Clinical trial NCT04362761
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2020-05-04; Completion date: 2022-12-21
Enrollment: 172 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluate the long-term safety and tolerability of elexacaftor (ELX)/tezacaftor (TEZ)/ ivacaftor (IVA) triple combination (TC) in participants with cystic fibrosis (CF) who are homozygous for F508del.

Detailed description:

Arms: arm 1: Part A: Participants received elexacaftor (ELX) 200 milligram (mg) once daily (qd)/tezacaftor (TEZ)100 mg qd/ivacaftor (IVA)150 mg every 12 hours (q12h) in the treatment period for 48 weeks.

Part B: Participants received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period up to 86 weeks.
Interventions: intervention 1: ELX/TEZ/IVA intervention 2: IVA
Intervention descriptions: intervention 1: Fixed-dose combination (FDC) tablet for oral administration. intervention 2: Tablet for oral administration.

Protocol documents:
Prot_000.pdf: 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 2 of 51 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 3 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3b Open-label Study Evaluating the Safety of Elexacaftor/Tezacaftor/Ivacaftor 
Combination Therapy in Cystic Fibrosis Subjects 
  
Brief Title 
A Study Evaluating the Safety of Elexacaftor Combination Therapy 
 
 
Clinical Phase and 
Clinical Study 
Type  
Phase 3b, safety  
 
 
Objectives 
Primary Objective 
To evaluate the safety and tolerability of elexacaftor (VX-445; ELX)/tezacaftor 
(TEZ)/ivacaftor (IVA)  
 
 
Endpoints 
Primary Endpoint 
Safety and tolerability of ELX/TEZ/IVA based on adverse events (AEs), clinical 
laboratory values, ECGs, vital signs, and pulse oximetry 
 
 
Number of 
Subjects 
Up to approximately 158 subjects are expected to enroll in this open-label study 
 
 
Study Population 
Male and female cystic fibrosis (CF) subjects with an F/F mutation 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); increased 
Clˉ secretion 
 
Strength and route of administration: 100 mg/50 mg/75 mg, oral 
 
 
 
Active substance: IVA (VX-770) 
 
Activity: CFTR potentiator; increased Clˉ secretion 
 
Strength and route of administration: 150 mg, oral 
 
 
Study Duration 
For subjects who participate in both Parts A and B, the total study duration is 
approximately 148 weeks (from the first dose of study drug in this study), including a 
treatment duration of 144 weeks (Treatment Periods of 48 weeks in Part A and 96 weeks 
in Part B), and a 4-week Safety Follow-up Visit. 
 
 
 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 4 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
Study Design 
This is a Phase 3b, 2-part, multicenter, open-label study for subjects who complete a 
parent study and meet eligibility criteria. A schematic of the study design is shown in 
Figure 2-1. 
All subjects in Parts A and B will receive the triple combination of ELX 200 mg qd/TEZ 
100 mg qd/IVA 150 mg q12h. Subjects who complete Part A will have the opportunity to 
participate in Part B for an additional 96 weeks. For all subjects, a Safety Follow-up Visit 
is scheduled to occur 28 (± 7) days after the last dose of study drug in Parts A and B.  
Figure 2-1 
VX19-445-115 Study Design 
ELX: elexacaftor; IVA: ivacaftor; q12h: every 12 hours; qd: once daily; 
TEZ: tezacaftor 
Note: Figure is not drawn to scale. 
a 
All subjects will receive ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h. 
b 
Subjects whose Part B Day 1 is on the same day or within 1 calendar day as the 
Part A Week 48 Visit do NOT have to repeat any Part B Day 1 assessments that 
were specified to be performed at the Part A Week 48 Visit. Subjects whose Part B 
Day 1 is more than 1 calendar day after Part A Week 48 Visit must complete all 
assessments specified for the Part A Week 48 AND Part B Day 1 Visits. 
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 receive 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, height (for subjects 
≤21 years of age on the date of informed consent in a parent study), weight, pulse 
oximetry, physical examinations (PE), and ophthalmologic examinations (for subjects 
<18 years of age on the date of informed consent in a parent study).  
 
 
Statistical 
Analyses 
The safety analyses will be performed for subjects who receive at least 1 dose of study 
drug in this study. The safety analyses will be descriptive only. 
 
 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 5 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
3 
SCHEDULE OF ASSESSMENTS 
The schedules of assessments for Parts A and B are in Table 3-1 and Table 3-2, respectively. All 
visits will be scheduled relative to the Part A 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. All assessments should be performed before study drug dosing 
(Section 9.6.1), 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.  
 














Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 12 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments ........................................................................................................ 5 
3.1 
Part A ................................................................................................................................ 6 
3.2 
Part B ................................................................................................................................ 9 
4 
Table of Contents ................................................................................................................. 12 
List of Tables ........................................................................................................................... 15 
List of Figures .......................................................................................................................... 15 
List of Abbreviations ............................................................................................................... 16 
5 
Introduction .......................................................................................................................... 18 
5.1 
Background ..................................................................................................................... 18 
5.2 
Study Rationale .............................................................................................................. 18 
6 
Study Objectives .................................................................................................................. 19 
6.1 
Primary Objective ........................................................................................................... 19 
7 
Study Endpoints ................................................................................................................... 19 
7.1 
Primary Endpoint ............................................................................................................ 19 
8 
Study Population .................................................................................................................. 19 
8.1 
Inclusion Criteria ............................................................................................................ 19 
8.2 
Exclusion Criteria ........................................................................................................... 20 
9 
Study Implementation ......................................................................................................... 20 
9.1 
Study Design .................................................................................................................. 20 
9.1.1 
Treatment Period .................................................................................................... 21 
9.1.2 
Safety Follow-up .................................................................................................... 22 
9.1.3 
Early Termination of Treatment ............................................................................. 23 
9.1.4 
Lost to Follow-up ................................................................................................... 23 
9.1.5 
Completion of Study Participation ......................................................................... 23 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 24 
9.3 
Rationale for Study Elements ......................................................................................... 24 
9.3.1 
Study Design and Population ................................................................................. 24 
9.3.2 
Study Drug Dose and Duration .............................................................................. 24 
9.3.3 
Rationale for Study Assessments ........................................................................... 24 
9.4 
Study Restrictions ........................................................................................................... 24 
9.5 
Prior and Concomitant Medications ............................................................................... 25 
9.6 
Administration ................................................................................................................ 26 
9.6.1 
Dosing ..................................................................................................................... 26 
9.6.2 
Missed Doses .......................................................................................................... 26 
9.7 
Dose Modification for Toxicity ...................................................................................... 26 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 26 
9.8.1 
Liver Function Tests ............................................................................................... 27 
9.8.2 
Rash ........................................................................................................................ 28 
9.9 
Removal of Subjects ....................................................................................................... 28 
9.10 Replacement of Subjects ................................................................................................ 28 
10 Study Drug Information and Management ....................................................................... 29 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 13 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
10.1 Preparation and Dispensing ............................................................................................ 29 
10.2 Packaging and Labeling ................................................................................................. 29 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 29 
10.4 Drug Accountability ....................................................................................................... 29 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 30 
10.6 Compliance ..................................................................................................................... 30 
10.7 Blinding and Unblinding ................................................................................................ 30 
11 Assessments .......................................................................................................................... 30 
11.1 Subject and Disease Characteristics ............................................................................... 30 
11.2 Safety .............................................................................................................................. 30 
11.2.1 
Adverse Events ....................................................................................................... 30 
11.2.2 
Clinical Laboratory Assessments ........................................................................... 30 
11.2.3 
Physical Examinations and Vital Signs .................................................................. 32 
11.2.4 
Height and Weight .................................................................................................. 32 
11.2.5 
Pulse Oximetry ....................................................................................................... 32 
11.2.6 
Electrocardiograms ................................................................................................. 32 
11.2.7 
Ophthalmologic Examination ................................................................................. 33 
11.2.8 
Contraception and Pregnancy ................................................................................. 33 
11.2.8.1 Contraception ................................................................................................... 33 
11.2.8.2 Pregnancy ......................................................................................................... 35 
12 Statistical and Analytical Plans .......................................................................................... 35 
12.1 Sample Size .................................................................................................................... 35 
12.2 Analysis Sets .................................................................................................................. 36 
12.3 Statistical Analysis ......................................................................................................... 36 
12.3.1 
General Considerations ........................................................................................... 36 
12.3.2 
Background Characteristics .................................................................................... 36 
12.3.2.1 Subject Disposition .......................................................................................... 36 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 37 
12.3.2.3 Prior and Concomitant Medications ................................................................ 37 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 37 
12.3.2.5 Important Protocol Deviations ......................................................................... 38 
12.3.3 
Efficacy Analysis .................................................................................................... 38 
12.3.4 
Safety Analysis ....................................................................................................... 38 
12.3.4.1 Adverse Events ................................................................................................ 38 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 39 
12.3.4.3 Electrocardiogram ............................................................................................ 39 
12.3.4.4 Vital Signs ........................................................................................................ 40 
12.3.4.5 Pulse Oximetry ................................................................................................. 40 
12.3.5 
Independent Data Monitoring Committee Analyses .............................................. 40 
12.3.5.1 IDMC Analysis ................................................................................................ 40 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 40 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 40 
13.1.1 
Adverse Events ....................................................................................................... 40 
13.1.1.1 Definition of an Adverse Event........................................................................ 40 
13.1.1.2 Clinically Significant Assessments .................................................................. 40 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 14 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
13.1.1.3 Documentation of Adverse Events................................................................... 41 
13.1.1.4 Adverse Event Severity .................................................................................... 42 
13.1.1.5 Adverse Event Causality .................................................................................. 42 
13.1.1.6 Study Drug Action Taken ................................................................................ 42 
13.1.1.7 Adverse Event Outcome .................................................................................. 43 
13.1.1.8 Treatment Given............................................................................................... 43 
13.1.2 
Serious Adverse Events .......................................................................................... 43 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 43 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 44 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 45 
13.2 Administrative Requirements ......................................................................................... 45 
13.2.1 
Ethical Considerations ............................................................................................ 45 
13.2.2 
Subject Information and Informed Consent ........................................................... 45 
13.2.3 
Investigator Compliance ......................................................................................... 45 
13.2.4 
Access to Records ................................................................................................... 46 
13.2.5 
Subject Privacy ....................................................................................................... 46 
13.2.6 
Record Retention .................................................................................................... 46 
13.2.7 
Study Termination .................................................................................................. 46 
13.2.8 
End of Study ........................................................................................................... 47 
13.3 Data Quality Assurance .................................................................................................. 47 
13.4 Monitoring ...................................................................................................................... 47 
13.5 Electronic Data Capture ................................................................................................. 47 
13.6 Confidentiality and Disclosure ....................................................................................... 47 
13.7 Publications and Clinical Study Report .......................................................................... 48 
13.7.2 
Clinical Study Report ............................................................................................. 48 
14 Reference .............................................................................................................................. 49 
15 Protocol Signature Pages .................................................................................................... 50 
15.1 Sponsor Signature Page .................................................................................................. 50 
15.2 Investigator Signature Page ............................................................................................ 51 
 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 15 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
List of Tables 
Table 3-1 
Study VX19-445-115: Part A Treatment Period and Safety Follow-up Visit ........ 6 
Table 3-2 
Study VX19-445-115: Part B Treatment Period and Safety Follow-up Visit ........ 9 
Table 9-1 
Prohibited Medications ......................................................................................... 25 
Table 10-1 
Study Drug: Strength/Dosing Form/Route ........................................................... 29 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 31 
Table 11-2 
Acceptable Methods of Contraception .................................................................. 34 
Table 13-1 
Grading of AE Severity ........................................................................................ 42 
Table 13-2 
Classifications for AE Causality ........................................................................... 42 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 43 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 43 
 
