Clinical trial NCT03525574
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2018-10-09; Completion date: 2023-01-09
Enrollment: 507 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study evaluates the long-term safety and tolerability of VX-445 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are homozygous or heterozygous for the F508del mutation

Detailed description:

Arms: arm 1: Treatment Period: Participants received ELX 200 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hrs (q12h) in the treatment period for 192 weeks.

Extension Period: Participants from certain countries participated in extension period and continued to receive ELX 200 mg qd /TEZ 100 mg qd/IVA 150 mg q12h in the extension 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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1 
TITLE PAGE 
 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
 
 
 
 
Clinical Study Protocol 
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 Homozygous or Heterozygous for 
the F508del Mutation 
Vertex Study Number: VX17-445-105 
IND Number: 132547 
EudraCT Number: 2018-000185-11 
 
Date of Protocol: 23 June 2020 (Version 5.0) 
 
 
 
 
Vertex Phannaceuticals Incorporated 
50 No1ihem Avenue 
Boston, MA 02210-1862, USA 
 
 
 
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. 


Protocol VX17-445-105, Version 5.0 
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Vertex Pharmaceuticals Incorporated 
Confidential Information 
Protocol VX17-445-105, Version 5.0 
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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 
Homozygous or Heterozygous for the F508del Mutation 
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 in triple combination 
(TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis 
(CF) who are homozygous or heterozygous for the F508del mutation 
Secondary Objectives 
• To evaluate the long-term efficacy of VX-445 in TC with TEZ and IVA 
• To evaluate the pharmacodynamics (PD) of VX-445 in TC with TEZ and IVA 
 
Endpoints 
Primary Endpoint 
Safety and tolerability of long-term treatment with VX-445 in TC with TEZ and 
IVA based on adverse events (AEs), clinical laboratory values, ECGs, vital signs, 
and pulse oximetry. 
Secondary Endpoints 
• 
Absolute change from baseline in percent predicted forced expiratory volume 
in 1 second (ppFEV1) 
• 
Absolute change in sweat chloride (SwCl) 
• 
Number of pulmonary exacerbations (PEx) 
• 
Time-to-first PEx 
• 
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 score 
Additional Endpoints 
• 
Absolute change in CFQ-R non-respiratory domain scores 
• 
Changes in inflammatory mediators 
• 
Changes in microbiology analysis 
 
Number of Subjects Subjects who complete the last Treatment Period visit in a parent study and meet 
eligibility criteria are eligible to enroll. Parent studies are Phase 3 Vertex studies 
investigating VX-445 in combination with TEZ and IVA. These include, but are 
not limited to, Study VX17-445-102 (Study 445-102) and Study VX17-445-103 
(Study 445-103). Over 400 subjects are expected to enroll in this study. 
 
Study Population Male and female subjects with CF who are 12 years of age or older who are 
homozygous or heterozygous for the F508del mutation 


Protocol VXl 7-445-105, Version 5.0 
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Confidential Info1mation 
 
 
 
lnvestigational Drug 
Study drug refers to VX-445/TEZ/IVA. 
Study drugs will be orally administered as 2 fixed-dose combination (FDC) 
film-coated tablets (VX-445/TEZ/IV A) in the moming and as 1 film-coated IVA 
tablet in the evening. 
Active substance: VX-445, TEZ (tezacaftor; VX-661), and IVA (ivacaftor; 
VX-770) 
Activity: CFTR coITector, CFTR co1Tector, and CFTR potentiator (increased 
c1- secretion) 
Strength: 100-mg VX-445/50 mg TEZ/75 mg IVA FDC tablet 
 
Active substance: IVA (ivacaftor; VX-770) 
Activity: CFTR potentiator (increased c1- secretion) 
Strength: 150-mg tablet 
 
Study Duration The total study dmation is approximately 196 weeks (from the first dose of study 
dmg in this study), including a 192-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 a parent study and meet eligibility criteria. 
All subjects will receive the TC ofVX-445/TEZ/IV A at the same dose level as that 
evaluated in Study 445-102 and Study 445-103. 
 
 
Day 1 
Week 192 
Week 196 
 
IVA: ivacaftor; TEZ: tezacaftor 
Notes: Parent studies are Phase 3 Vertex studies investigating VX-445 in combination with 
TEZ and IVA. These include, but are not limited to, VXl 7-445-102 (Study 445-102) 
and Study VXl 7-445-103 (Study 445-103). The timing of the Day 1 Visit, relative to 
the last scheduled visit of the parent study, is detailed in Section 9.1.1. Note that the 
figure is not drawn to scale. 
 
 
Assessments Safety: AEs, clinical laborato1y assessments, ECGs, vital signs, pulse oximetty,I 
physical examinations, and ophthalmologic examinations (for subjects <18 years 
of age on the date of info1med consent in the parent study) 
Efficacy: Spirometty, documentation of events related to health outcomes 
(e.g., PEx), height (for21 years of age on the date of informed consent in the 
parent study only), weight, and CFQ-R 
PD: SwCl 
PK: VX-445, TEZ, Ml-TEZ, and IVA plasma concentrations 
Exploratory: Inflammato1y mediators, blood biomarker samples, and sputum 
samples 
Treatment Period 
VX-445/TEZ/IVA 
Parent 
Studies 
Safety 
Follow-up 


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Statistical Analyses The primary objective of the study is the evaluation of the long-term safety and 
tolerability of VX-445 in TC with 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, and in general will be performed for the pooled 
population. 
The secondary objective of the study is the evaluation of long-term efficacy of 
VX-445 in TC with TEZ/IVA, as assessed by spirometry, documentation of 
events related to health outcomes (e.g., PEx), height (for ≤21 years of age on the 
date of informed consent in the parent study only), weight, and CFQ-R. Methods 
of efficacy analyses will be similar as those used in parent studies. 
 
Interim Analyses Interim analyses may take place at any time during the study at the discretion of 
the sponsor. In the event that a parent study is still ongoing, a limited Vertex team 
may be unblinded to the treatment assignments in the parent studies 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 regular safety 
reviews of study data as outlined in the IDMC charter. 


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3 
SCHEDULE OF ASSESSMENTS 
Table 3-1 provides the schedule of assessments during the study. 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 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 
VX17-445-105: Treatment Period and Safety Follow-up Visit 
 
Treatment Period 
Weeks 12, 20, 
28, 32, 40, 44, 
52, 56, 64, 68, 
76, 80, 88, 92, 
100, 104, 112, 
116, 124, 128, 
Weeks 60, 
Safety 
136, 140, 148, 
72, 84, 
Follow-up 
Weeks 4, 
152, 160, 164, 
108, 120, 
Visit 28 
8, 16, 24, 
172, 176, 184, 
132, 156, 
(± 7) Days 
Day 15 
36 
188 
Week 48 
168, 180 
Week 96 
Week 144 
Week 192 
ETT 
After Last 
Event/Assessmenta 
Day 1d 
(± 3 Days) 
(± 5 Days) 
(± 5 Days) 
(± 5 Days) 
(± 5 Days) 
(± 5 Days) 
(± 5 Days) 
(± 5 Days) 
Visitb 
Dosec 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone contact 
Xk 
ICF and assent 
(when applicable) 
Xe 
Inclusion and 
exclusion criteria 
confirmation 
X 
CFQ-Rf 
X 
Weeks 4, 
8, 24 
X 
Weeks 72, 
120, 168 
X 
X 
X 
X 
X 
Weight and heightg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
All assessments will be performed before dosing 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 will be on the same day as the last scheduled visit of the parent study. Subjects will NOT have to repeat any Day 1 assessments that were 
specified to be performed at the last scheduled visit in the parent study. Subjects who were enrolled and remained clinically stable but had Day 1 study drug administration 
procedures delayed by no more than 7 days for reasons not related to their clinical status will have to repeat the safety (Section 11.7) and spirometry (Section 11.6.1) 
assessments that were specified to be performed at the Day 1 Visit before receiving their first dose of study drug. Subjects who have not received the first dose of study drug 
within 7 days of the last dose of study drug in the parent study, or subjects who had Day 1 study drug administration procedures delayed by no more than 7 days for a reason 
related to clinical status, will have to repeat all Day 1 assessments (Section 9.1.1). 
e 
The ICF and, when appropriate, assent form, can be signed up to 28 days prior to Day 1. 
f 
The CFQ-R must be completed before the start of any other assessments scheduled at relevant visits (Section 11.6.3). 
g  Weight and height will be measured with shoes off. Height will be collected only for subjects ≤21 years of age (on the date of informed consent in the parent study). For 
subjects >21 years of age, the height value obtained from the Screening Visit in the parent study will be used for BMI calculations. Refer to Section 11.6.2 for additional 
information. 


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Table 3-1 
VX17-445-105: Treatment Period and Safety Follow-up Visit 
 
Event/Assessmenta 
Treatment Period 
ETT 
Visitb 
Safety 
Follow-up 
Visit 28 
(± 7) Days 
After Last 
Dosec 
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, 
100, 104, 112, 
116, 124, 128, 
136, 140, 148, 
152, 160, 164, 
172, 176, 184, 
188 
(± 5 Days) 
Week 48 
(± 5 Days) 
Weeks 60, 
72, 84, 
108, 120, 
132, 156, 
168, 180 
(± 5 Days) 
Week 96 
(± 5 Days) 
Week 144 
(± 5 Days) 
Week 192 
(± 5 Days) 
Ophthalmologic 
examinationh 
X 
(± 4 weeks) 
X 
(± 4 weeks) 
X 
(± 4 weeks) 
Xi 
(- 4 weeks) 
Xi 
(- 4 weeks) 
Xi 
(- 4 weeks) 
Complete physical 
examinationj 
X 
X 
X 
X 
X 
Pregnancy testk 
Urine 
Urine 
Urine 
Urine 
Urine 
Serum 
Urine 
Serum 
Serum 
Serum 
FSHl 
Standard 12-lead 
ECGm 
X 
X 
Weeks 8, 
24 
X 
Weeks 72, 
120, 168 
X 
X 
X 
X 
X 
Vital signsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometryo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
h 
Ophthalmologic examinations will only be conducted on subjects <18 years of age (on the date of informed consent in the parent study) by a licensed ophthalmologist or 
optometrist. These examinations should be completed within the specified 4-week window around the relevant study visit. 
i 
A single ophthalmologic examination is required at completion of study participation (defined in Section 9.1.5) for subjects <18 years of age (on the date of informed consent 
in the parent study) except for those subjects who have withdrawn consent or assent. Ophthalmologic examinations are only required if the cumulative drug exposure (in the 
parent study and current study) is at least 12 weeks since the last study ophthalmologic examination (Section 11.7.6). 
j 
Subjects will have a complete physical examination as defined in Section 11.7.3. Symptom-directed physical examinations will occur at any time during the study if deemed 
necessary by the investigator. 
k 
Pregnancy tests will be performed for all female subjects of childbearing potential as described in Section 11.7.2. At assessment time points when telephone contact takes the 
place of a clinic visit, a urine pregnancy test will be performed with a home kit provided by the study site. Results will be reported to the site by telephone. 
l 
Blood samples for FSH will be measured as outlined in Section 11.7.2. 
m 
All standard 12-lead ECGs will be performed after the subject has been at rest for at least 5 minutes. ECGs will be collected before dosing (as applicable). 
n 
Vital signs and pulse oximetry will be collected before dosing and after the subject has been at rest for at least 5 minutes (Section 11.7.3 and Section 11.7.4). 
o 
Spirometry assessments must be performed before study drug dosing (Section 9.6.1) and should be performed pre-bronchodilator (Section 11.6.1) at approximately the same 
time each visit. 


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Table 3-1 
VX17-445-105: Treatment Period and Safety Follow-up Visit 
 
Event/Assessmenta 
Treatment Period 
ETT 
Visitb 
Safety 
Follow-up 
Visit 28 
(± 7) Days 
After Last 
Dosec 
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, 
100, 104, 112, 
116, 124, 128, 
136, 140, 148, 
152, 160, 164, 
172, 176, 184, 
188 
(± 5 Days) 
Week 48 
(± 5 Days) 
Weeks 60, 
72, 84, 
108, 120, 
132, 156, 
168, 180 
(± 5 Days) 
Week 96 
(± 5 Days) 
Week 144 
(± 5 Days) 
Week 192 
(± 5 Days) 
SwClp 
X 
X 
Weeks 4, 
8, 16, 24 
Weeks 72, 
120, 168 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
Week 24 
X 
Weeks 72, 
120, 168 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingq 
Week 4 
Inflammatory 
mediator samples 
X 
Week 24 
X 
X 
X 
Blood biomarker 
samples 
X 
Week 24 
X 
X 
X 
Sputum samplesr 
X 
Week 24 
X 
Study drug count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
p 
Sweat chloride collection will occur before study drug dosing (Section 11.4). At each time point, 2 samples will be collected, 1 from each arm (left and right). 
q 
PK samples will be collected predose on Week 4 only as described in Section 11.3.1. 
r 
Sputum will be collected from subjects who can produce a sample spontaneously. The sputum sample will be processed for microbiology analysis and sputum biomarkers as 
described in Section 11.5.3. 


