Conditions: Cystic Fibrosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 86
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) in participants with CF who are 12 years of age or older.

Detailed description:

Arms:
arm 1: Participants received ELX 200 mg once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in the treatment period for up to 36 weeks.

Interventions: intervention 1: ELX/TEZ/IVA intervention 2: IVA
Intervention descriptions: intervention 1: Fixed-dose combination tablets for oral administration. intervention 2: Tablets for oral administration.

Protocol document:
Prot_000.pdf: 


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PROTOCOL SYNOPSIS 
Title 
A Phase 3b Open-label Study Evaluating the Safety of 
Elexacaftor/Tezacaftor/Ivacaftor Combination Therapy in Subjects With Cystic 
Fibrosis  
  
Brief Title 
A Study Evaluating the Safety of Elexacaftor/Tezacaftor/Ivacaftor in Subjects 
With Cystic Fibrosis   
 
 
Clinical Phase and 
Clinical Study Type  
Phase 3b, safety 
 
 
Objectives 
Primary Objective 
To evaluate the safety and tolerability of Elexacaftor (ELX)/Tezacaftor 
(TEZ)/Ivacaftor (IVA) in subjects with Cystic Fibrosis (CF) 
 
 
Endpoints 
Primary Endpoint 
Safety and tolerability of ELX/TEZ/IVA based on adverse events (AEs), clinical 
laboratory values, ECGs, vital signs, and pulse oximetry 
 
 
Number of Subjects 
Subjects who participated in a parent study (VX19-445-117 or VX20-445-126) 
and meet the eligibility criteria may enroll. Up to approximately 160 subjects are 
expected to enroll in this open-label extension study. 
  
 
Study Population 
Male and female subjects with CF who are 12 years of age or older  
 
 
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: 100-mg ELX/50-mg TEZ/75-mg IVA 
FDC tablets for oral administration 
 
 
 
Active substance: IVA (VX-770) 
 
Activity: CFTR potentiator 
 
Strength and route of administration: 150-mg IVA tablets for oral 
administration 
 
 
Study Duration 
The total study duration is approximately 52 weeks (from the first dose of study 
drug in this study), including a Treatment Period of 48 weeks and a Safety 
Follow-up Visit 4 weeks after the last dose of study drug. 
 
 
Study Design 
This is a Phase 3b, multicenter, open-label study for subjects who complete a 
parent study (VX19-445-117 or VX20-445-126) and meet eligibility criteria. A 
schematic of the study design is shown in Figure 2-1. 
 
 
 


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Figure 2-1 
VX20-445-121 Study Design 
ELX: elexacaftor; IVA: ivacaftor; TEZ: tezacaftor 
Note: Figure is not drawn to scale. 
Subjects will receive a dose of ELX 200 mg once daily (qd)/TEZ 100 mg qd/IVA 
150 mg every 12 hours (q12h). 
For treatment continuity in regions where ELX/TEZ/IVA is not commercially 
available, an option to return to this study will be offered to subjects who depart 
this study to enroll in another Vertex study of investigational CFTR modulators 
(hereafter referred to as “another qualified Vertex study”) based on the following:  
• 
Subjects have received open-label ELX/TEZ/IVA during the other study’s 
Run-in Period but have not received study drug in the Treatment Period of the 
other study, and 
• 
Meet all eligibility criteria for this study at their Returning Visit 
Subjects who resume participation in this study will resume treatment with study 
drug after completion of a Returning Visit. Resumption of participation in this 
study following departure to another qualified Vertex study will be permitted only 
once. 
 
 
Assessments 
Safety: AEs, clinical laboratory assessments, ECGs, vital signs and pulse 
oximetry, physical examinations (PEs), and ophthalmologic examinations 
 
 
Statistical Analyses 
The safety analysis will be conducted for subjects who have received at least 
1 dose of study drug in this open-label study. The safety analysis will be 
descriptive only. 
 
 


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SCHEDULE OF ASSESSMENTS 
Schedules 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. 
Subjects who depart this study to enroll in another qualified Vertex study, and who meet the 
eligibility criteria in Section 8, may resume participation in this study only once. 
 








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TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments ........................................................................................................ 5 
4 
Table of Contents ................................................................................................................... 9 
List of Tables ........................................................................................................................... 12 
List of Figures .......................................................................................................................... 12 
List of Abbreviations ............................................................................................................... 13 
5 
Introduction .......................................................................................................................... 15 
5.1 
Background ..................................................................................................................... 15 
5.2 
Study Rationale .............................................................................................................. 15 
6 
Study Objectives .................................................................................................................. 15 
6.1 
Primary Objective ........................................................................................................... 15 
7 
Study Endpoints ................................................................................................................... 16 
7.1 
Primary Endpoint ............................................................................................................ 16 
8 
Study Population .................................................................................................................. 16 
8.1 
Inclusion Criteria ............................................................................................................ 16 
8.2 
Exclusion Criteria ........................................................................................................... 16 
9 
Study Implementation ......................................................................................................... 17 
9.1 
Study Design .................................................................................................................. 17 
9.1.1 
Treatment Period .................................................................................................... 18 
9.1.2 
Follow-up ................................................................................................................ 18 
9.1.3 
Early Termination of Treatment ............................................................................. 19 
9.1.4 
Lost to Follow-up ................................................................................................... 19 
9.1.5 
Completion of Study Participation ......................................................................... 20 
9.1.6 
Use of Remote Measures ........................................................................................ 20 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 20 
9.3 
Rationale for Study Elements ......................................................................................... 20 
9.3.1 
Study Design and Population ................................................................................. 20 
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 ............................................................................... 21 
9.6 
Administration ................................................................................................................ 22 
9.6.1 
Dosing ..................................................................................................................... 22 
9.6.2 
Missed Doses .......................................................................................................... 23 
9.7 
Dose Modification for Toxicity ...................................................................................... 23 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 23 
9.8.1 
Liver Function Tests ............................................................................................... 23 
9.8.2 
Rash ........................................................................................................................ 24 
9.9 
Removal of Subjects ....................................................................................................... 24 
9.10 Replacement of Subjects ................................................................................................ 25 
10 Study Drug Information and Management ....................................................................... 25 
10.1 Preparation and Dispensing ............................................................................................ 25 


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10.2 Packaging and Labeling ................................................................................................. 25 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 25 
10.4 Drug Accountability ....................................................................................................... 26 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 26 
10.6 Compliance ..................................................................................................................... 26 
10.7 Blinding and Unblinding ................................................................................................ 26 
11 Assessments .......................................................................................................................... 27 
11.1 Subject and Disease Characteristics ............................................................................... 27 
11.2 Safety .............................................................................................................................. 27 
11.2.1 
Adverse Events ....................................................................................................... 27 
11.2.2 
Clinical Laboratory Assessments ........................................................................... 27 
11.2.3 
Physical Examinations and Vital Signs .................................................................. 29 
11.2.4 
Height and Weight .................................................................................................. 29 
11.2.5 
Pulse Oximetry ....................................................................................................... 29 
11.2.6 
Electrocardiograms ................................................................................................. 29 
11.2.7 
Ophthalmologic Examination ................................................................................. 30 
11.2.8 
Contraception and Pregnancy ................................................................................. 30 
11.2.8.1 Contraception ................................................................................................... 30 
11.2.8.2 Pregnancy ......................................................................................................... 32 
12 Statistical Analysis ............................................................................................................... 32 
12.1 Sample Size .................................................................................................................... 32 
12.2 Analysis Sets .................................................................................................................. 32 
12.3 Statistical Analysis ......................................................................................................... 32 
12.3.1 
General Considerations ........................................................................................... 32 
12.3.2 
Background Characteristics .................................................................................... 33 
12.3.2.1 Subject Disposition .......................................................................................... 33 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 33 
12.3.2.3 Prior and Concomitant Medications ................................................................ 33 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 34 
12.3.2.5 Important Protocol Deviations ......................................................................... 34 
12.3.3 
Efficacy Analysis .................................................................................................... 34 
12.3.4 
Safety Analysis ....................................................................................................... 34 
12.3.4.1 Adverse Events ................................................................................................ 35 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 36 
12.3.4.3 Electrocardiogram ............................................................................................ 36 
12.3.4.4 Vital Signs ........................................................................................................ 36 
12.3.4.5 Pulse Oximetry ................................................................................................. 37 
12.3.4.6 Other Safety Analyses ...................................................................................... 37 
12.4 Interim Analysis ............................................................................................................. 37 
12.5 Data Monitoring Committee Analysis ............................................................................ 37 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 37 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 37 
13.1.1 
Adverse Events ....................................................................................................... 37 
13.1.1.1 Definition of an Adverse Event........................................................................ 37 
13.1.1.2 Clinically Significant Assessments .................................................................. 37 


