Clinical trial NCT04058366
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2019-12-05; Completion date: 2022-12-16
Enrollment: 251 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluated the long-term safety, efficacy, and pharmacodynamics of elexacaftor (ELX, VX-445) in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are heterozygous for the F508del mutation and a gating or residual function mutation (F/G and F/RF genotypes).

Detailed description:

Arms: arm 1: Part A: Participants received ELX (elexacaftor) 200 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in the treatment period for 96 weeks.

Part B: Participants from certain countries participated in Part B and continued to receive ELX 200 mg qd /TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 48 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: 


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2 
PROTOCOL SYNOPSIS 
 
Title 
A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of 
VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are 
Heterozygous for the F508del Mutation and a Gating or Residual Function 
Mutation (F/G and F/RF Genotypes) 
  
Brief Title 
A Study Evaluating the Long-term Safety and Efficacy of VX-445 Combination 
Therapy 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 3, safety and efficacy 
 
 
Objectives 
Primary Objective 
To evaluate the long-term safety and tolerability of VX-445/tezacaftor 
(TEZ)/ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are heterozygous 
for the F508del mutation and a gating (F/G) or residual function (F/RF) mutation 
Secondary Objectives 
 To evaluate the long-term efficacy of VX-445/TEZ/IVA 
 To evaluate the pharmacodynamics (PD) of VX-445/TEZ/IVA 
 
 
Endpoints 
Primary Endpoint 
Safety and tolerability of long-term treatment with VX-445/TEZ/IVA based on 
adverse events (AEs), clinical laboratory values, ECGs, vital signs, and pulse 
oximetry 
Secondary Endpoints 
 
Absolute change in percent predicted forced expiratory volume in 1 second 
(ppFEV1) 
 
Absolute change in sweat chloride (SwCl) 
 
Absolute change in body mass index (BMI) 
 
Absolute change in BMI z-score  
 
Absolute change in body weight 
 
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
respiratory domain (RD) score 
Exploratory Endpoints 
 
Absolute change in CFQ-R non-RD scores 
 
Inflammatory mediators 
 
Blood biomarkers 
 
 
Number of Subjects 
Subjects who complete the last Treatment Period visit in the parent study (Study 
VX18-445-104 [Study 104]) and meet eligibility criteria are eligible to enroll. 
Approximately 250 subjects are expected to enroll. 
 
 
Study Population 
Male and female CF subjects 12 years of age or older with F/G or F/RF genotypes 
 
 


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Investigational Drug 
Study drug refers to VX-445/TEZ/IVA and IVA 
Study drugs will be orally administered as 2 fixed-dose combination (FDC) 
film-coated tablets of VX-445/TEZ/IVA in the morning, and 1 film-coated IVA 
tablet in the evening. 
 
Active substance: VX-445/TEZ/IVA 
 
Activity: VX-445 is a CFTR corrector, TEZ is a CFTR corrector, and IVA is a 
CFTR potentiator (increased Clˉ secretion) 
 
Strength: 100 mg/50 mg/75 mg FDC tablet 
 
 
 
Active substance: IVA 
 
Activity: CFTR potentiator (increased Clˉ secretion) 
 
Strength: 150 mg tablet 
 
 
Study Duration 
The total study duration is approximately 100 weeks (from the first dose of study 
drug in this study), including a 96-week Treatment Period and a 4-week Safety 
Follow-up Period. 
 
 
Study Design 
This is a Phase 3, multicenter, open-label study for subjects who completed the 
last Treatment Period visit in the parent study (Study 104) and meet eligibility 
criteria (Figure 2-1). 
All subjects will receive the triple combination (TC) of VX-445/TEZ/IVA at the 
same dosage as that evaluated in Study 104. 
Figure 2-1 
VX18-445-110 Study Design 
 
IVA: ivacaftor; TEZ: tezacaftor 
Note: Parent study refers to Study 104. 
 
 
Assessments 
Safety: AEs, clinical laboratory assessments, ECGs, vital signs, pulse oximetry, 
physical examinations, and ophthalmologic examinations (for subjects <18 years 
of age on the date of informed consent in the parent study) 
Efficacy: Spirometry, height (for ≤21 years of age), weight, and CFQ-R 
PD: SwCl 
Exploratory: Inflammatory mediators, blood biomarker samples, and sputum 
samples 
 
 
Statistical Analyses 
The primary objective of the study is the evaluation of the long-term safety and 
tolerability of VX-445/TEZ/IVA. The safety endpoints of long-term treatment 
include AEs, clinical laboratory values, ECGs, vital signs, and pulse oximetry 
from the first dose of study drug in the open-label study, for subjects who received 
at least 1 dose of study drug in the open-label study. The safety analysis will be 
descriptive only. 
 
 


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The secondary objective of the study is the evaluation of long-term efficacy and 
PD of VX-445/TEZ/IVA, as assessed by spirometry, SwCl, BMI, BMI z-score, 
weight, and CFQ-R. Methods of efficacy analyses will be similar as those used in 
the parent study. 
Interim Analyses 
Interim analyses (IAs) may take place at any time during the study at the 
discretion of the sponsor. In the event that the parent study is still ongoing, a 
limited Vertex team may be unblinded to the treatment assignments in the parent 
study for the purpose of reviewing the interim results and will not be involved in 
or influence the conduct of the remaining part of the parent study to protect the 
integrity of the parent study. 
IDMC Reviews 
The independent data monitoring committee (IDMC) will conduct periodic safety 
reviews of study data as outlined in the IDMC charter. 


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3 
SCHEDULE OF ASSESSMENTS 
The schedule of assessments is in Table 3-1. All visits will be scheduled relative to the Day 1 
Visit in this study. 
The Cystic Fibrosis Questionnaire–Revised (CFQ-R) must be completed before any other 
assessment (except signing of the informed consent form [ICF]) at relevant clinic visits. 
Remaining assessments may be performed in any order when more than 1 assessment is required 
at a particular time point. All assessments will be performed before study drug dosing 
(Section 9.6.1), unless noted otherwise. 


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Table 3-1 
VX18-445-110: Treatment Period and Safety Follow-up Visit  
Event/Assessmenta 
Treatment Period 
ETT 
Visitb 
Safety 
Follow-up 
Visit 28 
(± 7) Days 
After Last 
Dosec 
Comments 
Day 1d 
Day 15 
(± 3 Days) 
Weeks 4, 8, 
16, 24, 36 
(± 5 Days) 
Weeks 12, 20, 
28, 32, 40, 44, 
52, 56, 64, 68, 
76, 80, 88, 92 
(± 5 Days) 
Week 48 
(± 5 Days) 
Weeks 60, 
72, 84 
(± 5 Days) 
Week 96 
(± 5 Days) 
Clinic visit 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Telephone contact 
 
 
 
X 
 
 
 
 
 
Assess the subject’s 
status, any AEs, 
concomitant 
medications, 
treatments, and 
procedures 
ICF and assent 
(when applicable) 
X 
 
 
 
 
 
 
 
 
Section 8 
Inclusion and 
exclusion criteria 
confirmation 
X 
 
 
 
 
 
 
 
 
Section 8 
CFQ-R  
X 
 
Weeks 4, 8, 
24 
 
X 
Week 72 
X 
X 
X 
Must be completed 
before any other 
assessments (except 
signing of ICF) at 
relevant clinic visits 
(Section 11.5.3) 
Weight and height 
X 
X 
X 
 
X 
X 
X 
X 
X 
Measured with shoes 
off. Height will be 
collected only for 
subjects ≤21 years of 
age (Section 11.5.2) 
 a 
All assessments will be performed before study drug dosing (Section 9.6.1), unless noted otherwise. 
b 
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to discontinue treatment (Section 9.1.3). 
c 
The Safety Follow-up Visit is required for all subjects. Refer to Section 9.1.2 for subjects who transition to a commercially available or managed access program-supplied 
next-generation corrector TC regimen. 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). 
d 
The Day 1 Visit of this study should be on the same day as the last scheduled visit of the parent study. Subjects whose Day 1 Visit is NOT within 1 day of the last scheduled 
visit in the Treatment Period of the parent study will have all Day 1 assessments performed (Section 9.1.1). Subjects whose Day 1 Visit is within 1 day of the last scheduled 
visit in the Treatment Period of the parent study will NOT have to repeat assessments that were performed as part of the last scheduled visit of the parent study Treatment 
Period.  


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Table 3-1 
VX18-445-110: Treatment Period and Safety Follow-up Visit  
Event/Assessmenta 
Treatment Period 
ETT 
Visitb 
Safety 
Follow-up 
Visit 28 
(± 7) Days 
After Last 
Dosec 
Comments 
Day 1d 
Day 15 
(± 3 Days) 
Weeks 4, 8, 
16, 24, 36 
(± 5 Days) 
Weeks 12, 20, 
28, 32, 40, 44, 
52, 56, 64, 68, 
76, 80, 88, 92 
(± 5 Days) 
Week 48 
(± 5 Days) 
Weeks 60, 
72, 84 
(± 5 Days) 
Week 96 
(± 5 Days) 
OE 
 
 
 
 
X 
 
X 
X 
 
Subjects <18 years of 
age on the date of 
informed consent in 
the parent study will 
have an OE within 
28 days of the 
Week 48 and Week 96 
Visits. In addition, an 
OE will be performed 
within 28 days of the 
ETT Visit for subjects 
whose cumulative 
study drug exposure 
(in the parent study 
and current study) is at 
least 12 weeks since 
their last study OE. 
(Section 11.6.6) 
Complete physical 
examination 
X 
 
 
 
 
 
X 
X 
 
Section 11.6.3 
Pregnancy test (all 
female subjects) 
Urine 
 
Urine 
Urine 
Urine 
Urine 
Serum 
Serum 
Serum 
At telephone contact 
visits, a urine 
pregnancy test will be 
performed with a home 
kit provided by the 
study site 
(Section 11.6.2) 
Serum FSH 
 
 
 
 
 
 
 
 
 
As needed for any 
suspected 
postmenopausal 
female with at least 12 
months of continuous 
spontaneous 
amenorrhea 
(Section 11.6.2) 


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Table 3-1 
VX18-445-110: Treatment Period and Safety Follow-up Visit  
Event/Assessmenta 
Treatment Period 
ETT 
Visitb 
Safety 
Follow-up 
Visit 28 
(± 7) Days 
After Last 
Dosec 
Comments 
Day 1d 
Day 15 
(± 3 Days) 
Weeks 4, 8, 
16, 24, 36 
(± 5 Days) 
Weeks 12, 20, 
28, 32, 40, 44, 
52, 56, 64, 68, 
76, 80, 88, 92 
(± 5 Days) 
Week 48 
(± 5 Days) 
Weeks 60, 
72, 84 
(± 5 Days) 
Week 96 
(± 5 Days) 
Standard 12-lead 
ECG 
X 
X 
Weeks 4, 8, 
24 
 
X 
Week 72 
X 
X 
X 
After subjects have 
rested for at least 
5 minutes and before 
dosing, as applicable 
(Sections 11.6.3, 
11.6.4, and 11.6.5) 
Vital signs 
X 
X 
X 
 
X 
X 
X 
X 
X 
Pulse oximetry 
X 
X 
X 
 
X 
X 
X 
X 
X 
Spirometry 
X 
X 
X 
 
X 
X 
X 
X 
X 
Before dosing, as 
applicable, and should 
be performed 
pre-bronchodilator 
(Section 11.5.1) 
SwCl 
X 
X 
Weeks 4, 8, 
24 
 
X 
Week 72 
X 
X 
 
Must occur before 
dosing. At each time 
point, 2 samples will 
be collected, 1 from 
each arm (left and 
right) (Section 11.3). 
Urinalysis 
X 
 
 
 
Week 48 
 
X 
X 
 
Section 11.6.2 
Hematology 
X 
X 
X 
 
X 
X 
X 
X 
X 
Section 11.6.2 
Coagulation 
X 
 
Weeks 4, 24 
 
X 
Week 72 
X 
X 
X 
Section 11.6.2 
Serum chemistry 
X 
X 
X 
 
X 
X 
X 
X 
X 
Section 11.6.2 
Inflammatory 
mediator samples 
X 
 
Weeks 4, 24 
 
 
 
X 
X 
 
Section 11.4.1 
Blood biomarker 
samples 
X 
 
Weeks 4, 24 
 
 
 
X 
X 
 
Section 11.4.2 
Blood sample for 
RNA  
X 
 
Weeks 4, 24 
 
 
 
X 
X 
 
Section 11.4.2 
Sputum samples 
X 
 
Weeks 4, 24 
 
 
 
X 
X 
 
Collected from 
subjects who can 
produce a sample 
spontaneously 
(Section 11.4.3) 
Study drug count 
X 
X 
X 
 
X 
X 
X 
X 
 
Section 10.6 


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Table 3-1 
VX18-445-110: Treatment Period and Safety Follow-up Visit  
Event/Assessmenta 
Treatment Period 
ETT 
Visitb 
Safety 
Follow-up 
Visit 28 
(± 7) Days 
After Last 
Dosec 
Comments 
Day 1d 
Day 15 
(± 3 Days) 
Weeks 4, 8, 
16, 24, 36 
(± 5 Days) 
Weeks 12, 20, 
28, 32, 40, 44, 
52, 56, 64, 68, 
76, 80, 88, 92 
(± 5 Days) 
Week 48 
(± 5 Days) 
Weeks 60, 
72, 84 
(± 5 Days) 
Week 96 
(± 5 Days) 
Study drug dosing 
Day 1 through evening before Week 96 Visit 
 
Section 9.6.1 
Medications review 
Continuous from signing of the ICF through completion of study participation 
Completion of study 
participation is defined 
in Section 9.1.5 
Treatments and 
procedures review 
AEs and SAEs 
Continuous from signing of the ICF through completion of study participation 
Sections 13.1.1.3 
and 13.1.2.2 
AE: adverse event; CFQ-R: Cystic Fibrosis Questionnaire-Revised; ETT: Early Termination of Treatment; FSH: follicle-stimulating hormone; ICF: informed consent form; OE: 
ophthalmologic examination; SAE: serious adverse event; SwCl: sweat chloride; TC: triple combination 