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Table 3-1 
VX17-445-105: Treatment Period and Safety Follow-up Visit 
 
Event/Assessmenta 
Treatment Period 
ETT 
Visitb 
Safety 
Follow-up 
Visit 28 
(± 7) Days 
After Last 
Dosec 
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, 
100, 104, 112, 
116, 124, 128, 
136, 140, 148, 
152, 160, 164, 
172, 176, 184, 
188 
(± 5 Days) 
Week 48 
(± 5 Days) 
Weeks 60, 
72, 84, 
108, 120, 
132, 156, 
168, 180 
(± 5 Days) 
Week 96 
(± 5 Days) 
Week 144 
(± 5 Days) 
Week 192 
(± 5 Days) 
Study drug dosings 
Day 1 through evening before Week 192 Visit 
Other events 
related to 
outcomet,u 
Continuous from signing of the ICF through completion of study participation 
Medications 
reviewu 
Continuous from signing of the ICF through completion of study participation 
Treatments and 
procedures reviewu 
Continuous from signing of the ICF through completion of study participation 
AEs and SAEsu, v 
Continuous from signing of the ICF through completion of study participation 
AE: adverse event; BMI: body mass index; CF: cystic fibrosis; CFQ-R: CF Questionnaire-Revised; ETT: Early Termination of Treatment; FSH: follicle stimulating hormone; 
GPS: Global Patient Safety; ICF: informed consent form; PEx: pulmonary exacerbation(s); PK: pharmacokinetic; SAE: serious adverse event; SwCl: sweat chloride 
 
 
 
s 
The study drug regimen should be administered as outlined in Section 9.6.1. On days of scheduled visits, refer to Section 9.6.1 for the timing of dosing relative to the 
assessments. The final dose of study drug will be administered the evening before the Week 192 Visit. 
t 
Other events related to outcome include assessments relating to PEx, administration of antibiotic therapy for sinopulmonary signs/symptoms, and hospitalizations for CF 
(Section 11.6.4). 
u 
Completion of study participation is defined in Section 9.1.5. 
v 
SAEs that occur after completion of study participation and are considered related to study drug will be reported to Vertex GPS within 24 hours as described in 
Section 13.1.2.2. 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................. 1 
2 
Protocol Synopsis .................................................................................................................... 3 
3 
Schedule of Assessments ......................................................................................................... 6 
4 
Table of Contents .................................................................................................................. 11 
List of Tables ............................................................................................................................. 15 
List of Figures ........................................................................................................................... 15 
List of Abbreviations ................................................................................................................. 16 
5 
Introduction ........................................................................................................................... 18 
5.1 
Background ...................................................................................................................... 18 
5.2 
Rationale for the Present Study ........................................................................................ 18 
6 
Study Objectives .................................................................................................................... 19 
6.1 
Primary Objective ............................................................................................................ 19 
6.2 
Secondary Objectives....................................................................................................... 19 
7 
Study Endpoints .................................................................................................................... 19 
7.1 
Primary Endpoint ............................................................................................................. 19 
7.2 
Secondary Endpoints ....................................................................................................... 19 
7.3 
Additional Endpoints ....................................................................................................... 19 
8 
Study Population ................................................................................................................... 19 
8.1 
Inclusion Criteria ............................................................................................................. 20 
8.2 
Exclusion Criteria ............................................................................................................ 20 
9 
Study Implementation .......................................................................................................... 20 
9.1 
Study Design .................................................................................................................... 20 
9.1.1 
Treatment Period ...................................................................................................... 21 
9.1.2 
Safety Follow-up ...................................................................................................... 21 
9.1.3 
Early Termination of Treatment .............................................................................. 22 
9.1.4 
Lost to Follow-up ..................................................................................................... 22 
9.1.5 
Completion of Study Participation ........................................................................... 22 
9.1.6 
Independent Data Monitoring Committee ............................................................... 22 
9.2 
Method of Assigning Subjects to Treatment Groups ....................................................... 23 
9.3 
Rationale for Study Design and Study Drug Regimens ................................................... 23 
9.3.1 
Study Design ............................................................................................................ 23 
9.3.2 
Study Drug Dose and Duration ................................................................................ 23 
9.3.3 
Rationale for Study Assessments ............................................................................. 23 
9.4 
Study Restrictions ............................................................................................................ 23 
9.4.1 
Prohibited Medications ............................................................................................ 23 
9.5 
Prior and Concomitant Medications ................................................................................ 24 
9.6 
Administration ................................................................................................................. 25 
9.6.1 
Dosing ...................................................................................................................... 25 
9.6.2 
Missed Doses ........................................................................................................... 25 
9.7 
Dose Modification for Toxicity ....................................................................................... 26 
9.8 
Study Drug Interruption and Stopping Rules .................................................................. 26 
9.8.1 
Liver Function Tests ................................................................................................ 26 
9.8.2 
Rash ......................................................................................................................... 27 


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9.9 
Removal of Subjects ........................................................................................................ 27 
9.10 Replacement of Subjects .................................................................................................. 28 
10 Study Drug Information and Management ........................................................................ 28 
10.1 Preparation and Dispensing ............................................................................................. 28 
10.2 Packaging and Labeling ................................................................................................... 28 
10.3 Study Drug Supply, Storage, and Handling ..................................................................... 28 
10.4 Drug Accountability ......................................................................................................... 28 
10.5 Disposal, Return, or Retention of Unused Drug .............................................................. 29 
10.6 Compliance ...................................................................................................................... 29 
10.7 Blinding and Unblinding .................................................................................................. 29 
11 Assessments ............................................................................................................................ 29 
11.1 Timing of Assessments .................................................................................................... 29 
11.2 Subject and Disease Characteristics ................................................................................. 29 
11.3 Pharmacokinetics ............................................................................................................. 30 
11.3.1 
Blood Sampling ....................................................................................................... 30 
11.3.2 
Processing and Handling of Pharmacokinetic Samples ........................................... 30 
11.3.3 
Bioanalysis ............................................................................................................... 30 
11.4 Pharmacodynamics: Sweat Chloride ............................................................................... 30 
11.5 Exploratory Assessments ................................................................................................. 30 
11.5.1 
Inflammatory Mediators .......................................................................................... 31 
11.5.2 
Other Blood Biomarkers .......................................................................................... 31 
11.5.3 
Microbiology and Other Sputum Biomarkers .......................................................... 31 
11.6 Efficacy ............................................................................................................................ 31 
11.6.1 
Spirometry ................................................................................................................ 31 
11.6.2 
Height and Weight ................................................................................................... 32 
11.6.3 
Cystic Fibrosis Questionnaire-Revised .................................................................... 32 
11.6.4 
Other Events Related to Outcome ............................................................................ 33 
11.6.4.1 Antibiotic Therapy for Sinopulmonary Sign/Symptoms ................................... 33 
11.6.4.2 Hospitalization for CF ....................................................................................... 33 
11.7 Safety ............................................................................................................................... 33 
11.7.1 
Adverse Events ........................................................................................................ 34 
11.7.2 
Clinical Laboratory Assessments ............................................................................. 34 
11.7.3 
Physical Examinations and Vital Signs ................................................................... 36 
11.7.4 
Pulse Oximetry ........................................................................................................ 36 
11.7.5 
Electrocardiograms .................................................................................................. 36 
11.7.6 
Ophthalmologic Examination .................................................................................. 37 
11.7.7 
Contraception and Pregnancy .................................................................................. 37 
11.7.7.1 Contraception .................................................................................................... 37 
11.7.7.2 Pregnancy .......................................................................................................... 39 
12 Statistical and Analytical Plans ........................................................................................... 39 
12.1 Sample Size and Power .................................................................................................... 39 
12.2 Analysis Sets .................................................................................................................... 39 
12.3 Statistical Analysis ........................................................................................................... 40 
12.3.1 
General Considerations ............................................................................................ 40 
12.3.2 
Background Characteristics ..................................................................................... 41 
12.3.2.1 Subject Disposition ............................................................................................ 41 


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12.3.2.2 Demographics and Baseline Characteristics ..................................................... 41 
12.3.2.3 Prior and Concomitant Medications ................................................................. 41 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 42 
12.3.2.5 Important Protocol Deviations ......................................................................... 42 
12.3.3 
Efficacy and Pharmacodynamic Analyses .............................................................. 42 
12.3.3.1 Analysis of Primary Variables .......................................................................... 42 
12.3.3.2 Analysis of Secondary Variables ...................................................................... 42 
12.3.3.3 Analysis of Other Variables ............................................................................. 43 
12.3.3.4 Multiplicity Adjustment ................................................................................... 43 
12.3.4 
Safety Analysis ....................................................................................................... 44 
12.3.4.1 Adverse Events ................................................................................................. 44 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 45 
12.3.4.3 Electrocardiogram............................................................................................. 45 
12.3.4.4 Vital Signs ........................................................................................................ 45 
12.3.4.5 Pulse Oximetry ................................................................................................. 46 
12.3.4.6 Physical Examination ....................................................................................... 46 
12.3.4.7 Other Safety Analyses ...................................................................................... 46 
12.3.5 
Other Analyses ........................................................................................................ 46 
12.3.6 
Interim and IDMC Analyses ................................................................................... 46 
12.3.6.1 Interim Analysis ............................................................................................... 46 
12.3.6.2 IDMC Analysis ................................................................................................. 46 
12.4 Clinical Pharmacology Analysis ..................................................................................... 46 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ............................ 47 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 47 
13.1.1 
Adverse Events ....................................................................................................... 47 
13.1.1.1 Definition of an Adverse Event ........................................................................ 47 
13.1.1.2 Clinically Significant Assessments .................................................................. 47 
13.1.1.3 Documentation of Adverse Events ................................................................... 47 
13.1.1.4 Adverse Event Severity .................................................................................... 48 
13.1.1.5 Adverse Event Causality .................................................................................. 48 
13.1.1.6 Study Drug Action Taken ................................................................................. 49 
13.1.1.7 Adverse Event Outcome ................................................................................... 49 
13.1.1.8 Treatment Given ............................................................................................... 50 
13.1.2 
Serious Adverse Events .......................................................................................... 50 
13.1.2.1 Definition of a Serious Adverse Event ............................................................. 50 
13.1.2.2 Documentation of Serious Adverse Events ...................................................... 51 
13.1.2.3 Reporting Serious Adverse Events ................................................................... 51 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ....................................... 51 
13.2 Administrative Requirements ......................................................................................... 52 
13.2.1 
Ethical Considerations ............................................................................................ 52 
13.2.2 
Subject Information and Informed Consent ............................................................ 52 
13.2.3 
Investigator Compliance ......................................................................................... 52 
13.2.4 
Access to Records ................................................................................................... 52 
13.2.5 
Subject Privacy ....................................................................................................... 52 
13.2.6 
Record Retention .................................................................................................... 53 


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13.2.7 
Study Termination.................................................................................................... 53 
13.2.8 
End of Study ............................................................................................................ 53 
13.3 Data Quality Assurance ................................................................................................... 54 
13.4 Monitoring ....................................................................................................................... 54 
13.5 Electronic Data Capture ................................................................................................... 54 
13.6 Publications and Clinical Study Report ........................................................................... 55 
13.6.1 
Publication of Study Results .................................................................................... 55 
13.6.2 
Clinical Study Report ............................................................................................... 55 
14 References .............................................................................................................................. 56 
15 Protocol Signature Pages ...................................................................................................... 57 
15.1 Sponsor Signature Page ................................................................................................... 57 
15.2 Investigator Signature Page ............................................................................................. 58 


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List of Tables 
Table 3-1 
VX17-445-105: Treatment Period and Safety Follow-up Visit .............................. 7 
Table 9-1 
Prohibited Medications ......................................................................................... 24 
Table 10-1 
Study Drug: Strength/Dosing Form/Route ............................................................ 28 
Table 11-1 
Safety Laboratory Test Panels ............................................................................... 35 
Table 11-2 
Acceptable Methods of Contraception .................................................................. 38 
Table 13-1 
Grading of AE Severity ......................................................................................... 48 
Table 13-2 
Classifications for AE Causality ........................................................................... 49 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE ................... 49 
Table 13-4 
Classifications for Outcome of an AE ................................................................... 50 
List of Figures 
Figure 9-1 
VX17-445-105 Study Design ................................................................................ 21 


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List of Abbreviations 
 
Abbreviation 
Term 
 
AE 
adverse event 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BMI 
body mass index 
CBC 
complete blood count 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
CI 
confidence interval 
Cl− 
chloride ion 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRP 
C-reactive protein 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ETT 
Early Termination of Treatment 
EU 
European Union 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
F/F 
homozygous for F508del 
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 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IgG 
immunoglobulin G 
IL-8 
interleukin-8 
IPD 
important protocol deviation 
IRB 
institutional review board 
IV 
intravenous 
IVA 
ivacaftor 


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Abbreviation 
Term 
LUM 
lumacaftor 
M1-TEZ 
metabolite of TEZ 
MAA 
Marketing Authorization Application 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
n 
number of subjects 
NDA 
New Drug Application 
OATP1B1 
organic anion transporting polypeptide 1B1 
OATP1B3 
organic anion transporting polypeptide 1B3 
OL-FAS 
Open-label Full Analysis Set 
OL-SS 
Open-label Safety Set 
P 
probability 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PEx 
pulmonary exacerbation(s) 
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 
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 reactions 
SwCl 
sweat chloride 
TC 
triple combination 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
WBC 
white blood cell 


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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. At present, there is no cure. CF affects approximately 
70,000 individuals worldwide1 (approximately 30,000 in the US1,2 and 39,000 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. The CFTR protein is an epithelial chloride channel that aids in regulating salt and 
water absorption and secretion and pH balance in sweat glands and multiple organs, including 
the lungs, pancreas, and other gastrointestinal organs. Despite progress in the treatment of CF 
with antibiotics and mucolytics, the predicted median age of survival for a person with CF is 
approximately 40 years.2,6 Progressive loss of lung function is the leading cause of mortality.7 
More effective treatments are needed for CF. 
The most common disease-causing CFTR mutation, F508del, accounts for 70% of the identified 
alleles in people with CF8, and approximately 40% of people with CF are homozygous for 
F508del (F/F). 2, 3, 8 
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 functional CFTR at the cell 
surface. Potentiators increase the channel open probability of the CFTR protein delivered to the 
cell surface to enhance ion transport. Depending on the amount of residual CFTR channel 
activity in the membrane, and the pathophysiology of that activity (reflecting the CFTR genotype 
of the patient and possibly other factors), both approaches may be required. 
The therapeutic activity of CFTR correctors and potentiators has been established with products 
that were developed by Vertex and approved for the treatment of CF: ivacaftor (IVA) 
monotherapy (Kalydeco®), and lumacaftor (LUM) in combination with IVA (Orkambi®). 
Kalydeco and Orkambi are approved to treat CF in patients with specific CFTR genotypes. A 
second corrector/potentiator combination, tezacaftor (TEZ)/IVA (Symdeko®) is approved in 
certain countries. 
VX-445 is a next-generation CFTR corrector being developed for administration in triple 
combination (TC) with TEZ/IVA for the treatment of CF. 
5.2 
Rationale for the Present Study 
Subjects who complete the last Treatment Period visit in a parent study and meet eligibility are 
eligible to enroll. Parent studies are Phase 3 Vertex studies investigating VX-445 in combination 
with TEZ and IVA. These include, but are not limited to, Study VX17-445-102 (Study 445-102) 
and Study VX17-445-103 (Study 445-103). This study will provide data on the long-term safety, 
efficacy, and durability of VX-445 in TC with TEZ and IVA in subjects with CF who are 
homozygous or heterozygous for the F508del mutation. 
Based on the data from nonclinical and clinical studies of VX-445, TEZ, and IVA to date and the 
current unmet medical need for new CF treatments, the development of this treatment offers 
potential benefit for CF patients. 


