pulse Oximetry ...................................... 40 
11.5.4 
Electrocardiograms ................................................................................................. 40 
11.5.5 
Ophthalmological Examinations (Subjects <18 Years of Age).............................. 41 
11.5.6 
Contraception and Pregnancy ................................................................................. 41 
11.5.6.1 Contraception ................................................................................................... 42 
11.5.6.2 Pregnancy ......................................................................................................... 43 
12 Statistical Analysis ............................................................................................................... 44 
12.1 Sample Size and Power .................................................................................................. 44 
12.2 Analysis Sets .................................................................................................................. 44 
12.3 Statistical Analysis ......................................................................................................... 44 
12.3.1 
General Considerations ........................................................................................... 44 


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12.3.2 
Background Characteristics .................................................................................... 45 
12.3.3 
Efficacy and Pharmacodynamics Analysis ............................................................. 45 
12.3.3.1 Analysis of Primary Efficacy Endpoint ........................................................... 45 
12.3.3.2 Analysis of Secondary Efficacy Endpoints ...................................................... 45 
12.3.3.3 Analysis of Other Efficacy Endpoints.............................................................. 46 
12.3.3.4 Multiplicity Adjustment ................................................................................... 46 
12.3.3.5 Missing Data Handling .................................................................................... 46 
12.3.4 
Safety Analysis ....................................................................................................... 46 
12.4 Interim Analysis ............................................................................................................. 47 
12.5 Independent Data Monitoring Committee Analysis ....................................................... 47 
12.6 Clinical Pharmacology Analysis .................................................................................... 47 
12.6.1 
Pharmacokinetic Analysis ...................................................................................... 47 
12.6.2 
Pharmacodynamic Analysis ................................................................................... 47 
12.6.3 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 47 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 47 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 47 
13.1.1 
Adverse Events ....................................................................................................... 47 
13.1.1.1 Definition of an Adverse Event........................................................................ 47 
13.1.1.2 Clinically Significant Assessments .................................................................. 47 
13.1.1.3 Documentation of Adverse Events................................................................... 48 
13.1.1.4 Adverse Event Severity .................................................................................... 48 
13.1.1.5 Adverse Event Causality .................................................................................. 49 
13.1.1.6 Study Drug Action Taken ................................................................................ 49 
13.1.1.7 Adverse Event Outcome .................................................................................. 50 
13.1.1.8 Treatment Given............................................................................................... 50 
13.1.2 
Serious Adverse Events .......................................................................................... 50 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 50 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 51 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 52 
13.2 Administrative Requirements ......................................................................................... 52 
13.2.1 
Product Complaints ................................................................................................ 52 
13.2.2 
Ethical Considerations ............................................................................................ 52 
13.2.3 
Subject Information and Informed Consent ........................................................... 52 
13.2.4 
Investigator Compliance ......................................................................................... 53 
13.2.5 
Access to Records ................................................................................................... 53 
13.2.6 
Subject Privacy ....................................................................................................... 53 
13.2.7 
Record Retention .................................................................................................... 53 
13.2.8 
Study Termination .................................................................................................. 53 
13.2.9 
End of Study ........................................................................................................... 54 
13.3 Data Quality Assurance .................................................................................................. 54 
13.4 Monitoring ...................................................................................................................... 54 
13.5 Data Capture ................................................................................................................... 54 
13.6 Confidentiality and Disclosure ....................................................................................... 55 
13.7 Publications and Clinical Study Report .......................................................................... 55 
13.7.1 
Publication of Study Results ................................................................................... 55 


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13.7.2 
Clinical Study Report ............................................................................................. 56 
14 References ............................................................................................................................. 57 
15 Appendix A: Eligible CFTR Genotypes ............................................................................. 59 
16 Appendix B: Blood Sample Volumes by Visit ................................................................... 60 
17 Protocol Signature Pages .................................................................................................... 61 
17.1 Sponsor Signature Page .................................................................................................. 61 
17.2 Investigator Signature Page ............................................................................................ 62 
 
List of Tables 
Table 2-1 
Treatment Period Dosages ...................................................................................... 5 
Table 3-1 
Study VX21-445-124: Screening ............................................................................ 7 
Table 3-2 
Study VX21-445-124: Treatment Period and Safety Follow-up Visit ................... 8 
Table 9-1 
Treatment Period Dosages .................................................................................... 22 
Table 9-2 
ELX/TEZ/IVA Dosing.......................................................................................... 26 
Table 9-3 
Prohibited Medications ......................................................................................... 26 
Table 10-1 
Study Drug ............................................................................................................ 31 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 39 
Table 11-2 
Acceptable Methods of Contraception (Applies to Subjects For Whom 
Contraception Requirements Are Not Waived) .................................................... 42 
Table 13-1 
Grading of AE Severity ........................................................................................ 49 
Table 13-2 
Classifications for AE Causality ........................................................................... 49 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 49 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 50 
Table 15-1 
Eligible ELX/TEZ/IVA-responsive CFTR mutations .......................................... 59 
Table 15-2 
Exclusionary CFTR mutations .............................................................................. 59 
Table 16-1 
Blood Sample Volumes by Visit (mL) ................................................................. 60 
List of Figures 
Figure 2-1 
Study VX21-445-124 Design ................................................................................. 4 
Figure 9-1 
Study VX21-445-124 Design ............................................................................... 21 
 
List of Appendices 
Appendix A: Eligible CFTR Genotypes 
Appendix B: Blood Sample Volumes by Visit 


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List of Abbreviations 
Abbreviation 
Definition 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFQ-R RD 
Cystic Fibrosis Questionnaire- Revised respiratory domain 
CFTR 
cystic fibrosis transmembrane conductance regulator gene 
CI 
confidence interval 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
EDC 
electronic data capture 
etc. 
et cetera 
ETT 
Early Termination of Treatment 
EU 
European Union 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
FEV1 
forced expiratory volume in 1 second 
FRT 
Fischer Rat Thyroid 
FSH 
follicle-stimulating hormone 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 


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Abbreviation 
Definition 
IXRS 
interactive response system in which X represents voice or web, such as IWRS 
max 
maximum value 
MF 
minimal function 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
P 
probability 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PEx 
pulmonary exacerbations 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic, pharmacokinetics 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
QTcF 
QT interval corrected by Fridericia’s formula 
RF 
residual function 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SwCl 
sweat chloride 
TE 
Treatment-emergent 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
 
 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is a rare autosomal recessive disease with serious, chronically debilitating 
morbidities and high premature mortality for which there is currently no cure. CF affects more 
than 80,000 individuals worldwide1-4, including more than 49,000 individuals in the EU.2 
CF is caused by decreased quantity and/or function of the CFTR protein due to mutations in the 
CFTR gene.5 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.6 Decreased CFTR quantity or function results in the failure to regulate chloride 
transport in these tissues leading to the multisystem pathology associated with CF.7 Progressive 
loss of lung function is the leading cause of mortality.8  
The most common disease-causing mutation is F508del: approximately 85% of individuals in the 
US1 and 80% of individuals in Europe2 have at least one F508del mutation. In the EU, patients 
with one F508del mutation are eligible for treatment with the CFTR modulator ELX/TEZ/IVA 
(Kaftrio™/Trikafta™). The ELX/TEZ/IVA regimen is the first medicine to demonstrate clinical 
benefit in patients with a single F508del mutation, regardless of the mutation on the second 
allele. The Phase 3 program in CF subjects 6 years of age and older demonstrated that treatment 
with ELX/TEZ/IVA results in substantial improvements in lung function, CFTR function, and 
nutritional status in this population, and was generally safe and well tolerated with a low rate of 
treatment discontinuation.  
The ELX/TEZ/IVA pivotal Phase 3 program demonstrated efficacy in subjects who have at least 
one F508del mutation. However, more than 160 additional CFTR mutations have been shown to 
be responsive to ELX/TEZ/IVA in vitro. CF patients with these mutations do not currently have 
an indicated CFTR modulator treatment in the EU, nonetheless they are expected to derive 
clinical benefit from ELX/TEZ/IVA based on (1) current understanding of the biology of the 
CFTR mutations (2) the known mechanism by which CFTR modulators act on defective CFTR 
proteins that contain these mutations (3) in vitro evidence indicating responsiveness of these 
proteins to ELX/TEZ/IVA and (4) the established relationship between in vitro responsiveness 
and clinical benefit.  
5.2 
Study Rationale 
This study will evaluate the efficacy and safety of ELX/TEZ/IVA in patients in the EU who have 
the more prevalent ELX/TEZ/IVA-responsive non-F508del CFTR mutations which are not 
currently indicated for a CFTR modulator regimen (Section 15). 
These mutations are considered ELX/TEZ/IVA-responsive based on either (a) in vitro evidence 
from the Fischer Rat Thyroid (FRT) cell system, a robust and reproducible in vitro model to 
measure CFTR-mediated chloride transport10 or (b) the ability of ELX/TEZ/IVA to increase the 
activity of the small amounts of functional, full-length CFTR protein produced by non-canonical 
splice mutations. Extensive clinical data evaluating CF subjects with different CFTR mutations 
indicate that an in vitro FRT response to a CFTR modulator regimen has been predictive of 
clinical benefits, including improvements in lung functions (as measured by percent predicted 
forced expiratory volume in 1 second [ppFEV1]), CFTR function (as measured by sweat chloride 
[SwCl]), and CF-related quality of life (as measured by Cystic Fibrosis Questionnaire – Revised 
[CFQ-R RD]). The non-canonical splice mutations selected for this study result in low amounts 


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of functional, full-length CFTR protein, which can be acted upon by CFTR modulators to 
increase CFTR activity at the cell surface, as demonstrated in a clinical trial of TEZ/IVA and 
IVA (Study 661-108). 
5.3 
Risk Assessment 
The safety profile of ELX/TEZ/IVA has been adequately characterized, with risks that are 
readily identified clinically or with routine laboratory monitoring. In previous clinical trials of 
subjects ≥6 years of age, the rate of adverse events (AEs) leading to treatment discontinuation 
was low. The most common adverse drug reactions (ADRs) observed on ELX/TEZ/IVA were 
headache, diarrhea, upper respiratory tract infection, abdominal pain, alanine transaminase 
(ALT) increased, aspartate transaminase (AST) increased, blood creatine kinase increased, nasal 
congestion, rash, and rhinorrhea. Serious ADRs that occurred more frequently in the 
ELX/TEZ/IVA group than in the placebo group were rash events in 3 (1.5%) subjects treated 
with ELX/TEZ/IVA.  
Subjects in this study will continue on their usual standard-of-care CF treatments (e.g., inhaled 
antibiotics, prednisone, and bronchodilators [Section 9.5]). The overall risk and burden to 
subjects participating in this study will be minimized as much as possible. Key safety eligibility 
criteria, close safety monitoring of subjects, prudent stopping rules, and guidance regarding use 
of concomitant medications have been included in this study protocol. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the efficacy and pharmacodynamics (PD) of ELX/TEZ/IVA  
6.2 
Secondary Objective 
To evaluate safety and tolerability of ELX/TEZ/IVA 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) through Week 24 
7.2 
Secondary Endpoints 
• Absolute change from baseline in SwCl through Week 24 
• Absolute change from baseline in Cystic Fibrosis Questionnaire- Revised respiratory 
domain (CFQ-R RD) score through Week 24 
• Absolute change from baseline in body mass index (BMI) at Week 24 
• Absolute change from baseline in weight at Week 24 
• Number of pulmonary exacerbations (PEx) through Week 24 
• Safety and tolerability assessments based on AE, clinical laboratory values, ECGs, vital 
signs, and pulse oximetry 


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7.3 
Other Endpoints 
• Absolute change from baseline in BMI z-score (subjects ≤20 years of age) at Week 24 
• Absolute change from baseline in weight z-score (subjects ≤20 years of age) at Week 24 
• Plasma pharmacokinetic (PK) parameters including ELX, TEZ, IVA, and relevant 
metabolites 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
8.1 
Inclusion Criteria 
1. Subject (or the subject’s legally appointed and authorized representative) will sign and date 
an informed consent form (ICF) and, when appropriate, an assent form.  
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines (as applicable), and other study procedures.  
• For subjects <18 years of age: as judged by the investigator, 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. 
3. Subjects (male or female) 6 years of age and older on the date of informed consent.  
4. Subjects has an eligible ELX/TEZ/IVA-responsive CFTR mutation listed in Table 15-1 and 
none of the exclusionary mutations in Table 15-2. 
5. Subject has stable CF disease, as deemed by the investigator, before randomization. 
6. Forced expiratory volume in 1 second (FEV1) value ≥40% and ≤100% of predicted mean for 
age, sex, and height (equations of the Global Lung Function Initiative [GLI])11 at the 
Screening Visit (spirometry measurements must meet American Thoracic Society/European 
Respiratory Society criteria12 for acceptability and repeatability). 
7. Subject is able to swallow tablets. 
8.2 
Exclusion Criteria 
1. History of any illness or any clinical condition that might confound the results of the study or 
pose an additional risk in administering study drug(s) to the subject. This may include, but is 
not limited to: 
• History of allergy, intolerance, or hypersensitivity to any component of the 
investigational drug product (ELX/TEZ/IVA tablets and IVA tablets) or placebo, 
including excipients  
• 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) 
• AST, ALT, gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) ≥3 × 
ULN 
• Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 
(calculated by the Modification of Diet in Renal Disease Study Equation)13, 14for subjects 
≥18 years of age and ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt 
equation)15 for subjects <18 years of age. 
4. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy 
(including antibiotics) for sinopulmonary 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 
Mycobaterium abscessus). For subjects who have had a history of a positive culture, the 
investigator will apply the following criteria to establish whether the subject is free of 
infection with such organisms. 
• The subject has not had a respiratory tract culture positive for these organisms within the 
12 months before the date of informed consent, and  
• 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 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. 


