Clinical trial NCT04545515
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2021-01-11; Completion date: 2023-03-24
Enrollment: 120 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study evaluates the long-term safety and efficacy of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) triple combination (TC) in participants with CF who are 6 years of age and older with F/MF genotypes.

Detailed description:

Arms: arm 1: Participants 6 to less than \<12 year of age and weighing \<30 kilogram (kg) at Day 1 received ELX 100 milligram (mg)/TEZ 50 mg /IVA 75 mg as fixed dose combination (FDC) tablets in the morning and IVA as mono tablet in the evening and those weighing more than or equal to (≥) 30 kg at Day 1 received ELX 200 mg/TEZ 100 mg /IVA 150 mg as FDC tablets in the morning and IVA as mono tablet in the evening for 96 weeks. Doses were adjusted upward with subsequent changes in weight. Participants ≥12 years age at Day 1 received ELX 200 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA as mono tablet in the evening for 96 weeks.
Interventions: intervention 1: ELX/TEZ/IVA intervention 2: IVA
Intervention descriptions: intervention 1: Fixed dose combination (FDC) tablets for oral administration. intervention 2: Tablet for oral administration.

Protocol documents:
Prot_000.pdf: 


Protocol VX20-445-119, Version 1.0 
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PROTOCOL SYNOPSIS 
Title A Phase 3b Open‑label Study Evaluating the Long-term Safety and 
Efficacy of Elexacaftor/Tezacaftor/Ivacaftor Combination Therapy in 
Cystic Fibrosis Subjects Ages 6 Years and Older Who Are Heterozygous 
for the F508del Mutation and a Minimal Function Mutation (F/MF) 
  
Brief Title 
A Study Evaluating the Long-term Safety and Efficacy of 
Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis (CF) Subjects 6 Years and 
Older and F/MF genotypes 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 3b, safety, efficacy 
 
 
Objectives 
Primary Objective 
To evaluate the long-term safety and tolerability of elexacaftor (ELX)/tezacaftor 
(TEZ)/ivacaftor (IVA) in subjects with CF 
Secondary Objectives 
• 
To evaluate the efficacy of ELX/TEZ/IVA 
• 
To evaluate the pharmacodynamics (PD) of ELX/TEZ/IVA 
 
 
Endpoints 
Primary Endpoint 
Safety and tolerability of ELX/TEZ/IVA based on adverse events (AEs), clinical 
laboratory values, ECGs, vital signs, and pulse oximetry 
Secondary Endpoints 
• 
Absolute change in sweat chloride (SwCl) from baseline 
• 
Absolute change in lung clearance index2.5 (LCI2.5) from baseline 
Other Endpoints 
• 
Absolute change in percent predicted forced expiratory volume in 1 second 
(ppFEV1) from baseline 
• 
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
respiratory domain score from baseline 
 
 
Number of Subjects 
Subjects who participated in the parent study (VX19-445-116) and meet the 
eligibility criteria may enroll. Approximately 108 subjects are expected to enroll 
in this extension study. 
 
 
Study Population 
Male and female CF subjects who are 6 years of age or older who have F/MF 
genotypes. 
 
 
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:  
• 
50‑mg ELX/25‑mg TEZ/37.5‑mg IVA fixed‑dose combination (FDC) tablets 
for oral administration 




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Assessments 
Safety: AEs, clinical laboratory assessments, ECGs, vital signs, height, weight, 
pulse oximetry, physical examinations (PEs), and ophthalmologic examinations 
Efficacy: Multiple-breath washout (MBW), spirometry, and CFQ-R 
Pharmacodynamics (PD): SwCl 
Other: blood samples for blood biomarker analysis 
 
 
Statistical Analyses 
The primary objective of the study is the evaluation of the long-term safety and 
tolerability of ELX/TEZ/IVA in subjects with CF. The safety endpoints of long-
term treatment include AEs, clinical laboratory values, ECGs, vital signs, and 
pulse oximetry from the first dose of study drug in the open label study, for 
subjects who have received at least 1 dose of study drug in the open label study. 
The safety analysis will be descriptive only, and in general will be performed for 
the pooled population. 
 
The secondary objective of the study is the evaluation of long-term efficacy of 
ELX/TEZ/IVA, as assessed by SwCl, LCI2.5, spirometry, and CFQ-R. Methods of 
efficacy analyses will be similar as those used in parent studies 
 
 
Interim Analyses 
Interim analyses may take place at any time at the discretion of the sponsor. 
 
 
DMC Reviews 
 
A data monitoring committee (DMC) will conduct periodic safety review(s) of 
study data as outlined in the DMC charter. 
 


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SCHEDULE OF ASSESSMENTS 
The schedule of assessments is in Table 3-1. All visits will be scheduled relative to the Day 1 
Visit in this study.   
Assessments may be performed in any order when more than 1 assessment is required at a 
particular time point, unless noted otherwise. All assessments should be performed before study 
drug dosing (Section 9.6), unless noted otherwise. 








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TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Protocol Synopsis ................................................................................................................... 2 
3 
Schedule of Assessments ........................................................................................................ 5 
4 
Table of Contents ................................................................................................................... 9 
List of Tables ........................................................................................................................... 12 
List of Figures .......................................................................................................................... 12 
List of Abbreviations ............................................................................................................... 13 
5 
Introduction .......................................................................................................................... 16 
5.1 
Background ..................................................................................................................... 16 
5.2 
Study Rationale .............................................................................................................. 16 
6 
Study Objectives .................................................................................................................. 16 
6.1 
Primary Objective ........................................................................................................... 16 
6.2 
Secondary Objectives ..................................................................................................... 16 
7 
Study Endpoints ................................................................................................................... 17 
7.1 
Primary Endpoint ............................................................................................................ 17 
7.2 
Secondary Endpoints ...................................................................................................... 17 
7.3 
Other Endpoints .............................................................................................................. 17 
8 
Study Population .................................................................................................................. 17 
8.1 
Inclusion Criteria ............................................................................................................ 17 
8.2 
Exclusion Criteria ........................................................................................................... 17 
9 
Study Implementation ......................................................................................................... 18 
9.1 
Study Design .................................................................................................................. 18 
9.1.1 
Treatment Period .................................................................................................... 19 
9.1.2 
Follow-up ................................................................................................................ 19 
9.1.3 
Early Termination of Treatment ............................................................................. 19 
9.1.4 
Lost to Follow-up ................................................................................................... 20 
9.1.5 
Completion of Study Participation ......................................................................... 20 
9.1.6 
Use of Remote Measures in Extenuating Circumstances ....................................... 20 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 21 
9.3 
Rationale for Study Elements ......................................................................................... 21 
9.3.1 
Study Design ........................................................................................................... 21 
9.3.2 
Study Drug Dose and Duration .............................................................................. 21 
9.3.3 
Rationale for Study Assessments ........................................................................... 21 
9.4 
Study Restrictions ........................................................................................................... 21 
9.5 
Prior and Concomitant Medications ............................................................................... 22 
9.6 
Administration ................................................................................................................ 23 
9.6.1 
Dosing ..................................................................................................................... 23 
9.6.2 
Missed Doses .......................................................................................................... 24 
9.7 
Dose Modification for Toxicity ...................................................................................... 24 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 24 
9.8.1 
Liver Function Tests ............................................................................................... 24 
9.8.2 
Rash ........................................................................................................................ 25 
9.9 
Removal of Subjects ....................................................................................................... 25 
9.10 Replacement of Subjects ................................................................................................ 26 


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10 Study Drug Information and Management ....................................................................... 26 
10.1 Preparation and Dispensing ............................................................................................ 26 
10.2 Packaging and Labeling ................................................................................................. 26 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 26 
10.4 Drug Accountability ....................................................................................................... 27 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 27 
10.6 Compliance ..................................................................................................................... 27 
10.7 Blinding and Unblinding ................................................................................................ 27 
11 Assessments .......................................................................................................................... 28 
11.1 Subject and Disease Characteristics ............................................................................... 28 
11.2 Efficacy and Pharmacodynamics ................................................................................... 28 
11.2.1 
Sweat Chloride ....................................................................................................... 28 
11.2.2 
Multiple-breath Washout ........................................................................................ 28 
11.2.3 
Spirometry .............................................................................................................. 28 
11.2.4 
Cystic Fibrosis Questionnaire-Revised .................................................................. 29 
11.3 Other Assessments .......................................................................................................... 30 
11.3.1 
Blood Biomarkers ................................................................................................... 30 
11.4 Safety .............................................................................................................................. 30 
11.4.1 
Adverse Events ....................................................................................................... 30 
11.4.2 
Clinical Laboratory Assessments ........................................................................... 30 
11.4.3 
Physical Examinations and Vital Signs .................................................................. 32 
11.4.4 
Height and Weight .................................................................................................. 32 
11.4.5 
Electrocardiograms ................................................................................................. 32 
11.4.6 
Ophthalmologic Examination ................................................................................. 32 
11.4.7 
Contraception and Pregnancy ................................................................................. 33 
11.4.7.1 Contraception ................................................................................................... 33 
11.4.7.2 Pregnancy ......................................................................................................... 34 
12 Statistical Analysis ............................................................................................................... 35 
12.1 Sample Size .................................................................................................................... 35 
12.2 Analysis Sets .................................................................................................................. 35 
12.3 Statistical Analysis ......................................................................................................... 35 
12.3.1 
General Considerations ........................................................................................... 35 
12.3.2 
Background Characteristics .................................................................................... 36 
12.3.2.1 Subject Disposition .......................................................................................... 36 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 36 
12.3.2.3 Prior and Concomitant Medications ................................................................ 37 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 37 
12.3.2.5 Important Protocol Deviations ......................................................................... 37 
12.3.3 
Efficacy Analysis .................................................................................................... 37 
12.3.3.1 Analysis of Primary Efficacy and Pharmacodynamic Endpoints .................... 38 
12.3.3.2 Analysis of Secondary Efficacy and Pharmacodynamic Endpoints ................ 38 
12.3.3.3 Analysis of Other Efficacy and Pharmacodynamic Endpoints ........................ 38 
12.3.3.4 Multiplicity Adjustment ................................................................................... 38 
12.3.4 
Safety Analysis ....................................................................................................... 38 
12.3.4.1 Adverse Events ................................................................................................ 39 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 40 


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12.3.4.3 Electrocardiogram ............................................................................................ 40 
12.3.4.4 Vital Signs ........................................................................................................ 40 
12.3.4.5 Pulse Oximetry ................................................................................................. 40 
12.3.4.6 Physical Examination ....................................................................................... 40 
12.3.4.7 Other Safety Analyses ...................................................................................... 40 
12.4 Interim Analysis ............................................................................................................. 41 
12.5 Data Monitoring Committee Analysis ............................................................................ 41 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 41 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 41 
13.1.1 
Adverse Events ....................................................................................................... 41 
13.1.1.1 Definition of an Adverse Event........................................................................ 41 
13.1.1.2 Clinically Significant Assessments .................................................................. 41 
13.1.1.3 Documentation of Adverse Events................................................................... 41 
13.1.1.4 Adverse Event Severity .................................................................................... 42 
13.1.1.5 Adverse Event Causality .................................................................................. 43 
13.1.1.6 Study Drug Action Taken ................................................................................ 43 
13.1.1.7 Adverse Event Outcome .................................................................................. 44 
13.1.1.8 Treatment Given............................................................................................... 44 
13.1.2 
Serious Adverse Events .......................................................................................... 44 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 44 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 45 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 45 
13.2 Administrative Requirements ......................................................................................... 46 
13.2.1 
Product Complaints ................................................................................................ 46 
13.2.2 
Ethical Considerations ............................................................................................ 46 
13.2.3 
Subject Information and Informed Consent ........................................................... 46 
13.2.4 
Investigator Compliance ......................................................................................... 46 
13.2.5 
Access to Records ................................................................................................... 46 
13.2.6 
Subject Privacy ....................................................................................................... 47 
13.2.7 
Record Retention .................................................................................................... 47 
13.2.8 
Study Termination .................................................................................................. 47 
13.2.9 
End of Study ........................................................................................................... 48 
13.3 Data Quality Assurance .................................................................................................. 48 
13.4 Monitoring ...................................................................................................................... 48 
13.5 Electronic Data Capture ................................................................................................. 48 
13.6 Confidentiality and Disclosure ....................................................................................... 49 
13.7 Publications and Clinical Study Report .......................................................................... 49 
13.7.1 
Publication of Study Results................................................................................... 49 
13.7.2 
Clinical Study Report ............................................................................................. 50 
14 References ............................................................................................................................. 51 
15 Protocol Signature Pages .................................................................................................... 53 
15.1 Sponsor Signature Page .................................................................................................. 53 
15.2 Investigator Signature Page ............................................................................................ 54 
 