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6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the long-term safety and tolerability of VX-445 in TC with TEZ and IVA in subjects 
with CF who are homozygous or heterozygous for the F508del mutation 
6.2 
Secondary Objectives 
• To evaluate the long-term efficacy of VX-445 in TC with TEZ and IVA 
• To evaluate the pharmacodynamics (PD) of VX-445 in TC with TEZ and IVA 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Safety and tolerability of long-term treatment with VX-445 in TC with TEZ and IVA based on 
adverse events (AEs), clinical laboratory values, ECGs, vital signs, and pulse oximetry. 
7.2 
Secondary Endpoints 
• Absolute change from baseline in ppFEV1 
• Absolute change in sweat chloride (SwCl) 
• Number of pulmonary exacerbations (PEx) 
• Time-to-first PEx 
• 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 score 
7.3 
Additional Endpoints 
• Absolute change in CFQ-R non-respiratory domain scores 
• Changes in inflammatory mediators 
• Changes in microbiology analysis 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
In the criteria below, “parent study” is defined as a Phase 3 Vertex study investigating VX-445 
in TC with TEZ and IVA. This includes, but is not limited to, Study 445-102 and Study 445-103. 


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8.1 
Inclusion Criteria 
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
informed consent form (ICF), and, when appropriate, an assent form. 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Did not withdraw consent from a parent study. 
4. Meets at least 1 of the following criteria: 
• Completed study drug treatment in a parent study. 
• Had study drug interruption(s) in a parent study, but completed study visits up to the last 
scheduled visit of the Treatment Period of a parent study. 
5. Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) through 
completion of study participation. 
8.2 
Exclusion Criteria 
1. History of any comorbidity that, in the opinion of the investigator, might confound the results 
of the study or pose an additional risk in administering study drug to the subject. 
2. Pregnant and nursing females. Females of childbearing potential 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 a parent study that would pose an additional risk to the subject 
in the opinion of the investigator. (e.g., subjects with a history of allergy or hypersensitivity 
to the study drug.) 
4. Current participation in an investigational drug trial (other than a parent study). Participation 
in a noninterventional study (including observational studies, registry studies, and studies 
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 a parent study and meet eligibility criteria (see Section 8). A schematic of the 
study design is shown in Figure 9-1. 
All subjects will receive a TC of VX-445/TEZ/IVA at the same dose level as that evaluated in 
Study 445-102 and Study 445-103. 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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Figure 9-1 
VX17-445-105 Study Design 
 
 
 
-+ 
 
 
 
 
 
Dayl 
Week 192 
Week 196 
 
IVA: ivacaftor; TEZ: tezacaftor 
Notes: Parent studies are Phase 3 Ve1tex studies investigating VX-445 in combination with TEZ and IVA. These 
include, but are not limited to, VXl7-445-102 (Study 445-102) and Study VXl7-445-103 (Study 445-103). The 
timing of the Day 1 Visit, relative to the last scheduled visit of the parent study, is detailed in Section 9.1.1. 
Note that the figure is not drawn to scale. 
 
9.1.1 
Treatment Period 
Treatment Period assessments are listed in Table 3-1. 
The ICF and, when appropriate, assent fo1m, can be signed up to 28 days prior to Day 1. After 
obtaining info1med consent and confoming eligibility, subjects will receive the first dose of 
study drng on Day 1. Administration details are provided in Section 9.6. 
The Day 1 Visit of this study will be on the same day as the last scheduled visit of the parent 
study. Subjects will NOT have to repeat any Day 1 assessments that were specified to be 
perfonned at the last scheduled visit in the parent study. 
Subjects who were emolled and remained clinically stable but had Day 1 study diug 
adininistration procedures delayed by no more than 7 days for reasons not related to their clinical 
status will have to repeat the safety (Section 11.7) and spirometiy (Section 11.6.1) assessments 
that were specified to be perfo1med at the Day 1 Visit before receiving their first dose of study 
diug. 
Subjects who have not received the first dose of study diug within 7 days of the last dose of 
study diug in the parent study, or subjects who had Day 1 study di11g adininish'ation procedures 
delayed by no more than 7 days for a reason related to clinical status, will have to repeat all 
Day 1 assessments. 
9.1.2 
Safety Follow-up 
The Safety Follow-up Visit is scheduled to occur 28 (± 7) days after the last dose of study diug. 
The Safety Follow-up Visit assessments are listed in Table 3-1. 
The Safety Follow-up Visit is required for all subjects. However, subjects who transition within 
28 days of the last dose of study di11g to either a commercially available or managed access 
program-supplied next-generation co1Tector TC regimen, or to another qualified Vertex study, 
will complete the Week 192 Visit (or the ETT Visit, if the ti·ansition occurs before the Week 192 
Visit). In these cases, the Week 192 Visit (or the ETT Visit) will replace the Safety Follow-up 
Treatment Period 
VX-445/IEZ/IVA 
Parent Studies 
Safety 
Follow-up 


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Visit. For subjects who complete an ETT Visit 3 weeks or later following the last dose of study 
drug, the ETT Visit will replace the Safety Follow-up Visit (Section 9.1.3). 
9.1.3 
Early Termination of Treatment 
If a subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as 
soon as possible after the decision to discontinue treatment. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, 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 192 Visit replace the Safety Follow- 
up Visit (Section 9.1.2), the ETT Visit or the Week 192 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 reviews of safety data (Section 12.3.6.2). Procedural details of the IDMC 
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. 


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9.2 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study. Randomization is not required because all subjects will be treated 
identically in a single cohort. 
9.3 
Rationale for Study Design and Study Drug Regimens 
9.3.1 
Study Design 
This Phase 3 study will enroll subjects who completed the last Treatment Period visit in a parent 
study of TC 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 
subjects with CF who are aged 12 years and older and homozygous or heterozygous for the 
F508del mutation, as per the populations enrolled in the parent studies. 
9.3.2 
Study Drug Dose and Duration 
All subjects will receive a TC of VX-445/TEZ/IVA at the same dosage as that in the parent 
studies (including, but not limited to, Study 445-102 and Study 445-103). 
The overall treatment duration will be 192 weeks. This duration will be used to evaluate the 
long-term efficacy of VX-445/TEZ/IVA beyond 96 weeks of treatment. 
9.3.3 
Rationale for Study Assessments 
All safety assessments are standard parameters for clinical studies in drug development. The PD 
and efficacy parameters being evaluated (e.g., SwCl, spirometry, PEx, anthropometric 
measurements, and patient-reported outcomes) are widely accepted and generally recognized as 
reliable, accurate, and relevant to the study of patients in CF. These parameters were routinely 
measured in the parent studies, as well as the registration studies of IVA (Kalydeco) or 
LUM/IVA combination therapy (Orkambi). 
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 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. 


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Table 9-1 
Prohibited Medications 
Timing of Restriction 
Start of 
Medication 
Restriction 
End of Restriction 
Rationale 
Moderate and strong 
CYP3A inducers 
 
 
 
Moderate and strong 
CYP3A inhibitors 
(except ciprofloxacin)a 
 
 
CFTR modulators 
(investigational or 
approved), except for 
study drug in the 
parent studies and this 
study 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
through completion 
of study 
participation 
 
None allowed 
through completion 
of study 
participation 
 
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. 
 
 
 
 
These agents may confound the results of 
this study. 
 
 
CYP: cytochrome P450; 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. 


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• 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 11.6.1. 
9.6 
Administration 
9.6.1 
Dosing 
Study drug will be administered orally. Additional information is provided in the Pharmacy 
Manual. 
Study drug will 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 will be taken 
at approximately the same time (± 2 hours) each day. 
3. The date, amount taken, and time of study drug administration, including whether food was 
taken with each dose, will be recorded for the 2 doses before pharmacokinetic (PK) sample 
collection (Week 4) and the dose received on the morning of PK sample collection (Week 4). 
4. 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. 
5. If a subject’s scheduled visit is to occur in the afternoon, the following guidelines must 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. 
6. 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. 


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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 
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. 
9.8.1 
Liver Function Tests 
The central laboratory will notify the medical monitor of ALT or 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 


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transaminases return to baseline or are ≤2 × ULN, whichever is higher. Regardless of the 
duration of interruption, the medical monitor should be notified prior to resumption of study 
drug. Upon resumption of study drug, transaminases and bilirubin should be assessed weekly for 
4 weeks. If a protocol-defined transaminase elevation interruption threshold recurs within 
4 weeks of rechallenge with the study drug (with confirmation of the initial elevation by repeat 
testing within 48 to 72 hours), then the study drug must be permanently discontinued, regardless 
of the presumed etiology. 
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. 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 a serious 
adverse event (SAE). Investigators should consider additional evaluation including laboratory 
testing (e.g., complete blood count [CBC] with differential, LFTs), 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. If a subject 
has been withdrawn from study drug treatment, the subject will continue to be followed, 
provided that the subject has not withdrawn consent (and assent, as applicable). 
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 11.7.7.2) 
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 the subject withdraws consent or assent for the study, no further assessments will be 
performed. Vertex may retain and continue using the study data and samples after the study is 
over, and may use the samples and information in the development of the study compound, and 
for other drugs and diagnostics, in publications and presentations, and for education purposes. If 
the subject withdraws from the study, the study data and samples collected will remain part of 
the study. A subject will not be able to request the withdrawal of his/her information from the 
study data. A subject may request destruction of the samples collected from him/her during the 
study as long as those samples can be identified as his/her samples. 
If evaluation of efficacy data from the parent studies suggests that the VX-445/TEZ/IVA 
treatment does not provide clinically meaningful benefit for subsets of subjects included in these 


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studies, 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 tablet containing 150 mg IVA (Table 10-1). 
Blister cards must be stored under conditions noted in the Pharmacy Manual. The investigator, or 
an authorized designee (e.g., a licensed pharmacist), will ensure that all investigational product is 
stored in a secured area, under recommended storage conditions, and in accordance with 
applicable regulatory requirements. To ensure adequate records, all study drugs will be 
accounted for via the drug accountability forms as instructed by Vertex. 
Table 10-1 
Study Drug: Strength/Dosing Form/Route 
Drug Name, Dosing Form, Route 
Strength 
VX-445/TEZ/IVA, FDC tablets, 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/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, as outlined in Section 11.4 and Section 11.6.1, 
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., 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 the present study 
until the database lock of the parent study. 
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments is shown in Section 3 and Table 3-1. 
11.2 
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. 


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11.3 
Pharmacokinetics 
11.3.1 
Blood Sampling 
At the Week 4 Visit only, predose blood samples will be collected to determine plasma 
concentrations of VX-445, TEZ, M1-TEZ, and IVA. These samples may also be used to evaluate 
metabolites of VX-445 and IVA, and additional TEZ metabolites, for further evaluation of the 
bioanalytical method, or for exploratory analyses that provide information on the metabolic 
pathways used by or affected by VX-445, which may not be included in the CSR. 
The Week 4 predose samples must be collected within 60 minutes before dosing; all efforts 
should be made to obtain the PK samples during this specified window. Samples collected 
outside of the window will be considered protocol deviations. 
A record of study drug administration that coincides with the Week 4 PK blood draw will be 
collected as described in Section 9.6. The collection date and exact time that each PK blood 
sample is drawn will also be recorded. 
Samples from the PK sampling will be kept frozen by Vertex or its designee until all analyses 
have been completed and then disposed of according to Vertex or designee standard operating 
procedures. 
11.3.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be provided in the PK Sample Handling 
Guidelines. 
11.3.3 
Bioanalysis 
Samples will be analyzed using validated analytical methods in compliance with Vertex or 
designee standard operating procedures. A description of the assays and validation data will be 
provided in separate reports. 
11.4 
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. Individual SwCl test results will not be disclosed to the study sites. 
Specific instructions for the collection, handling, processing, and shipping of SwCl samples to 
the central laboratory will be provided separately. 
Subjects (and their parents/caregivers/companions) should not be informed of their study-related 
SwCl results until Vertex has determined that the study has completed (i.e., CSR finalization), 
regardless of whether the subject has prematurely discontinued treatment. 
11.5 
Exploratory Assessments 
These data will be used for internal exploratory purposes and may or may not be included in the 
CSR. Detailed procedures for the collection of blood samples and additional procedures for 
processing and handling samples will be provided in a separate document. 


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11.5.1 
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 (CRP), immunoglobulin G (IgG), white blood cell (WBC, 
leukocyte) count, and interleukin-8 (IL-8). Specific instructions for the collection, processing, 
storage, and shipment of inflammatory mediator samples will be provided in the Laboratory 
Manual. 
11.5.2 
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 PK, PD, treatment response, AEs, and 
various disease manifestations of CF. 
Specific instructions for the collection, processing, storage, and shipment of blood biomarker 
samples will be provided in the Laboratory Manual. 
11.5.3 
Microbiology and Other Sputum Biomarkers 
Sputum samples will be collected at the time points noted 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. 
Specific instructions for the collection, processing, aliquoting, storage, and shipment of sputum 
samples will be provided in the Laboratory Manual. 
11.6 
Efficacy 
11.6.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines9 and according to the additional guidelines that follow. 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
• withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 
• 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 


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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 forgot to withhold his/her dose of bronchodilator, 
spirometry should be performed post-bronchodilator and all subsequent spirometric 
measurements in this study (according to the schedule of assessments detailed 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. 
Subjects (and their parents/caregivers/companions) should not be informed of their study-related 
spirometry results until Vertex has determined that the study has completed (i.e., CSR 
finalization), regardless of whether the subject has prematurely discontinued treatment. 
The measured spirometric values listed below will be converted to percent predicted values using 
the standard equations of Global Lung Function Initiative.10 
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 
• Forced expiratory flow, midexpiratory phase (FEF25%-75%) (L/s) 
11.6.2 
Height and Weight 
Height and weight will be measured and with shoes off. For subjects whose date of informed 
consent occurs after their 21st birthday, height will not be collected in this study. For subjects 
whose date of informed consent occurs on or before their 21st birthday, height will be collected 
through the first visit after the subject’s 21st birthday and does not need to be collected at future 
visits. 
11.6.3 
Cystic Fibrosis Questionnaire-Revised 
The questionnaires provide information about demographics; general quality of life, school, 
work, or daily activities; and symptom difficulties (pertaining to CF). 
Subjects will be asked to complete the CFQ-R in their native language, if validated translations 
are available.11, 12 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.13, 14 
The CFQ-R will be completed before any other assessments are performed at that visit. 