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TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Protocol Synopsis ................................................................................................................... 2 
3 
Schedule of Assessments........................................................................................................ 5 
4 
Table of Contents ................................................................................................................. 10 
List of Tables............................................................................................................................ 13 
List of Figures .......................................................................................................................... 13 
List of Abbreviations................................................................................................................ 14 
5 
Introduction.......................................................................................................................... 16 
5.1 
Background ..................................................................................................................... 16 
5.2 
Study Rationale .............................................................................................................. 17 
6 
Study Objectives .................................................................................................................. 17 
6.1 
Primary Objective ........................................................................................................... 17 
6.2 
Secondary Objectives ..................................................................................................... 17 
7 
Study Endpoints ................................................................................................................... 17 
7.1 
Primary Endpoint ............................................................................................................ 17 
7.2 
Secondary Endpoints ...................................................................................................... 17 
7.3 
Exploratory Endpoints .................................................................................................... 17 
8 
Study Population .................................................................................................................. 17 
8.1 
Inclusion Criteria ............................................................................................................ 18 
8.2 
Exclusion Criteria ........................................................................................................... 18 
9 
Study Implementation ......................................................................................................... 18 
9.1 
Study Design .................................................................................................................. 18 
9.1.1 
Treatment Period .................................................................................................... 19 
9.1.2 
Safety Follow-up .................................................................................................... 19 
9.1.3 
Early Termination of Treatment ............................................................................. 20 
9.1.4 
Lost to Follow-up ................................................................................................... 20 
9.1.5 
Completion of Study Participation ......................................................................... 20 
9.1.6 
Independent Data Monitoring Committee .............................................................. 20 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 20 
9.3 
Rationale for Study Elements ......................................................................................... 21 
9.3.1 
Study Design and Population ................................................................................. 21 
9.3.2 
Study Drug Dose and Duration .............................................................................. 21 
9.3.3 
Rationale for Study Assessments ........................................................................... 21 
9.4 
Study Restrictions ........................................................................................................... 21 
9.4.1 
Prohibited Medications ........................................................................................... 21 
9.5 
Prior and Concomitant Medications ............................................................................... 22 
9.6 
Administration ................................................................................................................ 23 
9.6.1 
Dosing ..................................................................................................................... 23 
9.6.2 
Missed Doses .......................................................................................................... 23 
9.7 
Dose Modification for Toxicity ...................................................................................... 23 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 23 
9.8.1 
Liver Function Tests ............................................................................................... 24 
9.8.2 
Rash ........................................................................................................................ 25 
9.9 
Removal of Subjects ....................................................................................................... 25 


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9.10 Replacement of Subjects ................................................................................................ 26 
10 Study Drug Information and Management ....................................................................... 26 
10.1 Preparation and Dispensing ............................................................................................ 26 
10.2 Packaging and Labeling ................................................................................................. 26 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 26 
10.4 Drug Accountability ....................................................................................................... 26 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 27 
10.6 Compliance ..................................................................................................................... 27 
10.7 Blinding and Unblinding ................................................................................................ 27 
11 Assessments .......................................................................................................................... 27 
11.1 Subject and Disease Characteristics ............................................................................... 27 
11.2 Pharmacokinetics ............................................................................................................ 27 
11.3 Pharmacodynamics: Sweat Chloride .............................................................................. 28 
11.4 Exploratory Assessments ................................................................................................ 28 
11.4.1 
Inflammatory Mediators ......................................................................................... 28 
11.4.2 
Other Blood Biomarkers ......................................................................................... 28 
11.4.3 
Microbiology and Other Sputum Biomarkers ........................................................ 28 
11.5 Efficacy ........................................................................................................................... 28 
11.5.1 
Spirometry .............................................................................................................. 28 
11.5.2 
Height and Weight .................................................................................................. 29 
11.5.3 
Cystic Fibrosis Questionnaire-Revised .................................................................. 30 
11.6 Safety .............................................................................................................................. 30 
11.6.1 
Adverse Events ....................................................................................................... 30 
11.6.2 
Clinical Laboratory Assessments ........................................................................... 30 
11.6.3 
Physical Examinations and Vital Signs .................................................................. 32 
11.6.4 
Pulse Oximetry ....................................................................................................... 32 
11.6.5 
Electrocardiograms ................................................................................................. 32 
11.6.6 
Ophthalmologic Examination ................................................................................. 33 
11.6.7 
Contraception and Pregnancy ................................................................................. 33 
11.6.7.1 Contraception ................................................................................................... 33 
11.6.7.2 Pregnancy ......................................................................................................... 35 
12 Statistical and Analytical Plans .......................................................................................... 35 
12.1 Sample Size .................................................................................................................... 35 
12.2 Analysis Sets .................................................................................................................. 35 
12.3 Statistical Analysis ......................................................................................................... 35 
12.3.1 
General Considerations ........................................................................................... 35 
12.3.2 
Background Characteristics .................................................................................... 36 
12.3.2.1 Subject Disposition .......................................................................................... 36 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 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 and Pharmacodynamic Analyses ............................................................. 38 
12.3.3.1 Analysis of Primary Endpoint .......................................................................... 38 
12.3.3.2 Analysis of Secondary Efficacy Endpoints ...................................................... 38 
12.3.3.3 Analysis of Exploratory Efficacy Endpoints.................................................... 39 


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12.3.3.4 Multiplicity Adjustment ................................................................................... 39 
12.3.4 
Safety Analysis ....................................................................................................... 39 
12.3.4.1 Adverse Events................................................................................................. 39 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 40 
12.3.4.3 Electrocardiogram ............................................................................................ 40 
12.3.4.4 Vital Signs ........................................................................................................ 41 
12.3.4.5 Pulse Oximetry ................................................................................................. 41 
12.3.4.6 Physical Examination ....................................................................................... 41 
12.3.4.7 Other Safety Analyses ...................................................................................... 41 
12.3.5 
Exploratory Endpoints ............................................................................................ 41 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses ........................... 41 
12.3.6.1 Interim Analysis ............................................................................................... 41 
12.3.6.2 Independent Data Monitoring Committee Analysis ........................................ 41 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 42 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 42 
13.1.1 
Adverse Events ....................................................................................................... 42 
13.1.1.1 Definition of an Adverse Event........................................................................ 42 
13.1.1.2 Clinically Significant Assessments .................................................................. 42 
13.1.1.3 Documentation of Adverse Events................................................................... 42 
13.1.1.4 Adverse Event Severity .................................................................................... 43 
13.1.1.5 Adverse Event Causality .................................................................................. 43 
13.1.1.6 Study Drug Action Taken ................................................................................ 44 
13.1.1.7 Adverse Event Outcome .................................................................................. 44 
13.1.1.8 Treatment Given............................................................................................... 45 
13.1.2 
Serious Adverse Events .......................................................................................... 45 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 45 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 45 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 46 
13.2 Administrative Requirements ......................................................................................... 46 
13.2.1 
Ethical Considerations ............................................................................................ 46 
13.2.2 
Subject Information and Informed Consent ........................................................... 47 
13.2.3 
Investigator Compliance ......................................................................................... 47 
13.2.4 
Access to Records ................................................................................................... 47 
13.2.5 
Subject Privacy ....................................................................................................... 47 
13.2.6 
Record Retention .................................................................................................... 48 
13.2.7 
Study Termination .................................................................................................. 48 
13.2.8 
End of Study ........................................................................................................... 48 
13.3 Data Quality Assurance .................................................................................................. 48 
13.4 Monitoring ...................................................................................................................... 49 
13.5 Electronic Data Capture ................................................................................................. 49 
13.6 Confidentiality and Disclosure ....................................................................................... 49 
13.7 Publications and Clinical Study Report .......................................................................... 50 
13.7.1 
Publication of Study Results ................................................................................... 50 
13.7.2 
Clinical Study Report ............................................................................................. 50 
14 References ............................................................................................................................. 51 


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15 Protocol Signature Pages .................................................................................................... 53 
15.1 Sponsor Signature Page .................................................................................................. 53 
15.2 Investigator Signature Page ............................................................................................ 54 
 
List of Tables 
Table 3-1 
VX18-445-110: Treatment Period and Safety Follow-up Visit .............................. 6 
Table 9-1 
Prohibited Medications ......................................................................................... 21 
Table 10-1 
Study Drug: Dosing Form/Route/Strength ........................................................... 26 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 31 
Table 11-2 
Acceptable Methods of Contraception.................................................................. 34 
Table 13-1 
Grading of AE Severity ........................................................................................ 43 
Table 13-2 
Classifications for AE Causality ........................................................................... 43 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 44 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 44 
List of Figures 
Figure 2-1 
VX18-445-110 Study Design ................................................................................. 3 
Figure 9-1 
VX18-445-110 Study Design ............................................................................... 19 
  
 
 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BMI 
body mass index 
bpm 
beats per minute 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator protein 
CFTR 
CF transmembrane conductance regulator gene 
Clˉ 
chloride ion 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ETT 
Early Termination of Treatment 
EU 
European Union 
F/F 
homozygous for F508del 
F/G 
heterozygous for F508del and a gating mutation 
F/MF 
heterozygous for F508del with a second CFTR allele carrying a minimal function 
mutation that is not responsive to TEZ, IVA, and TEZ/IVA 
F/RF 
heterozygous for F508del and a residual function mutation 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon corresponding 
to position 508 of 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 
FEF25%-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GPS 
Global Patient Safety 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
IA 
interim analysis 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IND 
Investigational New Drug (application) (US) 
IPD 
important protocol deviation 
IRB 
institutional review board 


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Abbreviation 
Definition 
IVA 
ivacaftor 
LUM 
lumacaftor 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
minimal function 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
OATP1B1 
organic anion transporting polypeptide 1B1 
OL-FAS 
Open-label Full Analysis Set 
OL-SS 
Open-label Safety Set 
PD 
pharmacodynamic, pharmacodynamics 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic, pharmacokinetics 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval, segment 
PT 
Preferred Term 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QT 
QT interval 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia’s formula 
RD 
respiratory domain 
RF 
residual function 
RNA 
ribonucleic acid 
RR 
interval from the onset of 1 QRS complex to the next 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SUSAR 
suspected, unexpected, serious adverse reaction 
SwCl 
sweat chloride 
TC 
triple combination 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
ULN 
upper limit of normal 
US 
United States 
 


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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 
1 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®).   
VX-445 is a next-generation CFTR corrector. In vitro, the triple combination (TC) of VX-445, 
TEZ, and IVA (VX-445/TEZ/IVA) increased CFTR chloride transport more than any of the dual 
combinations (VX-445/TEZ, VX-445/IVA, and TEZ/IVA) or individual components (VX-445, 
TEZ, and IVA) when added to human bronchial epithelial (HBE) 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 VX-445/TEZ/IVA can be found in the Investigator’s Brochure. 


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5.2 
Study Rationale 
This study will provide data on the long-term safety, efficacy, and durability of 
VX-445/TEZ/IVA in CF subjects who are heterozygous for the F508del mutation and a gating 
(F/G) or residual function (F/RF) mutation. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the long-term safety and tolerability of VX-445/TEZ/IVA in subjects with CF who 
are heterozygous for the F508del mutation and a gating (F/G) or residual function (F/RF) 
mutation 
6.2 
Secondary Objectives 
 To evaluate the long-term efficacy of VX-445/TEZ/IVA 
 To evaluate the pharmacodynamics (PD) of VX-445/TEZ/IVA 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Safety and tolerability of long-term treatment with VX-445/TEZ/IVA based on adverse events 
(AEs), clinical laboratory values, ECGs, vital signs, and pulse oximetry. 
7.2 
Secondary Endpoints 
 Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
 Absolute change in sweat chloride (SwCl) 
 Absolute change in body mass index (BMI) 
 Absolute change in BMI z-score  
 Absolute change in body weight 
 Absolute change in CFQ-R respiratory domain (RD) score 
7.3 
Exploratory Endpoints 
 Absolute change in CFQ-R non-RD scores 
 Inflammatory mediators 
 Blood biomarkers 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
In the criteria below, “parent study” refers to Study VX18-445-104 (Study 104). 


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8.1 
Inclusion Criteria 
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
ICF, and, when appropriate, an assent form. 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Did not withdraw consent from the parent study.  
4. Meets at least 1 of the following criteria: 
 Completed study drug treatment in the parent study. 
 Had study drug interruption(s) in the parent study, but without prematurely discontinuing 
study drug in the parent study and completed study visits up to the last scheduled visit of 
the Treatment Period of the parent study.  
5. Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) through 
completion of study participation. 
8.2 
Exclusion Criteria 
1. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study drug to the 
subject.  
2. Pregnant and breast-feeding females. All female subjects, regardless of childbearing potential 
status, must have a negative pregnancy test at the Day 1 Visit before receiving the first dose 
of study drug. 
3. History of drug intolerance in the parent study that would pose an additional risk to the 
subject in the opinion of the investigator (e.g., subjects with a history of allergy or 
hypersensitivity to the study drug). 
4. Current participation in an investigational drug study (other than the parent study). 
Participation in a non-interventional study (including observational studies, registry studies, 
and studies requiring blood collections without administration of study drug) and screening 
for another Vertex study is permitted.  
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3, multicenter, open-label study for subjects who completed the last Treatment 
Period visit in the parent study (Study 104) and meet eligibility criteria (see Section 8). A 
schematic of the study design is shown in Figure 9-1. 
All subjects will receive VX-445/TEZ/IVA at the same dosage as that evaluated in Study 104. 
Study drug administration is described in Section 9.6. 
Study visits and assessments to be conducted are shown in Table 3-1. All visits will occur within 
the windows specified. 
Study drug is defined in Section 10. 




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9.1.3 
Early Termination of Treatment  
If a subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as 
soon as possible after the decision to discontinue treatment. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
During the course of study conduct, if local health authorities decline to approve the TC of 
VX-445/TEZ/IVA, or if clinical benefit is not demonstrated for the use of the TC for the 
treatment of CF in specific subpopulations enrolled in this study, subjects with the relevant 
CFTR genotypes may be discontinued after communication to investigators and IRBs/IECs of 
the risks/benefits related to the safety and efficacy observed for the relevant subset of subjects.  
If a subject withdraws from the study and also withdraws consent or assent, no further 
assessments will be performed. Vertex may retain and continue to use any data and samples 
collected before such withdrawal of consent or assent. 
9.1.4 
Lost to Follow-up 
A subject will be considered lost to follow-up if both of the following occur: 
 The subject misses 2 consecutive study visits (telephone contact and/or clinic visit) and is 
subsequently unable to be contacted by telephone (3 documented attempts by telephone 
within 2 weeks following the second missed visit) 
 The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 
9.1.5 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as: the Safety Follow-up 
Visit; or, in situations in which the ETT Visit or the Week 96 Visit replace the Safety Follow-up 
Visit (Section 9.1.2), the ETT Visit or the Week 96 Visit. 
If subjects withdraw consent or assent, completion of study participation is defined as date of 
withdrawal of consent or assent, whichever is earlier (Section 9.9). 
If subjects are lost to follow-up (Section 9.1.4), the date of completion of study participation will 
be defined as the date of last contact.  
The end of study is defined in Section 13.2.8. 
9.1.6 
Independent Data Monitoring Committee 
This study will be monitored by an independent data monitoring committee (IDMC), which will 
conduct periodic safety reviews of study data (Section 12.3.6.2). Procedural details of the 
IDMC’s structure and function, frequency of meetings, and data planned for review will be 
included in the IDMC charter. The IDMC charter will be finalized before the first subject is 
enrolled. 
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. 