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List of Tables 
Table 2-1 
Treatment Period Dosages ...................................................................................... 3 
Table 3-1 
Study VX20-445-119: Treatment Period and Safety Follow-up Visit ................... 6 
Table 9-1 
Treatment Period Dosages .................................................................................... 18 
Table 9-2 
Prohibited Medications ......................................................................................... 22 
Table 9-3 
Study Drug Administration ................................................................................... 23 
Table 10-1 
Study Drug: Dosing Form/Route/Strength ........................................................... 27 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 31 
Table 11-2 
Acceptable Methods of Contraception .................................................................. 34 
Table 13-1 
Grading of AE Severity ........................................................................................ 42 
Table 13-2 
Classifications for AE Causality ........................................................................... 43 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 43 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 44 
List of Figures 
Figure 2-1 
VX20-445-119 Study Design ................................................................................. 3 
Figure 9-1 
VX20-445-119 Study Design ............................................................................... 18 
 


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List of Abbreviations  
Abbreviation 
Definition 
ADL 
activities of daily living 
AEs 
adverse events 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
β 
beta, apparent elimination rate constant 
BMI 
body mass index 
CD 
compact disc 
CF 
Cystic Fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator gene 
CI 
confidence interval 
COVID-19 
coronavirus disease 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
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 
F/MF 
F508del Mutation and a Minimal Function Mutation 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine 
codon corresponding to position 508 of the wild-type protein 
FDA 
Food and Drug Administration 
FDC 
fixed‑dose combination 
FEF25%-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GLI 
Global Lung Function Initiative 
GPP3 
Good Publishing Practices 


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Abbreviation 
Definition 
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 
IPD 
important protocol deviation 
IRB 
institutional review board 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LCI 
lung clearance index 
LCI2.5 
number of lung turnovers required to reduce the end tidal inert gas 
concentration to 1/40th of its starting value 
LS 
least squares 
LUM 
lumacaftor 
max 
maximum value 
MBW 
Multiple-breath washout 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
N 
total sample size 
OATP1B1 
organic anion transporting polypeptide 1B1 
OATP1B3 
organic anion transporting polypeptide 1B3 
OL-FAS 
Open-label Full Analysis Set 
OL-SS 
Open-label Safety Set 
PC 
publication committee 
PD 
pharmacodynamics 
PEs 
physical examinations 
P-gp 
P-glycoprotein 
PIs 
principal investigators 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval, segment 
PT 
Preferred Term 
q12h 
every 12 hours 


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Abbreviation 
Definition 
qd 
once daily 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together 
representing ventricular depolarization 
QT 
QT interval 
QTcF 
QT interval corrected by Fridericia’s formula 
RNA 
ribonucleic acid 
RR 
interval from the onset of 1 QRS complex to the next; use R-R if using 
with “intervals”, i.e., “R-R interval” 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
steering committee 
SD 
standard deviation 
SET 
Study Execution Team 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SUSARs 
serious adverse reactions 
SwCl 
sweat chloride 
TE 
Treatment-emergent 
TEAEs 
treatment-emergent adverse events 
TEZ 
tezacaftor 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
VAS 
visual analog scale 
 


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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 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 
This study will provide data on the long-term safety and efficacy of ELX/TEZ/IVA in subjects 
with CF who are 6 years of age and older. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the long-term safety and tolerability of ELX/TEZ/IVA in subjects with CF 
6.2 
Secondary Objectives 
• To evaluate the efficacy of ELX/TEZ/IVA 
• To evaluate the pharmacodynamics (PD) of ELX/TEZ/IVA 


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7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Safety and tolerability of ELX/TEZ/IVA based on adverse events (AEs), clinical laboratory 
values, ECGs, vital signs, and pulse oximetry 
7.2 
Secondary Endpoints 
• Absolute change in sweat chloride (SwCl) from baseline 
• Absolute change in lung clearance index2.5 (LCI2.5) from baseline 
7.3 
Other Endpoints 
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline 
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score 
from baseline 
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. 
In the criteria below, “parent study” is defined as VX19-445-116. 
8.1 
Inclusion Criteria 
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
informed consent form (ICF) and, when appropriate, an assent form. 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Did not withdraw consent from the parent study. 
4. Meets at least 1 of the following criteria: 
• Completed study drug treatment in the parent study. 
• Had study drug interruption(s) in the parent study, but did not permanently 
discontinue study drug, and completed study visits up to the last scheduled visit of the 
Treatment Period of the parent study. 
5. Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) through 
completion of study participation. 
8.2 
Exclusion Criteria 
1. History of any comorbidity 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. 
2. History of drug intolerance in the parent study that would pose an additional risk to the 
subject in the opinion of the investigator (e.g., subjects with a history of allergy or 
hypersensitivity to the study drug). 




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If a subject enters the current study weighing <30 kg and subsequently weighs ≥30 kg at 
2 consecutive clinic visits (excluding unscheduled visits), the dose will be adjusted to the higher 
dose of ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for the remainder of the study, 
starting with the second visit where subject’s weight is ≥30 kg. 
 
Subjects ≥12 years of age will receive a dose of ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg 
q12h, starting from the first study visit at which the subject is ≥12 years old. 
9.1.1 
Treatment Period 
Treatment Period assessments are listed in Table 3-1. 
Subjects will receive the first dose of study drug on Day 1 after obtaining informed consent (and 
assent, when applicable) and confirming eligibility. Subjects who enroll in this study on a study 
drug interruption will NOT receive the first dose of study drug until they meet the resumption 
criteria in Section 9.8; before receiving study drug, subjects will repeat all Day 1 assessments. 
Study drug administration details are provided in Section 9.6. 
Subjects whose Day 1 Visit is NOT within 1 day of the last scheduled visit of the parent study 
will repeat all Day 1 assessments. 
Subjects whose Day 1 Visit is within 1 day of the last scheduled visit of the parent study will 
NOT have to repeat any Day 1 assessments that were specified to be performed at the last 
scheduled visit in the parent study.  
9.1.2 
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 assessments are listed in Table 3-1.  
The Safety Follow-up Visit is required for all subjects. However, subjects who transition within 
28 days of the last dose of study drug to either: 
• a commercially available Vertex CFTR modulator regimen 
• managed access program-supplied Vertex CFTR modulator regimen  
• or, to another qualified Vertex study  
will complete the Week 96 Visit (or the Early Termination of Treatment [ETT] Visit, if the 
transition occurs before the Week 96 Visit). In these cases, the Week 96 Visit (or the ETT Visit) 
will replace the Safety Follow-up Visit. 
For subjects who complete an ETT Visit 3 weeks or later following the last dose of study drug, 
the ETT Visit will replace the Safety Follow-up Visit (Section 9.1.3). 
9.1.3 
Early Termination of Treatment 
If a subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as 
soon as possible after the decision to discontinue treatment. 
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. 


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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. 
9.1.4 
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. 
9.1.5 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as: the Safety Follow-up 
Visit; or, in situations in which the ETT Visit or the Week 96 Visit replaces the Safety Follow-up 
Visit (Section 9.1.2), the ETT Visit or the Week 96 Visit. 
If subjects withdraw consent or assent, completion of study participation is defined as date of 
withdrawal of consent or assent, whichever is earlier (Section 9.9). 
If subjects are lost to follow-up (Section 9.1.4), the date of completion of study participation will 
be defined as the date of last contact.  
The end of study is defined in Section 13.2.9. 
9.1.6 
Use of Remote Measures in Extenuating Circumstances 
Study visits should be performed in the clinic as specified in Table 3-1, 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 study visits 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 Day 1 Visit must 
be performed in the clinic. 
Whenever local regulations or site practice do not allow remote measures, visits will be 
conducted at the site. 
The following remote measures may be implemented. Additional details can be found in the 
Study Reference Manual. 
• 
Consent or 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 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 multiple-breath washout (MBW) assessments. 


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• 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 Phase 3b study will enroll subjects who completed the last Treatment Period visit in the 
parent study of ELX/TEZ/IVA and meet eligibility criteria. Results from this study will provide 
information on the long-term safety and efficacy of ELX/TEZ/IVA in subjects with CF who are 
6 years of age and older. 
9.3.2 
Study Drug Dose and Duration 
To evaluate safety, tolerability, and efficacy, the study drug doses evaluated are the same as the 
doses evaluated in the parent study. Subjects will receive a study drug dose appropriate for their 
age and weight (as applicable), as described in Section 9.1. 
The overall treatment duration will be 96 weeks, which is considered sufficient for evaluating the 
long-term safety and efficacy of ELX/TEZ/IVA treatment in individual subjects at the current 
stage of clinical development. 
9.3.3 
Rationale for Study Assessments 
Most of the safety, efficacy, and PD assessments are standard parameters for clinical studies in 
drug development and are generally recognized as reliable, accurate, and relevant to the study of 
subjects with CF. Ophthalmologic examinations are recommended for monitoring of pediatric 
patients treated with IVA-containing drug regimens, and have been added to the standard safety 
assessments. 
LCI is a measure of ventilation inhomogeneity assessed by MBW that is based on tidal breathing 
techniques that have been evaluated in patients as young as infants.8, 9 Studies have shown that 
LCI correlates with FEV1 in its ability to measure airway disease and can detect lung disease at 
an earlier stage than spirometry.10, 11 
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. Guidance for concomitant 
medications is provided in Section 9.5. 


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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 of CYP3A and 
moderate and strong 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 in the 
parent study and this 
study 
None allowed 
within 28 days or 
5 terminal half-
lives (whichever is 
longer) 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 in each subject’s source 
documentation for medications taken within the 56 days before the first dose of study drug in this 
study through completion of study participation, as defined in Section 9.1.5. 
• Subjects should remain on a stable treatment regimen for their CF 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 Day 1. 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. 
o Subjects who alternate between 2 different inhaled antibiotics should remain on the 
same cycling schedule during the study. 
• 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. 


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• 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 spirometry assessments performed 
according to the guidelines provided in Section 11.2.3. 
9.6 
Administration 
9.6.1 
Dosing 
Study drug will be administered orally as shown in Table 9-3. Additional information is provided 
in the Pharmacy Manual. 
Table 9-3 
Study Drug Administration 
Subject Age   
      Weight  
Tablet Strength 
Time 
Number of Tablets Taken 
≥6 to <12 years 
 
<30 kg 
50-mg ELX/25-mg TEZ/37.5-mg IVA 
AM 
2 tablets 
75-mg IVA 
PM 
1 tablet 
≥6 to <12 years 
 
≥30 kg 
100-mg ELX/50-mg TEZ/75-mg IVA 
AM 
2 tablets 
150-mg IVA 
PM 
1 tablet 
≥12 years 
 
All weights 
100-mg ELX/50-mg TEZ/75-mg IVA 
AM 
2 tablets 
150-mg IVA 
PM 
1 tablet 
ELX: elexacaftor; IVA: ivacaftor; TEZ: tezacaftor 
 
Study drug should be administered with a fat-containing meal or snack, such as a standard “CF” 
meal or snack or a standard meal according to the following guidelines: 
1. It is recommended that the dose be taken within 30 minutes of the start of the meal or 
snack. 
2. Study drug will be administered as 2 ELX/TEZ/IVA FDC tablets in the morning (see 
Table 9-3 for details) and as 1 IVA tablet in the evening. All doses of study drug 
(morning and evening, as applicable) should be administered at approximately every 
12 hours (± 2 hours) on each dosing occasion (e.g., if the morning doses of study drug are 
administered at 08:00 hour on Day 1, all subsequent morning doses should be 
administered between 06:00 hour and 10:00 hour). 


