Clinical trial NCT04537793
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2020-11-19; Completion date: 2022-06-03
Enrollment: 83 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) triple combination therapy in CF subjects 2 through 5 years of age.

Detailed description:

Arms: arm 1: Participants weighing greater than or equal to (\>=)14 kilograms (kg) at screening received elexacaftor (ELX) 100 milligrams (mg) once daily (qd)/tezacaftor (TEZ) 50 mg qd/ivacaftor (IVA) 75 mg every 12 hours (q12h) in the treatment period for 15 days. arm 2: Participants weighing (\>=)14 kg at screening received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h. Participants weighing (\>=)10 kg to less than (\<)14 kg received ELX 80 mg qd/TEZ 40 mg qd/IVA 60 mg once every morning (qAM) and 59.5 mg once every evening (qPM) in the treatment period for 24 weeks.
Interventions: intervention 1: ELX/TEZ/IVA intervention 2: IVA
Intervention descriptions: intervention 1: Fixed dose combination granules for oral administration. intervention 2: Granules for oral administration.

Protocol documents:
Prot_000.pdf: 




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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3 Study Evaluating the Safety, Tolerability, and Pharmacokinetics of 
Elexacaftor/Tezacaftor/Ivacaftor Triple Combination Therapy in Cystic Fibrosis 
Subjects 2 Through 5 Years of Age 
 
 
Brief Title 
Evaluation of ELX/TEZ/IVA in Cystic Fibrosis (CF) Subjects 2 Through 5 Years 
 
 
Clinical Phase and 
Clinical Study Type 
Phase 3, safety, tolerability, and pharmacokinetics (PK) 
 
 
Objectives 
Part A 
Primary Objectives 
• 
To evaluate the PK of elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor 
(IVA) when dosed in triple combination (TC) 
• 
To evaluate the safety and tolerability of ELX/TEZ/IVA 
Part B 
Primary Objective 
To evaluate the safety and tolerability of ELX/TEZ/IVA 
Secondary Objectives 
• 
To evaluate the PK of ELX, TEZ, and IVA 
• 
To evaluate the pharmacodynamics (PD) of ELX/TEZ/IVA 
• 
To evaluate the efficacy of ELX/TEZ/IVA 
 
 
Endpoints 
Part A 
Primary Endpoints 
• 
PK parameters of ELX, TEZ, IVA, and relevant metabolites 
• 
Safety and tolerability assessments as determined by adverse events (AEs), 
clinical laboratory values, standard 12-lead ECGs, vital signs, and pulse 
oximetry 
Part B 
Primary Endpoint 
Safety and tolerability assessments as determined by AEs, clinical laboratory 
values, standard 12-lead ECGs, vital signs, and pulse oximetry 
Secondary Endpoints 
• 
PK parameters of ELX, TEZ, IVA, and relevant metabolites 
• 
Absolute change in sweat chloride (SwCl) from baseline through Week 24 
• 
Absolute change in lung clearance index (LCI)2 5 from baseline through 
Week 24 


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Number of Subjects 
Part A 
Approximately 14 subjects with F/F or F/MF genotypes are planned for 
enrollment. Subjects who participate in Part A may participate in Part B. 
Part B 
Approximately 70 subjects are planned for enrollment. At least 30 subjects with 
F/MF genotypes and at least 15 subjects with F/F genotypes are targeted for 
enrollment. At least 25 subjects should be between 2 and 3 years of age 
(inclusive). 
 
 
Study Population 
Part A 
Male and female CF subjects 2 through 5 years of age (inclusive) with F/MF or 
F/F genotypes. Subjects must weigh ≥14 kg at Day 1.  
Part B 
Male and female CF subjects 2 through 5 years of age (inclusive) who have at 
least 1 F508del mutation in the CFTR gene or an ELX/TEZ/IVA-responsive 
CFTR mutation. Subjects must weigh ≥10 kg at the Screening Visit. 
 
 
Investigational Drug 
Active substance: ELX (VX-445)/TEZ (VX-661)/IVA (VX-770) 
Activity: CFTR correctors (ELX and TEZ) and potentiator (IVA) 
Strength and route of administration: 
• 
Parts A and B: 100 mg ELX/50 mg TEZ/75 mg IVA FDC granules for oral 
administration AND 75 mg IVA granules for oral administration 
• 
Part B Only: 80 mg ELX/40 mg TEZ/60 mg IVA FDC granules for oral 
administration AND 59.5 mg IVA granules for oral administration 
 
 
Study Duration 
Part A 
Excluding the Screening Period, subjects will participate in the study for up to 
6 weeks (± 7 days) 
Part B 
Excluding the Screening Period, subjects will participate in the study for up to 
28 weeks (± 7 days) 
 
 
Study Design 
This is a Phase 3, 2-part (Parts A and B), multicenter study evaluating the safety, 
tolerability, PK, PD, and efficacy of ELX/TEZ/IVA in CF subjects 2 through 
5 years of age (inclusive). 
Part A 
A schematic of the study design for Part A is provided below. Approximately 
14 subjects (F/F or F/MF genotypes) will be enrolled. During the Treatment 
Period, subjects will be administered ELX/TEZ/IVA for approximately 15 days. 
Safety, tolerability, and available PK data from Part A will be reviewed by Vertex 




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Table 2-1 
Parts A and B Doses 
Subject Weight at Day 1 
ELX Dose 
TEZ Dose 
IVA Dose 
Part A 
 
 
 
≥14 kg only 
100 mg qd 
50 mg qd 
75 mg q12h 
Part B 
 
 
 
≥14 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
≥10 kg to <14 kg 
80 mg qd 
40 mg qd 
60 mg qAM 
59.5 mg qPM 
ELX: elexacaftor; IVA: ivacaftor; qAM: once every morning; qd: once daily; q12h: 
every 12 hours; qPM: once every evening; TEZ: tezacaftor 
 
 
Assessments 
Parts A and B 
PK Assessments: 
PK parameters of ELX, TEZ, IVA, and relevant metabolites 
Safety Assessments: 
AEs, clinical laboratory assessments (serum chemistry, hematology, coagulation, 
and urinalysis), standard 12-lead ECGs, vital signs, pulse oximetry, 
ophthalmologic examinations, and physical examinations (PEs) 
Part B 
PD Assessment: 
SwCl 
Efficacy Assessments: 
Multiple-breath washout (MBW; subjects ≥3 years of age at screening of Part B), 
 
 
Statistical Analyses 
Data from Part A and Part B will be analyzed separately. 
Part A 
Approximately 14 subjects will be enrolled in Part A. Sample size calculations 
were determined based on ELX and M23-445 estimates of clearance. Assuming 
that the variability in this age group is the same as the variability observed in 
adults, data from 14 subjects will allow at least 80% power to target a 95% CI 
within 60% and 140% of the geometric mean estimate of clearance for ELX and 
M23-445. 
Part B 
Approximately 70 subjects will be enrolled. With 56 subjects expected to 
complete Part B, there is a >90% chance of observing an AE in at least 1 subject if 
the true incidence rate is 5%, and a >95% chance of observing an AE in at least 
1 subject if the true incidence rate is 10%. 
For the primary endpoint, summary statistics will be provided for 
treatment-emergent AEs, clinical laboratory assessments, standard 12-lead ECGs, 
vital signs, and pulse oximetry. 
 
 


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DMC Reviews 
An external data monitoring committee (DMC) will conduct periodic safety 
review(s) of study data as outlined in the DMC charter. 


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SCHEDULE OF ASSESSMENTS 
Schedules of assessments are shown in Table 3-1 (Part A Screening Period), Table 3-2 (Part A 
Treatment Period and Safety Follow-up Visit), Table 3-3 (Part B Screening Period), and 
Table 3-4 (Part B Treatment Period and Safety Follow-up Visit). 
Table 3-1 
Study VX20-445-111, Part A Screening Period 
Event/Assessment 
Screening Visit 
Day -28 to Day -1 
Comments 
Informed consent (and assent) 
X 
 
Demographics 
X 
Section 11.1 
Medical history 
X 
Section 11.1 
Ophthalmologic examination 
X 
Conducted by an ophthalmologist or 
optometrist (Section 11.5.5) 
Full physical examination 
X 
Section 11.5.3 
Weight 
 
X 
Measured with shoes off (Section 11.4.3) 
Vital signs and pulse oximetry 
X 
Performed after the subject has been at rest 
for at least 5 minutes (Section 11.5.3) 
Standard 12-lead ECG 
X 
Performed before any other procedures that 
may affect heart rate (HR), such as blood 
draws, and in the supine position after the 
subject has been at rest for at least 5 minutes 
(Section 11.5.4) 
CF genotype (all subjects) 
X 
If the CFTR genotype result is not received 
before the first dose of study drug, a previous 
CFTR genotype laboratory report may be used 
to establish eligibility (Section 8.1). Subjects 
who have been enrolled whose screening 
genotype does not confirm study eligibility 
must be discontinued from the study 
(Section 9.9). 
Serum chemistry 
X 
Section 11.5.2 
Hematology 
X 
Coagulation 
X 
Urinalysis 
X 
Medications review 
X 
Information regarding medications taken 
within 56 days before the Screening Visit will 
be collected (Section 9.5) 
Adverse events 
Continuous, From Signing of ICF 
through Completion of Study 
Participation 
Section 13.1; completion of study 
participation is defined in Section 9.1.6. 
AE: adverse event; CFTR: cystic fibrosis transmembrane conductance regulator gene; ECG: electrocardiogram; HR: heart 
rate; ICF: informed consent form; SAE: serious adverse event 
 






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Table 3-3 
Study VX20-445-111, Part B Screening Period 
Event/Assessment 
Screening Visit 
Day -28 to Day -1 
Comments 
Informed consent (and assent) 
X 
 
Demographics 
X 
Section 11.1 
Medical history 
X 
Section 11.1 
Ophthalmologic examination 
X 
Conducted by an ophthalmologist or optometrist 
(Section 11.5.5) 
Full physical examination 
X 
Section 11.5.3 
Weight 
 
X 
Measured with shoes off (Section 11.4.3) 
Vital signs and pulse oximetry 
X 
Performed after the subject has been at rest for at least 
5 minutes (Section 11.5.3) 
Standard 12-lead ECG 
X 
Performed before any other procedures that may affect 
heart rate (HR), such as blood draws, and in the supine 
position after the subject has been at rest for at least 
5 minutes (Section 11.5.4) 
Multiple-breath washout 
X 
Performed in multiple replicates pre- or post-
bronchodilator in subjects 3 years of age at screening 
(Section 11.4.2). 
Sweat chloride 
X 
Section 11.4.1 
CF genotype (all subjects) 
X 
If the CFTR genotype result is not received before the first 
dose of study drug, a previous CFTR genotype laboratory 
report may be used to establish eligibility (Section 8.1). 
This assessment does not need to be repeated for 
confirmed subjects in Part A who wish to participate in 
Part B. Subjects who have been enrolled whose screening 
genotype does not confirm study eligibility must be 
discontinued from the study (Section 9.9). If a subject 
weighs <11 kg at the Screening Visit and requires an 
additional blood sample for a deletion/duplication assay, 
this second tube should be drawn at the Day 1 Visit. 
Serum chemistry 
X 
Must be obtained from a blood draw taken up to 9 days 
before Day 1 dosing. The results must be received and 
reviewed before the first dose of study drug 
(Section 11.5.2). 
Hematology 
X 
A single set of pre-dose hematology and coagulation 
assessments will be obtained from a blood draw taken up 
to 9 days before Day 1 dosing. The results must be 
received and reviewed before the first dose of study drug 
(Section 11.5.2). 
Coagulation 
X 
Urinalysis 
X 
Section 11.5.2 
Medications review 
X 
Information regarding medications taken within 56 days 
before the Screening Visit will be collected (Section 9.5) 
Adverse events 
Continuous, From 
Signing of ICF through 
Completion of Study 
Participation 
Section 13.1; completion of study participation is defined 
in Section 9.1.6. 
AE: adverse event; CFTR: cystic fibrosis transmembrane conductance regulator gene; ECG: electrocardiogram; HR: heart 
rate; ICF: informed consent form; SAE: serious adverse event 
 














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TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 8 
4 
Table of Contents ................................................................................................................. 18 
List of Tables............................................................................................................................ 22 
List of Figures .......................................................................................................................... 22 
List of Abbreviations................................................................................................................ 23 
5 
Introduction.......................................................................................................................... 26 
5.1 
Background ..................................................................................................................... 26 
5.2 
Study Rationale .............................................................................................................. 26 
6 
Study Objectives .................................................................................................................. 27 
6.1 
Primary Objectives ......................................................................................................... 27 
6.2 
Secondary Objectives ..................................................................................................... 27 
7 
Study Endpoints ................................................................................................................... 27 
7.1 
Primary Endpoints .......................................................................................................... 27 
7.2 
Secondary Endpoints ...................................................................................................... 27 
 
 
8 
Study Population .................................................................................................................. 28 
8.1 
Inclusion Criteria ............................................................................................................ 28 
8.2 
Exclusion Criteria ........................................................................................................... 29 
9 
Study Implementation ......................................................................................................... 30 
9.1 
Study Design .................................................................................................................. 30 
9.1.1 
Screening ................................................................................................................ 32 
9.1.1.1 
Repetition of Screening Assessments .............................................................. 32 
9.1.1.2 
Rescreening ...................................................................................................... 33 
9.1.1.3 
Extension of Screening Period Window .......................................................... 33 
9.1.2 
Treatment Period .................................................................................................... 33 
9.1.3 
Follow-up................................................................................................................ 33 
9.1.4 
Early Termination of Treatment ............................................................................. 33 
9.1.5 
Lost to Follow-up ................................................................................................... 34 
9.1.6 
Completion of Study Participation ......................................................................... 34 
9.1.7 
Data Monitoring Committee ................................................................................... 34 
9.1.8 
Use of Remote Measures in Extenuating Circumstances ....................................... 35 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 35 
9.3 
Rationale for Study Elements ......................................................................................... 35 
9.3.1 
Study Design........................................................................................................... 35 
9.3.2 
Study Population..................................................................................................... 35 
9.3.3 
Study Drug Dose and Duration .............................................................................. 36 
9.3.4 
Rationale for Study Assessments ........................................................................... 36 
9.4 
Study Restrictions ........................................................................................................... 37 
9.5 
Prior and Concomitant Medications ............................................................................... 37 
9.6 
Administration ................................................................................................................ 38 
9.6.1 
Dosing ..................................................................................................................... 38 


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9.6.2 
Missed Doses .......................................................................................................... 39 
9.7 
Dose Modification for Toxicity ...................................................................................... 39 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 39 
9.8.1 
Liver Function Tests ............................................................................................... 40 
9.8.2 
Rash ........................................................................................................................ 41 
9.9 
Removal of Subjects ....................................................................................................... 41 
9.10 Replacement of Subjects ................................................................................................ 42 
10 Study Drug Information and Management ....................................................................... 42 
10.1 Preparation and Dispensing ............................................................................................ 42 
10.2 Packaging and Labeling ................................................................................................. 42 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 42 
10.4 Drug Accountability ....................................................................................................... 43 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 43 
10.6 Compliance ..................................................................................................................... 43 
10.7 Blinding and Unblinding ................................................................................................ 43 
11 Assessments .......................................................................................................................... 43 
11.1 Subject and Disease Characteristics ............................................................................... 43 
11.2 Pharmacokinetics ............................................................................................................ 44 
11.2.1 
Blood Sampling ...................................................................................................... 44 
11.2.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 44 
11.2.3 
Bioanalysis.............................................................................................................. 44 
11.4 Efficacy and Pharmacodynamics (Part B Only) ............................................................. 45 
11.4.1 
Sweat Chloride ....................................................................................................... 45 
11.4.2 
Multiple-breath Washout ........................................................................................ 45 
11.5 Safety .............................................................................................................................. 48 
11.5.1 
Adverse Events ....................................................................................................... 48 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 48 
11.5.3 
Physical Examinations and Vital Signs .................................................................. 49 
11.5.4 
Electrocardiograms ................................................................................................. 50 
11.5.5 
Ophthalmologic Examination ................................................................................. 50 
11.5.6 
Contraception and Pregnancy ................................................................................. 51 
12 Statistical Analysis ............................................................................................................... 51 
12.1 Sample Size and Power .................................................................................................. 51 
12.2 Analysis Sets .................................................................................................................. 52 
12.3 Statistical Analysis ......................................................................................................... 52 
12.3.1 
General Considerations ........................................................................................... 52 
12.3.2 
Background Characteristics .................................................................................... 53 
12.3.3 
Efficacy and Pharmacodynamic Analysis .............................................................. 53 
12.3.3.1 Analysis of Primary Efficacy Endpoints .......................................................... 53 