List of Figures 
Figure 2-1 
VX19-445-115 Study Design ................................................................................. 4 
Figure 9-1 
VX19-445-115 Study Design ............................................................................... 21 
 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 16 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BMI 
body mass index 
CF 
cystic fibrosis 
CFTR 
CF transmembrane conductance regulator protein 
CFTR 
CF transmembrane conductance regulator gene 
Clˉ 
chloride ion 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
EDC 
electronic data capture 
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 on the wild-type protein 
F508del 
CFTR protein lacking the phenylalanine normally found at position 508 of the wild-
type protein 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
F/F 
homozygous for F508del 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GPS 
Global Patient Safety 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IPD 
important protocol deviation 
IRB 
institutional review board 
IVA 
ivacaftor 
LUM 
lumacaftor 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
minimal function 
min 
minimum value 
PE 
physical examination 
P-gp 
P-glycoprotein 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval, segment 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 17 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
Abbreviation 
Definition 
PT 
Preferred Term 
q12h 
every 12 hours 
qd 
once daily 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QT 
QT interval 
QTc 
QT interval corrected 
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 
SE 
standard error 
SUSAR 
suspected, unexpected, serious adverse reaction 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 18 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive chronic disease with serious morbidities and 
frequent premature mortality. CF affects more than 70,000 individuals worldwide1 
(approximately 30,000 in the US2 and 45,000 in the EU3). Based on its prevalence, CF qualifies 
as an orphan disease.4, 5 
CF is caused by decreased quantity and/or function of the CFTR protein due to mutations in the 
CFTR gene.6 CFTR is an ion channel that regulates the flow of chloride and other ions across 
epithelia in various tissues, including the lungs, pancreas and other gastrointestinal organs, and 
sweat glands.7 Decreased CFTR quantity or function results in the failure to regulate chloride 
transport in these tissues, leading to the multisystem pathology associated with CF.8 In the lungs, 
obstruction of airways with thick mucus, establishment of a chronic bacterial infection in the 
airways, and damaging inflammatory responses are all thought to play a role in causing 
irreversible structural changes in the lungs, leading to respiratory failure. Progressive loss of lung 
function is the leading cause of mortality.9 
The most common disease-causing CFTR mutation is F508del, which accounts for 
approximately 70% of the identified alleles in people with CF.10 Approximately 40% to 45% of 
people with CF are homozygous for F508del (F/F), and approximately 85% have at least 
one F508del allele. 2, 3  
Based on the understanding of the molecular defects caused by CFTR mutations, 
2 complementary approaches have been developed to address the decreased quantity and/or 
function of CFTR in order to enhance chloride transport in patients with CF. Correctors facilitate 
the cellular processing and trafficking to increase the quantity of CFTR at the cell surface. 
Potentiators increase the channel open probability (channel gating activity) of the CFTR protein 
delivered to the cell surface to enhance ion transport. With differing mechanisms of action, a 
combination of correctors and potentiators increases F508del CFTR-mediated chloride transport 
more than either type of modulator alone. 
The therapeutic activity of CFTR modulators has been established with products developed by 
Vertex and approved for the treatment of CF: ivacaftor (IVA) monotherapy (Kalydeco), 
lumacaftor (LUM)/IVA (Orkambi®), and tezacaftor (TEZ)/IVA (Symdeko/Symkevi®). 
Elexacaftor (VX-445; ELX) is a next-generation CFTR corrector. In vitro, the triple combination 
of ELX, TEZ, and IVA (ELX/TEZ/IVA) increased CFTR chloride transport more than any of the 
dual combinations (ELX/TEZ, ELX/IVA, and TEZ/IVA) or individual components (ELX, TEZ, 
and IVA) when added to human bronchial epithelial cells derived from 2 groups of CF patients: 
those heterozygous for F508del with a second CFTR allele carrying a minimal function (MF) 
mutation that is not responsive to TEZ, IVA, and TEZ/IVA (F/MF genotypes); and those 
homozygous for F508del (F/F genotypes). 
Additional information about ELX/TEZ/IVA can be found in the Investigator’s Brochure. 
5.2 
Study Rationale 
This study will evaluate the safety of up to 144 weeks of treatment with ELX/TEZ/IVA in 
subjects with CF who have an F/F genotype who complete a parent study 
(Study VX18-445-109). The potential for benefit in these patients is supported by published 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 19 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
Phase 2 and publicly disclosed Phase 3 clinical data in subjects with F/F genotypes. In addition, 
ELX/TEZ/IVA is generally safe and well tolerated (refer to ELX 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 F/F genotypes.  
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the safety and tolerability of ELX/TEZ/IVA 
7 
STUDY ENDPOINTS 
7.1 
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 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled in Part A and Part B. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
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 and (if continuing on to Part B of this study) 
did not withdraw consent in Part A. 
4. For each part of the study, meets the following criteria: 
• For subjects entering Part A of this study: 
o Completed study drug treatment in a parent study, or 
o Had study drug interruptions(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. 
• For subjects continuing on to Part B of this study: 
o Completed study drug treatment in Part A, or 
o Had study drug interruptions(s) in Part A, but did not permanently discontinue study 
drug, and completed study visits up to the last scheduled visit of the Treatment Period 
of Part A. 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 20 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
• For subjects being considered for resumption of participation in this study after enrolling 
in another qualified Vertex study: 
o 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, 
and 
o Did not depart this study more than once to participate in another qualified Vertex 
study.  
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. Pregnant and breast-feeding females. Female subjects must have a negative pregnancy test at 
the Part A Day 1 and Part B Day 1 Visits before receiving the first dose of study drug in each 
Part. 
3. History of drug intolerance in a parent study or in the current 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). 
4. Current participation in an investigational drug trial other than a parent study or the current 
study. Participation in a noninterventional study (including observational studies, registry 
studies, and studies 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, or 
• Subject has access to commercially available or managed-access-program-supplied 
ELX/TEZ/IVA. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3b, 2-part, multicenter, open-label study for subjects who complete a parent study 
(Study VX18-445-109; a Phase 3b study evaluating ELX/TEZ/IVA) and meet eligibility criteria 
(Section 8). A schematic of the study design is shown in Figure 9-1. 
All subjects in Parts A and B will receive the triple combination of ELX 200 mg once daily 
(qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) (the same dose level as that evaluated 
in the Phase 3 program of ELX/TEZ/IVA). Study drug administration is described in 
Section 9.6.1. Subjects who complete Part A will have the opportunity to participate in Part B for 
an additional 96 weeks.  
Study visits and assessments for Parts A and B are shown in Table 3-1 and Table 3-2, 
respectively. All visits will occur within the windows specified. 




Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 22 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
Subjects whose Part A Day 1 Visit is within 1 day of the last scheduled visit in the Treatment 
Period of a parent study will NOT have to repeat assessments that were performed as part of the 
last scheduled visit in a parent study Treatment Period. 
Part B 
For subjects who elect to participate in Part B, the Part A Week 48 Visit will be the start of 
treatment in Part B (i.e., Part B Day 1).  
Subjects whose Part B Day 1 is on the same day or within 1 calendar day of the Part A Week 48 
Visit do NOT have to repeat any Part B Day 1 assessments that were specified to be performed at 
the Part A Week 48 Visit. Subjects whose Part B Day 1 is more than 1 calendar day after Part A 
Week 48 Visit must complete all assessments specified for the Part A Week 48 AND Part B 
Day 1 Visits. 
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. 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.  
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).  
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.  
9.1.2 
Safety Follow-up 
The Safety Follow-up Visit is scheduled to occur 28 (± 7) days after the last dose of study drug 
in Parts A and B. The Safety Follow-up Visit assessments are listed in Table 3-1 and Table 3-2, 
respectively.  
The Safety Follow-up Visit is required for all subjects. However, subjects in Parts A and B who 
transition within 28 days of the last dose of study drug to either: 
• a commercially available Vertex CFTR modulator regimen 
• managed access program-supplied Vertex CFTR modulator regimen  
• or, to another Part of the current study or another qualified Vertex study  
will complete the respective Part A Week 48 or Part B Week 96 Visit. If the transition occurs 
before the Part A Week 48 Visit or Part B Week 96 Visit, then subjects will complete the Early 
Termination of Treatment (ETT) Visit. In these cases, the Part A Week 48/Part B Week 96 
Visit or the ETT Visit, whichever is applicable, will replace the Safety Follow-up Visit. 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 23 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
For subjects who complete an ETT Visit 3 weeks or later following the last dose of study drug, 
the ETT Visit will replace the Safety Follow-up Visit (Section 9.1.3). 
9.1.3 
Early Termination of Treatment 
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 drug 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 
decision to discontinue treatment. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
If a subject withdraws from the study and also withdraws consent or assent, no further 
assessments will be performed. Vertex may retain and continue to use any data and samples 
collected before such withdrawal of consent or assent. 
9.1.4 
Lost to Follow-up 
A subject will be considered lost to follow-up if both of the following occur: 
• The subject misses 2 consecutive study visits (telephone contact and/or clinic visit) and is 
subsequently unable to be contacted by telephone (3 documented attempts by telephone 
within 2 weeks following the second missed visit) 
• The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 
9.1.5 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as: the Safety Follow-up 
Visit; or, in situations in which the ETT Visit or the Part A Week 48 or Part B Week 96 Visit 
replaces the Safety Follow-up Visit (Section 9.1.2), the ETT Visit or the Part A Week 48 or 
Part B Week 96 Visit. 
If subjects withdraw consent or assent, completion of study participation is defined as date of 
withdrawal of consent or assent, whichever is earlier (Section 9.9). 
If subjects are lost to follow-up (Section 9.1.4), the date of completion of study participation will 
be defined as the date of last contact. 
The end of study is defined in Section 13.2.8. 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 24 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
9.2 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study. Randomization is not required because all subjects will be treated 
identically in a single cohort. 
9.3 
Rationale for Study Elements 
9.3.1 
Study Design and Population 
Subjects who completed treatment in a parent study (Study VX18-445-109) and met eligibility 
criteria will be able enroll in Part A of this study, which is designed to provide long-term safety 
data in CF subjects, homozygous for F508del (F/F), 12 years of age or older, treated with 
ELX/TEZ/IVA. 
9.3.2 
Study Drug Dose and Duration 
All subjects in Parts A and B of the study will receive ELX 200 mg qd/TEZ 100 mg qd/IVA 
150 mg q12h (the same dosage as that used in the ELX Phase 3 program). This dose was 
demonstrated to be generally safe and efficacious in Phase 3 studies of ELX/TEZ/IVA. 
The overall treatment duration will be up to 144 weeks, which is considered sufficient for the 
evaluation of 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 medication will be provided in the Study Reference Manual. Guidance for concomitant 
medications is provided in Section 9.5. 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 25 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
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 study drug on 
Part A 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, will be prohibited. 
Moderate and 
strong CYP3A 
inhibitors (except 
ciprofloxacin)a 
None allowed 
within 14 days 
before the first dose 
of study drug on 
Part A 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 from 
the first dose of 
study drug on 
Part A Day 1 
None allowed 
through completion 
of study participation 
These agents may confound the results of 
this study. 
CYP: cytochrome P450; ELX: elexacaftor; IVA: ivacaftor; TEZ: tezacaftor 
a 
Ciprofloxacin is not a moderate CYP3A inhibitor on the basis of results of a drug-drug interaction study 
conducted with IVA, a sensitive CYP3A substrate (Kalydeco [ivacaftor] US Package Insert). 
9.5 
Prior and Concomitant Medications 
Information regarding prior and concomitant medications, including CF medications, other 
medications, and herbal and naturopathic remedies, will be collected from each subject’s source 
documentation for medications taken within 56 days before the 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.  
• 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. 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 26 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
9.6 
Administration 
9.6.1 
Dosing 
Study drug will be administered orally. 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. 
• It is recommended that the dose be taken within 30 minutes of the start of the meal or snack. 
• Study drug will be administered as fixed-dose combination (FDC) tablet(s) 
(e.g., 2 ELX/TEZ/IVA) in the morning and as 1 IVA tablet in the evening. For each subject, 
doses of study drugs should be taken at approximately the same time (± 2 hours) each day. 
• On days of scheduled visits, the morning dose of study drug will be administered at the site 
after predose assessments have been completed. A meal or snack will be provided by the site 
for the morning dose of study drug. 
• If a subject’s scheduled visit is to occur in the afternoon, the following guidelines should be 
used: 
o If the dose in the clinic will be within 6 hours of the subject’s scheduled morning dose, 
the subject should withhold their morning dose of study drug and the morning dose will 
be administered in the clinic. 
o If the dose in the clinic will be more than 6 hours after the subject’s scheduled morning 
dose, the subject should take the morning dose of study drug at home.  
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. Treatment may be interrupted; 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 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 27 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
drug only after the subject is clinically stable and there is no comorbidity or condition that, in the 
opinion of the investigator, might confound the results of the study or pose an additional risk in 
administering study drug to the subject. 
The medical monitor should be notified of an interruption of study drug that lasts >72 hours for 
any reason and of the resumption of study drug after such interruption. In study subjects for 
whom study drug was previously interrupted, the medical monitor should be notified of any plan 
to discontinue study drug, before the discontinuation has occurred, if possible. 
9.8.1 
Liver Function Tests 
The central laboratory will notify the medical monitor of 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: 
• 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 criterion is met: 
• Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral 
hepatitis, alcohol ingestion) is identified, regardless of whether transaminase levels have 
improved. 
All subjects in whom treatment is discontinued for elevated transaminases (and bilirubin, as 
applicable) should have these levels monitored closely until levels normalize or return to 
baseline. 
If an alternative, reversible cause of transaminase elevation with or without increased bilirubin or 
clinical jaundice has been identified, subjects may receive study drug once transaminases return 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 28 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
to baseline or are ≤2 × ULN, whichever is higher. Regardless of the duration of interruption, the 
medical monitor should be notified prior to resumption of study drug. Upon resumption of study 
drug, transaminases and bilirubin should be assessed weekly for 4 weeks. If a protocol-defined 
transaminase elevation interruption threshold recurs within 4 weeks of rechallenge with the study 
drug (with confirmation of the initial elevation by repeat testing within 48 to 72 hours), then the 
study drug must be permanently discontinued, regardless of the presumed etiology. 
9.8.2 
Rash 
Individuals who develop a generalized rash will be monitored closely. Study drug dosing should 
be interrupted if a subject develops a generalized rash of Grade 3 or higher (Section 13.1.1.4), or 
a rash that is considered a serious adverse event (SAE). The investigator will notify the medical 
monitor of any rash that results in interruption of study drug, is Grade 3 or higher, or is an SAE. 
Investigators should consider additional evaluation including laboratory testing (e.g., complete 
blood count with differential, liver function tests), photographs of the rash, and dermatology 
consultation. The investigator may consider resumption of study drug if considered clinically 
appropriate. 
9.9 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons. A subject 
who withdraws from study drug treatment will continue to be followed unless the subject 
withdraws consent or assent. 
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 an ETT Visit and Safety 
Follow-up Visit, if applicable (see Section 9.1.3), and follow up with the subject regarding any 
unresolved AEs. 
If the subject withdraws consent or assent for the study, no further assessments will be 
performed. Vertex may retain and continue using the study data and samples after the study ends, 
and may use the samples and information in the development of the study compound, for other 
drugs and diagnostics, in publications and presentations, and for education purposes. If the 
subject withdraws from the study, the study data and samples collected will remain part of the 
study. A subject will not be able to request the withdrawal of his/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(s) will not be 
replaced. 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 29 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
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 
ELX/TEZ/IVA will be supplied as FDC film-coated tablets containing 100 mg ELX, 50 mg 
TEZ, and 75 mg IVA (Table 10-1). 
IVA will be supplied as a film-coated tablet containing 150 mg IVA (Table 10-1). 
Blister cards must be stored under conditions noted in the Pharmacy Manual. The investigator, or 
an authorized designee (e.g., a licensed pharmacist), will ensure that all investigational product is 
stored in a secured area, under recommended storage conditions, and in accordance with 
applicable regulatory requirements. To ensure adequate records, all study drugs will be 
accounted for via the drug accountability forms as instructed by Vertex. 
Table 10-1 
Study Drug: Strength/Dosing Form/Route 
Drug Name, Dosing Form, Route 
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 regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee. The study monitor will review study drug 
records and inventory throughout the study. 
If a site uses a site-specific drug accountability system and/or process, including processes 
associated with the destruction of returned materials, the process must be documented and 
approved by Vertex. The study monitor must review the drug accountability documentation on a 
regular basis. The study monitor will promptly communicate to Vertex any discrepancies he/she 
is unable to resolve with the site. 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 30 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should consider discontinuing the subject from the study. 
10.7 
Blinding and Unblinding 
This is an open-label study. 
11 
ASSESSMENTS 
The schedule of assessments for Parts A and B are shown in Table 3-1 and Table 3-2, 
respectively.  
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. Select demographic and baseline characteristic data 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 for Parts A and B in Table 3-1 
and Table 3-2, respectively. 
11.2.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP Guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF completion 
guidelines for investigators as well as training will be provided. 
11.2.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, with the exception of the urine 
pregnancy tests. As described below, urine pregnancy tests will either be analyzed by the site or 
at home using a home pregnancy test kit. On Part A Day 1 and Part B Day 1 (and the Returning 
Visit if applicable), blood samples will be collected before the first dose of the study drug.  