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8. Pregnant and breast-feeding females. Female subjects of childbearing potential 
(Section 11.5.6.1) must have a negative pregnancy test at the Screening Visit and the  
Day 1 Visit. 
9. Use of restricted medication within specified duration before the first dose of study drug as 
defined in Table 9-3. 
10. Subject, or close relative of the subject, is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study at that site. However, an adult (aged 18 years or older) who is a relative of a study 
staff member may be enrolled in the study provided that: 
• the adult lives independently of and does not reside with the study staff member, and 
• the adult participates in the study at a site other than the site at which the family member 
is employed. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3 randomized, placebo-controlled, double-blind, parallel group study. Subjects 
6 years of age and older with a qualifying non-F508del, ELX/TEZ/IVA-responsive CFTR 
mutation listed in Table 15-1 and none of the exclusionary mutations in Table 15-2 may be 
eligible for enrollment. These qualifying ELX/TEZ/IVA-responsive mutations can be 
categorized as minimal function (MF)-like and residual function (RF)-like mutations. MF-like 
mutations have a clinical phenotype without evidence of residual CFTR function. RF-like 
mutations result in residual CFTR function.  
Subjects will be randomized 2:1 (ELX/TEZ/IVA group: placebo group). Randomization will be 
stratified based on ppFEV1 determined during the Screening Period (<70 versus ≥70), age at the 
Screening Visit (<18 years old versus ≥18 years old) and CFTR genotype (contains ≥1 RF-like 
mutation versus does not contain an RF-like mutation [as defined in Section 15]). 
Figure 9-1 
Study VX21-445-124 Design 
 
ELX: elexacaftor; IVA: ivacaftor; TEZ: tezacaftor 




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• 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) 
• 28-day washout period for subjects who have been on an investigational or commercially 
available CFTR modulator (Table 9-3) 
9.1.2 
Treatment Period 
Treatment Period assessments are listed in Table 3-2. 
The Treatment Period will last approximately 24 weeks. Randomization details are provided in 
Section 9.2 and study drug administration details are provided in Section 9.6. 
9.1.3 
Follow-up 
The Safety Follow-up Visit will occur 28 (± 7) days after the last dose of study drug for subjects 
who complete study drug dosing and for subjects who prematurely discontinue study drug 
dosing, as described in Section 9.1.4. 
An optional open-label extension safety study will be available for subjects who meet eligibility 
requirements. 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 treatment, an Early Termination of Treatment (ETT) 
Visit should be scheduled as soon as possible after the decision to discontinue study treatment. 
Subjects who prematurely discontinue treatment will also be required to complete the Safety 
Follow-up Visit, approximately 28 (± 7) days after their last dose of study drug. The assessments 
performed at the Safety Follow-up Visit are listed in Table 3-2. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
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 3-1 and Table 3-2. Data regarding concomitant antibiotic therapy for sinopulmonary 
signs/symptoms will also continue to be collected for these subjects. 


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If a subject withdraws consent or assent for the study, 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; study data and samples collected will remain part of the study (Section 9.10). 
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 one 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 9.1.4) 
If subjects are lost to follow-up (Section 9.1.5), the date of completion of study participation will 
be defined as the date of the last contact.  
The end of study is defined in Section 13.2.9. 
9.1.7 
Use of Remote Measures in Extenuating Circumstances  
Study visits should be performed in the clinic as specified in Table 3-1 and Table 3-2, if at all 
possible. However, under extenuating circumstances, remote measures may be implemented 
(e.g., if a subject is unable to travel to the study site due to safety concerns and/or local 
restrictions related to COVID-19 or other emerging events). The decision whether to conduct a 
study visit remotely or in clinic will be at the discretion of the investigator; if the investigator 
determines that study visits will be conducted remotely, the medical monitor should be notified. 
The Screening visits (including initial consent), Day 1 Visit, and Week 24 Visit must be 
performed in the clinic. 
Whenever local regulations or site practice do not allow remote measures, visits will be 
conducted at the site. 
The following remote measures may be implemented. Additional details can be found in the 
Study Reference Manual. 
• Reconsent may be obtained remotely in writing (or verbally, with follow-up written 
confirmation), as allowed by local regulations.  


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• Study drug may be shipped directly from the site to the subject, as applicable and as allowed 
by local regulations. 
• Study visits (except at Screening, Day 1, and Week 24) may be conducted as in-home visits 
by qualified personnel. 
• Study assessments (other than SwCl assessments) may be performed or overseen by qualified 
personnel conducting the in-home visits. 
• Remote monitoring visits may be implemented as applicable (including remote source data 
verification) and as allowed per local regulations.   
9.1.8 
Independent Data Monitoring Committee 
Safety and tolerability data will be reviewed by an independent data monitoring committee 
(IDMC) to ensure the safety of the subjects (Section 12.5). Procedural details of the IDMC’s 
structure and function, frequency of meetings, and data planned for review will be in the IDMC 
charter. The IDMC charter will be finalized before the first subject is screened.  
9.2 
Method of Assigning Subjects to Treatment Groups 
An interactive web or voice response system (IXRS) will be used to assign subjects to treatment. 
Subjects will be stratified as described in Section 9.1. 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.  
9.3 
Rationale for Study Elements 
9.3.1 
Study Design 
A randomized, double-blind, controlled study design was selected to evaluate the effects of 
ELX/TEZ/IVA while avoiding observer bias. Placebo is an appropriate comparator because 
ELX/TEZ/IVA is not approved for the treatment of CF for the study’s patient population in the 
region(s) where the study will be conducted. A 2:1 (ELX/TEZ/IVA: placebo) randomization 
ratio will appropriately blind the study, while also providing adequate power for a between-
group analysis of efficacy in this rare patient population. 
This study will have a 24-week treatment duration to allow for the collection of data for 
outcomes that require longer treatment durations to demonstrate an effect (e.g., changes in 
nutritional status and rates of PEx).  
9.3.2 
Study Population 
The study population will include subjects with non-F508del ELX/TEZ/IVA-
responsive CFTR mutations that are more prevalent in the EU but are not currently indicated for 
a CFTR modulator regimen (Section 15).These mutations are considered ELX/TEZ/IVA-
responsive based on either (a) in vitro (FRT cell) evidence from the FRT cell system, a robust 
and reproducible in vitro model to measure CFTR-mediated chloride transport or (b) the ability 
of ELX/TEZ/IVA to increase the activity of the small amounts of normal, full-length CFTR 
protein produced by non-canonical splice mutations (Section 5.2). 




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Table 9-3 
Prohibited Medications 
Medication 
Timing of Restriction 
Rationale 
Start of Restriction 
End of Restriction 
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. 
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 randomized, details of prior medication 
will be documented only in the subjects’ source documents. 
• Subjects should remain on a stable treatment regimen for their CF from 28 days before the 
Day 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 


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increase or prolong their therapeutic effect and adverse reactions. Digoxin or other substrates 
of P-gp with a narrow therapeutic index, such as cyclosporine, everolimus, sirolimus, and 
tacrolimus, should be used with caution and appropriate monitoring.  
• IVA may inhibit CYP2C9; therefore, during coadministration with warfarin, additional 
monitoring of the international normalized ratio is recommended. Other medicinal products 
that are CYP2C9 substrates for which exposure may be increased include glimepiride and 
glipizide; these should be used with caution. 
• Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator should have their spirometry assessments performed 
according to the guidelines provided in Section 11.4.1. 
9.6 
Administration 
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. On days of scheduled visits, the morning dose of study drug will be administered under the 
supervision of site medical staff or a home health nurse after predose assessments have been 
completed. The meal or snack will be provided by the site on in-clinic visit days for the 
morning dose of study drug. 
4. For visits after the Day 1 Visit, subjects will be instructed to return all used and unused study 
drug to the site or the home health nurse; study drug will be dispensed at each visit, as 
appropriate. 
5. At the Week 24 Visit, the morning dose of study drug will NOT be administered. The last 
dose of study drug will be the evening dose administered the day before the Week 24 Visit. 
9.7 
Missed Doses 
If 6 hours or less have passed since the missed morning or evening dose, the subject should take 
the missed dose as soon as possible and continue on the original schedule.  
Morning dose: If more than 6 hours have passed since the missed morning dose, the subject 
should take the missed dose as soon as possible and should not take the evening dose. 
Evening dose: If more than 6 hours have passed since the missed evening dose, the subject 
should not take the missed dose. The next scheduled morning dose should be taken at the usual 
time. 
Morning and evening doses should not be taken at the same time. 


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9.8 
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 (Section 9.1.4). 
9.9 
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 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. 
9.9.1 
Liver Function Tests 
The central laboratory will notify the medical monitor of ALT or AST >3 × ULN and total 
bilirubin >2 × ULN that are derived from centrally submitted samples. 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, with or without 
total bilirubin >2 × ULN, must be followed closely, including confirmatory testing performed by 
the central laboratory within 48 to 72 hours of the initial finding and subsequent close 
monitoring of ALT, AST, and bilirubin levels, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results must be reported immediately to the medical monitor, and the subject 
must have the tests repeated and sent to the central laboratory as soon as possible (ideally within 
48 to 72 hours). 
Study drug administration must be interrupted immediately (prior to confirmatory testing) if 
any of the following criteria are met: 
• ALT or AST >8 × ULN 
• ALT or AST >5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical 
jaundice 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression. 
Study drug administration must be discontinued if the following criterion is met: 
• Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral 
hepatitis, alcohol ingestion) is identified, regardless of whether transaminase levels have 
improved. 


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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.  
9.9.2 
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; Section 13.1.2.1). 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. 
9.10 
Removal of Subjects  
Subjects (or subjects’ parent/legal guardian) may withdraw from the study at any time at their 
own request. Subjects may be withdrawn from study drug treatment at any time at the discretion 
of the investigator or Vertex for safety, behavior, noncompliance with study procedures, or 
administrative reasons. A subject who withdraws from study drug treatment will continue to be 
followed unless the subject withdraws consent.  
In addition, a subject must be discontinued from study drug treatment if the subject meets any of 
the following criteria: 
• Meets any of the stopping (discontinuation) criteria (Section 9.9) 
• Becomes pregnant (Section 11.5.6.2) 
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 a Safety Follow-up Visit, if 
applicable (see Section 9.1.3), and follow up with the subject regarding any unresolved AEs. 
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends, and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study, the study data and samples collected will remain part of the study. A subject will 
not be able to request the withdrawal of his/her information from the study data. A subject may 


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request destruction of the samples collected from him/her during the study as long as those 
samples can be identified as his/her samples. 
9.11 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study drug treatment period(s) will not be 
replaced. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
Study drug refers to ELX/TEZ/IVA, IVA and their matching placebos. 
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 about packaging, 
labeling, and dispensing for ELX/TEZ/IVA will be in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
ELX/TEZ/IVA will be supplied as FDC film-coated tablets containing at the strengths shown in 
Table 10-1. Matching ELX/TEZ/IVA placebo tablets will be of similar size and appearance and 
contain 0 mg ELX, 0 mg TEZ, and 0 mg IVA. 
IVA will be supplied as tablets at strengths shown in Table 10-1. Matching IVA placebo tablets 
will be of similar size and appearance and contain 0 mg IVA. 
Table 10-1 
Study Drug 
Drug Name, Dosing Form, Route 
Tablet Strengths 
ELX/TEZ/IVA, FDC tablet, oral 
 
 
ELX 
100 mg 
50 mg 
TEZ 
50 mg 
25 mg 
IVA 
75 mg 
37.5 mg 
ELX/TEZ/IVA-matching placebo, 
tablet oral 
0/0/0 mg 
0/0/0 mg 
IVA, tablet, oral 
150 mg 
75 mg 
IVA-matching placebo, tablet oral 
0 mg 
0 mg 
ELX: elexacaftor; FDC: fixed-dose combination; IVA: ivacaftor; TEZ: tezacaftor 
Note: See Section 9.6 for details on study drug administration. 
All study drugs will be stored in accordance with the drug label or the Pharmacy Manual. The 
investigator, or an authorized designee (e.g., a licensed pharmacist), will ensure that all 
investigational product is stored in a secured area, under recommended storage conditions, and in 
accordance with applicable regulatory requirements. To ensure adequate records, all study drugs 
will be accounted for via the drug accountability forms as instructed by Vertex. 