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12.3.3.2 Analysis of Secondary Efficacy and Pharmacodynamic Endpoints ................ 53 
12.3.3.3 Multiplicity Adjustment ................................................................................... 53 
12.3.4 
Safety Analysis ....................................................................................................... 54 
12.3.4.1 Adverse Events................................................................................................. 54 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 55 
12.3.4.3 Electrocardiogram ............................................................................................ 55 
12.3.4.4 Vital Signs ........................................................................................................ 55 
12.3.4.5 Pulse Oximetry ................................................................................................. 56 
12.3.4.6 Ophthalmologic Examinations ......................................................................... 56 
12.3.4.7 Physical Examination ....................................................................................... 56 
12.4 Interim Analysis ............................................................................................................. 56 
12.5 Data Monitoring Committee Analysis ............................................................................ 56 
12.6 Clinical Pharmacology Analysis .................................................................................... 56 
12.6.1 
Pharmacokinetic Analysis ...................................................................................... 56 
12.6.2 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 56 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 57 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 57 
13.1.1 
Adverse Events ....................................................................................................... 57 
13.1.1.1 Definition of an Adverse Event........................................................................ 57 
13.1.1.2 Clinically Significant Assessments .................................................................. 57 
13.1.1.3 Documentation of Adverse Events................................................................... 57 
13.1.1.4 Adverse Event Severity .................................................................................... 58 
13.1.1.5 Adverse Event Causality .................................................................................. 59 
13.1.1.6 Study Drug Action Taken ................................................................................ 59 
13.1.1.7 Adverse Event Outcome .................................................................................. 59 
13.1.1.8 Treatment Given............................................................................................... 60 
13.1.2 
Serious Adverse Events .......................................................................................... 60 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 60 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 61 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 61 
13.2 Administrative Requirements ......................................................................................... 61 
13.2.1 
Product Complaints ................................................................................................ 61 
13.2.2 
Ethical Considerations ............................................................................................ 62 
13.2.3 
Subject Information and Informed Consent ........................................................... 62 
13.2.4 
Investigator Compliance ......................................................................................... 62 
13.2.5 
Access to Records ................................................................................................... 62 
13.2.6 
Subject Privacy ....................................................................................................... 62 
13.2.7 
Record Retention .................................................................................................... 63 
13.2.8 
Study Termination .................................................................................................. 63 
13.2.9 
End of Study ........................................................................................................... 63 
13.3 Data Quality Assurance .................................................................................................. 64 
13.4 Monitoring ...................................................................................................................... 64 
13.5 Electronic Data Capture ................................................................................................. 64 
13.6 Confidentiality and Disclosure ....................................................................................... 65 


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13.7 Publications and Clinical Study Report .......................................................................... 65 
13.7.2 
Clinical Study Report ............................................................................................. 66 
14 References ............................................................................................................................. 67 
APPENDIX A Eligible MF CFTR Mutations ....................................................................... 69 
APPENDIX B Eligible ELX/TEZ/IVA-Responsive CFTR Mutations ................................ 72 
15 Protocol Signature Pages .................................................................................................... 73 
15.1 Sponsor Signature Page .................................................................................................. 73 
15.2 Investigator Signature Page ............................................................................................ 74 
 


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List of Tables 
Table 2-1 
Parts A and B Doses ............................................................................................... 6 
Table 3-1 
Study VX20-445-111, Part A Screening Period ..................................................... 8 
Table 3-2 
Study VX20-445-111, Part A Treatment Period and Safety Follow-up Visit ........ 9 
Table 3-3 
Study VX20-445-111, Part B Screening Period ................................................... 11 
Table 3-4 
Study VX20-445-111, Part B Treatment Period and Safety Follow-up Visit ...... 12 
Table 9-1 
Parts A and B Doses ............................................................................................. 32 
Table 9-2 
Prohibited Medications ......................................................................................... 37 
Table 10-1 
Study Drug: Dosing Form/Route/Strength ........................................................... 42 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 44 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 49 
Table 12-1 
Probability of Observing At Least 1 Subject With an AE in the Study if the AE 
Incidence () is 5% and 10% ................................................................................ 52 
Table 13-1 
Grading of AE Severity ........................................................................................ 58 
Table 13-2 
Classifications for AE Causality ........................................................................... 59 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 59 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 59 
List of Figures 
Figure 2-1 
VX20-445-111 Part A Study Design ...................................................................... 5 
Figure 2-2 
VX20-445-111 Part B Study Design ...................................................................... 5 
Figure 9-1 
VX20-445-111 Part A Study Design .................................................................... 31 
Figure 9-2 
VX20-445-111 Part B Study Design .................................................................... 31 
 


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List of Abbreviations 
Abbreviation 
Definition 
ADL 
activities of daily living 
AEs 
adverse events 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
 
 
CD 
compact disc 
CF 
Cystic Fibrosis 
CFTR 
cystic fibrosis transmembrane conductance regulator gene 
CI 
confidence interval 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ELX 
elexacaftor 
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 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GPS 
Global Patient Safety 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) (US) 
IRB 
institutional review board 


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Abbreviation 
Definition 
 
 
IV 
intravenous 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LCI 
lung clearance index 
LCI2 5 
number of lung turnovers required to reduce the end tidal inert gas concentration to 
1/40th of its starting value 
LUM 
lumacaftor 
max 
maximum value 
MBW 
Multiple-breath washout 
MF 
minimal function 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
N 
total sample size 
P 
probability 
PC 
publication committee 
PD 
Pharmacodynamic(s) 
PEs 
physical examinations 
PEx 
pulmonary exacerbations 
P-gp 
P-glycoprotein 
PIs 
principal investigators 
PK 
Pharmacokinetic(s) 
PR 
PR interval, segment 
q12h 
every 12 hours 
qAM 
once every morning 
qd 
once daily 
qPM 
once every evening 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QT 
QT interval 
QTcF 
QT interval corrected by Fredericia’s formula 
RR 
interval from the onset of 1 QRS complex to the next; use R-R if using with 
“intervals”, i.e., “R-R interval” 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
steering committee 
SD 
standard deviation 
SI 
SI units (International System of Units) 
SUSARs 
suspected, unexpected, serious adverse reaction 
SwCl 
sweat chloride 
TC 
triple combination 
TE 
Treatment-emergent 


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Abbreviation 
Definition 
TEAEs 
Treatment-emergent adverse events 
TEZ 
tezacaftor 
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 an autosomal recessive genetic disease with serious morbidities and 
frequent premature mortality. CF affects more than 70,000 individuals worldwide1 
(approximately 31,000 in the US2 and 48,000 in the EU3). 
CF is caused by decreased quantity and/or function of the CFTR protein due to mutations in the 
CFTR gene.4 CFTR is a channel that regulates the flow of chloride and other anions across 
epithelia in multiple organs and tissues, including the lungs, pancreas and other gastrointestinal 
organs, and sweat glands.5 Despite progress in the treatment of CF with antibiotics and 
mucolytics, the current median age at death among people with CF is approximately 30 years, 
and the predicted median age of survival is approximately 47 years.2, 3 More effective treatments 
are needed for CF. 
The most common disease-causing mutation is F508del: approximately 84.7% of people with CF 
in the US and 81.1% in Europe have at least one F508del allele.2, 3 
At present CF does not have a cure. CFTR modulators (i.e., correctors and potentiators) represent 
a major advancement in the treatment of CF because they are systemic therapies that target the 
underlying cause of the disease and have been shown to improve CF survival by modifying the 
course of disease.6, 7 The clinical testing and regulatory approval of CFTR modulators in certain 
countries for the treatment of people with CF caused by specific CFTR genotypes has established 
the therapeutic value of specific regimens developed by Vertex. These treatment regimens 
include ivacaftor (IVA) monotherapy (Kalydeco™), lumacaftor (LUM)/IVA dual combination 
therapy (Orkambi™), tezacaftor (TEZ)/IVA dual combination therapy (Symdeko™, Symkevi™) 
and elexacaftor (ELX)/TEZ/IVA triple combination (TC) therapy. 
The ELX/TEZ/IVA regimen is the first medicine to demonstrate clinical benefit in patients with 
a single F508del allele, regardless of the mutation of the second allele. A pivotal Phase 3 
program in CF subjects 12 years of age or older demonstrated that ELX/TEZ/IVA provides 
substantial improvements in lung function, CFTR function, and nutritional status, and was 
generally safe and well tolerated with a low rate of treatment discontinuation. 
5.2 
Study Rationale 
Given the progressive nature of CF, there is a strong rationale for preventing disease progression 
by treating patients earlier in life. Vertex evaluated ELX/TEZ/IVA TC therapy in Phase 3 studies 
in adult and adolescent CF subjects with 1 or 2 copies of the F508del mutation, namely those 
with F/MF and F/F genotypes. Given the clinical benefit seen in a Phase 3 study of adults with 
CF with ELX/TEZ/IVA, the present study is designed to obtain pharmacokinetic (PK), safety, 
tolerability, and pharmacodynamic (PD) information to expand the evaluation of ELX/TEZ/IVA 
in the pediatric population 2 through 5 years of age (inclusive) with F/MF or F/F genotypes 
(Part A) or who have at least 1 F508del mutation in the CFTR gene or an ELX/TEZ/IVA-
responsive CFTR mutation (Part B). 


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6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
Part A 
• To evaluate the PK of ELX, TEZ, and IVA when dosed in TC 
• To evaluate the safety and tolerability of ELX/TEZ/IVA 
Part B 
To evaluate the safety and tolerability of ELX/TEZ/IVA 
6.2 
Secondary Objectives 
Part A 
None 
Part B 
• To evaluate the PK of ELX, TEZ, and IVA 
• To evaluate the PD of ELX/TEZ/IVA 
• To evaluate the efficacy of ELX/TEZ/IVA 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoints 
Part A 
• PK parameters of ELX, TEZ, IVA, and relevant metabolites 
• Safety and tolerability assessments as determined by adverse events (AEs), clinical 
laboratory values, standard 12-lead electrocardiograms (ECGs), vital signs, and pulse 
oximetry 
Part B 
Safety and tolerability assessments as determined by AEs, clinical laboratory values, standard 
12-lead ECGs, vital signs, and pulse oximetry 
7.2 
Secondary Endpoints 
Part A 
None 
Part B 
• PK parameters of ELX, TEZ, IVA, and relevant metabolites 
• Absolute change in sweat chloride (SwCl) from baseline through Week 24 
• Absolute change in lung clearance index (LCI)2.5 from baseline through Week 24 


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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’s legally appointed and authorized representative will sign and date an informed 
consent form (ICF). 
2. Subjects (males and females), 2 through 5 years of age, inclusive, on the date of informed 
consent (and assent, as applicable). 
3. In Part A, subjects must weigh ≥14 kg at Day 1. In Part B, subjects must weigh ≥10 kg at 
the Screening Visit. 
4. Confirmed diagnosis of CF as determined by the investigator. 
5. In Part A, subjects who are homozygous for F508del (F/F genotype) or heterozygous for 
F508del and an MF mutation that is not responsive to IVA and TEZ/IVA (F/MF genotypes; 
Appendix A). In Part B, subjects who have at least 1 F508del mutation in the CFTR gene or 
an ELX/TEZ/IVA-responsive CFTR mutation (Appendix B).  
• Genotype should be confirmed at the Screening Visit. This assessment does not need to 
be repeated for confirmed subjects in Part A who wish to participate in Part B. 
• If the screening CFTR genotype result is not received before the first dose of study drug, 
a previous CFTR genotype laboratory report may be used to establish eligibility. 


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• Subjects who have been enrolled and whose screening genotype does not confirm study 
eligibility must be discontinued from the study (Section 9.9). 
6. Subjects with stable CF disease at the start of the Treatment Period as deemed by the 
investigator. 
7. Subjects who are willing to remain on a stable CF medication regimen (other than CFTR 
modulators) through Day 15 (Part A) or through Week 24 (Part B) or, if applicable, through 
the Safety Follow-up Visit. 
8. As judged by the investigator, the parent or legal guardian must be able to understand 
protocol requirements, restrictions, and instructions and the parent or legal guardian should 
be able to ensure that the subject will comply with and is likely to complete the study as 
planned. 
8.2 
Exclusion Criteria 
1. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study drug(s) to 
the subject. This includes, but is not limited to, the following: 
• Clinically significant cirrhosis with or without portal hypertension 
• Solid organ or hematological transplantation 
• Cancer 
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, aspartate transaminase (AST), or alanine transaminase (ALT) ≥2 × upper 
limit of normal (ULN) 
• Alkaline phosphatase (ALP) or gamma-glutamyl transferase (GGT) ≥3 × ULN 
• Abnormal renal function defined as glomerular filtration rate ≤45 mL/min/1.73 m2 
(calculated by the Counahan-Barratt equation)8 
4. An acute upper or lower respiratory infection, PEx, or changes in therapy (including 
antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug). 
5. Lung infection with organisms associated with a more rapid decline in pulmonary status 
(including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and 
Mycobacterium abscessus). For subjects who have had a history of a positive culture, the 
investigator will apply the following criteria to establish whether the subject is free of 
infection with such organisms: 
• The subject has not had a respiratory tract culture positive for these organisms within the 
12 months before the date of informed consent. 


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• The subject has had at least 2 respiratory tract cultures negative for such organisms 
within the 12 months before the date of informed consent, with the first and last of these 
separated by at least 3 months, and the most recent one within the 6 months before the 
date of informed consent. 
6. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of 
study drug (Day 1). 
7. Ongoing or prior participation in an investigational drug study (including studies 
investigating ELX with or without coadministration with other study drugs) within 28 days 
of the Screening Visit. 
• A washout period of 5 terminal half-lives of the previous investigational study drug, or 
28 days, whichever is longer, must elapse before the Screening Visit. 
• The duration of the elapsed time may be longer if required by local regulations. 
Note: Ongoing participation in a noninterventional study (including observational 
studies) is permitted. 
8. Use of restricted medication within specified duration before the first dose of study drug as 
defined in Table 9-2. 
9. The subject or a close relative of the subject is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study. 
10. Part B only: Elevated serum ALT or AST ≥3 × ULN or total bilirubin ≥2 × ULN in the 
previous year. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3, 2-part (Parts A and B), multicenter study evaluating the safety, tolerability, 
PK, PD, and efficacy of ELX/TEZ/IVA in CF subjects 2 through 5 years of age (inclusive). 
Part A 
A schematic of the study design for Part A is provided in Figure 9-1. Approximately 14 subjects 
(F/F or F/MF genotypes) will be enrolled. During the Treatment Period, subjects will be 
administered ELX/TEZ/IVA for approximately 15 days (Table 9-1). Safety, tolerability, and 
available PK data from Part A will be reviewed by Vertex to confirm or adjust the dose(s) 
chosen for Part B. Additional subjects may be enrolled as needed in Part A, based on emerging 
PK data, in order to provide sufficient information to select the dose(s) for Part B. Subjects who 
participate in Part A may participate in Part B. 