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3. On days of scheduled visits, the morning dose of ELX/TEZ/IVA will be administered at 
the site after predose assessments have been completed. The meal or snack will be 
provided by the site for the morning dose of ELX/TEZ/IVA. 
4. Subjects will be instructed to bring all used and unused materials associated with the 
study drug to the site; study drug will be dispensed at each visit, as appropriate. 
9.6.2 
Missed Doses 
If 6 hours or less have passed since the missed morning or evening dose, the subject should take 
the missed dose as soon as possible and continue on the original schedule.  
Morning dose: If more than 6 hours have passed since the missed morning dose, the subject 
should take the missed dose as soon as possible and should not take the evening dose. 
Evening dose: If more than 6 hours have passed since the missed evening dose, the subject 
should not take the missed dose. The next scheduled morning dose should be taken at the usual 
time. 
Morning and evening doses should not be taken at the same time. 
9.7 
Dose Modification for Toxicity 
No dose modifications for toxicity are allowed. If any unacceptable toxicity arises, individual 
subjects will discontinue dosing. 
9.8 
Study Drug Interruption and Stopping Rules 
In subjects who have interrupted study drug for >72 hours for any reason, the investigator should 
resume study drug only after a thorough investigation of the cause for interruption. The 
investigator will evaluate the subject’s clinical stability and should consider resumption of study 
drug only after the subject is clinically stable and there is no comorbidity or condition that, in the 
opinion of the investigator, might confound the results of the study or pose an additional risk in 
administering study drug to the subject. 
The medical monitor should be notified of an interruption of study drug that lasts >72 hours for 
any reason and of the resumption of study drug after such interruption. In 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 alanine transaminase (ALT) or 
aspartate transaminase (AST) >3 × upper limit of normal (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). 


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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. 
Subjects who enroll in this study on a drug interruption because of transaminase elevations in a 
parent study may NOT receive the first dose of study drug until transaminases return to baseline 
values or ≤2 × ULN, whichever is higher. 
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 
transaminase levels return to baseline or are ≤2 × ULN, whichever is higher. Regardless of the 
duration of interruption, the medical monitor should be notified before resumption of study drug. 
Upon resumption of study drug, transaminases and bilirubin should be assessed weekly for 
4 weeks. If a protocol-defined transaminase elevation interruption threshold recurs within 
4 weeks of rechallenge with the study drug (with confirmation of the initial elevation by repeat 
testing within 48 to 72 hours), then the study drug must be permanently discontinued, regardless 
of the presumed etiology. 
9.8.2 
Rash 
Individuals who develop a generalized rash will be monitored closely. Study drug dosing should 
be interrupted if a subject develops a generalized rash of Grade 3 or higher (Section 13.1.1.4), or 
a rash that is considered a serious adverse event (SAE). The investigator will notify the medical 
monitor of any rash that results in interruption of study drug, is Grade 3 or higher, or is an SAE. 
Investigators should consider additional evaluation including laboratory testing (e.g., complete 
blood count with differential, liver function tests), photographs of the rash, and dermatology 
consultation. The investigator may consider resumption of study drug if considered clinically 
appropriate. 
9.9 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request or the request of the 
subject’s parent or legal guardian. Subjects may be withdrawn at any time at the discretion of the 
investigator or Vertex for safety, behavior, noncompliance (study drug dosing or study 


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procedures), or administrative reasons. A subject who withdraws from study drug treatment will 
continue to be followed unless the subject withdraws consent. 
In addition, a subject must be discontinued from study drug treatment if the subject meets any of 
the following criteria: 
• Meets any of the stopping (discontinuation) criteria (Section 9.8) 
• Becomes pregnant (Section 11.4.7.2) 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a Safety Follow-up Visit, if 
applicable (see Section 9.1.3), and follow up with the subject regarding any unresolved AEs. 
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends, and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study, the study data and samples collected will remain part of the study. A subject will 
not be able to request the withdrawal of his/her information from the study data. A subject may 
request destruction of the samples collected from him/her during the study as long as those 
samples can be identified as his/her samples. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study drug Treatment Period will not be 
replaced. 
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 and age. 
10.2 
Packaging and Labeling 
Study drug tablets will be supplied in blister cards by Vertex. Study drug labeling will be in 
compliance with applicable local and national regulations. Additional details regarding 
packaging, labeling, and dispensing for study drug will be in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
Table 10-1 provides the study drug information. The investigator, or an authorized designee 
(e.g., a licensed pharmacist), will ensure that all investigational product is stored in a secured 
area, under recommended storage conditions, and in accordance with applicable regulatory 
requirements. To ensure adequate records, all study drugs will be accounted for via the drug 
accountability forms as instructed by Vertex. 
Detailed instructions regarding the storage, handling, and dispensation of the study drug will be 
provided in the Pharmacy Manual. 


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Table 10-1 
Study Drug: Dosing Form/Route/Strength 
Drug Name, Dosing Form, Route 
Tablet Strength 
Subjects 6 to <12 years and 
<30 kg 
Subjects 6 to <12 years and  
≥30 kg or ≥12 years  
ELX/TEZ/IVA, FDC tablet, oral 
 
 
ELX 
50 mg 
100 mg 
TEZ 
25 mg 
50 mg 
IVA 
37.5 mg 
75 mg 
IVA, tablet, oral 
75 mg 
150 mg 
ELX: elexacaftor; FDC: fixed-dose combination; IVA: ivacaftor; TEZ: tezacaftor 
Note: See Table 9-3 for details on study drug administration. 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information 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 or she is unable to resolve with the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
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 subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should consider discontinuing the subject from the study.   
10.7 
Blinding and Unblinding 
This is an open-label study; however, subjects and their legally appointed and authorized 
representative (e.g., parent or legal guardian) should not be informed of their study-related SwCl, 


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LCI, and spirometry results until the study has been completed, regardless if the subject 
permanently discontinues treatment. In addition, the Vertex study team will not have access to 
the SwCl, LCI, or spirometry of the present study until the data lock of the parent study. 
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1. 
The following assessments must be performed in the order specified below when more than 
1 assessment is required at a particular time point: 
1. The CFQ-R should be completed before the start of any other assessments (except signing of 
ICF or assent) scheduled at that visit. 
2. The MBW assessment should be performed before spirometry. 
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. Select demographic and medical history will be derived from the parent study. 
11.2 
Efficacy and Pharmacodynamics 
11.2.1 
Sweat Chloride 
The sweat chloride test is a standard diagnostic tool for CF, serving as a biomarker of CFTR 
activity. Sweat samples will be sent to a central laboratory for testing and interpretation of 
results. Individual sweat chloride test results will not be disclosed to the study sites. Specific 
instructions for collection, handling, processing, and shipping of sweat chloride samples to the 
central laboratory will be provided separately. The sweat chloride test must be conducted 
predose relative to the morning dose of study drug during the Treatment Period. At each time 
point, 2 samples will be collected, 1 sample from each arm (left and right). 
See Section 10.7 for information about access to SwCl results. 
11.2.2 
Multiple-breath Washout 
The N2-MBW testing will be performed in multiple replicates for each visit and the final LCI 
value will be calculated from the technically acceptable washout replicates by a central reader. 
The final LCI value at each visit will be the value provided by the LCI vendor based on the 
replicates. 
At all visits, all MBW tests should be performed pre-bronchodilator as described in 
Section 11.2.3. The MBW should be performed before the spirometry assessment (Section 11). 
See Section 10.7 for information about access to LCI results. 
11.2.3 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines12 and according to the additional guidelines that follow. 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
• withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 


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• withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the 
spirometry assessment; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 
At all visits, all spirometry assessments should be performed pre-bronchodilator. During the 
Treatment Period, spirometry assessments must be performed before study drug dosing 
(Section 9.6.1) at approximately the same time at each visit. In the event that a subject forgets to 
withhold bronchodilator(s), spirometry should be performed according to the following: 
• If a subject’s Day 1 spirometry assessment is pre-bronchodilator, but, on a subsequent visit, 
the subject forgets to withhold bronchodilator use, a post-bronchodilator spirometry 
assessment will be obtained for that visit only, and the visit will not be rescheduled. 
• If, on Day 1, the subject forgets to withhold his/her dose of bronchodilator, spirometry 
should be performed post-bronchodilator, and all subsequent spirometric measurements 
(according to the schedule of assessments) should be performed post-bronchodilator. 
• Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator. 
All sites will be provided with spirometers to be used for all study assessments. Spirometry data 
will be transmitted to a centralized spirometry service for quality review. 
See Section 10.7 for information about access to spirometry results. 
The measured spirometric values listed below will be converted to percent predicted values using 
the standard equations of the Global Lung Function Initiative (GLI).13  
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 
• Forced expiratory flow, midexpiratory phase (FEF25%-75%) (L/s) 
11.2.4 
Cystic Fibrosis Questionnaire-Revised 
The questionnaires provide information about demographics; general quality of life, school, 
work, or daily activities; and symptom difficulties (pertaining to CF). 
Subjects/caregivers will be asked to complete the CFQ-R in their native language, if validated 
translations are available.14, 15 If there is no validated translation available in the subject’s native 
language, the subject will not complete the questionnaire. Copies of the CFQ-R used will be 
provided in the Study Reference Manual. Validated translations of the CFQ-R, if available, will 
be provided for participating centers in non-English-speaking countries.16, 17 
The CFQ-R will be completed before any other assessments are performed at that visit.  


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11.3 
Other Assessments 
11.3.1 
Blood Biomarkers 
Blood samples for blood biomarker analysis will be collected and banked for potential 
exploratory evaluation of correlations between blood biomarkers (e.g., proteins, peptides, lipids, 
vitamins, endogenous metabolites, and RNA) with PD, treatment benefit, and AEs.  
Specific instructions for the collection, processing, storage, and shipment of blood biomarker 
samples will be provided in the Laboratory Manual. 
11.4 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of 
ECGs, vital signs, height, weight, pulse oximetry, physical examinations (PEs), and 
ophthalmologic examinations. 
11.4.1 
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. 
11.4.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, with the exception of the urine 
pregnancy tests. As described below, urine pregnancy tests will either be analyzed by the site or 
at home using a home kit. On Day 1, blood samples will be collected before the 
first dose of the study drug. Specific instructions for the collection, processing, and shipment of 
samples will be provided in a separate Laboratory Manual. 
Laboratory test results that are abnormal and considered clinically significant will be reported as 
AEs (see Section 13.1). 
The safety laboratory test panels are shown in Table 11-1. 


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Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Total bilirubin, direct bilirubin, 
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. 
Pregnancy (β-human chorionic gonadotropin) Tests for all Female Subjects: All female subjects 
must have a pregnancy test every 4 weeks. Serum pregnancy tests will be performed at the study 
site and analyzed at the central laboratory. Urine pregnancy tests will be performed and analyzed 
at the site or, at assessment time points when telephone contact takes the place of a clinic visit, at 
home by using a home kit provided by the study site. Results of a home urine pregnancy test will 
be reported to the site by telephone. The urine pregnancy test on Day 1 must be negative before 
the first dose of study drug is administered to the subject. Additional pregnancy tests may be 
required according to local regulations and/or requirements. 
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. 