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10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information about the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee. The study monitor will review study drug 
records and inventory throughout the study.  
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 they 
are unable to resolve with the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
The principal investigator, study site staff, including pharmacy personnel will assist Vertex with 
any recall activities (as applicable) and place impacted investigational medicinal product (IMP) 
in quarantine when requested. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit (in-clinic and telephone contact), site personnel will review 
that the subject is compliant with study drug dosing and remind the subject of study drug dosing 
requirements. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should consider discontinuing the subject from the study. 
10.7 
Blinding and Unblinding 
This is a double-blind study. 
10.7.1 
Blinding  
All subjects (and their parents/caregivers/companions) and study personnel will be blinded to 
subject treatment assignments except for the following individuals:  
• Any site personnel for whom this information is important to ensure the safety of a subject in 
the event of a life-threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of a subject 
and a fetus in the event of a pregnancy 
• The unblinded site monitor and unblinded trip report reviewer 


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• An unblinded pharmacist at the contract research organization (CRO) for dispensing study 
drug 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy SAE 
processing and reporting regulations 
• External vendor (unblinded) statistician preparing the final (production) randomization list 
who is not part of the study team 
• Vertex IXRS Management for IXRS oversight and system administration 
• Vertex Clinical Supply Chain 
• The bioanalytical CRO laboratory/vendor personnel managed by Vertex Bioanalysis   
• The Vertex bioanalytical personnel responsible for reviewing raw data from the bioanalytical 
CRO, who is not a member of the Study Team (the Vertex bioanalytical Study Team member 
will continue to be blinded) 
Vertex medical monitor may, for matters relating to safety, unblind individual subjects at any 
time.  
Access to Spirometry and SwCl Results: 
During the conduct of the study, the Vertex study team will not have access to the spirometry or 
SwCl results after the first dose of study drug in the Treatment Period.  
Shortly before any planned efficacy analysis is conducted, the spirometry and SwCl data will be 
reviewed for data cleaning purposes by a biostatistician who does not have access to the 
treatment codes. 
Individual SwCl test results will not be disclosed to the study sites with the exception of the 
screening values. Subjects and their parents/caregivers/companions should not be informed of 
study‑related spirometry results until Vertex has determined that the study has completed (i.e., 
clinical study report [CSR] finalization), regardless of whether the subject has prematurely 
discontinued treatment.  
10.7.2 
Unblinding 
At the initiation of the study, study site personnel will be instructed on the method for breaking 
the blind. The unblinding method will be either manual or electronic. 
Unblinding of the individual subject’s treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject’s study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss unblinding. 
If investigators deem it unnecessary to unblind immediately, they will first attempt to contact the 
medical monitor to discuss unblinding. If investigators have tried but are unable to reach the 
medical monitor, they will use their best judgment, based on the nature and urgency of the 
clinical situation, and may proceed with unblinding. 
Contact information for the medical monitor (or appropriate backup) will be in a separate 
document. 


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If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding event. 
The reason and the date of the unblinding will be documented clearly in the subject’s study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with Vertex, the CRO, or any site 
personnel (other than the physician treating the subject). In addition, the investigator will 
consider whether the clinical event that prompted unblinding will be considered an SAE, 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to 
Vertex GPS or designee, per Section 13.1.2. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety, unblind individual 
subjects at any time.  
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1 and Table 3-2.  
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 
Medical history will be elicited from each subject and extracted from medical records during 
screening. Based on the medical history, the subject will be assessed for any disqualifying 
medical conditions as specified in the inclusion and exclusion criteria. The medical history will 
include a complete review of systems, medical and surgical histories, and any allergies. 
11.2 
Pharmacokinetics 
11.2.1 
Blood Sampling 
Blood samples will be collected as shown in Table 3-2 to determine plasma concentrations of 
ELX, TEZ, IVA and their relevant metabolites. Blood samples will be collected within 
60 minutes before the morning dose of ELX/TEZ/IVA. To reduce subject burden and minimize 
discomfort of blood draws, a topical or local anesthetic may be used at the discretion of the 
investigator. Site personnel may only make a maximum of 3 attempts to draw blood at any single 
visit. 
These samples may also be used for further evaluation of the bioanalytical method, or for 
exploratory analyses that provide information on the metabolic pathways used by or affected by 
ELX, which may not be included in the CSR. 
Samples from the PK sampling will be stored by Vertex or its designee until all analyses have 
been completed and then disposed of according to Vertex or designee standard operating 
procedures. 
Plasma concentration samples collected from subjects treated with placebo will not be routinely 
analyzed. 


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11.2.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be in the Laboratory Manual and the PK Sample 
Handling Guidelines.  
11.2.3 
Bioanalysis 
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee standard operating procedures. A description of the assay and validation data will be 
provided in separate reports. 
11.3 
Exploratory Assessments 
Blood samples will also be collected from subjects who weigh ≥22 kg at the screening visit for 
potential exploratory evaluation of changes in ribonucleic acid (RNA) and protein markers 
(serum and plasma) following treatment with ELX/TEZ/IVA, or evaluation of associations 
between RNA or protein markers with PK, PD, treatment response, and AEs. To reduce subject 
burden and minimize discomfort of blood draws, a topical or local anesthetic may be used at the 
discretion of the investigator. Site personnel may only make a maximum of 3 attempts to draw 
blood at any single visit. 
These data will be used for internal exploratory purposes. Detailed procedures for the collection 
of blood samples and additional procedures for processing and handling samples will be 
provided in a separate document.  
11.4 
Efficacy 
11.4.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines12 and 
according to the additional guidelines that follow. 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
• withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 
• withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the 
spirometry assessment; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilator. At all other visits, all spirometry assessments should be performed 
pre-bronchodilator. During the Treatment Period, spirometry assessments must be performed 
before study drug dosing (Section 9.6) at approximately the same time at each visit. In the event 
that a subject forgets to withhold bronchodilator(s), spirometry should be performed according to 
the following: 
• If a subject’s Day 1 spirometry assessment is pre-bronchodilator, but, on a subsequent visit, 
the subject forgets to withhold bronchodilator use, a post-bronchodilator spirometry 
assessment will be obtained for that visit only, and the visit will not be rescheduled. 


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• If, on Day 1, the subject forgets to withhold his/her dose of bronchodilator, spirometry 
should be performed post-bronchodilator, and all subsequent spirometric measurements 
(according to the schedule of assessments) should be performed post-bronchodilator. 
• Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator. 
Spirometers will be provided to be used for all study assessments. During study visits, 
spirometry assessments will be conducted per Table 3-1 and Table 3-2 and will be performed on 
more than one spirometer as applicable. All spirometry data will be transmitted to a centralized 
spirometry service for quality review. The investigator’s assessment of the spirometry results 
will be used for the screening assessment and determination of eligibility. 
See Section 10.7.1 for information about access to spirometry results. 
The measured spirometric values listed below will be converted to percent predicted values using 
the standard equations of GLI.11  
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 
• Forced expiratory flow, midexpiratory phase (FEF25%-75%) (L/s) 
11.4.2 
Sweat Chloride 
The SwCl 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 SwCl test results will not be disclosed to the study sites. Specific instructions for 
collection, handling, processing, and shipping of SwCl samples to the central laboratory will be 
provided separately. The SwCl 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 about access to SwCl results. 
11.4.3 
Cystic Fibrosis Questionnaire – Revised 
The questionnaires provide information about demographics; general quality of life, school, 
work, or daily activities; and symptom difficulties (pertaining to CF). 
Subjects/caregivers will be asked to complete the CFQ-R in their native language, if validated 
translations are available.16, 17 If there is no validated translation available in the subject’s native 
language, the subject will not complete the questionnaire. Copies of the CFQ-R used will be 
provided in the Study Reference Manual. Validated translations of the CFQ-R, if available, will 
be provided for participating centers in non-English-speaking countries.18, 19 The version and 
format of CFQ-R will be based on age at informed consent, regardless of whether the subject 
changes age during the study. 
The CFQ-R will be completed before any other assessments are performed at that visit. 


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11.4.4 
Height and Weight 
Height and weight will be measured with shoes off and before the dose of the study drug during 
the Treatment Period. 
For subjects whose date of informed consent occurs after their 21st birthday, height will not be 
collected in this study. For subjects whose date of informed consent occurs on or before their 21st 
birthday, height will be collected through the first visit after the subject’s 21st birthday and does 
not need to be collected at future visits 
11.4.5 
Other Events Related to Outcome 
11.4.5.1 
Antibiotic Therapy for Sinopulmonary Sign/Symptoms 
New or changed antibiotic therapy (intravenous [IV], inhaled, or oral) for the following 
sinopulmonary signs/symptoms will be determined and documented at visits as indicated in 
Table 3-1 and Table 3-2: 
• Change in sputum 
• New or increased hemoptysis 
• Increased cough 
• Increased dyspnea 
• Malaise, fatigue, or lethargy 
• Temperature above 38°C (equivalent to approximately 100.4°F) 
• Anorexia or weight loss 
• Sinus pain or tenderness 
• Change in sinus discharge 
• Change in physical examination (PE) of the chest 
• Decrease in pulmonary function by 10% 
• Radiographic changes indicative of pulmonary infection 
For this study, PEx is defined as a new or change in antibiotic therapy (IV, inhaled, or oral) 
for any 4 or more of the above signs/symptoms. This definition is based on the definition of a 
PEx used in previous clinical studies, including IVA clinical studies.20, 21  
It is recommended that the study drug not be interrupted during a PEx unless, in the opinion of 
the investigator, it would be in the best interest of the subject. 
11.4.5.2 
Hospitalization for CF 
Subjects will be queried about planned and unplanned hospitalizations lasting ≥24 hours that 
occurred during the study. The dates of hospitalizations and the reasons for hospitalizations will 
be documented. 
For any hospitalization (planned and unplanned), the procedures for safety reporting should also 
be followed. 


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11.5 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, and PEs. Safety will be monitored continuously from the signing of the ICF 
through completion of study participation (defined in Section 9.1.6) according to the schedule of 
assessments (Table 3-1 and Table 3-2). 
11.5.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with current ICH E6 GCP 
Guidelines. Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs.  
11.5.2 
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 pregnancy test kit. 
On Day 1, blood samples will be collected before the first dose of the study drug. At all other 
scheduled visits, these samples will be collected at any time during the visit. To reduce subject 
burden and minimize discomfort of blood draws, local anesthetic may be used at the discretion of 
the investigator. Site personnel may only make a maximum of 3 attempts to draw blood.  
Laboratory test results that are abnormal and considered clinically significant will be reported as 
AEs (see Section 13.1). 
The safety laboratory test panels are shown in Table 11-1. 


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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  
Hemoglobin  
Erythrocytes 
Mean corpuscular volume 
Platelets  
Reticulocytes  
Leukocytes  
Differential (absolute and percent): 
Eosinophils 
Basophils  
Neutrophils 
Lymphocytes 
Monocytes  
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
Leukocyte esterase  
Nitrite  
Urobilinogen  
Urine protein  
pH 
Urine blood  
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose  
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be done, and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
b 
If blood urea nitrogen cannot be collected, urea may be substituted. 
Additional Tests at Screening: The following additional tests will be performed during screening 
to assess eligibility:  
• Beta-human chorionic gonadotropin (β-hCG) for all female subjects ≥9 years of age and for 
all female subjects who have undergone menarche. 
• Serum follicle-stimulating hormone (FSH) for suspected postmenopausal female subjects 
only. Levels will be within the laboratories range for postmenopausal for subjects to be 
considered of non-childbearing potential. 
Pregnancy Testing: All female subjects who are ≥9 years of age and all female subjects who 
have undergone menarche (regardless of age) will have a serum pregnancy test at the Screening 
Visit. Females of childbearing potential (as defined in Section 11.5.6.1) will also have pregnancy 
tests at in-clinic visits and at-home urine pregnancy tests as shown in Table 3-2. 
Serum pregnancy tests will be performed by site medical staff and analyzed at the central 
laboratory. Urine pregnancy tests will either be performed and analyzed at the site or at home 
using a home kit provided by the site. Results will be reported to the site by telephone or 
telemedicine contact.  


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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. 
FSH (Screening Period only): Blood samples for FSH will be measured for any suspected 
postmenopausal female with at least 12 months of continuous spontaneous amenorrhea 
(Section 11.5.6.1). Serum FSH levels must be in the postmenopausal range as determined by the 
laboratory performing the test. 
CFTR genotyping (Screening Period only): CFTR genotyping will be performed for all subjects. 
A subject’s screening CFTR genotype must confirm eligibility before the subject is randomized. 
Specific instructions will be provided in the Laboratory Manual. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 
becomes aware of the abnormal result. If it is not possible to send a timely specimen to the 
central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base the 
assessment of an AE on the local laboratory value. 
11.5.3 
Physical Examinations, Vital Signs, and Pulse Oximetry 
A full PE of all body systems and vital signs assessment will be performed at screening and 
select study visits. At other visits, symptom-directed PEs and symptom-directed vital signs 
assessments can be performed at the discretion of the investigator or healthcare provider. 
A PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, nose, and 
throat (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. 
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. 
Weight and height will also be assessed (Section 11.4.4). 
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. 