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 31 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
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. 
Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose 
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate 
Inorganic phosphate  
Total and direct bilirubin 
Alkaline phosphatase 
Aspartate transaminase  
Alanine transaminase 
Amylase 
Lipase 
Gamma-glutamyl transferase 
Protein 
Albumin 
Creatine kinase 
Total cholesterol 
Lactate dehydrogenase 
Hemoglobin 
Erythrocytes 
Mean corpuscular volume 
Platelets 
Reticulocytes  
Leukocytes 
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes  
Monocytes 
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio 
Leukocyte esterase 
Nitrite 
Urobilinogen  
Urine protein  
pH 
Urine blood 
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose 
Note: Haptoglobin may be analyzed if judged to be clinically appropriate by the investigator. 
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be performed, 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 (beta-human chorionic gonadotropin) Tests for female subjects: Serum pregnancy 
tests will be performed at the study site and analyzed at the central laboratory. Urine pregnancy 
tests will either be performed and analyzed at the site or, when there is no clinic visit scheduled, 
at home by using a home pregnancy test kit provided by the site. Results will be reported to the 
site by telephone. The urine pregnancy test on Part A Day 1 and on Part B Day 1 (and the 
Returning Visit if applicable) must be negative before the first dose of study drug. Additional 
pregnancy tests may be required according to local regulations and/or requirements. 
Follicle-stimulating Hormone (FSH): Blood samples for FSH will 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.  


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 32 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
For the purposes of study conduct and unless noted otherwise, only laboratory tests done in the 
central laboratory may be used. Local laboratories may be used at the discretion of the local 
investigator for management of urgent medical issues. If a local laboratory test value is found to 
be abnormal and clinically significant, it will be verified by the central laboratory as soon as 
possible after the investigator becomes aware of the abnormal result. If it is not possible to send a 
timely specimen to the central laboratory (e.g., the subject was hospitalized elsewhere), the 
investigator may base the assessment of an AE on the local laboratory value. 
11.2.3 
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; respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After enrollment, 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. These will be assessed before dosing and following at least a 5-minute rest. A 
consistent methodology should be used for repeat measurements of these parameters at a clinical 
site. 
11.2.4 
Height and Weight 
Height and weight will be measured with shoes off, as applicable. 
• Height will not be collected for subjects whose date of informed consent in Part A occurs 
after their 21st birthday.  
• Height will be collected through the first visit after the subject’s 21st birthday for subjects 
whose date of informed consent in Part A occurs on or before their 21st birthday; height will 
not be collected at subsequent 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. 
Subjects will be instructed to rest for at least 5 minutes before having an ECG performed. 
The ECG traces will be manually read at the study site. A printout of the ECG traces will be 
made for safety review by the investigator and maintained with source documentation. Clinically 
significant ECG abnormalities occurring during the study through completion of study 
participation will be recorded as AEs. 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 33 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
To ensure the safety of the subjects, a qualified individual at the study site will make 
comparisons to baseline measurements. If the QTcF is increased by >60 msec from the baseline 
or an absolute QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be 
performed approximately 2 to 4 minutes apart to confirm the original measurement. If either of 
the QTcF values from these repeated ECGs remains above the threshold value (>60 msec from 
baseline or ≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement. Further 
details pertaining to ECGs will be provided to sites in the ECG Manual. 
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 
An ophthalmologic examination should occur within 4 weeks before the Part A Week 48 Visit 
for those subjects completing Part A. For subjects continuing on to Part B, an ophthalmologic 
examination should occur within 4 weeks before the Part B Week 96 Visit. In both Parts A and 
B, this examination should be completed within 4 weeks before the Part A Week 48 Visit or the 
Part B Week 96 Visit, unless the subject prematurely discontinues study drug, in which case this 
examination should occur by the Safety Follow-up Visit (or ETT Visit for subjects who do not 
complete a Safety Follow-up Visit), as described for Parts A and B in Table 3-1 and Table 3-2, 
respectively. 
Subjects <18 years of age on the date of informed consent in a parent study and who have 
completed at least 12 weeks of study drug treatment since their last ophthalmologic examination 
will have an ophthalmologic examination at either the Part A Week 48/Part B Week 96 Visit or 
the ETT Visit, whichever comes first, in both Parts A and B as applicable, except for those 
subjects who have withdrawn consent or assent. 
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 for a couple is waived for the following: 
• True abstinence for the subject, when this is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. True 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 34 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
abstinence must be practiced from the Part A Day 1 Visit through 90 days after the last 
dose of study drug. 
• If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the 
first dose of study drug (e.g., examination of a semen specimen or by demonstration of 
the absence of the vas deferens by ultrasound). 
• If the female is of non-childbearing potential. To be considered of non-childbearing 
potential, the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH 
level within the laboratory’s reference range for postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
• Note: All other females (including females with tubal ligations and pre-menarchal 
females) will be considered to be of childbearing potential. 
• Same-sex relationships 
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used as a couple. Acceptable methods of contraception must be used as specified (Table 11-2) 
from signing of consent, before the first dose of study drug, 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.  
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 post-vasectomy 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. 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 35 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
Additional notes: 
• If over the course of the study, the subject meets the criteria for waiving the contraception 
requirements, the subject does not need to follow the contraceptive methods listed in 
Table 11-2.  
• If, over the course of the study, the subject’s status changes and the subject does not meet 
the criteria for waiving the contraception requirements, the subject must begin following 
the contraceptive methods listed in Table 11-2. 
• Male subjects must not donate sperm during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
• Female subjects should not nurse a child during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
• For male subjects with a female partner of childbearing potential, the couple should not 
plan to become pregnant during the study or within 90 days after the last dose of study 
drug, with the exception of couples who plan to become pregnant by artificial 
insemination using sperm banked by the male subject before the first dose of study drug 
or sperm from another source. 
11.2.8.2 
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 (and assent, as applicable) is 
obtained. A separate ICF will be provided to explain these follow-up activities. Pregnancy itself 
does not constitute an AE. 
12 
STATISTICAL AND ANALYTICAL PLANS 
12.1 
Sample Size  
The primary objective of the study is the evaluation of the safety and tolerability of 
ELX/TEZ/IVA. This is an open-label extension study that will enroll subjects who did not 
discontinue study drug during the Treatment Period in a parent study and meet eligibility criteria 
in this study.  
Up to approximately 158 subjects are expected to enroll in this open-label extension study. 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 36 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
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 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. 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 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, SE, median, minimum value (min), and maximum value 
(max). 
Categorical variables will be summarized using counts and percentages. 
Baseline value, unless otherwise specified, for the safety analysis will be 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. 
Treatment-emergent (TE) Period will include the time period starting from the date of the first 
dose of study drug in Part A or Part B of this open-label study to 28 days after the last dose of the 
study drug in Part A or Part B, or to the completion date 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.   
Additional details of the analysis will be specified in the statistical analysis plan (SAP). 
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
Subject disposition will be summarized for the Open-label All Subjects Set. The number and 
percentage of subjects in the following categories will be summarized as appropriate: 
• 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 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 37 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
• 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 the 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, baseline 
body mass index (BMI), and baseline percent predicted forced expiratory volume in 1 second 
(ppFEV1).  
Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT) for the Safety Set. 
12.3.2.3 
Prior and Concomitant Medications 
Medications used will be coded using the World Health Organization-Drug Dictionary and 
categorized as the following: 
• Prior medication: any medication that was administered within the 56 days before the 
first dose of study drug in this open-label study. 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 minus the first day of study drug 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 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 38 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
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 important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being.  
All IPDs will be provided in an individual subject data listing, as appropriate. 
12.3.3 
Efficacy Analysis 
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. 
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. 
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 this 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 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 39 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
• TEAEs 
• Related TEAEs 
• TEAEs by maximum severity 
• Grade 3/4 TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same AE or a 
continuing AE will be counted once, only the maximum severity level will be presented in the 
severity summaries, and the strongest relationship level in the relationship summaries.  
Listings containing individual subject level AE data will be provided separately for: 
• Serious TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• TEAEs leading to death 
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 event during the 
TE Period will be summarized. The threshold criteria and selected parameters will be provided in 
the SAP. 
Results of urinalysis and pregnancy tests will be listed in individual subject data listings only. In 
addition, a listing containing individual subject laboratory assessment values will be provided. 
This listing will include data from scheduled and unscheduled time points. 
Additional safety laboratory data analyses may be described in the SAP. 
12.3.4.3 
Electrocardiogram 
For the TE ECG measurements, a summary of observed values and change from baseline values 
will be provided at each time point during the TE Period, for the following ECG interval 
measurements (in msec): RR, PR, QT, QT corrected for heart rate (HR) intervals (QTcF), QRS 
duration, and HR (beats per minute). 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 40 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
For threshold analysis, the number and percentage of subjects with at least 1 event during the 
TE Period will be summarized. The threshold criteria will be provided in the SAP.  
Additional ECG analyses may be described in the SAP. 
12.3.4.4 
Vital Signs 
For the TE vital signs measurements, the observed values and change from baseline values will 
be summarized at each time point during the TE Period in this open-label study. The following 
vital signs parameters will be summarized: systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), pulse rate (beats per minute), and respiratory rate (breaths per minute). 
For threshold analysis, the number and percentage of subjects with at least 1 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. 
12.3.5 
Independent Data Monitoring Committee Analyses 
12.3.5.1 
IDMC 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). 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 41 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the following times: 
• For 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 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  


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 42 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
July 2018). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” When 
considering the severity of an AE in a pediatric subject, the investigator will consider that 
reference ranges for pediatric clinical laboratory parameters may differ from those in the 
CTCAE. The severity of an AE described by a term that does not appear in the CTCAE will be 
determined according to the definitions in Table 13-1. 
Table 13-1 
Grading of AE Severity  
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening 
(Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
AE: adverse event 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the subject’s medical record). 
AE: adverse event 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories in Table 13-3. 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 43 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduceda 
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. 
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  


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 44 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
• 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 through the Safety Follow-up Visit, 
regardless of causality, will be reported by the investigator to Vertex GPS within 24 hours of 
identification. In addition, all SAEs that occur after the Safety Follow-up Visit and are 
considered related to study drug(s) will be reported to Vertex GPS within 24 hours of 
identification.  
For 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 through the Safety Follow-up Visit, the 
SAE Form will be completed for new/initial events as well as to report follow-up information on 
previously reported events. Investigators are asked to report follow-up information as soon as it 
becomes available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email: 
 
Fax: 
  
For technical issues related to submitting the form, contact telephone: 
 
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) will 
be recorded on the Vertex Clinical Trial Safety Information Collection Form (hereafter referred 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 45 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
to as the “SAE Form”) using a recognized medical term or diagnosis that accurately reflects the 
event. SAEs will be assessed by the investigator for relationship to the investigational study 
drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be assessed 
only as related (includes possibly related) or not related (includes unlikely related), and severity 
assessment will not be required. For the purposes of study analysis, if the event has not resolved 
at the end of the study reporting period, it will be documented as ongoing. For purposes of 
regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report the outcome to Vertex using the SAE Form. 
13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IECs, and 
participating investigators in accordance with ICH Guidelines and/or local regulatory 
requirements, as applicable. In addition, Vertex, or authorized designee, will be responsible for 
the submission of safety letters to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/IEC of all 
unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will be 
conducted only at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
ICH GCP and all applicable laws and regulations and will be subject to approval by Vertex or its 
designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study 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 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 46 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log. 
13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol. 
13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all 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. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP Guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 47 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
Written notification that includes the reason for the clinical study termination is required. 
13.2.8 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 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. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP Guidelines. On-site checking of the data captured for the study/SAE Forms for 
completeness and clarity, and clarification of administrative matters will be performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex or designee (study site monitor), who will review the data 
captured for the study/SAE Forms and source documents. The study site monitor will ensure that 
the investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture  
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 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 48 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 
13.7.2 
Clinical Study Report 
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in 
accordance with local regulations. 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 49 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
14 
REFERENCE 
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 22 March 2018. 
2 
Cystic Fibrosis Foundation. Patient Registry: 2017 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2018. 
3 
European Cystic Fibrosis Society. 2016 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: European Cystic Fibrosis Society; 2018. 
4 
United States Department of Health and Human Services. Food and Drug Administration. 
Office of Orphan Products Development. Developing Products for Rare Diseases & 
Conditions. Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.
htm. Accessed 19 September 2016. 
5 
European Medicines Agency [Internet]. Committee for Orphan Medicinal Products 
(COMP). Available at: https://www.ema.europa.eu/en/committees/committee-orphan-
medicinal-products-comp. Accessed 07 December 2018. 
6 
Rommens J, Iannuzzi M, Kerem B, Drumm M, Melmer G, Dean M, et al. Identification 
of the cystic fibrosis gene: chromosome walking and jumping. Science. 
1989;245(4922):1059-65. 
7 
Kreindler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
8 
Sheppard MN, Nicholson AG. The pathology of cystic fibrosis. Curr Diagn Pathol. 
2002;8(1):50-59. 
9 
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
10 
CFTR2.org. Clinical and functional translation of CFTR. The Clinical and Functional 
TRanslation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins 
University, the Hospital for Sick Children. Available at: http://www.cftr2.org. Accessed 
09 January 2018. 
11 
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. 
12 
International Committee of Medical Journal Editors (ICMJE). December 2017. 
Recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals. Available at: http://www.icmje.org/recommendations/. Accessed 03 
August 2018. 
 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 50 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol #: 
VX19-445-115 
Version #: 
2.2 AU 
and BE 
Version Date: 21 December 2021 
Study Title: A Phase 3b Open-label Study Evaluating the Safety of 
Elexacaftor/Tezacaftor/Ivacaftor Combination Therapy in Cystic Fibrosis Subjects 
This clinical study protocol has been reviewed and approved by the sponsor. 
Printed Name 
 
Title 
Signature 
 
Date 


Protocol VX19-445-115, Version 2.2 AU and BE 
 
 Page 51 of 51 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
Confidential Information 
15.2 
Investigator Signature Page 
Protocol #:  
VX19-445-115 
Version #: 
2.2 AU 
and BE 
Version Date: 21 December 2021 
Study Title: A Phase 3b Open-label Study Evaluating the Safety of 
Elexacaftor/Tezacaftor/Ivacaftor Combination Therapy in Cystic Fibrosis Subjects 
 
 
I have read Protocol VX19-445-115, Version 2.2 AU and BE, and agree to conduct the study 
according to its terms. I understand that all information concerning ELX, TEZ, IVA, and this 
protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 




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













SAP_001.pdf: 
Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 1 of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
1 
TI T L E P A G E  
 