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9.3 
Rationale for Study Elements 
9.3.1 
Study Design and Population 
This Phase 3 study will enroll subjects who completed the last Treatment Period visit in the 
parent study of VX-445/TEZ/IVA and meet eligibility criteria. Results from this study will 
provide information on the long-term safety and efficacy of TC treatment with 
VX-445/TEZ/IVA in CF subjects 12 years of age or older with F/G or F/RF genotypes, as per the 
population enrolled in the parent study. 
9.3.2 
Study Drug Dose and Duration 
All subjects will receive VX-445/TEZ/IVA at the same dosage as that in the parent study 
(Study 104). 
The overall treatment duration will be 96 weeks. This duration was employed in open-label 
extension studies for previously approved CFTR modulators, Kalydeco and Orkambi, and is 
considered sufficient for the evaluation of long-term safety and efficacy.  
9.3.3 
Rationale for Study Assessments 
The safety, efficacy, and PD assessments are standard parameters for clinical studies in drug 
development and are generally recognized as reliable, accurate, and relevant to the study of CF 
subjects. Baseline and follow-up ophthalmologic examinations (OEs) are recommended for 
monitoring of CF subjects <18 years of age treated with regimens that contain IVA, therefore 
OEs have been included in the standard safety assessments for those who were <18 years of age 
on the date of informed consent in the parent study.  
Obstruction of airways with thick mucus, chronic bacterial infection of the airways, and 
inflammatory response all play a role in causing lung damage in CF. Therefore, assessments of 
inflammatory mediators and other blood biomarkers are included. 
9.4 
Study Restrictions 
9.4.1 
Prohibited Medications 
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. 
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 Day 1 
None allowed 
through 
completion of 
study 
participation 
VX-445, TEZ, and IVA are metabolized 
extensively via CYP3A4. Therefore, use of 
moderate and strong inducers and inhibitors of 
CYP3A, which have the potential to alter the 
exposure of VX-445, 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 Day 1 
None allowed 
through 
completion of 
study 
participation 


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Table 9-1 
Prohibited Medications 
Medication 
Timing of Restriction 
Rationale 
Start of 
Restriction 
End of 
Restriction 
CFTR modulators 
(investigational or 
approved), except for 
study drugs in the 
parent study and this 
study 
None allowed 
within 28 days or 5 
terminal half-lives 
(whichever is 
longer) before the 
first dose of study 
drug on Day 1 
None allowed 
until after the last 
dose of study 
drug 
These agents may confound the results of this 
study. 
IVA: ivacaftor; TEZ: tezacaftor 
a 
Ciprofloxacin is not a moderate CYP3A inhibitor on the basis of results of a drug-drug interaction study 
conducted with IVA, a sensitive CYP3A substrate (Kalydeco [ivacaftor] US Package Insert). 
9.5 
Prior and Concomitant Medications 
Information regarding prior and concomitant medications, including CF medications, other 
medications, and herbal and naturopathic remedies, will be collected in each subject’s source 
documentation for medications taken within the 56 days before the first dose of study drug in this 
study through completion of study participation, as defined in Section 9.1.5. 
 Subjects should remain on a stable treatment regimen for their CF through completion of 
study participation. Stable treatment regimen is defined as the current treatment regimen for 
CF that subjects have been following for at least 28 days before Day 1. Subjects should not 
initiate long-term treatment with new medication from 28 days before the Day 1 Visit 
through completion of study participation. Subjects who are taking inhaled tobramycin or 
other chronically inhaled antibiotics should remain on that regimen throughout the study. 
 Subjects may receive doses of prednisone or prednisolone of up to 10 mg/day chronically, or 
up to 60 mg daily for up to 5 days. 
 VX-445 may inhibit OATP1B1 and OATP1B3, which may increase the exposure of 
medicinal products that are substrates for these transporters. Substrates such as statins, 
glyburide, nateglinide, and repaglinide should be used with caution. 
 IVA is a weak inhibitor of P-glycoprotein (P-gp). Administration of IVA may increase 
systemic exposure of medicinal products that are sensitive substrates of P-gp, which may 
increase or prolong their therapeutic effect and adverse reactions. Digoxin or other substrates 
of P-gp with a narrow therapeutic index, such as cyclosporine, everolimus, sirolimus, and 
tacrolimus, should be used with caution and appropriate monitoring.  
 IVA may inhibit CYP2C9; therefore during coadministration with warfarin, additional 
monitoring of the international normalized ratio is recommended. Other medicinal products 
that are CYP2C9 substrates for which exposure may be increased include glimepiride and 
glipizide; these should be used with caution. 
 Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments performed 
according to the guidelines provided in Section 11.5.1. 


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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. 
1. It is recommended that the dose be taken within 30 minutes of the start of the meal or snack. 
2. Study drug will be administered as 2 fixed-dose combination (FDC) TC tablets in the 
morning and 1 IVA tablet in the evening. For each subject, doses of study drug should be 
taken at approximately the same time (± 2 hours) each day. 
3. On days of scheduled visits, the morning dose of TC 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 TC. 
4. If a subject’s scheduled visit is to occur in the afternoon, the following guidelines should be 
used: 
 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 TC and the morning dose of TC will be 
administered in the clinic. 
 If the dose in the clinic will be more than 6 hours after the subject’s scheduled morning 
dose of TC, the subject should take the morning dose of TC at home. 
5. 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 as outlined in 
Section 9.8. If any unacceptable toxicity arises, individual subjects will discontinue dosing 
(Section 9.1.3). 
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 


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


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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 generalized rash will be monitored closely. Study drug dosing should 
be interrupted if a subject develops a generalized rash of Grade 3 or higher, or a rash that is 
considered a serious adverse event (SAE). The investigator will notify the medical monitor of 
any rash that results in interruption of study drug, is Grade 3 or higher (Section 13.1.1.4), or is an 
SAE. Investigators should consider additional evaluation including laboratory testing (e.g., 
complete blood count with differential, liver function test), 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.  
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 11.6.7.2) 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for 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 a 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 compounds, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study, the study data and samples collected will remain part of the study. A subject will 
not be able to request the withdrawal of his or her information from the study data. A subject 
may request destruction of the samples collected from him or her during the study as long as 
those samples can be identified as his or her samples. 
With the exception of subjects who cannot access the commercial product after regulatory 
approval because reimbursement by the subject’s insurance carrier (whether government or 
private payer) is not yet available or because the subject lacks insurance coverage, subjects who 
become eligible to receive commercially available TC by prescription of a physician may be 
discontinued from study drug dosing and will complete the ETT Visit before beginning 
commercially available TC dosing. The Safety Follow-up Visit will not be required if the subject 
immediately continues on commercially available TC. 
If evaluation of efficacy data from the parent study suggests that the VX-445/TEZ/IVA treatment 
does not provide clinically meaningful benefit for subsets of subjects included in these studies, 


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Vertex may recommend that subjects with relevant genotypes discontinue from the study. In 
addition, if local health authorities decline to approve VX-445/TEZ/IVA, or if clinical benefit is 
not demonstrated for the use of VX-445/TEZ/IVA for the treatment of CF in specific 
subpopulations enrolled in this study, subjects with the relevant CFTR genotypes may be 
discontinued after communication to investigators and IRBs/IECs of the risks/benefits related to 
the safety and efficacy observed for the relevant subset of subjects. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study drug Treatment Period will not be 
replaced. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
Study drug refers to VX-445/TEZ/IVA and IVA. 
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 
VX-445/TEZ/IVA will be supplied as FDC film-coated tablets containing 100 mg VX-445, 
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: Dosing Form/Route/Strength 
Drug Name, Dosing Form, Route 
Tablet Strength 
VX-445/TEZ/IVA, FDC tablet, oral 
 
VX-445 
100 mg 
TEZ 
50 mg 
IVA 
75 mg 
IVA, tablet, oral 
150 mg 
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 


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returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee. The study monitor will review study drug 
records and inventory throughout the study. 
If a site uses a site-specific drug accountability system and/or process, including processes 
associated with the destruction of returned materials, the process must be documented and 
approved by Vertex. The study monitor must review the drug accountability documentation on a 
regular basis. The study monitor will promptly communicate to Vertex any discrepancies he or 
she is unable to resolve with the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
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 will be an open-label study. However, subjects (and their parents/caregivers/companions) 
should not be informed of their study-related spirometry and SwCl results until Vertex has 
determined that the study has completed (i.e., clinical study report [CSR] finalization). Individual 
SwCl test results will also not be disclosed to the study sites. In addition, the Vertex study team 
will not have access to the spirometry or SwCl results of this study until the database lock of the 
parent study.  
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1.  
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. Select demographic and baseline characteristic data and medical history will be 
derived from the parent study. 
11.2 
Pharmacokinetics 
Not applicable 


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11.3 
Pharmacodynamics: Sweat Chloride 
SwCl samples will be collected with an approved collection device. Each collection will occur 
before study drug dosing (Section 9.6.1). At each time point, 2 samples will be collected; 1 from 
each arm (left and right). Sweat samples will be sent to a central laboratory for testing and 
interpretation of results. Specific instructions for the collection, handling, processing, and 
shipping of SwCl samples to the central laboratory will be provided separately. 
See Section 10.7 for information about access to SwCl results.  
11.4 
Exploratory Assessments 
These data will be used for exploratory purposes. Detailed procedures for the collection, 
processing, storage, and shipment of samples for exploratory assessments will be provided in a 
separate document. 
11.4.1 
Inflammatory Mediators 
Blood samples (inflammatory mediator samples) will be collected at the time points noted in 
Table 3-1 and tested to assess markers related to inflammation. These may include, but are not 
limited to, C-reactive protein, immunoglobulin G, white blood cell (leukocyte) count, and 
interleukin-8.  
11.4.2 
Other Blood Biomarkers 
Serum from an inflammatory mediator sample and an additional blood sample for plasma will be 
collected and banked for potential future exploratory evaluation of other blood biomarkers (e.g., 
proteins, peptides, lipids, metabolites, etc.) in relation to pharmacokinetics (PK), PD, treatment 
response, AEs, and various disease manifestations of CF. 
A blood sample for RNA isolation will be collected as indicated in Table 3-1 for potential 
exploratory evaluation of gene signatures associated with various disease manifestations of CF 
and/or treatment response.  
11.4.3 
Microbiology and Other Sputum Biomarkers 
Sputum samples will be collected as indicated in Table 3-1 from subjects who can produce a 
sample spontaneously. Each sample will be processed and frozen for potential exploratory 
evaluation of microbiology analysis and sputum biomarkers (which may include, but are not 
limited to, qualitative and quantitative bacterial and viral assessments including genomic 
analyses, analysis of immune cells, inflammatory markers, proteins, peptides, lipids, and 
endogenous metabolites) in relation to PK, PD, treatment response, AEs, and various disease 
manifestations of CF. 
11.5 
Efficacy 
11.5.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines11 and according to the additional guidelines that follow. 


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Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
 withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 
 withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the 
spirometry assessment; and 
 withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 
All spirometry assessments should be performed pre-bronchodilator. During the Treatment 
Period, spirometry assessments must be performed before study drug dosing (Section 9.6.1) at 
approximately the same time at each visit. In the event that a subject forgets to withhold 
bronchodilator(s), spirometry should be performed according to the following: 
 If a subject’s Day 1 spirometry assessment from the parent study is pre-bronchodilator, but, 
on a subsequent visit in this study, the subject forgets to withhold bronchodilator use, a 
post-bronchodilator spirometry assessment will be obtained for that visit only and the visit 
will not be rescheduled. 
 If, on Day 1 of the parent study, the subject forgets to withhold his or her dose of 
bronchodilator, spirometry should be performed post-bronchodilator and all subsequent 
spirometric measurements in this study (according to the schedule of assessments in 
Table 3-1) should be performed post-bronchodilator. 
 Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator. 
All sites will be provided with spirometers to be used for all study assessments. Spirometry data 
will be transmitted to a centralized spirometry service for quality review. 
See Section 10.7 for information about access to spirometry results. 
The measured spirometric values listed below will be converted to percent predicted values using 
the standard equations of Global Lung Function Initiative.12 
 Forced expiratory volume in 1 second (FEV1) (L) 
 Forced vital capacity (FVC) (L) 
 FEV1/FVC (ratio) 
 Forced expiratory flow, midexpiratory phase (FEF25%-75%) (L/s) 
11.5.2 
Height and Weight 
Height and weight will be measured with shoes off. For subjects whose date of informed consent 
occurs after their 21st birthday, height will not be collected in this study. For subjects whose date 
of informed consent occurs on or before their 21st birthday, height will be collected through the 
first visit after the subject’s 21st birthday and does not need to be collected at future visits.  


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11.5.3 
Cystic Fibrosis Questionnaire-Revised 
The CFQ-R provides information about demographics; general quality of life, school, work, or 
daily activities; and symptom difficulties (pertaining to CF). 
Subjects will be asked to complete the CFQ-R in their native language, if validated translations 
are available.13, 14 If there is no validated translation available in the subject’s native language, 
the subject will not complete the questionnaire. Copies of the CFQ-R used will be provided in 
the Study Reference Manual. Validated translations of the CFQ-R, if available, will be provided 
for participating centers in non-English-speaking countries.15, 16 
The CFQ-R will be completed before any other assessments are performed at that visit. 
At the Day 1 Visit of this study, subjects will complete the same version of the CFQ-R that was 
completed in the parent study. At all subsequent visits, subjects will complete the version of the 
CFQ-R appropriate for the subject’s age at the time of the visit. Subjects who are 12 and 13 years 
of age will complete the CFQ-R Child version themselves, and their parents/caregivers will 
complete the CFQ-R Parent version. Subjects 14 years of age or older at the date of informed 
consent will complete the Adolescent/Adult version of the questionnaire themselves at all visits.  
11.6 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, physical examinations, and 
clinical evaluation of vital signs, ECGs, and pulse oximetry. 
OEs will be conducted only on subjects who are <18 years of age on the date of informed 
consent in the parent study. 
11.6.1 
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. 
11.6.2 
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 at the site or 
at home using a home kit. On Day 1, blood samples will be collected before the first dose of the 
study drug in this study. 
Laboratory test results that are abnormal and considered clinically significant will be reported as 
AEs (Section 13.1). 
The safety laboratory test panels are shown in Table 11-1. 