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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 who are 14 years of age and older will complete 
the Adolescent and Adult version. 
11.6.4 
Other Events Related to Outcome 
11.6.4.1 
Antibiotic Therapy for Sinopulmonary Sign/Symptoms 
New or changed antibiotic therapy (IV, inhaled, or oral) for the following sinopulmonary 
signs/symptoms will be determined and documented at visits as indicated in Table 3-1: 
• Change in sputum 
• New or increased hemoptysis 
• Increased cough 
• Increased dyspnea 
• Malaise, fatigue, or lethargy 
• Temperature above 38°C (equivalent to approximately 100.4°F) 
• Anorexia or weight loss 
• Sinus pain or tenderness 
• Change in sinus discharge 
• Change in physical examination (PE) of the chest 
• Decrease in pulmonary function by 10% 
• Radiographic changes indicative of pulmonary infection 
For this study, PEx is defined as a new or change in antibiotic therapy (IV, inhaled, or oral) 
for any 4 or more of the above signs/symptoms. This definition is based on the definition of a 
PEx used in previous clinical studies, including IVA clinical studies.15,16 
It is recommended that the study drug not be interrupted during a PEx unless, in the opinion of 
the investigator, it would be in the best interest of the subject. 
11.6.4.2 
Hospitalization for CF 
Subjects will be queried about planned and unplanned hospitalizations lasting ≥24 hours that 
occurred during the study. The dates of hospitalizations and the reasons for hospitalizations will 
be documented. 
For any hospitalization (planned and unplanned), the procedures for safety reporting should also 
be followed. 
11.7 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, and clinical evaluation of 
vital signs, ECGs, PEs, and pulse oximetry. 


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Ophthalmologic examinations will be conducted only on subjects who are <18 years of age on 
the date of informed consent in the parent study. 
11.7.1 
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 case report form 
(CRF) completion guidelines for investigators as well as training will be provided. 
11.7.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, with the exception of the urine 
pregnancy tests. As described below, urine pregnancy tests will either be analyzed by the site or 
at home using a home kit. On Day 1, blood samples will be collected before the first dose of the 
study drug. 
Laboratory test results that are abnormal and considered clinically significant will be reported as 
AEs. 
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 Studies 
 
Activated partial thromboplastin time 
Prothrombin time 
Prothrombin time International 
Normalized Ratio 
Leukocyte esterase 
Nitrite 
Urobilinogen 
Urine protein 
pH 
Urine blood 
Specific gravity 
Urine ketones 
Urine bilirubin 
Urine glucose 
Note: Haptoglobin may be analyzed if judged to be clinically appropriate by the investigator. 
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be performed, and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and 
casts. 
b 
If blood urea nitrogen cannot be collected, urea may be substituted. 
 
Pregnancy (β-human chorionic gonadotropin) Tests for Females of Childbearing Potential: Any 
female subject who does not meet the criteria for non-childbearing potential is considered to be 
of childbearing potential and must have a pregnancy test every 4 weeks. A definition of 
non-childbearing potential is provided in Section 11.7.7.1. 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. The urine pregnancy test on 
Day 1 must be negative before the first dose of study drug. Additional pregnancy tests may be 
required according to local regulations and/or requirements. 


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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 
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. 
11.7.3 
Physical Examinations and Vital Signs 
A PE 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 PEs and symptom-directed vital sign 
assessments will occur at any time if deemed necessary by the investigator or healthcare 
provider. 
A complete PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, 
nose, and throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; 
musculoskeletal; and neurological. Breast, anorectal, and genital examinations will be performed 
when medically indicated. Any clinically significant abnormal findings in PEs will be reported as 
AEs. 
Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse rate, and 
respiration rate. These will be assessed before dosing and following at least a 5-minute rest. 
11.7.4 
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. At visits when 
study drug is taken at the site, pulse oximetry will be collected before study drug dosing. 
11.7.5 
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. Subjects will be instructed to rest for at least 5 minutes before 
having an ECG performed. 
The ECG traces will be manually read at the study site. A printout of the ECG traces will be 
made for safety review by the investigator and maintained with source documentation. Clinically 
significant ECG abnormalities occurring during the study through completion of study 
participation will be recorded as AEs. 
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 


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or an absolute QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be 
performed approximately 2 to 4 minutes apart to confirm the original measurement. If either of 
the QTcF values from these repeated ECGs remains above the threshold value (>60 msec from 
baseline or ≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement. Further 
details pertaining to ECGs will be provided to sites in the ECG Manual. 
11.7.6 
Ophthalmologic Examination 
Ophthalmologic examinations will be conducted only for subjects who are <18 years of age on 
the date of informed consent in the parent study. The examination does not need to be completed 
if there is documentation of bilateral lens removal for the subject. 
All examinations will be conducted by a licensed ophthalmologist or optometrist and will 
include 
• measurement of best-corrected distance visual acuity of each eye; and 
• pharmacologically dilated examination of the lens with a slit lamp. 
Subjects <18 years of age on the date of informed consent in the parent study are required to 
complete ophthalmologic examinations as indicated in Table 3-1. These examinations should be 
completed within the specified 4-week window around the relevant study visit. A single 
ophthalmologic examination is required at completion of study participation (defined in 
Section 9.1.5); this examination should be completed within 4 weeks prior to the last study visit 
except for subjects who have withdrawn consent or assent. Ophthalmologic examinations are 
only required if the cumulative study drug exposure (in the parent study and current study) is at 
least 12 weeks since the last study ophthalmologic examination. 
Any clinically significant abnormal findings will be reported as AEs. 
11.7.7 
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. 
11.7.7.1 
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). 


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• 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 
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 
 
 
 
Vasectomy performed at least 6 months previously, 
Male Subjects and Their 
Female (Non-study) 
Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
with a documented negative postvasectomy semen 
analysis for sperm 
Bilateral tubal occlusion (e.g., ligation) performed 
at least 6 months previously 
Yes 
Yes 
 
Yes 
Yes 
 
Male or female condom with or without spermicidea 
Yes 
Yes 
Female barrier contraception (such as diaphragm, 
cervical cap, or sponge) with spermicide 
Continuous use of an intrauterine device for at least 
90 days before the first dose of study drug 
Oral, implanted, injected, or vaginal hormonal 
contraceptives, if successfully used for at least 
60 days before the first dose of study drug 
Yes 
Yes 
 
Yes 
Yes 
 
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. 
• 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. 


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• For male subjects with a female partner of childbearing potential, the couple should not plan 
to become pregnant during the study or within 90 days after the last dose of study drug, with 
the exception of couples who plan to become pregnant by artificial insemination using sperm 
banked by the male subject before the first dose of study drug or sperm from another source. 
11.7.7.2 
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 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 (CPAP), both of which will be 
finalized before the clinical data lock for the study. 
12.1 
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 VX-445 in TC with TEZ/IVA. This is an open-label study 
that will enroll subjects who complete the last Treatment Period visit in a parent study and meet 
eligibility criteria. Parent studies are Phase 3 Vertex studies investigating VX-445 in 
combination with TEZ and IVA. These include, but are not limited to, Study 445-102 and 
Study 445-103. 
Over 400 subjects are expected to enroll in this open-label study of 196 weeks’ duration. With 
this number of subjects exposed to VX-445/TEZ/IVA treatment, AEs by Preferred Term (PT) 
that occur with a frequency of >1% will be ruled out with 95% confidence, when zero events are 
observed in that PT. Further, with over 400 subjects exposed to VX-445/TEZ/IVA treatment for 
at least 24 weeks, the half-width of the 95% CI for estimating the cumulative incidence of PEx of 
CF is less than 6% assuming an observed incidence of 30%. 
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 


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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 
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 in TC with 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, with the only exception of time to first PEx where events in the 
parent study may also be included. 
In general, long-term safety analysis will be performed in a pooled fashion. 


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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 
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 respiratory 
domain. 
Medical history will be summarized by MedDRA System Organ Class (SOC) and PT for the 
OL-FAS. 
No statistical tests will be carried out to evaluate any baseline imbalance between treatment 
groups. 
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 


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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 (in days), defined as the last day of study drug in the open-label 
study minus the first day of study drug in the open-label study plus 1, 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 
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 in TC with TEZ/IVA. 
12.3.3.1 
Analysis of Primary Variables 
Not applicable since efficacy and pharmacodynamics are not primary objectives. 
12.3.3.2 
Analysis of Secondary Variables 
The secondary variables include: 
• Absolute change from baseline in ppFEV1 
One of the secondary efficacy endpoints is the absolute change from baseline 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) for each individual parent study, with the absolute change from 
baseline in ppFEV1 as the dependent variable for visits in the open-label study. 


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The details including sensitivity analyses and supportive analysis will be described in the SAP. 
• Absolute change from baseline in SwCl 
Analysis of this PD variable will be based on an MMRM model similar to the analysis of the 
absolute change from baseline in ppFEV1. 
• Number of PEx 
The analysis of the number of PEx starting from the first dose of TC in the parent/open-label 
study will be performed using a negative binomial regression model for each individual parent 
study, unless otherwise specified. 
• Time-to-first PEx 
Time-to-first PEx is defined as the number of days starting from the first dose of TC in the 
parent/open-label study to the first event of PEx. Note that for patients who were randomized to 
placebo or TEZ/IVA group, the first dose of TC will occur in the open-label study. A subject 
who does not experience an exacerbation prior to the end of the Efficacy Analysis Period in the 
open-label study will be considered censored at the end of the Efficacy Analysis Period. The 
Kaplan-Meier method will be used to produce a graphical presentation of the cumulative 
exacerbation-free survival rate. 
• Absolute change from baseline in BMI 
Analysis of this variable will be based on an MMRM model similar to the analysis of the 
absolute change from baseline in ppFEV1. 
• Absolute change from baseline in BMI z-score 
Analysis of this variable will be based on an MMRM model similar to the analysis of the 
absolute change from baseline in ppFEV1. 
• Absolute change from baseline in body weight 
Analysis for this variable will be based on an MMRM model similar to the analysis of the 
absolute change from baseline in ppFEV1. 
• Absolute change from baseline in CFQ-R respiratory domain score 
Analysis of this variable will be based on an MMRM model similar to the analysis of the 
absolute change from baseline in ppFEV1. 
12.3.3.3 
Analysis of Other Variables 
Other variables include: 
• Absolute change from baseline in CFQ-R non-respiratory domain scores 
Analysis of this variable will be based on an MMRM model similar to the analysis of the 
absolute change from baseline in ppFEV1. 
12.3.3.4 
Multiplicity Adjustment 
Not applicable. 


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12.3.4 
Safety Analysis 
The primary objective of the study is the evaluation of the long-term safety and tolerability of 
VX-445 in TC with 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 adverse events (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 since the end of the TE Period in the parent study 
and 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: 
• 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 


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• Frequently reported TEAEs 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same AE or a 
continuing AE will be counted once, only the maximum severity level will be presented in the 
severity summaries, and the strongest relationship level in the relationship summaries. 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 treatment-emergent 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 treatment-emergent 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 digital ECG interval measurements (in msec): RR, PR, QT, QTc for 
heart rate (HR) interval (QTcF), QRS duration, and HR (beats 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 ECG analyses may be described in the SAP. 
12.3.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each 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), body temperature (°C), pulse rate (beats per minute), 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. 


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Additional vital signs analyses may be described in the SAP. 
12.3.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each 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/listings will be provided for PE data. 
12.3.4.7 
Other Safety Analyses 
Details of other safety analyses will be included in the SAP. 
12.3.5 
Other Analyses 
Other analyses will include: 
• Changes from baseline in inflammatory mediators 
Details of this analysis will be provided in a separate document. 
• Changes from baseline in microbiology analysis 
Details of this analysis will be provided in a separate document. 
12.3.6 
Interim and IDMC Analyses 
12.3.6.1 
Interim Analysis 
Interim analyses may take place at any time at the discretion of the sponsor. In the event that a 
parent study is still ongoing, a limited Vertex team may be unblinded to the treatment 
assignments of the parent studies 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 
IDMC Analysis 
The IDMC (Section 9.1.6) will conduct regular safety reviews of study data as outlined in the 
IDMC charter. 
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. 
12.4 
Clinical Pharmacology Analysis 
For the PK analysis, trough concentrations of VX-445, TEZ, and IVA may be summarized using 
descriptive statistics. Trough concentrations may also be analyzed with prior study PK data using 
nonlinear mixed-effects modeling, as data allow. A detailed description of the planned PK 
analysis will be presented in the CPAP. 


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


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• 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 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
28 September 2017). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” 
In 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 given in the 
CTCAE. The severity of an AE 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 
 
 
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 presented in Table 13-2. 


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Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug. 
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject’s medical record). 
 
 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories shown 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. 
 
 
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 shown in Table 13-4. 


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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 
Not recovered/not 
resolved (continuing) 
Resolution of an AE with residual signs or symptoms 
 
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) 
 
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 in the study 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. 


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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 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent through completion of study participation, 
regardless of causality, will be reported by the investigator to Vertex GPS. In addition, all SAEs 
that occur after completion of study participation and are considered related to study drug(s) will 
be reported to Vertex GPS within 24 hours. 
SAEs will be recorded on the Vertex Organized 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 to Vertex the outcome of the event using the SAE Form. 
13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. 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 questions, contact telephone: +1-617-341-6677 
13.1.2.4 
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/local IEC 
of all unexpected serious adverse drug reactions involving risk to human subjects. 


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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 only 
be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
ICH GCP and all applicable laws and regulations and will be subject to approval by Vertex or its 
designee. 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 


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Confidential Information 
 
 
 
numbers shall be limited to the site and the study physician and shall 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 study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act (HIPAA) and associated regulations an executed HIPAA 
authorization shall be obtained by the site from each subject (or the legal representative of the 
subject) before research activities may begin. Each HIPAA authorization shall comply with all 
HIPAA requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.6 
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, for subjects who have been lost to 
follow-up, the last contact, whichever occurs later, for the latest completing subject in the study. 


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13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
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 study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated, web-based electronic data capture (EDC) application. Vertex 
will have read-only access to site-entered clinical data in the EDC application. 
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by 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 the CRFs, 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. 


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Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
 
 
13.6 
Publications and Clinical Study Report 
13.6.1 
Publication of Study Results 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between Vertex and the investigator and/or the 
investigator’s institution. 
13.6.2 
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 22 March 2018. 
2 
Cystic Fibrosis Foundation. 2014 Patient Registry Annual Data Report. Bethesda, MD: 
2015. 
3 
European Cystic Fibrosis Society. 2013 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: European Cystic Fibrosis Society; 2016. 
4 
United States Department of Health and Human Services. Food and Drug Administration. 
Office of Orphan Products Development. Developing Products for Rare Diseases & 
Conditions. Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default. 
htm. Accessed 19 September 2016. 
5 
European Medicines Agency [Internet]. Committee for Orphan Medicinal Products 
(COMP). Available at: https://www.ema.europa.eu/en/committees/committee-orphan- 
medicinal-products-comp. Accessed 07 December 2018. 
6 
Cystic Fibrosis Trust. UK Cystic Fibrosis Registry: Annual Data Report 2014. Bromley, 
Kent, UK: 2015. 
7 
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10:88. 
8 
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 
01 April 2019. 
9 
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. 
10 
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. 
11 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 
12 
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. 
13 
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. 
14 
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. 
15 
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR 
potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 
2011;365(18):1663-72. 
16 
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 
1994;331(10):637-42. 