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13.1.1.3 Documentation of Adverse Events................................................................... 38 
13.1.1.4 Adverse Event Severity .................................................................................... 39 
13.1.1.5 Adverse Event Causality .................................................................................. 39 
13.1.1.6 Study Drug Action Taken ................................................................................ 40 
13.1.1.7 Adverse Event Outcome .................................................................................. 40 
13.1.1.8 Treatment Given............................................................................................... 40 
13.1.2 
Serious Adverse Events .......................................................................................... 41 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 41 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 41 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 42 
13.2 Administrative Requirements ......................................................................................... 42 
13.2.1 
Product Complaints ................................................................................................ 42 
13.2.2 
Ethical Considerations ............................................................................................ 42 
13.2.3 
Subject Information and Informed Consent ........................................................... 43 
13.2.4 
Investigator Compliance ......................................................................................... 43 
13.2.5 
Access to Records ................................................................................................... 43 
13.2.6 
Subject Privacy ....................................................................................................... 43 
13.2.7 
Record Retention .................................................................................................... 44 
13.2.8 
Study Termination .................................................................................................. 44 
13.2.9 
End of Study ........................................................................................................... 44 
13.3 Data Quality Assurance .................................................................................................. 44 
13.4 Monitoring ...................................................................................................................... 45 
13.5 Electronic Data Capture ................................................................................................. 45 
13.6 Confidentiality and Disclosure ....................................................................................... 45 
13.7 Publications and Clinical Study Report .......................................................................... 45 
 
 
13.7.2 
Clinical Study Report ............................................................................................. 46 
14 References ............................................................................................................................. 47 
15 Protocol Signature Pages .................................................................................................... 48 
15.1 Sponsor Signature Page .................................................................................................. 48 
15.2 Investigator Signature Page ............................................................................................ 49 
 


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List of Tables 
Table 3-1 
Study VX20-445-121: Treatment Period and Safety Follow-up Visit ................... 6 
Table 9-1 
Prohibited Medications ......................................................................................... 21 
Table 10-1 
Study Drug: Dosing Form/Route/Strength ........................................................... 26 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 28 
Table 11-2 
Acceptable Methods of Contraception .................................................................. 31 
Table 13-1 
Grading of AE Severity ........................................................................................ 39 
Table 13-2 
Classifications for AE Causality ........................................................................... 39 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 40 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 40 
List of Figures 
Figure 2-1 
VX20-445-121 Study Design ................................................................................. 4 
Figure 9-1 
VX20-445-121 Study Design ............................................................................... 17 
 


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List of Abbreviations 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BMI 
body mass index 
CF 
cystic fibrosis 
CFTR 
cystic fibrosis transmembrane conductance regulator gene 
CFTR 
cystic fibrosis transmembrane conductance regulator protein 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ELX 
elexacaftor 
ETT 
Early Termination of Treatment 
EU 
European Union 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GPS 
Global Patient Safety 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) (US) 
IPD 
important protocol deviation 
IRB 
institutional review board 
IVA 
ivacaftor 
LUM 
lumacaftor 
max 
maximum value 
min 
minimum value 
n 
size of subsample 
OATP1B1 
organic anion transporter protein 1B1 
PE 
physical examination 
P-gp 
P-glycoprotein 


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Abbreviation 
Definition 
PI 
principal investigator 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval, segment 
PT 
Preferred Term 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QT 
QT interval 
QTcF 
QT interval corrected by Fridericia’s formula 
RR 
interval from the onset of 1 QRS complex to the next 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SUSAR 
suspected, unexpected, serious adverse reaction 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
 
 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive genetic disease with serious morbidities and 
frequent premature mortality. CF affects more than 80,000 individuals worldwide 
(approximately 31,000 in the US and 49,000 in the EU).1-4  
CF is caused by decreased quantity and/or function of the CFTR protein due to mutations in the 
CFTR gene.5 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.6 Despite progress in the treatment of CF with symptomatic therapies, 
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.1, 2 More effective treatments are 
needed for CF. 
The most common disease-causing mutation is F508del: approximately 85.3% of people with CF 
in the US and 80.6% in Europe have at least one F508del allele.1, 2 
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.7, 8 The clinical testing and regulatory approval of CFTR modulators in certain 
countries for the treatment of people with CF caused by specific CFTR genotypes have 
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 
(Trikafta™, Kaftrio™).  
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 evaluate the safety of 48 weeks of treatment with ELX/TEZ/IVA in subjects with 
CF who complete a parent study (VX19-445-117 or VX20-445-126). The potential for benefit in 
these patients is supported by published Phase 2 and publicly disclosed Phase 3 clinical data in 
subjects with CF. In addition, ELX/TEZ/IVA is generally safe and well tolerated (refer to 
ELX/TEZ/IVA Investigator’s Brochure). 
Data from this study are intended to enrich the body of evidence showing that ELX/TEZ/IVA is 
safe and well tolerated in subjects with CF.  
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the safety and tolerability of ELX/TEZ/IVA in subjects with CF 


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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  
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 VX19-445-117 or VX20-445-126. 
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 a parent study. 
4. Meets at least 1 of the following criteria: 
• Completed study drug treatment in a parent study. 
• Had study drug interruption(s) in a parent study, but did not permanently discontinue 
study drug, and completed study visits up to the last scheduled visit of the Treatment 
Period of a parent study. 
5. For subjects being considered for resumption of participation in this study after enrolling in 
another Vertex study of investigational CFTR modulators (referred to as “another qualified 
Vertex study”): Completed the ETT visit in another qualified Vertex study before or on the 
same day as the Returning Visit in this study. If more than 30 days have elapsed since the 
ETT visit in the other qualified Vertex study, approval of the medical monitor is required. 
6. 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 a 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). 
3. Pregnant and breast-feeding females. Female subjects must have a negative pregnancy test at 
the Day 1 Visit before receiving the first dose of study drug. 
4. Current participation in an investigational drug trial other than a parent study. Participation in 
a noninterventional study (including observational studies, registry studies, and studies 


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requiring blood collections without administration of study drug) and screening for another 
Vertex study is permitted. 
5. For subjects being considered for resumption of participation in this study after enrolling in 
another qualified Vertex study, the following exclusion criteria also apply: 
• Subject received the first dose of study drug in the Treatment Period of another qualified 
Vertex study, 
• Subject has access to commercially available ELX/TEZ/IVA or is receiving 
managed-access-program-supplied ELX/TEZ/IVA, or 
• Subject departed this study more than once to participate in another qualified Vertex 
study.  
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3b, multicenter, open-label study for subjects who complete a parent study 
(VX19-445-117 or VX20-445-126) and meet eligibility criteria (Section 8). A schematic of the 
study design is shown in Figure 9-1.  
Study visits and assessments are shown in Table 3-1. All visits will occur within the windows 
specified. 
Figure 9-1 
VX20-445-121 Study Design 
 
ELX: elexacaftor; IVA: ivacaftor; TEZ: tezacaftor 
Note: Figure is not drawn to scale. 
Subjects will receive a dose of ELX 200 mg once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 
12 hours (q12h). 
For treatment continuity in regions where ELX/TEZ/IVA is not commercially available, an 
option to return to this study will be offered to subjects who depart this study to enroll in another 
qualified Vertex study based on the following: 
• Subjects have received open-label ELX/TEZ/IVA during the other study’s Run-in Period but 
have not received study drug in the Treatment Period of the other study, and 
• Meet all eligibility criteria for this study (Section 8) at their Returning Visit. 