V E R T E X P H A R M A C E U TI C A L S IN C O R P O R A T E D  
St ati sti c al A n al y si s Pl a n 
( M et h o d s) 
Pr ot o c ol N u m b er V X 1 9 -4 4 5 -1 1 5 V er si o n 2. 2 
( Fi n al A n al y si s) 
 
 
A P h a s e 3 b O p e n -l a b el St u d y E v al u ati n g t h e S af et y of 
El e x a c aft or/ T e z a c aft or/I v a c aft or C o m bi n ati o n T h er a p y i n C y sti c 
Fi br o si s S u bj e ct s  
 
A ut h ors of S A P:   
 
 
Versi o n:  2. 0 
Versi o n D ate of S A P:  1 8  Ja n uar y 2 0 2 2 
 
Verte x P har mace uticals I nc or p orate d  
5 0 N ort her n A ve n ue  
B ost o n, Massac h usetts 0 2 2 1 0- 1 8 6 2 
 
C O N FI D E N TI A L  
T hi s d o c u m e nt c o nt ai n s c o nfi d e nti al i nf or m ati o n.  A n y u s e, di stri b uti o n, or di s cl o s ur e wit h o ut t h e pri or writt e n 
c o n s e nt of V ert e x P h ar m a c e uti c al s I n c or p or at e d i s stri ctl y pr o hi bit e d e x c e pt t o t h e e xt e nt r e q uir e d u n d er 
a p pli c a bl e l a w s or r e g ul ati o n s.  P er s o n s t o w h o m t h e i nf or m ati o n i s di s cl o s e d m u st b e i nf or m e d t h at t h e 
i nf or m ati o n i s c o nfi d e nti al a n d m a y n ot b e f urt h er di s cl o s e d b y t h e m. 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 2 of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
2 
T A B L E O F C O N T E N T S  
 
1  
Title P a ge  ................................................................................................................................ 1 
2  
T a ble of C o nte nts  ................................................................................................................... 2 
4  
I ntr o d ucti o n ............................................................................................................................ 5 
5  
St u d y O bjecti ves  .................................................................................................................... 5 
5. 1  
Pri mar y O bjecti ve  ............................................................................................................. 5 
6  
St u d y E n d p oi nts  ..................................................................................................................... 5 
6. 1  
Pri mar y e n d p oi nt .............................................................................................................. 5 
7  
St u d y desi g n  ........................................................................................................................... 5 
7. 1  
O verall Desi g n  .................................................................................................................. 5 
7. 2  
Sa m ple Size a n d P o wer  .................................................................................................... 6 
7. 3  
Ra n d o mizati o n .................................................................................................................. 6 
7. 4  
Bli n di n g a n d U n bli n di n g .................................................................................................. 6 
8  
A n al ysis Sets  ........................................................................................................................... 6 
8. 1  
A nal ysis Sets f or Part A  ................................................................................................... 6 
8. 1. 1  
All S u bjects Set  ........................................................................................................ 6 
8. 1. 2  
Safet y Set  .................................................................................................................. 6 
8. 2  
A nal ysis Sets f or Part B  .................................................................................................... 7 
8. 2. 1  
All S u bjects Set  ........................................................................................................ 7 
8. 2. 2  
Safet y Set  .................................................................................................................. 7 
9  
St atistic al A n al ysis  ................................................................................................................. 7 
9. 1  
Statistical A nal ysis f or Part A  .......................................................................................... 7 
9. 1. 1  
Ge neral C o nsi derati o ns  ............................................................................................. 7 
9. 1. 2  
Bac k gr o u n d C haracteristics ...................................................................................... 7 
9. 1. 3  
Safet y A nal ysis  ....................................................................................................... 1 0 
9. 2  
Statistical A nal ysis f or Part B  ......................................................................................... 1 4 
9. 2. 1  
Ge neral C o nsi derati o ns  ........................................................................................... 1 4 
9. 2. 2  
Bac k gr o u n d C haracteristics .................................................................................... 1 5  
9. 2. 3  
Safet y A nal ysis  ....................................................................................................... 1 5 
1 0  I nteri m a n d D M C A n al yses ................................................................................................ 1 5 
1 0. 1  I nteri m A nal ysis ............................................................................................................. 1 5 
1 0. 2  D M C a nal ysis  ................................................................................................................. 1 5 
1 1  Refere nces  ............................................................................................................................. 1 6 
1 2  A p pe n dices  ............................................................................................................................ 1 7 
1 2. 1  A nal ysis Visit Wi n d o ws f or Safet y Assess me nts  ........................................................... 1 7 
1 2. 2  I m p utati o n R ules f or Missi n g Pri or/ C o nc o mita nt Me dicati o n Dates ............................. 2 0 
1 2. 3  I m p utati o n R ules f or Missi n g A E dates ......................................................................... 2 1 
1 2. 4  Criteria f or T hres h ol d A nal ysis  ...................................................................................... 2 2 
1 2. 5  A d verse E ve nts of S pecial I nterest  ................................................................................. 2 7 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 3 of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
 
 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 4 of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 5 of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
4 
I N T R O D U C TI O N 
T his statistical a nal ysis pla n ( S A P) d oc u me nts t he pla n ne d fi nal a nal yses of V X 1 9- 4 4 5- 1 1 5 
( St u d y 1 1 5) w hic h is base d o n a n a p pr o ve d cli nical st u d y pr ot oc ol ( C S P) ( Versi o n 2. 2, date d 2 1 
Dece m ber  2 0 2 1), as well as t he m ost rece nt a p pr o ve d electr o nic case re p ort f or m (e C R F), a n d 
t he m ost rece nt a p pr o ve d e C R F c o m pleti o n g ui deli nes. 
T he Verte x Bi o metrics De part me nt will perf or m t he statistical a nal ysis descri be d i n t his 
d oc u me nt; S A S ( Versi o n 9. 4 or hi g her) wil l be use d t o ge nerate all statistical o ut p uts (ta bles, 
fi g ures, listi n gs, a n d datasets). T he S A P ( Met h o ds) will be fi nalize d a n d a p pr o ve d pri or t o 
data base l oc k of St u d y 1 1 5 Part A. A n y re visi o ns t o t he a p pr o ve d S A P will be d oc u me nte d a n d 
a p pr o ve d i n a n a m e n d me nt t o t he S A P.  
5 
S T U D Y O B J E C TI V E S  
5. 1  
Pri m ar y O bj e cti v e  
T o e val uate t he safet y a n d t olera bilit y of ele xacaft or ( V X -4 4 5; E L X)/tezacaft or ( T E Z)/i vacaft or 
(I V A) 
6 
S T U D Y E N D P OI N T S  
6. 1  
Pri m ar y e n d p oi nt  
Safet y a n d t olera bilit y of treat me nt wit h E L X / T E Z/I V A base d o n ad verse e ve nts ( A Es), cli nical 
la b orat or y val ues, E C Gs, vital si g ns, a n d p ulse o xi metr y 
7 
S T U D Y D E SI G N  
7. 1  
O v er all D e si g n  
T his is a P hase  3 b, 2- part, m ultice nter, o pe n-la bel st u d y f or s u bjects w h o c o m plete a pare nt st u d y 
( St u d y V X 1 8- 4 4 5- 1 0 9; a P hase 3 b st u d y e valuati n g E L X/ T E Z/I V A) a n d meet eli gi bilit y criteria. 
A sc he matic of t he st u d y desi g n is s h o w n i n Fi g ure 7- 1. 
All s u bjects i n Parts A a n d B will recei ve t he tri ple c o m bi nati o n of E L X 2 0 0  m g o nce dail y 
( q d)/ T E Z 1 0 0 m g q d/I V A 1 5 0 m g e ver y 1 2 h o urs ( q 1 2 h) (t he sa me d ose le vel as t hat e val uate d 
i n t he P hase 3 pr o gra m of E L X/ T E Z/I V A). St u d y dr u g a d mi nistrati o n is descri be d i n 
Secti o n  9. 6. 1 of t he C S P. S o me s u bjects w h o c o m plete Part A will ha ve a n o p p ort u nit y t o 
partici pate i n Part B f or a n a d diti o nal 9 6 wee ks.  
Treat me nt Peri o d assess me nts f or Parts A a n d B are liste d i n Ta ble 3 - 1 a n d Ta ble 3 - 2 of t he C S P, 
res pecti vel y. M ore details a b o ut t he rati o nale f or st u d y desi g n a n d st u d y dr u g re gi me ns ca n be 
f o u n d i n Secti o n 9. 3 of t he pr ot oc ol.  
T his st u d y pr o vi des t he o p p ort u nit y f or s u bjects w h o de part t his st u d y t o e nr oll i n a n ot her 
q ualifie d Verte x st u d y of i n vesti gati o nal C F T R m o d ulat ors, b ut d o n ot recei ve st u d y dr u g i n t he 
Treat me nt Peri o d of t he ot her st u d y, t o ret ur n t o t his st u d y (a p plies t o b ot h Parts). H o we ver, d ue 
t o t he ti mi n g of t he ot her Verte x st u dies, t his will o nl y be a p plica ble f or Part B. 
 




Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 7 of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
8. 2  
A n al y si s S et s f or P art B  
8. 2. 1  
All S u bj e ct s S et  
T he All S u bjects Set  f or Part B is defi ne d as all s u bjects w h o were e nr olle d ( defi ne d as s u bject 
ha vi n g data i n t he cli nical data base) i n Part B of St u d y 1 1 5. T his a nal ysis set will be use d f or 
i n di vi d ual s u bject data listi n gs a n d t he dis p ositi o n s u m mar y ta ble, u nless ot her wise s pecifie d. 
8. 2. 2  
S af et y S et  
T he S afet y Set f or Part B is defi ne d as all s u bjects w h o ha ve recei ve d at least 1 d ose of st u d y 
dr u g i n Part B of St u d y 1 1 5. T he Safet y Set will be use d f or s u bject de m o gra p hics a n d baseli ne 
c haracteristics a n d f or all safet y a nal yses u nless ot her wise s pecifie d . 
9 
S T A TI S TI C A L A N A L Y SI S  
T he a nal yses will be perf or me d se paratel y f or Part A a n d Part B, u nless ot her wise s pecifie d.  
9. 1  
St ati sti c al A n al y si s f or P art A  
9. 1. 1  
G e n er al C o n si d er ati o n s  
T he safet y a nal yses f or Part A will be prese nte d f or o verall wit h all t he s u bjects p o ole d t o get her, 
u nless ot her wise s pecifie d.  
T he precisi o n sta n dar ds f or re p orti n g safet y varia bles are pr o vi de d i n a n i nter nal Bi o metrics 
d oc u me nt t hat s pecifies t he pr o gra m mi n g r ules i ncl u di n g t he precisi o n f or deri ve d varia bles.  
C o nti n u o us v ari a bles  will  be s u m marize d usi n g t he f oll o wi n g descri pti ve s u m mar y statistics: 
t he n u m ber of s u bjects ( n), mea n, S D, S E, me dia n, mi ni m u m val ue ( mi n), a n d ma xi m u m val ue 
( ma x). 
C ate g oric al v ari a bles  will be s u m marize d usi n g c o u nts a n d perce nta ges.  
B aseli ne v al ue , u nless ot her wise s pecifie d, f or t he safet y a nal ysis will be t he m ost rece nt 
n o n- missi n g meas ure me nt (sc he d ule d or u nsc he d ule d) c ollecte d bef ore t he first d ose of 
E L X/ T E Z/I V A eit her i n a pare nt st u d y or i n Part A of St u d y 1 1 5, as a p plica ble. F or assess me nts 
c ollecte d i n d u plicate or tri plicate, t he baseli ne val ue will be defi ne d as t he a vera ge of 
n o n- missi n g val ues.  
C h a n ge ( a bs ol ute c h a n ge) fr o m b aseli ne  will be calc ulate d as P ost -baseli ne  val ue − Baseli ne 
val ue. 
Tre at me nt -e mer ge nt ( T E) Peri o d  f or P art A wil l i ncl u de t he ti me peri o d starti n g fr o m t he date 
of t he first d ose of st u d y dr u g i n Part A of t his o pe n- la bel st u d y t o 2 8 da ys after t he last d ose of 
t he st u d y dr u g, or t o t he c o m pleti o n date of st u d y partici pati o n (as defi ne d i n Secti o n 9. 1. 5  of 
st u d y pr ot oc ol), w hic he ver occ urs first.  
9. 1. 2  
B a c k gr o u n d C h ar a ct eri sti c s  
9. 1. 2. 1  
S u bj e ct Di s p o siti o n  
S u bject dis p ositi o n will be s u m marize d f or t he All S u bjects Set. T h e n u m ber a n d perce nta ge of 
s u bjects i n t he f oll o wi n g cate g ories f or Part A will be s u m marize d as a p pr o priate: 
•  All S u bjects Set  


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 8 of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
•  Safet y Set  
•  C o m plete d Treat me nt i n Part A  
•  Pre mat urel y disc o nti n ue d treat me nt i n Part A a n d t he reas o ns f or disc o nti n uati o n 
•  C o m plete d st u d y i n Part A 
•  Pre mat urel y disc o nti n ue d i n Part A a n d t he reas o ns f or disc o nti n uati o n  
A listi n g will be pr o vi de d f or s u bjects w h o disc o nti n ue d treat me nt i n Part A or w h o disc o nti n ue d 
st u d y i n Part A wit h reas o ns f or disc o nti n uati o n.  
9. 1. 2. 2  
D e m o gr a p hi c s a n d B a s eli n e C h ar a ct eri sti c s  
De m o gra p hics a n d baseli ne c haracteristics will be s u m marize d b y descri pti ve s u m mar y statistics 
f or t he Safet y Set. De m o gra p hic data will i ncl u de t he f oll o wi n g: 
•  A ge at pare nt st u d y baseli ne (i n years)  
•  Se x (fe m ale a n d male) 
•  Et h nicit y ( His pa nic or Lati n o, n ot His pa nic or Lati n o, a n d n ot c ollecte d per l ocal re g ulati o ns) 
•  Race ( W hite, Blac k or Africa n A merica n, Asia n, A merica n I n dia n or Alas ka Nati ve, Nati ve 
Ha waiia n or Ot her Pacific Isla n der, N ot C ollecte d per L oca l Re g ulati o ns a n d Ot her) 
•  C o u ntr y     
Pare nt st u d y baseli ne c haracteristics will i ncl u de t he f oll o wi n g:  
•  Wei g ht ( k g)  
•  Hei g ht (c m)  
•  B MI ( k g/ m 2) 
Stratificati o n cate g ories (i n a d diti o n t o se x, if a p plica ble) use d i n t he pare nt st u d y will i ncl u de 
t he f oll o wi n g: 
•  A ge at Scree ni n g Visit of pare nt st u d y ( < 1 8, ≥1 8 years)  
•  p p F E V 1 at Da y - 1 4 of pare nt st u d y ( < 7 0, ≥7 0) 
•  C F T R m o d ulat or use at t he Scree ni n g Visit of pare nt st u d y ( Yes, N o)  
N ote t hat t he pare nt st u d y (st u d y 1 0 9) ha d a 4- wee k T E Z/I V A r u n -i n peri o d d uri n g w hic h t he 
p p F E V 1 use d i n stratificati o n was deter mi ne d.  
Disease c haracteristics base d o n pare nt st u d y baseli ne will i ncl u de t he f oll o wi n g:  
•  p p F E V 1 at pare nt st u d y baseli ne ( < 4 0, ≥ 4 0 t o < 7 0, ≥7 0 t o ≤9 0, a n d > 9 0)  
•  p p F E V 1 at pare nt st u d y baseli ne (c o nti n u o us)  
•  Pri or  use of d or nase alfa ( Yes, N o)  
•  Pri or use of azit hr o m yci n ( Yes, N o)  
•  Pri or use of i n hale d a nti bi otic ( Yes, N o)  