Confidential Information 
Vertex Pharmaceuticals lncorporated 
 
 
 
Protocol VX17-445-105, Version 5.0 
Page 57 of58 
15 
15.1 
Protocol#: 
PROTOCOL SIGNATURE PAGES 
Sponsor Signature Page 
VXl7-445-J 05 
Version#: 
5.0 
Version Date: 
23 June 2020 
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 Homozygous or 
Heterozygous for the F508del Mutation 
This Clinical Study Protocol has been reviewed and approved by the sponsor. 


Vertex Pharmaceuticals Incorporated 
Confidential Information 
Protocol VX17-445-105, Version 5.0 
Page 58 of 58 
 
 
 
15.2 
Investigator Signature Page 
 
Protocol #: VX17-445-105 Version #: 
5.0 
Version Date: 
23 June 2020 
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 Homozygous or 
Heterozygous for the F508del Mutation 
 
 
I have read Protocol VX17-445-105, Version 5.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-445, tezacaftor, ivacaftor, and this 
protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
 
Printed Name 
 
 
 
Signature 
Date 


 
Page 1 of8 
 
 
1 
TITLE PAGE 
 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
 
 
 
 
Clinical Study Protocol Addendum 
for Cystic Fibrosis 
 
 
Elexacaftor/Tezacaftor/lvacaftor (VX-445NX-661NX-770) 
 
 
Version and Date of Protocol Addendum: Version 3.0, 29 July 2020 
Replaces Version 2.0, dated 15 May 2020 
 
Vertex Phannaceuticals Incorporated 
50 No1ihem Avenue 
Boston, MA 02210-1862, USA 
 
 
 
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. 
C stic Fibrosis Studies for the Followin 


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


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 3 of8 
Ve1tex Pha1maceuticals Incorporated 
Confidential Info1mation 
 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
 
Protocol Change 
Rationale for Change 
Study Number 
Addendum Ve.-sion 3.0, dated 29 July 2020 
Assessments 
Unscheduled visit(s) will be pennissible at the discretion of the investigator(s) 
or Ve1tex. The unscheduled visit(s) may be conducted at any time during the 
study (including after the protocol defined last study visit) in the event 
assessments specified to be collected at a scheduled visit were not collected 
due to COVID-19. 
To ensure subject safety and/or to facilitate evaluation of 
safety and/or efficacy if assessments are not perfo1med 
per the schedule in the protocol due to COVID-19. 
Implementaion of measures described in addenda versions 1.0 and 2.0, as 
applicable. 
To ensure subject safety and/or to facilitate evaluation of 
safety and/or efficacy while maintaining study integrity 
and the safety of subjects and site personnel. 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 4 of8 
Ve1tex Pha1maceuticals Incorporated 
Confidential Info1mation 
 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
 
Protocol Change 
Rationale for Change 
Study Number 
Addendum Ve.-sion 2.0, dated 15 May 2020 
 
Assessments 
Weight and height/length/stature may be assessed by subjects or their 
caregivers using medical grade scales and stadiometers, as indicated per 
protocol and per local regulation. Sites and subjects will receive training and 
guidance as needed on these devices. 
Subjects or caregivers will provide these measurements to site personnel by 
telephone or video call. Investigators will review results and contact subjects 
for follow-up as needed. All data will continue to be retained in the subject's 
source files. 
To allow for collection of key data to assess safety and/or 
efficacy while maintaining study integrity and the safety 
of subjects and site personnel. 
Addendum 1 allowed for these assessments to be 
pe,formed by qualified personnel conducting the in-home 
visits. Addendum 2 allows for these assessments to be 
pe1formed by subjects or caregivers. 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 5 of8 
Ve1tex Pha1ma.ceuticals Incorporated 
Confidential Info1ma.tion 
 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Consenting of Subjects 
ICFs may be provided electronically or by post mail to subjects (and/or caregivers, as 
indicated per protocol). The subjects and/or caregivers will review the ICF with an 
appropriately qualified member of the investigator's team via.telephone contact or video call. 
After this review, subjects and/or caregivers will consent (or assent, if applicable), and/or 
reconsent verbally and by signing and dating the ICF and returning it to the site via.post mail. 
The signed and dated ICF will then be signed and dated by the investigator. 
Subjects participating in select studies may have the opportunity to enroll in longterm 
extension studies. Informed consent (or assent, if applicable), and/or reconsent for subjects 
(and/or caregivers, as indicated per protocol) may be obtained per the same process described 
above, as applicable. 
To provide alternative methods of 
obtaining reconsent or consent, as 
applicable, while ensuring subject 
safety. 
Study Drug Shipping 
Study drug may be shipped directly from the site to the subject, as applicable, and if pemutted 
by local regulations; subject protected health infonnation will not be released to Vertex. 
Reconciliation, return, and destrnction of study dmg will continue to occur at the clinical site 
as indicated per protocol and in adherence to local regulations. 
To ensure subjects can continue 
treatment with study dmg without 
intem1ption while ensuring their safety. 
To clarify that despite these alternative 
measures, reconciliation, retum, and 
destrnction of study drug will remain as 
indicated per protocol. 
In-home Visits and/or Telephone Contact 
Study visits may be conducted as in-home visits by qualified personnel as requested by 
participating sites on a. per-subject basis. In addition, all subjects may be contacted by site 
personnel by telephone or video call, iiTespective of in-home visits. 
To provide subjects the opportunity to 
continue participation in the clinical 
studies while ensuring their safety by 
nunimizing the risk to COVID-19 
exposure through travel. 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 6 of8 
Ve1tex Pha1ma.ceuticals Incorporated 
Confidential Info1mation 
 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
 
Safety Assessments and Repo11ing 
Safety assessments, as indicated per protocol, may be perfo1med by qualified personnel 
conducting the in-home visits (e.g., personnel from site or qualified health care agency). These 
assessments may include the following, as indicated per protocol, and per local regulation: 
• vital signs 
•  urinalysis 
• pulse oximetiy 
•  blood draws for safety test panels 
• height/length/stature 
(chemistiy, LFT panel, lipid panel, 
• 
weight 
hematology, coagulation). 
• physical examination 
(complete or abbreviated) 
• pregnancy test 
(sernm or urine) 
Blood and/or urine samples for safety assessments are analyzed as indicated per protocol for 
subjects who have in-home visits. 
Blood and/or urine samples for safety assessments may be collected and analyzed at local 
laboratories for subjects who do not have in-home visits, but do not complete the assessment 
at the site. 
In addition, safety assessents will be evaluated by telephone. These assessments may include 
the review of the following: 
• AEs 
• signs and symptoms/systems for CF 
• medications 
• planned or unplanned hospitalizations for CF 
• study drng administration 
• outcomes related to PEx 
• outcomes related to antibiotic treatment 
Investigators will review results (in-home and telephone) and contact subjects for follow-up as 
needed. 
All data. will continue to be retained in the subject's source files. 
Any clinically significant finding (e.g., AE, SAE, laboratory a.bnonnalities) will continue to be 
repo1ted as indicated per protocol. 
To assess the safety and tolerability of 
the CFTR modulator evaluated in the 
specific clinical study while ensuring 
subject safety. These safety 
assessments will continue to provide 
safety data while minimizing burden to 
subjects and site personnel. 
To clarify that despite these altemative 
measures, all adverse events and 
serious adverse events should be 
repo1ted as indicated per protocol. 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 7  
Ve1tex Pha1maceuticals Incorporated 
Confidential Info1mation 
 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Efficacy and Other Assessments 
Efficacy and other assessments, as indicated per protocol, may be perfo1med by qualified 
personnel conducting the in-home visits. These assessments may include the following, as 
indicated per protocol, and per local regulation. 
In-home Spirometiy Assessment 
A spirometty device may be provided to subjects for in-home assessments oflung function as 
indicated per protocol. Sites and subjects will receive training and guidance as needed. 
Patient Repo1ted Outcome 
CFQ-R questionnaires may be provided to subjects (electt·onically or post mail) to be 
completed at home as indicated per protocol. Subjects v.•ill retum these questionnaires to the 
site via post mail. 
Other Assessments 
• ECGs 
• sweat chloride 
• blood samples for CFTR genotype testing, IRT, PK, FSH, inflammatory mediator, 
biomarkers, and vitamin levels 
• fecal samples for FE-1, fecal calprotectin, and other markers of intestinal inflammation 
other patient reported outcomes (e.g., TSQM, SF-12) 
To be able to assess safety, treatment 
effectiveness, and quality oflife 
measw-es of the CFTR modulator 
evaluated in the specific clinical study 
while ensw-ing subject safety. 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 8 of8 
Ve1tex Pha1maceuticals Incorporated 
Confidential Info1ma.tion 
 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Remote Monitoring 
Ve1tex has implemented remote monitoring visits where applicable, including remote source 
data verification, as allowed per local regulations. Remote monitoring will focus on collection 
of safety data, and data supporting primary and key seconda.1y endpoints. 
To allow for review of key data to 
inform on the safety of subjects 
receiving treatment. 
To allow for review of other key data 
to inform on the objectives of the study 
while maintaining study integrity and 
the safety of subjects and site 
personnel. 
AE: adverse event; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; ECG: electrocardiogram; FE-1: fecal elastase-1; 
FSH: follicle-stimulating hormone; GCP: Good Clinical Practice; ICF: informed consent fonn; IRT: immunoreactive tiypsinogen; LFT: liver function test; 
PEx: pulmona1y exacerbation; PK: phannacokinetic; SAE: serious adverse event; SF-12: 12-Item Sho1i Form Health Survey; TSQM: Treatment Satisfaction 
Questionnaire for Medication 

SAP_001.pdf: 
Statistical Analysis Plan (Methods) – Interim and Final Analysis 
Page 1 of 47 
Protocol Number: VX17-445-105 Version 5.0 
 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX17-445-105 Version 5.0 and  
Protocol Number VX17-445-105 Version 5.4BE 
(Final 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 Homozygous or Heterozygous for the F508del 
Mutation 
 
Authors of SAP: 
 
 
Version: 5.0 
Version Date of SAP: 27 OCT 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) – Interim and Final Analysis 
Page 2 of 47 
Protocol Number: VX17-445-105 Version 5.0 
 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
1 
TABLE OF CONTENTS 
 
1 
Table of Contents ................................................................................................................... 2 
2.3 
Modifications to the Approved DMC Charter .................................................................. 5 
3 
Introduction............................................................................................................................ 6 
4 
Objectives For Study 105 ...................................................................................................... 6 
4.1 
Primary Objective (Treatment and Extension Period) ..................................................... 6 
4.2 
Secondary Objectives (Treatment Period Only) ............................................................... 6 
5 
Endpoints For Study 105....................................................................................................... 6 
5.1 
Efficacy and Pharmacodynamic Endpoints (Treatment Period Only) ............................. 6 
5.1.1 
Primary Efficacy Endpoint ....................................................................................... 6 
5.1.2 
Secondary Efficacy and Pharmacodynamic Endpoints ............................................ 7 
5.2 
Safety Endpoints (Treatment and Extension Period) ....................................................... 7 
5.3 
Additional Endpoints (Treatment Period Only) ............................................................... 7 
6 
Design For Study 105............................................................................................................. 7 
6.1 
Overall Design .................................................................................................................. 7 
6.2 
Sample Size and Power .................................................................................................... 8 
6.3 
Randomization .................................................................................................................. 9 
6.4 
Blinding and Unblinding .................................................................................................. 9 
6.5 
Interim Analysis ............................................................................................................... 9 
7 
Analysis Sets ........................................................................................................................... 9 
7.1 
Efficacy Analysis Sets (Treatment Period only) .............................................................. 9 
7.1.1 
Parent Study Efficacy Analysis Set ........................................................................ 10 
7.1.2 
OL Full Analysis Set (OL-FAS) ............................................................................. 10 
7.1.3 
Cumulative TC Efficacy Set ................................................................................... 10 
7.2 
Safety Analysis Set ......................................................................................................... 10 
7.2.1 
OL Safety Set (OL-SS) ........................................................................................... 10 
7.2.2 
OL Extension Period Safety Set (OL-EP-SS) ........................................................ 10 
8 
Analysis Period..................................................................................................................... 11 
8.1 
Parent Study Efficacy Period .......................................................................................... 11 
8.2 
Open Label (OL) Period ................................................................................................. 11 
8.3 
Cumulative TC Efficacy Period ..................................................................................... 11 
8.4 
OL Safety Extension Period ........................................................................................... 12 
9 
Statistical Analysis ............................................................................................................... 12 
9.1 
General Considerations .................................................................................................. 12 
9.2 
Background Characteristics ............................................................................................ 13 
9.2.1 
Subject Disposition ................................................................................................. 13 
9.2.2 
Demographics and Baseline Characteristics ........................................................... 13 
9.2.3 
Medical History ...................................................................................................... 15 
9.2.4 
Prior and Concomitant Medications ....................................................................... 15 


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9.2.5 
Study Drug Exposure.............................................................................................. 15 
9.2.6 
Study Drug Compliance ......................................................................................... 15 
9.2.7 
Important Protocol Deviation ................................................................................. 16 
9.2.8 
Summary of Analysis of Background Characteristics ............................................ 16 
9.3 
Efficacy Analysis ............................................................................................................ 17 
9.3.1 
Analysis of Primary Efficacy Endpoint .................................................................. 17 
9.3.2 
Analysis of Secondary Efficacy and Pharmacodynamic Endpoint ........................ 17 
9.3.3 
Analysis of Additional Efficacy Variables ............................................................. 21 
9.3.4 
Summary of Efficacy Analysis ............................................................................... 22 
9.4 
Safety Analysis ............................................................................................................... 22 
9.4.1 
Adverse Events ....................................................................................................... 23 
9.4.2 
Clinical Laboratory Assessments ........................................................................... 24 
9.4.3 
Electrocardiogram .................................................................................................. 25 
9.4.4 
Vital Signs .............................................................................................................. 25 
9.4.5 
Pulse Oximetry ....................................................................................................... 25 
9.4.6 
Physical Examination ............................................................................................. 25 
9.4.7 
Ophthalmologic Examination ................................................................................. 25 
9.4.8 
COVID-19 Impacted Visits .................................................................................... 26 
9.4.9 
Safety Supportive Analysis .................................................................................... 26 
9.4.10 
Summary of Safety Analysis .................................................................................. 26 
9.5 
Additional Analysis ........................................................................................................ 27 
9.5.1 
Analysis of absolute change from baseline in CFQ-R non-respiratory domain 
score ........................................................................................................................ 27 
9.6 
Extension Period ............................................................................................................. 27 
9.6.1 
General Considerations ........................................................................................... 27 
9.6.2 
Background Characteristics .................................................................................... 27 
9.6.3 
Safety Analysis ....................................................................................................... 29 
10 Interim and DMC Analysis for Study 105 ......................................................................... 32 
10.1 Interim Analysis ............................................................................................................. 32 
10.2 DMC Analysis ................................................................................................................ 32 
11 References ............................................................................................................................. 33 
12 Appendices............................................................................................................................ 34 
12.1 Analysis Visit Windows for Efficacy and Safety Assessments (Treatment Period Only)
 
34 
12.2 Imputation Rules for Missing Prior/Concomitant Medication Dates ............................. 38 
12.3 Imputation Rules for Missing AE dates ......................................................................... 39 
12.4 Criteria for Threshold Analysis ...................................................................................... 40 
12.5 Adverse Events of Special Interest ................................................................................. 46 
12.6 Details of GLI Equations for Calculating ppFEV1 ......................................................... 47 
 
 


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2.3 
Modifications to the Approved DMC Charter 
Not Applicable. 
 