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Subjects who resume participation in this study will resume treatment with study drug after 
completion of a Returning Visit. Resumption of participation in this study following departure to 
another qualified Vertex study will be permitted only once.  
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 from a parent study or another qualified Vertex study 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. 
The Day 1 Visit should be on the same day as the last scheduled visit of a parent study. Subjects 
whose Day 1 Visit is NOT within 1 day of the last scheduled visit of a parent study will repeat all 
Day 1 assessments. 
Subjects whose Day 1 Visit is within 1 day of the last scheduled visit of a parent study will NOT 
have to repeat any Day 1 assessments that were specified to be performed at the last scheduled 
visit in a parent study.  
Subjects Resuming Participation After Discontinuation From Another Qualified Vertex 
Study 
Subjects who resume participation in this study will complete the Returning Visit and resume 
treatment with ELX/TEZ/IVA after completion of the Returning Visit. Study visit numbering for 
returning subjects will resume based on the last study visit before the Departing Visit in this 
study.  
The Early Termination of Treatment (ETT) Visit in another qualified Vertex study and the 
Returning Visit in this study may occur on the same day. If completed on the same day or within 
1 calendar day, any assessments completed at the ETT in the other qualified Vertex study do not 
have to be repeated at the Returning Visit in this study. 
Subjects who resume participation but have their first dose of study drug in this study delayed 
will repeat the safety assessments specified to be performed at the Returning Visit before 
receiving their first dose of study drug (see Section 3).  
If the subject’s Returning Visit window coincides with a scheduled study visit in this study, only 
the Returning Visit assessments will be completed, after which subjects will resume study visits 
in this study.  
9.1.2 
Follow-up 
Subjects will have a Safety Follow-up Visit 28 (± 7) days after the last dose of study drug. 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 


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• managed-access-program-supplied Vertex CFTR modulator regimen  
• or, to another qualified Vertex study  
will complete the Week 48 Visit (or the Early Termination of Treatment [ETT] Visit/Departing 
Visit, if the transition occurs before the Week 48 Visit). In these cases, the Week 48 Visit (or the 
ETT Visit/Departing Visit) will replace the Safety Follow-up Visit. 
For subjects who complete an ETT Visit/Departing Visit 3 weeks or later following the last dose 
of study drug, the ETT Visit/Departing Visit will replace the Safety Follow-up Visit 
(Section 9.1.3). 
9.1.3 
Early Termination of Treatment  
Departing Visit 
If a subject enrolls in another qualified Vertex study, the Departing Visit should be completed 
before or on the same day as the visit at which they receive the first dose of study drug in the 
Run-in Period of the other qualified Vertex study. If completed on the same day, the Schedule of 
Assessments in the other qualified Vertex study should be followed and study assessments in this 
study that were specified to be performed in the other qualified Vertex study do not have to be 
repeated. If the subject does not resume participation in this study, they will not be required to 
complete a separate ETT visit.  
ETT Visit 
If a subject prematurely discontinues study treatment for any reason other than to enroll in 
another qualified Vertex study, an ETT Visit should be scheduled as soon as possible after the 
subject decides to terminate study 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, and a separate Safety Follow-up Visit will not be 
required.  
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 (Section 9.9). 
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 study visit) and is 
subsequently unable to be contacted by telephone (3 documented attempts by telephone 
within 2 weeks following the second missed visit) 
• The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 


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9.1.5 
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, Departing Visit, or the Week 48 Visit replaces the 
Safety Follow-up Visit (Section 9.1.2), the ETT Visit, Departing Visit, or the Week 48 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  
Remote measures may be used for a number of study visits as detailed in Table 3-1. The decision 
whether to conduct a study visit remotely or in clinic will be at the discretion of the investigator; 
if the investigator determines that study visits will be conducted remotely, the medical monitor 
should be notified.  
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. 
• Electronic or remote consent and reconsent may be used, 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 may be conducted as in-home visits by qualified personnel. All visits must have 
a consultation between the subject and investigator (i.e., in person, phone, or telemedicine 
video conference) within 1 business day after the home health visit, which can be outside the 
visit window. 
• Study assessments may be performed or overseen by qualified personnel conducting the 
in-home visits using Vertex supplied equipment, as applicable (e.g., weight measurement). 
• 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 and Population 
This Phase 3b study will enroll subjects who completed a parent study of ELX/TEZ/IVA and 
meet eligibility criteria. Results from this study will provide information on the safety of 
ELX/TEZ/IVA in subjects with CF who are 12 years of age and older. 


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9.3.2 
Study Drug Dose and Duration 
To evaluate safety and tolerability the study drug doses evaluated are the same as the doses 
evaluated in a parent study.  
The overall treatment duration will be 48 weeks, which is considered sufficient for evaluating the 
safety of treatment with ELX/TEZ/IVA. 
9.3.3 
Rationale for Study Assessments 
All safety assessments are standard parameters for clinical studies in drug development. 
9.4 
Study Restrictions 
Table 9-1 lists prohibited medications. A non-exhaustive list of study prohibitions and cautions 
for medications will be provided in the Study Reference Manual. Guidance of concomitant 
medications is provided in Section 9.5. 
Table 9-1 
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 a 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. For subjects who 
enroll in another qualified Vertex study and resume participation in this study, any new 
medications started after the subject first departs this study will be collected for the period after 
the Departing Visit and before study drug dosing resumes in this study, through completion of 
study participation. 
• 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 


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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. 
• 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.  
9.6 
Administration 
9.6.1 
Dosing 
Study drug tablets will be administered orally as ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg 
q12h (e.g., 2 ELX/TEZ/IVA fixed-dose combination [FDC] tablets in the morning and 1 IVA 
tablet in the evening). Additional information is provided in the Pharmacy Manual. 
Study drug should be administered with a fat-containing meal or snack, such as a standard “CF” 
meal or snack or a standard meal according to the following guidelines: 
1. It is recommended that the dose be taken within 30 minutes of the start of the meal or snack. 
2. All doses of study drug (morning and evening, as applicable) should be administered at 
approximately every 12 hours (± 2 hours) on each dosing occasion (e.g., if the morning doses 
of study drug are administered at 08:00 hour on Day 1, all subsequent morning doses should 
be administered between 06:00 hour and 10:00 hour). 
3. On days of scheduled clinic visits, the morning dose of ELX/TEZ/IVA will be administered 
at the site after predose assessments have been completed, if applicable. The meal or snack 
will be provided by the site for the morning dose of ELX/TEZ/IVA. 


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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 (TE) ALT or AST elevations of >3 × ULN, with or 
without total bilirubin >2 × ULN, must be followed closely, including confirmatory testing 
performed by the central laboratory within 48 to 72 hours of the initial finding and subsequent 
close monitoring of ALT, AST, and bilirubin levels, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results must be reported immediately to the medical monitor, and the subject 
must have the tests repeated and sent to the central laboratory as soon as possible (ideally within 
48 to 72 hours). 
Study drug administration must be interrupted immediately (prior to confirmatory testing) if 
any of the following criteria are met: 


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• 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 from study drug treatment at any 
time at the discretion of the investigator or Vertex for safety, behavior, noncompliance with 
study procedures, or administrative reasons. A subject who withdraws from study drug treatment 
will continue to be followed unless the subject withdraws consent.  


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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 11.2.8.2) 
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 9.1.2), 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.  
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 
ELX/TEZ/IVA, FDC tablet, oral 
 
ELX 
100 mg 
TEZ 
50 mg 
IVA 
75 mg 
IVA, tablet, oral 
150 mg 
ELX: elexacaftor; FDC: fixed-dose combination; IVA: ivacaftor; TEZ: tezacaftor 
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 should review the 
drug accountability documentation on a regular basis. The study monitor will promptly 
communicate to Vertex any discrepancies he/she is unable to resolve with the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
The principal investigator, study site staff, including pharmacy personnel will assist Vertex with 
any recall activities (as applicable) and place impacted investigational medicinal product (IMP) 
in quarantine when requested. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the 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. 