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Table 9-1 
Parts A and B Doses 
Subject Weight at Day 1 
ELX Dose 
TEZ Dose 
IVA Dose 
Part A 
 
 
 
≥14 kg only 
100 mg qd 
50 mg qd 
75 mg q12h 
Part B 
 
 
 
≥14 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
≥10 kg to <14 kg 
80 mg qd 
40 mg qd 
60 mg qAM 
59.5 mg qPM 
ELX: elexacaftor; IVA: ivacaftor; qAM: once every morning; qd: once daily; qPM: once every evening; 
q12h: every 12 hours; TEZ: tezacaftor 
9.1.1 
Screening 
Screening Visit assessments are listed in Table 3-1 (Part A) and Table 3-3 (Part B). 
Screening will occur within 28 days before administration of study drug. The investigator (or an 
appropriate authorized designee at the study site) will obtain informed consent and assent for 
each subject before any study procedure takes place. 
Subjects who participate in Part A may participate in Part B. Subjects from Part A will be 
screened for Part B and must be deemed eligible before enrolling in Part B. 
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.4) and concomitant medications (Section 9.5). 
9.1.1.1 
Repetition of Screening Assessments 
Part A 
Screening assessments may be repeated once to establish study eligibility. If repeat values of the 
individual assessment(s) are within the eligibility criteria and completed within the screening 
window, then the subject may qualify for the study. 
Part B 
Screening assessments may be repeated once to establish study eligibility, except for LFT 
assessment(s) if LFT values at the original Screening Visit were elevated (total bilirubin, AST, or 
ALT ≥2 × ULN). If repeat values of the individual assessment(s) are within the eligibility criteria 
and completed within the screening window, then the subject may qualify for the study. 
Repetition of LFT screening assessment(s) that do not meet eligibility criteria is not permitted, 
with the following exceptions:  
• If there is clear evidence of a laboratory error or equipment malfunction, then collection of a 
repeat sample for the appropriate laboratory test may be permitted after discussion with the 
Vertex medical monitor or authorized designee. 
• If an acute non-CF etiology is identified for elevated transaminases, exclusionary LFT levels 
may be retested within 2 weeks of the original Screening Visit date. 
If the repeat values satisfy the eligibility criteria and have been completed within the screening 
window or extended screening window (Section 9.1.1.3), then the results can be considered 
qualifying for the study. 


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9.1.1.2 
Rescreening 
Subjects may be rescreened once. If a subject is rescreened, the subject will provide informed 
consent and assent (as applicable), and all screening assessments will be repeated, except for: 
• CFTR genotyping 
• Ophthalmologic examination (if performed within 3 months before the date of informed 
consent) 
If a subject is rescreened, a new screening window will begin when the first rescreening 
assessment has been initiated. 
In Part B, rescreening is not allowed if the LFT values obtained at the original Screening Visit 
and retesting (if applicable) were exclusionary (i.e., total bilirubin, AST, or ALT ≥2 × ULN). 
9.1.1.3 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 2 weeks for the following 
reasons: 
• Repetition of the Screening Period assessments (Section 9.1.1.1) 
• Unexpected operational or logistic delays, or to meet the eligibility criteria 
• Scheduling of ophthalmologic examination (Section 11.5.5) 
9.1.2 
Treatment Period 
Treatment Period assessments are listed in Table 3-2 (Part A) and Table 3-4 (Part B). 
The Treatment Period will last approximately 15 days in Part A and 24 weeks in Part B. Study 
drug administration details are provided in Section 9.6. 
Subjects who prematurely discontinue study drug treatment will remain in the study from the 
time of discontinuation of study drug treatment through the last scheduled study visit and 
complete assessments for all study visits, as described in Section 9.1.4. 
9.1.3 
Follow-up 
The Safety Follow-up Visit is scheduled to occur 28 (± 7) days after the last dose of study drug. 
The Safety Follow-up Visit is not required for Part B subjects who complete the Week 24 Visit 
and enroll in the OLE safety study within 28 days after the last dose of study drug. 
9.1.4 
Early Termination of Treatment 
If a subject prematurely discontinues study drug treatment, an Early Termination of Treatment 
(ETT) Visit should be scheduled as soon as possible after the decision to discontinue treatment. 
Subjects who prematurely discontinue treatment will also be required to complete the Safety 
Follow-up Visit (Table 3-2 for Part A and Table 3-4 for Part B), if applicable (Section 9.1.3). 
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. 
Subjects who prematurely discontinue study drug treatment will continue to complete all 
scheduled study visits for assessments following completion of the ETT Visit, as detailed in 
Table 3-4. 


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If a subject withdraws from the study and also withdraws consent or assent, no further 
assessments will be performed. Vertex may retain and continue to use any data and samples 
collected before such withdrawal of consent or assent (Section 9.9). 
9.1.5 
Lost to Follow-up 
A subject will be considered lost to follow-up if both of the following occur: 
• The subject misses 2 consecutive study visits (telephone contact and/or clinic visit) and is 
subsequently unable to be contacted by telephone (3 documented attempts by telephone 
within 2 weeks following the second missed visit) 
• The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 
9.1.6 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as 1 of the following: 
Part A 
• For subjects who complete the Treatment Period: the Safety Follow-up Visit 
• For subjects who prematurely discontinue study drug treatment but do not withdraw consent 
(and assent, as applicable): the latest of the Day 15 Visit, ETT Visit, or Safety Follow-up 
Visit 
• For subjects who withdraw consent or assent: date of withdrawal of consent or assent, 
whichever is earlier (Section 9.9) 
Part B 
• For subjects who complete the Treatment Period and enter an OLE 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 OLE safety study within 
28 days of the Week 24 Visit: the Safety Follow-up Visit 
• For subjects who prematurely discontinue study drug treatment but do not withdraw consent 
(and assent, as applicable): the latest of the Week 24 Visit, ETT Visit, or Safety Follow-up 
Visit (if required) 
• For subjects who withdraw consent or assent: date of withdrawal of consent or assent, 
whichever is earlier (Section 9.9) 
If subjects are lost to follow-up (Section 9.1.5), the date of completion of study participation will 
be defined as the date of the last contact. 
The end of study is defined in Section 13.2.9. 
9.1.7 
Data Monitoring Committee 
Safety and tolerability data will be reviewed by a data monitoring committee (DMC) to ensure 
the safety of the subjects (Section 12.5). Procedural details of the DMC’s structure and function, 
frequency of meetings, and data planned for review will be in the DMC charter. The DMC 
charter will be finalized before the first subject is screened. 


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9.1.8 
Use of Remote Measures in Extenuating Circumstances 
Study visits should be performed in the clinic as specified in Table 3-2 and Table 3-4, 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) and Day 1 visits 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.  
• 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 and Day 1) may be conducted as in-home visits by qualified 
personnel. 
• Study assessments may be performed or overseen by qualified personnel conducting the 
in-home visits, except for MBW assessments. 
• Remote monitoring visits may be implemented as applicable (including remote source data 
verification) and as allowed per local regulations.   
9.2 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study. 
9.3 
Rationale for Study Elements 
9.3.1 
Study Design 
This open-label study is designed to evaluate the PK and safety of ELX/TEZ/IVA in this 
pediatric CF population and confirm the doses and appropriate weight cut-off. The design is 
consistent with ICH guidelines for the study of human subjects, especially children, and balances 
safety concerns with potential benefits for the individual. 
9.3.2 
Study Population 
This study will enroll CF subjects 2 through 5 years of age (inclusive). Part A will enroll CF 
subjects with F/MF or F/F genotypes. Part B will enroll CF subjects who have at least 1 F508del 
mutation in the CFTR gene or an ELX/TEZ/IVA-responsive CFTR mutation as listed in 
Appendix B. ELX/TEZ/IVA is expected to provide clinical benefit to these patients based on the 
results of Phase 3 studies (Studies VX17-445-102 and VX17-445-103), which demonstrated the 
efficacy and safety of ELX/TEZ/IVA in CF subjects ≥12 years of age who have F/MF and F/F 
genotypes. A pivotal study of ELX/TEZ/IVA in CF subjects 6 through 11 years of age 
(inclusive; VX18-445-106) demonstrated efficacy and safety similar to results seen in CF 
subjects ≥12 years of age. 


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Given the progressive nature of CF, there is a strong rationale for treating patients earlier in life. 
Experience with other CFTR modulators in pediatric subjects 2 through 5 years of age, including 
LUM/IVA and IVA, suggests that the safety profile of ELX/TEZ/IVA will be similar in children 
and adults, which supports evaluation of ELX/TEZ/IVA in pediatric subjects in the present 
study. 
9.3.3 
Study Drug Dose and Duration 
An ELX dose of 200 mg once daily (qd) in TC with TEZ 100 mg qd/IVA 150 mg every 12 hours 
(q12h) was evaluated in pivotal Phase 3 studies of adult and adolescent (≥12 years of age) CF 
subjects with F/MF and F/F genotypes. These studies demonstrated that treatment with this 
ELX/TEZ/IVA regimen resulted in rapid, robust, clinically meaningful, and statistically 
significant improvements in all primary and key secondary efficacy and PD endpoints. 
TC regimens of ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h and ELX 100 mg qd/TEZ 
50 mg qd/IVA 75 mg q12h were evaluated in a Phase 3 study of pediatric (6 to <12 years of age) 
CF subjects with F/MF and F/F genotypes. This study demonstrated safety and efficacy similar 
to results seen in CF subjects ≥12 years of age. 
Part A 
The TC regimen of ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h selected for evaluation in 
Part A is the same dose studied in lower weight 6 to <12 year old subjects, and was based on 
population PK modeling. This modeling used TC data from CF subjects >6 years of age and 
simulated exposures for body weights typical of the 2- to <6-year-old population. The 
simulations indicated that the proposed dosing regimen for Part A is predicted to provide ELX, 
TEZ, and IVA exposures similar to those shown to be safe and efficacious in adults from Phase 3 
studies. 
Part B 
For Part B, subjects will be administered either ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h 
or ELX 80 mg qd/TEZ 40 mg qd/IVA 60 mg once every morning (qAM) and 59.5 mg once 
every evening (qPM). The appropriate weight cut-off for the switch between these regimens was 
determined based on population PK modeling that included PK data from Part A and additional 
PK data from TC studies conducted in CF subjects >6 years of age. 
Duration of Dosing 
The 15-day duration of dosing in Part A provides an adequate assessment PK, safety, and 
tolerability of ELX/TEZ/IVA before exposing subjects to a longer treatment duration of 
24 weeks in Part B. 
9.3.4 
Rationale for Study Assessments 
The PK, safety, efficacy, and PD assessments are standard parameters for clinical studies in drug 
development and are generally recognized as reliable, accurate, and relevant to the study of 
subjects with CF. Baseline and follow-up ophthalmologic examinations are recommended for 
monitoring of pediatric patients treated with IVA-containing drug regimens, and have been 
added to the standard safety assessments. 


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LCI is a measure of ventilation inhomogeneity assessed by multiple-breath washout (MBW) that 
is based on tidal breathing techniques that have been evaluated in patients as young as infants.9, 10 
Studies have shown that LCI correlates with forced expiratory volume in 1 second (FEV1) in its 
ability to measure airway disease and can detect lung disease at an earlier stage than 
spirometry.11, 12 Furthermore, data from Study VX10-770-106 in CF patients with an FEV1 
>90% showed LCI to be a more sensitive outcome measure than FEV1. As with spirometry 
testing, performing MBW assessments in young children can be difficult.13 Therefore, only 
subjects who are ≥3 years of age at screening will undergo the MBW assessments in Part B. 
9.4 
Study Restrictions 
Table 9-2 lists prohibited medications. A non-exhaustive list of study prohibitions and cautions 
for medication will be provided in the Study Reference Manual. 
Table 9-2 
Prohibited Medications 
Medication 
Timing of Restriction 
Rationale 
Start of 
Restriction 
End of 
Restriction 
Moderate and strong 
CYP3A inducers 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
through 
completion of 
study 
participation 
ELX, TEZ, and IVA are metabolized 
extensively via CYP3A4. Therefore, use of 
moderate and strong inducers and inhibitors of 
CYP3A, which have the potential to alter the 
exposure of ELX, TEZ, or IVA, are prohibited. 
Moderate and strong 
CYP3A inhibitors 
(except 
ciprofloxacin)a 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
through 
completion of 
study 
participation 
CFTR modulators 
(investigational or 
approved), except for 
study drugs 
None allowed 
within 28 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
until after the 
last dose of 
study drug 
These agents may confound the results of this 
study. 
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. 


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For subjects who are screened but are not subsequently enrolled, details of prior medication will 
be documented only in the subject’s source documents. 
• Subjects should remain on a stable treatment regimen for their CF from 28 days before the 
Day 1 Visit through completion of study participation. Stable treatment regimen is defined as 
the current treatment regimen for CF that subjects have been following for at least 28 days 
before the Day 1 Visit. Subjects should not initiate long-term treatment with new medication 
from 28 days before the Day 1 Visit through completion of study participation. Guidelines 
for stable treatment regimens for CF are as follows: 
o Subjects who are taking inhaled tobramycin or other chronically inhaled antibiotics 
should remain on that regimen throughout the study. 
o Subjects who cycle onto and off of an inhaled antibiotic should continue on their prior 
schedule. The timing of the first dose of study drug on the Day 1 Visit should be 
synchronized as closely as possible (e.g., not more than ± 3 days) to the first day in 
the cycle onto the inhaled antibiotic. 
o Subjects who alternate between 2 different inhaled antibiotics should remain on the 
same cycling schedule during the study. The timing of the first dose of study drug on 
the Day 1 Visit should be synchronized as closely as possible (e.g., not more than 
± 3 days) to the first day in the cycle onto 1 of the inhaled antibiotics. 
• Subjects may receive doses of prednisone or prednisolone of up to 10 mg/day chronically, or 
up to 60 mg daily for up to 5 days. 
• ELX may inhibit OATP1B1 and OATP1B3, which may increase the exposure of medicinal 
products that are substrates for these transporters. Substrates such as statins, glyburide, 
nateglinide, and repaglinide should be used with caution.  
• IVA is a weak inhibitor of P-glycoprotein (P-gp). Administration of IVA may increase 
systemic exposure of medicinal products that are sensitive substrates of P-gp, which may 
increase or prolong their therapeutic effect and adverse reactions. Digoxin or other substrates 
of P-gp with a narrow therapeutic index, such as cyclosporine, everolimus, sirolimus, and 
tacrolimus, should be used with caution and appropriate monitoring.  
• 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 MBW assessments performed 
according to the guidelines provided in Section 11.4.2. 
9.6 
Administration 
9.6.1 
Dosing 
Study drug will be orally administered with the approved foods and liquids listed in the Study 
Manual (e.g., apple sauce). The doses to be administered are shown in Table 9-1. 


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Study drug should be administered within approximately 30 minutes of the start of a 
fat-containing meal or snack, such as a standard “CF” meal or snack or a standard meal 
according to the following guidelines: 
1. On days of scheduled visits, the morning dose of study drug will be administered at the site 
after predose assessments have been completed. 
2. All doses of study drug (morning and evening, as applicable) should be administered at 
approximately every 12 hours (± 1 hour for Part A and ± 2 hours for Part B) on each dosing 
occasion. For example, if the morning doses of study drug are administered at 08:00 hour on 
Day 1, all subsequent morning doses should be administered between 07:00 hour and 
09:00 hour for Part A, and between 06:00 hour and 10:00 hour for Part B. 
3. At the Day 1 Visit, all subjects will be observed for 4 hours after the morning dose of the 
study drug. 
4. The date, amount taken, and time of study drug administration including whether food was 
taken with each dose, will be recorded for 2 days before PK sample collection and on the 
days of PK sample collection. 
5. For visits after the Day 1 Visit, subjects will be instructed to bring all used and unused study 
drug to the site; study drug will be dispensed at each visit, as appropriate. 
6. Part A: At the Day 15 Visit, only the morning dose of study drug will be administered. 
Part B: At the Week 24 Visit, the morning dose of study drug will NOT be administered. 
The last dose of study drug will be the evening dose administered the day before the 
Week 24 Visit. 
9.6.2 
Missed Doses 
If 6 hours or less have passed since the missed morning or evening dose, the subject should take 
the missed dose as soon as possible and continue on the original schedule. 
Morning dose: If more than 6 hours have passed since the missed morning dose, the subject 
should take the missed dose as soon as possible and should not take the evening dose. 
Evening dose: If more than 6 hours have passed since the missed evening dose, the subject 
should not take the missed dose. The next scheduled morning dose should be taken at the usual 
time. 
Morning and evening doses should not be taken at the same time. 
9.7 
Dose Modification for Toxicity 
No dose modifications for toxicity are allowed. If any unacceptable toxicity arises, individual 
subjects will discontinue dosing (Section 9.1.4). 
9.8 
Study Drug Interruption and Stopping Rules 
In subjects who have interrupted study drug for >72 hours for any reason, the investigator should 
resume study drug only after a thorough investigation of the cause for interruption. The 
investigator will evaluate the subject’s clinical stability and should consider resumption of study 
drug only after the subject is clinically stable and there is no comorbidity or condition that, in the 
opinion of the investigator, might confound the results of the study or pose an additional risk in 
administering study drug to the subject. 