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 9 of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
•  Pri or use of a n y br o nc h o dilat or ( Yes, N o)  
•  Pri or use of a n y i n hale d br o nc h o dilat or ( Yes, N o)  
•  Pri or use of a n y i n hale d h y pert o nic sali ne ( Yes, N o)  
•  Pri or use of a n y i n hale d c ortic oster oi ds ( Yes, N o) 
•  I nfecti o n wit h Pse u d o m o n as aer u gi n os a wit hi n 2 years pri or t o scree ni n g visit ( P ositi ve, 
Ne gati ve) of pare nt st u d y 
Pri or me dicati o n use defi niti o n is sa me as t hat f or t he baseli ne c haracteristics s u m ma r y prese nte d 
i n t he pare nt st u dies. 
9. 1. 2. 3  
M e di c al Hi st or y  
Me dical hist or y (refere nce d t o t he start of pare nt st u d y) will be c o de d b y usi n g t he Me dical 
Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A). Me dical hist or y will be s u m marize d 
descri pti vel y b y S yste m Or ga n  Class ( S O C) a n d Preferre d Ter m ( P T) base d o n t he Safet y Set. 
T he c orres p o n di n g data listi n g will als o be pr o vi de d. 
9. 1. 2. 4  
Pri or a n d C o n c o mit a nt M e di c ati o n s  
Me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n- Dr u g Dicti o nar y a n d 
cate g orize d as f oll o ws:  
•  Pri or me dic ati o n:  a n y me dicati o n t hat was a d mi nistere d wit hi n t he 5 6 da ys bef ore t he first 
d ose of st u d y dr u g i n Part A i n t his o pe n-la bel st u d y. 
•  C o nc o mit a nt me dic ati o n:  me dicati o n c o nti n ue d or ne wl y recei ve d d uri n g t he T E Peri o d f or 
Part A i n t his o pe n -label st u d y.  
•  P ost -tre at me nt me dic ati o n: me dicati o n c o nti n ue d or ne wl y recei ve d after t he T E Peri o d f or 
Part A i n t his o pe n -la bel st u d y. 
A gi ve n me dicati o n ma y be classifie d as a pri or me dicati o n, a c o nc o mita nt me dicati o n, or a 
p ost- treat me nt me dicati o n; b ot h pri or a n d c o nc o mita nt; b ot h c o nc o mita nt a n d p ost- treat me nt; or 
pri or, c o nc o mita nt, a n d p ost- treat me nt.  
If a me dicati o n has a missi n g or partiall y missi n g start/e n d date or ti me a n d if it ca n n ot be 
deter mi ne d w het her it was ta ke n bef ore i n itial d osi n g, c o nc o mita ntl y d uri n g t he T E Peri o d, or 
be y o n d t he T E Peri o d, it will be c o nsi dere d i n all 3 cate g ories of pri or, c o nc o mita nt, a n d 
p ost- treat me nt me dicati o n. Details f or i m p uti n g missi n g or partial start a n d/ or st o p dates of 
me dicati o n are des cri be d i n Secti o n 1 2. 2 . 
Pri or me dicati o ns a n d c o nc o mita nt me dicati o ns will be s u m marize d descri pti vel y b y Preferre d 
Na me base d o n t he Safet y Set  b y 1) preferre d na me ( P N); a n d 2) a n at o mic class ( A T C) le vel 1, 
A T C le vel 2, a n d P N . P ost-treat me nt me dicati o ns will be pr o vi de d se paratel y i n a n i n di vi d ual 
s u bject data listi n g. 
9. 1. 2. 5  
St u d y Dr u g E x p o s ur e  
St u d y dr u g e x p os ure will be s u m marize d base d o n t he Safet y Set 。 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 1 0  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
D urati o n of st u d y dr u g e x p os ure (i n da ys) will be calc ulate d as [last d ose date – first d ose date + 
1 da y] wit hi n t he T E peri o d f or Part A, re gar dless of a n y i nterr u pti o n i n d osi n g bet wee n t he first 
a n d t he last d ose.  
St u d y dr u g e x p os ure (i n wee ks) will be s u m marize d descri pti vel y b y t he n u m ber of s u bjects ( n), 
mea n, S D, me dia n, mi n, a n d ma x. It will als o be s u m marize d b y i nter val, usi n g c o u nts a n d 
perce nta ges . 
9. 1. 2. 6  
St u d y Dr u g C o m pli a n c e  
St u d y dr u g c o m plia nce will be s u m marize d base d o n t he Safet y Set a n d will be calc ulate d as: 
1 0 0 ×  [ 1 – (t otal n u m ber of da ys of st u d y dr u g i nterr u pti o n i n Part A of t his o pe n-la bel st u d y) / 
( d urati o n of st u d y dr u g e x p os ure i n da ys i n Part A t his o pe n-la bel st u d y)]. A st u d y dr u g 
i nterr u pti o n o n a gi ve n da y is defi ne d as a n i nterr u pti o n of a n y st u d y dr u g o n t hat da y.  
Perce nta ge of st u d y dr u g c o m plia nce will be s u m marize d base d o n Safet y Set . Perce nta ge of 
st u d y dr u g c o m plia nce will be s u m marize d descri pti vel y b y t he n u m ber of s u bjects ( n), mea n, 
S D, me dia n, mi n, a n d ma x.  It will als o be s u m marize d i n cate g ories: < 8 0 % a n d ≥8 0 % usi n g 
fre q ue nc y ta bles.  
9. 1. 2. 7  
I m p ort a nt Pr ot o c ol D e vi ati o n  
A n i m p orta nt pr ot oc ol de viati o n (I P D) is a de viati o n t hat ma y si g nifica ntl y affect t he 
c o m plete ness, acc urac y, or relia bilit y of t he st u d y data or t hat ma y si g nifica ntl y affect a s u bject’s 
ri g hts, safet y, or well-bei n g. A pr ot oc ol de viati o n re vie w tea m will cate g orize I P Ds acc or di n g t o 
t he Pr ot oc ol De viati o n Pla n d uri n g t he st u d y. I P D r ules will be de vel o pe d a n d fi nalize d bef ore 
data base l oc k. 
I P Ds (fr o m t he cli nical data base or fr o m t he site de viati o n l o g) d uri n g Part A of t his o pe n-la bel 
st u d y will be s u m marize d descri pti vel y base d o n t he Safet y Set. A d diti o nall y, I P Ds will be 
pr o vi de d i n a n i n di vi d ual s u bject data listi n g.  
9. 1. 3  
S af et y A n al y si s  
T he pri mar y o bjecti ve of t his st u d y is t he e val uati o n of safet y a n d t olera bilit y of E L X/ T E Z/I V A. 
All safet y a nal yses will be base d o n t he T E Peri o d f or Part A f or s u bjects i n t he Safet y Set.  
T he o verall l o n g- ter m safet y pr ofile of st u d y dr u g will be assesse d i n ter ms of t he f oll o wi n g 
safet y a n d t olera bilit y e n d p oi nts: 
•  Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es)  
•  Cli nical la b orat or y val ues  
•  E C Gs  
•  Vital si g ns  
•  P ulse o xi metr y  
O nl y descri pti ve a nal ysis of safet y will be perf or me d a n d n o statistical testi n g will be perf or me d.  
9. 1. 3. 1  
A d v e r s e E v e nt s  
A Es will be classifie d as pretreat me nt A Es, T E A Es, or p ost -treat me nt A Es, defi ne d as f oll o ws:  


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 1 1  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
•  Pre -tre at me nt A E: a n y A E occ urre d bef ore t he first d ose date of st u d y dr u g i n t he T E 
Peri o d f or Part A.  
•  T E A E : a n y A E t hat w orse ne d (eit her i n se verit y or seri o us ness) or ne wl y de vel o pe d at or 
after t he first d ose date of E L X/ T E Z/I V A i n t he T E Peri o d f or Part A i n t his o pe n -la bel 
st u d y. 
•  P ost -tre at me nt A E: a n y A E t hat w orse ne d (eit her i n se verit y or seri o us ness) o r ne wl y 
de vel o pe d after t he T E Peri o d f or Part A.  
F or A Es wit h missi n g or partial start dates, if t here is n o clear e vi de nce t hat t he A Es starte d 
bef ore or after st u d y dr u g treat me nt start date i n t his O L S, t he n t he A Es will be classifie d as 
T E A Es.  
Details  f or i m p uti n g missi n g or partial start dates of a d verse e ve nts are descri be d i n Secti o n 1 2. 3 . 
A n o ver vie w of all T E A Es d uri n g T E peri o d will be s u m marize d a n d i ncl u de t he f oll o wi n g 
cate g ories: 
•  N u m ber of T E A Es (t otal n u m ber of T E A Es o nl y) 
•  S u bjects wit h a n y T E A Es  
•  S u bjects wit h T E A Es b y str o n gest relati o ns hi p 
•  S u bjects wit h T E A Es b y ma xi m u m se verit y 
•  S u bjects wit h T E A Es lea di n g t o st u d y dr u g disc o nti n uati o n 
•  S u bjects wit h T E A Es lea di n g t o st u d y dr u g i nterr u pti o n 
•  S u bjects wit h Gra de 3/ 4 T E A Es 
•  S u bjects wit h relate d T E A Es  
•  S u bjects wit h seri o us T E A Es  
•  S u bjects wit h relate d seri o us T E A Es  
•  S u bjects wit h T E A E lea di n g t o deat h  
T he fre q ue nc y c o u nts a n d perce nta ges as well as t he e x p os ure a dj uste d e ve nt rate will be 
prese nte d f or t he a b o ve o ver vie w ta ble. T he e x p os ure a dj uste d rate will n ot be prese nte d f or 
str o n gest relati o ns hi p a n d ma xi m u m se verit y cate g ories. 
T he f oll o wi n g s u m mar y ta bles of T E A Es will be prese nte d f or o verall:  
•  All T E A Es  
•  T E A Es b y str o n gest relati o ns hi p 
•  T E A Es b y ma xi m u m se verit y 
•  Relate d T E A Es  
•  Gra de 3/ 4 T E A Es 
•  Seri o us T E A Es  