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11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1.  
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. Select demographic and baseline characteristic and medical history will be derived 
from a parent study. 
11.2 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, physical examinations (PEs), and pulse oximetry.  
For subjects <18 years of age on the date of informed consent in a parent study, 
ophthalmological examinations will be performed as specified in Table 3-1. 
11.2.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with current ICH E6 GCP 
Guidelines. Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs.  
11.2.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, with the exception of the urine 
pregnancy test. As described below, urine pregnancy tests will either be analyzed by the site or at 
home using a home pregnancy test kit. On Day 1 (and the Returning Visit if applicable), blood 
samples will be collected before the first dose of the study drug.  
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 Female Subjects: 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 study 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 (and the Returning Visit 
if applicable) 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. 
Follicle-stimulating Hormone (FSH): Blood samples for FSH may be measured as needed for 
any suspected postmenopausal female with at least 12 months of continuous spontaneous 
amenorrhea. Serum FSH levels must be in the postmenopausal range as determined by the 
laboratory performing the test. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 
becomes aware of the abnormal result. If it is not possible to send a timely specimen to the 


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central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base the 
assessment of an AE on the local laboratory value. 
11.2.3 
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 Day 1, 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.  
11.2.4 
Height and Weight 
Height and weight will be measured with shoes off. For subjects whose date of informed consent 
occurs after their 21st birthday, height will not be collected in this study. For subjects whose date 
of informed consent occurs on or before their 21st birthday, height will be collected through the 
first visit after the subject’s 21st birthday and does not need to be collected at future visits. 
11.2.5 
Pulse Oximetry 
Pulse oximetry is a noninvasive measure of oxygen delivery to the tissues and has been 
correlated with clinical status and lung function. Arterial oxygen saturation by pulse oximetry 
will be assessed following at least a 5-minute rest and before study drug dosing. 
11.2.6 
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 (HR), such as 
blood draws. 
• The subject will be instructed to rest for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position. 
A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. Clinically significant ECG abnormalities occurring during the study 
through study completion 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 


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ECGs fall below the threshold value that triggered the repeat measurement. A subject with a 
QTcF value above the threshold value will discontinue dosing. 
11.2.7 
Ophthalmologic Examination 
Ophthalmologic examinations will be conducted only for subjects who are <18 years of age on 
the date of informed consent in a parent study. The examination does not need to be completed if 
there is documentation of bilateral lens removal for the subject. 
All examinations will be conducted by a licensed ophthalmologist or optometrist and will 
include: 
• measurement of best-corrected distance visual acuity of each eye; and 
• pharmacologically dilated examination of the lens with a slit lamp. 
Subjects who are <18 years of age on the date of informed consent in a parent study will have an 
ophthalmologic examination by the Week 48 Visit or the ETT Visit/Departing Visit (for subjects 
who prematurely discontinue study drug if the subject has received at least 12 weeks of study 
drug [in a parent study and current study] since their last ophthalmologic examination), 
whichever comes first; except for those subjects who have withdrawn consent or assent. This 
examination should be completed within 4 weeks before the Week 48 Visit, unless the subject 
prematurely discontinues study drug, in which case this examination should occur by the Safety 
Follow-up Visit (or ETT Visit/Departing Visit for subjects who do not complete a Safety 
Follow-up Visit), as described in Table 3-1. 
Any clinically significant abnormal findings will be reported as AEs. 
11.2.8 
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. 
11.2.8.1 
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 subject is male and is infertile (e.g., bilateral orchiectomy). If a male subject is assumed 
to have complete bilateral absence of the vas deferens, infertility must be documented before 
the first dose of study drug (e.g., examination of a semen specimen or by demonstration of 
the absence of the vas deferens by ultrasound). 
• If the subject is female and is of non-childbearing potential. To be considered of 
non-childbearing potential, the female must meet at least 1 of the following criteria: 


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o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH 
level within the laboratory’s reference range for postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
o Note: All other females (including females with tubal ligations and premenarchal 
females) will be considered to be of childbearing potential. 
• Same-sex relationships 
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used. Methods of contraception must be in successful use from signing of consent (or assent, 
when applicable), approximately 28 days before the first dose of study drug (unless otherwise 
noted), and until 90 days following the last dose of study drug. Additional contraception 
requirements may need to be followed according to local regulations and/or requirements. 
Acceptable methods of contraception are listed in Table 11-2. 
Table 11-2 
Acceptable Methods of Contraception 
 
Male Subjects and 
Their Female 
(Non-study) Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy performed at least 6 months previously, 
with a documented negative postvasectomy semen 
analysis for sperm 
Yes 
Yes 
Bilateral tubal occlusion (e.g., ligation) performed at 
least 6 months previously 
Yes 
Yes 
Male or female condom with or without spermicidea 
Yes 
Yes 
Female barrier contraception (such as diaphragm, 
cervical cap, or sponge) with spermicide 
Yes 
Yes 
Continuous use of an intrauterine device for at least 
90 days before the first dose of study drug 
 
 
 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. 


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• 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. 
11.2.8.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a female subject becomes pregnant during study participation, study drug will be permanently 
discontinued immediately. The investigator will notify the medical monitor and Vertex Global 
Patient Safety (GPS) within 24 hours of the site’s knowledge of the subject’s (or partner’s) 
pregnancy using the Pregnancy Information Collection Form. Male subjects with female partners 
who become pregnant during the study must use a male condom to avoid exposure of a potential 
embryo or fetus to study drug via the seminal fluid. 
The subject or partner will be followed until the end of the pregnancy and the infant will be 
followed for 1 year after the birth, provided informed consent is obtained. A separate ICF will be 
provided to explain these follow-up activities. Pregnancy itself does not constitute an AE. 
12 
STATISTICAL ANALYSIS 
12.1 
Sample Size 
The primary objective of the study is the evaluation of the safety of ELX/TEZ/IVA. This is an 
open-label extension study that will enroll the subjects from parent studies who meet eligibility 
criteria in this study.  
Up to approximately 160 subjects are expected to enroll in this open-label extension study. 
12.2 
Analysis Sets 
The All Subjects Set is defined as all subjects who were enrolled (defined as subject having data 
in the clinical database) in this study. This analysis set will be used for individual subject data 
listings and disposition summary tables unless otherwise specified. 
The Safety Set is defined as all subjects who have received at least 1 dose of study drug in this 
study. The Safety Set will be used for subject demographics and baseline characteristics and for 
all safety analyses unless otherwise specified.  
12.3 
Statistical Analysis 
12.3.1 
General Considerations 
All individual subject data for subjects who were enrolled or received at least 1 dose of study 
drug will be presented in individual subject data listings. 
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. 
Baseline value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of ELX/TEZ/IVA either 
in a parent study or this study, as applicable. For assessments collected in duplicate or triplicate, 
the baseline value will be defined as the average of non-missing values. 
Change (absolute change) from baseline will be calculated as Post-baseline value − Baseline 
value. 
TE Period will include the time from the first dose of study drug in this study to 28 days after 
the last dose of study drug or to the completion of study participation (as defined in 
Section 9.1.5), whichever occurs first. For subjects who enroll in another qualified Vertex study 
before completing this study and resume participation in this study, the TE Period will exclude 
the time spent in the other study.   
12.3.2 
Background Characteristics 
Subject disposition, demographic and baseline characteristics, prior and concomitant 
medications, exposure, compliance, and important protocol deviations (IPDs) will be 
summarized. 
12.3.2.1 
Subject Disposition 
Subject disposition will be summarized for the All Subjects Set. The number and percentage of 
subjects in the following categories will be summarized as appropriate: 
• All Subjects Set 
• Safety Set 
• Completed treatment 
• Prematurely discontinued treatment and the reasons for discontinuation 
• Completed study 
• Prematurely discontinued the study and the reasons for discontinuation 
• Departed this study to enroll in another qualified Vertex study 
• Departed this study to enroll in another qualified Vertex study and returned to this study 
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 a parent study baseline.  
The following demographics and baseline characteristics will be summarized for the Safety Set 
and will include (but are not limited to) sex, race, age, baseline weight, baseline height, and 
baseline body mass index (BMI), and baseline percent predicted forced expiratory volume in 
1 second (ppFEV1). 
Medical history will be summarized descriptively for the Safety Set. 
12.3.2.3 
Prior and Concomitant Medications 
Medications used will summarized descriptively and categorized as the following: 


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• Prior medication: any medication that was administered within the 56 days before the first 
dose of study drug in this open-label study. For subjects who enroll in another qualified 
Vertex study and resume participation in this study, any new or changed medication 
administered after the Departing Visit and prior to the first dose of study drug after resuming 
participation in this study will also be considered prior medication. 
• 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 Safety Set. 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 Safety Set, 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. For subjects who enroll in another qualified Vertex study 
and resume participation in this study, time spent in the other study will be excluded. 
Study drug compliance will be summarized based on the Safety Set 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. For subjects who enroll in 
another qualified Vertex study and resume participation in this study, time spent in the other 
study will be excluded. 
12.3.2.5 
Important Protocol Deviations 
An 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 
Not applicable. 
12.3.4 
Safety Analysis 
All safety analyses will be based on the TE Period in this open-label study for subjects in the 
Safety Set, unless otherwise specified. 