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The medical monitor should be notified of an interruption of study drug that lasts >72 hours for 
any reason and of the resumption of study drug after such interruption. In subjects for whom 
study drug was previously interrupted, the medical monitor should be notified of any plan to 
discontinue study drug, before the discontinuation has occurred, if possible. 
9.8.1 
Liver Function Tests 
The central laboratory will notify the medical monitor of ALT or AST >3 × ULN and total 
bilirubin >2 × ULN that are derived from centrally submitted samples. 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, with or without 
total bilirubin >2 × ULN, must be followed closely, including confirmatory testing performed by 
the central laboratory within 48 to 72 hours of the initial finding and subsequent close 
monitoring of ALT, AST, and bilirubin levels, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results must be reported immediately to the medical monitor, and the subject 
must have the tests repeated and sent to the central laboratory as soon as possible (ideally within 
48 to 72 hours). 
Study drug administration must be interrupted immediately (prior to confirmatory testing) if 
any of the following criteria are met: 
• ALT or AST >8 × ULN 
• ALT or AST >5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical jaundice 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression. 
Study drug administration must be discontinued if the following criteria are met: 
• Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, 
alcohol ingestion) is identified, regardless of whether transaminase levels have improved 
All subjects in whom treatment is discontinued for elevated transaminases (and bilirubin, as 
applicable) should have these levels monitored closely until levels normalize or return to 
baseline. 
If an alternative, reversible cause of transaminase elevation with or without increased bilirubin or 
clinical jaundice has been identified, study drug administration may be resumed once 
transaminases return to baseline or are ≤2 × ULN, whichever is higher. Regardless of the 
duration of interruption, the medical monitor should be notified prior to resumption of study 
drug. Upon resumption of study drug, transaminases and bilirubin should be assessed weekly for 
4 weeks. If a protocol-defined transaminase elevation interruption threshold recurs within 
4 weeks of rechallenge with the study drug (with confirmation of the initial elevation by repeat 
testing within 48 to 72 hours), then the study drug must be permanently discontinued, regardless 
of the presumed etiology. 


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9.8.2 
Rash 
Individuals who develop a generalized rash will be monitored closely. Study drug dosing should 
be interrupted if a subject develops a generalized rash of Grade 3 or higher (Section 13.1.1.4), or 
a rash that is considered a serious adverse event (SAE). The investigator will notify the medical 
monitor of any rash that results in interruption of study drug, is Grade 3 or higher 
(Section 13.1.1.4), or is an SAE. Investigators should consider additional evaluation including 
laboratory testing (e.g., complete blood count with differential, liver function tests), photographs 
of the rash, and dermatology consultation. The investigator may consider resumption of study 
drug if considered clinically appropriate. 
9.9 
Removal of Subjects 
Subjects (or subjects' parent/legal guardian) may withdraw from the study at any time at their 
own request. Subjects may be withdrawn at any time at the discretion of the investigator or 
Vertex for safety, behavior, noncompliance (study drug dosing or study procedures), or 
administrative reasons. A subject who withdraws (or is withdrawn by parent/legal guardian) 
from study drug treatment will continue to be followed unless the subject (or parent/legal 
guardian) withdraws consent. 
In addition, a subject must be discontinued from study drug treatment if the subject meets any of 
the following criteria: 
• Has a screening CFTR genotype that does not confirm study eligibility if a previous CFTR 
genotype laboratory report was used to establish eligibility. These subjects must be 
discontinued from the study (Section 8.1) 
• Meets any of the stopping (discontinuation) criteria (Section 9.8) 
Subjects who discontinue study treatment early should continue to return for study assessments, 
as noted in Section 9.1.4. 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a Safety Follow-up Visit, if 
applicable (see Section 9.1.4), and follow up with the subject regarding any unresolved AEs. 
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends, and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study, the study data and samples collected will remain part of the study. A subject will 
not be able to request the withdrawal of his/her information from the study data. A subject may 
request destruction of the samples collected from him/her during the study as long as those 
samples can be identified as his/her samples. 


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9.10 
Replacement of Subjects 
Part A 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug Treatment 
Period may be replaced as needed in Part A, based on emerging PK data, to confirm the dose(s) 
for Part B. 
Part B 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug Treatment 
Period may be replaced at Vertex's discretion. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
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. An interactive web response system 
(IWRS) will be used to dispense dosage based on subject weight. 
10.2 
Packaging and Labeling 
Study drug granules will be supplied in capsules in bottles in Part A and in sachets in Part B by 
Vertex. Study drug labeling will be in compliance with applicable local and national regulations. 
Additional details regarding packaging, labeling, and dispensing for study drug will be in the 
Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
Table 10-1 provides the study drug information. The investigator, or an authorized designee 
(e.g., a licensed pharmacist), will ensure that all investigational product is stored in a secured 
area, under recommended storage conditions, and in accordance with applicable regulatory 
requirements. To ensure adequate records, all study drugs will be accounted for as described in 
Section 10.4 or via the drug accountability forms as instructed by Vertex. 
Detailed instructions regarding the storage, handling, and dispensation of the study drug will be 
provided in the Pharmacy Manual. 
Table 10-1 
Study Drug: Dosing Form/Route/Strength 
Drug Name, Dosing Form, Route 
Study Drug Strength 
Part A: 
All Subjects 
Part B: 
Subjects ≥10 kg to 
<14 kg at Day 1 
Part B: 
Subjects ≥14 kg at 
Day 1 
ELX/TEZ/IVA, FDC granules, oral 
 
 
 
ELX 
100 mg 
80 mg 
100 mg 
TEZ 
50 mg 
40 mg 
50 mg 
IVA 
75 mg 
60 mg 
75 mg 
IVA, granules, oral 
75 mg 
59.5 mg 
75 mg 
ELX: elexacaftor; FDC: fixed-dose combination; IVA: ivacaftor; TEZ: tezacaftor 


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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 he/she 
is unable to resolve with the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
The principal investigator, study site staff, including pharmacy personnel will assist Vertex with 
any recall activities (as applicable) and place impacted investigational medicinal product (IMP) 
in quarantine when requested. 
10.6 
Compliance 
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subjects’ parents or legal guardians of study drug dosing 
requirements. Compliance will also be assessed by ongoing study drug count. 
If a subject’s parent or legal guardian demonstrates continued noncompliance of study drug 
dosing despite educational efforts, the investigator should consider discontinuing the subject 
from the study. 
10.7 
Blinding and Unblinding 
This will be an open-label study; however, subjects and their parent or legal guardian should not 
be informed of their study-related LCI, SwCl, 
 results during the 
Treatment Period (Part B only), regardless if the subject permanently discontinues treatment. 
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1 through Table 3-4. 
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 


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Medical history will be elicited from each subject and extracted from medical records during 
screening. Based on the medical history, the subject will be assessed for any disqualifying 
medical conditions as specified in the inclusion and exclusion criteria. The medical history will 
include a complete review of systems, medical and surgical histories, and any allergies. 
11.2 
Pharmacokinetics 
11.2.1 
Blood Sampling 
Blood samples will be collected to determine plasma concentrations of ELX, TEZ, IVA, and 
relevant metabolites. 
Acceptable windows for sampling times are shown in Table 11-1. Samples collected outside of 
these acceptable windows will be considered protocol deviations. 
Actual sampling times may change upon agreement between the clinical pharmacologist and 
investigator, but the number of samples will remain the same. All efforts will be made to obtain 
the PK samples at the exact nominal time relative to dosing. Acceptable windows for sampling 
times are shown in Table 11-1. Samples collected outside of these acceptable windows will be 
considered protocol deviations. The exact time of the sample collection will be noted. 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Sampling Time 
Time From Scheduled Sampling Allowed 
Predose (before morning dose) 
within 60 minutes before dosing 
>0.25 and ≤6 hours after morning dose 
 10 minutes 
 
For each visit with a PK blood draw, a record of study drug administration will be collected as 
described in Section 9.6. The collection date and exact time that each PK blood sample is drawn 
will also be recorded. 
Samples from the PK sampling will be kept frozen by Vertex or its designee until all analyses 
have been completed and then disposed of according to Vertex or designee standard operating 
procedures. 
11.2.2 
Processing and Handling of Pharmacokinetic Samples 
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. 
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. 


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11.4 
Efficacy and Pharmacodynamics (Part B Only) 
11.4.1 
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). 
11.4.2 
Multiple-breath Washout 
The N2-MBW testing will be performed in multiple replicates for subjects ≥3 years of age at 
screening and at time points noted in Table 3-4, and the final LCI value will be calculated from 


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the technically acceptable washout replicates by a central reader. The final LCI value at each 
visit will be the value provided by the LCI vendor based on the replicates. 
Pre-bronchodilator MBW is defined as MBW 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 MBW test; 
• withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the 
MBW test; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the MBW test. 
During the Screening Period, the MBW test may be performed pre- or post-bronchodilator. At all 
other visits, all MBW tests should be performed pre-bronchodilator. During the Treatment 
Period, MBW testing must be performed before study drug dosing (Section 9.6.1) at 
approximately the same time at each visit. In the event that a subject forgets to withhold 
bronchodilator(s), MBW testing should be performed according to the following: 
• If a subject’s Day 1 MBW test is pre-bronchodilator, but, on a subsequent visit, the subject 
forgets to withhold bronchodilator use, a post-bronchodilator MBW test will be obtained for 
that visit only, and the visit will not be rescheduled. 
• If, on Day 1, the subject forgets to withhold his/her dose of bronchodilator, the MBW test 
should be performed post-bronchodilator, and all subsequent MBW tests (according to the 
schedule of assessments) should be performed post-bronchodilator. 
• Each MBW test will be recorded in the source documents as pre- or post-bronchodilator. 
Subjects and parents/legal guardians should not be informed of study-related LCI results. 
Detailed MBW procedures will be supplied separately in a Study Manual. 


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11.5 
Safety 
Safety evaluations will include reporting of AEs, clinical laboratory assessments, physical 
examinations (PEs), clinical evaluation of vital signs, pulse oximetry, standard 12-lead ECGs, 
and ophthalmologic examinations. 
Medical history and PE information will be collected during the course of the study and will be 
captured in the source documentation. PEs post-baseline will not be captured for inclusion into 
the study database. However, any untoward findings identified on PEs conducted after the 
administration of the first dose of study drug will be captured as an AE if those findings meet the 
definition of an AE. Demographic data collected at the Screening Visit will be included in the 
study database. 
11.5.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with current ICH E6 GCP 
Guidelines. Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. Electronic AE case report form (CRF) completion 
guidelines for investigators as well as training will be provided. 
11.5.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory. A local laboratory may be used 
for the Week 20 (Part B) assessments if the subject cannot return to the site for a blood draw. All 
blood samples will be collected while subjects are in a seated or supine position. To minimize 
the total amount of blood taken during screening and at Day 1, a single set of pre-dose 
hematology and coagulation assessments will be obtained from a blood draw taken up to 9 days 
before Day 1 dosing in Part B. Screening serum chemistry assessments must also be obtained 
from a blood draw taken up to 9 days before Day 1 dosing in Part B. Serum chemistry will also 
be drawn prior to study drug dosing on Day 1. Specific instructions for the collection, 
processing, and shipment for centrally drawn samples will be provided in a separate Laboratory 
Manual. Laboratory test results that are abnormal and considered clinically significant will be 
reported as AEs (see Section 13.1). 
The safety laboratory test panels are shown in Table 11-2. 


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Table 11-2 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Total bilirubin, direct bilirubin, 
indirect bilirubin  
Alkaline phosphatase  
Aspartate transaminase 
Alanine transaminase 
Amylase  
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Cholesterol  
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. 
CF genotype (Screening Period only): CF genotyping will be performed on all subjects. If the 
CFTR genotype result is not received before the first dose of study drug, a previous CFTR 
genotype laboratory report may be used to establish eligibility (Section 8.1). Subjects who have 
been enrolled and whose screening genotype does not confirm study eligibility must be 
discontinued from the study (Section 9.9). This assessment does not need to be repeated in the 
case of rescreening or for confirmed subjects in Part A who wish to participate in Part B. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged by the investigator to be clinically appropriate.  
For the purposes of study conduct and unless noted otherwise, only laboratory tests done in the 
central laboratory may be used. Local laboratories may be used at the discretion of the local 
investigator for management of urgent medical issues. If a local laboratory test value is found to 
be abnormal and clinically significant, it will be verified by the central laboratory as soon as 
possible after the investigator becomes aware of the abnormal result. If it is not possible to send a 
timely specimen to the central laboratory (e.g., the subject was hospitalized elsewhere), the 
investigator may base the assessment of an AE on the local laboratory value. 
11.5.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits. At other visits, symptom-directed PEs and symptom-directed vital signs assessments 
can be performed at the discretion of the investigator or healthcare provider. 


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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. 
Height and weight will be measured with shoes off and before the dose of the study drug during 
the Treatment Period. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed. 
Arterial oxygen saturation by pulse oximetry will be assessed following at least a 5-minute rest 
and before study drug dosing. At visits when study drug is taken at the site, pulse oximetry will 
be collected before study drug dosing. 
11.5.4 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines: 
• The ECG will be done before any other procedures that may affect heart rate, such as blood 
draws. 
• The subject will be instructed to rest for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position. 
A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. Clinically significant ECG abnormalities occurring during the study 
through completion of study participation will be recorded as AEs. 
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. 
11.5.5 
Ophthalmologic Examination 
Ophthalmologic examinations do not need to be completed if there is documentation of bilateral 
lens removal for the subject. 
All examinations will be conducted by a licensed ophthalmologist or optometrist and will 
include: 
• measurement of best-corrected distance visual acuity of each eye; and 
• pharmacologically dilated examination of the lens with a slit lamp. 


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The screening examination does not need to be conducted if there is documentation of an 
examination meeting the protocol requirements that was conducted within 3 months before the 
date of informed consent. 
Any clinically significant abnormal findings will be reported as AEs. 
Part B Only 
In addition to the screening ophthalmologic examination, all subjects who have completed at 
least 12 weeks of study drug treatment will have a single follow-up ophthalmologic examination. 
This examination should be completed at or up to 4 weeks before the Week 24 Visit, unless the 
subject prematurely discontinues study drug, in which case this examination should occur by the 
Safety Follow-up Visit (or ETT Visit for subjects who do not complete a Safety Follow-up 
Visit), as described in Table 3-4. 
11.5.6 
Contraception and Pregnancy 
Not applicable. 
12 
STATISTICAL ANALYSIS 
This section presents a summary of the principal features of the planned 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. 
12.1 
Sample Size and Power 
Part A 
Approximately 14 subjects will be enrolled in Part A. Sample size calculations were determined 
based on ELX and M23-445 estimates of clearance. Assuming that the variability in this age 
group is the same as the variability observed in adults, data from 14 subjects will allow at least 
80% power to target a 95% CI within 60% and 140% of the geometric mean estimate of 
clearance for ELX and M23-445. 
Part B 
No formal power calculation is performed. The number of subjects in Part B is deemed adequate 
to meet the primary safety objective. The planned enrollment is approximately 70 subjects. 
Assuming a dropout rate of 10% or 20%, approximately 63 or 56 subjects, respectively, are 
expected to complete Part B. Incidence of AEs is a safety endpoint. Table 12-1 presents 
estimated probabilities for observing at least 1 subject with an AE for the given incidence rate (θ) 
and number of subjects completing Part B. The probabilities were calculated by assuming a 
binomial distribution for the number of AEs using SAS®. 


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Table 12-1 
Probability of Observing At Least 1 Subject With an AE in the Study if the 
AE Incidence () is 5% and 10% 
Number of Subjects 
Completing Part B 
 = 5% 
 = 10% 
56 
94.3% 
99.7% 
63 
96.1% 
99.9% 
: incidence; AE: adverse event 
12.2 
Analysis Sets 
Assignment of subjects to analysis sets will be done before the clinical data lock for the study. 
The following analysis sets will be defined separately for Part A and Part B. 
All Subjects Set 
The All Subjects Set will include all subjects who are enrolled (defined as subjects having data in 
the clinical database) 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.  
Full Analysis Set (FAS) 
The FAS will include all subjects who are enrolled (defined as subjects having data in the 
clinical database) and carry the intended CFTR allele mutation and received at least 1 dose of 
study drug. The FAS will be used to summarize subject demographics and baseline 
characteristics, and for analyses of all efficacy and PD endpoints, unless otherwise specified. 
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, unless otherwise specified. 
12.3 
Statistical Analysis 
12.3.1 
General Considerations 
Data from Part A and Part B will be analyzed separately. All individual subject data will be 
presented in individual subject data listings. 
Continuous variables will be summarized using the following descriptive summary statistics: 
number of subjects (n), mean, SD, median, minimum value (min), and maximum value (max). 
The precision of the measurement for each continuous variable will be specified in the SAP. 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Treatment-emergent (TE) period for Parts A and B will include the time from the first dose of 
study drug in the respective Part through 28 days after the last dose, or the completion of study 
participation date (Section 9.1.6), whichever is earlier. 
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 SAP. 
Absolute change from baseline will be calculated as post-baseline value – baseline value. 