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• The subject will be instructed to rest for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position 
A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. Clinically significant ECG abnormalities occurring during the study 
through the Safety Follow-up Visit will be recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QT interval corrected by Fridericia’s formula (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. A subject with a QTcF value above the threshold value will discontinue 
dosing. 
11.5.5 
Ophthalmological Examinations (Subjects <18 Years of Age) 
Ophthalmologic examinations will be conducted only for subjects who are <18 years of age on 
the date of initial consent. The examination does not need to be completed if there is 
documentation of bilateral lens removal for the subject. 
All examinations will be conducted by a licensed ophthalmologist or optometrist and will 
include: 
• measurement of best-corrected distance visual acuity of each eye; and 
• pharmacologically dilated examination of the lens with a slit lamp. 
The screening examination does not need to be conducted if there is documentation of an 
examination meeting the protocol requirements that was conducted within 3 months before the 
date of informed consent. 
In addition to the screening ophthalmologic examination, a single follow-up ophthalmologic 
examination will be conducted for all subjects who were <18 years of age on the date of initial 
consent and who completed at least 12 weeks of study drug treatment. 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. 


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11.5.6.1 
Contraception 
Contraception requirement for a couple is waived for the following: 
• True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception. True abstinence must 
be practiced from the Screening Visit through 90 days after the last dose of study drug. 
• If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the first 
dose of study drug (e.g., examination of a semen specimen or by demonstration of the 
absence of the vas deferens by ultrasound). 
• Same-sex relationships 
• If the female is of non-childbearing potential. For a subject to be considered of 
non-childbearing potential, the female must meet at least 1 of the following criteria: 
o Less than 9 years of age and has not achieved menarche 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum 
FSH level within the laboratory’s reference range for postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
Note: All other females (including females <9 years of age who have achieved menarche and 
females with tubal ligations) will be considered to be of childbearing potential.  
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used as a couple. Methods of contraception must be in successful use from signing of consent 
approximately 28 days before the first dose of study drug (unless otherwise noted), and until 
90 days following the last dose of study drug. Additional contraception requirements may need 
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 (Applies to Subjects For Whom 
Contraception Requirements Are Not Waived) 
 
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 


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Table 11-2 
Acceptable Methods of Contraception (Applies to Subjects For Whom 
Contraception Requirements Are Not Waived) 
 
Male Subjects and Their 
Female (Non-study) 
Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
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. 
• Male subjects must not donate sperm during the period starting from the first dose of study 
drug until 90 days after the last dose of study drug. 
• Female subjects should not nurse a child during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
• For male subjects with a female partner of childbearing potential, the couple should not plan 
to become pregnant during the study or within 90 days after the last dose of study drug, with 
the exception of couples who plan to become pregnant by artificial insemination using sperm 
banked by the male subject before the first dose of study drug or sperm from another source. 
11.5.6.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a female subject becomes pregnant 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. Male subjects with 
female partners who become pregnant during the study must use a male condom to avoid 
exposure of a potential embryo or fetus to study drug via the seminal fluid. 
The subject or partner will be followed until the end of the pregnancy only if on blinded 
treatment, or if they have been unblinded and have received active drug. The infant will be 
followed for 1 year after birth, provided informed consent is obtained. A separate ICF will be 
provided to explain these follow-up activities. Pregnancy itself is not an AE.  


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12 
STATISTICAL ANALYSIS 
12.1 
Sample Size and Power 
Approximately 270 subjects will be enrolled and randomized (2:1) to the ELX/TEZ/IVA arm or 
the placebo arm.  
The primary endpoint is the absolute change from baseline in ppFEV1 through Week 24. The 
primary null hypothesis to be tested is that the mean absolute change from baseline in ppFEV1 
through Week 24 is the same for the ELX/TEZ/IVA and placebo treatment groups. The null 
hypothesis will be tested at a 2-sided significance level of 0.05. 
Assuming a within-group SD of 9 percentage points and a 10% dropout rate at Week 24, a total 
sample size of 270 subjects (180 subjects in the ELX/TEZ/IVA group and 90 subjects in placebo 
group) will have approximately 90% power to detect a difference of 4.0 percentage points for the 
mean absolute change from baseline in ppFEV1 through Week 24 between the 2 treatment 
groups, based on a 2-sided 2-sample t-test at a significance level of 0.05. 
12.2 
Analysis Sets 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), 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 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. 
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 received, unless otherwise specified. 
12.3 
Statistical Analysis 
This section presents a summary of the principal features of the planned statistical analyses. 
Statistical analysis details will be in the statistical analysis plan (SAP), and clinical 
pharmacologic analysis details will be provided in the clinical pharmacology analysis plan 
(CPAP), both of which will be finalized before clinical database lock. 
12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max).  
Categorical variables will be summarized using counts and percentages. 
Baseline value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug.  Details 
will be provided in the SAP. 


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Absolute change from baseline will be calculated as Post-baseline value − Baseline value. 
The Treatment-emergent (TE) Period will include the time from the first dose of study drug to 
28 days after the last dose of study drug or to the completion of study participation (as defined in 
Section 9.1.6), whichever occurs first. 
12.3.2 
Background Characteristics 
Subject disposition, demographic and baseline characteristics, prior and concomitant 
medications, exposure, compliance, and important protocol deviations will be summarized. 
Details of the analysis will be provided in the SAP. 
12.3.3 
Efficacy and Pharmacodynamics Analysis 
12.3.3.1 
Analysis of Primary Efficacy Endpoint 
The primary endpoint is the absolute change from baseline in ppFEV1 through Week 24.  
The primary analysis will be based on a mixed-effects model for repeated measures (MMRM). 
The model will include the absolute change from baseline in ppFEV1 at Day 15, Week 4, 
Week 8, Week 16, and Week 24 as the dependent variable; treatment group, visit, and 
treatment-by-visit as fixed effects; additional covariates will be included as appropriate and 
details will be specified in the SAP. The model will be estimated using restricted maximum 
likelihood. Denominator degrees of freedom for the F test for fixed effects will be estimated 
using the Kenward-Roger approximation. An unstructured covariance structure will be used to 
model the within-subject errors. If the model estimation does not converge, a compound 
symmetry covariance structure will be used instead. Conditional on the observed data and 
covariates, missing data will be assumed to be missing at random; consequently, no imputation 
of missing data will be performed.  
The primary result obtained from the model will be the estimated treatment difference through 
Week 24. The adjusted mean with a 2-sided 95% CI and a 2-sided P value will be provided. 
Furthermore, the adjusted mean and treatment difference at each post-baseline visit will also be 
provided, obtained from the model.  
Sensitivity analyses for handling missing data will be described in the SAP.  
Supportive analyses and subgroup analyses of the primary efficacy variable will also be 
described in the SAP. 
12.3.3.2 
Analysis of Secondary Efficacy Endpoints 
The secondary efficacy variables include: 
• Absolute change from baseline in SwCl through Week 24: Analysis of this PD variable 
will be based on an MMRM model similar to the analysis of the primary efficacy variable. 
Data obtained from Day 15, Week 4, Week 8, Week 16, and Week 24 Visits will be included 
in the model. 
• Absolute change from baseline in the CFQ-R RD score through Week 24: Analysis of 
this domain will be based on an MMRM model similar to the analysis of the primary efficacy 
variable. Data obtained from Week 4, Week 8, Week 16, and Week 24 Visits will be 
included in the model. 


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• Absolute change from baseline in BMI at Week 24: Analysis of this variable will be based 
on an MMRM model similar to the analysis of the primary efficacy variables. Data obtained 
from Day 15, Week 4, Week 8, Week 16, and Week 24 Visits will be included in the model. 
• Absolute change from baseline in weight at Week 24: Analysis of this variable will be 
based on an MMRM model similar to the analysis of the primary efficacy variables. Data 
obtained from Day 15, Week 4, Week 8, Week 16, and Week 24 Visits will be included in 
the model. 
• Number of PEx through Week 24: Analysis of this variable will be performed using a 
negative binomial regression model with a fixed effect for treatment, as well as additional 
covariates as appropriate (details will be specified in the SAP). The logarithm of the subject 
specific PEx analysis period duration (defined in the SAP) will be treated as the offset in the 
model. 
12.3.3.3 
Analysis of Other Efficacy Endpoints 
The other efficacy variables include absolute change from baseline in BMI z-score at Week 24 
and absolute change from baseline in weight z-score at Week 24. The analysis details for these 
variables will be described in the SAP. 
12.3.3.4 
Multiplicity Adjustment 
A hierarchical testing procedure will be used to control the overall type I error at an alpha of 
0.05. The secondary endpoints described in Section 12.3.3.2 will be formally tested at an alpha 
of 0.05 only if the primary analysis of absolute change from baseline in ppFEV1 through 
Week 24 is statistically significant. For a test at any step to be considered statistically significant 
within the testing hierarchy, it must be statistically significant, and all previous tests (if any) 
within the hierarchy must be statistically significant at the 0.05 level 2-sided. Additional details 
will be provided in the SAP. 
12.3.3.5 
Missing Data Handling 
Details of the handling of missing data for the primary and secondary endpoints will be 
described in the SAP.  
12.3.4 
Safety Analysis 
The overall safety profile will be assessed based on the following safety and tolerability 
endpoints: 
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis as 
applicable) 
• Standard 12-lead ECGs 
• Vital signs 
• Pulse oximetry 
• Ophthalmological examinations 
For safety analyses, no statistical hypothesis testing will be conducted. Additional details will be 
provided in the SAP. 


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12.4 
Interim Analysis 
Not applicable. 
12.5 
Independent Data Monitoring Committee Analysis 
The IDMC (Section 9.1.8) will conduct safety reviews of study data. Details will be described in 
the IDMC charter. 
12.6 
Clinical Pharmacology Analysis 
12.6.1 
Pharmacokinetic Analysis 
The PK of ELX, TEZ, IVA and their relevant metabolites will be described using summary 
statistics. Preliminary review and analyses of the drug concentrations may be done before 
database lock under the conditions of masked identifications of the subject concentrations. 
Details of the analyses will be in the CPAP. 
12.6.2 
Pharmacodynamic Analysis 
12.6.3 
Pharmacokinetic/Pharmacodynamic Analyses 
A population PK analysis of plasma concentration versus time data of ELX/TEZ/IVA may be 
performed using the nonlinear mixed-effects modeling approach. A more detailed description of 
the methodology to be followed will be in either the CPAP or the population PK/PD analysis 
plan. Listings of ELX, TEZ, and IVA and relevant metabolite plasma concentration data will be 
in the bioanalytical report. The population PK analysis will be in a stand-alone document. 
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). 


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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 in source documents from the time the ICF is signed until completion 
of study participation (Section 9.1.6) 
All subjects, or their parents or legal guardians, 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 source documents. AEs for subjects who are screened but not subsequently enrolled 
will be recorded only in the subject’s source documents. The following data will be documented 
for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed July 
2021). When considering the severity of an AE in a pediatric subject, the investigator will 
consider that reference ranges for pediatric clinical laboratory parameters may differ from those 
in the CTCAE. The severity of an AE described by a term that does not appear in the CTCAE 
will be determined according to the definitions in Table 13-1.  


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


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Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classificationa 
Definition 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
AE: adverse event 
a 
Refer to Sections 9.7 and 9.9 for directions regarding what drug actions are permitted per protocol.  
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
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 


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• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious”, which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
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: globalpatientsafety@vrtx.com (preferred choice) 
Fax: +1-617-341-6159  
For technical issues related to submitting the form, contact telephone: +1-617-341-6677 
SAEs that occur after the 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 


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


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13.2.4 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
13.2.5 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.6 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all data, 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 regulatory authorities, including the IRB/IEC, may 
also request access to all study records, including source documentation, for inspection. 
13.2.7 
Record Retention 
The investigator will maintain all study records according to current ICH E6 GCP Guidelines 
and/or applicable local regulatory requirement(s), whichever is longest, as described in the 
Clinical Trial Agreement. If the investigator withdraws from the responsibility of keeping the 
study records, custody will be transferred to a person willing to accept the responsibility and 
Vertex will be notified. 
13.2.8 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 


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Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.2.9 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation per 
current ICH E6 GCP Guidelines. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each subject. Study 
data for each enrolled subject will be entered into a CRF by study site personnel using a secure, 
validated, web-based electronic data capture (EDC) application. The investigator will affirm the 
completeness and accuracy of the data by signing each casebook before data lock. If applicable, 
periodic investigator signatures may also be required. 
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 
The study will be monitored by Vertex or its designee in accordance with written procedures. 
Monitoring and auditing procedures developed or approved by Vertex for these activities comply 
with GCP regulatory requirements and guidelines. 
The monitoring strategy may include onsite, remote, and central monitoring activities, in 
accordance with local regulations. The study site monitor will ensure that the study is conducted 
according to the protocol design and regulatory requirements. 
13.5 
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.  