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Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
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  
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 (β-human Chorionic Gonadotropin) Tests for Female Subjects: All female subjects, 
regardless of childbearing potential status, must have a negative pregnancy test at the Day 1 Visit 
before receiving the first dose of study drug.  
All female subjects must have a pregnancy test every 4 weeks. Serum pregnancy tests will be 
performed at the study site and analyzed at the central laboratory. Urine pregnancy tests will 
either be performed and analyzed at the site or, at assessment time points when telephone contact 
takes the place of a clinic visit, at home by using a home kit provided by the site. Results of a 
home urine pregnancy test will be reported to the site by telephone. 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. 
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 


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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. 
11.6.3 
Physical Examinations and Vital Signs 
A physical examination of all body systems and vital signs assessment will be performed at the 
select study visits (see Table 3-1). At other visits, symptom-directed physical examinations and 
symptom-directed vital signs assessments can be performed at the discretion of the investigator 
or healthcare provider. 
A complete physical examination 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. Any clinically significant abnormal findings in physical examinations 
will be reported as AEs. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiratory rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed. 
11.6.4 
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.  
11.6.5 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout according to the 
schedule of assessments (Table 3-1). Additional standard 12-lead ECGs will be performed at any 
other time if clinically indicated. The performance of all ECGs will adhere to the following 
guidelines: 
 The subject will be instructed to rest for at least 5 minutes before having an ECG. 
 The test should be performed in the supine position. 
A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. Clinically significant ECG abnormalities occurring during the study 
through completion of study participation will be recorded as AEs.  
To ensure 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. 


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11.6.6 
Ophthalmologic Examination 
OEs are required only for subjects who are <18 years of age on the date of informed consent in 
the parent study. OEs do not need to be completed if there is documentation of bilateral lens 
removal for the subject. 
All examinations will be conducted by a licensed ophthalmologist or optometrist and will 
include  
 measurement of best-corrected distance visual acuity of each eye; and 
 pharmacologically dilated examination of the lens with a slit lamp. 
Subjects <18 years of age on the date of informed consent in the parent study are required to 
complete OEs as indicated in Table 3-1. These examinations should be completed within 28 days 
of the relevant study visit. An OE is also required within 28 days of the ETT Visit for subjects 
whose cumulative study drug exposure (in the parent study and current study) is at least 
12 weeks since the last study OE. 
Any clinically significant abnormal findings will be reported as AEs. 
11.6.7 
Contraception and Pregnancy 
The effects of VX-445, TEZ, and IVA on conception, pregnancy, and lactation in humans are not 
known. VX-445, 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 VX-445, TEZ, and IVA have 
not shown teratogenicity in rats and rabbits.  
11.6.7.1 
Contraception 
Contraception requirement for a couple is waived for the following: 
 True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception. True abstinence must 
be practiced from the date of informed consent 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) will be considered to be of 
childbearing potential. 
 Same-sex relationships 


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For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used as a couple. Methods of contraception must be in successful use from signing of consent (or 
assent, when applicable), approximately 28 days before the first dose of study drug (unless 
otherwise noted), and until 90 days following the last dose of study drug. Additional 
contraception requirements may need to be followed according to local regulations and/or 
requirements. Acceptable methods of contraception are listed in Table 11-2.  
Table 11-2 
Acceptable Methods of Contraception 
Method 
Male Subjects and Their 
Female (Non-study) 
Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy performed at least 6 months previously, 
with a documented negative postvasectomy semen 
analysis for sperm 
Yes 
Yes 
Bilateral tubal occlusion (e.g., ligation) performed at 
least 6 months previously 
Yes 
Yes 
Male or female condom with or without spermicidea 
Yes 
Yes 
Female barrier contraception (such as diaphragm, 
cervical cap, or sponge) with spermicide 
Yes 
Yes 
Continuous use of an intrauterine device for at least 
90 days before the first dose of study drug 
Yes 
Yes 
Oral, implanted, injected, or vaginal hormonal 
contraceptives, if successfully used for at least 
60 days before the first dose of study drug 
Yes 
Yes 
a 
A female condom cannot be used with a male condom due to risk of tearing.  
 
Additional notes: 
 If over the course of the study the subject meets the criteria for waiving the contraception 
requirements, the subject does not need to follow the contraceptive methods listed in 
Table 11-2. 
 If over the course of the study the subject’s status changes and the subject does not meet the 
criteria for waiving the contraception requirements, the subject must begin following the 
contraceptive methods listed in Table 11-2.  
 Male subjects must not donate sperm during the period starting from the first dose of study 
drug until 90 days after the last dose of study drug. 
 Female subjects should not nurse a child during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
 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. 


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11.6.7.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a female subject becomes pregnant during study participation, study drug will be permanently 
discontinued immediately. The investigator will notify the medical monitor and Vertex Global 
Patient Safety (GPS) within 24 hours of the site’s knowledge of the subject’s (or partner’s) 
pregnancy using the Pregnancy Information Collection Form. Male subjects with female partners 
who become pregnant during the study must use a male condom to avoid exposure of a potential 
embryo or fetus to study drug via the seminal fluid.  
The subject or partner will be followed until the end of the pregnancy and the infant will be 
followed for 1 year after the birth, provided informed consent is obtained. A separate ICF will be 
provided to explain these follow-up activities. Pregnancy itself does not constitute an AE. 
12 
STATISTICAL AND ANALYTICAL PLANS 
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the statistical analysis plan (SAP) and clinical pharmacologic analysis 
details will be provided in the clinical pharmacology analysis plan, both of which will be 
finalized before the clinical data lock for the study. 
12.1 
Sample Size 
The primary and secondary objectives of the study are the evaluation of the long-term safety and 
tolerability, and long-term efficacy of VX-445/TEZ/IVA. This is an open-label study that will 
enroll subjects who complete the last Treatment Period visit in the parent study and meet 
eligibility criteria. The parent study is a Phase 3 Vertex study investigating VX-445/TEZ/IVA 
(Study 104). Approximately 250 subjects are expected to enroll in this open-label study.  
12.2 
Analysis Sets 
The Open-label All Subjects Set is defined as all subjects who were enrolled (defined as subject 
having data in the clinical database) in the open-label study. This analysis set will be used for 
individual subject data listings and disposition summary tables unless otherwise specified. 
The Open-label Full Analysis Set (OL-FAS) is defined as all enrolled subjects who have 
received at least 1 dose of study drug in the open-label study. The OL-FAS will be used to 
summarize subject demographics and baseline characteristics and for all efficacy analyses unless 
otherwise specified. 
The Open-label Safety Set (OL-SS) is defined as all subjects who have received at least 1 dose 
of study drug in the open-label study. The OL-SS will be used 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, median, minimum value (min), and maximum value 
(max). The precision of the measurement for each continuous variable will be specified in the 
SAP. Unless otherwise specified, min and max values will be reported with the same precision as 


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the units of the raw data. The mean, median, and SD will be reported to 1 additional decimal 
place. Any values that require a transformation to standard units (metric or SI) will be converted 
with the appropriate precision. 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
The baseline value, unless otherwise specified, for the long-term safety analysis will be the most 
recent non-missing measurement (scheduled or unscheduled) collected before the first dose of 
VX-445/TEZ/IVA either in the parent study or the open-label study, as applicable. The baseline 
value for the long-term efficacy analysis will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
parent study. For assessments collected in duplicate or triplicate, the baseline will be defined as 
the average of non-missing values. 
Baseline characteristics of subjects in the open-label study will be the same as the baseline 
characteristics in the parent study. 
Change (absolute change) from baseline will be calculated as post-baseline value - baseline 
value. 
The Efficacy Analysis Period in the open-label study will include the time from the first dose of 
study drug in the open-label study to the last scheduled efficacy visit in the open-label study, 
unless otherwise specified. 
The Treatment-emergent (TE) Period in the open-label study will include the time from the 
first dose of study drug in the open-label study to 28 days after the last dose of the study drug in 
the open-label study or to the completion date of study participation (as defined in Section 9.1.5), 
whichever occurs first. 
The long-term efficacy analysis will be performed by parent study for the Efficacy Analysis 
Period in the open-label study. 
In general, long-term safety analyses will be performed in a pooled fashion. 
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 for the open-label study will be summarized as 
appropriate: 
 Open-label All Subjects Set 
 Dosed (OL-SS) 
 Enrolled and dosed (OL-FAS) 
 Completed Treatment Period 
 Prematurely discontinued treatment and the reasons for discontinuation 
 Completed study 
 Prematurely discontinued the study and the reasons for discontinuation 


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12.3.2.2 
Demographics and Baseline Characteristics 
Demographics, background (e.g., medical history), and baseline characteristics will be 
summarized by descriptive summary statistics. Baseline characteristics will be the same as the 
parent study baseline characteristics. 
The following demographics and baseline characteristics will be summarized for the OL-FAS 
and will include (but not limited to) sex, race, ethnicity, baseline age, baseline weight, baseline 
height, baseline BMI, baseline ppFEV1, baseline SwCl, and baseline score of CFQ-R RD. 
Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT) for the OL-FAS. 
12.3.2.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization-Drug Dictionary and 
categorized as follows: 
 Prior medication: any medication that was administered during the 56 days before the first 
dose of study drug in the open-label study 
 Concomitant medication: medication continued or newly received during the TE Period in 
the open-label study 
 Post-treatment medication: medication continued or newly received after the TE Period in 
the 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 in 
the open-label study, concomitantly during the TE Period in the open-label study, or beyond the 
TE Period in the open-label study, it will be considered in all 3 categories of prior, concomitant, 
and post-treatment medication. 
Prior medications and concomitant medications will be summarized descriptively by Preferred 
Name based on the OL-FAS. 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 for the OL-SS in terms of treatment a subject received 
in the open-label study, defined as [(the last day of study drug in the open-label study − the first 
day of study drug in the open-label study) + 1 day], regardless of study drug interruption. 
Study drug compliance will be summarized overall and by treatment group based on the 
OL-FAS, and will be calculated as: 100  [1 – (total number of days of study drug interruption in 
the open-label study) / (duration of study drug exposure in days in the open-label study)]. A 
study drug interruption on a given day is defined as an interruption of any study drug on that day. 
In addition, percentage of tablets taken in the open-label study will also be summarized overall 
and by treatment group based on the OL-FAS, and will be calculated as 100  [(total number of 
tablets dispensed in the open-label study) – (total number of tablets returned in the open-label 


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study)] / (total number of tablets planned to be taken per day  duration of study drug exposure 
in days for the open-label study). 
12.3.2.5 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. The rules for identifying an IPD in the open-label study will be 
described in the SAP. 
All IPDs will be provided in an individual subject data listing, and summarized, as appropriate. 
12.3.3 
Efficacy and Pharmacodynamic Analyses 
The secondary objectives of the study are the evaluation of the long-term efficacy and PD of 
VX-445/TEZ/IVA. 
12.3.3.1 
Analysis of Primary Endpoint 
Not applicable since efficacy and PD are not primary objectives. 
12.3.3.2 
Analysis of Secondary Efficacy Endpoints 
The secondary endpoints include: 
 Absolute change in ppFEV1 
One of the secondary efficacy endpoints is the absolute change in ppFEV1 at visits in the 
open-label study, for subjects who receive at least 1 dose of study drug in the open-label study. 
The primary analysis for this secondary endpoint will be based on a mixed-effects model for 
repeated measures (MMRM), with the absolute change from baseline in ppFEV1 as the 
dependent variable for visits in the open-label study. The model will be similar to the one used 
for the primary efficacy analysis in the parent study. 
The details including sensitivity analyses and supportive analyses will be described in the SAP. 
 Absolute change in SwCl 
Analysis of this PD endpoint will be based on an MMRM similar to the analysis of the absolute 
change in ppFEV1. 
 Absolute change in BMI 
Analysis of this endpoint will be based on an MMRM similar to the analysis of the absolute 
change in ppFEV1. 
 Absolute change in BMI z-score 
Analysis of this endpoint will be based on an MMRM similar to the analysis of the absolute 
change in ppFEV1. 
 Absolute change in body weight 
Analysis for this endpoint will be based on an MMRM similar to the analysis of the absolute 
change in ppFEV1. 


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 Absolute change in CFQ-R RD score 
Analysis of this endpoint will be based on an MMRM similar to the analysis of the absolute 
change in ppFEV1. 
12.3.3.3 
Analysis of Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include: 
 Absolute change in CFQ-R non-RD scores  
Analysis of this endpoint will be based on an MMRM similar to the analysis of the absolute 
change in ppFEV1. Additional details will be specified in the SAP. 
12.3.3.4 
Multiplicity Adjustment 
Not applicable 
12.3.4 
Safety Analysis 
The primary objective of the study is the evaluation of the long-term safety and tolerability of 
VX-445/TEZ/IVA. All safety analyses will be based on the TE Period in the open-label study for 
subjects in the OL-SS. 
The overall long-term safety profile of study drug will be assessed in terms of the following 
safety and tolerability endpoints: 
 Incidence of treatment-emergent AEs (TEAEs) 
 Clinical laboratory values (i.e., serum chemistry, hematology, coagulation, and urinalysis) 
 ECGs 
 Vital signs 
 Pulse oximetry 
In general, long-term safety analysis will be performed in a pooled fashion. All safety data will 
be presented in individual subject data listings. Only a descriptive analysis 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 before the first dose of VX-445/TEZ/IVA in the 
TE Period in the open-label study 
 TEAE: any AE that worsened (either in severity or seriousness) or newly developed at or 
after the first dose date of VX-445/TEZ/IVA in the TE Period in the open-label study 
 Post-treatment AE: any AE that worsened (either in severity or seriousness) or newly 
developed after the TE Period in the 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: 


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 All TEAEs 
 TEAEs by strongest relationship  
 TEAEs by maximum severity 
 TEAEs leading to treatment discontinuation 
 TEAEs leading to treatment interruption 
 Serious TEAEs 
 TEAEs leading to death 
 Grade 3 and Grade 4 TEAEs 
 Frequently reported TEAEs 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same AE or a 
continuing AE will be counted once. Only the maximum severity level will be presented in the 
severity summaries, and the strongest relationship level will be presented in the relationship 
summaries. An AE overview table will be provided. In addition, a listing containing individual 
subject level AE data for all deaths and other serious and significant AEs will be provided 
separately. All AEs, including pre- and post-treatment AEs, will be presented in individual 
subject data listings. 
Exposure-adjusted event rates may also be provided.  
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 for the pooled population at 
each time point during the TE Period in the open-label study. 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period in the open-label study will be summarized. The shift of the threshold analysis criteria 
from baseline to post-baseline will also be summarized for selected laboratory parameters. The 
threshold analysis and parameter selection criteria 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 in the open-label study, for the 
following standard 12-lead ECG interval measurements (in msec): RR, PR, QT, QTc for heart 
rate (HR) interval (QTcF), QRS duration, and HR (beats per minute [bpm]). 