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12.3.2 
Background Characteristics 
Subject disposition, demographic and baseline characteristics, prior and concomitant 
medications, study drug exposure, compliance (Part B only), and other background 
characteristics will be summarized for Part A and Part B. 
12.3.3 
Efficacy and Pharmacodynamic Analysis 
Two of the secondary objectives for Part B are to evaluate the efficacy and PD of 
ELX/TEZ/IVA. Principal features of the efficacy and PD analyses are presented in this section. 
Further details will be provided in the SAP. 
12.3.3.1 
Analysis of Primary Efficacy Endpoints 
Not applicable as efficacy is not a primary endpoint. 
12.3.3.2 
Analysis of Secondary Efficacy and Pharmacodynamic Endpoints 
A summary of observed values and change from baseline will be provided for all secondary 
efficacy endpoints based on the FAS in Part B. 
• Absolute change in SwCl from baseline through Week 24 
Absolute change from baseline in SwCl will be analyzed using a mixed-effects model for 
repeated measures (MMRM) approach based on the FAS. The MMRM will be used to 
estimate the mean absolute change in SwCl through Week 24. The model will include 
absolute change from baseline in SwCl as the dependent variable, and with visit, baseline 
SwCl value, and genotype group as covariates. Data obtained from Week 4, Week 12, and 
Week 24 Visits will be included in the model. An unstructured covariance structure will be 
used to model the within-subject variations. 
The primary results obtained from the model will be the average treatment effect through 
Week 24. The estimated mean change from baseline in SwCl through Week 24, along with 
the corresponding 95% CI and 2-sided P value will be provided. The treatment effect at each 
post-baseline visit, obtained from the model, will be provided as well. 
• Absolute change in LCI2.5 from baseline through Week 24 
Analysis of this endpoint will be based on an MMRM model that is similar to the analysis of 
absolute change from baseline in SwCl through Week 24, with the baseline LCI2.5 value 
included as a covariate instead of baseline SwCl. 
12.3.3.3 
Multiplicity Adjustment 
No multiplicity adjustment is planned. 


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12.3.4 
Safety Analysis 
Safety is a secondary objective of Part A, and the primary objective of Part B. All safety analyses 
will be conducted for the Safety Set in Part A and Part B separately. The safety profile of study 
drug will be assessed based on the following safety and tolerability endpoints: 
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis as 
applicable) 
• Standard 12-lead ECGs 
• Vital signs 
• Pulse oximetry 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
• Pretreatment AE: any AE that occurred before the first dose of study drug 
• TEAE: any AE that is worsened (either in severity or seriousness) or newly developed at or 
after the first dose of study drug through the end of the TE Period 
• Post-treatment AE: any AE that worsened (either in severity or seriousness) or newly 
developed after the TE Period 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study drug treatment, then the AEs will be classified as TEAEs. 
AE summary tables will be presented for TEAEs only, and will include the following: 
• All TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 


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• Serious TEAEs 
• TEAEs leading to death 
• Grade 3 and Grade 4 TEAEs (Section 13.1.1.4) 
Summaries will be presented by System Organ Class and Preferred Term using frequency counts 
and percentages (i.e., number and percentage of subjects with an event). When summarizing the 
number and percentage of subjects with an event, subjects with multiple occurrences of the same 
AE or a continuing AE will be counted once, only the maximum severity level will be presented 
in the severity summaries, and the strongest relationship level in the relationship summaries. An 
AE overview table will be provided. In addition, a listing containing individual subject level AE 
data for all deaths and other serious and significant AEs will be provided separately. All AEs, 
including pre- and post-treatment AEs, will be presented in individual subject data listings. 
12.3.4.2 
Clinical Laboratory Assessments 
For the treatment-emergent laboratory measurements, the observed values and change from 
baseline values of the continuous hematology, serum chemistry, and coagulation results will be 
summarized in SI units at each scheduled visit. 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized. The threshold analysis criterion shift from baseline will also be 
summarized for select laboratory parameters. The threshold analysis criteria and the parameter 
selection criteria will be provided in the SAP. 
Results of urinalysis will be listed in individual subject data listings only. In addition, a listing 
containing individual subject hematology, chemistry, and coagulation values outside the 
reference ranges will be provided. This listing will include data from scheduled and unscheduled 
visits. 
12.3.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided, at each scheduled visit and time point, as applicable, for the 
following ECG interval measurements (in msec): RR, PR, QT, and QT interval corrected by 
Fredericia’s formula (QTcF), QRS duration, and heart rate (HR) (beats per minute). 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized. The threshold analysis criteria will be provided in the SAP. 
12.3.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each scheduled visit. The following vital signs parameters 
will be summarized: systolic and diastolic blood pressure (mm Hg), body temperature (C), pulse 
rate (heart rate, beats per minute), and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized. The threshold analysis criteria will be provided in the SAP. 


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12.3.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each scheduled visit for the percent of oxygen 
saturation by pulse oximetry. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
Period will be summarized. 
12.3.4.6 
Ophthalmologic Examinations 
The ophthalmologic examination results will be presented in individual subject data listings. 
12.3.4.7 
Physical Examination 
PE findings will be presented in an individual subject data listing only. 
12.4 
Interim Analysis 
Not applicable. 
12.5 
Data Monitoring Committee Analysis 
The DMC (Section 9.1.7) will conduct periodic planned safety review(s) of study data. Details of 
the safety and efficacy review(s) will be described in the DMC Charter. 
12.6 
Clinical Pharmacology Analysis 
12.6.1 
Pharmacokinetic Analysis 
The PK analysis of ELX, TEZ, IVA, and relevant metabolites may be performed using nonlinear 
mixed effects modeling and/or standard noncompartmental analysis, as data allow. Metabolites 
may be included in the analyses as supported by data. Descriptive statistics will be used to 
summarize PK parameter values for all analytes. 
A detailed description of the planned PK analysis will be presented in the CPAP. 
12.6.2 
Pharmacokinetic/Pharmacodynamic Analyses 
PK/PD analyses may be performed on selected PD assessments, which include SwCl, LCI2.5, as 
well as other endpoints such as 
 
A sequential approach will be used to perform the population PK/PD analysis. The Bayesian 
estimates of individual PK parameters from the final population PK model will be used to 
simulate PK profiles for each subject. The simulated ELX, TEZ, IVA, or metabolite plasma 
concentrations will be used in the potential pharmacological response models to describe 
changes in each endpoint. Fixed- and random-effect parameter estimates and their uncertainty 
will be estimated. 


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13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed. 
An AE is considered serious if it meets the definition in Section 13.1.2.1. 
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the following times: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, withdrawal of 
consent) 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up Visit 
• For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of 
o 28 days after the last dose of study drug, or 
o the ETT Visit, if that visit is 3 weeks or later following the last dose of study drug 
(see Section 9.1.4) 


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All subjects’ 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 the CRF and source document. AEs for subjects who are screened but not subsequently 
enrolled will be recorded only in the subject’s source documents. The following data will be 
documented for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity 
• Causal relationship to study drug(s) 
• Action taken 
• Outcome 
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology 
Criteria for Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
September 2019). When considering the severity of an AE in a pediatric subject, the investigator 
will consider that reference ranges for pediatric clinical laboratory parameters may differ from 
those in the CTCAE. The severity of an AE described by a term that does not appear in the 
CTCAE will be determined according to the definitions in Table 13-1. 
Table 13-1 
Grading of AE Severity 
Classification 
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 September 2019) 
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. 


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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). 
 
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 
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. 
a 
Refer to Sections 9.7 and 9.8 for directions regarding what drug actions are permitted per protocol. 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 


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


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“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 through the Safety Follow-up Visit, 
regardless of causality, will be reported by the investigator to Vertex Global Patient Safety 
(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 through the Safety Follow-up Visit, the 
SAE Form will be completed for new/initial events as well as to report follow-up information on 
previously reported events. Investigators are asked to report follow-up information as soon as it 
becomes available to ensure timely reporting to health authorities. 
Please send completed SAE Forms to Vertex GPS via: 
Email: 
 (preferred choice) 
Fax: 
  
For technical issues related to submitting the form, contact telephone: 
 
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) will 
be recorded on the Vertex Clinical Trial Safety Information Collection Form (hereafter referred 
to as the “SAE Form”) using a recognized medical term or diagnosis that accurately reflects the 
event. SAEs will be assessed by the investigator for relationship to the investigational study 
drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be assessed 
only as related (includes possibly related) or not related (includes unlikely related), and severity 
assessment will not be required. For the purposes of study analysis, if the event has not resolved 
at the end of the study reporting period, it will be documented as ongoing. For purposes of 
regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report the outcome to Vertex using the SAE Form. 
13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, 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. 
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 


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drug product, IMP, or medical device. In addition, suspected counterfeit/falsified product is 
considered a product complaint. 
Product complaints are to be reported to Vertex. 
13.2.2 
Ethical Considerations 
The study will be conducted in accordance with the current ICH E6 GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will be 
conducted only at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.3 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
current ICH E6 GCP Guidelines and all applicable laws and regulations and will be subject to 
approval by Vertex or its designee. 
13.2.4 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log. 
13.2.5 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol. 
13.2.6 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 


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identify subjects by assigned subject numbers, and access to subject names linked to such 
numbers will be limited to the site and the study physician and will not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE Forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 
For sites participating in the US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will comply with all HIPAA 
requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.7 
Record Retention 
The investigator will maintain all study records according to current ICH E6 GCP Guidelines 
and/or applicable local regulatory requirement(s), whichever is longest, as described in the 
Clinical Trial Agreement. If the investigator withdraws from the responsibility of keeping the 
study records, custody will be transferred to a person willing to accept the responsibility and 
Vertex will be notified. 
13.2.8 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.2.9 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 


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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. Vertex will have read-only 
access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP Guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by a 
representative of Vertex or designee (study site monitor), who will review the CRFs/SAE Forms 
and source documents per current ICH E6 GCP Guidelines. The study site monitor will ensure 
that the investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible. 
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected. 
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible. 
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc (CD) or other electronic media will be placed in the investigator’s 
study file. 


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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 


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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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17 
International Committee of Medical Journal Editors (ICMJE). December 2017. 
Recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals. Available at: http://www.icmje.org/recommendations/. Accessed 03 
August 2018. 
 


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


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Non-exhaustive List of Minimal Function CFTR Mutations Eligible for VX20-445-111 
 
 
 
 
 
Q2X 
L218X 
Q525X 
R792X 
E1104X 
S4X 
Q220X 
G542X 
E822X 
W1145X 
W19X 
Y275X 
G550X 
W882X 
R1158X 
G27X 
C276X 
Q552X 
W846X 
R1162X 
Q39X 
Q290X 
R553X 
Y849X 
S1196X 
W57X 
G330X 
E585X 
R851X 
W1204X 
E60X 
W401X 
G673X 
Q890X 
L1254X 
R75X 
Q414X 
Q685X 
S912X 
S1255X 
L88X 
S434X 
R709X 
Y913X 
W1282X 
E92X 
S466X 
K710X 
Q1042X 
Q1313X 
Q98X 
S489X 
Q715X 
W1089X 
Q1330X 
Y122X 
Q493X 
L732X 
Y1092X 
E1371X 
E193X 
W496X 
R764X 
W1098X 
Q1382X 
W216X 
C524X 
R785X 
R1102X 
Q1411X 
 
 
 
185+1G>T 
711+5G>A 
1717-8G>A 
2622+1G>A 
3121-1G>A 
296+1G>A 
712-1G>T 
1717-1G>A 
2790-1G>C 
3500-2A>G 
296+1G>T 
1248+1G>A 
1811+1G>C 
3040G>C (G970R) 
3600+2insT 
405+1G>A 
1249-1G>A 
1811+1.6kbA>G 
3850-1G>A 
405+3A>C 
1341+1G>A 
1811+1643G>T  
3120G>A 
4005+1G>A 
406-1G>A 
1525-2A>G 
1812-1G>A 
3120+1G>A 
4374+1G>T 
621+1G>T 
1525-1G>A 
1898+1G>A 
3121-2A>G 
711+1G>T 
1898+1G>C 
 
 
 
 
182delT 
1119delA 
1782delA 
2732insA 
3791delC 
306insA 
1138insG 
1824delA 
2869insG 
3821delT 
365-366insT 
1154insTC 
1833delT 
2896insAG 
3876delA 
394delTT 
1161delC 
2043delG 
2942insT 
3878delG 
442delA 
1213delT 
2143delT 
2957delT 
3905insT 
444delA 
1259insA 
2183AA>G a 
3007delG 
4016insT 
457TAT>G 
1288insTA 
2184delA 
3028delA 
4021dupT 
541delC 
1343delG 
2184insA 
3171delC 
4022insT 
574delA 
1471delA 
2307insA 
3171insC 
4040delA 
663delT 
1497delGG 
2347delG 
3271delGG 
4279insA 
849delG  
1548delG 
2585delT 
3349insT 
4326delTC 
935delA 
1609del CA 
2594delGT 
3659delC 
1078delT 
1677delTA 
2711delT 
3737delA 
 
 
 
 


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Non-exhaustive List of Minimal Function CFTR Mutations Eligible for VX20-445-111 
 
 
 
 
 
CFTRdele1 
CFTRdele16-17b 
991del5 
CFTRdele2 
CFTRdele17a,17b 
1461ins4 
CFTRdele2,3 
CFTRdele17a-18 
1924del7 
CFTRdele2-4 
CFTRdele19 
2055del9>A 
CFTRdele3-10,14b-16 
CFTRdele19-21 
2105-2117del13insAGAAA 
CFTRdele4-7 
CFTRdele21 
2372del8 
CFTRdele4-11 
CFTRdele22-24 
2721del11 
CFTR50kbdel 
CFTRdele22,23 
2991del32 
CFTRdup6b-10 
124del23bp 
3121-977_3499+248del2515 
CFTRdele11 
306delTAGA 
3667ins4 
CFTRdele13,14a 
602del14  
4010del4 
CFTRdele14b-17b 
852del22 
4209TGTT>AA 
 
 
 
 
A46D 
V520F 
Y569D 
N1303K 
 
G85E 
A559T 
L1065P 
 
R347P 
R560T 
R1066C 
 
L467P 
R560S 
L1077P 
 
I507del 
A561E 
M1101K 
 
 
 
 
CFTR: cystic fibrosis transmembrane conductance regulator gene 
Source: CFTR2.org. Clinical and functional translation of CFTR. The Clinical and Functional Translation of CFTR (CFTR2), 
US Cystic Fibrosis Foundation, Johns Hopkins University, the Hospital for Sick Children. Available at: 
http://www.cftr2.org. Accessed 15 February 2016. 
a 
Also known as 2183delAA>G. 