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11.4.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at select study visits. At 
other visits, symptom-directed PEs and symptom-directed vital signs assessments can be 
performed at the discretion of the investigator or healthcare provider. 
A PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, nose, and 
throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed.  
Arterial oxygen saturation by pulse oximetry will be assessed following at least a 5-minute rest 
and before study drug dosing. 
11.4.4 
Height and Weight 
Height and weight will be measured with shoes off.  
11.4.5 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines: 
• The ECG will be done before any other procedures that may affect heart rate, such as blood 
draws 
• The subject will be instructed to rest for at least 5 minutes before having an ECG 
A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. Clinically significant ECG abnormalities occurring during the study 
through the Safety Follow-up Visit will be recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement.  
11.4.6 
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 


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• pharmacologically dilated examination of the lens with a slit lamp. 
Ophthalmologic examinations are required at select study visits in the Treatment Period 
(Table 3-1). These examinations should be completed within the specified 4-week window 
around the relevant study visit. A single ophthalmologic examination is required at completion 
of study participation (defined in Section 9.1.5); this examination should be completed 
within 4 weeks prior to the last study visit except for subjects who have withdrawn consent 
or assent. Ophthalmologic examinations are only required if the cumulative study drug 
exposure (in the parent study and current study) is at least 12 weeks since the last study 
ophthalmologic examination.  
Any clinically significant abnormal findings will be reported as AEs. 
11.4.7 
Contraception and Pregnancy 
The effects of ELX monotherapy or in combination with TEZ/IVA on conception, pregnancy, 
and lactation in humans are not known. ELX, TEZ, and IVA did not show genotoxic potential in 
a standard battery of in vitro (Ames test, chromosomal aberration, or micronucleus in cultured 
mammalian cells) and in vivo (rodent micronucleus) studies. Reproductive toxicology studies of 
ELX, TEZ, and IVA have not shown teratogenicity in rats and rabbits. 
11.4.7.1 
Contraception 
Contraception requirement is waived for the following: 
• True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception. True abstinence must 
be practiced from the date of informed consent through 90 days after the last dose of study 
drug. 
• If the subjects is male and is infertile (e.g., bilateral orchiectomy). If a male subject is 
assumed to have complete bilateral absence of the vas deferens, infertility must be 
documented before the first dose of study drug (e.g., examination of a semen specimen or by 
demonstration of the absence of the vas deferens by ultrasound). 
• If the subject is female is of non-childbearing potential. To be considered of non-childbearing 
potential, the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum 
follicle-stimulating hormone (FSH) level within the laboratory’s reference range for 
postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
o Note: All other females (including females with tubal ligations) will be considered to 
be of childbearing potential. 
• Same-sex relationships 
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used. Methods of contraception must be in successful use from signing of consent (or assent, 
when applicable), approximately 28 days before the first dose of study drug (unless otherwise 


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noted), and until 90 days following the last dose of study drug. Additional contraception 
requirements may need to be followed according to local regulations and/or requirements. 
Acceptable methods of contraception are listed in Table 11-2. 
Table 11-2 
Acceptable Methods of Contraception 
 
Male Subjects and 
Their Female 
(Non-study) Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy performed at least 6 months previously, 
with a documented negative postvasectomy semen 
analysis for sperm 
Yes 
Yes 
Bilateral tubal occlusion (e.g., ligation) performed at 
least 6 months previously 
Yes 
Yes 
Male or female condom with or without spermicidea 
Yes 
Yes 
Female barrier contraception (such as diaphragm, 
cervical cap, or sponge) with spermicide 
Yes 
Yes 
Continuous use of an intrauterine device for at least 
90 days before the first dose of study drug 
 
 
 
Hormone-releasing 
Yes 
Yes 
 
Non-hormone releasing 
Yes 
Yes 
Oral, implanted, injected, or vaginal hormonal 
contraceptives, if successfully used for at least 60 days 
before the first dose of study drug 
Yes 
Yes 
a 
A female condom cannot be used with a male condom due to risk of tearing.  
Additional notes: 
• If over the course of the study the subject meets the criteria for waiving the contraception 
requirements, the subject does not need to follow the contraceptive methods listed in 
Table 11-2. 
• If over the course of the study the subject’s status changes and the subject does not meet 
the criteria for waiving the contraception requirements, the subject must begin following 
the contraceptive methods listed in Table 11-2.  
• Male subjects must not donate sperm during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
• Female subjects should not nurse a child during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
• Female partners of male subjects should not plan to become pregnant during the study or 
within 90 days after the last dose of study drug, with the exception of those who plan to 
become pregnant by artificial insemination using sperm banked by the male subject 
before the first dose of study drug or sperm from another source. 
11.4.7.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 


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If a subject, or the female partner of a male subject, becomes pregnant while participating in the 
study, the study drug will be permanently discontinued immediately. The investigator will 
1) notify the medical monitor and Vertex Global Patient Safety (GPS) within 24 hours of the 
site’s knowledge of the subject’s (or partner’s) pregnancy, and 2) send the Pregnancy 
Information Collection Form to Vertex GPS. Male subjects with female partners who become 
pregnant during the study must use a male condom to avoid exposure of a potential embryo or 
fetus to study drug via the seminal fluid. 
The subject or partner will be followed until the end of the pregnancy and the infant will be 
followed for 1 year after the birth, provided informed consent (and assent, as applicable) is 
obtained. A separate ICF will be provided to explain these follow-up activities. Pregnancy itself 
does not constitute an AE. 
12 
STATISTICAL ANALYSIS  
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the statistical analysis plan (SAP), which will be finalized before the 
clinical data lock for the study. 
12.1 
Sample Size 
The primary objective of the study is the evaluation of the long-term safety and tolerability of 
ELX/TEZ/IVA. This is an open-label extension study that will enroll subjects who did not 
discontinue study drug during the Treatment Period in the parent study and meet eligibility 
criteria in this study.  
Approximately 108 subjects are expected to enroll in this extension study. 
12.2 
Analysis Sets 
The Open-label All Subjects Set is defined as all subjects who were enrolled (defined as subject 
having data in the clinical database) in this open-label study. This analysis set will be used for 
individual subject data listings and disposition summary tables unless otherwise specified. 
The Open-label Full Analysis Set (OL-FAS) is defined as all enrolled subjects who have 
received at least 1 dose of study drug in this open-label study. The OL-FAS will be used to 
summarize subject demographics and baseline characteristics and for all efficacy analyses unless 
otherwise specified. 
The Open-label Safety Set (OL-SS) is defined as all subjects who have received at least 1 dose 
of study drug in this open-label study. The OL-SS will be used for all safety analyses unless 
otherwise specified.  
12.3 
Statistical Analysis 
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the statistical analysis plan (SAP), which will be finalized before the 
clinical data lock for the study. 
12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). 


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Categorical variables will be summarized using counts and percentages. 
The baseline value, unless otherwise specified, for the long-term safety analysis will be the most 
recent non-missing measurement (scheduled or unscheduled) collected before the first dose of 
ELX/TEZ/IVA either in the parent study or the open label study, as applicable. The baseline 
value for the long-term efficacy analysis will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
parent study. For assessments collected in duplicate or triplicate, the baseline will be defined as 
the average of non-missing values.  
Change (absolute change) from baseline will be calculated as Post-baseline value − Baseline 
value. 
The Efficacy Analysis Period in the open-label study will include the time from the first dose of 
study drug in the open-label study to the last scheduled efficacy visit in the open-label study, 
unless otherwise specified. 
The Treatment-emergent (TE) Period in the open‑label study will include the time from the 
first dose of study drug in the open‑label study to 28 days after the last dose of the study drug in 
the open‑label study or to the completion date of study participation (as defined in Section 9.1.5), 
whichever occurs first. 
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
Subject disposition will be summarized for the Open-label All Subjects Set. The number and 
percentage of subjects in the following categories will be summarized as appropriate: 
• Open‑label All Subjects Set 
• Dosed (OL‑SS) 
• Enrolled and dosed (OL‑FAS) 
• Completed Treatment Period 
• Prematurely discontinued treatment and the reasons for discontinuation 
• Completed study 
• Prematurely discontinued the study and the reasons for discontinuation 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by descriptive summary statistics. 
Demographics and baseline characteristics will be obtained from the parent study baseline.  
The following demographics and baseline characteristics will be summarized for the OL-SS and 
will include (but are not limited to) sex, race, age, baseline weight, baseline height, and baseline 
body mass index (BMI). 
Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT) for the OL-SS. 


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12.3.2.3 
Prior and Concomitant Medications 
Medications used will be coded using the World Health Organization-Drug Dictionary and 
categorized as the following: 
• Prior medication: any medication that was administered within the 56 days before the first 
dose of study drug in this open-label study 
• Concomitant medication: medication continued or newly received during the TE Period in 
this open-label study 
• Post-treatment medication: medication continued or newly received after the TE Period in 
this open-label study 
A given medication may be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; or 
prior, concomitant, and post-treatment. If a medication has a missing or partially missing 
start/end date or time and if it cannot be determined whether it was taken before initial dosing, 
concomitantly during the TE Period, or beyond the TE Period, it will be considered in all 
3 categories of prior, concomitant, and post-treatment medication. 
Prior medications and concomitant medications will be summarized descriptively by Preferred 
Name based on the OL-SS. Post-treatment medications will be provided separately in an 
individual subject data listing. 
12.3.2.4 
Study Drug Exposure and Compliance 
Study drug exposure will be summarized based on the OL-SS, defined as the last day of study 
drug in this open-label study minus the first day of study drug in this open-label study plus 1, 
regardless of study drug interruption. 
Study drug compliance will be summarized based on the OL-FAS and will be calculated as: 100 
× [1 – (total number of days of study drug interruption in this open-label study) / (duration of 
study drug exposure in days in this open-label study)]. A study drug interruption on a given day 
is defined as an interruption of any study drug on that day. 
In addition, percentage of tablets taken in the open‑label study will also be summarized based on 
the OL-FAS, and will be calculated as 100 × [(total number of tablets dispensed in the open‑label 
study) – (total number of tablets returned in the open-label study)] / (total number of tablets 
planned to be taken per day × duration of study drug exposure in days for the open‑label study). 
12.3.2.5 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. 
All IPDs will be provided in an individual subject data listing, as appropriate. 
12.3.3 
Efficacy Analysis 
The secondary objectives of the study are the evaluation of the efficacy and PD of 
ELX/TEZ/IVA. 