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3 
INTRODUCTION 
This statistical analysis plan (SAP) for the final analysis of Study VX17-445-105 (Study 105) is 
based on the most recent approved clinical study protocol (CSP), the most recent approved 
electronic case report form (eCRF), and the most recent approved eCRF completion guidelines.  
This SAP (Methods) documents the planned statistical analyses and data presentations of safety 
and efficacy endpoints during Study 105 for subjects who previously participated in Study 
VX17-445-102 (Study 102), or Study VX17-445-103 (Study 103), and subsequently enrolled in 
Study 105. Four interim analyses (IA) were conducted (data cut date for IA1:10 July, 2019, data 
cut date for IA2: 31 October, 2019, data cut date for IA3: 25 March, 2021, and data cut for IA4: 
28 March, 2022) for Study 105 after the datalock for the parent studies 102 and 103 based on 
SAP Version 1.0 for IA1 and IA2; SAP Version 2.0 for IA3; and SAP Version 4.0 for IA4.  
The intent of the analysis proposed in this document is to conduct the final analysis when all 
subjects complete the study. 
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. The SAP Version 2.0, 
SAP Version 3.0, SAP Version 4.0, and SAP Version 5.0 summarize 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 Version 5.0 will be finalized and approved prior to the 
Study 105 final datalock date. Any revisions to the approved SAP will be documented and 
approved in an amendment to the SAP. 
4 
OBJECTIVES FOR STUDY 105 
4.1 
Primary Objective (Treatment and Extension Period) 
To evaluate the long-term safety and tolerability of elexacaftor (ELX; VX-445) in triple 
combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with CF who are 
homozygous or heterozygous for the F508del mutation 
4.2 
Secondary Objectives (Treatment Period Only) 
• To evaluate the long-term efficacy of ELX in TC with TEZ and IVA 
• To evaluate the pharmacodynamics (PD) of ELX in TC with TEZ and IVA 
5 
ENDPOINTS FOR STUDY 105 
5.1 
Efficacy and Pharmacodynamic Endpoints (Treatment Period Only) 
5.1.1 
Primary Efficacy Endpoint 
Not applicable 


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5.1.2 
Secondary Efficacy and Pharmacodynamic Endpoints 
• Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) 
• Absolute change in sweat chloride (SwCl) 
• Number of pulmonary exacerbations (PEx) 
• Time-to-first PEx 
• 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 score 
 
5.2 
Safety Endpoints (Treatment and Extension Period) 
 
• Adverse events (AEs) 
• Clinical laboratory values 
• Standard 12-lead ECGs 
• Vital signs 
• Pulse oximetry 
 
5.3 
Additional Endpoints (Treatment Period Only) 
• Absolute change in CFQ-R non-respiratory domain scores 
• Changes in inflammatory mediators 
• Changes in microbiology analysis 
6 
DESIGN FOR STUDY 105 
6.1 
Overall Design 
This is a Phase 3, multicenter, open-label study (OLS) for subjects who completed the last 
Treatment Period visit in a parent study and meet eligibility criteria. A schematic of the study 
design is shown in Figure 6-1. 
All subjects will receive a TC of ELX/TEZ/IVA at the same dose level as that evaluated in 
Study 102 and Study 103. Subjects who complete the Treatment Period will have the opportunity 
to participate in the Extension Period for an additional 48 weeks. The dosages for the Treatment 
and Extension Period are shown in Table 6-1.   
 




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This is an open-label study that will enroll subjects from qualifying previous studies (Study 102 
and 103) who meet the inclusion and exclusion criteria for this study. Over 400 subjects are 
expected to enroll in this open-label study of 196 weeks’ duration. With this number of subjects 
exposed to ELX/TEZ/IVA treatment, AEs by Preferred Term (PT) that occur with a frequency of 
>1% will be ruled out with 95% confidence, when zero events are observed in that PT. 
Furthermore, with over 400 subjects exposed to ELX/TEZ/IVA treatment for at least 24 weeks, 
the half-width of the 95% CI for estimating the cumulative incidence of PEx is less than 6% 
assuming an observed incidence of 30%. 
Approximately 30 subjects are expected to participate in the Extension Period. 
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 study 105 CSP section 10.7 for details. 
6.5 
Interim Analysis 
Four interim analyses (IA) were conducted (data cut date for IA1:10 July 2019, data cut date for 
IA2: 31 October 2019, data cut date for IA3: 25 March 2021, and data cut for IA4: 28 March 
2022) for Study 105 after the datalock of the parent studies 102 and 103 based on SAP Version 
1.0 for IA1 and IA2; SAP Version 2.0 for IA3; and SAP Version 4.0 for IA4. 
7 
ANALYSIS SETS 
The following analysis sets are defined: Open-label (OL) All Subjects Set, OL Extension Period 
All Subjects Set, OL Full Analysis Set, OL Safety Set, Cumulative Triple Combination (TC) 
Efficacy Set, and OL Extension Period Safety Set.  
The OL All Subjects Set is defined as all subjects who were enrolled (defined as subject having 
data in the clinical database for the OLS) in the OLS Treatment Period. This analysis set will be 
used for Treatment Period individual subject data listings and disposition summary tables unless 
otherwise specified. 
The OL Extension Period All Subjects Set is defined as all subjects who were enrolled (defined 
as subject having data in the clinical database for the Extension Period) in the Extension Period. 
This analysis set will be used for Extension Period individual subject data listings and disposition 
summary tables unless otherwise specified. 
7.1 
Efficacy Analysis Sets (Treatment Period only) 
A summary of efficacy analysis sets is presented in Table 7-1. 
 
Table 7-1 
Summary of Efficacy Analysis Sets 
Efficacy Set 
Purpose 
Studies 
Treatment Label§ 
Study 102 FAS 
To evaluate efficacy data during study 102 
445-102 
ELX/TEZ/IVA in 445-102  
PBO in 445-102 
Study 103 FAS 
To evaluate efficacy data during study 103  
445-103 
ELX/TEZ/IVA in 445-103  
TEZ/IVA in 445-103 


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† does not apply for MMRM and descriptive summary of continuous efficacy endpoints 
§ Treatment label is based on the treatment the subject was assigned to in the parent study. The “Any 
ELX/TEZ/IVA” group refers to all the subjects in the corresponding analysis set.  
 
7.1.1 
Parent Study Efficacy Analysis Set  
The Parent Study Efficacy Analysis Sets are Study 102 Full Analysis Set (FAS) and Study 103 
FAS. The definition of these analysis sets is same as the FAS definition in the SAP for Studies 
102 and 103.  
 
7.1.2 
OL Full Analysis Set (OL-FAS) 
The OL Full Analysis Set is defined as all enrolled subjects who received at least 1 dose of study 
drug in the OLS Treatment Period. The OL-FAS will be used for efficacy analysis in those 
subjects who had participated in Study 102, or Study 103 and then transitioned to the treatment 
cohort of Study 105. The efficacy data from subjects from the Parent Study 102 will be presented 
separately from the efficacy data for subjects from the Parent Study 103. 
 
7.1.3 
Cumulative TC Efficacy Set  
The Cumulative TC Efficacy Set includes subjects who were randomized to ELX/TEZ/IVA and 
received at least one dose of study drug during the parent study and/or received at least one dose 
of study drug during the OLS Treatment Period. The Cumulative TC Efficacy Set will be used to 
analyze PEx data on ELX/TEZ/IVA during the parent study or during study 105 Treatment 
Period. PEx data for subjects from parent study 102 will be presented separately from the PEx 
data for subjects from parent study 103.    
 
7.2 
Safety Analysis Set 
7.2.1 
OL Safety Set (OL-SS) 
The OL Safety Set is defined as all subjects who received at least 1 dose of study drug in the 
OLS Treatment Period. The OL-SS will be used primarily for safety analyses during OLS 
Treatment Period with the treatment label “Any ELX/TEZ/IVA”.  
7.2.2 
OL Extension Period Safety Set (OL-EP-SS) 
The Open-label Extension Period Safety Set (OL-EP-SS) is defined as all subjects who have 
received at least 1 dose of study drug in the Extension Period of the OLS. The OL-EP-SS will be 
used primarily for safety analyses during OLS Extension Period with the treatment label “Any 
ELX/TEZ/IVA”. 
OL Full 
Analysis Set 
(OL-FAS) 
To evaluate efficacy data during study 105 
445-105 
ELX/TEZ/IVA in 445-102  
PBO in 445-102 
ELX/TEZ/IVA in 445-103 
TEZ/IVA in 445-103 
Any ELX/TEZ/IVA† 
Cumulative TC 
Efficacy Set 
To evaluate PEx data on ELX/TEZ/IVA during 
the parent study or during study 105 
445-102 
445-103 
445-105 
ELX/TEZ/IVA in 445-102  
PBO in 445-102 
Any ELX/TEZ/IVA 






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3) In the derivation of maximum and minimum values, and maximum and minimum change 
from baseline values during the analysis period for the safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits for study 105 are 
provided in Section 12.1. The visit window for the parent studies is described in the SAP for the 
individual parent studies. 
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, unless specified otherwise. 
9.2 
Background Characteristics  
The analysis described in this section (except for study drug exposure) will be presented 
separately for subjects from parent studies 102 and 103. 
9.2.1 
Subject Disposition 
A summary table of subject disposition in the OLS will be presented for the OL All Subjects Set 
by treatment group in the parent studies and overall, with the following categories:  
• Enrolled (OL All Subjects Set) 
• Dosed (OL-SS) 
• Enrolled and dosed (OL-FAS) 
The number and percentage (based on OL-FAS) of subjects in each of the following disposition 
categories will be summarized by treatment group in parent studies and overall: 
• Completed Treatment 
• Prematurely discontinued treatment and the reasons for discontinuation 
• Completed study 
• Prematurely discontinued the study and the reasons for discontinuation 
A listing will be provided for subjects who discontinued treatment during OLS or who 
discontinued OLS with reasons for discontinuation.  
9.2.2 
Demographics and Baseline Characteristics 
Demographics and parent study baseline characteristics will be summarized based on the OL-
FAS, and presented by treatment group in parent studies 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) 


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• 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 parent study baseline) 
Stratification categories (in addition to sex, if applicable) used in the parent study will include 
the following: 
• Age at the Screening Visit of parent study (<18, and ≥18 years) 
• ppFEV1 determined during the Screening/Run-in Period of parent study (<70, and ≥70) 
Note that one of the parent studies (study 103) had a 4-week TEZ/IVA run-in period during 
which the ppFEV1 used in stratification was determined. 
Disease characteristics based on parent study baseline will include the following: 
• ppFEV1 at parent study baseline (<40, ≥ 40 to <70, ≥70 to ≤90, and >90) 
• ppFEV1 at parent study baseline (continuous)  
• Sweat chloride at parent study baseline (continuous) 
• CFQ-R respiratory symptoms domain score at parent study baseline (continuous) 
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 
• Prior use of any bronchodilator (Yes, No)  
• Prior use of any inhaled bronchodilator (Yes, No)  
• Prior use of any inhaled hypertonic saline (Yes, No) 
• Prior use of any inhaled corticosteroids (Yes, No) 
• Infection with Pseudomonas aeruginosa within 2 years prior to screening visit (Positive, 
Negative) of parent study 
Prior medication use definition is same as that for the baseline characteristics summary presented 
in the parent studies. 
No statistical tests will be carried out to evaluate any baseline imbalance between treatment 
groups. 


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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, medical history will be 
summarized descriptively by treatment group in parent studies 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 WHO-Drug Dictionary 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 OL safety 
period 
• Post-treatment medication: medication continued or newly received after the OL safety 
period. 
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 in the study 105 database 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 OL safety period, or after the OL safety period, it will be considered in 
all 3 categories of prior, concomitant, and post-treatment medication. Details for imputing 
missing or partial start and/or stop dates of medication are described in Section 12.2. 
For the OL-FAS, prior medications and concomitant medications will be summarized 
descriptively by: 1) treatment group in parent studies and overall, Preferred Name (PN); and 2) 
treatment group in parent studies and overall, anatomic class (ATC) level 1, ATC level 2, and 
PN. Post-treatment medications will be listed for each subject. 
9.2.5 
Study Drug Exposure  
Duration of study drug exposure is defined as [last dose date – first dose date + 1 day] within the 
OL safety period, regardless of any interruption in dosing between the first and the last dose. 
Study drug exposure (in weeks) during the OL safety period for the OL-SS 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 to <=120 weeks, >120 to <=144 weeks, >144 to <=168 weeks, >168 to 
<=192 weeks, and >192 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 by “Any ELX/TEZ/IVA” group. 
 
9.2.6 
Study Drug Compliance  
Study drug compliance for the OL efficacy period 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.  


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Percentage of study drug compliance will be summarized based on the OL-FAS and presented by 
treatment group in parent studies and overall. It will be summarized descriptively by the number 
of subjects (n), mean, SD, median, min, and max and summarized in categories (<80% vs. 
≥80%) using frequency tables.  
In addition, for the final analysis only, percentage of tablets taken during the OL efficacy period 
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). A similar summary to those for the study drug compliance will be 
produced based on the OL-FAS. 
9.2.7 
Important Protocol Deviation  
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. IPD rules will be developed and finalized prior to the clinical data 
lock for study 105. 
The protocol deviations that should be considered as potential IPDs include, but are not limited 
to: 
• Subject was enrolled in the study despite the violation of inclusion/exclusion criteria 
• Subject received prohibited concomitant medications 
• Subject received the wrong treatment or incorrect doses  
• Subject remained in the study despite meeting withdrawal criteria 
Occurrence of any of these events should be considered as potential IPDs, but a team should 
categorize them as IPDs only if they have the potential to significantly affect the completeness, 
accuracy, or reliability of the study data or that may significantly affect a subject’s rights, safety, 
or well-being. 
IPDs (from the site deviation log) during the OL Efficacy period will be summarized 
descriptively based on the OL-FAS and presented by treatment group in parent studies and 
overall. Additionally, IPDs during the OL Efficacy period will be provided in an individual 
subject data listing. IPDs will be analyzed only as part of final analysis. 
9.2.8 
Summary of Analysis of Background Characteristics  
Background characteristics that will be analyzed for each analysis set is presented in Table 9-1.  
 