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APPENDIX B 
Eligible ELX/TEZ/IVA-Responsive CFTR Mutations 
As described in Section 8.1, in Part B, subjects with at least 1 F508del mutation in the CFTR 
gene or an ELX/TEZ/IVA-responsive CFTR mutation based on in vitro data, qualify to be 
screened for the study. The list of qualifying ELX/TEZ/IVA-responsive CFTR mutations is 
presented below. 
CFTR Mutations Responsive to ELX/TEZ/IVA Based on In Vitro Data 
3141del9 
G126D 
R334L 
S549R 
H939R 
W1098C 
546insCTA 
H139R 
R334Q 
G551D 
S945L 
F1099L 
P5L 
I148T 
I336K 
G551S 
M952I 
M1101K 
S13F 
M152V 
T338I 
R553Q 
M952T 
I1139V 
L15P 
Y161D 
S341P 
A554E 
L967S 
D1152H 
G27R 
Y161S 
L346P 
V562I 
G970D 
V1153E 
R31L 
L165S 
R347H 
Y563N 
S977F 
S1159F 
A46D 
R170H 
R347L 
P574H 
D979V 
S1159P 
E56K 
I175V 
R347P 
F575Y 
I980K 
R1162L 
E60K 
G178E 
A349V 
G576A 
L997F 
V1240G 
P67L 
G178R 
R352Q 
G576A;R668C † 
A1006E 
G1244E 
R74Q 
F191V 
R352W 
D579G 
Y1014C 
G1249R 
R74W 
D192G 
Q359R 
E588V 
F1016S 
S1251N 
R74W;V201M † 
E193K 
W361R 
S589N 
I1027T 
S1255P 
R74W;V201M;D1270N † 
G194R 
S364P 
I601F 
Y1032C 
I1269N 
R74W;D1270N † 
G194V 
E403D 
D614G 
T1036N 
D1270N 
R75Q 
H199Y 
D443Y;G576A;R668C † 
I618T 
F1052V 
W1282R 
G85E 
V201M 
D443Y 
G622D 
T1053I 
R1283M 
E92K 
P205S 
L453S 
G628R 
H1054D 
R1283S 
Q98R 
L206W 
A455E 
R668C 
K1060T 
Q1291R 
Y109N 
V232D 
V456A 
S737F 
G1061R 
V1293G 
D110E 
A234D 
V456F 
R751L 
R1066H 
L1324P 
D110H 
Q237E 
G463V 
V754M 
A1067T 
L1335P 
E116K 
Q237H 
E474K 
R792G 
G1069R 
G1349D 
R117C 
R258G 
G480C 
I807M 
R1070Q 
I1366N 
R117G 
M265R 
S492F 
E822K 
R1070W 
H1375P 
R117H 
F311del 
I502T 
D836Y 
F1074L 
L1480P 
R117L 
F311L 
F508C 
S912L 
L1077P 
 
R117P 
G314E 
F508C;S1251N † 
D924N 
H1085P 
 
A120T 
L320V 
S549N 
R933G 
H1085R 
 
† 
Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist 
independent of the presence of mutations on the other allele. 




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15.2 
Investigator Signature Page 
Protocol #:  
VX20-445-111 Version #: 
3.0 
Version Date: 
21 October 2021 
Study Title: A Phase 3 Study Evaluating the Safety, Tolerability, and Pharmacokinetics of 
Elexacaftor/Tezacaftor/Ivacaftor Triple Combination Therapy in Cystic Fibrosis Subjects 2 
Through 5 Years of Age 
 
 
I have read Protocol VX20-445-111, Version 3.0, and agree to conduct the study according to its 
terms. I understand that all information concerning elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor 
(IVA) and this protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is 
confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 43 
Protocol Number: VX20-445-111 
 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan  
(Methods) 
 
 
Protocol Number VX20-445-111, Version 3.0 
 
 
A Phase 3 Study Evaluating the Safety, Tolerability, and Pharmacokinetics of 
Elexacaftor/Tezacaftor/Ivacaftor Triple Combination Therapy in Cystic Fibrosis 
Subjects 2 Through 5 Years of Age 
 
 
Author of SAP: 
 
 
 
Version: 2.0 
Version Date of SAP: 02 May 2022 
 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods)  
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1 
TABLE OF CONTENTS 
1 
Table of Contents ........................................................................................................................... 2 
2 
List of Abbreviations ..................................................................................................................... 4 
4 
Introduction.................................................................................................................................... 7 
5 
Study Objectives ............................................................................................................................ 8 
5.1 
Primary Objectives ................................................................................................................... 8 
5.2 
Secondary Objectives ............................................................................................................... 8 
6 
Study Endpoints ............................................................................................................................. 9 
6.1 
Primary Endpoints .................................................................................................................... 9 
6.2 
Secondary Endpoints ................................................................................................................ 9 
7 
Study Design ................................................................................................................................. 10 
7.1 
Overall Design ........................................................................................................................ 10 
7.2 
Sample Size and Power .......................................................................................................... 11 
7.3 
Randomization ........................................................................................................................ 12 
7.4 
Blinding and Unblinding ........................................................................................................ 12 
8 
Analysis Sets ................................................................................................................................. 12 
8.1 
All Subjects Set ...................................................................................................................... 12 
8.2 
Safety Set ................................................................................................................................ 12 
8.3 
Full Analysis Set ..................................................................................................................... 12 
9 
Statistical Analysis ....................................................................................................................... 12 
9.1 
General Considerations .......................................................................................................... 12 
9.2 
Background Characteristics .................................................................................................... 13 
9.2.1 
Background Characteristics for Part A ........................................................................... 13 
9.2.1.1 
Subject Disposition .................................................................................................. 13 
9.2.1.2 
Demographics and Baseline Characteristics ............................................................ 14 
9.2.1.3 
Medical History ........................................................................................................ 14 
9.2.1.4 
Prior and Concomitant Medications......................................................................... 15 
9.2.1.5 
Study Drug Exposure ............................................................................................... 15 
9.2.1.6 
Study Drug Compliance ........................................................................................... 15 
9.2.1.7 
Important Protocol Deviations ................................................................................. 16 
9.2.2 
Background Characteristics for Part B ........................................................................... 16 
9.2.2.1 
Subject Disposition .................................................................................................. 16 
9.2.2.2 
Demographics and Baseline Characteristics ............................................................ 16 
9.2.2.3 
Medical History ........................................................................................................ 17 
9.2.2.4 
Prior and Concomitant Medications......................................................................... 17 
9.2.2.5 
Study Drug Exposure ............................................................................................... 18 
9.2.2.6 
Study Drug Compliance ........................................................................................... 18 
9.2.2.7 
Important Protocol Deviations ................................................................................. 19 


Statistical Analysis Plan (Methods)  
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9.3 
Efficacy Analysis .................................................................................................................... 19 
9.3.1 
Efficacy Analysis for Part A ........................................................................................... 19 
9.3.2 
Efficacy Analysis for Part B ........................................................................................... 19 
9.3.2.1 
Analysis of Primary Efficacy Variables ................................................................... 19 
9.3.2.2 
Analysis of Secondary Efficacy Variables ............................................................... 19 
9.3.2.4 
Sensitivity Analysis .................................................................................................. 23 
9.  
 
9.4.1 
Safety Analysis for Part A .............................................................................................. 23 
9.4.1.1 
Adverse Events......................................................................................................... 24 
9.4.1.2 
Clinical Laboratory .................................................................................................. 25 
9.4.1.3 
Electrocardiogram .................................................................................................... 25 
9.4.1.4 
Vital Signs ................................................................................................................ 26 
9.4.1.5 
Pulse Oximetry ......................................................................................................... 26 
9.4.1.6 
Ophthalmologic Examinations ................................................................................. 26 
9.4.1.7 
Physical Examination ............................................................................................... 26 
9.4.1.8 
Visit Type ................................................................................................................. 26 
9.4.2 
Safety Analysis for Part B .............................................................................................. 26 
9.4.2.1 
Adverse Events......................................................................................................... 27 
9.4.2.2 
Clinical Laboratory .................................................................................................. 28 
9.4.2.3 
Electrocardiogram .................................................................................................... 29 
9.4.2.4 
Vital Signs ................................................................................................................ 29 
9.4.2.5 
Pulse Oximetry ......................................................................................................... 29 
9.4.2.6 
Ophthalmologic Examinations ................................................................................. 29 
9.4.2.7 
Physical Examination ............................................................................................... 29 
9.4.2.8 
Visit Type ................................................................................................................. 30 
10 Interim and IDMC Analyses ....................................................................................................... 30 
10.1 Interim Analysis ..................................................................................................................... 30 
10.2 IDMC Analysis ....................................................................................................................... 30 
11 References ..................................................................................................................................... 31 
12 List of Appendices........................................................................................................................ 32 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments ................................. 32 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ......................... 37 
Appendix C: Imputation Rules for Missing AE Dates .................................................................... 38 
Appendix D: Criteria for Threshold Analysis .................................................................................. 39 
Appendix E: Criteria for Threshold Analysis on SBP and DBP ...................................................... 43 
 


Statistical Analysis Plan (Methods)  
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2 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
 
 
bpm 
beats per minute 
CF 
cystic fibrosis 
CFTR 
cystic fibrosis transmembrane conductance regulator protein or the gene 
encoding the protein. 
CI 
confidence interval 
CRF 
case report form 
CRO 
contract research organization 
CSP 
clinical study protocol 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ELX 
elexacaftor 
FAS 
full analysis set 
FDC 
fixed-dose combination 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
F/F 
homozygous for F508del 
F/MF 
heterozygous for F508del and a CFTR minimal function mutation 
IDMC 
independent data monitoring committee 
IVA 
ivacaftor 
LCI 
lung clearance index 
LS means 
least squares means 
LFT 
liver function test 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
minimal function 
MFHS 
modified facial hedonic scale 
min 
minimum value 
MMRM 
mixed model repeated measure 
N 
number of subjects 
PD 
pharmacodynamic/pharmacodynamics  
PK 
pharmacokinetic/pharmacokinetics 
PT 
preferred term 
q12h 
every 12 hours 
QRS 
Q, R, and S-wave define the QRS-complex in an ECG 
QT 
QT interval 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate with Fridericia’s correction  


Statistical Analysis Plan (Methods)  
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Abbreviation 
Term 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
SwCl 
sweat chloride 
TC 
triple combination 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
ULN 
upper limit of normal 
WHODrug 
World Health Organization Drug Dictionary Enhanced 
 
 


Statistical Analysis Plan (Methods)  
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Protocol Number: VX20-445-111 


Statistical Analysis Plan (Methods)  
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4 
INTRODUCTION 
Study VX20-445-111 (Study 445-111) is a Phase 3, 2-part (Parts A and B), multicenter study 
evaluating the safety, tolerability, and pharmacokinetics (PK) of elexacaftor (ELX, VX-445) in triple 
combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects 2 through 5 years of age 
(inclusive) with cystic fibrosis (CF). Part B will initiate after the completion of Part A. Safety, 
tolerability, and available PK data from Part A will be reviewed by Vertex to confirm or adjust the 
dose(s) chosen for Part B. 
To provide analysis of the safety and tolerability data for Part A, the previous statistical analysis plan 
(SAP, Version 1.0, dated 01 FEB 2021) was finalized and approved before data lock of Part A. This 
SAP (Version 2.0) is a preplanned amendment to provide analysis of the safety and efficacy data for 
Part B. All changes from SAP Version 1.0 are made to Part B analysis only. Any revisions to this 
approved SAP will be documented and approved in an amendment to this SAP.  
This statistical analysis plan (SAP) Version 2.0 is based on the most recent approved clinical study 
protocol (CSP), the most recent approved electronic case report form (eCRF), and the most recent 
approved eCRF completion guidelines. 
PK and PD (if applicable) analyses will be documented separately in the clinical pharmacology 
analysis plan (CPAP). 
The Vertex Biometrics Department or designee will perform the statistical analysis of the safety and 
efficacy data; SAS (Version 9.4 or higher) will be used to generate all statistical outputs (tables, 
figures, listings, and datasets).  


Statistical Analysis Plan (Methods)  
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5 
STUDY OBJECTIVES 
5.1 
Primary Objectives 
Part A 
• 
To evaluate the PK of ELX, TEZ, and IVA when dosed in TC 
• 
To evaluate the safety and tolerability of ELX/TEZ/IVA 
Part B 
To evaluate the safety and tolerability of ELX/TEZ/IVA 
5.2 
Secondary Objectives 
Part A 
None 
Part B 
• 
To evaluate the PK of ELX, TEZ, and IVA 
• 
To evaluate the PD of ELX/TEZ/IVA 
• 
To evaluate the efficacy of ELX/TEZ/IVA 
 


Statistical Analysis Plan (Methods)  
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6 
STUDY ENDPOINTS 
6.1 
Primary Endpoints 
Part A 
• 
PK parameters of ELX, TEZ, IVA, and relevant metabolites 
• 
Safety and tolerability assessments as determined by adverse events (AEs), clinical laboratory 
values, standard 12-lead electrocardiograms (ECGs), vital signs, and pulse oximetry 
Part B 
Safety and tolerability assessments as determined by AEs, clinical laboratory values, standard 12-lead 
ECGs, vital signs, and pulse oximetry 
6.2 
Secondary Endpoints 
Part A 
None 
Part B 
• 
PK parameters of ELX, TEZ, IVA, and relevant metabolites 
• 
Absolute change in sweat chloride (SwCl) from baseline through Week 24  
• 
Absolute change in lung clearance index (LCI)2.5 from baseline through Week 24 


Statistical Analysis Plan (Methods)  
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7 
STUDY DESIGN  
7.1 
Overall Design 
This is a Phase 3, 2-part (Parts A and B), multicenter study evaluating the safety, tolerability, PK, PD, 
and efficacy of ELX/TEZ/IVA in CF subjects 2 through 5 years of age (inclusive). 
Part A 
A schematic of the study design for Part A is provided in Figure 7-1. Approximately 14 subjects (F/F 
or F/MF genotypes) will be enrolled. During the Treatment Period, subjects will be administered 
ELX/TEZ/IVA for approximately 15 days (Table 7-1). Safety, tolerability, and available PK data 
from Part A will be reviewed by Vertex to confirm or adjust the dose(s) chosen for Part B. Additional 
subjects may be enrolled as needed in Part A, based on emerging PK data, in order to provide 
sufficient information to select the dose(s) for Part B. Subjects who participate in Part A may 
participate in Part B. 
Figure 7-1 
VX20-445-111 Part A Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
ELX: elexacaftor; IVA: ivacaftor; TEZ: tezacaftor 
Note: ELX/TEZ/IVA will be administered from Day 1 through Day 15. On Day 15, only the morning dose will be 
administered. 
Part B 
A schematic of the study design for Part B is provided in Figure 7-2. Part B will initiate after 
available data from Part A has been reviewed by Vertex and the Part B dose(s) has been confirmed or 
adjusted. Part B will enroll approximately 70 subjects, of which at least 30 subjects will have F/MF 
genotypes and at least 15 subjects with the F/F genotype. At least 25 subjects should be between 2 
and 3 years of age (inclusive). During the Treatment Period, subjects will be administered 
ELX/TEZ/IVA (Table 7-1) for approximately 24 weeks. 
Subjects who are eligible will be offered the opportunity to enroll in an open-label extension (OLE) 
safety study. 
Safety Follow-up Visit 
Treatment Period 
ELX/TEZ/IVA 
(N = 14) 
Screening Period 
Day 1 
Day -28 
Day 15 
28 days after 
last dose 


Statistical Analysis Plan (Methods)  
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Safety Follow-up 
Visita 
Treatment Period 
ELX/TEZ/IVA 
(N = 70) 
Screening Period 
Day 1 
Day -28 
Week 12 
28 days after 
last dose 
Week 24 
Open-label Extension 
(OLE) Safety Studyb 
Figure 7-2 
VX20-445-111 Part B Study Design 
ELX: elexacaftor; IVA: ivacaftor; OLE: open-label extension; TEZ: tezacaftor 
a 
The Safety Follow-up Visit is not required for subjects who enroll in an OLE safety study within 28 days of the last 
scheduled visit in the Treatment Period. 
b 
Subjects who are eligible will be offered the opportunity to enroll in an OLE safety study evaluating ELX/TEZ/IVA. 
 