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 1 2  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
•  Relate d seri o us T E A Es  
•  T E A Es lea di n g t o treat me nt disc o nti n uati o n 
•  T E A Es lea di n g t o treat me nt i nterr u pti o n  
•  T E A Es lea di n g t o deat h 
S u m maries will be prese nte d b y Me d D R A S O C a n d P T usi n g fre q ue nc y c o u nts a n d perce nta ges 
(i.e., n u m ber a n d perce nta ge of s u bjects wit h a n e ve nt) a n d t he e x p os ure a dj uste d e ve nt rate 
(e xce pt f or s u m mar y b y str o n gest relati o ns hi p a n d ma xi m u m se verit y). W he n su m marizi n g t he 
n u m ber a n d perce nta ges of s u bjects, s u bjects wit h m ulti ple occ urre nces of t he sa me a d verse 
e ve nt will be c o u nte d o nce, a n d o nl y t he ma xi m u m se verit y le vel will be prese nte d i n t he 
se verit y s u m maries, a n d t he str o n gest relati o ns hi p le vel i n the relati o ns hi p s u m maries. Missi n g 
se verit y le vels will n ot be i ncl u de d i n t he Gra de 3/ 4 T E A E s u m maries; missi n g relati o ns hi p will 
be c o nsi dere d as relate d a n d i ncl u de d i n t he relate d T E A E a n d relate d seri o us T E A E s u m maries.   
A d diti o nal s u m mar y ta ble will  be prese nte d f or T E A Es o verall i n n u m ber a n d perce nta ge of 
s u bjects. 
•  All T E A Es b y P T  
All A Es, i ncl u di n g pre-treat me nt A Es, T E A Es, a n d p ost- treat me nt A Es, will be prese nte d i n a n 
i n di vi d ual s u bject data listi n g base d o n t he All S u bjects Set. I n a d diti o n, se parate listi n gs 
c o ntai ni n g i n di vi d ual s u bject a d verse e ve nt data f or T E A Es lea di n g t o treat me nt disc o nti n uati o n, 
T E A Es lea di n g t o treat me nt i nterr u pti o n, Gra de 3/ 4 T E A Es, S A Es a n d A Es lea di n g t o deat h will 
be pr o vi de d, wit h a fla g i n dicati n g t he T E A E stat us f or S A Es a n d deat hs. 
9. 1. 3. 2  
Cli ni c al L a b or at or y A s s e s s m e nt s  
F or t he la b orat or y assess me nts d uri n g T E peri o d f or Part A, t he o bser ve d val ues a n d c ha n ge 
fr o m baseli ne val ues of t he c o nti n u o us he mat ol o g y, c oa g ulati o n a n d c he mistr y res ults will be 
s u m marize d i n SI u nits at eac h visit.  
T he n u m ber a n d perce nta ge of s u bjects meeti n g at least 1 t hres h ol d a nal ysis criteri o n e ve nt 
d uri n g t he T E peri o d f or Part A will be s u m marize d. T he t hres h ol d a nal ysis criteri o n s hift fr o m 
baseli ne will als o be s u m marize d f or selecte d  la b orat or y para meters. T he t hres h ol d a nal ysis 
criteria are pr o vi de d i n Secti o n 1 2. 4 .  
Res ults of p ositi ve uri ne/ser u m pre g na nc y test will be prese nte d i n i n di vi d ual s u bject data 
listi n gs o nl y. F or p ositi ve ser u m pre g na nc y listi n g, s u bjects wit h ser u m H C G w hic h are 
a b n or mall y hi g h will be selecte d.  
I n a d diti o n, a listi n g c o ntai ni n g i n di vi d ual s u bject he mat ol o g y, c he mistr y, a n d c oa g ulati o n val ues 
will be pr o vi de d. T his listi n g will i ncl u de data fr o m b ot h sc he d ule d a n d u nsc he d ule d visits.  
9. 1. 3. 3  
El e ctr o c ar di o gr a m  
F or t he f oll o wi n g E C G i nter val meas ure me nts d uri n g t he T E peri o d f or Part A, a s u m mar y of 
o bser ve d val ues a n d c ha n ge fr o m baseli ne val ues will be pr o vi de d at eac h visit (i n msec): R R, 
P R, Q T, a n d Q T c orrecte d f or H R ( Q Tc F), Q R S d urati o n, a n d H R ( beats per mi n ute). 
T he n u m ber a n d perce nta ge of s u bjects meeti n g at least 1 t hres h ol d a nal ysis criteri o n e ve nt 
d uri n g t he T E peri o d f or Part A  will be s u m marize d. T he t hres h ol d a nal ysis criteria  are pr o vide d 
i n Secti o n 1 2. 4 . 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 1 3  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
9. 1. 3. 4  
Vit al Si g n s  
F or t he vital si g ns meas ure me nts d uri n g t he T E peri o d f or Part A, t he o bser ve d val ues a n d 
c ha n ge fr o m baseli ne val ues will be s u m marize d at eac h visit. T he f oll o wi n g vital si g ns 
para meters will be s u m marize d: B MI ( k g/ m 2), wei g ht ( k g), s yst olic a n d diast olic bl o o d press ure 
( m m H g), b o d y te m perat ure (°C), p ulse rate ( beats per mi n ute), a n d res pirat or y rate ( breat hs  per 
mi n ute).  
T he n u m ber a n d perce nta ge of s u bjects meeti n g at least 1 t hres h ol d a nal ysis criteri o n e ve nt 
d uri n g t he T E peri o d f or Part A  will be s u m marize d. T he t hres h ol d a nal ysis criteria are pr o vi de d 
i n Secti o n 1 2. 4 . 
9. 1. 3. 5  
P ul s e O xi m etr y  
F or t he perce nt of o x y ge n sat urati o n meas ure me nts usi n g p ulse o xi metr y d uri n g t he T E peri o d 
f or Part A, a s u m mar y of o bser ve d val ues a n d c ha n ge fr o m baseli ne val ues will be pr o vi de d at 
eac h visit. 
T he n u m ber a n d perce nta ge of s u bjects wit h s hift c ha n ges fr o m baseli ne ( n or mal/ missi n g a n d 
l o w acc or di n g t o t he refere nce ra n ge) t o t he l o west perce nt of o x y ge n sat urati o n d uri n g t he T E 
peri o d f or Part A  will be s u m marize d.  
9. 1. 3. 6  
P h y si c al E x a mi n ati o n  
N o ta bles/fi g ures/listi n gs will be pr o vi de d f or p h ysical e xa mi nati o n data.  
9. 1. 3. 7  
O p ht h al m ol o g y E x a mi n ati o n  
O p ht hal m ol o g y e xa mi nati o n res ults will be pr o vi de d i n a data listi n g. 
9. 1. 3. 8  
C O VI D -1 9 I m p a ct e d Vi sit s  
A listi n g c o ntai ni n g s u bjects’ visits i m p acte d d ue t o C O VI D- 1 9 will be pr o vi de d. 
9. 1. 3. 9  
S af et y S u p p orti v e A n al y si s  
9. 1. 3. 1 0  
A d v er s e E v e nt s of S p e ci al I nt er e st  
F or t his st u d y, ele vate d tra nsa mi nases e ve nts a n d ras h e ve nts, as deter mi ne d b y Me d D R A 
Preferre d Ter ms i n t he res pecti ve C ust o mize d Me d D R A Q ueries ( C M Q), are c o nsi dere d as 
a d verse e ve nts of s pecial i nterest. T he c orres p o n di n g A E data will be s u m marize d i n ter ms of 
fre q ue nc y c o u nts a n d e x p os ure a dj uste d rates. 
F or treat me nt-e mer ge nt  ele vate d tra nsa mi nases e ve nts a n d ras h e ve nts, t he f oll o wi n g cate g ories 
will be s u m marize d:  
•  S u bjects wit h e ve nts 
•  S u bjects wit h e ve nts b y ma xi m u m se verit y 
•  S u bjects wit h e ve nts leadi n g t o treat me nt disc o nti n uati o n  
•  S u bjects wit h e ve nts lea di n g t o treat me nt i nterr u pti o n  
•  S u bjects wit h seri o us e ve nts  
•  S u bjects wit h relate d seri o us e ve nts  


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 1 4  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
•  S u bjects wit h e ve nts lea di n g t o deat h 
•  D urati o n of e ve nts  
•  Ti me -t o-o nset of first e ve nt ( wit h t he first  d ose date of E L X/ T E Z/I V A i n t he o pe n-la bel 
st u d y Part A as t he refere nce w hile calc ulati n g ti me-t o- o nset) 
N ote t hat f or ma xi m u m se verit y, d urati o n of e ve nts a n d ti me t o o nset of first e ve nt, t he e x p os ure 
a dj uste d rates will n ot be prese nte d. 
I n a d diti o n, f or treat me nt-e mer ge nt ras h e ve nts, t he a b o ve cate g ories will be s u m marize d f or t he 
f oll o wi n g s u b gr o u ps: 
•  Se x ( male, fe male)  
•  Fe male s u bjects wit h c o nc o mita nt h or m o nal t hera p y ( Yes, N o) 
9. 2  
St ati sti c al A n al y si s f or P art B  
9. 2. 1  
G e n er al C o n si d er ati o n s  
T he safet y a nal ys es f or Part B, u nless ot her wise s pecifie d, will be si milar t o t he safet y a nal yses 
f or Part A. F or s u bjects w h o de part t his st u d y t o e nr oll i n a n ot her q ualifie d Verte x st u d y a n d 
ret ur n t o t his st u d y, details of t he ass ociate d a nal ysis will be s pecifie d i n this Secti o n. 
I n t he u nli kel y sce nari o t hat o nl y a fe w patie nts r oll o ver i nt o Part B, a descri pti ve s u m mar y ma y 
n ot be perf or me d. 
B aseli ne v al ue , u nless ot her wise s pecifie d, f or t he safet y a nal ysis will be t he m ost rece nt 
n o n- missi n g meas ure me nt (sc he d ule d or u nsc he d ule d) c ollecte d bef ore t he first d ose of 
E L X/ T E Z/I V A eit her i n a pare nt st u d y or i n Part A of St u d y 1 1 5, w hic he ver is 
earlier . F or assess me nts c ollecte d i n d u plicate or tri plicate, t he baseli ne val ue will be defi ne d as 
t he a vera ge of n o n-missi n g val ues.  
Tre at me nt -e mer ge nt ( T E) Peri o d  f or P art B will i ncl u de t he ti me peri o d starti n g fr o m t he date 
of t he first d ose of st u d y dr u g i n Part B of t his o pe n- la bel st u d y t o 2 8 da ys after t he last d ose of 
t he st u d y dr u g, or t o t he c o m pleti o n date of st u d y partici pati o n (as defi ne d i n Secti o n 9. 1. 5  of 
st u d y pr ot oc ol), w hic he ver occ urs first. F or s u bjects w h o e nr oll i n a n ot her q ualifie d Verte x st u d y 
bef ore c o m pleti n g t his st u d y a n d res u me partici pati o n i n t his st u d y, t he T E Peri o d will e xcl u de 
t he ti me s pe nt i n t he ot her st u d y.   
Pri or a n d C o nc o mit a nt Me dic ati o ns  
F or Part B, me dicati o ns will be cate g orize d as : 
•  Pri or me dic ati o n:  a n y me dicati o n t hat was a d mi nistere d wit hi n t he 5 6 da ys bef ore t he 
first d ose of st u d y dr u g i n Part B of St u d y 1 1 5. F or s u bjects w h o e nr oll i n a n ot her 
q ualifie d Verte x st u d y a n d res u me partici pati o n i n t his st u d y, a n y ne w or c ha n ge d 
me dicati o n a d mi nistere d aft er t he De parti n g Visit a n d pri or t o t he first d ose of st u d y dr u g 
after res u mi n g partici pati o n i n t his st u d y will als o be c o nsi dere d pri or me dicati o n.  
•  C o nc o mit a nt me dic ati o n: me dicati o n c o nti n ue d or ne wl y recei ve d at, or after, i nitial 
d osi n g of st u d y dr u g t hr o u g h t he e n d of 1 1 5 Part B T E Peri o d. 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 1 5  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
•  P ost -tre at me nt me dic ati o n: me dicati o n c o nti n ue d or ne wl y recei ve d after 1 1 5 Part B 
T E Peri o d.  
St u d y Dr u g E x p os ure  
St u d y dr u g e x p os ure will be s u m marize d base d o n t he Safet y Set f or Part B.  D urati o n of st u d y 
dr u g e x p os ure (i n da ys) will be calc ulate d as [last d ose date – first d ose date + 1 da y] wit hi n t he 
T E peri o d f or Part B, re gar dless of a n y i nterr u pti o n i n d osi n g bet wee n t he first a n d t he last d ose. 
F or s u bjects w h o e nr oll i n a n ot her q ualifie d Verte x st u d y a n d res u me partici pati o n i n t his st u d y, 
ti me s pe nt i n t he ot her st u d y will be e xcl u de d.  
St u d y Dr u g C o m pli a nce  
St u d y dr u g c o m plia nce will be s u m marize d base d o n t he Safet y Set a n d will be calc ulate d as: 
1 0 0 ×  [ 1 – (t otal n u m ber of da ys of st u d y dr u g i nterr u pti o n i n Part B of t his o pe n-la bel st u d y) / 
( d urati o n of st u d y dr u g e x p os ure i n da ys i n Part B t his o pe n-la bel st u d y)]. A st u d y dr u g 
i nterr u pti o n o n a gi ve n da y is defi ne d as a n i nterr u pti o n of a n y st u d y dr u g o n t hat da y. F or 
s u bjects w h o e nr oll i n a n ot her q ualifie d Verte x st u d y a n d res u me partici pati o n i n t his st u d y, ti me 
s pe nt i n t he ot her st u d y will be e xcl u de d. 
9. 2. 2  
B a c k gr o u n d C h ar a ct eri sti c s  
T he sa me set of a nal yses as Part A will be perf or me d f or Part B base d o n Part B’s a nal ysis sets  
a n d t he defi niti o ns i n t he Ge neral C o nsi derati o n Secti o n 9. 2. 1.  
9. 2. 3  
S af et y A n al y si s  
A Es i n Part B are defi ne d as f oll o ws:  
•  Pretre at me nt A E : a n y A E t hat occ urre d bef ore t he first d ose date of st u d y dr u g i n t he 
T E Peri o d f or Part B. F or s u bjects w h o de part t his st u d y t o e nr oll i n a n ot her q ualifie d 
Verte x st u d y bef ore c o m pleti n g t his st u d y a n d ret ur n t o t his st u d y, pretreat me nt A Es als o 
i ncl u de a n y A E t hat occ urre d after partici pati n g i n t he ot her q ualifie d Verte x st u d y a n d 
bef ore t he first d ose of st u d y dr u g af ter res u mi n g partici pati o n i n St u d y 1 1 5 Part B. 
•  T E A E : a n y A E t hat w orse ne d (eit her i n se verit y or seri o us ness) or ne wl y de vel o pe d at or 
after t he first d ose date of E L X/ T E Z/I V A i n t he T E Peri o d f or Part B i n t his o pe n -la bel 
st u d y. 
•  P ost -tre at me nt A E: a n y A E t hat w orse ne d (eit her i n se verit y or seri o us ness) or ne wl y 
de vel o pe d after t he T E Peri o d f or Part B.  
T he sa me set of safet y a nal yses as Part A will be perf or me d f or Part B base d o n Part B’s Safet y 
Set a n d its treat me nt e mer ge nt peri o d  w he n a p plica ble. 
1 0  
I nteri m a n d D M C A n al y s e s  
1 0. 1  
I nt eri m A n al y si s 
N ot a p plica ble.  
1 0. 2  
D M C a n al y si s  
N ot a p plica ble.  


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 1 6  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
1 1  
R E F E R E N C E S  
1.  Ce nters f or Disease C o ntr ol a n d Pre ve nti o n. C D C Gr o wt h C harts. A vaila ble at: 
htt p:// w w w.c dc. g o v/ gr o wt hc harts/ perce ntile _ data _files. ht m. 
 