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The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period in this open-label study will be summarized. The threshold analysis 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 the open-label study. The following 
vital signs parameters will be summarized: systolic and diastolic blood pressure (mm Hg), 
temperature (C), pulse rate (bpm), and respiratory rate (breaths per minute). 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period in the open-label study will be summarized. The threshold analysis 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 in the open-label study, 
for the percent of oxygen saturation by pulse oximetry. 
The number and percentage of subjects with shift changes from baseline (normal/missing 
and low according to the reference range) to the lowest percent of oxygen saturation during the 
TE Period will be summarized. 
12.3.4.6 
Physical Examination 
No tables, figures, or listings will be provided for physical examination data. 
12.3.4.7 
Other Safety Analyses 
Details of other safety analyses may be included in the SAP. 
12.3.5 
Exploratory Endpoints 
Details of other analyses, including inflammatory mediators and blood biomarkers will be 
provided in a separate document. 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses 
12.3.6.1 
Interim Analysis 
Interim analyses (IAs) may take place at any time during the study at the discretion of the 
sponsor. In the event that the parent study is still ongoing, a limited Vertex team may be 
unblinded to the treatment assignments in the parent study for the purpose of reviewing the 
interim results, and will not be involved in or influence the conduct of the remaining part of the 
parent study to protect the integrity of the parent study. 
12.3.6.2 
Independent Data Monitoring Committee Analysis 
The IDMC (Section 9.1.6) will conduct periodic safety reviews of study data as outlined in the 
IDMC charter. 


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The IDMC’s objectives, responsibilities, and operational details will be defined in a separate 
document (IDMC charter), which will be finalized before the first subject is enrolled in the 
study. 
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, physical examinations, and vital signs will 
be assessed and those deemed to have clinically significant worsening from baseline will be 
documented as an AE. When possible, a clinical diagnosis for the study assessment will be 
provided, rather than the abnormal test result alone (e.g., urinary tract infection, anemia). In the 
absence of a diagnosis, the abnormal study assessment itself will be listed as the AE 
(e.g., bacteria in urine or decreased hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
 Concomitant signs or symptoms related to the abnormal study assessment 
 Further diagnostic testing or medical/surgical intervention 
 A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the subject completes study 
participation, as defined in Section 9.1.5. 
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 


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recorded only in the subject’s source documents. The following data will be documented for 
each AE: 
 Description of the event 
 Classification of “serious” or “nonserious” 
 Date of first occurrence and date of resolution (if applicable) 
 Severity  
 Causal relationship to study drug(s)  
 Action taken  
 Outcome  
 Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
July 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. 


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Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, such 
as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the subject’s medical record). 
AE: adverse event 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
AE: adverse event 
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 


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13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
 Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation and is suspected of being a delayed toxicity due to administration of the study 
drug) 
 Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
 Inpatient hospitalization or prolongation of hospitalization 
 Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
 Congenital anomaly or birth defect 
 Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious”, which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through 
completion of study participation, regardless of causality, will be reported by the investigator to 
Vertex GPS within 24 hours of identification. In addition, all SAEs that occur after the Safety 


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Follow-up Visit and are considered related to study drug(s) will be reported to Vertex GPS 
within 24 hours of identification.  
For SAEs that occur after obtaining informed consent and assent (where applicable) through 
completion of study participation, the SAE Form will be completed for new/initial events as well 
as to report follow-up information on previously reported events. Investigators are asked to 
report follow-up information as soon as it becomes available to ensure timely reporting to health 
authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email: globalpatientsafety@vrtx.com (preferred choice) 
Fax: +1-617-341-6159  
For technical issues related to submitting the form, contact telephone: +1-617-341-6677 
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) will 
be recorded on the Vertex Clinical Trial Safety Information Collection Form (hereafter referred 
to as the “SAE Form”) using a recognized medical term or diagnosis that accurately reflects the 
event. SAEs will be assessed by the investigator for relationship to the investigational study 
drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be assessed 
only as related (includes possibly related) or not related (includes unlikely related), and severity 
assessment will not be required. For the purposes of study analysis, if the event has not resolved 
at the end of the study reporting period, it will be documented as ongoing. For purposes of 
regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report the outcome to Vertex using the SAE Form. 
13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, 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. 


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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. When determining the age of the subject, other study eligibility criteria, and timing of 
collection applicable assessments, the informed consent will be used as the reference (e.g., age at 
time of informed consent, date of informed consent, timing of AE collection). 
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 (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
13.2.4 
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 CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers, and access to subject names linked to such 
numbers will be limited to the site and the study physician and will not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE Forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 
For sites participating in the US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will comply with all HIPAA 
requirements including authorization allowing the site access to and use of the subject’s 


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personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.6 
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 
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. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each subject. Study 
data for each enrolled subject will be entered into a CRF by study site personnel using a secure, 
validated, web-based electronic data capture (EDC) application. Vertex will have read-only 
access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 


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13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP Guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
Protocol deviations will be monitored and identified throughout study conduct as outlined in the 
Protocol Deviation Plan. 
13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc or other electronic media will be placed in the investigator’s 
study file. 
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 


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associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 
13.7.1 
Publication of Study Results 
Vertex is committed to reporting the design and results of all clinical studies in a complete, 
accurate, balanced, transparent, and timely manner, consistent with Good Publication 
Practices.17_ENREF_17  
Publication Planning: Vertex staff along with the lead principal investigators, the steering 
committee, and/or the publication committee will work together to develop a publication plan.  
Authorship: Authorship of publications will be determined based on the Recommendations for 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, which 
states that authorship should be based on the following 4 criteria18: 
1. Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data;  
2. Drafting of the article or revising it critically for important intellectual content;  
3. Final approval of the version to be published; and 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
All authors must meet conditions 1, 2, 3, and 4. All persons designated as authors should qualify 
for authorship, and all those who qualify should be listed. Contributions such as medical writing, 
enrollment of subjects, acquisition of funding, collection of data, or general supervision of the 
research group, alone, do not justify authorship.  
Contributors: Contributors who meet fewer than all 4 of International Committee of Medical 
Journal Editors criteria for authorship will not be listed as authors, but their contribution will be 
acknowledged and specified either as a group (e.g., “study investigators”) or individually (e.g., 
“served as scientific advisor”).  
Publication Review: As required by a separate clinical study agreement, Vertex must have the 
opportunity to review all publications, including any manuscripts, abstracts, oral/slide 
presentations, and book chapters regarding this study before submission to congresses or journals 
for consideration.  
13.7.2 
Clinical Study Report  
A CSR, written in accordance with the ICH E3 Guideline, will be submitted in accordance with 
local regulations. 


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14 
REFERENCES 
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 24 March 2019. 
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 24 March 2019. 
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 24 March 2019. 
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 
24 March 2019. 
11 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
12 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
13 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 
14 
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of 
the Cystic Fibrosis Questionnaire in the United States. Chest. 2005;128(4):2347-54. 
15 
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life 
Res. 2003;12(1):63-76. 
16 
Wenninger K, Aussage P, Wahn U, Staab D, German Cystic Fibrosis Questionnaire study 
group. The revised German Cystic Fibrosis Questionnaire: validation of a disease-
specific health-related quality of life instrument. Qual Life Res. 2003;12(1):77-85. 


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17 
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. 
18 
International Committee of Medical Journal Editors (ICMJE). Recommendations for 
conduct, reporting, editing, and publication of scholarly work in medical journals. 
Available at: http://www.icmje.org/recommendations/. Accessed April 9, 2018. 




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15.2 
Investigator Signature Page 
Protocol #: 
VX18-445-110 
Version #: 
1.0 
Version Date: 
30 May 2019 
Study Title: A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of 
VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Heterozygous for the 
F508del Mutation and a Gating or Residual Function Mutation (F/G and F/RF Genotypes) 
I have read Protocol VX18-445-110, Version 1.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-445, 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 
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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: 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
Statistical Analysis Plan (Methods) – Part A Analysis 
Page 1 of 32 
Protocol Number: VX18-445-110 
 
 
 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
 
Statistical Analysis Plan 
(Methods) 
Protocol Number VX18-445-110 Version 1.3 
(Part A Analysis) 
 
 
A Phase 3, Open-label Study Evaluating the Long-term Safety and 
Efficacy of VX-445 Combination Therapy in Subjects With Cystic 
Fibrosis Who Are Heterozygous for the F508del Mutation and a 
Gating or Residual Function Mutation (F/G and F/RF Genotypes) 
 
Authors of SAP: 
 
Version: 1.0 
Version Date of SAP: 2 Feb 2022 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations. Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods) – Part A Analysis 
Protocol Number: VX18-445-110 
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1 
TABLE OF CONTENTS 
1 
Table of Contents .................................................................................................................... 2 
2 
Modifications ........................................................................................................................... 4 
2.1 
Modifications to the Approved Clinical Study Protocol .................................................... 4 
2.2 
Modifications to the Approved Statistical Analysis Plan .................................................. 4 
2.3 
Modifications to the Approved DMC Charter ................................................................... 4 
3 
Introduction ............................................................................................................................. 5 
4 
Study Objectives ...................................................................................................................... 5 
4.1 
Primary Objective .............................................................................................................. 5 
4.2 
Secondary Objectives ......................................................................................................... 5 
5 
Study Endpoints ...................................................................................................................... 6 
5.1 
Primary Endpoint (Parts A and B) ..................................................................................... 6 
5.2 
Secondary Endpoints (Part A only) ................................................................................... 6 
5.3 
Exploratory Endpoints (Part A only) ................................................................................. 6 
6 
Study Design ............................................................................................................................ 6 
6.1 
Overall Design ................................................................................................................... 6 
6.2 
Sample Size and Power ...................................................................................................... 7 
6.3 
Randomization ................................................................................................................... 7 
6.4 
Blinding and Unblinding.................................................................................................... 7 
7 
Analysis Sets ............................................................................................................................ 7 
7.1 
OL All Subjects Set ........................................................................................................... 7 
7.2 
104 and OL Full Analysis Set ............................................................................................ 8 
7.3 
OL Safety Set ..................................................................................................................... 8 
8 
Analysis period ........................................................................................................................ 8 
8.1 
Parent Study Efficacy Period ............................................................................................. 8 
8.2 
Open Label Extension Period ............................................................................................ 8 
9 
Statistical Analysis .................................................................................................................. 8 
9.1 
General Considerations ...................................................................................................... 8 
9.2 
Background Characteristics ............................................................................................... 9 
9.2.1 
Subject Disposition .................................................................................................... 9 
9.2.2 
Demographics and Baseline Characteristics ............................................................ 10 
9.2.3 
Medical History ....................................................................................................... 11 
9.2.4 
Prior and Concomitant Medications ........................................................................ 11 
9.2.5 
Study Drug Exposure ............................................................................................... 12 
9.2.6 
Study Drug Compliance ........................................................................................... 12 
9.2.7 
Important Protocol Deviations ................................................................................. 12 
9.3 
Efficacy Analysis ............................................................................................................. 12 
9.3.1 
Analysis of Primary Efficacy Endpoint ................................................................... 13 
9.3.2 
Analysis of Secondary Efficacy and Pharmacodynamic Endpoint .......................... 13 
9.3.3 
Analysis of Additional Efficacy Variables .............................................................. 15 
9.4 
Safety Analysis ................................................................................................................ 16 
9.4.1 
Adverse Events ........................................................................................................ 16 


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9.4.2 
Clinical Laboratory Assessments ............................................................................. 18 
9.4.3 
Electrocardiogram .................................................................................................... 18 
9.4.4 
Vital Signs ............................................................................................................... 18 
9.4.5 
Pulse Oximetry ........................................................................................................ 19 
9.4.6 
Physical Examination ............................................................................................... 19 
9.4.7 
Ophthalmology Examination ................................................................................... 19 
9.5 
Safety Supportive Analysis .............................................................................................. 19 
9.5.1 
Adverse Events of Special Interest .......................................................................... 19 
9.6 
Exploratory Analysis ....................................................................................................... 20 
9.6.1 
Analysis of absolute change from baseline in CFQ-R non-respiratory domain 
score ......................................................................................................................... 20 
10 Interim and DMC Analyses.................................................................................................. 20 
10.1 Interim Analysis ............................................................................................................... 20 
10.2 DMC Analysis ................................................................................................................. 20 
11 References .............................................................................................................................. 21 
12 Appendices ............................................................................................................................. 22 
12.1 Analysis Visit Windows for Safety and Efficacy Assessments ....................................... 22 
12.2 Imputation Rules for Missing Prior/Concomitant Medication Dates .............................. 25 
12.3 Imputation Rules for Missing AE dates ........................................................................... 26 
12.4 Criteria for Threshold Analysis ....................................................................................... 27 
12.5 Details of GLI Equations for Calculating ppFEV1 ........................................................................................ 32 


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2 
MODIFICATIONS 
 
2.1 
Modifications to the Approved Clinical Study Protocol 
Not Applicable. 
2.2 
Modifications to the Approved Statistical Analysis Plan 
This is the 1st version of Statistical Analysis Plan for the interim analysis and final analysis. 
2.3 
Modifications to the Approved DMC Charter 
Not Applicable. 