Table 7-1 
Parts A and B Doses 
Subject Weight at Day 1 
ELX Dose 
TEZ Dose 
IVA Dose 
Part A 
 
 
 
≥14 kg only 
100 mg qd 
50 mg qd 
75 mg q12h 
Part B 
 
 
 
≥14 kg 
100 mg qd 
50 mg qd 
75 mg q12h 
≥10 kg to <14 kg 
80 mg qd 
40 mg qd 
60 mg qAM 
59.5 mg qPM 
ELX: elexacaftor; IVA: ivacaftor; qAM: once every morning; qd: once daily; qPM: once every evening; q12h: every 
12 hours; TEZ: tezacaftor 
7.2 
Sample Size and Power 
Part A 
Approximately 14 subjects will be enrolled in Part A. Sample size calculations were determined based 
on ELX and M23-445 estimates of clearance. Assuming that the variability in this age group is the 
same as the variability observed in adults, data from 14 subjects will allow at least 80% power to 
target a 95% CI within 60% and 140% of the geometric mean estimate of clearance for ELX and 
M23-445. 
Part B 
No formal power calculation is performed. The number of subjects in Part B is deemed adequate to 
meet the primary safety objective. The planned enrollment is approximately 70 subjects. Assuming a 
dropout rate of 10% or 20%, approximately 63 or 56 subjects, respectively, are expected to complete 
Part B. Incidence of AEs is a safety endpoint. Table 7-2 presents estimated probabilities for observing 
at least 1 subject with an AE for the given incidence rate (θ) and number of subjects completing 


Statistical Analysis Plan (Methods)  
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Part B. The probabilities were calculated by assuming a binomial distribution for the number of AEs 
using SAS®. 
Table 7-2 
Probability of Observing At Least 1 Subject With an AE in the Study if the AE 
Incidence () is 5% and 10% 
Number of Subjects 
Completing Part B 
 = 5% 
 = 10% 
56 
94.3% 
99.7% 
63 
96.1% 
99.9% 
: incidence; AE: adverse event 
7.3 
Randomization 
Not needed. Both Part A and Part B are designed to be single arm and open-label. 
7.4 
Blinding and Unblinding 
This is an open-label study. Refer to Section 10.7 of the CSP for details. 
8 
ANALYSIS SETS 
Part A and Part B 
The following analysis sets will be defined separately for Part A and Part B. 
8.1 
All Subjects Set 
The All Subjects Set will include all subjects who are enrolled (defined as subjects having data in the 
clinical database for this study) or receive at least 1 dose of study drug. This analysis set will be used 
for all individual subject data listings and disposition summary tables, unless otherwise specified. 
8.2 
Safety Set 
The Safety Set will include all subjects who receive at least 1 dose of study drug. The Safety Set will 
be used for all safety analyses. 
8.3 
Full Analysis Set 
The Full Analysis Set (FAS) will include all subjects who are enrolled and carry the intended CFTR 
allele mutation and receive at least 1 dose of study drug. The FAS will be used to summarize subject 
demographics and baseline characteristics, and for analyses of all efficacy and PD endpoints, unless 
otherwise specified. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
Data from Part A and Part B will be analyzed separately.  


Statistical Analysis Plan (Methods)  
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The Schedule of Assessments is provided in Section 3 of the CSP. The precision standards for 
reporting safety and efficacy variables are provided in an internal Biometrics document that specifies 
the programming rules including the precision for derived variables. 
Continuous variables will be summarized using the following descriptive summary statistics: the 
number of subjects (n), mean, standard deviation (SD), median, minimum value (min), and maximum 
value (max). 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline unless otherwise specified, is defined as the most recent non-missing measurement 
(scheduled or unscheduled) collected prior to the first dose of study drug in the corresponding Part. 
Note: in Part B, for subjects who take CFTR modulators (e.g., Orkambi) during the 28 days before the 
screening visit, the data collected at the screening visit will not be used for baseline derivation for 
sweat chloride and LCI. 
Absolute change from baseline will be calculated as Post-baseline value − Baseline value. 
Relative change from baseline will be calculated and expressed in percentage as 100% × (Post-
baseline value − Baseline value) / Baseline value. 
Treatment-emergent (TE) Period for Part A and Part B will include the time from the first dose of 
study drug in the corresponding Part through 28 days after the last dose or the completion of study 
participation date in the corresponding Part, whichever occurs first. Refer to Section 9.1.6 of the CSP 
for the definition of completion of study participation.  
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
• In scheduled visit windows per specified visit windowing rules 
• In the derivation of baseline and last on-treatment measurements 
• In the derivation of maximum and minimum values during TE periods, and maximum and 
minimum change from baseline values during TE periods for safety analyses 
• In individual subject data listings as appropriate 
Visit windowing rules for protocol-defined visits in Part A are provided in Appendix A.  
Incomplete/missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
9.2 
Background Characteristics  
9.2.1 
Background Characteristics for Part A 
9.2.1.1 
Subject Disposition 
The number of subjects in the following categories will be summarized based on the All Subjects Set:  
• All Subjects Set 


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• Safety Set 
• FAS 
The number and percentage (based on FAS) of subjects in each of the following disposition categories 
will be summarized: 
• Completed treatment 
• Prematurely discontinued treatment and the reason for discontinuation 
• Completed study  
• Prematurely discontinued study and the reason for discontinuation 
A listing will be provided for subjects who discontinued treatment or who discontinued study with 
reasons for discontinuation.  
9.2.1.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the FAS. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Sex (male, female) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• 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) 
Baseline characteristics will include the following: 
• CFTR genotype group (F/F, F/MF) 
In addition, the following data listings will also be provided: 
• Informed consent/assent; 
• Inclusion/Exclusion criteria violation for subjects with any such violations.  
9.2.1.3 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). For 
the FAS, medical history will be summarized descriptively by system organ class (SOC) and 
preferred term (PT). 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.  


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9.2.1.4 
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 administered during the 56 days before the first dose 
of study drug in the corresponding Part of the study. 
• Concomitant medication: medication continued or newly received during the corresponding 
TE period. 
• Post-treatment medication: medication continued or newly received after the corresponding 
TE period. 
A given medication may be classified as follows: prior, concomitant, post-treatment, both prior and 
concomitant, both concomitant and post-treatment, or prior, concomitant, and post-treatment.  
If a medication has a completely missing or partially missing start date or stop date and it cannot be 
determined whether it was taken before the first dose date, concomitantly, or after the TE period, it 
will be classified as prior, concomitant, and post-treatment. Details for imputing missing or partial 
start and/or stop dates of medication are described in Appendix B. 
Concomitant medications will be summarized descriptively for the FAS using frequency tables by: 1) 
preferred name (PN); and 2) anatomic class (ATC) level 1, ATC level 2, and PN. All medications will 
be listed for each subject.  
9.2.1.5 
Study Drug Exposure 
Study drug exposure summaries will be based on the Safety Set. 
Duration of study drug exposure (in days) will be calculated as: last dose date – first dose date 
+ 1 day, regardless of study drug interruption. 
Study drug exposure in days will be summarized descriptively by the number of subjects (n), mean, 
SD, median, min, and max. It will also be summarized using counts and percentages for Treatment 
Period categories. The categories are specified as: ≤2 days; >2 and ≤4 days; >4 and ≤8 days; >8 and 
≤15 days; >15 days. Additionally, the total study drug exposure, defined as the sum total of the study 
drug exposure across all subjects (in patient-weeks), will be provided.  
9.2.1.6 
Study Drug Compliance 
Study drug compliance will be summarized based on the FAS. 
Study drug compliance will be calculated as: 100 × [1 − (total number of days of study drug 
interruption) / (duration of study drug exposure in days)]. A study drug interruption on a given day is 
defined as an interruption of any study drug dose or component on that day.  
Study drug compliance will be summarized descriptively by the number of subjects (n), mean, SD, 
median, min, and max. It will also be summarized in categories: <80% and ≥80% using frequency 
tables.  


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9.2.1.7 
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.  
For Part A, IPDs will only be provided in an individual subject data listing.  
9.2.2 
Background Characteristics for Part B 
9.2.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized based on the All Subjects Set:  
• All Subjects Set 
• Safety Set 
• FAS 
The number and percentage (based on FAS) of subjects in each of the following disposition categories 
will be summarized: 
• Completed treatment 
• Prematurely discontinued treatment and the reason for discontinuation 
• Completed study  
• Prematurely discontinued the study and the reason for discontinuation 
• Rolled over to the extension study   
A listing will be provided for subjects who discontinued treatment or who discontinued study with 
reasons for discontinuation. 
9.2.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the FAS. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Age group at screening (≥2 to <3, ≥3 to <4, ≥4 to <5, and ≥5 to <6 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, Europe [including Australia]) 
Baseline characteristics will include the following: 


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• CFTR genotype group (F/F, F/MF, Other) 
• Weight group (<14 kg, and ≥14 kg) 
Disease characteristics will include the following: 
• Sweat chloride at baseline (continuous) 
• LCI2.5 at baseline (continuous) 
• Prior use of CFTR modulator (Yes, No) 
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 
• Prior use of any bronchodilator (Yes, No) 
• Prior use of any inhaled bronchodilator (Yes, No) 
• Prior use of any inhaled hypertonic saline (Yes, No) 
• Infection with Pseudomonas aeruginosa within 2 years prior to screening (Positive, Negative) 
In addition, the following data listings will also be provided: 
• Informed consent/assent; 
• Inclusion/Exclusion criteria violation for subjects with any such violations. 
9.2.2.3 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). For 
the FAS, medical history will be summarized descriptively by system organ class (SOC) and 
preferred term (PT). 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. 
9.2.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHODrug) and 
categorized as follows: 


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• Prior medication: any medication that administered during the 56 days before the first dose 
of study drug in Part B. 
• Concomitant medication: medication continued or newly received during the TE period in 
Part B. 
• Post-treatment medication: medication continued or newly received after the TE period in 
Part B. 
A given medication may be classified as follows: prior, concomitant, post-treatment, both prior and 
concomitant, both concomitant and post-treatment, or prior, concomitant, and post-treatment.  
If a medication has a completely missing or partially missing start date or stop date and it cannot be 
determined whether it was taken before the first dose date, concomitantly, or after the TE period, it 
will be classified as prior, concomitant, and post-treatment. Details for imputing missing or partial 
start and/or stop dates of medication are described in Appendix B. 
Concomitant medications will be summarized descriptively for the FAS using frequency tables by: 1) 
preferred name (PN); and 2) anatomic class (ATC) level 1, ATC level 2, and PN. Prior medications 
will also be summarized the same way as concomitant medications. All medications will be listed for 
each subject. 
9.2.2.5 
Study Drug Exposure 
Study drug exposure summaries will be based on the Safety Set. 
Duration of study drug exposure (in days) will be calculated as: last dose date – first dose date in Part 
B + 1 day, 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 using counts and percentages for Treatment 
Period categories. The categories are specified as: ≤15 days; >15 days and ≤4 weeks; >4 and ≤8 
weeks; >8 and ≤12 weeks; >12 and ≤16 weeks; >16 and ≤20 weeks; >20 and ≤24 weeks; >24 weeks. 
Additionally, the total study drug exposure, defined as the sum total of the study drug exposure across 
all subjects in patient-weeks and patient-years, will be provided. 
9.2.2.6 
Study Drug Compliance 
 Study drug compliance will be summarized based on the FAS. 
Study drug compliance will be calculated as: 100 × [1 − (total number of days of study drug 
interruption) / (duration of study drug exposure in days)]. A study drug interruption on a given day is 
defined as an interruption of any study drug dose or component on that day. In addition, a study drug 
interruption that continues through the end of the study participation (i.e., subject does not resume 
study drug before the end of the study participation) will not be included in the compliance 
calculation. 
Study drug compliance will be summarized descriptively by the number of subjects (n), mean, SD, 
median, min, and max. It will also be summarized in categories: <80% and ≥80% using frequency 
tables.  


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9.2.2.7 
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. 
9.3 
Efficacy Analysis 
9.3.1 
Efficacy Analysis for Part A 
Not applicable. There is no efficacy endpoint in Part A. 
9.3.2 
Efficacy Analysis for Part B 
There is no multiplicity adjustment; P-values provided for the secondary and other efficacy endpoints 
are considered nominal. 
All efficacy analyses described in this section will be based on the FAS, unless otherwise specified. 
The analysis will include all available measurements through the last visit, including measurements 
after treatment discontinuation. 
9.3.2.1 
Analysis of Primary Efficacy Variables 
Not applicable as efficacy is not a primary endpoint. 
9.3.2.2 
Analysis of Secondary Efficacy Variables 
9.3.2.2.1 
Definition of Variables 
Sweat chloride (SwCl): the SwCl value for a given visit will be calculated as the mean of the non-
missing sweat chloride measurements obtained on the left and right arms at that visit. If one of the 
two arm measurements at a time point is missing, the other will be used as the mean. A volume ≥15 
µL is required for an accurate determination of sweat chloride. Any results reported as having volume 
<15 µL will be considered missing for analysis purposes. Any sweat chloride values reported as <10 
mmol/L or >160 mmol/L will be considered missing for analysis purposes. 
Lung clearance index (LCI): the LCI assessments are derived from N2-multiple-breath washout 
(MBW) testing. Each MBW will be performed in multiple replicates for each visit and the final LCI 
value will be calculated from the technically acceptable washout replicates as graded and determined 
by a central reader. The following algorithm is used to derive the LCI values at each visit based on the 
multiple replicates: 
• When there is only one acceptable replicate at the visit, the LCI values will not be calculated.  
The assessment for that subject at the corresponding visit will be missing. 
• When there are 2 or more acceptable replicates at the visit, the mean of the values for the 
acceptable replicates will be calculated as the LCI value at the corresponding visit. 


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9.3.2.2.2 
Analysis Method 
Absolute change in sweat chloride from baseline through Week 24: 
Absolute change from baseline in sweat chloride will be analyzed using a mixed-effects model for 
repeated measures (MMRM) approach based on the FAS. The MMRM will be used to estimate the 
within-group mean absolute change in sweat chloride through Week 24. The model will include 
absolute change from baseline in sweat chloride (including all measurements up to and including 
Week 24) as the dependent variable, and visit as the fixed effect, with baseline sweat chloride value 
and genotype group (F/F vs F/MF) as covariates. The model will be estimated using restricted 
maximum likelihood. Denominator degrees of freedom for the F-test of fixed effects will be estimated 
using the Kenward-Roger approximation2. An unstructured covariance structure will be used to model 
the within-subject errors. If the model estimation does not converge, a compound symmetry 
covariance structure will be used instead. Conditional on the observed data and covariates, missing 
data will be assumed to be missing at random; consequently, no imputation of missing data will be 
performed. 
The results obtained from the model will be the average treatment effect through Week 24, estimated 
using all post-baseline visits up to and including Week 24. The estimated mean change from baseline 
in sweat chloride through Week 24, along with the corresponding 2-sided 95% confidence interval 
(CI) and P-value, will be provided.  
 Absolute change in LCI2.5 from baseline through Week 24: 
Analysis of this variable will be based on an MMRM similar to the analysis of the absolute change in 
sweat chloride from baseline through Week 24, with the baseline LCI2.5 included as a covariate 
instead of baseline sweat chloride. The analysis will be based on subjects in the FAS who have 
performed MBW as an assessment at least once. 
To better assess the longitudinal profile of sweat chloride and LCI2.5 with repeated measures up to 
Week 24, the LS mean (SE) of the change from baseline at each post-baseline visit along with the 
95% CI will be estimated from the corresponding MMRM. The LS mean (SE) at each visit will also 
be plotted. In addition, the post-baseline raw values and the absolute change from baseline at each 
post-baseline visit will be summarized descriptively (n, mean, SD, median, minimum, and 
maximum). 


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• Pulse oximetry 
Only descriptive analysis of safety will be performed, and no statistical testing will be performed.  
9.4.1.1 
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 in the 
corresponding Part. 
• TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed 
at or after the first dose of study drug through the end of the TE period in the corresponding 
Part. 
• Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed after the TE period in the corresponding Part. 
For AEs with completely missing or partially missing start dates, if there is no clear evidence that the 
AEs were pretreatment or post-treatment, the AEs will be classified as TEAEs.  
Details for imputing missing or partial start dates of adverse events are defined in Appendix C. 
An overview of all TEAEs will be provided with the following categories: 
• Number of TEAEs (total number of TEAEs only) 
• Subjects with any TEAEs 
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation (discontinuation of any study 
drug) 
• Subjects with TEAEs leading to study drug interruption (interruption of any study drug) 
• Subjects with grade 3/4/5 TEAEs  
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAEs leading to death 
The following summary tables of TEAEs will be presented: 
• All TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Serious TEAEs 


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• TEAEs leading to death 
• Grade 3/4/5 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• Related TEAEs 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentage of subjects, subjects with multiple occurrences of the same AE or a continuing AE will be 
counted once and only the maximum severity level will be presented in the severity summaries, and 
the strongest relationship level will be presented in the relationship summaries.  
Additional summary tables will be provided for TEAEs showing number and percentage of subjects 
• All TEAEs by PT 
All AEs, including pretreatment AEs, TEAEs, and post-treatment AEs, will be presented in an 
individual subject data listing based on the All Subjects Set. In addition, a listing containing 
individual subject adverse event data for TEAEs leading to treatment discontinuation, TEAEs leading 
to treatment interruption, Grade 3/4/5 TEAEs, SAEs and all deaths will be provided separately, with a 
flag indicating the TEAE status for SAEs and deaths.  
9.4.1.2 
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.  
The number and percentage of subjects meeting at least 1 threshold analysis criterion event for 
selected LFT parameters during the TE period will be summarized. The threshold analysis criterion 
shift from baseline will also be summarized for selected LFT laboratory parameters. The threshold 
analysis criteria are provided in Appendix D. 
Results of urinalysis will be listed in individual subject data listings only. In addition, a listing 
containing individual subject hematology, chemistry, and coagulation values will be provided. This 
listing will include data from both scheduled and unscheduled visits.  
9.4.1.3 
Electrocardiogram  
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided at each visit and time point for the following ECG measurements (in 
msec): RR interval, PR interval, QT interval, QTcF interval, QRS duration, and Heart Rate (beats per 
minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion for selected 
parameters during the TE period will be summarized. The threshold analysis criteria are provided in 
Appendix D. 