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A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
will be placed in the investigator’s study file. 
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 
13.7.1 
Publication of Study Results 
Vertex is committed to reporting the design and results of all clinical studies in a complete, 
accurate, balanced, transparent, and timely manner, consistent with Good Publication Practices 
(GPP3).22  
Publication Planning: Vertex staff along with the lead principal investigators, the steering 
committee, and/or the publication committee will work together to develop a publication plan.  
Authorship: Authorship of publications will be determined based on the Recommendations for 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, which 
states that authorship should be based on the following 4 criteria23: 
1. Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data;  
2. Drafting of the article or revising it critically for important intellectual content;  


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


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14 
REFERENCES 
1 
Cystic Fibrosis Foundation. 2019 Patient Registry Annual Data Report. Bethesda, MD: 
2020. 
2 
European Cystic Fibrosis Society. 2018 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: 2020. 
3 
Cystic Fibrosis Canada. The Canadian Cystic Fibrosis Registry 2019 Annual Data 
Report. Toronto, Ontario: Cystic Fibrosis Canada; 2020. 
4 
Ahern S, Ruseckaite R, Salimi F, Caruso M, Bell S, Burke N, et al. Australian Cystic 
Fibrosis Registry Annual Report 2019. Monash University: Department of Epidemiology 
and Preventative Medicine; 2021. 
5 
Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, et al. 
Identification of the cystic fibrosis gene: Chromosome walking and jumping. Science. 
1989;245(4922):1059-65. 
6 
Kreindler JL. Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
7 
Sheppard MN, Nicholson AG. The pathology of cystic fibrosis. Curr Diagn Pathol. 
2002;8(1):50-59. 
8 
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10:88. 
9 
Cystic Fibrosis Centre at the Hospital for Sick Children in Toronto [Internet]. Cystic 
Fibrosis Mutation Database (CFTR1). Available at: 
http://www.genet.sickkids.on.ca/cftr/Home.html. Accessed 15 September 2021. 
10 
Sheppard DN, Carson MR, Ostedgaard LS, Denning GM, Welsh MJ. Expression of 
cystic fibrosis transmembrane conductance regulator in a model epithelium. Am J 
Physiol. 1994;266(4 Pt 1):L405-13. 
11 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
12 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
13 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-
70. 
14 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-54. 
15 
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51(11):875-78. 
16 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 
17 
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of 
the Cystic Fibrosis Questionnaire in the United States. Chest. 2005;128(4):2347-54. 


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18 
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life 
Res. 2003;12(1):63-76. 
19 
Wenninger K, Aussage P, Wahn U, Staab D, German Cystic Fibrosis Questionnaire study 
group. The revised German Cystic Fibrosis Questionnaire: validation of a disease-
specific health-related quality of life instrument. Qual Life Res. 2003;12(1):77-85. 
20 
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR 
potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 
2011;365(18):1663-72. 
21 
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 
1994;331(10):637-42. 
22 
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. 
23 
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 15 
September 2021. 
 
 


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15 
APPENDIX A: ELIGIBLE CFTR GENOTYPES 
To be eligible for enrollment, subjects must meet both of the following criteria: 
• At least 1 ELX/TEZ/IVA-responsive mutation listed in Table 15-1. Sections 5.2 and 9.3.2 
describe the rationale for why these mutations are considered to be responsive to 
ELX/TEZ/IVA. 
• None of the exclusionary mutations listed in Table 15-2. Subjects with these mutations 
are eligible for treatment with a commercial approved CFTR modulator; subjects with 
F508del are eligible for treatment with ELX/TEZ/IVA (Kaftrio™/Trikafta™) and 
subjects with the remaining mutations are eligible for treatment with IVA (Kalydeco™). 
A subject who has 1 eligible mutation and 1 exclusionary mutation will not be eligible for 
enrollment in the study. 
Table 15-1 
Eligible ELX/TEZ/IVA-responsive CFTR mutations 
RF-like mutations 
MF-like mutations 
2789+5G>A 
L206W  
S945L  
G85E 
3272-26A>G 
V232D  
L997F  
R347P 
3849+10kbC>T 
T338I  
R1066H 
L1077P 
P5L  
R347H 
D1152H 
M1101K 
R117C 
A455E 
 
 
Note: A subject must have at least 1 of the mutations listed above to be eligible for the study. 
 
Table 15-2 
Exclusionary CFTR mutations 
F508del 
S549N  
G551S 
S1255P  
R117H 
S549R  
G1244E  
G1349D  
G178R  
G551D  
S1251N  
  
Note: If a subject has any of the mutations listed above, they will not be eligible for the study. 
Maximum Enrollment Per Mutation 
Enrollment for each CFTR mutation listed in Table 15-1 will be capped at approximately 
30 subjects.  
If a subject has 2 eligible CFTR mutations, the subject may be screened if at least 1 of their 
2 eligible mutations has less than approximately 30 subjects enrolled at the time of screening.


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16 
APPENDIX B: BLOOD SAMPLE VOLUMES BY VISIT 
Blood sample volumes to be drawn at each visit are presented in Table 16-1. 
Table 16-1 
Blood Sample Volumes by Visit (mL) 
 
Study Visit 
 
Subject weight 
Screening 
Day 1 
Day 15 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
ETT 
SFU 
Totala 
≥22 kg 
10.0 
17.5 
6.0 
8.0 
6.0 
0 
13.5 
0 
10.0 
8.0 
8.0 
79.0 
<22 kg 
10.0 
10.0 
6.0 
8.0 
6.0 
0 
6.0 
0 
10.0 
8.0 
8.0 
64.0 
ETT: Early Termination of Treatment; SFU: Safety Follow-up 
a 
Total does not include sample volumes from the ETT Visit 




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17.2 
Investigator Signature Page 
Protocol #:  
VX21-445-124 
Version #: 3.0 
Version Date: 
21 April 2022 
Study Title: A Phase 3 Double-blind, Randomized, Placebo-controlled Study Evaluating the 
Efficacy and Safety of ELX/TEZ/IVA in Cystic Fibrosis Subjects 6 Years of Age and Older 
With a Non-F508del ELX/TEZ/IVA-responsive CFTR Mutation 
 
 
I have read Protocol VX21-445-124, Version 3.0, and agree to conduct the study according to its 
terms. I understand that all information concerning ELX/TEZ/IVA and this protocol supplied to 
me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 
 

SAP_001.pdf: 


Statistical Analysis Plan (Methods) 
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2 
TABLE OF CONTENTS 
Title Page ....................................................................................................................................... 1 
2 
Table of Contents ................................................................................................................... 2 
List of Abbreviations.................................................................................................................. 4 
3 
Modifications .......................................................................................................................... 6 
3.1 
Modifications to the Approved Clinical Study Protocol .................................................. 6 
3.2 
Modifications to the Approved Statistical Analysis Plan ................................................. 6 
3.3 
Modifications to the Approved IDMC Charter ................................................................ 6 
4 
Introduction............................................................................................................................ 7 
5 
Study Objectives .................................................................................................................... 7 
5.1 
Primary Objective ............................................................................................................. 7 
5.2 
Secondary Objectives ....................................................................................................... 7 
6 
Study Endpoints ..................................................................................................................... 7 
6.1 
Primary Endpoint .............................................................................................................. 7 
6.2 
Secondary Endpoints ........................................................................................................ 7 
6.3 
Other Endpoints ................................................................................................................ 7 
7 
Study Design ........................................................................................................................... 8 
7.1 
Overall Design .................................................................................................................. 8 
7.2 
Sample Size and Power .................................................................................................... 9 
7.3 
Randomization .................................................................................................................. 9 
7.4 
Blinding and Unblinding .................................................................................................. 9 
7.5 
Interim Analysis ............................................................................................................... 9 
8 
Analysis Sets ........................................................................................................................... 9 
8.1 
All Subjects Set ................................................................................................................ 9 
8.2 
Full Analysis Set ............................................................................................................... 9 
8.3 
Safety Set .......................................................................................................................... 9 
9 
Statistical Analysis ............................................................................................................... 10 
9.1 
General Considerations .................................................................................................. 10 
9.2 
Background Characteristics ............................................................................................ 10 
9.2.1 
Subject Disposition ................................................................................................. 10 
9.2.2 
Demographics and Baseline Characteristics ........................................................... 11 
9.2.3 
Medical History ...................................................................................................... 12 
9.2.4 
Prior and Concomitant Medications ....................................................................... 12 
9.2.5 
Study Drug Exposure.............................................................................................. 13 
9.2.6 
Study Drug Compliance ......................................................................................... 13 
9.2.7 
Important Protocol Deviations ................................................................................ 13 
9.3 
Efficacy Analysis ............................................................................................................ 14 
9.3.1 
Analysis of Primary Efficacy Endpoint .................................................................. 14 
9.3.1.1 
Definition of Variables ..................................................................................... 14 
9.3.1.2 
Primary Analysis .............................................................................................. 14 
9.3.1.3 
Supportive Analyses ........................................................................................ 14 
9.3.1.4 
Sensitivity Analyses ......................................................................................... 14 
9.3.1.5 
Subgroup Analysis ........................................................................................... 15 
9.3.2 
Analysis of Secondary Endpoints ........................................................................... 15 
9.3.2.1 
Definition of Variables ..................................................................................... 15 


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9.3.2.2 
Analysis Method .............................................................................................. 16 
9.3.2.3 
Multiplicity Adjustment ................................................................................... 17 
9.3.3 
Analysis of Other Endpoints ................................................................................... 18 
9.3.3.1 
Definition of Variables ..................................................................................... 18 
9.3.3.2 
Analysis Method .............................................................................................. 18 
9.3.4 
Analysis of Additional Efficacy Variables ............................................................. 18 
9.3.4.1 
Analysis of Additional Spirometry Variables .................................................. 18 
9.3.4.2 
Analysis of Other CFQ-R Variables ................................................................ 19 
9.3.5 
Additional Analysis ................................................................................................ 19 
9.3.6 
Remote Measures in Extenuating Circumstances .................................................. 19 
9.4 
Safety Analysis ............................................................................................................... 19 
9.4.1 
Adverse Events ....................................................................................................... 20 
9.4.2 
Clinical Laboratory ................................................................................................. 21 
9.4.3 
Electrocardiogram .................................................................................................. 22 
9.4.4 
Vital Signs .............................................................................................................. 22 
9.4.5 
Pulse Oximetry ....................................................................................................... 22 
9.4.6 
Ophthalmologic Examinations ............................................................................... 22 
9.4.7 
Physical Examination ............................................................................................. 22 
9.4.8 
COVID-19 Impacted Visits .................................................................................... 22 
9.4.9 
Supportive Safety Analysis .................................................................................... 23 
9.4.9.1 
Adverse Events of Special Interest .................................................................. 23 
9.4.9.2 
Hormonal Therapy ........................................................................................... 23 
10 SUMMARY OF Interim and IDMC ANALYSIS............................................................. 23 
10.1 Interim analysis .............................................................................................................. 23 
10.2 IDMC Analysis ............................................................................................................... 23 
11 References ............................................................................................................................. 24 
12 List of Appendices................................................................................................................ 25 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments ......................... 25 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 27 
Appendix C: Details of GLI Equations for Calculating ppFEV1 ............................................. 28 
Appendix D: Steps for Multiple Imputation ............................................................................ 29 
Appendix E: Imputation Rules for Missing AE dates .............................................................. 31 
Appendix F: Criteria for Threshold Analysis .......................................................................... 32 
 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFQ-R RD 
Cystic Fibrosis Questionnaire- Revised respiratory domain 
CFTR 
cystic fibrosis transmembrane conductance regulator gene 
CI 
confidence interval 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CSP 
clinical study protocol 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ETT 
Early Termination of Treatment 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine 
codon corresponding to position 508 of the wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
FEV1 
forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GGT 
Gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
IDMC 
Independent Data Monitoring Committee 
max 
maximum value 
MF 
minimal function 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
PD 
pharmacodynamic, pharmacodynamics 
PEx 
pulmonary exacerbations 
PK 
pharmacokinetic, pharmacokinetics 


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Abbreviation 
Definition 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
QTcF 
QT interval corrected by Fridericia’s formula 
RF 
residual function 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SwCl 
sweat chloride 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
 


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3 
MODIFICATIONS  
3.1 
Modifications to the Approved Clinical Study Protocol 
Not Applicable. 
3.2 
Modifications to the Approved Statistical Analysis Plan 
Not Applicable.   
3.3 
Modifications to the Approved IDMC Charter 
Not Applicable. 
 