Table 9-1 
Analysis of Background Characteristics 
Analysis Set 
Background characteristics 
OL All Subjects Set 
Disposition 
OL-FAS 
Demographics (parent study baseline) 
Baseline characteristics (parent study baseline) 
Medical History 
Prior and Concomitant Medications 
Study drug compliance  
Important Protocol Deviation (final analysis only) 
OL-SS 
Study drug exposure 


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9.3 
Efficacy Analysis  
The parent study baseline will be used to calculate the change from baseline for continuous 
efficacy endpoints unless otherwise specified. The efficacy data from subjects with parent study 
102 will be presented separately from those with parent study 103. Continuous endpoints during 
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 what is available in the final CSR of the parent study.  Similarly, continuous 
endpoints during the OL efficacy period will be analyzed using a separate MMRM. The 
descriptive summary for continuous endpoints and MMRM analysis during OL efficacy period 
will be restricted up to the Week 192 Visit. 
The focus of the efficacy analysis will be on within-group comparison. No between-groups 
comparisons will be performed. P values will not be presented for any of the comparisons.    
 
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. See Section 12.6 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 <10 
mmol/L or >160 mmol/L will be considered missing. 
Pulmonary exacerbation (PEx): A PEx is defined as a new event or change in antibiotic therapy 
(IV, inhaled, or oral) for any 4 or more of the following signs/symptoms: 
• Change in sputum 
• New or increased hemoptysis 
• Increased cough 
• Increased dyspnea 
• Malaise, fatigue, or lethargy 
• Temperature above 38°C (equivalent to approximately 100.4°F) 
• Anorexia or weight loss 
• Sinus pain or tenderness 
• Change in sinus discharge 


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• Change in physical examination (PE) of the chest 
• Decrease in pulmonary function by 10% 
• Radiographic changes indicative of pulmonary infection 
The number of PEx is then defined as the total number of PEx for each treatment group during 
the cumulative TC Efficacy period. 
The time to first PEx is the number of days from the start of the cumulative TC Efficacy period 
to the date of the first pulmonary exacerbation during the cumulative TC Efficacy period. A 
subject who does not experience a PEx during the cumulative TC Efficacy period will be 
censored at the cumulative TC Efficacy period end date. 
Body mass index (BMI): the BMI at each visit is calculated using the weight and height at each 
visit as follows: 
BMI = Weight (kg)
Height (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 charts6, with the age (in months) used for the calculation defined in 
Section 12.1. 
Cystic Fibrosis Questionnaire-Revised (CFQ-R): The CFQ-R1,3,5 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 
(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. 
9.3.2.2 
Analysis Method 
Absolute change from baseline in ppFEV1 


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• Subjects in Study 102 FAS and the corresponding subjects in OL-FAS 
The MMRM for the parent study efficacy period will be same as that described in the SAP for 
study 102. In the MMRM for the OL efficacy period, 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, age at screening of parent study (<18 versus ≥18 years of age) and 
sex (male versus female) 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-Roger2. If 
the model fails to converge due to the unstructured covariance assumption, a compound 
symmetry covariance structure will be used to model the within-subject errors. In the MMRM 
approach, assuming that the data are missing at random, no imputation of missing data will be 
performed. 
Results from the 2 MMRMs will be presented in a single summary table. The number of 
subjects, least-squares means (LS means) for absolute change from baseline at scheduled visits 
within each treatment group 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.  
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 in OL-FAS.  
• Subjects in Study 103 FAS and the corresponding subjects in OL-FAS 
The MMRM for the parent study efficacy period will be same as that described in the SAP for 
study 103. In the MMRM for OL efficacy period, 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, and age at screening of parent study (<18 versus ≥18 years of age) as 
covariates. Other details of the analysis and presentation of the results is similar to those for 
subjects from study 102. 
Absolute change from baseline in SwCl 
Analysis of this PD variable will be based on an MMRM similar to the analysis of the absolute 
change from baseline in ppFEV1. Note that baseline ppFEV1 from parent study will be retained 
as a covariate in the MMRM and baseline SwCl from parent study will not be included as a 
covariate. A descriptive summary of raw values and absolute changes from baseline will also be 
presented.  
Number of PEx 
• Cumulative TC Efficacy Set for subjects from study 102 
The number of PEx during the cumulative TC efficacy period will be analyzed for subjects in the 
cumulative TC efficacy set using a negative binomial regression model and reported as event rate 
along with the 95% CI. The model will include treatment as a fixed effect and continuous 
baseline ppFEV1 from parent study, age at screening of parent study (<18 versus ≥18 years of 


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age), and sex (male versus female) as covariates. The logarithm of the subject-specific 
cumulative TC efficacy period duration (in years; 1 year=48 weeks) will be treated as the offset 
in the model. If the model does not converge, the negative binomial regression model will be 
replaced with a Poisson regression model. 
Similarly, the number of PEx (i) requiring hospitalization, and (ii) requiring IV antibiotic therapy 
will be analyzed. 
• Cumulative TC Efficacy Set for subjects from study 103  
The analysis of number of PEx during the cumulative TC efficacy period will be similar to that 
for subjects from study 102. The only exception is that sex will not be a covariate in the negative 
binomial model and the analysis will be based only on one treatment group (“Any 
ELX/TEZ/IVA”). The number of PEx requiring hospitalization as well as the number of PEx 
requiring IV antibiotic therapy will only be summarized descriptively by “Any ELX/TEZ/IVA” 
group; the descriptive summary will include number of subjects with PEx, sum of days (weeks) 
in cumulative TC efficacy period over all the subjects, the number of PEx, and the observed PEx 
rate. 
Time to First PEx 
The time to first PEx (in weeks) during the cumulative TC efficacy period will be analyzed based 
on the cumulative TC efficacy set (separately for subjects from study 102 and study 103). The 
Kaplan-Meier method will be used to produce a graphical presentation of the cumulative 
exacerbation-free rate and to estimate the cumulative exacerbation-free rate for the “Any 
ELX/TEZ/IVA” group for subjects from study 102 and study 103. 
Absolute change from baseline in BMI  
Analysis of this variable will be based on an MMRM similar to the analysis of the absolute 
change from baseline in ppFEV1. Note that baseline ppFEV1 from parent study will be retained 
as a covariate in the MMRM and baseline BMI from parent study will not be included as a 
covariate. The analysis will be conducted with the clinic assessed data only. An additional 
analysis may also be performed to include pooled data obtained in clinic and at home, if the 
home assessed data are reasonably consistent with the clinic assessed data. A descriptive 
summary of raw values and absolute changes from baseline will also be presented.  
Absolute change from baseline in BMI Z-score (for subjects ≤20 years of age at parent study 
baseline) 
Analysis of this variable will be based on an MMRM similar to the analysis of the absolute 
change from baseline in ppFEV1 (except that age at screening of parent study will not be a 
covariate). Note that baseline ppFEV1 from parent study will be retained as a covariate in the 
MMRM and baseline BMI Z-score from parent study will not be included as a covariate. The 
analysis will be conducted with the clinic assessed data only. An additional analysis may also be 
performed to include pooled data obtained in clinic and at home, if the home assessed data are 
reasonably consistent with the clinic assessed data. A descriptive summary of raw values and 
absolute changes from baseline will also be presented.  
Absolute change from baseline in body weight 
Analysis of this variable will be based on an MMRM similar to the analysis of the absolute 
change from baseline in ppFEV1. Note that baseline ppFEV1 from parent study will be retained 


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as a covariate in the MMRM and baseline weight from parent study will not be included as a 
covariate. The analysis will be conducted with the clinic assessed data only. An additional 
analysis may also be performed to include pooled data obtained in clinic and at home, if the 
home assessed data are reasonably consistent with the clinic assessed data. 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 
Analysis of this variable will be based on an MMRM similar to the analysis of the absolute 
change from baseline in ppFEV1. Note that baseline ppFEV1 from parent study will be retained 
as a covariate in the MMRM and baseline CFQ-R respiratory domain score from parent study 
will not be included as a covariate. 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 inconsistent with the clinic assessed data. A 
descriptive summary of raw values and absolute changes from baseline will also be presented.  
9.3.2.3 
Sensitivity and Supportive Analysis of Secondary Endpoints 
No sensitivity or supportive analysis is planned for the secondary endpoints. 
9.3.2.4 
Subgroup Analysis 
No subgroup analysis is planned for the secondary endpoint. 
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 within OL-FAS 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) 
o Relative change from parent study baseline in FEF25-75% (%) 
o Absolute change from parent study baseline in percent predicted FEF25-75% (percentage 
points) 


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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 (%) 
9.3.4 
Summary of Efficacy Analysis  
Efficacy endpoint analysis for each efficacy analysis set is presented in Table 9-2. 
Table 9-2 
Summary of Efficacy Analysis 
Note: baseline used is parent study baseline 
9.4 
Safety Analysis 
The primary objective of study 105 is the evaluation of the long-term safety and tolerability of 
ELX/TEZ/IVA. All safety analyses for study 105 will be based on the OL safety period for 
subjects in the OL-SS.  
The following safety and tolerability endpoints will be assessed: 
• Treatment-emergent adverse events (TEAEs) 
Analysis Set (Analysis description) 
Efficacy Endpoint 
Study 102 FAS and Study 103 FAS 
(MMRM)  
Note: Analysis is the same as what is 
specified in the SAP for studies 102 and 103  
 
• Absolute change from baseline in ppFEV1  
• Absolute change from baseline in SwCl (PD endpoint) 
• Absolute change from baseline in BMI 
• Absolute change from baseline in BMI Z-score 
• Absolute change from baseline in weight 
• Absolute change from baseline in CFQ-R respiratory domain 
 
 
OL-FAS (MMRM and descriptive summary; 
separately for subjects from study 102 and 
103) 
• Absolute change from baseline in ppFEV1 
• Absolute change from baseline in SwCl 
• Absolute change from baseline in BMI 
• Absolute change from baseline in BMI Z-score 
• Absolute change from baseline in weight 
• Absolute change from baseline in CFQ-R respiratory domain 
• Additional spirometry (descriptive summary only) 
 
 
 
Cumulative TC Efficacy Set (Negative 
Binomial regression for counts, Kaplan-
Meier for time to first PEx; separately for 
subjects from study 102 and 103) 
• Number of PEx 
• Number of PEx requiring hospitalization (only descriptive for subjects 
from study 103) 
• Number of PEx requiring IV antibiotic therapy (only descriptive for 
subjects from study 103) 
• Time to First PEx  


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• Clinical laboratory values 
• ECGs 
• Vital signs 
• Pulse oximetry 
The safety analysis will be performed by pooling the safety data from patients with parent 
studies 102 and 103. 
The TC safety baseline will be used to calculate change from baseline for continuous safety 
endpoints. 
In the AE summary tables, AE data from the OLS safety period may be displayed side-by-side 
with the AE data from study 102.  
Only descriptive analysis of safety will be performed. No statistical testing will be performed. 
9.4.1 
Adverse Events  
AEs will be classified as pretreatment AEs, TEAEs, or post-treatment AEs, defined as follows:  
Pretreatment AE: any AE that occurred prior to the start of the OL safety period 
TEAE: any AE that worsened (either in severity or seriousness) or newly developed during the 
OL safety period 
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was newly 
developed after the OL safety period 
For AEs in the study 105 database with completely missing or partially missing start dates, if 
there is no clear evidence that the AEs started before the OL safety period or after the OL safety 
period, the AEs will be 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 during OL safety period will be summarized 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 


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• Subjects with TEAE leading to death  
The frequency counts and percentages as well as the exposure adjusted event rate will be 
presented for the above overview table. The exposure adjusted rate will not be presented for 
strongest relationship and maximum severity categories. 
The following summary tables of TEAEs during OL safety period will be presented: 
• All TEAEs 
• Grade 3/4 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Related TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to death 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event) and the exposure adjusted event rate 
(except for summary by strongest relationship and maximum severity). When summarizing the 
number and percentages of subjects, subjects with multiple occurrences of the same adverse 
event will be counted once, and only the maximum severity level will be presented in the 
severity summaries, and the strongest relationship level in the relationship summaries. Missing 
severity levels will not be included in the Grade 3/4 TEAE summaries; missing relationship will 
be considered as related and included in the related TEAE and related serious TEAE summaries.   
Additional summary table in which the frequency counts and percentages as well as the exposure 
adjusted event rate will be presented for TEAEs during the OL safety period: 
• All TEAEs by PT 
All AEs in study 105 database, including pretreatment AEs, TEAEs, and post-treatment AEs, 
will be presented in an individual subject data listing based on the OL All Subjects Set. In 
addition, a listing containing individual subject adverse event data for TEAEs leading to 
treatment discontinuation, TEAEs leading to treatment interruption, Grade 3/4 TEAEs, SAEs and 
all deaths will be provided separately, with a flag indicating the TEAE status for SAEs and 
deaths. 
9.4.2 
Clinical Laboratory Assessments 
For the laboratory assessments during OL safety period, the observed values and change from 
TC safety baseline values of the continuous hematology, coagulation and chemistry results will 
be summarized in SI units at each visit.  


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The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
during the OL safety period will be summarized. The threshold analysis criterion shift from TC 
safety 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 from study 105 will be presented in individual 
subject data listings only. For positive serum pregnancy listing, subjects with serum HCG which 
are abnormally high will be selected. In addition, a listing containing individual subject 
hematology, chemistry, and coagulation values from study 105 will be provided. This listing will 
include data from both scheduled and unscheduled visits. The listings will be based on OL All 
Subjects set. 
9.4.3 
Electrocardiogram 
For the following ECG interval measurements during the OL safety period, a summary of 
observed values and change from TC safety baseline values will be provided at each visit (in 
msec): RR, PR, QT, and QT corrected for HR (QTcF), QRS duration, and HR (beats per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
during the OL safety period will be summarized. The threshold analysis criteria are provided in 
Section 12.4. 
9.4.4 
Vital Signs 
For the vital signs measurements during the OL safety period, the observed values and change 
from TC safety baseline values will be summarized at each visit. The following vital signs 
parameters will be summarized: systolic and diastolic blood pressure (mm Hg), body 
temperature (C), pulse rate (beats per minute), and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
during the OL safety period will be summarized. 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 OL safety 
period, a summary of observed values and change from TC safety baseline values will be 
provided at each visit. 
The number and percentage of subjects with shift changes from TC safety baseline 
(normal/missing and low according to the reference range) to the lowest percent of oxygen 
saturation during the OL safety period will be summarized. 
 