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In addition, a listing containing individual subject ECG values will be provided. This listing will 
include data from both scheduled and unscheduled visits.   
9.4.1.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from baseline 
values will be summarized at each visit. The following vital signs parameters will be summarized: 
 systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), pulse rate (breaths per minute), and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion for selected 
parameters during the TE period will be summarized. The threshold analysis criteria are provided in 
Appendix D. 
In addition, a listing containing individual subject vital sign values will be provided. This listing will 
include data from both scheduled and unscheduled visits.  
9.4.1.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and change 
from baseline values will be provided at each visit for the percent of oxygen saturation. 
The number and percentage of subjects with shift change from baseline (normal/missing and low 
according to the reference range) to the lowest percent of oxygen saturation during the TE period will 
be summarized. The reference range for normal oxygen saturation is specified as >95%, and <=95% 
for low oxygen saturation.  
9.4.1.6 
Ophthalmologic Examinations 
The ophthalmologic examination results will be presented in individual subject data listings.  
9.4.1.7 
Physical Examination 
PE findings will be presented as an individual subject data listing only.  
9.4.1.8 
Visit Type 
A listing containing the impact of COVID-19 pandemic on subjects’ visits will be provided.   
9.4.2 
Safety Analysis for Part B 
Safety is the primary objective of Part B. All safety analyses will be conducted based on data from the 
TE period using the Safety Set. 
The following safety and tolerability endpoints will be assessed:  


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• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values 
• Standard 12-lead ECGs 
• Vital signs  
• Pulse oximetry 
Only descriptive analysis of safety will be performed, and no statistical testing will be performed. 
9.4.2.1 
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 in Part B. 
• TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed 
at or after the first dose of study drug through the end of the TE period in Part B. 
• Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed after the TE period in Part B. 
For AEs with completely missing or partially missing start dates, if there is no clear evidence that the 
AEs were pretreatment or post-treatment, the AEs will be classified as TEAEs. Details for imputing 
missing or partial start dates of adverse events are defined in Appendix C. 
An overview of all TEAEs will be provided with the following categories: 
• Number of TEAEs (total number of TEAEs only) 
• Subjects with any TEAEs 
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation (discontinuation of any study 
drug) 
• Subjects with TEAEs leading to study drug interruption (interruption of any study drug) 
• Subjects with grade 3/4/5 TEAEs  
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAEs leading to death 
The following summary tables of TEAEs will be presented: 
• All TEAEs 


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• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Serious TEAEs 
• TEAEs leading to death 
• Grade 3/4/5 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• Related TEAEs 
• Related serious TEAEs  
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentage of subjects, subjects with multiple occurrences of the same AE or a continuing AE will be 
counted once and only the maximum severity level will be presented in the severity summaries, and 
the strongest relationship level will be presented in the relationship summaries.  
Additional summary tables will be provided for TEAEs showing number and percentage of subjects 
• All TEAEs by PT 
All AEs, including pretreatment AEs, TEAEs, and post-treatment AEs, will be presented in an 
individual subject data listing based on the All Subjects Set. In addition, a listing containing 
individual subject adverse event data for TEAEs leading to treatment discontinuation, TEAEs leading 
to treatment interruption, Grade 3/4/5 TEAEs, SAEs and all deaths will be provided separately, with a 
flag indicating the TEAE status for SAEs and deaths. 
9.4.2.2 
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.  
The number and percentage of subjects meeting at least 1 threshold analysis criterion event for 
selected parameters during the TE period will be summarized. The threshold analysis criterion shift 
from baseline will also be summarized for selected laboratory parameters. The threshold analysis 
criteria are provided in Appendix D.  
Results of urinalysis will be listed in individual subject data listings only. In addition, a listing 
containing individual subject hematology, chemistry, and coagulation values will be provided. This 
listing will include data from both scheduled and unscheduled visits. 
For selected LFT laboratory tests (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase [ALP], and total bilirubin), a scatter plot of the maximum treatment-emergent 
value versus the baseline value corresponding to ×ULN (upper limit of normal) will be presented. 
Further, a scatter plot of the maximum treatment-emergent value of ALT and AST, separately, versus 


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the maximum treatment-emergent value of total bilirubin corresponding to ×ULN will also be 
presented. 
When summarizing laboratory values at a visit, local laboratory values will be used if no central 
laboratory value is available. When deriving threshold analysis criterion and maximum treatment-
emergent values, both local laboratory values and central laboratory values will be included.  
9.4.2.3 
Electrocardiogram  
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided at each visit for the following ECG measurements (in msec): RR 
interval, PR interval, QT interval, QTcF interval, QRS duration, and Heart Rate (beats per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion for selected 
parameters during the TE period will be summarized. The threshold analysis criteria are provided in 
Appendix D. 
In addition, a listing containing individual subject ECG values will be provided. This listing will 
include data from both scheduled and unscheduled visits. 
9.4.2.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from baseline 
values will be summarized at each visit. The following vital signs parameters will be summarized: 
systolic and diastolic blood pressure (mm Hg), body temperature (°C), pulse rate (breaths per minute), 
and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion for selected 
parameters during the TE period will be summarized. The threshold analysis criteria are provided in 
Appendix D. The number and percentage of subjects meeting each threshold analysis criterion at each 
visit will be summarized for blood pressure (systolic and diastolic). 
In addition, a listing containing individual subject vital sign values will be provided. This listing will 
include data from both scheduled and unscheduled visits. 
9.4.2.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and change 
from baseline values will be provided at each visit for the percent of oxygen saturation. 
The number and percentage of subjects with shift change from baseline (normal/missing and low 
according to the reference range) to the lowest percent of oxygen saturation during the TE period will 
be summarized. The reference range for normal oxygen saturation is specified as >95%, and <=95% 
for low oxygen saturation. 
9.4.2.6 
Ophthalmologic Examinations 
The ophthalmologic examination results will be presented in individual subject data listings. 
9.4.2.7 
Physical Examination 
PE findings will be presented as an individual subject data listing only. 


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9.4.2.8 
Visit Type 
A listing containing subjects’ visits impacted due to COVID-19 will be provided.  
10 
INTERIM AND IDMC ANALYSES 
10.1 
Interim Analysis 
Part A and Part B 
No interim analysis is planned at this moment; otherwise, the SAP will be amended. 
10.2 
IDMC Analysis 
Part A and Part B 
The IDMC’s objectives and operational details will be defined in a separate document (IDMC 
Charter) which will be finalized before the first subject is screened in Part A of the study. The 
IDMC’s planned safety reviews of study data will be outlined in the IDMC Charter and IDMC 
Statistical Analysis Plan. 


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11 
REFERENCES 
1 Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
2 Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97 
 


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12 
LIST OF APPENDICES 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments in Part A 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3, 4, 5 
• Serum Chemistry 
• Hematology 
Day 1 (Baseline)  
Day 8 
Day 15 
Safety Follow-up 
1 
8 
15 
Not applicable 
1 Pre-dose 
[1, 12] 
(12, 29] 
Use nominal visit 
• Vital Signs and Pulse 
Oximetry 
Day 1 (Baseline)  
Day 8 
Day 15 
Safety Follow-up 
1 
8 
15 
Not applicable 
1 
[1, 12] 
(12, 29] 
Use nominal visit 
• Standard 12-lead ECG 
Day 1 (Baseline)  
Day 8 
1 
8 
1 Pre-dose 
[1, 12] 
Day 15 Pre-dose 
and Post-dose 
Not applicable 
Use nominal visit 
Safety Follow-up 
Not applicable 
Use nominal visit 
• Coagulation 
 
Day 1 (Baseline)  
Day 15 
1 
15 
1 Pre-dose 
[1, 29] 


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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. 
 
3 For measurement collected on the date of first dose of study drug, if it cannot be determined whether the measurement is 
before or after the first dose: 
a. 
Scheduled measurement will be treated as pre-dose observation. 
b. Unscheduled measurement will be treated as post-dose observation. 
 
4 For safety Assessment, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a subject 
doesn’t have a nominal Safety Follow-up visit but has an ETT visit with study day >29, then the ETT visit will be mapped 
into Safety Follow-up analysis visit.  
Derived Variables: 
1. Age (in years) at first dose date and nominal visit (for demographics and listing): 
Obtain the age at informed consent/assent (in days) in “yy, mm” format (e.g., 24 years, 6 months) from the Vital 
Signs (VS) page at the Screening Visit, and add 0.5 month to convert to days. 
Obtain the informed consent/assent date. 
Then age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed 
consent/assent date) in days + age at informed consent/assent (in days)]/365.25. 
2. Age (in months) at nominal visit 
 
Obtain the age at informed consent/assent (in months) in “yy, mm” format (e.g., 24 years, 6 months) from Vital 
Signs (VS) page at the Screening Visit. 
Obtain the informed consent/assent date. 
Then age (in months) at nominal visit = integer part of {[(age at informed consent/assent (in months) + 0.5 + diff 
(first dose date or nominal visit date, informed consent/assent date) in months]} + 0.5. 
3. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date to impute. 
If the last dose date is missing or partial date is reported, the last dose date will be imputed based on, in 
descending order priority, the Early Treatment Termination (ETT) visit date, last visit date before the Safety 
Follow-up, or the last study drug administration date from EX SDTM domain, as appropriate.  The imputation 
algorithm will ensure the imputed last dose date does not exceed the study participation end date. 
 




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Table 12-2 
Analysis Visit Windows for Safety and Efficacy Assessments in Part B 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
2, 3, 4,5
• Sweat Chloride 
• Lung Clearance Index 
 
Day 1 (Baseline) 
Week 4 
Week 12 
Week 24 
1 
29 
85 
169 
1 Pre-dose 
(1, 57] 
(57, 127] 
(127 197]
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: 
c. If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
d. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. 
The measurement closest to the target day will be used; or  
ii. 
If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. If the latest measurement cannot be determined, then unscheduled visit will be selected 
 
3 For measurements collected on the date of first dose of study drug, if it cannot be determined whether the 
measurement is before or after the first dose: 
a. Scheduled measurement will be treated as pre-dose observation. 
b. Unscheduled measurement will be treated as post-dose observation. 
 
4 For safety assessment, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a subject 
doesn’t have a nominal Safety Follow-up visit but has an ETT visit with study day >183, then the ETT visit will be 
mapped into Safety Follow-up analysis visit. 
 
5 For efficacy analysis of Part B, if there is Safety Follow-up visit with study day > 197, the nominal Safety Follow-
up visit will be mapped to the Safety Follow-up analysis visit. Else, if there is ETT visit with study day > 197, the 
ETT visit will be mapped to the Safety Follow-up analysis visit. Else, if there are multiple assessments with study 
days >197, 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): 


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Obtain the age at informed consent/assent (in days) in “yy, mm” format (e.g., 24 years, 6 months) from the Vital 
Signs (VS) page at the Screening Visit, and add 0.5 month to convert to days. 
Obtain the informed consent/assent date. 
Then age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed 
consent/assent date) in days + age at informed consent/assent (in days)]/365.25. 
2. Age (in months) at nominal visit 
 
Obtain the age at informed consent/assent (in months) in “yy, mm” format (e.g., 24 years, 6 months) from Vital 
Signs (VS) page at the Screening Visit. 
Obtain the informed consent/assent date. 
Then age (in months) at nominal visit = integer part of {[(age at informed consent/assent (in months) + 0.5 + diff 
(first dose date or nominal visit date, informed consent/assent date) in months]} + 0.5. 
3. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date to impute. 
If the last dose date is missing or partial date is reported, the last dose date will be imputed based on, in 
descending order priority, the Early Treatment Termination (ETT) visit date, last visit date before the Safety 
Follow-up, or the last study drug administration date from EX SDTM domain, as appropriate.  The imputation 
algorithm will ensure the imputed last dose date does not exceed the study participation end date. 
4. Sweat Chloride: 
Non-missing sweat chloride concentrations from the left arm and right arm with assessment end date/time for a 
given arm up to 30 minutes after first dose time in treatment period will be considered for baseline. 
5. Electrocardiogram: 
Baseline will be defined as the most recent non-missing measurement (or the average, for example, if the most 
recent non-missing measurement is obtained in triplicate), before the first dose of study drug in the Treatment 
Period. If multiple ECG measurements are obtained on the same calendar day during the TE period,  
o For summary purpose, the calculated average ECG will be used as the ECG value on that day. 
o For threshold analysis purpose, all reported ECG values will be used. 
 




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


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Appendix D: Criteria for Threshold Analysis 
Table 12-4 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤ 3xULN) or (AST>ULN - 
≤3xULN) 
(ALT>3x - ≤5xULN) or (AST>3x - 
≤5xULN) 
(ALT>5x - ≤8xULN) or (AST>5x - 
≤8xULN) 
(ALT>8x - ≤20xULN) or (AST>8x - 
≤20xULN) 
ALT>20xULN or AST>20xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤1.5xULN 
>1.5x - ≤2.5xULN 
>2.5x - ≤5xULN 
>5x - ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤3xULN  
>3x - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤3xULN  
>3x - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Indirect Bilirubin 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤3xULN  
>3x - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 


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Table 12-4 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and Total Bilirubin (ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 
GGT 
>ULN - ≤2.5xULN 
>2.5x - ≤5xULN 
>5x - ≤20xULN  
>20xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN  
 
CTCAE grade 1-3 
Amylase 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤1.5xULN 
>1.5x - ≤3xULN 
>3x - ≤6xULN 
>6xULN 
CTCAE grades 1-4 
Lipase 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine kinase 
>ULN - ≤2.5xULN 
>2.5x - ≤5xULN 
>5x - ≤10xULN  
>10xULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥100 g/L 
<100 - ≥80 g/L  
<80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤20 g/L above ULN 
>20 g/L above ULN - ≤40 g/L above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 


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Table 12-4 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Platelets 
Platelet decreased 
<LLN - ≥75 x 10e9 /L 
<75 - ≥50 x 10e9 /L  
<50 - ≥25 x 10e9 /L  
<25 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 
Reticulocytes/Erythrocytes (%)    <LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated partial thromboplastin 
time  (PTT)  
 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5xULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5 x ULN 
CTCAE grade 1-3 
 
Table 12-5 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
<55 bpm  
 
Tachycardia 
>134 bpm 
 
PR 
>180 ms and increase from baseline ≥20 ms 
 
QRS 
>89 ms 
 
QTc 
Absolute values (ms) 
>449 ms 
≥500 ms 
 
Increase from baseline 
Increase from baseline >60 ms 
To be applied to any kind of QT 
correction formula.  
 
Table 12-6 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
SBP 
≥95 percentile 
See Appendix E for details 
DBP 
≥95 percentile 
See Appendix E for details 
Weight 
Weight gain 
≥5% increase from baseline 
 


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Table 12-6 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Weight loss 
≥5% decrease from baseline 
 
 


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Appendix E: Criteria for Threshold Analysis on SBP and DBP 
The percentiles for SBP and DBP threshold criteria in Table 12-6 are adjusted for gender, age 
and height. The values are provided in the table on the National Heart, Lung, and Blood 
Institute (NHLBI) website (https://www.nhlbi.nih.gov/files/docs/guidelines/child_tbl.pdf ) 
[Accessed Oct 28, 2020].  
For the implementation of the table, the grouped height-for-age percentiles are determined 
based on the calculated height-for-age percentiles, using the rules in Table 12-7.  
Table 12-7 
Grouped Percentiles for height-for-age percentiles 
Calculated Percentiles (%) 
Grouped Percentiles (%) 
0 – <7.5 
5 
7.5 – <17.5 
10 
17.5 – <37.5 
25 
37.5 – <62.5 
50 
62.5 – <82.5 
75 
82.5 – <92.5 
90 
92.5 – 100 
95