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4 
INTRODUCTION 
This SAP for the final analysis is based on the most recent approved clinical study protocol 
(CSP), electronic case report form (eCRF), and eCRF completion guidelines. 
This SAP (Methods) documents the planned statistical analyses of efficacy endpoints and safety 
endpoints for the final analysis. Analyses related to sweat chloride will be documented in this 
SAP. Other PK and PD analyses will be documented separately in the CPAP for the study. 
This SAP (Methods) will be finalized and approved prior to data lock and treatment unblinding. 
Any revisions to the approved SAP prior to data lock will be documented and approved in an 
amendment to the SAP and deviations from the approved SAP after data lock will be 
summarized in the CSR. 
The Vertex Biometrics Department will perform the statistical analysis for the final analysis and 
prepare the analysis package for the final analysis; SAS (Version 9.4 or higher) will be used to 
generate all statistical outputs (tables, figures, listings, and datasets).  
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
To evaluate the efficacy and PD of ELX/TEZ/IVA  
5.2 
Secondary Objectives  
To evaluate safety and tolerability of ELX/TEZ/IVA 
6 
STUDY ENDPOINTS  
6.1 
Primary Endpoint 
Absolute change from baseline in ppFEV1 through Week 24 
6.2 
Secondary Endpoints  
• Absolute change from baseline in SwCl through Week 24 
• Absolute change from baseline in CFQ-R RD score through Week 24 
• Absolute change from baseline in BMI at Week 24 
• Absolute change from baseline in weight at Week 24 
• Number of PEx through Week 24 
• Safety and tolerability assessments based on AEs), clinical laboratory values, ECGs, vital 
signs, and pulse oximetry 
6.3 
Other Endpoints  
• Absolute change from baseline in BMI z-score (subjects ≤20 years of age) at Week 24 
• Absolute change from baseline in weight z-score (subjects ≤20 years of age) at Week 24 
• Plasma PK parameters including ELX, TEZ, IVA, and relevant metabolites 




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Please refer to the Table 3-1 and Table 3-2 of the CSP for more details about study visits and 
assessments. 
7.2 
Sample Size and Power 
Approximately 270 subjects will be enrolled and randomized (2:1) to the ELX/TEZ/IVA arm or 
the placebo arm.  
The primary endpoint is the absolute change from baseline in ppFEV1 through Week 24. The 
primary null hypothesis to be tested is that the mean absolute change from baseline in ppFEV1 
through Week 24 is the same for the ELX/TEZ/IVA and placebo treatment groups. The null 
hypothesis will be tested at a 2-sided significance level of 0.05. 
Assuming a within group SD of 9 percentage points and a 10% dropout rate at Week 24, a total 
sample size of 270 subjects (180 subjects in the ELX/TEZ/IVA group and 90 subjects in placebo 
group) will have approximately 90% power to detect a difference of 4.0 percentage points for the 
mean absolute change from baseline in ppFEV1 through Week 24 between the 2 treatment 
groups, based on a 2-sided 2-sample t-test at a significance level of 0.05. 
7.3 
Randomization 
Subjects will be randomized 2:1 (ELX/TEZ/IVA group: placebo group). Randomization will be 
stratified based on ppFEV1 determined during the Screening Period (<70 versus ≥70), age at the 
Screening Visit (<18 years old versus ≥18 years old) and CFTR mutation group (contains ≥ 1 
RF-like mutation versus does not contain an RF-like mutation).  
7.4 
Blinding and Unblinding 
Refer to the CSP section 10.7 for details. 
7.5 
Interim Analysis 
No Interim Analysis was planned for this study. 
8 
ANALYSIS SETS 
8.1 
All Subjects Set 
The All Subjects Set will include all subjects who were randomized or received at least 1 dose 
of study drug. This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified. 
8.2 
Full Analysis Set  
The Full Analysis Set (FAS) will include all randomized subjects who carry the intended 
mutation and received at least 1 dose of study drug. The FAS will be used to summarize subject 
demographics and baseline characteristics, and for analyses of all efficacy endpoints in which 
subjects will be analyzed according to their randomized treatment group, unless otherwise 
specified. 
8.3 
Safety Set 
The Safety Set will include all subjects who received at least 1 dose of study drug. The Safety 
Set will be used for all safety analyses in which subjects will be analyzed according to the 
treatment they received, unless otherwise specified.  If a subject received study drug from both 


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the placebo group and the treatment group, the subject will be analyzed in the Safety Set of the 
treatment group.  
9 
STATISTICAL ANALYSIS 
This section discusses the analyses planned for the final analysis.  
9.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of the CSP.  The precision standards for 
reporting safety and efficacy variables are provided in an internal Biometrics document that 
specifies the programming rules including the precision for derived variables.  
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, min, and max.  
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place.  
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. For ECGs, the baseline value 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. 
Absolute change from baseline will be calculated as post-baseline value - baseline value. 
Relative change from baseline will be calculated as (post-baseline value - baseline 
value)/baseline value. 
The Treatment Emergent (TE) Period 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 completion of study participation 
date, whichever occurs first. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
1) In scheduled visit windows per specified visit windowing rules 
2) In the derivation of baseline and last on-treatment measurements 
3) In the derivation of max and min during TE period, and maximum and minimum change 
from baseline values during TE period for safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix A.  
Incomplete/missing data will not be imputed, unless otherwise specified.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless otherwise specified. 
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized: 


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• All Subjects Set 
 
• Full Analysis Set 
• Safety Set 
• Randomized 
• Randomized but not dosed 
The number and percentage (based on the FAS) of subjects in each of the following disposition 
categories will be summarized by treatment group and overall: 
• Completed treatment 
• Prematurely discontinued treatment and the reason for discontinuation  
• Completed study 
• Prematurely discontinued the study and the reason for discontinuation 
• Rollover to open-label study 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. 
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group and overall 
based on the FAS. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Sex (male, female) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Other, and not collected per local regulations) 
• Geographic Region (North America and Europe) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• BMI z-score (for subjects ≤20 years old at Baseline) 
• Weight z-score (for subjects ≤20 years old at Baseline) 
Stratification categories will include the following: 
• Age at the Screening Visit (<18, and ≥18 years) 
• ppFEV1 at the Screening Visit (<70 and ≥70) 


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• CFTR mutation group (contains ≥ 1 RF-like mutation versus does not contain an RF-like 
mutation)  
Disease characteristics will include the following: 
• ppFEV1 at baseline (≥ 40 to <70, ≥70 to ≤90, and >90) 
• ppFEV1 at baseline (continuous)  
• Sweat chloride at baseline (continuous) 
• CFQ-R respiratory domain score at baseline (continuous) 
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 
• Prior use of any bronchodilator (Yes, No)  
• Prior use of any inhaled bronchodilator (Yes, No)  
• Prior use of any inhaled hypertonic saline (Yes, No) 
• Infection with Pseudomonas aeruginosa within 2 years prior to screening (Positive, 
Negative) 
In addition, data listings will also be provided for: 
• Informed consent; 
• 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.  
In addition, the number of subjects reported to have had positive cultures for respiratory 
pathogens within the 2 years prior to screening (i.e., answered yes on the respiratory 
microbiology form) will be summarized for the FAS.  The corresponding data listing will be 
provided.   
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHODrug) 
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 follows: prior, concomitant, post-treatment, both prior 
and concomitant, both concomitant and post-treatment, or prior, concomitant, and 


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post-treatment. 
If a medication has a completely missing or partially missing start/stop date and if it cannot be 
determined whether it was taken before the first dose date of study drug, concomitantly, or after 
the TE period, it will be classified as prior, concomitant, and post-treatment. Details for imputing 
missing or partial start and/or stop dates of medication are described in Appendix B. 
Prior medications and concomitant medications will be summarized descriptively for FAS using 
frequency tables by: 1) treatment group and overall, preferred name (PN); and 2) treatment group 
and overall, Anatomical Therapeutic Chemical class (ATC) level 1, ATC level 2, and PN.  
Post-treatment medications will be listed in all medication listing. 
9.2.5 
Study Drug Exposure  
Duration of study drug exposure (in days) will be calculated as: last dose date of study drug – 
first dose date of study drug, regardless of study drug interruption. 
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max.  It will also be summarized by interval: ≤1 week, >1 to ≤2 
weeks, >2 to ≤4 weeks, >4 to ≤8 weeks, >8 to ≤12 weeks, >12 to ≤16 weeks, >16 to ≤20 weeks, 
>20 to ≤24 weeks, and >24 weeks using counts and percentages.  Additionally, the total study 
drug exposure, defined as the sum total of the study drug exposure across all subjects (in patient-
weeks and patient-years), will be provided. 
Exposure summaries will be based on the Safety Set and presented by treatment group and 
overall. 
9.2.6 
Study Drug Compliance 
Study drug compliance will be summarized by treatment group and overall based on the FAS. 
Study drug compliance will be calculated as: 100  [1 - (total number of days of study drug 
interruption) / (duration of study drug exposure in days)].  A study drug interruption on a given 
day is defined as an interruption of any study drug on that day.  A study drug interruption that 
continues through the end of the study participation (i.e., subject does not resume study drug 
before the end of the study participation) will not be included in the compliance calculation. 
Percentage of study drug compliance will be summarized descriptively by the number of subjects 
(n), mean, SD, median, min, and max and based on the FAS, and presented by treatment group 
and overall. 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. A protocol deviation review team will categorize IPDs according to 
the Protocol Deviation Plan during the study.  
IPDs will be provided in an individual subject data listing. A summary table of IPDs based on 
the FAS will also be provided. 


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9.3 
Efficacy Analysis 
All efficacy analyses described in this section will be based on the FAS, unless otherwise 
specified.  
9.3.1 
Analysis of Primary Efficacy Endpoint 
9.3.1.1 
Definition of Variables 
The primary efficacy variable is the absolute change in ppFEV1 from baseline through Week 24.  
Percent predicted FEV1 is the ratio of FEV1 (L) and predicted FEV1 (L), expressed as a 
percentage.  See Appendix C for more details. 
9.3.1.2 
Primary Analysis 
The primary analysis will be performed using a MMRM with change from baseline at Day 15, 
Week 4, Week 8, Week 16, and Week 24 as the dependent variable. The model will include 
treatment group, visit, and treatment by visit interaction as fixed effects, with continuous 
baseline ppFEV1, age at screening (<18 versus ≥18 years of age) and mutation group (contains ≥ 
1 RF-like mutation versus does not contain an RF-like mutation) 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. 
The primary result obtained from the model will be the estimated treatment difference through 
Week 24, defined as the averaged treatment effects estimated at Week 4, Week 8, Week 16, and 
Week 24. The adjusted means with 2-sided 95% CIs and 2-sided P value will be provided. 
Furthermore, the treatment difference at each post-baseline visit obtained from the model will 
also be provided. 
The estimated within group change from baseline and treatment difference at each post-baseline 
visit, obtained from the model, will be provided. The estimated within group change and its SE 
at each post-baseline visit will also be plotted by treatment group. In addition, the post-baseline 
raw values and the absolute change from baseline at each post-baseline visit will be summarized 
descriptively (n, mean, SD, median, minimum, and maximum). 
9.3.1.3 
Supportive Analyses 
There will be no supportive analysis for the primary efficacy endpoint.  
9.3.1.4 
Sensitivity Analyses 
MMRM based on Multiple Imputation (MI)  
An underlying assumption of the MMRM method is that data are missing at random. To 
minimize the amount of missing data, subjects who prematurely discontinue study drug 
treatment will continue to complete all scheduled study visits for spirometry and other efficacy 
assessments. 
To assess the impact of missing data and the assumption that data are missing at random, a 
multiple imputation algorithm will be used if at least 10% of the subjects have missing changes 


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in ppFEV1 at Week 24 in any treatment group. Missing absolute change from baseline in 
ppFEV1 assessments will be imputed starting from the first visit with missing values, for which 
all subsequent visits through Week 24 are also missing. For intermediate missing data, i.e., 
missing values that fall between two non-missing ones, it is reasonable to assume that they are 
missing at random and therefore will not be imputed. An MMRM analogous to that for the 
primary analysis of the primary endpoint will be applied to each imputed dataset and the relevant 
MI estimators will be reported. Details for the MI steps are presented in Appendix D. 
9.3.1.5 
Subgroup Analysis 
Subgroup analyses of the primary efficacy endpoint will be performed using a model similar to 
that of the primary analysis for each of the following subgroups.  
• Age at Screening (<18, ≥18 years) 
• ppFEV1 at baseline (< 70, ≥ 70)  
• Sex (male, female)  
The MMRM used for the primary analysis will be used for the subgroup analysis, where the 
same model will be applied to each category of the subgroup. Note that for the subgroup analysis 
based on age, the covariate of age at screening (<18 versus ≥18 years of age) from the MMRM 
will be removed. The adjusted means with 2-sided 95% CIs will be provided. Furthermore, 
estimated between group difference through Week 24 within a subgroup will also be presented in 
a forest plot. Note: Due to potential small sample size, the results from above mentioned 
subgroup analysis should be interpreted with caution. 
9.3.2 
Analysis of Secondary Endpoints  
9.3.2.1 
Definition of Variables 
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 sweat volume 
≥15 μL is required for an accurate determination of sweat chloride.  Any results reported as 
having sweat volume <15 μL or SwCl values reported as >160 mmol/L, will be considered 
missing.  Any sweat chloride values reported as <10 mmol/L will be imputed as 10 mmol/L. 
CFQ-R: The CFQ-R1,3,5 is a validated CF-specific instrument that measures quality-of-life 
domains. This study utilizes four different versions of CFQ-R: 
CFQ-R for Children ages 6 to 11 
CFQ-R for Children ages 12 and 13 
CFQ-R for Adolescents and Adults (subjects 14 years and older) 
CFQ-R for Parents/Caregivers (subjects 13 years and younger) 
In all four versions, specific question belonging to a domain is scored 1, 2, 3, or 4. The CFQ-R 
domain score, e.g., physical domain score or respiratory domain score, is defined as a scaled 
score as follows: 
 