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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 
All safety data will be presented in individual subject data listings. Only descriptive analyses of 
safety data will be performed. Additional details will be described in the statistical analysis plan 
(SAP). 
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 a parent study and 
before the first dose of ELX/TEZ/IVA in the TE Period in the open-label study. For subjects 
who depart this study to enroll in another qualified Vertex study and resume participation in 
this study, details of pre-treatment AEs will be specified in the SAP. 
• 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: 
• Overview of TEAEs 
• TEAEs 
• Related TEAEs 
• TEAEs by maximum severity 
• TEAEs by strongest relationship  
• Grade 3 and Grade 4 TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• TEAEs leading to death 


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Summaries will be presented 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 
• Grade 3/4 TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• TEAEs leading to death 
In addition, all AEs, including pre- and post-treatment AEs, will be presented in individual 
subject data listings 
12.3.4.2 
Clinical Laboratory Assessments 
For the 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 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). 


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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 
Other Safety Analyses 
Details of other safety analyses may be included in the SAP. 
12.4 
Interim Analysis 
Not applicable 
12.5 
Data Monitoring Committee Analysis 
Not applicable.  
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 


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Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the following times: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, withdrawal of 
consent) 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up Visit 
• For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of 
o 28 days after the last dose of study drug, or 
o the ETT Visit, if that visit is 3 weeks or later following the last dose of study drug 
(see Section 9.1.3) 
• For subjects who depart this study to enroll in another qualified Vertex study: through the 
time of enrollment in another qualified Vertex study 
• For subjects who depart this study to enroll in another qualified Vertex study and resume 
participation in this study, AEs will be collected from the time of the Returning Visit until 
the subject completes study participation in this study. AEs that fully occur (start and end) in 
the other qualified Vertex study will be recorded as medical history; AEs that started during 
participation in the other qualified Vertex study and are ongoing at the time of the Returning 
Visit in this study will be recorded as AEs in this study.  
All subjects or the subjects’ parents or legal guardians, as appropriate, 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 


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13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
February 2022). When considering the severity of an AE in a pediatric subject, the investigator 
will consider that reference ranges for pediatric clinical laboratory parameters may differ from 
those in the CTCAE. The severity of an AE described by a term that does not appear in the 
CTCAE will be determined according to the definitions in Table 13-1.  
Table 13-1 
Grading of AE Severity  
Classification 
Description 
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 (Moderate) 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADLa 
Grade 3 (Severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADLb 
Grade 4 (Life-
threatening) 
Life-threatening consequences; urgent intervention indicated  
Grade 5 (Death) 
Death related to adverse event 
Source: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed February 2022) 
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.  


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Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
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 9.7 and 9.8 for directions regarding what drug actions are permitted per protocol.  
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow up) 
AE: adverse event 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE. 


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13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation and is suspected of being a delayed toxicity due to administration of the study 
drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious”, which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through 
completion of study participation, 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 subjects who depart this study to participate in another qualified Vertex study, SAEs will be 
collected in the same manner as described for AEs (Section 13.1.1.3). 
For SAEs that occur after obtaining informed consent and assent (where applicable) through 
completion of study participation, the SAE Form will be completed for new/initial events as well 


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as to report follow-up information on previously reported events. Investigators are asked to 
report follow-up information as soon as it becomes available to ensure timely reporting to health 
authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email:
(preferred choice) 
Fax: 
  
For technical issues related to submitting the form, contact telephone: 
 
SAEs that occur after completion of study participation and are considered related to study 
drug(s) will be recorded on the Vertex Clinical Trial Safety Information Collection Form 
(hereafter referred to as the “SAE Form”) using a recognized medical term or diagnosis that 
accurately reflects the event. SAEs will be assessed by the investigator for relationship to the 
investigational study drug(s) and possible etiologies. On the SAE Form, relationship to study 
drug(s) will be assessed only as related (includes possibly related) or not related (includes 
unlikely related), and severity assessment will not be required. For the purposes of study 
analysis, if the event has not resolved at the end of the study reporting period, it will be 
documented as ongoing. For purposes of regulatory safety monitoring, the investigator is 
required to follow the event to resolution and report the outcome to Vertex using the SAE Form. 
13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IEC, and 
participating investigators in accordance with current ICH E2A Guidelines and/or local 
regulatory requirements, as applicable. In addition, Vertex, or authorized designee, will be 
responsible for the submission of safety letters to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/ IEC of all 
unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Product Complaints 
A product complaint is defined as any verbal or written communication addressed to Vertex, or 
designee, of inquiry or dissatisfaction with the identity, strength, quality, or purity of a released 
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 


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documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.3 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
current ICH E6 GCP Guidelines and all applicable laws and regulations and will be subject to 
approval by Vertex or its designee. 
13.2.4 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
13.2.5 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.6 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all data provided to Vertex, 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 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 


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requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.7 
Record Retention 
The investigator will maintain all study records according to current ICH E6 GCP Guidelines 
and/or applicable local regulatory requirement(s), whichever is longest, as described in the 
Clinical Trial Agreement. If the investigator withdraws from the responsibility of keeping the 
study records, custody will be transferred to a person willing to accept the responsibility and 
Vertex will be notified. 
13.2.8 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.2.9 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
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. Vertex 
will provide, or assess and approve, any electronic data capture (EDC) tools. 
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. Data 
collected during the study will be recorded in a data capture system for each enrolled subject. 
Each subject’s set of captured data records, once complete, will be signed and dated by the 
investigator. 


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13.4 
Monitoring 
The study will be monitored by Vertex or its designee in accordance with written procedures. 
Monitoring and auditing procedures developed or approved by Vertex for these activities comply 
with GCP regulatory requirements and guidelines. The monitoring strategy may include onsite, 
remote, and central monitoring activities, in accordance with local regulations. The study site 
monitor will ensure that the investigation is conducted according to the protocol design and 
regulatory requirements. 
13.5 
Electronic Data Capture  
Sites will use an EDC tool to record data for each enrolled subject.  
It is the investigator’s responsibility to ensure the accuracy, completeness, clarity, and timeliness 
of the data reported. 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, including the dates and details of study procedures, AEs, other observations, and subject 
status.  
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 data reported to Vertex, including 
any changes made, to endorse the final submitted data for the subjects for whom the investigator 
is responsible.  
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 


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13.7.2 
Clinical Study Report  
A clinical study report, written in accordance with the current ICH E3 Guideline, will be 
submitted in accordance with local regulations. 


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14 
REFERENCES 
1 
Cystic Fibrosis Foundation. 2019 Patient Registry Annual Data Report. Bethesda, MD: 
2020. 
2 
European Cystic Fibrosis Society. 2018 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: 2020. 
3 
Ruseckaite R, Ahern S, Ranger T, Dean J, Gardam M, Bell S, et al. The Australian Cystic 
Fibrosis Data Registry Annual Report, 2017. Monash University: Department of 
Epidemiology and Preventative Medicine; March 2019, Report #20. 
4 
Cystic Fibrosis Canada. The Canadian Cystic Fibrosis Registry 2019 Annual Data 
Report. Toronto, Ontario: Cystic Fibrosis Canada; 2020. 
5 
Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, et al. 
Identification of the cystic fibrosis gene: Chromosome walking and jumping. Science. 
1989;245(4922):1059-65. 
6 
Kreindler JL. Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
7 
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. 
8 
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. 
9 
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. 
10 
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 14 
February 2022. 
 