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12.3.3.1 
Analysis of Primary Efficacy and Pharmacodynamic Endpoints 
Not applicable, as efficacy and PD are not primary objectives. 
12.3.3.2 
Analysis of Secondary Efficacy and Pharmacodynamic Endpoints 
The Secondary Endpoints include: 
• Absolute change from baseline in SwCl 
The analysis of this endpoint will be performed using a mixed-effects model for repeated 
measures (MMRM) with absolute change from baseline in SwCl at each post-baseline visit in 
this current open-label study as the dependent variable. The model will include the parent study 
treatment group, visit, and parent study treatment-by-visit interaction as fixed effects, and will be 
adjusted for main covariates as appropriate. The least squares (LS) mean estimate with a 2-sided 
95% CI at each visit will be provided. 
• Absolute change from baseline in LCI2.5 
Analysis of this efficacy endpoint will be based on a MMRM model similar to the analysis of the 
absolute change from baseline in SwCl. 
12.3.3.3 
Analysis of Other Efficacy and Pharmacodynamic Endpoints 
Other Endpoints include: 
• Absolute change from baseline in ppFEV1 
Analysis of this variable will be based on an MMRM model similar to the analysis of the 
absolute change from baseline in LCI2.5. 
• Absolute change from baseline in CFQ-R respiratory domain score 
Analysis of this variable will be based on an MMRM model similar to the analysis of the 
absolute change from baseline in LCI2.5. 
12.3.3.4 
Multiplicity Adjustment 
No multiplicity adjustment is planned. 
12.3.4 
Safety Analysis 
The primary objective of the study is the evaluation of the long-term safety and tolerability of 
ELX/TEZ/IVA. All safety analyses will be based on the TE Period in this open-label study for 
subjects in the OL-SS, unless otherwise specified. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., serum chemistry, hematology, coagulation, and urinalysis) 
• ECGs 
• Vital signs 
• Pulse oximetry 


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In general, long term safety analysis will be performed in a pooled fashion. All safety data will 
be presented in individual subject data listings. Only descriptive analyses of safety data will be 
performed. 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows: 
• Pretreatment AE: any AE that occurred since the end of the TE Period in the parent study 
and before the first dose of ELX/TEZ/IVA in the TE Period in the open-label study 
• TEAE: any AE that worsened (either in severity or seriousness) or newly developed at or 
after the first dose date of ELX/TEZ/IVA in the TE Period in this open-label study 
• Post-treatment AE: any AE that worsened (either in severity or seriousness) or newly 
developed after the TE Period in this open-label study 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study drug treatment, then the AEs will be classified as TEAEs. 
AE summary tables will be presented for TEAEs only and will include the following: 
• All TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Serious TEAEs 
• TEAEs leading to death 
• Grade 3 and Grade 4 TEAEs 
• Frequently reported TEAEs 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same AE or a 
continuing AE will be counted once, only the maximum severity level will be presented in the 
severity summaries, and the strongest relationship level in the relationship summaries. 
Listings containing individual subject level AE data will be provided separately for: 
• Serious TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• TEAEs leading to death 


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In addition, all AEs, including pre- and post-treatment AEs, will be presented in individual 
subject data listings 
12.3.4.2 
Clinical Laboratory Assessments 
For the TE laboratory measurements, the observed values and change from baseline values of the 
continuous laboratory parameters will be summarized in SI units at each time point during the 
TE Period. 
For threshold analysis, the number and percentage of subjects with at least 1 threshold event 
during the TE Period will be summarized. The threshold criteria and selected parameters will be 
provided in the SAP. 
Results of urinalysis and pregnancy tests will be listed in individual subject data listings only. In 
addition, a listing containing individual subject laboratory assessment values will be provided. 
This listing will include data from scheduled and unscheduled time points. 
Additional safety laboratory data analyses may be described in the SAP. 
12.3.4.3 
Electrocardiogram 
For the TE ECG measurements, a summary of observed values and change from baseline values 
will be provided at each time point during the TE Period, for the following ECG interval 
measurements (in msec): RR, PR, QT, QT corrected for heart rate (HR) intervals (QTcF), QRS 
duration, and HR (beats per minute). 
For threshold analysis, the number and percentage of subjects with at least 1 threshold event 
during the TE Period will be summarized. The threshold criteria will be provided in the SAP. 
Additional ECG analyses may be described in the SAP. 
12.3.4.4 
Vital Signs 
For the TE vital signs measurements, the observed values and change from baseline values will 
be summarized at each time point during the TE Period in this open-label study. The following 
vital signs parameters will be summarized: systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), pulse rate (beats per minute), and respiratory rate (breaths per minute). 
For threshold analysis, the number and percentage of subjects with at least 1 threshold event 
during the TE Period will be summarized. The threshold criteria will be provided in the SAP. 
Additional vital signs analyses may be described in the SAP. 
12.3.4.5 
Pulse Oximetry 
For the TE pulse oximetry measurements, a summary of observed values and change from 
baseline values will be provided at each time point during the TE Period, for the percent of 
oxygen saturation by pulse oximetry. 
12.3.4.6 
Physical Examination 
No tables/figures/listings will be provided for PE data. 
12.3.4.7 
Other Safety Analyses 
Details of other safety analyses may be included in the SAP. 


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12.4 
Interim Analysis 
Interim analyses may take place at any time at the discretion of the sponsor. 
12.5 
Data Monitoring Committee Analysis 
A data monitoring committee (DMC) will conduct periodic safety review(s) of study data as 
outlined in the DMC charter. 
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) 


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• 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 9.1.3) 
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 


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Table 13-1 
Grading of AE Severity  
Classification 
Description 
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. 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the subject’s medical record). 
AE: adverse event 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classificationa 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
AE: adverse event 
a 
Refer to Sections 9.6.1 and 9.8 for directions regarding what drug actions are permitted per protocol.  


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13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to followup) 
AE: adverse event 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation and is suspected of being a delayed toxicity due to administration of the study 
drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
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 


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indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious”, which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent through the Safety Follow-up Visit, 
regardless of causality, will be reported by the investigator to Vertex GPS within 24 hours of 
identification. In addition, all SAEs that occur after the Safety Follow-up Visit and are 
considered related to study drug(s) will be reported to Vertex GPS within 24 hours of 
identification.  
For SAEs that occur after obtaining informed consent through the Safety Follow-up Visit, the 
SAE Form will be completed for new/initial events as well as to report follow-up information on 
previously reported events. Investigators are asked to report follow-up information as soon as it 
becomes available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email: globalpatientsafety@vrtx.com (preferred choice) 
Fax: +1-617-341-6159  
For technical issues related to submitting the form, contact telephone: +1-617-341-6677 
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) will 
be recorded on the Vertex Clinical Trial Safety Information Collection Form (hereafter referred 
to as the “SAE Form”) using a recognized medical term or diagnosis that accurately reflects the 
event. SAEs will be assessed by the investigator for relationship to the investigational study 
drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be assessed 
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.  


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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 
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 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 


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(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 
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 


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Written notification that includes the reason for the clinical study termination is required. 
13.2.9 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation per 
current ICH E6 GCP Guidelines. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each subject. Study 
data for each enrolled subject will be entered into a CRF by study site personnel using a secure, 
validated, web-based electronic data capture (EDC) application. 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.  


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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. 
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 
13.7.1 
Publication of Study Results 
Vertex is committed to reporting the design and results of all clinical studies in a complete, 
accurate, balanced, transparent, and timely manner, consistent with Good Publication Practices 
(GPP3).18  
Publication Planning: Vertex staff along with the lead principal investigators (PIs), the steering 
committee (SC), and/or the publication committee (PC) will work together to develop a 
publication plan.  
Authorship: Authorship of publications will be determined based on the Recommendations for 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, which 
states that authorship should be based on the following 4 criteria19: 
1. Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data;  
2. Drafting of the article or revising it critically for important intellectual content;  
3. Final approval of the version to be published; and 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
All authors must meet conditions 1, 2, 3, and 4. All persons designated as authors should qualify 
for authorship, and all those who qualify should be listed. Contributions such as medical writing, 
enrollment of subjects, acquisition of funding, collection of data, or general supervision of the 
research group, alone, do not justify authorship.  


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Contributors: Contributors who meet fewer than all 4 of International Committee of Medical 
Journal Editors (ICMJE) criteria for authorship will not be listed as authors, but their 
contribution will be acknowledged and specified either as a group (e.g., “study investigators”) or 
individually (e.g., “served as scientific advisor”).  
Publication Review: As required by a separate clinical study agreement, Vertex must have the 
opportunity to review all publications, including any manuscripts, abstracts, oral/slide 
presentations, and book chapters regarding this study before submission to congresses or journals 
for consideration.  
13.7.2 
Clinical Study Report  
A clinical study report (CSR), written in accordance with the current ICH E3 Guideline, will be 
submitted in accordance with local regulations. 


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14 
REFERENCES 
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 22 March 2018. 
2 
Cystic Fibrosis Foundation. 2018 Patient Registry Annual Data Report. Bethesda, MD: 
2019. 
3 
European Cystic Fibrosis Society. 2017 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: 2019. 
4 
Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, et al. 
Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 
1989;245(4922):1059-65. 
5 
Kreindler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
6 
Konstan MW, McKone EF, Moss RB, Marigowda G, Tian S, Waltz D, et al. Assessment 
of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor 
therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation 
(PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017;5(2):107-18. 
7 
Sawicki GS, McKone E, Pasta DJ, Wagener J, Johnson C, Konstan MW. The effect of 
ivacaftor on the rate of lung function decline in CF patients with a G551D-CFTR 
mutation. J Cyst Fibros. 2014;13:S6. 
8 
Horsley A. Lung clearance index in the assessment of airways disease. Respir Med. 
2009;103(6):793-99. 
9 
Sinhal S, Galati J, Baldwin DN, Stocks J, Pillow JJ. Reproducibility of multiple breath 
washout indices in the unsedated preterm neonate. Pediatr Pulmonol. 2010;45(1):62-70. 
10 
Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection 
of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. 
Thorax. 2007;62(4):341-47. 
11 
Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout 
and spirometry versus structural lung disease in cystic fibrosis. Thorax. 2008;63(2):129-
34. 
12 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
13 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
14 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 
15 
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of 
the Cystic Fibrosis Questionnaire in the United States. Chest. 2005;128(4):2347-54. 
16 
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life 
Res. 2003;12(1):63-76. 
17 
Wenninger K, Aussage P, Wahn U, Staab D, German Cystic Fibrosis Questionnaire study 
group. The revised German Cystic Fibrosis Questionnaire: validation of a disease-
specific health-related quality of life instrument. Qual Life Res. 2003;12(1):77-85. 


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18 
Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
publication practice for communicating company-sponsored medical research: GPP3. 
Ann Intern Med. 2015;163(6):461-4. 
19 
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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15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol #: 
VX20-445-119 Version #: 
1.0 
Version Date: 
26 June 2020 
Study Title: A Phase 3b Open‑label Study Evaluating the Long-term Safety and Efficacy of 
Elexacaftor/Tezacaftor/Ivacaftor Combination Therapy in Cystic Fibrosis Subjects Ages 
6 Years and Older Who Are Heterozygous for the F508del Mutation and a Minimal Function 
Mutation (F/MF) 
This clinical study protocol has been reviewed and approved by the sponsor. 
Printed Name 
 
Title 
Signature 
 
Date 


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15.2 
Investigator Signature Page 
Protocol #:  
VX20-445-119 Version #: 
1.0 
Version Date: 
26 June 2020 
Study Title: A Phase 3b Open‑label Study Evaluating the Long-term Safety and Efficacy of 
Elexacaftor/Tezacaftor/Ivacaftor Combination Therapy in Cystic Fibrosis Subjects Ages 
6 Years and Older Who Are Heterozygous for the F508del Mutation and a Minimal Function 
Mutation (F/MF) 
 
 
I have read Protocol VX20-445-119, Version 1.0, 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 
 
 
 




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













SAP_001.pdf: 
Statistical Analysis Plan (Methods) – Final Analysis  
Page 1 of 27 
Protocol Number: VX20-445-119 
 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Statistical Analysis Plan 
(Methods) 
Protocol Number VX20-445-119 Version 1.0 
(Final Analysis) 
 
 
A Phase 3b Open-label Study Evaluating the Long-term Safety and 
Efficacy of Elexacaftor/Tezacaftor/Ivacaftor Combination Therapy in 
Cystic Fibrosis Subjects Ages 6 Years and Older Who Are 
Heterozygous for the F508del Mutation and a Minimal Function 
Mutation (F/MF) 
 
Authors of SAP: 
 
 
Version: 1.0 
Version Date of SAP:  22 March 2023 
 
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) – Final Analysis 
Page 2 of 27 
Protocol Number: VX20-445-119 
 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
1 
TABLE OF CONTENTS 
 