Scaled score for a domain = 100 × (mean (scores of all questions in the domain) − 1)/3, 


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where the score from a negatively phrased question is first reversed, i.e., reversed score = 5 – 
actual score, so that 1 always represents the worst condition and 4 the best condition. The 
(scaled) domain score ranges from 0 (worst condition) to 100 (best condition). The scaled score 
for a specific domain will not be calculated if more than half of the questions in the domain have 
missing scores. 
The (scaled) domain score from the CFQ-R for Children ages 6 to 11, for Children ages 12 and 
13 and for Adolescent and Adults will be pooled for the analysis purpose. 
BMI: the BMI at each visit is calculated using the weight and height at each visit as follows: 
𝐵𝑀𝐼= Weight (kg)
Heightଶ (mଶ) 
PEx: A PEx is defined as a new event or change in antibiotic therapy (IV, inhaled, or oral) for 
any 4 or more of the following signs/symptoms: 
• Change in sputum 
• New or increased hemoptysis 
• Increased cough 
• Increased dyspnea 
• Malaise, fatigue, or lethargy 
• Temperature above 38°C (equivalent to approximately 100.4°F) 
• Anorexia or weight loss 
• Sinus pain or tenderness 
• Change in sinus discharge 
• Change in PE of the chest 
• Decrease in pulmonary function by 10% 
• Radiographic changes indicative of pulmonary infection 
The PEx analysis period will include the time from the first dose date of study drug in the 
treatment period until the last efficacy assessment. For subjects with a Week 24 Visit, the last 
efficacy assessment will be the Week 24 visit. For subjects who do not have a Week 24 Visit, the 
last efficacy assessment will be the earlier of Day 169 and the end of study participation. 
The number of PEx through Week 24 is then defined as the total number of PEx for each 
treatment group during the PEx analysis period. 
9.3.2.2 
Analysis Method 
Absolute change in SwCl from baseline through Week 24: The analysis of absolute change from 
baseline in SwCl through Week 24 will be based on an MMRM similar to the analysis of the 
primary endpoint above, with absolute change from baseline in SwCl at Day 15, Week 4, Week 
8,  Week 16, and Week 24 as the dependent variable.   


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The primary result obtained from the model will be the estimated treatment difference through 
Week 24, defined as the averaged treatment effects estimated at Week 4, Week 8, Week 16, and 
Week 24. The adjusted mean with a 2-sided 95% CI and a 2-sided P value will be provided. 
The estimated within group change from baseline and treatment difference at each post-baseline 
visit, obtained from the model, will be provided. The estimated within group change and its SE 
at each post-baseline visit will also be plotted by treatment group.  In addition, the post-baseline 
raw values and the absolute change from baseline at each post-baseline visit will be summarized 
descriptively (n, mean, SD, median, minimum, and maximum). 
Absolute change from baseline in CFQ-R Respiratory Domain (RD) score through Week 24: 
Analysis of this domain will be based on an MMRM similar to the analysis of the primary 
efficacy variable. Data obtained from Week 4, Week 8, Week 16, and Week 24 Visits will be 
included in the model to estimate the treatment effect through Week 24. Plot and summary tables 
similar to those for ppFEV1 and SwCl will be provided. 
Absolute change from baseline in BMI at Week 24: Analysis of this variable will be based on an 
MMRM similar to the analysis of the primary efficacy variable. Data obtained from Day 15, 
Week 4, Week 8, Week 16, and Week 24 Visits will be included in the model. Plot and summary 
tables similar to those for ppFEV1 and SwCl will be provided. 
Absolute change from baseline in weight at Week 24: Analysis of this variable will be based on 
an MMRM similar to the analysis of the primary efficacy variable. Data obtained from Day 15, 
Week 4, Week 8, Week 16, and Week 24 Visits will be included in the model. Plot and summary 
tables similar to those for ppFEV1 and SwCl will be provided. 
Number of PEx through Week 24: The number of PEx during the PEx analysis period will be 
performed using a negative binomial regression model with a fixed effect for treatment, as well 
as continuous baseline ppFEV1, age at screening (<18 versus ≥18 years of age) and mutation 
group (contains ≥ 1 RF-like mutation versus does not contain an RF-like mutation) as covariates.  
The logarithm of the subject-specific PEx analysis period duration (in years) will be treated as 
the offset in the model. The estimated rate ratio and the associated 2-sided 95% CI and 2-sided p-
value will be provided. If model does not converge, alternative models (e.g., a Poisson model 
with the same covariates) might be used instead. 
9.3.2.3 
Multiplicity Adjustment 
The secondary endpoints will be formally tested at an alpha of 0.05 at the final analysis when all 
subjects complete study participation. A hierarchical testing procedure will be used to control the 
type I error rate for the multiple secondary endpoints tested at an alpha of 0.05. For a test at any 
step to be considered statistically significant within the testing hierarchy, it must be statistically 
significant, and all previous tests (if any) within the hierarchy must be statistically significant at 
the 0.05 level. The testing order of the secondary endpoints is as follows: 
1. First secondary endpoint: Absolute change in SwCl from baseline through Week 24 
2. Second secondary endpoint: Absolute change in CFQ-R respiratory domain from baseline 
through Week 24  
3. Third secondary endpoint: Absolute change in BMI from baseline at Week 24  
4. Fourth secondary endpoint: Absolute change in weight from baseline at Week 24 


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5. Fifth secondary endpoint: Number of PEx through Week 24  
9.3.3 
Analysis of Other Endpoints 
9.3.3.1 
Definition of Variables 
BMI z-score: the BMI score, adjusted for age and sex, will be referred to as BMI-for-age z-score 
(BMI z-score). The BMI z-score will be calculated by using Centers for Disease Control and 
Prevention (CDC) growth charts7, with the age (in months) used for the calculation defined in 
Appendix A. 
Weight z-score: weight, adjusted for age and sex, will be referred to as weight-for-age z-score 
(Weight z-score). The Weight z-score will be calculated by using Centers for Disease Control 
and Prevention (CDC) growth charts7, with the age (in months) used for the calculation defined 
in Appendix A. 
9.3.3.2 
Analysis Method 
Absolute change from baseline in BMI z-score at Week 24 (for subjects ≤20 years of age at 
Baseline): Analysis of this variable will be based on an MMRM similar to the analysis of the 
primary efficacy variable, excluding the covariate of age at screening (<18 versus ≥18 years of 
age), for subjects ≤20 years of age at Baseline. Data obtained from Day 15, Week 4, Week 8, 
Week 16, and Week 24 Visits will be included in the model. Plot and summary tables similar to 
those for ppFEV1 and SwCl will be provided. 
Absolute change from baseline in Weight z-score at Week 24 (for subjects ≤20 years of age at 
Baseline): Analysis of this variable will be based on an MMRM similar to the analysis of the 
primary efficacy variable, excluding the covariate of age at screening (<18 versus ≥18 years of 
age), for subjects ≤20 years of age at Baseline. Data obtained from Day 15, Week 4, Week 8, 
Week 16, and Week 24 Visits will be included in the model. Plot and summary tables similar to 
those for ppFEV1 and SwCl will be provided. 
9.3.4 
Analysis of Additional Efficacy Variables 
9.3.4.1 
Analysis of Additional Spirometry Variables 
Summary statistics for raw values and for changes from baseline of the following spirometry 
measurements will be presented by treatment group at each visit: 
• FEV1: 
o Absolute change from baseline in FEV1 (L) 
o Relative change from baseline in FEV1 (%) 
o Absolute change from baseline in percent predicted FEV1 (percentage points) 
o Relative change from baseline in percent predicted FEV1 (%) 
• FVC: 
o Absolute change from baseline in FVC (L) 
o Relative change from baseline in FVC (%) 
o Absolute change from baseline in percent predicted FVC (percentage points) 
o Relative change from baseline in percent predicted FVC (%) 


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• FEF25-75%: 
o Absolute change from baseline in FEF25-75% (L/sec) 
o Relative change from baseline in FEF25-75% (%) 
o Absolute change from baseline in percent predicted FEF25-75% (percentage points) 
o Relative change from baseline in percent predicted FEF25-75% (%) 
• FEV1/FVC: 
o Absolute change from baseline in FEV1/FVC 
o Relative change from baseline in FEV1/FVC (%) 
o Absolute change from baseline in percent predicted FEV1/FVC 
o Relative change from baseline in percent predicted FEV1/FVC (%) 
9.3.4.2 
Analysis of Other CFQ-R Variables 
Absolute change in the CFQ-R non-respiratory domain score from baseline through Week 24: 
Analysis of this domain(s) will be based on an MMRM similar to the analysis of the primary 
efficacy variable. Data obtained from Week 4, Week 8, Week 16, and Week 24 Visit will be 
included in the model and all these visits will be included in the estimation of the average 
treatment effect through Week 24. Summary tables similar to those for ppFEV1 and SwCl will be 
provided. 
9.3.5 
Additional Analysis 
For all subjects (pooled together) with any of these mutations 2789+5G>A, 3272-26A>G, and 
3849+10kbC>T, the absolute change from baseline through Week 24 in the following efficacy 
endpoints: 
• ppFEV1 
• SwCl 
• CFQ-R RD 
will be summarized descriptively (n, mean, SD, median, minimum, maximum, and 95% CI). 
These analyses will also be conducted for all subjects (pooled together) with any of these 
mutations: P5L, R117C, L206W, V232D, T338I, R347H, A455E, S945L, L997F, R1066H, 
D1152H, G85E, R347P, L1077P, and M1101K.  
9.3.6 
Remote Measures in Extenuating Circumstances 
CSP Section 9.1.7 states that, under extenuating circumstances, remote measures may be 
implemented (e.g., if a subject is unable to travel to the study site due to safety concerns and/or 
local restrictions related to COVID-19 or other emerging events). Such measures, pertaining to 
spirometry, will be listed if available.  
9.4 
Safety Analysis 
All safety analyses will be based on data from the TE period. Subjects will be analyzed 
according to the treatment they received in the Treatment Period.  For subjects receiving study 
drug from more than one treatment group, the treatment group allocation will ELX/TEZ/IVA.  


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The overall safety profile of the study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
• TEAEs 
• Clinical laboratory values 
• ECGs 
• Vital signs 
• Pulse oximetry 
• Ophthalmologic examination 
Only descriptive analysis of safety will be performed. 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 on 
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 started before or after study treatment, the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of AEs are described in Appendix E. 
An overview of all TEAEs by treatment group and overall will be summarized in the following 
categories: 
• Number of TEAEs (total number of TEAEs only) 
• Subjects with any TEAEs  
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation (discontinuation of any study 
drug) 
• Subjects with TEAEs leading to study drug interruption (interruption of any study drug) 
• Subjects with Grade 3/4/5 TEAEs 
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAE leading to death  


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The following summary tables of TEAEs will be presented by treatment group: 
• All TEAEs 
• Grade 3/4/5 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 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event).  When summarizing the number and 
percentages of subjects, subjects with multiple occurrences of the same adverse event or a 
continuing adverse event will be counted once, and only the maximum severity level will be 
presented in the severity summaries, and the strongest relationship level in the relationship 
summaries.  
Additional summary tables will be presented by treatment for TEAEs showing number and 
percentage of subjects 
• All TEAEs by PT 
• All Related TEAEs by PT 
All AEs, including pretreatment AEs, TEAEs, and post-treatment AEs, will be presented in an 
individual subject data listing based on the All Subjects Set.  In addition, a listing containing 
individual subject adverse event data for TEAEs leading to treatment discontinuation, TEAEs 
leading to treatment interruption, Grade 3/4/5 TEAEs, SAEs and all deaths will be provided 
separately, with a flag indicating the TEAE status for SAEs and deaths. 
9.4.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments, the observed values and change from 
baseline values of the continuous hematology, coagulation, and chemistry results will be 
summarized in SI units at each visit by treatment group.  
The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
during the TE period will be summarized by treatment group. The threshold analysis criterion 
shift from baseline will also be summarized for selected laboratory parameters. The threshold 
analysis criteria are provided in Appendix F.  
For select LFT laboratory tests (ALT, AST, ALP, and total bilirubin), a scatter plot of the 
maximum treatment-emergent value versus the baseline value corresponding to ×ULN will be 
presented. Further, a scatter plot of the maximum treatment-emergent value of ALT and AST, 


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separately, versus the maximum treatment-emergent value of total bilirubin corresponding to 
×ULN will also be presented by treatment group.  
Results of positive urine/serum pregnancy test will be listed in individual subject data listings 
only. For positive serum pregnancy listing, subjects with serum hCG above the upper limit of 
normal 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 by treatment group at each visit for the following ECG interval 
measurements (in msec): RR interval, PR interval, QT interval, and 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 F. 
9.4.4 
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 visit, as applicable. The following 
vital signs parameters will be summarized: systolic and diastolic blood pressure (mm Hg), body 
temperature (C), pulse rate (beats per minute), and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period will be summarized by treatment group. The threshold analysis criteria are provided in 
Appendix F. 
9.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided by treatment group at each visit, for the percent of 
oxygen saturation. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
period 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 
Ophthalmologic Examinations 
The ophthalmologic examination results will be conducted only for subjects who are <18 years 
of age on the date of informed consent and presented in individual subject data listings only. 
9.4.7 
Physical Examination  
All 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. 