 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 1 7  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
1 2  
A P P E N DI C E S  
1 2. 1  
A n al y si s Vi sit Wi n d o w s f or S af et y A s s e s s m e nt s  
T a ble 1 2- 1  
A n al ysis Visit Wi n d o ws S afet y Assess me nts  
P a nel A: A n al ysis Visit Wi n d o ws f or P art A  
Assess me nt  
Visit 1 
T ar get St u d y D a y  
A n al ysis Visit Wi n d o w  
(i n st u d y d a ys)2, 3, 4 
Wei g ht, Hei g ht a n d B MI  
 
Baseli ne  
Part A Wee k 4  
Part A Wee k 1 2  
Part A Wee k 2 4  
Part A Wee k 3 6  
Part A Wee k 4 8  
Part A Safet y F oll o w -u p  
- -  
2 9  
8 5  
1 6 9  
2 5 3  
3 3 7  
N ot a p plica ble  
defi ne d i n secti o n 9. 1. 1 
[1, 4 3]  
( 4 3, 1 1 3] 
( 1 1 3, 2 1 1] 
( 2 1 1, 2 9 5] 
( 2 9 5, 3 5 1] 
Use n o mi nal visit  
Vital Si g ns  
He mat ol o g y  
Ser u m C he mistr y  
 
Baseli ne  
Part A Da y 1 5  
Part A Wee k 4  
Part A Wee k 1 2  
Part A Wee k 2 4  
Part A Wee k 3 6  
Part A Wee k 4 8  
Part A Safet y F oll o w -u p  
- -  
1 5  
2 9  
8 5  
1 6 9  
2 5 3  
3 3 7  
N ot a p plica ble  
defi ne d i n secti o n 9. 1. 1  
[ 1, 2 2]  
( 2 2, 4 3]  
( 4 3, 1 1 3] 
( 1 1 3, 2 1 1] 
( 2 1 1, 2 9 5] 
( 2 9 5, 3 5 1] 
Use n o mi nal visit  
Sta n dar d 1 2 -lea d E C G  
Baseli ne  
Part A Da y 1 5  
Part A Wee k 1 2  
Part A Wee k 2 4  
Part A Wee k 4 8  
Part A Safet y F oll o w -u p  
- -  
1 5  
8 5  
1 6 9  
3 3 7  
N ot a p plica ble  
defi ne d i n secti o n 9. 1. 1  
[ 1, 2 2]  
( 2 2, 1 1 3]  
( 1 1 3, 2 5 3] 
( 2 5 3, 3 5 1] 
Use n o mi nal visit  
C oa g ulati o n  
Baseli ne  
Part A Wee k 2 4  
Part A Wee k 4 8  
Part A Safet y F oll o w -u p  
- -  
1 6 9  
3 3 7  
N ot a p plica ble  
defi ne d i n secti o n 9. 1. 1  
[ 1, 2 5 3]  
( 2 5 3, 3 5 1] 
Use n o mi nal visit  
 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 1 8  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
T a ble 1 2. 1  
A n al ysis Visit Wi n d o ws S afet y Assess me nts  
P a nel B: A n al ysis Visit Wi n d o ws f or P art B 
Assess me nt  
Visit 1 
T ar get St u d y D a y  
A n al ysis Visit Wi n d o w  
(i n st u d y d a ys)2, 3, 4 
Vital Si g ns  
He mat ol o g y  
Ser u m C he mistr y  
Wei g ht, Hei g ht a n d B MI  
 
Baseli ne  
Part B Wee k 1 2  
Part B Wee k 2 4  
Part B Wee k 3 6  
Part B Wee k 4 8  
Part B Wee k 6 0  
Part B Wee k 7 2  
Part B Wee k 8 4  
Part B Wee k 9 6  
Part B Safet y F oll o w -u p  
- -  
8 5  
1 6 9  
2 5 3  
3 3 7  
4 2 1  
5 0 5  
5 8 9  
6 7 3  
N ot a p plica ble  
defi ne d i n secti o n 9. 2. 1  
[ 1, 1 2 7 ]  
( 12 7 , 2 1 1] 
( 2 1 1, 2 9 5] 
( 2 9 5, 3 7 9] 
(3 7 9 , 4 6 3 ] 
(4 6 3 , 5 4 7 ] 
(5 4 7 , 6 3 1 ] 
(6 3 1 , 6 8 7 ] Use n o mi nal visit  
Sta n dar d 1 2 -lea d E C G  
Baseli ne  
Part B Wee k 2 4  
Part B Wee k 4 8  
Part B Wee k 9 6  
Part B Safet y F oll o w -u p  
- -  
1 6 9  
3 3 7  
6 7 3  
N ot a p plica ble  
defi ne d i n secti o n 9. 2. 1  
[ 1, 2 5 3 ]  
( 2 5 3, 5 05 
(5 0 5 , 6 8 7 ] 
Use n o mi nal visit  
C oa g ulati o n  
Baseli ne  
Part B Wee k 4 8  
Part B Wee k 9 6  
Part B Safet y F oll o w -u p  
- -  
3 3 7  
6 7 3  
N ot a p plica ble  
defi ne d i n secti o n 9. 2. 1  
[ 1, 5 0 5  
(5 0 5 6 8 7 ] 
Use n o mi nal visit  
N otes:  
1 Visit na me f or a nal ysis p ur p ose is use d t o re p ort data i n ta bles a n d fi g ures.   
 
 
2 T he a nal ysis visit wi n d o ws will be a p plie d usi n g t he f oll o wi n g r ules f or b ot h sc he d ule d a n d u nsc he d ule d visits:  
1.  If n o n u merical meas ure me nt is a vaila ble wit hi n a visit wi n d o w, t he meas ure me nt will be c o nsi dere d missi n g 
f or t he visit. 
2.  If t here is m ore t ha n 1 n u merical meas ure me nt a vaila ble wit hi n a visit wi n d o w, use t he f oll o wi n g r ules:  
i. T he meas ure me nt cl osest t o t he tar get da y will be use d; or  
ii. If t here are m ulti ple meas ure me nts wit h t he sa me cl osest dista nce fr o m t he tar get da y, t he latest 
meas ure me nt wi ll be use d. F or m ulti ple meas ure me nts o n t he sa me da y, u nsc he d ule d meas ure me nts will 
be treate d as later t ha n sc he d ule d meas ure me nt.  
 
3 F or meas ure me nt c ollecte d o n t he date of first d ose of st u d y dr u g i n Treat me nt Peri o d, if it ca n n ot be deter mi ne d 
w het h er t he meas ure me nt is bef ore or after t he first d ose:  
a. 
Sc he d ule d meas ure me nt will be treate d as pre -d ose o bser vati o n.  
b.  U nsc he d ule d meas ure me nt will be treate d as p ost -d ose o bser vati o n.  
 
4 F or safet y Assess me nt, Safet y F oll o w -u p a nal ysis visit will be base d o n n o mi nal Safet y F oll o w -u p visit. If a 
s u bject d oes n’t ha ve a n o mi nal Safet y F oll o w-u p visit b ut has a n E T T visit wit h st u d y da y > 3 5 1  i n t he 
c orres p o n di n g part , t he n t he E T T visit will be ma p pe d i nt o Safet y F oll o w-u p a nal ysis visit . 
Deri ve d Varia ble s: 
1.  A ge (i n years) at first d ose date a n d p ost -baseli ne visit (f or listi n g, if a p plica ble ): 
O btai n t he a ge at i nf or me d c o nse nt i n “ y y, m m” f or mat (e. g., 2 4 years, 6 m o nt hs) i n pare nt st u d y fr o m t he Vital 
Si g ns ( V S) pa ge at t he Scree ni n g Visit i n pare nt st u d y, a n d a d d 0. 5 m o nt h t o c o n vert t o da ys.  
O btai n t he i nf or me d c o nse nt date i n pare nt st u d y.  


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 1 9  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
T a ble 1 2. 1  
A n al ysis Visit Wi n d o ws S afet y Assess me nts  
P a nel B: A n al ysis Visit Wi n d o ws f or P art B 
Assess me nt  
Visit 1 
T ar get St u d y D a y  
A n al ysis Visit Wi n d o w  
(i n st u d y d a ys)2, 3, 4 
T he n a ge (i n years) at first d ose = [(first d ose date  –  i nf or me d c o nse nt date i n pare nt st u d y) i n da ys + a ge at 
i nf or me d c o nse nt (i n da ys) i n pare nt st u d y]/ 3 6 5. 2 5. 
2.  A ge (i n m o nt hs) at first d ose date a n d p ost -baseli ne visit (f or use i n calc ulati o n of Hei g h t, B MI a n d wei g ht z-
sc ores): 
O btai n t he a ge at i nf or me d c o nse nt i n “ y y, m m” f or mat (e. g., 2 4 years, 6 m o nt hs) i n pare nt st u d y fr o m t he V S 
pa ge at t he Scree ni n g Visit i n t he pare nt st u d y.  
O btai n t he i nf or me d c o nse nt date i n pare nt st u d y.  
T he n a ge (i n m o nt hs ) at first d ose or p ost-baseli ne visit = i nte ger part of {[(a ge at i nf or me d c o nse nt (i n m o nt hs) 
i n pare nt st u d y + 0. 5 + diff(first d ose date or p ost-baseli ne visit date, i nf or me d c o nse nt date) i n m o nt hs i n pare nt 
st u d y] } + 0. 5. 
3.  Missi n g first d ose date or l ast d ose date 
If t he first d ose date is missi n g, use Da y 1 visit date. 
If t he last d ose date of st u d y dr u g is n ot a vaila ble a n d t here is n o data t o i n dicate t hat t he s u bject disc o nti n ue d 
treat me nt, t he data c ut off date will be use d i nstea d.  
If t he s u bject disc o nti n ue d treat me nt a n d t he last d ose date is missi n g or partial date is re p orte d, t he last d ose 
date will be i m p ute d base d o n, i n desce n di n g or der pri orit y, t he Earl y Treat me nt Ter mi nati o n ( E T T) visit date, 
last visit date bef ore t he Safet y F oll o w-u p,  or t he last st u d y dr u g a d mi nistrati o n date fr o m E X S D T M d o mai n, 
as a p pr o priate. T he i m p utati o n al g orit h m will e ns ure t he i m p ute d last d ose date d oes n ot e xcee d t he st u d y 
partici pati o n e n d date.  
4.  Electr ocar di o gra m:  
        Baseli ne is defi ne d i n Secti o n 9. 1. 1 f or Part A a n d 9. 2. 1  f or Part B. If m ulti ple E C G meas ure me nts are o btai ne d 
o n t he sa me cale n dar da y d uri n g     
        t he T E peri o d, 
o  
F or s u m mar y p ur p ose, t he a vera ge val ue will be use d as t he E C G o n t hat da y;  
o  
F or t hres h ol d a nal ysis p ur p ose, all E C G val ues will be use d  
 
 
 




Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 2 1  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
1 2. 3  
I m p ut ati o n R ul e s f or Mi s si n g A E d at e s  
I m p utati o n r ules f or missi n g or partial A E start date are defi ne d bel o w. If t he i m p ute d A E start 
date is bef ore t he i nf or me d c o nse nt date f or t he O L S, t he A E start date will be i m p ute d usi n g t he 
i nf or me d c o nse nt date. O n g oi n g e ve nts fr o m t he pare nt st u d y will f oll o w t he i m p utati o n r ule 
d escri be d i n t he S A P f or pare nt st u d y.  
•  If o nl y D a y of A E st art d ate is missi n g:  
o  If t he f ull ( or partial) A E e n d date is N O T bef ore t he first d ose date of t he O L S or A E 
e n d date is missi n g, t he n  
 if A E start Year a n d M o nt h are e q ual t o t he Year a n d M o nt h of t he first d ose 
date of O L S, t he n i m p ute t he A E start Da y as t he Da y of t he first d ose date of  
O L S;  
 else i m p ute t he A E start da y as 1.  
o  else i m p ute t he A E start da y as 1.  
•  If D a y a n d M o nt h of A E st art d ate are missi n g: 
o  If t he f ull ( or partial) A E e n d date is N O T bef ore t he first d ose date of t he O L S or A E 
e n d date is missi n g, t he n  
 if A E start Year is e q ual t o t he Year of t he first d ose date of O L S, t he n i m p ute 
t he A E start M o nt h a n d Da y as t he M o nt h a n d Da y of t he first d ose date of  
O L S;  
 else i m p ute t he A E start M o nt h as Ja n uar y a n d Da y as 1.  
o  else i m p ute t he A E start M o nt h as Ja n uar y a n d Da y as 1.  
•  If Ye ar of A E st art d ate is missi n g: 
If t he Year of A E start date is missi n g or A E start date is c o m pletel y missi n g t he n q uer y site.  
o  If t he full ( or partial) A E e n d date is N O T bef ore t he first d ose date of t he Treat me nt 
Peri o d or A E e n d date is missi n g, t he n i m p ute t he A E start date as t he first d ose date 
of t he O L S.  
o  else i m p ute t he A E start date as t he i nf or me d c o nse nt date.  
C o m pare t he i m p ute d A E start date wit h T E peri o d t o deter mi ne w het her t he A E is pre-treat me nt 
A E, T E A E or p ost -treat me nt A E. 
 
I m p utati o n r ules f or partial A E e n d date are defi ne d bel o w:  
If partial e n d date, t he n i m p ute as mi n (t he last da y of t he m o nt h, data c ut-off f or I A, e n d of 
st u d y) if da y is missi n g, or mi n ( Dec, data c ut- off f or I A, e n d of st u d y) if m o nt h is missi n g. 
 
 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 2 2  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
1 2. 4  
Crit eri a f or T hr e s h ol d A n al y si s  
T a ble 1 2- 3 
T hres h ol d A n al ysis Criteri a f or L a b or at or y Tests ( as a p plic a ble)  
P ar a m eter 
T hres h ol d A n al ysis  
C o m me nts  
Cli nic al C he mistr y ( L F T)  
A L T  
> U L N –   ≤3 × U L N  
> 3 × –   ≤ 5 × U L N  
> 5 × –   ≤ 8 × U L N  
> 8 × –   ≤ 2 0 × U L N  
> 2 0. 0 × U L N  
F D A DI LI G ui da nce 
J ul 2 0 0 9.  
A S T  
> U L N –   ≤3 × U L N  
> 3 × –   ≤ 5 × U L N  
> 5 × –   ≤ 8 × U L N  
> 8 × –   ≤ 2 0 × U L N  
> 2 0. 0 × U L N  
F D A DI LI G ui da nce 
J ul 2 0 0 9.  
A L T or A S T  
( A L T > U L N –   ≤ 3 × U L N) or ( A S T > U L N –   ≤ 3 × U L N)  
( A L T > 3 × –   ≤5 × U L N) or  ( A S T > 3 × –   ≤5 × U L N)  
( A L T > 5 × –   ≤8 × U L N) or  ( A S T > 5 × –   ≤8 × U L N)  
( A L T > 8 × –   ≤2 0 × U L N) or ( A S T > 8 × –   ≤ 2 0 × U L N)  
A L T > 2 0 × U L N or A S T > 2 0 × U L N  
F D A DI LI G ui da nce  
Al kali ne P h os p hatase  
> U L N –   ≤ 1. 5 × U L N  
> 1. 5 × –   ≤ 2. 5 × U L N  
> 2. 5 × –   ≤ 5 × U L N  
> 5 × –   ≤ 2 0 × U L N  
> 2 0 × U L N  
F D A DI LI G ui da nce 
J ul 2 0 0 9.  
T otal Bilir u bi n  
> U L N –   ≤ 1. 5 × U L N  
> 1. 5 × –   ≤ 2 × U L N  
> 2 × –   ≤3 × U L N  
> 3 × –   ≤1 0 × U L N  
> 1 0 × U L N  
F D A DI LI G ui da nce 
J ul 2 0 0 9.  
Direct Bilir u bi n  
> U L N –   ≤1. 5 × U L N  
> 1. 5 × –   ≤2 × U L N  
> 2 × –   ≤3 × U L N  
> 3 × –   ≤1 0 × U L N  
> 1 0 × U L N  
F D A DI LI G ui da nce 
J ul 2 0 0 9.  
I n direct Bilir u bi n 
> U L N –   ≤1. 5 × U L N  
> 1. 5 × –   ≤2 × U L N  
> 2 × –   ≤3 × U L N  
> 3 × –   ≤1 0 × U L N  
> 1 0 × U L N  
F D A DI LI G ui da nce 
J ul 2 0 0 9.  
A L T a n d T otal Bilir u bi n  
A L T > 3 × U L N a n d T BI LI > 2 × U L N  
F D A DI LI G ui da nce 
J ul 2 0 0 9.  
 