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3 
INTRODUCTION 
 
VX18-445-110 (Study 110) is a Phase 3, 2-part, open-label extension study of VX18-445-104 
(Study 104). 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 96-week 
Treatment Period in Part A, a 48-week Treatment Period in Part B and a 4-week Safety Follow 
up Period. The primary objective is to evaluate the long-term safety and tolerability of VX-445 
(elexacaftor, ELX)/tezacaftor (TEZ)/ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are 
heterozygous for the F508del mutation and a gating (F/G) or residual function (F/RF) mutation. 
Safety data will be periodically reviewed by the independent data monitoring committee (DMC). 
This SAP (Methods) documents the planned statistical analyses and data presentations of safety 
and efficacy endpoints for Part A. The SAP will be amended to include Part B prior to Part B 
DBL. It is based on the most recent approved clinical study protocol (CSP), the most recent 
approved DMC charter, the most recent approved electronic case report form (eCRF), and the 
most recent approved eCRF completion guidelines. 
Due to the outbreak of COVID-19, 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. This SAP summarizes the 
additional statistical analyses that are related to these alternative measures. 
The Vertex Biometrics Department will perform the statistical analysis described in this 
document. SAS (Version 9.4 or higher) will be used to generate all statistical outputs (tables, 
figures, listings, and datasets). The SAP (Methods) will be finalized and approved prior to IA 
data lock. Any revisions to the approved SAP will be documented and approved in an 
amendment to the SAP. 
 
4 
STUDY OBJECTIVES 
 
4.1 
Primary Objective 
To evaluate the long-term safety and tolerability of ELX/TEZ/IVA in subjects with CF who are 
heterozygous for the F508del mutation and a gating (F/G) or residual function (F/RF) mutation. 
4.2 
Secondary Objectives 
• To evaluate the long-term efficacy of ELX/TEZ/IVA 
• To evaluate the pharmacodynamics (PD) of ELX/TEZ/IVA 


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5 
STUDY ENDPOINTS 
 
5.1 
Primary Endpoint (Parts A and B) 
Safety and tolerability of long-term treatment with ELX/TEZ/IVA based on adverse events 
(AEs), clinical laboratory values, ECGs, vital signs, and pulse oximetry. 
5.2 
Secondary Endpoints (Part A only) 
• Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) 
• Absolute change in sweat chloride (SwCl) 
• Absolute change in body mass index (BMI) 
• Absolute change in BMI z-score 
• Absolute change in body weight 
• Absolute change from baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
respiratory domain (RD) score 
5.3 
Exploratory Endpoints (Part A only) 
• Absolute change in CFQ-R non-respiratory domain scores 
• Inflammatory mediators 
• Blood biomarkers 
6 
STUDY DESIGN 
 
6.1 
Overall Design 
This is a Phase 3, 2-part, multicenter, open-label study (OLS) for subjects who completed the last 
Treatment Period visit in the parent study (Study 104) and meet eligibility criteria. A schematic 
of the study design is shown in Figure 6-1. 
 
Figure 6-1 
VX18-445-110 Study Design 
 
 
 
 


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ELX: elexacaftor; IVA: ivacaftor; TEZ: tezacaftor 
Notes: Parent study refers to Study 104. The timing of the Day 1 Visit, relative to the last scheduled visit of 
the parent study, is detailed in CSP Section 9.1.1. The figure is not drawn to scale. 
 
a 
Subjects whose Part B Day 1 is on the same day or within 1 calendar day as the Part A Week 96 Visit do 
NOT have to repeat any Part B Day 1 assessments that were specified to be performed at the Part A 
Week 96 Visit. Subjects whose Part B Day 1 is more than 1 calendar day after Part A Week 96 Visit 
must complete all assessments specified for the Part A Week 96 AND Part B Day 1 Visits. 
 
 
All subjects will receive ELX/TEZ/IVA (TC) at the same dosage as that in the parent study 
(Study 104). The planned dosages for the Treatment Period are shown in Table 6-1. 
 
Table 6-1 
Planned Dosages 
 
ELX Dosage 
TEZ Dosage 
IVA Dosage 
200 mg qd 
100 mg qd 
150 mg q12h 
ELX: elexacaftor; IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TEZ: tezacaftor 
 
 
All visits will occur within the windows specified. Please refer to Table 3-1 of the CSP for more 
details about study visits and assessments. 
6.2 
Sample Size and Power 
The primary and secondary objectives of the study are the evaluation of the long-term safety and 
tolerability, and long-term efficacy of ELX/TEZ/IVA. This is an open-label study that will enroll 
subjects who complete the last Treatment Period visit in the parent study and meet eligibility 
criteria. The parent study is a Phase 3 Vertex study investigating ELX/TEZ/IVA (Study 104). 
Approximately 250 subjects are expected to enroll in this open-label study. 
6.3 
Randomization 
Randomization is not required because all subjects will be treated identically in a single cohort. 
6.4 
Blinding and Unblinding 
Refer to the CSP section 10.7 for details. 
 
7 
ANALYSIS SETS 
 
The following analysis sets are defined: Open-label (OL) All Subjects Set for Part A, 104 Full 
Analysis Set, OL Full Analysis Set for Part A and OL Safety Set for Part A. Unless otherwise 
specified, all analysis sets defined in this section will be restricted to Part A data only. 
7.1 
OL All Subjects Set 
The OL All Subjects Set for Part A is defined as all subjects who were enrolled (defined as 
subject having data in the clinical database for the OLS) in the OLS. This analysis set will be 
used for individual subject data listings and disposition summary tables unless otherwise 
specified. 


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7.2 
104 and OL Full Analysis Set 
The Study 104 Full Analysis Set (104-FAS) is defined the same as the FAS definition in the 
SAP of Study 104. 
The OL Full Analysis Set (OL-FAS) for Part A is defined as all enrolled subjects who have 
received at least 1 dose of study drug in the open-label study. The OL-FAS for Part A will be 
used to summarize subject demographics and baseline characteristics and for all efficacy 
analyses unless otherwise specified. 
7.3 
OL Safety Set 
The OL Safety Set (OL-SS) for Part A is defined as all subjects who received at least 1 dose of 
study drug in the OLS. The OL-SS for Part A will be used for all safety analyses. 
 
8 
ANALYSIS PERIOD 
 
8.1 
Parent Study Efficacy Period 
The definition of this analysis period is the same as in Study 104 and will be used with the parent 
study efficacy analysis set (104-FAS) to analyze the efficacy data during the parent study. 
8.2 
Open Label Extension Period 
OL Efficacy Period for Part A: The time from the first dose of study drug in the OLS to the last 
efficacy assessment, which may be collected up to the Week 96 Visit or the earlier of Day 673 
and the end of study participation if subject does not have the Week 96 Visit. This analysis 
period will be used with the OL-FAS for Part A to analyze the efficacy data during the OLS. 
OL Safety Period for Part A: The time from the first dose of study drug in the OLS to 28 days 
after the last dose date of the study drug in the OLS or to the completion date of study 
participation (defined in CSP Section 9.1.5) in Part A, whichever occurs first. This analysis 
period will be used with the OL-SS for Part A to analyze the safety data during the OLS. 
The Treatment-emergent (TE) Period for Part A is same as the OL Safety Period for Part A. 
Note: for subjects who depart study 110 to participate in another qualified Vertex study and 
return in study 110, the above defined analysis period will exclude the time between the last dose 
before the discontinuation from study 110 and the first dose after re-enter in study 110. 
 
9 
STATISTICAL ANALYSIS 
 
9.1 
General Considerations 
The precision standards for reporting safety and efficacy variables are provided in an internal 
Biometrics document that specifies the programming rules including the precision for derived 
variables. 
Data will be summarized by treatment group in the parent study (“Control in 445-104” and 
“ELX/TEZ/IVA in 445-104”) and overall (“Any ELX/TEZ/IVA”). 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, standard deviation (SD), median, minimum value (min), and 
maximum value (max). 


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Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline value for clinical laboratory values, standard 12-lead ECGs, vital signs, and pulse 
oximetry will be the TC safety baseline defined as the most recent non-missing measurement 
(scheduled or unscheduled) collected before the first dose of study drug in the parent study (if the 
subject actually received at least one dose of ELX/TEZ/IVA during the parent study) or the first 
dose of study drug in the OLS (if the subject did not actually receive at least one dose of 
ELX/TEZ/IVA during the parent study). Baseline value for efficacy analyses, demographics, 
and baseline characteristics will be the parent study baseline defined as the most recent non 
missing measurement (scheduled or unscheduled) collected before the first dose of study drug in 
the Treatment Period of the parent study. 
Change (absolute change) from baseline will be calculated as post-baseline value ‒ baseline 
value. Relative change from baseline will be calculated as (post-baseline value ‒ baseline 
value)/baseline value. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
1) In scheduled visit windows per specified visit windowing rules 
2) In the derivation of baseline 
3) In the derivation of maximum and minimum values during TE period for Part A, and 
maximum and minimum change from baseline values during TE period for Part A for the 
long-term safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Section 12.1. 
Incomplete/missing data will not be imputed, unless specified otherwise. 
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
Multiplicity: There will be no multiplicity adjustment as no hypothesis test is planned for safety 
analysis, unless specified otherwise. 
9.2 
Background Characteristics 
9.2.1 
Subject Disposition 
A summary table of subject disposition in the OLS will be presented for the OL All Subjects Set 
for Part A by treatment group in parent study and overall with the following categories: 
• Enrolled (OL All Subjects Set for Part A) 
• Dosed (OL-SS for Part A) 
• Enrolled and dosed (OL-FAS for Part A) 
The number and percentage (based on OL-FAS for Part A) of subjects in each of the following 
disposition categories will be summarized by treatment group in parent study and overall: 
• Completed Treatment 
• Prematurely discontinued treatment and the reasons for discontinuation 


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• Completed study 
• Prematurely discontinued the study and the reasons for discontinuation 
• Rollover to Part B 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. 
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the OL-FAS for Part A, 
and presented by treatment group in parent study and overall. 
Demographic data will include the following: 
• Age at parent study baseline (in years) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Not Collected per Local Regulations and Other) 
• Geographic region (North America, Europe [including Australia]) 
Parent study baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• BMI z-score (for subjects <=20 years old at baseline) 
Stratification categories used in the parent study will include the following: 
• Comparator group in parent study (TEZ/IVA comparator group, IVA comparator group) 
• ppFEV1 at Day -14 of parent study (<70, ≥70) 
• SwCl at Day -14 of parent study (<30 mmol/L, ≥30 mmol/L) 
Disease characteristics based on the parent study will include the following: 
• ppFEV1 category at baseline (<40, ≥ 40 to <70, ≥70 to ≤90, and >90) 
• ppFEV1 at baseline (continuous) 
• Sweat chloride at baseline (continuous) 
• CFQ-R respiratory domain score at baseline (continuous) 
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 


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• Prior use of any bronchodilator (Yes, No) 
• Prior use of any inhaled bronchodilator (Yes, No) 
• Prior use of any inhaled hypertonic saline (Yes, No) 
• Infection with Pseudomonas aeruginosa within 2 years prior to screening visit of parent 
study (Positive, Negative) 
For subjects who received TC in the parent study, prior medication use refers to medication 
taken during 56 days before the first dose date of study drug in the parent study treatment period 
or medication taken during the Run-in period. For subjects who did not receive TC in the parent 
study, prior medication use refers to medication taken during 56 days before the first dose date of 
study drug in the OLS, if applicable. No statistical tests will be carried out to evaluate any 
baseline imbalance between treatment groups. 
9.2.3 
Medical History 
Medical history (referenced to the start of parent study) will be coded by using the Medical 
Dictionary for Regulatory Activities (MedDRA). For the OL-FAS for Part A, medical history 
will be summarized descriptively by treatment group in parent study and overall and by System 
Organ Class (SOC) and Preferred Term (PT). The corresponding data listing will also be 
provided. 
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization-Drug Dictionary (WHODrug) 
and categorized as follows: 
• Prior medication: any medication that was administered during the 56 days before the first 
dose date of study drug in the OLS. 
• Concomitant medication: medication continued or newly received during the TE Period for 
Part A for the OLS. 
• Post-treatment medication: medication continued or newly received after the TE Period for 
Part A for the OLS. 
A given medication may be classified as a prior medication, a concomitant medication, a 
post-treatment medication, both prior and concomitant, both concomitant and post-treatment, or 
all three categories of prior, concomitant, and post-treatment. 
If a medication has completely missing or partially missing start/stop date and if it cannot be 
determined whether it was taken before the first dose date of the OLS, concomitantly during the 
TE Period for Part A for the OLS, or after the TE Period for Part A for the OLS, it will be 
considered in all 3 categories of prior, concomitant, and post-treatment medication. Details for 
imputing missing or partial start and/or stop dates of medication are described in Section 12.2. 
For the OL-FAS for Part A, prior medications and concomitant medications will be summarized 
descriptively by: 1) treatment group in parent study and overall, Preferred Name (PN); and 2) 
treatment group in parent study and overall, anatomic class (ATC) level 1, ATC level 2, and PN. 
Post-treatment medications will be listed for each subject, if applicable. 