1 
Table of Contents ................................................................................................................... 2 
2 
Modifications .......................................................................................................................... 4 
2.1 
Modifications to the Approved Clinical Study Protocol .................................................. 4 
2.2 
Modifications to the Approved Statistical Analysis Plan ................................................. 4 
3 
Introduction ............................................................................................................................ 4 
4 
Study Objectives .................................................................................................................... 4 
4.1 
Primary Objective ............................................................................................................. 4 
4.2 
Secondary Objectives ....................................................................................................... 4 
5 
Study Endpoints ..................................................................................................................... 4 
5.1 
Primary Endpoint .............................................................................................................. 4 
5.2 
Secondary Endpoints ........................................................................................................ 5 
5.3 
Other Endpoints ................................................................................................................ 5 
6 
Study Design ........................................................................................................................... 5 
6.1 
Overall Design .................................................................................................................. 5 
6.2 
Sample Size and Power .................................................................................................... 6 
6.3 
Randomization .................................................................................................................. 6 
6.4 
Blinding and Unblinding .................................................................................................. 6 
7 
Analysis Sets ........................................................................................................................... 6 
7.1 
OL All Subjects Set .......................................................................................................... 6 
7.2 
116 and OL Full Analysis Set .......................................................................................... 6 
7.3 
OL Safety Set ................................................................................................................... 6 
8 
Statistical Analysis ................................................................................................................. 6 
8.1 
General Considerations .................................................................................................... 6 
8.2 
Background Characteristics .............................................................................................. 7 
8.2.1 
Subject Disposition ................................................................................................... 7 
8.2.2 
Demographics and Baseline Characteristics ............................................................. 8 
8.2.3 
Medical History ........................................................................................................ 9 
8.2.4 
Prior and Concomitant Medications ......................................................................... 9 
8.2.5 
Study Drug Exposure .............................................................................................. 10 
8.2.6 
Study Drug Compliance ......................................................................................... 10 
8.2.7 
Important Protocol Deviations ................................................................................ 10 
8.3 
Efficacy Analysis ............................................................................................................ 10 
8.3.1 
Analysis of Primary Efficacy Endpoint .................................................................. 10 
8.3.2 
Analysis of Secondary Efficacy Endpoint .............................................................. 10 
8.3.3 
Analysis of Additional Efficacy Variables ............................................................. 11 
8.4 
Safety Analysis ............................................................................................................... 12 
8.4.1 
Adverse Events ....................................................................................................... 13 
8.4.2 
Clinical Laboratory ................................................................................................. 15 
8.4.3 
Electrocardiogram .................................................................................................. 15 
8.4.4 
Vital Signs .............................................................................................................. 15 
8.4.5 
Pulse Oximetry ....................................................................................................... 16 


Statistical Analysis Plan (Methods) – Final Analysis 
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8.4.6 
Ophthalmologic Examinations ............................................................................... 16 
8.4.7 
Physical Examination ............................................................................................. 16 
8.4.8 
COVID-19 Impacted Visits .................................................................................... 16 
9 
Interim and DMC Analyses ................................................................................................ 16 
9.1 
Interim Analysis ............................................................................................................. 16 
9.2 
DMC Analysis ................................................................................................................ 16 
10 References ............................................................................................................................. 17 
11 List of Appendices ................................................................................................................ 18 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessment ........................... 18 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 21 
Appendix C: Details of GLI Equations for Calculating ppFEV1 ............................................. 22 
Appendix D: Imputation Rules for Missing AE dates ............................................................. 23 
Appendix E: Criteria for Threshold Analysis .......................................................................... 24 
Appendix F: Adverse Events of Special Interest ..................................................................... 27 
 
 
 


Statistical Analysis Plan (Methods) – Final Analysis 
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2 
MODIFICATIONS  
2.1 
Modifications to the Approved Clinical Study Protocol 
Not Applicable. 
2.2 
Modifications to the Approved Statistical Analysis Plan 
Not Applicable. This is the 1st version of Statistical Analysis Plan.   
3 
INTRODUCTION 
Study VX20-445-119 is a Phase 3b Open‑Label Extension (OLE) study evaluating the long-term 
safety and efficacy of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) combination therapy in 
subjects with cystic fibrosis who are at least 6 years of age and heterozygous for the F508del 
mutation and a minimal function mutation (F/MF).  
This statistical analysis plan (SAP) is based on the most recent approved clinical study protocol 
(CSP), the most recent approved electronic case report form (eCRF), and the most recent approved 
eCRF completion guidelines.  
This SAP (Methods) documents the planned statistical analyses of efficacy and safety endpoints 
defined in the VX20-445-119 study protocol. It also documents analyses for additional efficacy 
and safety variables not specified in the protocol, which will provide supportive information for 
the scientific understanding of the drug entity.  
The Vertex Biometrics Department will perform the statistical analysis of efficacy and safety data; 
SAS (Version 9.4 or higher) will be used to generate all statistical outputs (tables, figures, listings, 
and datasets). The SAP will be finalized and approved prior to the clinical database lock. Any 
revisions to the approved SAP will be documented and approved in an amendment prior to the 
clinical database lock.  
4 
STUDY OBJECTIVES  
4.1 
Primary Objective 
To evaluate the long-term safety and tolerability of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor 
(IVA) in subjects with CF 
4.2 
Secondary Objectives  
• To evaluate the efficacy of ELX/TEZ/IVA 
• To evaluate the pharmacodynamics (PD) of ELX/TEZ/IVA 
5 
STUDY ENDPOINTS 
5.1 
Primary Endpoint 
• Safety and tolerability of ELX/TEZ/IVA based on adverse events (AEs), clinical laboratory 
values, ECGs, vital signs, and pulse oximetry 




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dose of ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for the remainder of the study, 
starting with the second visit where the subject’s weight is ≥30 kg. 
Subjects ≥12 years of age will receive a dose of ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg 
q12h, starting from the first study visit at which the subject is ≥12 years old. 
6.2 
Sample Size and Power 
The primary objective of the study is the evaluation of the long-term safety and tolerability of 
ELX/TEZ/IVA. This is an OLE study that will enroll subjects who did not discontinue study drug 
during the Treatment Period in parent study (445-116) and meet eligibility criteria. Approximately 
108 subjects are expected to enroll in this OLE. 
6.3 
Randomization 
Not applicable. 
6.4 
Blinding and Unblinding 
Refer to the CSP Section 10 for details. 
7 
ANALYSIS SETS 
The following analysis sets are defined: Open-label (OL) All Subjects Set, 116 and OL Full 
Analysis Set, and OL Safety Set. 
7.1 
OL All Subjects Set 
The OL All Subjects Set (OL-AS) will include all subjects who were enrolled (defined as subject 
having data in the clinical database) in this OLE study. This analysis set will be used for individual 
subject data listings and disposition summary tables unless otherwise specified. 
7.2 
116 and OL Full Analysis Set 
The Study 116 Full Analysis Set (116-FAS) is defined the same as the FAS definition in the SAP 
of Study 116. 
The OL Full Analysis Set (OL-FAS) will include all enrolled subjects who have received at least 
1 dose of study drug in this OLE study. The OL-FAS will be used to summarize subject 
demographics and baseline characteristics and for all efficacy analyses unless otherwise specified. 
7.3 
OL Safety Set 
The OL Safety Set (OL-SS) will include all subjects who have received at least 1 dose of study 
drug in this OLE study. The OL-SS will be used for all safety analyses unless otherwise specified.  
8 
STATISTICAL ANALYSIS 
8.1 
General Considerations 
The precision standards for reporting safety variables are provided in an internal Biometrics 
document that specifies the programming rules including the precision for derived variables. 
The Schedule of Assessments is provided in Section 3 of CSP.  


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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. 
The baseline value, unless otherwise specified, for the long-term safety analysis will be the TC 
safety baseline, defined as the most recent non-missing measurement (scheduled or unscheduled) 
collected before the first dose of ELX/TEZ/IVA either in the parent study or the open label study, 
as applicable. The baseline value for the long-term efficacy analysis, unless otherwise specified, 
will be the parent study baseline, defined as the most recent non-missing measurement 
(scheduled or unscheduled) collected before the first dose of study drug in the parent study. For 
assessments collected in duplicate or triplicate, the baseline will be defined as the average of non-
missing values.  
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 will include the time from the first dose date of study drug in 
the OLE to 28 days after the last dose of the study drug in the OLE or to the date of completion of 
study participation (as defined in CSP Section 9.1.5), whichever occurs first. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
1) In scheduled visit windows per specified visit windowing rules 
2) In the derivation of baseline and last on-treatment measurements 
3) In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values during TE period for safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix A. 
Incomplete/missing data will not be imputed, unless otherwise specified.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
Multiplicity: There will be no multiplicity adjustment as no hypothesis test is planned for safety 
analysis, unless otherwise specified. 
8.2 
Background Characteristics  
8.2.1 
Subject Disposition 
A summary table of subject disposition will be presented for the OL-AS by treatment group in the 
parent study and overall with the following categories: 
• Enrolled (OL-AS) 
• Dosed (OL-SS) 
• Enrolled and dosed (OL-FAS) 


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The number and percentage (based on OL-FAS) of subjects in each of the following disposition 
categories will be summarized by treatment group and overall: 
• Completed treatment  
• Prematurely discontinued the treatment and the reason for discontinuation  
• Completed study 
• Prematurely discontinued the study and the reason for discontinuation  
A listing will be provided for subjects who discontinued treatment or who discontinued study with 
reasons for discontinuation. 
8.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the OL-FAS and 
presented by treatment group in the parent study and overall. 
Demographic data from the parent study (445-116) will include the following: 
• Age at parent study baseline (in years) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, multiracial, and not collected per local regulations) 
• Country 
Baseline characteristics from the parent study (445-116) will include the following: 
• Weight (kg) 
• Weight-for-age z-score 
• Height (cm) 
• Height-for-age z-score 
• BMI (kg/m2) 
• BMI-for-age z-score 
Stratification categories used in the parent study will include the following: 
• LCI2.5 at Screening Visit (<10, ≥10) 
• Weight at Screening Visit (<30, ≥30 kg) 
Disease characteristics from the parent study (445-116) baseline will include the following: 
• Sweat chloride at parent study baseline (continuous) 
• LCI2.5 at parent study baseline (continuous) 
• ppFEV1 category at parent study baseline (<70, ≥70 to ≤90, and >90) 
• ppFEV1 at parent study baseline (continuous) 


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• CFQ-R respiratory domain score at parent study baseline (child 6-11’s version, continuous) 
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 
• Prior use of any bronchodilator (Yes, No) 
• Prior use of any inhaled bronchodilator (Yes, No) 
• Prior use of any inhaled hypertonic saline (Yes, No) 
• Prior use of any inhaled corticosteroids (Yes, No) 
Prior medication use definition is same as that for the baseline characteristics summary presented 
in the parent studies. In addition, data listings will also be provided for: 
• Informed consent 
• Inclusion/Exclusion criteria violation for subjects with any such violations 
8.2.3 
Medical History 
Medical history (referenced to the start of parent study) will be coded by using the Medical 
Dictionary for Regulatory Activities (MedDRA). For the OL-FAS, medical history will be 
summarized descriptively by treatment group in parent study and overall and by System Organ 
Class (SOC) and Preferred Term (PT). The corresponding data listing will also be provided. 
8.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD) and 
categorized as follows: 
Prior medication: any medication that was administered during the 56 days before the first dose 
date of study drug in this OLE study.  
Concomitant medication: medication continued or newly received during the TE period in this 
OLE study. 
Post-treatment medication: medication continued or newly received after the TE period in this 
OLE study.  
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 completely missing or partially missing start/stop date and if it cannot be 
determined whether it was taken before the first dose date of the OLE, concomitantly during the 
TE Period for the OLE, or after the TE Period for the OLE, it will be considered in all 3 categories 
of prior, concomitant, and post-treatment medication. Details for imputing missing or partial start 
and/or stop dates of medication are described in Appendix B. 
For the OL-SS, prior medications and concomitant medications will be summarized descriptively 
by: 1) treatment group in parent study and overall, Preferred Name (PN); and 2) treatment group 
in parent study and overall, anatomic class (ATC) level 1, ATC level 2, and PN. Post-treatment 
medications will be listed for each subject, if applicable. 