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15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol #: 
VX20-445-121 Version #: 
2.0 
Version Date: 
14 February 2022 
Study Title: A Phase 3b Open-label Study Evaluating the Safety of 
Elexacaftor/Tezacaftor/Ivacaftor Combination Therapy in Subjects With Cystic Fibrosis  
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 #:  
VX20-445-121 
Version #: 2.0 
Version Date: 
14 February 2022 
Study Title: A Phase 3b Open-label Study Evaluating the Safety of 
Elexacaftor/Tezacaftor/Ivacaftor Combination Therapy in Subjects With Cystic Fibrosis  
 
 
I have read Protocol VX20-445-121, Version 2.0, and agree to conduct the study according to its 
terms. I understand that all information concerning ELX (VX-445)/TEZ (VX-661)/IVA 
(VX-770) and this protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is 
confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
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1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX20-445-121 Version 2.0 
(Final Analysis) 
 
 
A Phase 3b Open-label Study Evaluating the Safety of 
Elexacaftor/Tezacaftor/Ivacaftor Combination Therapy in Cystic 
Fibrosis Subjects 
 
Authors of SAP: 
 
 
Version: 1.0 
Version Date of SAP: 12 December 2022 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


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2 
TABLE OF CONTENTS 
 
1 
Title Page ................................................................................................................................ 1 
2 
Table of Contents ................................................................................................................... 2 
4 
Introduction............................................................................................................................ 4 
5 
Study Objectives .................................................................................................................... 4 
5.1 
Primary Objective ............................................................................................................. 4 
6 
Study Endpoints ..................................................................................................................... 4 
6.1 
Primary endpoint .............................................................................................................. 4 
7 
Study Design ........................................................................................................................... 4 
7.1 
Overall Design .................................................................................................................. 4 
7.2 
Sample Size and Power .................................................................................................... 5 
8 
Analysis Sets ........................................................................................................................... 5 
9 
Statistical Analysis ................................................................................................................. 5 
9.1 
General Considerations .................................................................................................... 5 
9.2 
Background Characteristics .............................................................................................. 6 
9.3 
Safety Analysis ................................................................................................................. 9 
10 Interim and DMC Analyses ................................................................................................ 12 
10.1 Interim Analysis ............................................................................................................. 12 
10.2 DMC analysis ................................................................................................................. 13 
11 References ............................................................................................................................. 14 
12 Appendices............................................................................................................................ 15 
Appendix A: Analysis Visit Windows for Safety Assessments............................................... 15 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 17 
Appendix C: Imputation Rules for Missing AE dates ............................................................. 18 
Appendix D: Adverse Events of Special Interest ..................................................................... 19 
Appendix E: Criteria for Threshold Analysis .......................................................................... 20 
 
 


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3 
MODIFICATIONS  


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4 
INTRODUCTION 
Study VX20-445-121 (Study 445-121) is a Phase 3b open-label study evaluating the safety of 
elexacaftor (ELX, VX-445) in triple combination (TC) with tezacaftor (TEZ) and ivacaftor 
(IVA) in subjects with cystic fibrosis (CF) who complete a parent study (VX19-445-117 or 
VX20-445-126). 
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 safety endpoints defined in 
the VX20-445-121 study protocol. It also documents analyses for additional 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 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 to the SAP.  
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
To evaluate the safety and tolerability of ELX/TEZ/IVA in subjects with CF. 
6 
STUDY ENDPOINTS 
6.1 
Primary endpoint  
Safety and tolerability of treatment with ELX/TEZ/IVA based on adverse events (AEs), clinical 
laboratory values, ECGs, vital signs, and pulse oximetry. 
7 
STUDY DESIGN 
7.1 
Overall Design 
This is a Phase 3b, multicenter, open-label study for subjects who complete a parent study 
(VX19-445-117 or VX20-445-126) and meet eligibility criteria (Section 8 of the CSP). Subjects 
will receive a dose of ELX 200 mg once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours 
(q12h). A schematic of the study design is shown in Figure 7-1. 
For treatment continuity in regions where ELX/TEZ/IVA is not commercially available, an 
option to return to this study will be offered to subjects who depart this study to enroll in another 
qualified Vertex study based on the following: 
• Subjects have received open-label ELX/TEZ/IVA during the other study’s Run-in Period but 
have not received study drug in the Treatment Period of the other study, and 
• Meet all eligibility criteria for this study (Section 8 of the CSP) at their Returning Visit. 


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Subjects who resume participation in this study will resume treatment with study drug after 
completion of a Returning Visit. Resumption of participation in this study following departure to 
another qualified Vertex study will be permitted only once.  
 
Figure 7-1 
VX20-445-121 Study Design 
 
ELX: elexacaftor; IVA: ivacaftor; TEZ: tezacaftor 
Note: Figure is not drawn to scale. 
 
7.2 
Sample Size and Power 
The primary objective of the study is the evaluation of the safety of ELX/TEZ/IVA. This is an 
open-label extension study that will enroll the subjects from parent studies who meet eligibility 
criteria in this study.  
Up to approximately 160 subjects are expected to enroll in this open-label extension study. 
8 
ANALYSIS SETS 
The All Subjects Set is defined as all subjects who were enrolled (defined as subject having data 
in the clinical database) in this study. This analysis set will be used for individual subject data 
listings and the disposition summary table, unless otherwise specified. 
The Safety Set is defined as all subjects who have received at least 1 dose of study drug in this 
study. This analysis set will be used for subject demographics and baseline characteristics and 
for all safety analyses unless otherwise specified. 
9 
STATISTICAL ANALYSIS 
9.1 
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. 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). 
Categorical variables will be summarized using counts and percentages. 


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Baseline value, unless otherwise specified, will be the most recent non-missing measurement 
(scheduled or unscheduled) collected before the first dose of ELX/TEZ/IVA in a parent study, as 
applicable.  
Change (absolute change) from baseline will be calculated as Post-baseline value − Baseline 
value. 
Treatment-emergent (TE) Period will include the time period starting from the date of the first 
dose of study drug of this open-label study to 28 days after the last dose of the study drug, or to 
the completion date of study participation (as defined in Section 9.1.5 of study protocol), 
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 the TE period 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix A. 
Incomplete/missing data will not be imputed, unless specified otherwise. 
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
9.2 
Background Characteristics 
9.2.1 
Subject Disposition 
Subject disposition will be summarized for the All Subjects Set. The number and percentage of 
subjects in the following categories will be summarized as appropriate: 
• All Subjects Set 
• Safety Set 
• Completed Treatment  
• Prematurely discontinued treatment and the reasons for discontinuation 
• Completed study  
• Prematurely discontinued study and the reasons for discontinuation 
• Departed Study VX20-445-121 to participate in another qualified Vertex study 
• Departed Study VX20-445-121 to participate in another qualified Vertex study and 
returned to VX20-445-121  
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. A separate listing will be provided for subjects who depart from 
the study. 


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9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by descriptive summary statistics 
for the Safety Set. Demographic data 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, Not Collected per Local Regulations and Other) 
• Country      
Parent study baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
Disease characteristics based on parent study baseline will include the following: 
• ppFEV1 at parent study baseline (<30, ≥30 to <40, ≥ 40 to <70, ≥70 to ≤90, and >90) 
• ppFEV1 at parent study baseline (continuous)  
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 
• Prior use of any bronchodilator (Yes, No)  
• Prior use of any inhaled bronchodilator (Yes, No)  
• Prior use of any inhaled hypertonic saline (Yes, No) 
• Prior use of any inhaled corticosteroids (Yes, No) 
Prior medication use definition is same as that for the baseline characteristics summary presented 
in the parent studies. 
9.2.3 
Medical History 
Medical history (referenced to the start of parent study) will be coded by using the Medical 
Dictionary for Regulatory Activities (MedDRA). Medical history will be summarized 
descriptively by System Organ Class (SOC) and Preferred Term (PT) based on the Safety Set. 
The corresponding data listing will also be provided. 
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization-Drug Dictionary and 
categorized as follows: 