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9.2.5 
Study Drug Exposure 
Duration of study drug exposure (in days) will be calculated as: last dose date of study drug in 
the OLS – first dose date of study drug in the OLS + 1, regardless of study drug interruption. For 
subjects who enroll in another qualified Vertex study before completing this study and resume 
participation in this study, time spent in the other study will be excluded. 
Study drug exposure (in weeks) during OL safety period for Part A for the OL-SS for Part A will 
be summarized descriptively by the number of subjects (n), mean, SD, median, min, and max. It 
will also be summarized into the following categories: <=24 weeks, >24 to <=48 weeks, >48 to 
<=72 weeks, >72 to <=96 weeks, >96 weeks. Additionally, the total study drug exposure, 
defined as the sum total of the study drug exposure across all subjects (in patient-weeks and 
patient-years), will be provided. The summary will be presented by treatment group in parent 
study and overall. 
9.2.6 
Study Drug Compliance 
Study drug compliance for the OL efficacy period for Part A will be calculated as: 100  [1 - 
(total number of days of study drug interruption) / (duration of study drug exposure in days)]. A 
study drug interruption on a given day is defined as an interruption of any study drug on that day. 
For subjects who enroll in another qualified Vertex study before completing this study and 
resume participation in this study, time spent in the other study will be excluded. 
Percentage of study drug compliance will be summarized based on the OL-FAS for Part A and 
presented by treatment group in parent study and overall. Percentage of study drug compliance 
will be summarized descriptively by the number of subjects (n), mean, SD, median, min, and 
max. It will also be summarized in categories: <80% and ≥80% using frequency tables. 
In addition, percentage of tablets taken during the OL efficacy period for Part A will be 
calculated using the following formula: 100  [(total number of tablets dispensed) – (total 
number of tablets returned)] / (total number of tablets planned to be taken per day  duration of 
study drug exposure in days). Summary similar to those for the study drug compliance will be 
produced based on the OL-FAS for Part A. 
9.2.7 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. A protocol deviation review team will categorize IPDs according to 
the Protocol Deviation Plan during the study. 
IPDs during the OL Efficacy period for Part A will be summarized descriptively based on the 
OL-FAS for Part A and presented by treatment group in parent studies and overall. Additionally, 
IPDs during the OL Efficacy period for Part A will be provided in an individual subject data 
listing. IPDs will be analyzed only as part of final analysis. 
9.3 
Efficacy Analysis 
The parent study baseline will be used to calculate the change from baseline for continuous 
efficacy endpoints unless otherwise specified. Data of continuous endpoints at visits in the parent 
study will be analyzed using the same mixed-effects model for repeated measures (MMRM) 
approach as described in the SAP for the parent study. The resulting estimates will be identical to 


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what is in the CSR of the parent study. Similarly, data of continuous endpoints at visits in the 
OL efficacy period for Part A will be analyzed using a separate MMRM. The results obtained 
from the parent study and OLE efficacy period will be displayed one followed by the other. 
The focus of the efficacy analysis is to characterize the long-term treatment effects using change 
from baseline for each treatment group in the parent study. P values will not be presented. 
9.3.1 
Analysis of Primary Efficacy Endpoint 
Not applicable since efficacy is not a primary objective. 
9.3.2 
Analysis of Secondary Efficacy and Pharmacodynamic Endpoint 
9.3.2.1 
Definition of Variables 
Percent predicted forced expiratory volume in 1 second (ppFEV1): Percent predicted FEV1 is the 
ratio of FEV1 (L) and predicted FEV1 (L), expressed as a percentage. The predicted FEV1 will be 
calculated using the Global Lung Function Initative1 (GLI). See Section 12.5 for more details. 
Sweat chloride (SwCl): the SwCl value for a given visit will be calculated as the mean of the 
non-missing sweat chloride measurements obtained on the left and right arms at that visit. If one 
of the two arm measurements at a time point is missing, the other will be used as the mean. A 
volume ≥15 μL is required for an accurate determination of sweat chloride. Any results reported 
as having volume <15 μL will be considered missing. Any sweat chloride values reported as 
>160 mmol/L will be considered missing. Any sweat chloride values reported as <10 mmol/L 
will be imputed as 10 mmol/L. 
Body mass index (BMI): the BMI at each visit is calculated using the weight and height at each 
visit as follows: 
BMI = Weight (kg) 
Height2 (m2) 
BMI z-score: the BMI score, adjusted for age and sex, will be referred to as BMI-for-age z-score 
(BMI z-score). The BMI z-score will be calculated by using Centers for Disease Control and 
Prevention (CDC) growth charts2, with the age (in months) used for the calculation defined in 
Section 12.1. 
Cystic Fibrosis Questionnaire-Revised (CFQ-R): The CFQ-R3,4,5 is a validated CF-specific 
instrument that measures quality-of-life domains. This study utilizes three different versions of 
CFQ-R: 
• CFQ-R for Children ages 12 and 13 
• CFQ-R for Adolescents and Adults (subjects 14 years and older) 
• CFQ-R for Parents/Caregivers (subjects 13 years and younger) 
In all three versions, specific question belonging to a domain is scored 1, 2, 3, or 4. The CFQ-R 
domain score, e.g., physical domain score or respiratory domain score, is defined as a scaled 
score as follows: 
Scaled score for a domain = 100 × (mean (scores of all questions in the domain) − 1)/3, 
where the score from a negatively phrased question is first reversed, i.e., reversed score = 5 – 
actual score, so that 1 always represents the worst condition and 4 the best condition. The 


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(scaled) domain score ranges from 0 (worst condition) to 100 (best condition). The scaled score 
for a specific domain will not be calculated if more than half of the questions in the domain have 
missing scores. 
The (scaled) domain score from the CFQ-R for Children ages 12 and 13 and for Adolescent and 
Adults will be pooled within and across subjects for the analysis purpose. 
9.3.2.1 
Analysis Method 
Absolute change from baseline in ppFEV1 
The MMRM for the parent study efficacy period will be same as that described in the SAP for 
Study 104. In the MMRM for the OL efficacy period for Part A, the absolute change from 
baseline in ppFEV1 will be the dependent variable. The model will include treatment group (as 
randomized in parent study), visit, and treatment by visit interaction as fixed effects, with 
continuous baseline ppFEV1 from parent study, continuous baseline SwCl from parent study and 
comparator group (IVA comparator versus TEZ/IVA comparator) as covariates. 
The repeated-measures analysis will be based on the restricted maximum likelihood method 
assuming an unstructured covariance structure to model the within-subject errors. The 
denominator degrees of freedom will be based on the method proposed by Kenward-Roger6. If 
the model fails to converge due to the unstructured covariance assumption, a compound 
symmetry covariance structure will be used to model the within-subject errors. In the MMRM 
approach, assuming that the data are missing at random, no imputation of missing data will be 
performed. 
The number of subjects, least-squares means (LS means) for absolute change from baseline at 
scheduled visits within each treatment group along with the corresponding standard error (SE), 
and 95% confidence interval (CI) will be presented. The LS means (±SE) for absolute change 
from baseline at each visit will also be plotted by treatment groups. For display purpose, the 
estimates and corresponding 95% CI obtained from both the parent study MMRM and OLS Part 
A will be summarized in a single summary table. 
The main analysis will be conducted with the clinic spirometry data only. In addition, the 
descriptive statistics for raw values and absolute changes from baseline in ppFEV1 by treatment 
group and visit will be presented for the OL efficacy period for Part A in OL-FAS for Part A. 
Absolute change from baseline in SwCl 
Analysis of this PD variable will be based on the same MMRM to the analysis of the absolute 
change from baseline in ppFEV1. A descriptive summary of raw values and absolute changes 
from baseline will also be presented. 
Absolute change from baseline in Weight, BMI and BMI Z-score (for subjects ≤20 years of age 
at parent study baseline) 
Analysis of these variables will be based on the same MMRM to the analysis of the absolute 
change from baseline in ppFEV1. A descriptive summary of raw values and absolute changes 
from baseline will also be presented. 
Absolute change from baseline in CFQ-R respiratory domain score 


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Analysis of this variable will be based on the same MMRM to the analysis of the absolute 
change from baseline in ppFEV1. A descriptive summary of raw values and absolute changes 
from baseline will also be presented. 
The analysis will include pooled CFQ-R RD score assessed at clinic and at home. An additional 
analysis may be performed to include only the clinic assessed CFQ-R RD score, if the home 
assessed data are assessed to be inconsistent with the clinic assessed data. 
9.3.2.1 
Sensitivity and Supportive Analysis of Secondary Endpoints 
No sensitivity or supportive analysis is planned for the secondary endpoints. 
9.3.2.2 
Subgroup Analysis 
Subgroup analysis of absolute change from baseline in ppFEV1 will be performed in a manner 
similar to that of the primary analysis of absolute change from baseline in ppFEV1 for the 
following subgroup: 
• Comparator group (TEZ/IVA comparator, IVA comparator) 
A similar MMRM used for the primary analysis will be used for the subgroup analysis, where 
the covariate of comparator group (TEZ/IVA comparator, IVA comparator) from the MMRM 
will be removed. The adjusted means with 2-sided 95% confidence intervals will be provided. 
Note that the proposed subgroup analysis will be implemented only if there are at least 20 
subjects in each treatment group. Due to potential small sample size, the results from above 
mentioned subgroup analysis, especially the comparison between two comparator groups, should 
be interpreted with caution. 
 
9.3.3 
Analysis of Additional Efficacy Variables 
9.3.3.1 
Additional Spirometry Variables 
Summary statistics for raw values and for changes from parent study baseline of the following 
spirometry measurements during the OL efficacy period for Part A within OL-FAS for Part A 
will be presented at each visit: 
• FEV1: 
o Absolute change from parent study baseline in FEV1 (L) 
o Relative change from parent study baseline in FEV1 (%) 
o Relative change from parent study baseline in percent predicted FEV1 (%) 
• FVC: 
o Absolute change from parent study baseline in FVC (L) 
o Relative change from parent study baseline in FVC (%) 
o Absolute change from parent study baseline in percent predicted FVC (percentage points) 
o Relative change from parent study baseline in percent predicted FVC (%) 
• FEF25-75%: 
o Absolute change from parent study baseline in FEF25-75% (L/sec) 


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o Relative change from parent study baseline in FEF25-75% (%) 
o Absolute change from parent study baseline in percent predicted FEF25-75% (percentage 
points) 
o Relative change from parent study baseline in percent predicted FEF25-75% (%) 
• FEV1/FVC: 
o Absolute change from parent study baseline in FEV1/FVC 
o Relative change from parent study baseline in FEV1/FVC (%) 
o Absolute change from parent study baseline in percent predicted FEV1 / FVC 
o Relative change from parent study baseline in percent predicted FEV1 / FVC (%) 
9.4 
Safety Analysis 
The primary objective of the study is the evaluation of long-term safety and tolerability of TC. 
All safety analyses will be based on the TE Period for Part A in the OLS for subjects in the OL- 
SS for Part A. The overall long-term safety profile of study drug will be assessed in terms of the 
following safety and tolerability endpoints: 
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values 
• ECGs 
• Vital signs 
• Pulse oximetry 
The TC safety baseline will be used to calculate change from baseline for continuous safety 
endpoints. 
Only descriptive analysis of safety will be performed, and no statistical testing will be 
performed. 
9.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pre-treatment AEs, treatment-emergent AEs 
(TEAEs), or post-treatment AEs, defined as follows: 
Pre-treatment AE: any AE that occurred prior to the start of the TE Period for Part A in the 
OLS. For subjects who enroll in another qualified Vertex study before completing this study and 
resume participation in this study, AEs that started during participation in another qualified 
Vertex study and are ongoing at the time of Returning Visit will be flagged as pre-treatment AE. 
TEAE: any AE that worsened (either in severity or seriousness) or newly developed during the 
TE Period for Part A in the OLS 
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was newly 
developed after the TE period for Part A in the OLS 
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment start date in the OLS, the AEs will be 


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classified as TEAEs. Details for imputing missing or partial start dates of adverse events are 
described in Section 12.3. 
An overview of all TEAEs for the OL-SS for Part A will be summarized for overall (“Any 
ELX/TEZ/IVA”) and include the following categories: 
• Number of TEAEs (total number of TEAEs only) 
• Subjects with any TEAEs 
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation 
• Subjects with TEAEs leading to study drug interruption 
• Subjects with Grade 3/4 TEAEs 
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAE leading to death 
The frequency counts and percentages as well as the exposure adjusted event rate will be 
presented for the above overview table. The exposure adjusted event rate will not be presented 
for strongest relationship and maximum severity categories. 
The following summary tables of TEAEs will be presented for overall: 
• All TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• Related TEAEs 
• Grade 3/4 TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• TEAEs leading to death 
• Serious TEAEs 
• Related serious TEAEs 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentages of subjects, subjects with multiple occurrences of the same adverse event or a 
continuing adverse event will be counted once, and only the maximum severity level will be 
presented in the severity summaries, and the strongest relationship level in the relationship 


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summaries. Missing severity levels will not be included in the Grade 3/4 TEAE summaries; 
missing relationship will be considered as related and included in the related TEAE and related 
serious TEAE summaries. 
Additional summary table will be presented for TEAEs overall in number and percentage of 
subjects. 
• All TEAEs by PT 
All AEs, including pre-treatment AEs, TEAEs, and post-treatment AEs, will be presented in an 
individual subject data listing based on the OL All Subjects Set. In addition, separate listings 
containing individual subject adverse event data for TEAEs leading to treatment discontinuation, 
TEAEs leading to treatment interruption, Grade 3/4 TEAEs, SAEs and AEs leading to death will 
be provided, with a flag indicating the TEAE status for SAEs and deaths. 
9.4.2 
Clinical Laboratory Assessments 
For the treatment-emergent laboratory assessments, the observed values and change from 
baseline values of the continuous hematology, coagulation, and chemistry results will be 
summarized in SI units for overall (“Any ELX/TEZ/IVA”) at each visit during the TE period for 
Part A for the OLS. 
The number and percentage of subjects with test values meeting at least 1 threshold analysis 
criterion event during the TE period for Part A for the OL-SS for Part A will be summarized for 
overall (“Any ELX/TEZ/IVA”). The threshold analysis criterion shift from baseline will also be 
summarized for selected laboratory parameters. The threshold analysis criteria are provided in 
Section 12.4. 
Results of positive urine/serum pregnancy test will be listed in individual subject data listings 
only. For positive serum pregnancy listing, subjects with serum HCG which are abnormally high 
will be selected. 
In addition, a listing containing individual subject hematology, chemistry, coagulation and 
urinalysis values will be provided. This listing will include data from both scheduled and 
unscheduled visits. 
9.4.3 
Electrocardiogram 
For the following ECG measurements during the TE period for Part A for OL-SS for Part A, a 
summary of observed values and change from baseline values will be provided for overall (“Any 
ELX/TEZ/IVA”) at each visit (in ms): RR interval, PR interval, QT interval, QTcF(QT 
corrected for HR), QRS duration, and Heart Rate (beats per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period for Part A for OL-SS for Part A will be summarized for overall (“Any 
ELX/TEZ/IVA”). The threshold analysis criteria are provided in Section 12.4. 
9.4.4 
Vital Signs 
For the vital signs measurements during the TE period for Part A for OL-SS for Part A, the 
observed values and change from baseline values will be summarized for overall (“Any 
ELX/TEZ/IVA”) at each visit. The following vital signs parameters will be summarized: systolic 
and diastolic blood pressure (mm Hg), body temperature (C), pulse rate (beats per minute), and 
respiratory rate (breaths per minute). 


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The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period for Part A for OL-SS for Part A will be summarized for overall (“Any 
ELX/TEZ/IVA”). The threshold analysis criteria are provided in Section 12.4. 
 