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8.2.5 
Study Drug Exposure  
Duration of study drug exposure (in days) will be calculated as: last dose date of study drug in the 
OLE – first dose date of study drug in the OLE + 1, regardless of study drug interruption.  
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max. It will also be summarized by interval (<=24 weeks, >24 to 
<=48 weeks, >48 to <=72 weeks, >72 to <=96 weeks, >96 weeks), using counts and percentages. 
Additionally, the total study drug exposure, defined as the sum total of the study drug exposure 
across all subjects (in patient-years), will be provided. Exposure summaries will be based on the 
OL-SS, and presented overall.  
8.2.6 
Study Drug Compliance 
Study drug compliance will be calculated as: 100 × [1 - (total number of days of study drug 
interruption) / (duration of study drug exposure in days)]. A study drug interruption on a given day 
is defined as an interruption of any study drug on that day.  
Percentage of study drug compliance will be summarized based on the OL-FAS and presented by 
treatment group in parent study and overall. Percentage of 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.  
8.2.7 
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 summarized descriptively based on the OL-FAS and presented by treatment group in 
parent studies and overall. Additionally, IPDs will be provided in an individual subject data listing.  
8.3 
Efficacy Analysis  
8.3.1 
Analysis of Primary Efficacy Endpoint  
Not applicable since efficacy is not a primary objective. 
8.3.2 
Analysis of Secondary Efficacy Endpoint  
8.3.2.1 
Definition of Variables 
Sweat chloride (SwCl): the SwCl value for a given visit will be calculated as the mean of the non-
missing sweat chloride measurements obtained on the left and right arms at that visit. If one of the 
two arm measurements at a time point is missing, the other will be used as the mean. A volume 
≥15 μL is required for an accurate determination of sweat chloride. Any results reported as having 
volume <15 μL will be considered missing. Any sweat chloride values reported as <10 mmol/L or 
>160 mmol/L will be considered missing.  
Lung clearance index 2.5 (LCI2.5): the LCI2.5 assessments are derived from N2-multiple-breath 
washout (MBW) testing. Each MBW will be performed in multiple replicates for each visit and 
the final LCI2.5 value will be calculated from the technically acceptable washout replicates as 
graded and determined by a central reader. The following algorithm is used to derive the valid 
LCI2.5 value at each visit based on the multiple attempt replicates: 


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• When there is only one acceptable replicate at the visit, the LCI2.5 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 LCI2.5 value at the corresponding visit. 
8.3.2.2 
Analysis Method 
Absolute change in SwCl from baseline: 
The mixed-effects model for repeated measures (MMRM) for the parent study 116-FAS will be 
same as that described in the SAP for Study 116. In the MMRM for the OL-FAS, the absolute 
change from baseline in SwCl will be the dependent variable. The model will include treatment 
group (as randomized in the parent study), visit, and treatment-by-visit interaction as fixed effects, 
with continuous baseline LCI2.5 from the parent study and weight at Screening (<30 versus ≥30 
kg) of the parent study as covariates.  
The repeated-measures analysis will be based on the restricted maximum likelihood method 
assuming an unstructured covariance structure to model the within-subject errors. The 
denominator degrees of freedom will be based on the method proposed by Kenward-Roger6. If the 
model fails to converge due to the unstructured covariance assumption, a compound symmetry 
covariance structure will be used to model the within-subject errors. In the MMRM approach, 
assuming that the data are missing at random, no imputation of missing data will be performed. 
Results from the 2 MMRMs (for the parent study and for the OE) will be presented in a single 
summary table. The number of subjects, least-squares means (LS means) for absolute change from 
baseline at scheduled visits within each treatment group (as randomized in the parent study) along 
with the corresponding standard error (SE), and 95% confidence interval (CI) will be presented. 
The LS means (±SE) for absolute change from baseline at each visit will also be plotted by 
treatment group (as randomized in the parent study).  
In addition, the descriptive statistics for raw values and absolute changes from baseline by 
treatment group (as randomized in the parent study) and OL visit will be presented for the OL-
FAS.  
Absolute change in LCI2.5 from baseline: 
Analysis of this endpoint will be based on an MMRM similar to the analysis of the absolute change 
from baseline in SwCl. A descriptive summary of raw values and absolute changes from baseline 
will also be presented.  
8.3.2.3 
Sensitivity and Supportive Analysis of Secondary Endpoints 
No sensitivity or supportive analysis is planned for the secondary endpoints.   
8.3.2.4 
Subgroup Analysis 
No subgroup analysis is planned for the secondary endpoints.  
8.3.3 
Analysis of Additional Efficacy Variables  
8.3.3.1 
Definition of Variables 
Percent predicted forced expiratory volume in 1 second (ppFEV1): Percent predicted FEV1 is the 
ratio of FEV1 (L) and predicted FEV1 (L), expressed as a percentage. The predicted FEV1 will be 
calculated using the Global Lung Function Initative1 (GLI). See Appendix C for more details. 


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Cystic Fibrosis Questionnaire-Revised (CFQ-R): The CFQ-R3,4,5 is a validated CF-specific 
instrument that measures quality-of-life domains.  This study utilizes four different versions of 
CFQ-R: 
• CFQ-R for Children ages 6 to 11 
• CFQ-R for Children ages 12 and 13 
• CFQ-R for Adolescents and Adults (subjects 14 years and older) 
• CFQ-R for Parents/Caregivers (subjects 13 years and younger) 
In all four versions, specific question belonging to a domain is scored 1, 2, 3, or 4.  The CFQ-R 
domain score, e.g., physical domain score or respiratory domain score, is defined as a scaled score 
as follows: 
Scaled score for a domain = 100 × (mean (scores of all questions in the domain) −1)/3, 
where the score from a negatively phrased question is first reversed, i.e., reversed score = 5 – actual 
score, so that 1 always represents the worst condition and 4 the best condition. The (scaled) domain 
score ranges from 0 (worst condition) to 100 (best condition). The scaled score for a specific 
domain will not be calculated if more than half of the questions in the domain have missing scores. 
The (scaled) domain score from the CFQ-R for Children ages 6 to 11, for Children ages 12 and 
13, and for Adolescent and Adults will be pooled within and across subjects for the analysis 
purpose. 
8.3.3.2 
Analysis Method 
Absolute change in ppFEV1 from baseline: 
Analysis of this endpoint will be based on an MMRM similar to the analysis of the absolute change 
in SwCl. A descriptive summary of raw values and absolute changes from parent study baseline 
will also be presented.  
The primary analysis will use the spirometry data obtained at clinic only. An additional analysis 
may be performed to include all available spirometry data obtained at clinic and obtained at home, 
if the spirometry data obtained at home are assessed to be reasonably consistent with the 
spirometry data obtained at clinic. 
Absolute change in CFQ-R respiratory domain (RD) score from baseline:  
Analysis of this endpoint will be based on an MMRM similar to the analysis of the absolute change 
in SwCl. A descriptive summary of raw values and absolute changes from parent study baseline 
will also be presented.  In addition, the descriptive summary for raw values and the absolute change 
from parent study baseline of the parent version’s CFQ-R RD score will be presented. 
8.4 
Safety Analysis 
The primary objective of the study is the evaluation of long-term safety and tolerability of TC. All 
safety analyses will be based on the TE Period in the OLE for subjects in the OL-SS. The overall 
long-term safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints: 
• Treatment-emergent adverse events (TEAEs)  


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• 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.  
8.4.1 
Adverse Events  
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, and post-treatment 
AEs, defined as follows:  
• Pretreatment AE: any AE before the first dose of ELX/TEZ/IVA in the TE Period in this 
OLE study 
• TEAE: any AE that worsened (either in severity or seriousness) or newly developed at or after 
the first dose date of ELX/TEZ/IVA in the TE Period in this OLE study 
• Post-treatment AE: any AE that worsened (either in severity or seriousness) or newly 
developed after the TE Period in this OLE study 
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. Details for imputing 
missing or partial start dates of adverse events are described in Appendix D. 
An overview of all TEAEs for the OL-SS during the TE Period will be summarized overall and 
include 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 treatment discontinuation  
• Subjects with TEAEs leading to treatment interruption 
• Subjects with Grade 3/4/5 TEAEs 
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAE leading to death  
The frequency counts and percentages, as well as the exposure adjusted event rate, will be 
presented for the above overview table. The exposure adjusted rate will not be presented for 
strongest relationship and maximum severity categories.  
The following summary tables of TEAEs will be presented overall:  


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• All TEAEs 
• Grade 3/4/5 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Related TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to death 
Summaries will be presented by MedDRA System Organ Class (SOC) and Preferred Term (PT) 
using frequency counts, percentages (i.e., number and percentage of subjects with an event), and 
the exposure adjusted event rate (except for summary by strongest relationship and maximum 
severity). When summarizing the number and percentages of subjects, subjects with multiple 
occurrences of the same adverse event or a continuing adverse event will be counted once, and 
only the maximum severity level will be presented in the severity summaries, and the strongest 
relationship level in the relationship summaries. Missing severity levels will not be included in the 
Grade 3/4/5 TEAE summaries; missing relationship will be considered as related and included in 
the related TEAE and related serious TEAE summaries. 
An additional summary table in which the frequency counts and percentages as well as the 
exposure adjusted event rate will be presented for TEAEs during the OL safety period: 
• 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 OL-AS. In addition, separate listings 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, with 
a flag indicating the TEAE status for SAEs and deaths. 
8.4.1.1 
Adverse Events of Special Interest 
For this study, elevated transaminases events and rash events, as determined by MedDRA PTs in 
Appendix F, are considered as AESIs. 
For treatment-emergent elevated transaminases events and rash events, the following categories 
will be summarized overall: 
• Subjects with events 
• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 


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• Subjects with serious events 
• Subjects with related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event (with the first dose date of TC in the OLE as the reference while 
calculating time-to-onset) 
8.4.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments, the observed values and change from baseline 
values of the continuous hematology, coagulation, and chemistry results will be summarized in SI 
units overall at each visit during the TE Period for the OLE. 
The number and percentage of subjects with test values meeting at least 1 threshold analysis 
criterion event during the TE Period for the OL-SS will be summarized overall. The threshold 
analysis shift from baseline will also be summarized for selected LFT laboratory parameters. The 
threshold analysis criteria are provided in Appendix E.  
For selected LFT laboratory tests (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase [ALP], and total bilirubin [TBILI]), a scatter plot of the maximum treatment-
emergent value versus the baseline value corresponding to ×ULN (upper limit of normal) will be 
presented overall. Furthermore, a scatter plot of the maximum treatment-emergent value of ALT 
and AST, separately, versus the maximum treatment-emergent value of TBILI corresponding to 
×ULN will also be presented.  
Results of urinalysis and positive urine/serum pregnancy test will be listed in individual subject 
data listings only. For positive serum pregnancy listing, subjects with serum HCG which are 
abnormally high will be selected. 
8.4.3 
Electrocardiogram 
For the following ECG measurements during the TE Period of OL-SS, a summary of observed 
values and change from baseline values will be provided at each visit (in msec): RR interval, PR 
interval, QT interval, and QTcF interval, QRS duration, and Heart Rate (beats per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE Period of OL-SS will be summarized overall. The threshold analysis criteria are provided in 
Appendix E. 
8.4.4 
Vital Signs 
For the vital sign measurements during the TE Period of OL-SS, 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 
(beats per minute), and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE Period will be summarized. The threshold analysis criteria are provided in Appendix E. 
In addition, a listing containing individual subject vital signs values will be provided. This listing 
will include data from both scheduled and unscheduled visits. 


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8.4.5 
Pulse Oximetry 
For the percent of oxygen saturation measurements using pulse oximetry during the TE Period for 
OL-SS, a summary of observed values and change from baseline values will be provided at each 
visit. 
The number and percentage of subjects with shift changes from baseline category (classified as 
normal/missing or low according to the reference range) to the category at the lowest percent of 
oxygen saturation during the TE Period for OL-SS will be summarized. The reference range for 
normal oxygen saturation is specified as >95%, and <=95% for low oxygen saturation. 
8.4.6 
Ophthalmologic Examinations 
Ophthalmologic examination results for the OL-AS will be provided in a data listing. 
8.4.7 
Physical Examination  
No tables/figures/listings will be provided for PE data. 
8.4.8 
COVID-19 Impacted Visits  
A listing containing subjects’ visits impacted due to COVID-19 will be provided. 
9 
INTERIM AND DMC ANALYSES 
9.1 
Interim Analysis 
No interim analysis is planned at this moment; otherwise, the SAP will be amended. 
9.2 
DMC Analysis 
An independent data monitoring committee (IDMC) was formed before initiation of study 119. 
The IDMC’s objectives and operational details are described in the IDMC charter. The IDMC will 
conduct regular planned safety reviews of study data as outlined in the IDMC Charter and IDMC 
Analysis Plan. 
 