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• Prior medication: any medication that was administered within the 56 days before the first 
dose of study drug in this open-label study. For subjects who were enrolled in another 
qualified Vertex study before completing this study and resume participation in this study, 
any new or changed medication administered after the Departing Visit and prior to the first 
dose of this study’s drug after resuming participation will also be considered as prior 
medication. 
• 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. Details for imputing missing or partial start and/or stop dates of 
medication are described in Appendix B. 
Prior medications and concomitant medications will be summarized descriptively by Preferred 
Name based on the Safety Set by 1) preferred name (PN); and 2) anatomic class (ATC) level 1, 
ATC level 2, and PN. Post-treatment medications will be provided separately in an individual 
subject data listing. 
9.2.5 
Study Drug Exposure  
Study drug exposure will be summarized based on the Safety Set. Duration of study drug 
exposure (in days) will be calculated as [last dose date – first dose date + 1 day] within the TE 
period, regardless of any interruption in dosing between the first and the last dose. For subjects 
who enroll in another qualified Vertex study and resume participation in this study, time spent in 
the other study will be excluded. 
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max. It will also be summarized by interval, using counts and 
percentages. 
9.2.6 
Study Drug Compliance  
Study drug compliance will be summarized based on the Safety Set, 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 his open-label study)]. A study drug interruption on a given day is 
defined as an interruption of any study drug on that day. For subjects who enroll in another 
qualified Vertex study and resume participation in this study, time spent in the other study will 
be excluded. 
Percentage of study drug compliance will be summarized based on the Safety Set. Percentage of 
study drug compliance will be summarized descriptively by the number of subjects (n), mean, 


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SD, median, min, and max.  It will also be summarized in categories: <80% and ≥80% using 
frequency tables.  
9.2.7 
Important Protocol Deviations  
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. A protocol deviation review team will categorize IPDs according to 
the Protocol Deviation Plan during the study.  
IPDs during this open-label study will be summarized descriptively based on the Safety Set. 
Additionally, IPDs will be provided in an individual subject data listing.  
9.3 
Safety Analysis 
The primary objective of this study is the evaluation of safety and tolerability of ELX/TEZ/IVA. 
All safety analyses will be based on the TE Period for subjects in the Safety Set. 
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) 
• Clinical laboratory values 
• ECGs 
• Vital signs 
• Pulse oximetry 
Only descriptive analysis of safety will be performed and no statistical testing will be performed. 
9.3.1 
Adverse Events  
AEs will be classified as pretreatment AEs, TEAEs, or post-treatment AEs, defined as follows:  
• Pre-treatment AE: any AE occurred before the first dose date of study drug in the TE 
Period. For subjects who were enrolled in another qualified Vertex study before 
completing this study and resume participation in this study, AEs that started during 
participation in another qualified Vertex study and were ongoing at the time of Returning 
Visit will be flagged as pre-treatment AE. 
• 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. 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study drug treatment start date in this OLS, then the AEs will be classified as 
TEAEs. 
Details for imputing missing or partial start dates of adverse events are described in Appendix C. 
An overview of all TEAEs during TE period will be summarized and include the following 
categories: 


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• Number of TEAEs (total number of TEAEs only) 
• Subjects with any TEAEs  
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation 
• Subjects with TEAEs leading to study drug 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 will be presented for the above overview table.  
The following summary tables of TEAEs will be presented for overall: 
• All TEAEs 
• Grade 3/4/5 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Related TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to death 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentages of subjects, subjects with multiple occurrences of the same adverse event 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 number and percentage of subjects will be presented 
for TEAEs: 
• All TEAEs by PT 


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All AEs in this OLS, including pre-treatment AEs, TEAEs, and post-treatment AEs, will be 
presented in an individual subject data listing based on the All Subjects Set. In addition, a listing 
containing individual subject adverse event data for TEAEs leading to treatment discontinuation, 
TEAEs leading to treatment interruption, Grade 3/4/5 TEAEs, SAEs and all deaths will be 
provided. Listings for SAEs and deaths will include a flag indicating the TEAE status. 
9.3.1.1 
Adverse Events of Special Interest  
For this study, elevated transaminases events and rash events, as determined by MedDRA 
Preferred Terms in Appendix D, are considered as adverse events of special interest. The 
corresponding AE data will be summarized in terms of frequency counts. 
For treatment-emergent elevated transaminases events and rash events, the following categories 
will be summarized: 
• Subjects with events 
• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 
• Subjects with serious events 
• Subjects with study drug related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event (with the first dose date of ELX/TEZ/IVA in the open-label 
study as the reference while calculating time-to-onset) 
In addition, for treatment-emergent rash events, the above categories will be summarized for the 
following subgroups: 
• Sex (male, female) 
• Female subjects with concomitant hormonal therapy (Yes, No) 
 
9.3.2 
Clinical Laboratory Assessments 
For the laboratory assessments during TE period, the observed values and change from baseline 
values of the continuous hematology, coagulation and chemistry results will be summarized in SI 
units at each visit. Change from baseline in coagulation will be summarized for subjects from 
parent study 445-117 only. 
The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
during the TE period will be summarized. The threshold analysis criterion shift from baseline 
will also be summarized for selected laboratory parameters. The threshold analysis criteria are 
provided in Appendix E.  


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Results of urinalysis and positive urine/serum pregnancy test will be presented in individual 
subject data listings only. For positive serum pregnancy listing, subjects with serum HCG which 
are abnormally high will be selected.  
In addition, a listing containing individual subject hematology, chemistry, and coagulation values 
will be provided. This listing will include data from both scheduled and unscheduled visits.  
9.3.3 
Electrocardiogram 
For the following ECG interval measurements during the TE period, a summary of observed 
values and change from baseline values will be provided at each visit (in msec): RR, PR, QT, 
and QT corrected for HR (QTcF), QRS duration, and HR (beats per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
during the TE period will be summarized. The threshold analysis criteria are provided in 
Appendix E. 
9.3.4 
Vital Signs 
For the vital signs measurements during the TE period, the observed values and change from 
baseline values will be summarized at each visit. The following vital signs parameters will be 
summarized: BMI (kg/m2), weight (kg), 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 event 
during the TE period will be summarized. The threshold analysis criteria are provided in 
Appendix E. 
9.3.5 
Pulse Oximetry 
For the percent of oxygen saturation measurements using pulse oximetry during the TE period, 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 (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
period will be summarized. 
9.3.6 
Physical Examination  
No tables/figures/listings will be provided for physical examination data. 
9.3.7 
Ophthalmology Examination  
Ophthalmology examination results will be provided in a data listing. 
9.3.8 
COVID-19 Impacted Visits  
A listing containing subjects’ visits impacted due to COVID-19 will be provided. 
10 
Interim and DMC Analyses 
10.1 
Interim Analysis 
Not applicable.  


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10.2 
DMC analysis 
Not applicable.  


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11 
REFERENCES 
1. Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
 
 


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12 
APPENDICES 
Appendix A: Analysis Visit Windows for Safety Assessments 
Table 12-1 
Analysis Visit Windows Safety Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3, 4 
Weight, Height and BMI  
 
Baseline 
OL Week 12 
 
OL Week 24 
OL Week 36 
OL Week 48 
OL Safety Follow-up 
-- 
85 
 
169 
253 
337 
Not applicable 
defined in section 9.1 
[1, 127] where Day 1 is post-
dose measurement 
(127, 211] 
(211, 295] 
(295, 351] 
Use nominal visit 
Vital Signs  
Hematology 
Serum Chemistry 
 
Baseline 
OL Week 12 
 
OL Week 24 
OL Week 36 
OL Week 48 
OL Safety Follow-up 
-- 
85 
 
169 
253 
337 
Not applicable 
defined in section 9.1 
[1, 127] where Day 1 is post-
dose measurement 
(127, 211] 
(211, 295] 
(295, 351] 
Use nominal visit 
Standard 12-lead ECG  
Baseline  
OL ETT or Departing 
 
OL Safety Follow-up 
-- 
Not applicable  
 
Not applicable 
defined in section 9.1 
Use nominal visit (ETT or 
Departing Visit) 
Use nominal visit 
Coagulation5 
Baseline  
OL Week 24 
 
OL Week 48 
OL Safety Follow-up 
-- 
169 
 
337 
Not applicable 
defined in section 9.1 
[1, 253] where Day 1 is post-
dose measurement 
(253, 351] 
Use nominal visit 


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Notes: 
1 Visit name for analysis purpose is used to report data in tables and figures. 
 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
1. If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
2. 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: 
1. Scheduled measurement will be treated as pre-dose observation. 
2. Unscheduled measurement will be treated as post-dose observation. 
 