9.4.5 
Pulse Oximetry 
 
For the percent of oxygen saturation measurements using pulse oximetry during the TE period 
for Part A for OL-SS for Part A, a summary of observed values and change from baseline values 
will be provided for overall (“Any ELX/TEZ/IVA”) at each visit. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
Period for Part A for OL-SS for Part A will be summarized for overall (“Any ELX/TEZ/IVA”). 
9.4.6 
Physical Examination 
No tables/figures/listings will be provided for PE data. 
9.4.7 
Ophthalmology Examination 
Ophthalmology examination results will be provided in a data listing. 
9.5 
Safety Supportive Analysis 
9.5.1 
Adverse Events of Special Interest 
For this study, elevated transaminases events and rash events, as determined by MedDRA 
Preferred Terms in Appendix F, are considered as adverse events of special interest. 
For treatment-emergent elevated transaminases events and rash events, the following categories 
will be summarized for overall (“Any ELX/TEZ/IVA”): 
• Subjects with events 
• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 
• Subjects with serious events 
• Subjects with related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event (with the first dose date of TC in the OLS as the reference while 
calculating time-to-onset) 
In addition, for treatment-emergent rash events, the above categories will be summarized for the 
following subgroups: 
• Sex (male, female) 
• Female subjects with concomitant hormonal therapy (Yes, No) 


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9.6 
Exploratory Analysis 
Analyses related to the exploratory endpoints of changes in inflammatory mediators and changes 
in microbiology analysis from baseline will be discussed in a separate document. 
9.6.1 
Analysis of absolute change from baseline in CFQ-R non-respiratory 
domain score 
Analysis of these domains will be based on an MMRM similar to the analysis of the absolute 
change from baseline in ppFEV1. The mean plot will not be produced for these domains. 
 
10 
Interim and DMC Analyses 
 
10.1 
Interim Analysis 
As mentioned in the protocol, IA for study 110 may take place at any time during the study at the 
discretion of the sponsor. 
10.2 
DMC Analysis 
An independent data monitoring committee (IDMC) was formed before initiation of study 110. 
The IDMC’s objectives and operational details are described in the IDMC charter. The IDMC 
will conduct regular planned safety reviews of study data as outlined in the IDMC Charter and 
IDMC Analysis Plan. 


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11 
REFERENCES 
 
1 Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 
2 Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
3 Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
4 Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of life 
for children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45. 
5 Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life measure for 
children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32. 
6 Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 


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12 
APPENDICES 
 
12.1 
Analysis Visit Windows for Safety and Efficacy Assessments 
 
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3,4,5 
Spirometry 
Parent study baseline 
-- 
≤1 corresponding to the first 
Weight, Height and BMI (and 
dose date of parent study 
the corresponding z-score)6 
OL Day 15 
15 
(1, 22] 
OL Week 4 
29 
(22, 43] 
OL Week 8 
57 
(43, 85] 
OL Week 16 
113 
(85, 141] 
OL Week 24 
169 
(141, 211] 
OL Week 36 
253 
(211, 295] 
OL Week 48 
337 
(295, 379] 
OL Week 60 
421 
(379, 463] 
OL Week 72 
505 
(463, 547] 
OL Week 84 
589 
(547, 631] 
OL Week 96 
673 
(631, 687] 
OL Safety Follow-up 
Not applicable 
>687 
Sweat Chloride 
Parent study baseline 
-- 
1 corresponding to the first 
dose date of parent study 
OL Day 15 
15 
(1, 22] 
OL Week 4 
29 
(22, 43] 
OL Week 8 
57 
(43, 113] 
OL Week 24 
169 
(113, 253] 
OL Week 48 
337 
(253, 421] 
OL Week 72 
505 
(421, 589] 
OL Week 96 
673 
(589, 687] 
CFQ-R 
Parent study baseline 
-- 
1 corresponding to the first 
dose date of parent study 
OL Week 4 
29 
(1, 43] 
OL Week 8 
57 
(43, 113] 
OL Week 24 
169 
(113, 253] 
OL Week 48 
337 
(253, 421] 
OL Week 72 
505 
(421, 589] 
OL Week 96 
673 
(589, 687] 
OL Safety Follow-up 
Not applicable 
>687 


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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3,4,5 
Hematology 
Serum Chemistry 
Vital Signs 
TC safety baseline 
OL Day 15 
OL Week 4 
OL Week 8 
OL Week 16 
OL Week 24 
OL Week 36 
OL Week 48 
OL Week 60 
OL Week 72 
OL Week 84 
OL Week 96 
OL Safety Follow-up 
1 
15 
29 
57 
113 
169 
253 
337 
421 
505 
589 
673 
Not applicable 
defined in section 8.1 
[1, 22] where day 1 is 
postdose measurement 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 211] 
(211, 295] 
(295, 379] 
(379, 463] 
(463, 547] 
(547, 631] 
(631, 687] 
Use nominal visit 
Standard 12-lead ECG 
TC safety baseline 
OL Day 15 
OL Week 4 
OL Week 8 
OL Week 24 
OL Week 48 
OL Week 72 
OL Week 96 
OL Safety Follow-up 
1 
15 
29 
57 
169 
337 
505 
673 
Not applicable 
defined in section 8.1 
[1, 22] where day 1 is 
postdose measurement 
(22, 43] 
(43, 113] 
(113, 253] 
(253, 421] 
(421, 589] 
(589, 687] 
Use nominal visit 
Coagulation 
TC safety baseline 
OL Week 4 
OL Week 24 
OL Week 48 
OL Week 72 
OL Week 96 
OL Safety Follow-up 
1 
29 
169 
337 
505 
673 
Not applicable 
defined in section 8.1 
[1, 99] where day 1 is 
postdose measurement 
(99, 253] 
(253, 421] 
(421, 589] 
(589, 687] 
Use nominal visit 
Notes: 
1 Visit name for analysis purpose is used to report data in tables and figures. 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
1. If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
2. If there is more than 1 numerical measurement available within a visit window, use the following rules: 
i. The measurement closest to the target day will be used; or 
ii. If there are multiple measurements with the same closest distance from the target day, the latest 
measurement will be used. For multiple measurements on the same day, unscheduled measurements will 
be treated as later than scheduled measurement. 
3 For measurement collected on the date of first dose of study drug in Treatment Period, if it cannot be determined 
whether the measurement is before or after the first dose: 
a. 
Scheduled measurement will be treated as pre-dose observation. 
b. Unscheduled measurement will be treated as post-dose observation. 


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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3,4,5 
4 For safety Assessment, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a 
subject doesn’t have a nominal Safety Follow-up visit but has an ETT visit with study day >687, then the ETT visit 
will be mapped into Safety Follow-up analysis visit. 
5 For efficacy assessment, if a subject has nominal safety follow up visit with study day >687, then nominal Safety 
Follow-up visit will be mapped to Safety Follow-up visit; else if subject doesn’t have a nominal safety follow-up 
visit with study day > 687 but has an ETT visit with study day >687, then the ETT visit will be mapped into Safety 
Follow-up analysis visit; else if there are multiple assessments with >687 then select the earliest record. 
6Weight will also be used in the threshold analysis in which the TC safety baseline will be used to calculate change. 
Derived Variables: 
1. Age (in years) at first dose date and post-baseline visit (for demographics, listing and the calculation of 
[percent] predicted spirometry variables): 
Obtain the age at informed consent in “yy, mm” format (e.g., 24 years, 6 months) in parent study from the Vital 
Signs (VS) page at the Screening Visit in parent study, and add 0.5 month to convert to days. 
Obtain the informed consent date in parent study. 
Then age (in years) at first dose or post-baseline visit = [(first dose date or post-baseline visit date – informed 
consent date in parent study) in days + age at informed consent (in days) in parent study]/365.25. 
2. Age (in months) at first dose date and post-baseline visit (for use in calculation of BMI and weight z-score): 
Obtain the age at informed consent in “yy, mm” format (e.g., 24 years, 6 months) in parent study from the VS 
page at the Screening Visit in the parent study. 
Obtain the informed consent date in parent study. 
Then age (in months) at first dose or post-baseline visit = integer part of {[(age at informed consent (in months) 
in parent study + 0.5 + diff(first dose date or post-baseline visit date, informed consent date) in months in parent 
study]} + 0.5. 
3. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date. 
If the last dose date of study drug is not available and there is no data to indicate that the subject discontinued 
treatment, the data cutoff date will be used instead. 
If the subject discontinued treatment and the last dose date is missing or partial date is reported, the last dose 
date will be imputed based on, in descending order priority, the Early Treatment Termination (ETT) visit date, 
last visit date before the Safety Follow-up, or the last study drug administration date from EX SDTM domain, 
as appropriate. The imputation algorithm will ensure the imputed last dose date does not exceed the study 
participation end date. 
4. Electrocardiogram: 
Baseline is defined in Section 8.1. If multiple ECG measurements are obtained on the same calendar day during 
the TE period for Part A, 
o 
For summary purpose, the average value will be used as the ECG on that day; 
o 
For threshold analysis purpose, all ECG values will be used 


 
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12.2 
Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rnles for missing or partial medication stait/stop dates are defined below: 
1. Missing or paiiial medication strut date: 
a. If only DAY is missing, use the first day of the month. 
b. If DAY and Month are both missing, use the first day of the year. 
c. IfDAY, Month and Year ai·e all missing, use a date before the first dose date (to 
impute in practical, use the pai·ent study info1med consent date). 
2. Missing or paiiial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. IfDAY, Month and yeai·are all missing, assign 'continuing' status to stop date (to 
impute in practical, use the end of study date). 
In summary, the prior, concomitant, or post categorization of a medication is described below. 
 Table 12-2 
Prior, Concomitant, and Post Categorization of a Medication 
 
Medication Stop Date 
 
 
 
 
Medication Start Date 
< First Dose Date of 
Study Drug 
First Dose Date 
and 
End Date of TE 
Period for Pait A 
> End Date of TE 
Period for Pait A 
< First dose date of study drug 
c::: First dose date and 
End date of TE period for Pait 
p 
PC 
C 
PCA 
CA 
A 
> End date of TE period for Pait 
A 
A 
P: Prior; C: Concomitant; A: Post 
 
Same imputation mle will be implemented for missing and/or pa1iial dates of non- 
phaimacological treatment/procedure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12.3 
Imputation Rules for Missing AE dates 
Imputation rules for missing or partial AE start date are defined below. If the imputed AE start 
date is before the informed consent date for the OLS, the AE start date will be imputed using the 
informed consent date. Ongoing events from the parent study will follow the imputation rule 
described in the SAP for parent study. 
• If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the OLS or AE 
end date is missing, then 
▪ if AE start Year and Month are equal to the Year and Month of the first dose 
date of OLS, then impute the AE start Day as the Day of the first dose date of 
OLS; 
▪ else impute the AE start day as 1. 
o else impute the AE start day as 1. 
• If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the OLS or AE 
end date is missing, then 
▪ if AE start Year is equal to the Year of the first dose date of OLS, then impute 
the AE start Month and Day as the Month and Day of the first dose date of 
OLS; 
▪ else impute the AE start Month as January and Day as 1. 
o else impute the AE start Month as January and Day as 1. 
• If Year of AE start date is missing: 
If the Year of AE start date is missing or AE start date is completely missing then query site. 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the first dose date 
of the OLS. 
o else impute the AE start date as the informed consent date. 
Compare the imputed AE start date with TE period to determine whether the AE is pre-treatment 
AE, TEAE or post-treatment AE. 
 
Imputation rules for partial AE end date are defined below: 
If partial end date, then impute as min (the last day of the month, data cut-off for IA, end of 
study) if day is missing, or min (Dec, data cut-off for IA, end of study) if month is missing. 


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12.4 
Criteria for Threshold Analysis 
 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN – ≤3×ULN 
>3× – ≤ 5×ULN 
FDA DILI Guidance 
Jul 2009. 
>5× – ≤ 8×ULN 
>8× – ≤ 20×ULN 
>20.0×ULN 
AST 
>ULN – ≤3×ULN 
>3× – ≤ 5×ULN 
FDA DILI Guidance 
Jul 2009. 
>5× – ≤ 8×ULN 
>8× – ≤ 20×ULN 
>20.0×ULN 
ALT or AST 
(ALT >ULN – ≤ 3×ULN) or (AST >ULN – ≤ 3×ULN) FDA DILI Guidance 
(ALT >3× – ≤5×ULN) or (AST >3× – ≤5×ULN) 
(ALT >5× – ≤8×ULN) or (AST >5× – ≤8×ULN) 
(ALT >8× – ≤20×ULN) or (AST >8× – ≤ 20×ULN) 
ALT >20×ULN or AST >20×ULN 
Alkaline Phosphatase 
>ULN – ≤ 1.5×ULN 
>1.5× – ≤ 2.5×ULN 
FDA DILI Guidance 
Jul 2009. 
>2.5× – ≤ 5×ULN 
>5× – ≤ 20×ULN 
>20×ULN 
Total Bilirubin 
>ULN – ≤ 1.5×ULN 
>1.5× – ≤ 2×ULN 
FDA DILI Guidance 
Jul 2009. 
>2× – ≤3×ULN 
>3× – ≤10×ULN 
>10×ULN 
Direct Bilirubin 
>ULN – ≤1.5×ULN 
>1.5× – ≤2×ULN 
FDA DILI Guidance 
Jul 2009. 
>2× – ≤3×ULN 
>3× – ≤10×ULN 
>10×ULN 
Indirect Bilirubin 
>ULN – ≤1.5×ULN 
>1.5× – ≤2×ULN 
FDA DILI Guidance 
Jul 2009. 
>2× – ≤3×ULN 
>3× – ≤10×ULN 
>10×ULN 
ALT and Total Bilirubin 
ALT >3×ULN and TBILI >2×ULN 
FDA DILI Guidance 
Jul 2009. 
AST and Total Bilirubin 
AST >3×ULN and TBILI >2×ULN 
FDA DILI Guidance 
Jul 2009. 
 


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


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


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


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


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12.5 
Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. Details of the 
derivation of the GLI equation are provided in the article by Quanjer et al. (2012). 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 Regression 
Equation and Lookup Tables (Version 7 April 2013). Global Lung Function Initiative. [online] 
Available at: https://www.ers-education.org/lr/show-details/?idP=138978 [Accessed September 
09, 2020]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] Available 
at: https://www.ers-education.org/lr/show-details/?idP=138979 [Accessed September 09, 2020]. 
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: https://www.ers-education.org/lr/show-details/?idP=138988 
[Accessed September 09, 2020]. 
Data handling rule for spirometry is as follows: 
 
• Input age and height with at least 2 decimal place 
• For subjects whose age at informed consent of the parent study is >21 years, height at 
screening of the parent study is used regardless if height is collected at other study visits. 
For subjects whose age at informed consent of the parent study is <=21 years, height 
collected at the respective visit is used, and if the height at the respective visit is not 
available, the last non-missing record will be used. 
• For race, map CRF race – “black or AA” to “black”, map all other CRF races (except 
white) to “other”; multiple checks for race in CRF are also mapped to “other”; white is a 
reference race in the equations and assumes 0 values for all race coefficients in the GLI 
equations.