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9.4.9 
Supportive Safety Analysis 
9.4.9.1 
Adverse Events of Special Interest 
For this study, elevated transaminases events and rash events, as determined by MedDRA 
preferred terms in the respective Customized MedDRA Queries (CMQ), are considered as 
adverse events of special interest. 
For treatment-emergent elevated transaminases events and rash events, the following categories 
will be summarized by treatment group: 
• Subjects with events 
• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 
• Subjects with serious events 
• Subjects with related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event 
In addition, for treatment-emergent rash events, these categories will be summarized for the 
following subgroups: 
• Sex (male, female) 
• Female subjects with concomitant hormonal therapy (Yes, No) 
9.4.9.2 
Hormonal Therapy 
The number of subjects who used hormonal therapy concomitantly will be summarized by 
treatment group based on the Safety Set. 
10 
SUMMARY OF Interim and IDMC ANALYSIS 
10.1 
Interim analysis 
No interim analysis is planned for this study. 
10.2 
IDMC Analysis 
The IDMC’s objectives and operational details are defined in a separate document (IDMC 
Charter) which was finalized before the first subject was screened in the study. The IDMC’s 
planned safety reviews of study data are outlined in the IDMC Charter and IDMC SAP.  


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11 
REFERENCES 
1 Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
2 Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 
3 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. 
4 Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 
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 Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
 
 


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12 
LIST OF APPENDICES 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2,3,4 
Safety Assessment  
Serum Chemistry 
Hematology 
Standard 12-lead ECG 
Vital Signs (excluding BMI, 
Weight, Height and their 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 Pre-dose 
[1, 22] 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 183] 
Use nominal visit 
Coagulation 
 
Day 1 (Baseline)  
Week 24 
Safety Follow-up 
1 
169 
Not applicable 
1 Pre-dose 
[1, 183] 
Use nominal visit 
Efficacy Assessment  
Spirometry, Weight, Height 
and BMI (and the 
corresponding z-score) 5 
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] 
>183 
Sweat Chloride 
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] 
CFQ-R5 
Day 1 (Baseline)  
Week 4 
Week 8 
Week 16 
Week 24 
Safety Follow-up 
1 
29 
57 
113 
169 
Not applicable 
1 
(1, 43] 
(43, 85] 
(85, 141] 
(141, 183] 
>183 
Notes: 
1 Visit name for analysis purpose is used to report data in tables and figures. 
 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
b. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. If the latest measurement cannot be determined, then unscheduled visit will be selected. 
 


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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 
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 analysis, 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 age at informed consent  (in days) in yy mm format (e.g., 24 years, 6 months) from screening vital signs 
page, and add 0.5 month to convert to days. 
Obtain informed consent date . 
Then age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed consent 
date) in days + age at informed consent (in days)]/365.25. 
2. Age (in months) at nominal visit (for use in calculation of BMI and weight z-score): 
Obtain age at informed consent (in months) in yy mm format (e.g., 24 years, 6 months) from screening vital 
signs page. 
Obtain informed consent date. 
Then age (in months) at nominal visit = integer part of {[(age at informed consent (in months) + 0.5 + 
diff(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 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 C: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 Regression 
Equation and Lookup Tables (Version 7 April 2013). Global Lung Function Initiative. [online] 
Available at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138978 
[Accessed  Jul. 9, 2019]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] Available 
at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138979 [Accessed  Jul. 
9, 2019].   
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: http://www.ers-education.org/home/browse-all-
content.aspx?idParent=138988 [Accessed  Jul. 9, 2019]. 
 Data handling rule for spirometry is as follows:  
• Input age with at least 2 decimal place 
• Use height at screening regardless if height is collected at other study visits for subjects 
whose age at informed consent is >21 years. For subjects with age <=21 years, height 
collected at the respective visit should be used.  
• For race, map CRF black or AA to black, all other races in CRF (except white) are 
mapped to 'other'; multiple checks for race in CRF are also mapped to 'other'; white is a 
reference race in the equations and assumes 0 values for all race coefficients in the       
GLI equations. 


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Appendix D: Steps for Multiple Imputation 
For the multiple imputation (MI) to be applied to the MMRM for the sensitivity analysis of the 
primary efficacy endpoint, the following steps will be followed: 
Imputation distribution  
The imputation distribution for the missing absolute change from baseline in ppFEV1 at visit t 
will be a normal distribution.  All subjects in the corresponding analysis set (e.g., FAS) will be 
classified into one of three categories based on the following rules:  
• Non-missing category: Subjects who have a ppFEV1 assessment at the last timepoint of 
the dependent variable.  Given the primary analysis method, this corresponds to the 
subjects who have a non-missing absolute change from baseline in ppFEV1 at Week 24.  
• Missing category 1: Subjects with missing absolute change from baseline in ppFEV1 at 
the last timepoint of the dependent variable (Week 24), who discontinued treatment 
because of AEs, noncompliance with study drug, death, or physician decision, or because 
the subject refused further dosing or required prohibited medication.  
• Missing category 2: Subjects with missing absolute change from baseline in ppFEV1 at 
the last timepoint of the dependent variable (Week 24), who completed the protocol-
specified treatment or discontinued treatment for any reason not listed in Category 1. 
Imputation algorithm 
We will use the following algorithm that relates the mean of the missing absolute change from 
baseline in ppFEV1 at visit t to the missing categories defined above.  The algorithm will be 
implemented within each treatment group as follows: 
• Missing category 1: randomly draw a sample from the normal distribution (𝜇ଶହ, 𝜎ଶ), 
where 𝜇ଶହ is the 25th percentile of the non-missing absolute changes from baseline in 
ppFEV1 at visit t and 𝜎ଶ the sample variance estimated using the non-missing absolute 
changes at visit t. 
• Missing category 2: randomly draw a sample from the normal distribution (𝜇, 𝜎ଶ), where 
𝜇 is the mean of the non-missing absolute changes from baseline in ppFEV1 at visit t and 
𝜎ଶ is the sample variance estimated using the non-missing absolute changes at visit t. 
Analysis model 
The complete MI method is described below:  
• Form an “imputed dataset” by imputing missing values at each visit for those subjects 
who have a missing value at the visit and have all subsequent values missing. The 
appropriate normal distribution specified in the algorithm above will be used for each 
such subject, based on their category.  
• Repeat this process K (K=20) times to form K imputed datasets.  
• Fit the same MMRM model as the one used for primary analysis to each imputed dataset 
to estimate the absolute change at Week 4. 
• Combine the results from the analyses of K imputed datasets using the SAS procedure 
MIANALYZE to derive the MI estimator.  


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Let θ be the true treatment difference. Denote by 𝜃෨௞ the estimate of θ from the 𝑘୲୦ imputed 
dataset, and the corresponding estimate of the variance is denoted by 𝑉௞. The MI estimator of θ, 
𝜃෨୑୍, is the average of the K individual estimates.  
The estimated variance of 𝜃෨୑୍ is a combination of the between- and within-imputation variability 
as follows: 𝑉୑୍= 𝑊+ ቀ1 + 
ଵ
௄ቁ𝐵, where 𝑊=
ଵ
௄∑
𝑉௞
௄
௞ୀଵ
 is the within-imputation variability 
and is 𝐵=
ଵ
௄ିଵ∑
(𝜃෨௞−𝜃෨୑୍)ଶ
௄
௞ୀଵ
 is the between-imputation variance. The statistic ்ୀഇ෩౉౅షഇ
ඥೇ౉౅ has an 
approximate 𝑡௏ distribution7, where 𝑉= (𝐾−1)(1 +
ௐ
஻)ଶ. 
 
 


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Appendix E: Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date are defined below.  If the imputed AE start 
date is before the informed consent date, the AE start date will be imputed using the 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.  
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the first dose date 
of the Treatment Period.  
o else impute the AE start date as the informed consent date. 
Imputation rules for partial AE end date are defined below:  
• Impute the AE end date as min (the last day of the month, end of study participation) if day is 
missing, or min (Dec, end of study participation) if month is missing. 
o For the IDMC purpose, if the end of study participation date is missing, then the 
IDMC data cutoff date will be used instead in the imputation 
 
 


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


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Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
GGT 
>ULN - ≤ 2.5xULN 
>2.5 –  ≤ 5.0xULN 
>5.0 –  ≤ 20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>ULN -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤ 1.5xULN 
>1.5 - ≤ 3.0xULN 
>3.0 - ≤ 6.0xULN 
>6.0xULN 
CTCAE grades 1-4 
Lipase 
>ULN -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine Kinase 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L  
< 80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L above 
ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L  
<50.0 – ≥ 25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 


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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 - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
  
Table 12-4 
Threshold Analysis Criteria for ECGs 
Thresholds for Subjects Aged 6 to 11 Years Old at Baseline 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
≤50 bpm  
 
 
Tachycardia 
≥140 bpm 
 
PR 
≥220 ms and increase from baseline ≥20 ms  
QRS 
≥120 ms 
 
QTc 
Absolute values (ms) 
>450 ms (Male); >470 ms (Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline 30-60 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction 
formula.  
Thresholds for Subjects Aged 12 and Older at Baseline 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 
bpm 
<50 bpm and decrease from baseline ≥20 
bpm 
 
Per HV grade 2, 3, plus shift change 
 
 


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Table 12-4 
Threshold Analysis Criteria for ECGs 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 
bpm 
>100 bpm and increase from baseline ≥20 
bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
QTc 
 
 
>450 to <500ms (Male) or >470 to <500ms 
(Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
 
To be applied to any kind of QT correction 
formula.  
 
 
 
 
Note: Based on CPMP 1997 guideline. 
 
 


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Table 12-5 
Threshold Analysis Criteria for Vital Signs 
Thresholds for Subjects Aged 6 to 11 Years Old at Baseline 
Parameter 
Threshold Analysis  
Comments 
SBP 
 
>120 mmHg 
 
 
<70 mmHg 
 
DBP 
 
>80 mmHg 
 
 
<50 mmHg 
 
Weight 
Weight gain 
≥5% increase from baseline 
 
 
Weight loss 
≥5% decrease from baseline 
 
 Thresholds for Subjects Aged 12 and Older at Baseline 
Parameter 
Threshold Analysis  
Comments 
Pulse Rate 
Same as ECG category for Subjects Aged 12 
and Older at Baseline 
 
 
SBP increased 
 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from 
baseline 
>140 mmHg & >20 mmHg increase from 
baseline 
>160 mmHg & >10 mmHg increase from 
baseline 
>160 mmHg & >20 mmHg increase from 
baseline 
 
809/770 analyses 


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Table 12-5 
Threshold Analysis Criteria for Vital Signs 
SBP decrease 
 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from 
baseline 
<90 mmHg and >20 mmHg decrease from 
baseline 
<80 mmHg and >10 mmHg decrease from 
baseline 
<80 mmHg and >20 mmHg decrease from 
baseline 
 
Per HV grade 1, 3, plus shift change 
DBP increased 
 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from 
baseline 
>90 mmHg and >10 mmHg increase from 
baseline 
>100 mmHg and >5 mmHg increase from 
baseline 
>100 mmHg and >10 mmHg increase from 
baseline 
 
 
DBP decreased 
 
 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from 
baseline 
<60 mmHg and >10 mmHg decrease from 
baseline 
<45 mmHg and >5 mmHg decrease from 
baseline 
<45 mmHg and >10 mmHg decrease from 
baseline 
 
 
 
 


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Table 12-5 
Threshold Analysis Criteria for Vital Signs 
Weight   
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
 
CTCAE grade 1-3 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
 
CTCAE grade 1-3