4 For safety assessments, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a 
subject does not have a nominal Safety Follow-up visit but has an ETT visit with study day >351, then the ETT visit 
will be mapped into Safety Follow-up analysis visit for the corresponding part.  
5 Baseline coagulation applies to subjects from parent study 445-117 only; baseline coagulation will be missing for 
subjects from parent study 445-126. 
Derived Variables for each part: 
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 “yy, mm” format (e.g., 24 years, 6 months) from the Vital Signs (VS) 
page at the Day 1 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 days)]/365.25. 
2. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date. 
If the last dose date of study drug is not available and there is no data to indicate that the subject discontinued 
treatment, the data cutoff date will be used instead.  
If the subject discontinued treatment and 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 data cutoff 
date. 
3. Electrocardiogram: 
Baseline is defined in Section 8.1. If multiple ECG measurements are obtained on the same calendar day during 
the TE period, 
o 
For summary purpose, the average value will be used as the ECG on that day; 
o 
For threshold analysis purpose, all ECG values will be used 
 




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Appendix C: Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date are defined below. If the imputed AE start 
date is before the informed consent date for the OLS, the AE start date will be imputed using the 
informed consent date. Ongoing events from the parent study will follow the imputation rule 
described in the SAP for parent study. 
• 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 OLS or AE 
end date is missing, then  
 if AE start Year and Month are equal to the Year and Month of the first dose 
date of OLS, then impute the AE start Day as the Day of the first dose date of  
OLS;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
• 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 OLS or AE 
end date is missing, then  
 if AE start Year is equal to the Year of the first dose date of OLS, then impute 
the AE start Month and Day as the Month and Day of the first dose date of  
OLS;  
 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.  
• If Year of AE start date is missing: 
If the Year of AE start date is missing or AE start date is completely missing then query site.  
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the first dose date 
of the OLS.  
o else impute the AE start date as the informed consent date. 
Compare the imputed AE start date with TE period to determine whether the AE is pre-treatment 
AE, TEAE or post-treatment AE. 
 
Imputation rules for partial AE end date are defined below:  
If partial end date, then impute as min (the last day of the month, data cut-off for IA, end of 
study) if day is missing, or min (Dec, data cut-off for IA, end of study) if month is missing. 
 
 


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Appendix D: Adverse Events of Special Interest  
Table 12-7 
MedDRA Preferred Terms for Event of Special Interest 
Adverse event of special interest 
MedDRA preferred terms 
Elevated transaminases 
Alanine aminotransferase abnormal, Alanine aminotransferase 
increased, Aspartate aminotransferase abnormal, Aspartate 
aminotransferase increased, Transaminases abnormal, 
Transaminases increased, Liver function test abnormal, Liver 
function test increased, Hypertransaminasaemia, Hepatic 
enzyme abnormal, Hepatic enzyme increased 
Rash 
Rash, Rash erythematous, Rash macular, Rash maculo-papular, 
Rash maculovesicular, Rash vesicular, Rash pruritic, Rash 
follicular, Rash pustular, Nodular rash, Drug eruption, Fixed 
eruption, Urticaria, Urticaria papular, Urticaria vesiculosa, 
Urticarial dermatitis, Rash morbilliform, Rash papular, Rash 
papulosquamous, Rash rubelliform, Rash scarlatiniform , Drug 
hypersensitivity, Type IV hypersensitivity reaction, Dermatitis, 
Dermatitis atopic, Epidermolysis, Skin toxicity, Dermatitis 
allergic, Dermatitis exfoliative, Dermatitis exfoliative 
generalised, Erythema multiforme, Exfoliative rash, 
Mucocutaneous rash, Acute generalised exanthematous 
pustulosis, Cutaneous vasculitis, Urticarial vasculitis, Dermatitis 
bullous, Drug reaction with eosinophilia and systemic 
symptoms, Epidermal necrosis, Oculomucocutaneous syndrome, 
Skin exfoliation, Skin necrosis, Stevens-Johnson syndrome, 
Toxic epidermal necrolysis, Toxic skin eruption, Perioral 
dermatitis, Vasculitic rash, Immune-mediated dermatitis, Penile 
rash, SJS-TEN overlap, Erythrodermic atopic dermatitis, Scrotal 
dermatitis, Anal Rash, Generalised bullous fixed drug eruption 
 
 
Note: The preferred terms listed in the table is based on the MedDRA version applicable at the 
time of finalization of the SAP. If the MedDRA version is upgraded at the time of the final 
analysis, the corresponding preferred terms based on the upgraded version will be used in the 
analysis of adverse events of special interest. 
 
 


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


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Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
(ALT or AST) and Total 
Bilirubin 
(ALT >3×ULN or AST >3×ULN) and TBILI >2×ULN FDA DILI Guidance Jul 
2009. 
GGT 
>ULN –  ≤ 2.5×ULN 
>2.5× –  ≤ 5.0×ULN 
>5.0× –  ≤ 20.0×ULN  
>20.0×ULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN – ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>ULN –  ≤  1.5×ULN 
>1.5× –  ≤  2×ULN 
>2× –  ≤  5×ULN 
>5×ULN 
Criteria based upon 
CTCAE 
Creatinine 
>ULN –  ≤ 1.5×ULN 
>1.5× –  ≤ 3.0×ULN 
>3.0× –  ≤ 6.0×ULN 
>6.0×ULN 
CTCAE grades 1-4 
Lipase 
>ULN –  ≤  1.5×ULN 
>1.5× –  ≤  2×ULN 
>2× –  ≤  5×ULN 
>5×ULN 
Criteria based upon 
CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine Kinase 
>ULN –  ≤ 2.5×ULN 
>2.5× –  ≤ 5×ULN 
>5× –  ≤ 10×ULN  
>10×ULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN –  ≥ 100 g/L 
<100 –  ≥ 80 g/L  
< 80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN –  ≤ 20 g/L above ULN 
>20 g/L above ULN –  ≤ 40 g/L above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN –  ≥ 75.0×10e9 /L 
<75.0× – ≥ 50.0×10e9 /L  
<50.0× – ≥ 25.0×10e9 /L  
<25.0 × 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 


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Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Reticulocytes/Erythrocytes 
(%)    
<LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated partial 
thromboplastin time (PTT)  
 
>ULN –  ≤ 1.5×ULN 
>1.5× –  ≤ 2.5×ULN 
>2.5×ULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN –  ≤ 1.5×ULN 
>1.5× –  ≤ 2.5×ULN 
>2.5×ULN 
CTCAE grade 1-3 
  
Table 12-4 
Threshold Analysis Criteria for Laboratory Tests (for labeling purpose) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT or AST 
>3×ULN 
>5×ULN 
>8×ULN 
For labeling purpose 
 
Table 12-5 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
 
Per HV grade 2, 3, plus shift 
change 
 
 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift 
change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 


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Table 12-5 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
QTc 
Borderline 
Prolonged* 
Additional 
 
 
>450 ms and <500ms (Male); >470 ms and <500ms (Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
 
To be applied to any kind of 
QT correction formula.  
 
 
 
 
Note: Based on CPMP 1997 guideline. 
 
Table 12-6 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Pulse Rate 
Same as above in ECG category 
 
 
SBP increased 
 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from baseline 
>140 mmHg & >20 mmHg increase from baseline 
>160 mmHg & >10 mmHg increase from baseline 
>160 mmHg & >20 mmHg increase from baseline 
 
809/770 analyses 
SBP decrease 
 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from baseline 
<90 mmHg and >20 mmHg decrease from baseline 
<80 mmHg and >10 mmHg decrease from baseline 
<80 mmHg and >20 mmHg decrease from baseline 
 
Per HV grade 1, 3, plus shift change 


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Table 12-6 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
DBP increased 
 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from baseline 
>90 mmHg and >10 mmHg increase from baseline 
>100 mmHg and >5 mmHg increase from baseline 
>100 mmHg and >10 mmHg increase from baseline 
 
 
DBP decreased 
 
 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from baseline 
<60 mmHg and >10 mmHg decrease from baseline 
<45 mmHg and >5 mmHg decrease from baseline 
<45 mmHg and >10 mmHg decrease from baseline 
 
 
Weight   
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
 
CTCAE grade 1-3 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
 
CTCAE grade 1-3