A S T a n d T otal Bilir u bi n  
A S T > 3 × U L N a n d T BI LI > 2 × U L N  
F D A DI LI G ui da nce 
J ul 2 0 0 9.  
 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 2 3  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
T a ble 1 2- 3 
T hres h ol d A n al ysis Criteri a f or L a b or at or y Tests ( as a p plic a ble)  
P ar a m eter 
T hres h ol d A n al ysis  
C o m me nts  
( A L T or A S T) a n d T otal 
Bilir u bi n  
( A L T > 3 × U L N or A S T > 3 × U L N) a n d T BI LI > 2 × U L N F D A DI LI G ui da nce J ul 
2 0 0 9.  
G G T  
> U L N –   ≤ 2. 5 × U L N  
> 2. 5 × –   ≤ 5. 0 × U L N  
> 5. 0 × –   ≤ 2 0. 0 × U L N  
> 2 0. 0 × U L N  
C T C A E gra de 1 -4  
Cli nic al C he mistr y ( N O N -L F T)  
 
Al b u mi n  
< L L N –  ≥ 3 0 g/ L  
< 3 0 – ≥ 2 0 g/ L  
< 2 0 g/ L  
C T C A E gra de 1 -3  
A m ylase  
> U L N –   ≤  1. 5 × U L N  
> 1. 5 × –   ≤  2 × U L N  
> 2 × –   ≤  5 × U L N  
> 5 × U L N  
Criteria base d u p o n 
C T C A E  
Creati ni ne  
> U L N –   ≤ 1. 5 × U L N  
> 1. 5 × –   ≤ 3. 0 × U L N  
> 3. 0 × –   ≤ 6. 0 × U L N  
> 6. 0 × U L N  
C T C A E gra des 1 -4  
Li pase  
> U L N –   ≤  1. 5 × U L N  
> 1. 5 × –   ≤  2 × U L N  
> 2 × –   ≤  5 × U L N  
> 5 × U L N  
Criteria base d u p o n 
C T C A E  
T otal pr otei n  
 
< L L N  
> U L N  
N o C T C A E  
Creati ne Ki nase  
> U L N  –   ≤ 2. 5 × U L N  
> 2. 5 × –   ≤ 5 × U L N  
> 5 × –   ≤ 1 0 × U L N  
> 1 0 × U L N  
C T C A E gra des 1 -4  
 
He m at ol o g y  
He m o gl o bi n  
H g b decrease d (a ne mia)  
< L L N –   ≥ 1 0 0 g/ L  
< 1 0 0 –   ≥ 8 0 g/ L  
< 8 0 g/ L  
C T C A E gra de 1 -3  
 
H g b i ncrease d  
> U L N –   ≤ 2 0 g/ L a b o ve U L N  
> 2 0 g/ L a b o ve U L N –   ≤ 4 0 g/ L a b o ve U L N  
> 4 0 g/ L a b o ve U L N  
C T C A E gra de 1 -3  
Platelets  
Platelet decrease d  
< L L N –   ≥ 7 5. 0 × 1 0e 9 / L  
< 7 5. 0 × – ≥ 5 0. 0 × 1 0e 9 / L  
< 5 0. 0 × – ≥ 2 5. 0 × 1 0e 9 / L  
< 2 5. 0 × 1 0e 9 / L  
C T C A E gra de 1 -4  
 
Platelet i ncrease d   
> U L N  
N o C T C A E a vaila ble  
 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 2 4  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
T a ble 1 2- 3 
T hres h ol d A n al ysis Criteri a f or L a b or at or y Tests ( as a p plic a ble)  
P ar a m eter 
T hres h ol d A n al ysis  
C o m me nts  
Retic ul oc ytes/ Er yt hr oc ytes 
( %)    
< L L N  
> U L N  
N o C T C A E  
C o a g ul ati o n  
 
 
Acti vate d partial 
t hr o m b o plasti n ti me  ( P T T)  
 
> U L N –   ≤ 1. 5 × U L N  
> 1. 5 × –   ≤ 2. 5 × U L N  
> 2. 5 × U L N  
C T C A E gra de 1 -3  
Pr ot hr o m bi n ti me ( P T) 
I nter nati o nal 
N or malize d Rati o (I N R)  
> U L N –   ≤ 1. 5 × U L N  
> 1. 5 × –   ≤ 2. 5 × U L N  
> 2. 5 × U L N  
C T C A E gra de 1 -3  
  
T a ble 1 2- 4 
T hres h ol d A n al ysis Criteri a f or L a b or at or y Tests (f or l a beli n g p ur p ose)  
P ar a meter  
T hres h ol d A n al ysis  
C o m me nts  
Cli nic al C he mistr y ( L F T)  
A L T or A S T  
> 3 × U L N  
> 5 × U L N  
> 8 × U L N  
F or la beli n g p ur p ose  
 
T a ble  1 2- 5 
T hres h ol d A n al ysis Criteri a f or E C Gs  
P ar a meter  
T hres h ol d A n al ysis  
C o m me nts  
H R  
Bra d ycar dia  
 
< 5 0 b p m  
< 4 5 b p m  
Decrease fr o m baseli ne ≥1 0 b p m  
Decrease fr o m baseli ne ≥2 0 b p m  
< 5 0 b p m a n d decrease fr o m baseli ne ≥1 0 b p m  
< 5 0 b p m a n d decrease fr o m baseli ne ≥2 0 b p m  
 
Per H V gra de 2, 3, pl us s hift 
c ha n ge 
 
 
 
Tac h ycar dia  
 
> 1 0 0 b p m  
> 1 1 5 b p m  
> 1 3 0 b p m  
I ncrease fr o m baseli ne ≥1 0 b p m  
I ncrease fr o m baseli ne ≥2 0 b p m  
> 1 0 0 b p m a n d i ncrease fr o m baseli ne ≥1 0 b p m  
> 1 0 0 b p m a n d i ncrease fr o m baseli ne ≥2 0 b p m  
Per H V gra de 1, 2, 3, pl us s hift 
c ha n ge 
 
 
P R  
≥2 4 0 ms  
≥3 0 0 ms  
≥2 0 0 ms a n d i ncrease fr o m baseli ne ≥4 0 ms  
≥2 0 0 ms a n d i nc rease fr o m baseli ne ≥1 0 0 ms 
 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 2 5  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
T a ble  1 2- 5 
T hres h ol d A n al ysis Criteri a f or E C Gs  
P ar a meter  
T hres h ol d A n al ysis  
C o m me nts  
Q R S  
> 1 1 0 ms  
> 1 6 0 ms  
I ncrease fr o m baseli ne ≥2 0 ms 
I ncrease fr o m baseli ne ≥4 0 ms 
 
Q Tc  
B or derli ne  
Pr ol o n ge d *  
A d diti o nal  
 
 
> 4 5 0 ms a n d < 5 0 0 ms ( Male); > 4 7 0 ms a n d < 5 0 0 ms ( Fe male)  
≥5 0 0 ms  
 
I ncrease fr o m baseli ne 
I ncrease fr o m baseli ne > 1 0 ms  
I ncrease fr o m baseli ne > 2 0 ms 
I ncrease fr o m baseli ne > 4 0 ms 
I ncrease fr o m baseli ne > 6 0 ms 
 
T o be a p plie d t o a n y ki n d of 
Q T c orrecti o n f or m ula.  
 
 
 
 
N ote: Base d o n C P M P 1 9 9 7 g ui deli ne.  
 
T a ble 1 2- 6 
T hres h ol d A n al ysis Criteri a f or Vit al Si g ns  
P ar a meter  
T hres h ol d A n al ysis  
C o m me nts  
P ulse Rate  
Sa me as a b o ve i n E C G cate g or y  
 
 
S B P i ncrease d  
 
 
> 1 4 0 m m H g  
> 1 6 0 m m H g  
> 1 0 m m H g i ncrease fr o m baseli ne  
> 2 0 m m H g i ncrease  fr o m baseli ne 
 
> 1 4 0 m m H g & > 1 0 m m H g i ncrease fr o m baseli ne  
> 1 4 0 m m H g & > 2 0 m m H g i ncrease fr o m baseli ne  
> 1 6 0 m m H g & > 1 0 m m H g i ncrease fr o m baseli ne  
> 1 6 0 m m H g & > 2 0 m m H g i ncrease fr o m baseli ne  
 
8 0 9/ 7 7 0 a nal yses  
S B P decrease  
 
 
< 9 0 m m H g  
< 8 0 m m H g  
> 1 0 m m H g decrease fr o m baseli ne  
> 2 0 m m H g decrease fr o m baseli ne  
 
< 9 0 m m H g a n d > 1 0 m m H g decrease fr o m baseli ne  
< 9 0 m m H g a n d > 2 0 m m H g decrease fr o m baseli ne  
< 8 0 m m H g a n d > 1 0 m m H g decrease fr o m baseli ne  
< 8 0 m m H g a n d > 2 0 m m H g decrease fr o m baseli ne  
 
Per H V gra de 1, 3, pl us s hift c ha n ge  


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 2 6  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
T a ble 1 2- 6 
T hres h ol d A n al ysis Criteri a f or Vit al Si g ns  
P ar a meter  
T hres h ol d A n al ysis  
C o m me nts  
D B P i ncrease d  
 
> 9 0 m m H g  
> 1 0 0 m m H g  
> 5 m m H g i ncrease fr o m baseli ne  
> 1 0 m m H g i ncrease fr o m baseli ne  
 
> 9 0 m m H g a n d > 5 m m H g i ncrease fr o m baseli ne  
> 9 0 m m H g a n d > 1 0 m m H g i ncrease fr o m baseli ne  
> 1 0 0 m m H g a n d > 5 m m H g i ncrease fr o m baseli ne  
> 1 0 0 m m H g a n d > 1 0 m m H g i ncrease fr o m baseli ne  
 
 
D B P decrease d  
 
 
< 6 0 m m H g  
< 4 5 m m H g  
> 5 m m H g decrease fr o m baseli ne  
> 1 0 m m H g decrease fr o m baseli ne  
 
< 6 0 m m H g a n d > 5 m m H g decrease fr o m baseli ne  
< 6 0 m m H g a n d > 1 0 m m H g decrease fr o m baseli ne  
< 4 5 m m H g a n d > 5 m m H g decrease fr o m baseli ne  
< 4 5 m m H g a n d > 1 0 m m H g decrease fr o m baseli ne  
 
 
Wei g ht   
Wei g ht gai n  
≥5 % i ncrease fr o m baseli ne   
≥1 0 % i ncrease fr o m baseli ne  
≥ 2 0 % i ncrease fr o m baseli ne  
 
C T C A E gra de 1 -3  
 
 
Wei g ht l oss  
≥5 % decrease fr o m baseli ne   
≥1 0 % decrease fr o m baseli ne  
≥ 2 0 % decrease fr o m baseli ne  
 
C T C A E gra de 1 -3  
 
  
 
 


Statistical A nal ysis Pla n ( Met h o ds)  
Pa ge 2 7  of 2 7  
Pr ot oc ol N u m ber: V X 1 9 -4 4 5 -1 1 5  
 
 
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
1 2. 5  
A d v er s e E v e nt s of S p e ci al I nt er e st  
T a ble 1 2- 7 
Me d D R A Preferre d Ter ms f or E ve nt of S peci al I nterest  
A d verse e ve nt of s peci al i nterest  
Me d D R A preferre d ter ms  
Ele vate d tra nsa mi nases  
Ala ni ne a mi n otra nsferase a b n or mal, Ala ni ne a mi n otra nsferase 
i ncrease d, As partate a mi n otra nsferase a b n or mal, As partate 
a mi n otra nsferase i ncrease d, Tra nsa mi nases a b n or mal, 
Tra nsa mi nases i ncrease d, Li ver f u ncti o n test a b n or mal, Li ver 
f u ncti o n test i ncrease d, H y pertra nsa mi nasae mia, He patic 
e nz y me a b n or mal, He patic e nz y me i ncrease d  
Ras h  
Ras h, Ras h er yt he mat o us, Ras h mac ular, Ras h mac ul o -pa p ular, 
Ras h mac ul o vesic ular, Ras h vesic ular, Ras h pr uritic, Ras h 
f ollic ular, Ras h p ust ular, N o d ular ras h, Dr u g er u pti o n, Fi xe d 
er u pti o n, Urticaria, Urticaria pa p ular, Urticaria vesic ul osa, 
Urticarial der matitis, Ras h m or billif or m, Ra s h pa p ular, Ras h 
pa p ul os q ua m o us, Ras h r u bellif or m, Ras h scarlati nif or m , Dr u g 
h y perse nsiti vit y, T y pe I V h y perse nsiti vit y reacti o n, Der matitis, 
Der matitis at o pic, E pi der m ol ysis, S ki n t o xicit y, Der matitis 
aller gic, Der matitis e xf oliati ve, Der matitis e xf oliat i ve 
ge neralise d, Er yt he ma m ultif or me, E xf oliati ve ras h, 
M uc oc uta ne o us ras h, Ac ute ge neralise d e xa nt he mat o us 
p ust ul osis, C uta ne o us vasc ulitis, Urticarial vasc ulitis, Der matitis 
b ull o us, Dr u g reacti o n wit h e osi n o p hilia a n d s yste mic 
s y m pt o ms, E pi der mal necr osis, Oc ul o m uc oc uta ne o us s y n dr o me, 
S ki n e xf oliati o n, S ki n necr osis, Ste ve ns -J o h ns o n s y n dr o me, 
T o xic e pi der mal necr ol ysis, T o xic s ki n er u pti o n, Peri oral 
der matitis, Vasc ulitic ras h, I m m u ne -me diate d der matitis, Pe nile 
ras h, SJ S-T E N o verla p, Er yt hr o der mic at o pi c der matitis, Scr otal 
der matitis, A nal Ras h, Ge neralise d b ull o us fi xe d dr u g er u pti o n  
 
 
N ote: T he preferre d ter ms liste d i n t he ta ble is base d o n t he Me d D R A versi o n a p plica ble at t he 
ti me of fi nalizati o n of t he S A P. If t he Me d D R A versi o n is u p gra de d at t he ti me of t he fi nal 
a nal ysis, t he c orres p o n di n g preferre d ter ms base d o n t he u p gra de d versi o n will be use d i n t he 
a nal ysis of a d verse e ve nts of s pecial i nterest.