 


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10 
REFERENCES 
1 Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 
2 Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
3 Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
4 Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of life 
for children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45. 
5 Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life measure for 
children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32. 
6  Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 
 
 


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11 
LIST OF APPENDICES 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessment 
Table 11-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3,4 
(in study days) 
Spirometry 
Weight, Height and BMI as well 
as the corresponding z-score 
 
 
Parent Study Baseline 
 
OL Week 4 
OL Week 8 
OL Week 16 
OL Week 24 
OL Week 36 
OL Week 48 
OL Week 60 
OL Week 72 
OL Week 84 
OL Week 96 
OL Safety Follow-up 
-- 
 
29 
57 
113 
169 
253 
337 
421 
505 
589 
673 
Not applicable 
≤1 corresponding to the first 
dose date of parent study 
(1, 43] 
(43, 85] 
(85, 141] 
(141, 211] 
(211, 295] 
(295, 379] 
(379, 463] 
(463, 547] 
(547, 631] 
(631, 729] 
Use nominal visit 
Sweat Chloride, LCI2.5, CFQ-R 
Parent Study Baseline 
 
OL Week 4 
OL Week 8 
OL Week 16 
OL Week 24 
OL Week 48 
OL Week 72 
OL Week 96 
-- 
 
29 
57 
113 
169 
337 
505 
673 
≤1 corresponding to the first 
dose date of parent study 
(1, 43] 
(43, 85] 
(85, 141] 
(141, 253] 
(253, 421] 
(421, 589] 
(589, 729] 
Hematology 
Serum Chemistry 
Pulse Oximetry 
Vital Signs (excluding Weight, 
Height and BMI as well as the 
corresponding z-score) 
 
 
TC Safety Baseline 
OL Week 4 
 
OL Week 8 
OL Week 16 
OL Week 24 
OL Week 36 
OL Week 48 
OL Week 60 
OL Week 72 
OL Week 84 
OL Week 96 
OL Safety Follow-up4 
1 
29 
 
57 
113 
169 
253 
337 
421 
505 
589 
673 
Not applicable 
Defined in Section 8.1 
[1, 43] where day 1 is post-
dose measurement 
(43, 85] 
(85, 141] 
(141, 211] 
(211, 295] 
(295, 379] 
(379, 463] 
(463, 547] 
(547, 631] 
(631, 687] 
Use nominal visit 
Standard 12-lead ECG 
TC Safety Baseline 
OL Week 8 
 
OL Week 16 
OL Week 24 
OL Week 48 
OL Week 72 
OL Week 96 
OL Safety Follow-up4 
1 
57 
 
113 
169 
337 
505 
673 
Not applicable 
Defined in Section 8.1 
[1, 85] where day 1 is post-
dose measurement 
(85, 141] 
(141, 253] 
(253, 421] 
(421, 589] 
(589, 687] 
Use nominal visit 


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Table 11-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3,4 
(in study days) 
Coagulation 
TC Safety Baseline 
OL Week 24 
 
OL Week 48 
OL Week 72 
OL Week 96 
1 
169 
 
337 
505 
673 
Defined in Section 8.1 
[1, 253] where day 1 is post-
dose measurement 
(253, 421] 
(421, 589] 
(589, 687] 
Notes: 
1Visit name for analysis purpose is used to report data in tables and figures. 
 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered 
missing for the visit. 
b. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. If the latest measurement cannot be determined, then unscheduled visit will be selected 
 
3 For measurement collected on the date of first dose of study drug in Treatment Period, if it cannot be determined 
whether the measurement is before or after the first dose:  
a. 
Scheduled measurement will be treated as pre-dose observation. 
b. Unscheduled measurement will be treated as post-dose observation. 
 
4 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 >687, then the ETT visit will be mapped into Safety 
Follow-up analysis visit.  
 
Derived Variables: 
1. Age (in years) at first dose date and post-baseline visit (for demographics, listing and the calculation of [percent] 
predicted spirometry variables): 
Obtain the age at informed consent in parent study (in days) in “yy, mm” format (e.g., 24 years, 6 months) from 
the Vital Signs (VS) page at the Screening Visit, and add 0.5 month to convert to days. 
Obtain the informed consent date. 
Then age (in years) at first dose or post-baseline visit = [(first dose date or post-baseline visit date – informed 
consent date) in days + age at informed consent in parent study (in days)]/365.25. 
2. Age (in months) at first dose or post-baseline visit (for use in calculation of BMI, height and weight z-score, as 
applicable): 
Obtain the age at informed consent (in months) in in parent study in “yy, mm” format (e.g., 24 years, 6 months) 
from Vital Signs (VS) page at the Screening Visit. 
Obtain the informed consent date. 
Then age (in months) at first dose or post-baseline visit = integer part of {[(age at informed consent (in months) 
+ 0.5 + diff (first dose or post-baseline visit date, informed consent date in parent study) 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. 


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Table 11-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3,4 
(in study days) 
If the last dose date is missing or partial date is reported, the last dose date will be imputed based on, in 
descending order priority, the Early Treatment Termination (ETT) visit date, last visit date before the Safety 
Follow-up, or the last study drug administration date from EX SDTM domain, as appropriate.  The imputation 
algorithm will ensure the imputed last dose date does not exceed the study participation end date. 
4. Sweat Chloride: 
Non-missing sweat chloride concentrations from the left arm and right arm with assessment end date/time for 
a given arm up to 30 minutes after first dose time in treatment period will be considered for baseline. 
5. Electrocardiogram: 
Baseline is defined as the most recent pretreatment measurement before the first dose of study drug in the 
Treatment Period.  If multiple ECG measurements are obtained on the same calendar day during the TE Period,  
o 
For summary purpose, the calculated average ECG will be used as the ECG value on that day;  
o For threshold analysis purpose, all reported ECG values will be used. 
 
 
 




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Appendix C: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and FEF25%-
75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 predicted 
values are available in: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 Regression 
Equation and Lookup Tables (Version 7 April 2013). Global Lung Function Initiative. [online] 
Available 
at: 
http://www.ers-education.org/home/browse-all-content.aspx?idParent=138978 
[Accessed Mar 26, 2018]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 regression 
equations (Version 19 July 2015). Global Lung Function Initiative. [online] Available at: 
http://www.ers-education.org/home/browse-all-content.aspx?idParent=138979 [Accessed Mar 
26, 2018].   
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. 
[online] 
Available 
at: 
http://www.ers-education.org/home/browse-all-
content.aspx?idParent=138988 [Accessed  Mar 26, 2018]. 
Data handling rule for spirometry is as follows:  
 Input age with at least 2 decimal places 
 Height collected at the respective visit should be used; if the height at the respective visit is not 
available, the last non-missing record will be used. 
 For race, map the CRF reported Black or African American to Black, all other races in CRF 
(except White) are mapped to 'other'; multiple checks for race in CRF are also mapped to 'other'; 
white is a reference race in the equations and assumes 0 values for all race coefficients in the 
GLI equations. 
 
 


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Appendix D: Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date are defined below.  If the imputed AE start 
date is before the 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 E: Criteria for Threshold Analysis 
Table 11-2 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤ 3xULN) or (AST>ULN - 
≤3xULN) 
(ALT>3x - ≤5xULN) or (AST>3x - 
≤5xULN) 
(ALT>5x - ≤8xULN) or (AST>5x - 
≤8xULN) 
(ALT>8x - ≤20xULN) or (AST>8x - 
≤20xULN) 
ALT>20xULN or AST>20xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5 - ≤5.0xULN 
>5.0 - ≤20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤1.5xULN 
>1.5 - ≤2xULN 
>2 - ≤3xULN  
>3 - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤1.5xULN 
>1.5 - ≤2xULN 
>2 - ≤3xULN  
>3 - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Indirect Bilirubin 
>ULN - ≤1.5xULN 
>1.5 - ≤2xULN 
>2 - ≤3xULN  
>3 - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 


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Table 11-2 
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 
>2.5 - ≤5.0xULN 
>5.0 - ≤20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN - ≥30 g/L 
<30 - ≥20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>1x - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤1.5xULN 
>1.5 - ≤3.0xULN 
>3.0 - ≤6.0xULN 
>6.0xULN 
CTCAE grades 1-4 
Lipase 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine kinase 
>ULN - ≤2.5xULN 
>2.5 - ≤5xULN 
>5 - ≤10xULN  
>10xULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥100 g/L 
<100 - ≥80 g/L  
<80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤20 g/L above ULN 
>20 g/L above ULN - ≤40 g/L above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥75.0 x 10e9 /L 
<75.0 - ≥50.0 x 10e9 /L  
<50.0 - ≥25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 


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Table 11-2 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
 
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 11-3 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
≤50 bpm  
 
Tachycardia 
≥140 bpm 
 
PR 
≥220 ms and increase from baseline ≥20 ms 
 
QRS 
≥120 ms 
 
QTc 
Absolute values (ms) 
>450 ms (Male); >470 ms (Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline 30-60 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction 
formula.  
 
Table 11-4 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
SBP 
 
>120 mmHg 
 
<70 mmHg 
 
DBP 
 
>80 mmHg 
 
<50 mmHg 
 
 
 


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Appendix F: Adverse Events of Special Interest  
Table 11.6 
MedDRA Preferred Terms for Event of Special Interest 
Adverse event of special interest 
MedDRA preferred terms 
Elevated transaminases 
Alanine aminotransferase abnormal, Alanine aminotransferase 
increased, Aspartate aminotransferase abnormal, Aspartate 
aminotransferase 
increased, 
Transaminases 
abnormal, 
Transaminases increased, Liver function test abnormal, Liver 
function test increased, Hypertransaminasaemia, Hepatic enzyme 
abnormal, Hepatic enzyme increased 
Rash 
Rash, Rash erythematous, Rash macular, Rash maculo-papular, 
Rash maculovesicular, Rash vesicular, Rash pruritic, Rash 
follicular, Rash pustular, Nodular rash, Drug eruption, Fixed 
eruption, Urticaria, Urticaria papular, Urticaria vesiculosa, 
Urticarial dermatitis, Rash morbilliform, Rash papular, Rash 
papulosquamous, Rash rubelliform, Rash scarlatiniform , Drug 
hypersensitivity, Type IV hypersensitivity reaction, Dermatitis, 
Dermatitis atopic, Epidermolysis, Skin toxicity, Dermatitis 
allergic, 
Dermatitis 
exfoliative, 
Dermatitis 
exfoliative 
generalised, 
Erythema 
multiforme, 
Exfoliative 
rash, 
Mucocutaneous 
rash, 
Acute 
generalised 
exanthematous 
pustulosis, Cutaneous vasculitis, Urticarial vasculitis, Dermatitis 
bullous, Drug reaction with eosinophilia and systemic symptoms, 
Epidermal necrosis, Oculomucocutaneous syndrome, Skin 
exfoliation, Skin necrosis, Stevens-Johnson syndrome, Toxic 
epidermal necrolysis, Toxic skin eruption, Perioral dermatitis, 
Vasculitic rash, Immune-mediated dermatitis, SJS-TEN overlap, 
Erythrodermic atopic dermatitis, Scrotal dermatitis, Anal rash 
Note: the preferred terms listed in the table is based on the MedDRA version applicable at the time of 
finalization of the SAP.  If the MedDRA version is upgraded at the time of the analysis, the 
corresponding preferred terms based on the upgraded version, including adding, removing and 
renaming the preferred terms, will be used in the analysis of adverse events of special interest.