9.4.6 
Physical Examination  
No tables/figures/listings will be provided for physical examination data. 
 
9.4.7 
Ophthalmologic Examination  
Ophthalmologic examination results for OL All Subjects Set will be provided in a data listing. 


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9.4.8 
COVID-19 Impacted Visits  
A listing containing subjects’ visits impacted due to COVID-19 will be provided. 
9.4.9 
Safety Supportive Analysis 
Elevated transaminases events and rash events, as determined by MedDRA PTs in Section 12.5, 
are considered as adverse events of special interest. The corresponding AE data will be 
summarized in terms of frequency counts and exposure adjusted rates. 
9.4.9.1 
Adverse Events of Special Interest  
For treatment-emergent elevated transaminases events and rash events corresponding to the OL 
safety period, the following categories will be summarized: 
• Subjects with events 
• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 
• Subjects with serious events 
• Subjects with related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event (with the first dose date of study drug in the OLS as the reference 
while calculating time-to-onset) 
Note that for maximum severity, duration of events and time to onset of first event, the exposure 
adjusted rates will not be presented. 
In addition, for treatment-emergent rash events, the above categories will be summarized for the 
following subgroups: 
• Sex (male, female) 
• Female subjects with concomitant hormonal therapy (Yes, No) 
 
9.4.10 
Summary of Safety Analysis  
Safety assessments for each safety analysis set is presented in Table 9-3. 
 
Table 9-3 
Summary of Safety Analysis 
Analysis Set 
Safety Assessment 
OL-SS  
 
• AEs, SAEs, Grade 3/4 AEs, AEs leading to discontinuation or interruption, related AEs and 
SAEs, overview (corresponding exposure adjusted rates) 
• Clinical laboratory (Summary of change from TC safety baseline, TA including shift from 
TC safety baseline) 
• Vital signs (Summary of change from TC safety baseline, TA) 


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9.5 
Additional Analysis 
Analyses related to the additional endpoints of changes in inflammatory mediators, changes in 
microbiology analysis and rate of change in ppFEV1 will be discussed in a separate document. 
9.5.1 
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. 
9.6 
Extension Period 
Unless otherwise specified, statistical analyses for Study 105 Extension Period will be similar to 
the analyses previously documented in Sections 9.1, 9.2, and 9.4.  
9.6.1 
General Considerations 
Baseline value: The Extension Period TC safety baseline is 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 received at least one dose of ELX/TEZ/IVA during the parent 
study) or the first dose of study drug in the Treatment Period (if the subject did not receive at 
least one dose of ELX/TEZ/IVA during the parent study). The Extension Period TC safety 
baseline will be used in the safety analyses for the Extension Period. 
 
The Treatment-emergent (TE) Period in the Extension Period is the same as the OL Safety 
Extension Period described in Section 8.4.  
9.6.2 
Background Characteristics  
9.6.2.1 
Subject Disposition 
A summary table of subject disposition in the Extension Period will be presented for the OL 
Extension Period All Subjects Set with the following categories:  
• Enrolled (OL Extension Period All Subjects Set) 
• Dosed (OL-EP-SS) 
The number and percentage (based on OL-EP-SS) of subjects in each of the following 
disposition categories will be summarized: 
• Completed Treatment in the Extension Period 
• Prematurely discontinued treatment in the Extension Period and the reasons for 
discontinuation 
• ECG (Summary of change from TC safety baseline, TA) 
• Pulse oximetry (Summary of change from TC safety baseline, Shift from TC safety baseline)  
• Ophthalmologic examination (listing) 
 
Special safety topics (includes exposure adjusted rates): 
• Rash (including by subgroup: sex, hormonal therapy) 
• Elevated transaminases events 
 
 


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• Completed Extension Period study 
• Prematurely discontinued the Extension Period study and the reasons for discontinuation 
A listing will be provided for subjects who discontinued treatment during Extension Period or 
who discontinued Extension Period with reasons for discontinuation.  
9.6.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the OL-EP-SS.  
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) 
Baseline characteristics based on parent study baseline will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• BMI z-score (for subjects <=20 years old at parent study baseline) 
Disease characteristics based on parent study baseline will include the following: 
• ppFEV1 at parent study baseline (<40, ≥ 40 to <70, ≥70 to ≤90, and >90) 
• ppFEV1 at parent study baseline (continuous)  
• Sweat chloride at parent study baseline (continuous) 
• CFQ-R respiratory symptoms domain score at parent study baseline (continuous) 
9.6.2.3 
Medical History 
Medical history (referenced to the start of parent study) will be coded by using MedDRA. A 
listing with System Organ Class (SOC) and Preferred Term (PT) will be provided. 
9.6.2.4 
Prior and Concomitant Medications 
Medications will be coded using the WHO-Drug Dictionary 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 Extension Period. 
• Concomitant medication: medication continued or newly received during the OL Safety 
Extension Period. 
• Post-treatment medication: medication continued or newly received after the OL Safety 
Extension Period. 


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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 in the study 105 Extension Period database 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 Extension Period, concomitantly during the OL Safety Extension Period, or after the 
OL Safety Extension Period, it will be considered in all 3 categories of prior, concomitant, and 
post-treatment medication. Details for imputing missing or partial start and/or stop dates of 
medication are described in Section 12.2. 
A listing will be provided. 
9.6.2.5 
Study Drug Exposure  
Duration of study drug exposure is defined as [last dose date – first dose date + 1 day] within the 
OL Safety Extension Period, regardless of any interruption in dosing between the first and the 
last dose. Study drug exposure (in weeks) during the OL Safety Extension Period for the OL-EP-
SS 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 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) in the Extension Period, 
will be provided. The summary will be by “Any ELX/TEZ/IVA” group. 
9.6.2.6 
Study Drug Compliance  
Study drug compliance for the OL Extension Period 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. A 
listing of the compliance rate will be provided. 
9.6.2.7 
Important Protocol Deviation  
IPD for the Extension Period is similarly defined but for the OL Extension Period. 
IPDs (from the site deviation log) during the OL Extension Period will be provided in an 
individual subject data listing. 
9.6.3 
Safety Analysis 
The primary objective of study 105 Extension Period is the evaluation of the long-term safety 
and tolerability of ELX/TEZ/IVA. All safety analyses for study 105 Extension Period will be 
based on the OL Extension Period for subjects in the OL-EP-SS.  
The following safety and tolerability endpoints will be assessed: 
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values 
• ECGs 
• Vital signs 
• Pulse oximetry 


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In the AE summary tables, AE data from the OL Safety Extension Period may be displayed side-
by-side with the AE data from study 102.  
Only descriptive analysis of safety will be performed. No statistical testing will be performed. 
9.6.3.1 
Adverse Events  
AEs will be classified as pretreatment AEs, TEAEs, or post-treatment AEs, defined as follows:  
Pretreatment AE: any AE that occurred prior to the start of the OL Safety Extension Period. 
TEAE: any AE that worsened (either in severity or seriousness) or newly developed during the 
OL Safety Extension Period 
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was newly 
developed after the OL Safety Extension Period 
For AEs in the study 105 Extension Period database with completely missing or partially missing 
start dates, if there is no clear evidence that the AEs started before the OL Safety Extension 
Period or after the OL Safety Extension Period, the AEs will be 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 during OL Safety Extension Period will be summarized 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 following summary tables of TEAEs will be presented for overall: 
• All TEAEs 
• All TEAEs by PT 
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.   


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All AEs, including pre-treatment AEs, TEAEs, and post-treatment AEs, will be presented in an 
individual subject data listing based on the OL Extension Period All Subjects Set. In addition, 
separate listings containing individual subject adverse event data for TEAEs leading to treatment 
discontinuation, and SAEs will be provided, with a flag indicating the TEAE status for SAEs. 
 
9.6.3.2 
Clinical Laboratory Assessments 
The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
during the OL Extension Period will be summarized. The threshold analysis criterion shift from 
TC safety 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 from study 105 Extension Period will be 
presented in individual subject data listings only. For positive serum pregnancy listing, subjects 
with serum HCG which are abnormally high will be selected. In addition, a listing containing 
individual subject hematology, chemistry, and coagulation values from study 105 Extension 
Period will be provided. This listing will include data from both scheduled and unscheduled 
visits. The listings will be based on OL Extension Period All Subjects set. 
9.6.3.3 
Electrocardiogram 
The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
during the OL Extension Period will be summarized. The threshold analysis criteria are provided 
in Section 12.4. A listing containing the RR, PR, QT, and QT corrected for HR (QTcF), QRS 
duration, and HR (beats per minute) measurements during the OL Extension Period will be 
provided. 
9.6.3.4 
Vital Signs 
The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
during the OL Extension Period will be summarized. The threshold analysis criteria are provided 
in Section 12.4. A listing containing the systolic and diastolic blood pressure (mm Hg), weight 
(kg), body temperature (C), pulse rate (beats per minute), and respiratory rate (breaths per 
minute) measurements during the OL Extension Period will be provided. 
9.6.3.5 
Pulse Oximetry 
A listing containing the percent of oxygen saturation measurements during the OL Extension 
Period will be provided. 
9.6.3.6 
Physical Examination 
No tables/figures/listings will be provided for PE data during the OL Extension Period. 
9.6.3.7 
Ophthalmologic Examination  
Ophthalmologic examination results for OL Extension Period All Subjects Set will be provided 
in a data listing. 
9.6.3.8 
COVID-19 Impacted Visits  
A listing containing subjects’ visits impacted due to COVID-19 during the OL Extension Period 
will be provided. 


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10 
Interim and DMC Analysis for Study 105 
10.1 
Interim Analysis 
Per the CSP, IAs for Study 105 may have taken place at any time during the study at the 
discretion of the sponsor to support regulatory and/or reimbursement dossiers. IA1 was 
conducted after the data lock of parent Studies 102 and 103 under SAP Version 1.0. As of 
November 2022, 3 additional IAs were conducted: IA2 (under SAP Version 1.0), IA3 (SAP 
Version 2.0), and IA4 (SAP Version 4.0). The analysis details of the IAs can be found in their 
respective SAP versions. 
 
10.2 
DMC Analysis 
An independent data monitoring committee (IDMC) was formed before initiation of study 105. 
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. Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
2. Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics. 1997;53:983-97. 
3. 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. 
4. 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. 
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. Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
 
 


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12 
APPENDICES 
12.1 
Analysis Visit Windows for Efficacy and Safety Assessments 
(Treatment Period Only) 
Table 12-1 
Analysis Visit Windows for Efficacy and Safety Assessments in Study 105  
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2 
Serum Chemistry 
Hematology 
Vital Signs3 
 
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 Week 108 
OL Week 120 
OL Week 132 
OL Week 144 
OL Week 156 
OL Week 168 
OL Week 180 
OL Week 192 
OL Safety Follow-up 
-- 
15 
 
29 
57 
113 
169 
253 
337 
421 
505 
589 
673 
757 
841 
925 
1009 
1093 
1177 
1261 
1345 
Not applicable 
Defined in Section 9.1 
[1, 22] where day 1 is post-
dose measurement 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 211] 
(211, 295] 
(295, 379] 
(379, 463] 
(463, 547] 
(547, 631] 
(631, 715] 
(715, 799] 
(799, 883] 
(883, 967] 
(967, 1051] 
(1051, 1135] 
(1135, 1219] 
(1219, 1303] 
(1303, 1359] 
Use nominal visit 
Standard 12-lead ECG  
TC Safety baseline  
OL Day 15 
 
OL Week 8 
OL Week 24 
OL Week 48 
OL Week 72 
OL Week 96 
OL Week 120 
OL Week 144 
OL Week 168 
OL Week 192 
OL Safety Follow-up 
-- 
15 
 
57 
169 
337 
505 
673 
841 
1009 
1177 
1345 
Not applicable 
Defined in Section 9.1 
 [1, 36] where day 1 is post-
dose measurement 
(36, 113] 
(113, 253] 
(253, 421] 
(421, 589] 
(589, 757] 
(757, 925] 
(925, 1093] 
(1093, 1261] 
(1261, 1359] 
Use nominal visit 


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Table 12-1 
Analysis Visit Windows for Efficacy and Safety Assessments in Study 105  
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2 
Coagulation 
TC Safety baseline  
OL Week 24 
 
OL Week 48 
OL Week 72 
OL Week 96 
OL Week 120 
OL Week 144 
OL Week 168 
OL Week 192 
OL Safety Follow-up 
-- 
169 
 
337 
505 
673 
 841 
1009 
1177 
1345 
Not applicable 
Defined in Section 9.1 
 [1, 253] where day 1 is post-
dose measurement 
(253, 421] 
(421, 589] 
(589, 757] 
(757, 925] 
(925, 1093] 
(1093, 1261] 
(1261, 1359] 
Use nominal visit 
Spirometry 
 
Parent Study 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 Week 108 
OL Week 120 
OL Week 132 
OL Week 144 
OL Week 156 
OL Week 168 
OL Week 180 
OL Week 192 
OL Safety Follow-up 
-- 
 
15 
29 
57 
113 
169 
253 
337 
421 
505 
589 
673 
757 
841 
925 
1009 
1093 
1177 
1261 
1345 
Not applicable 
≤1 corresponding to the first 
dose date of parent study 
 (1, 22] 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 211] 
(211, 295] 
(295, 379] 
(379, 463] 
(463, 547] 
(547, 631] 
(631, 715] 
(715, 799] 
(799, 883] 
(883, 967] 
(967, 1051] 
(1051, 1135] 
(1135, 1219] 
(1219, 1303] 
(1303, 1401] 
Use nominal visit 
CFQ-R  
Parent Study baseline 
 
OL Week 4 
OL Week 8 
OL Week 24 
OL Week 48 
OL Week 72 
OL Week 96 
OL Week 120 
OL Week 144 
OL Week 168 
OL Week 192 
OL Safety Follow-up 
-- 
 
29 
57 
169 
337 
505 
673 
841 
1009 
1177 
1345 
Not applicable 
≤1 corresponding to the first 
dose date of parent study 
 (1, 43] 
(43, 113] 
(113, 253] 
(253, 421] 
(421, 589] 
(589, 757] 
(757, 925] 
(925, 1093] 
(1093, 1261] 
(1261, 1401] 
Use nominal visit 


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Table 12-1 
Analysis Visit Windows for Efficacy and Safety Assessments in Study 105  
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2 
Weight, Height and BMI (and 
the corresponding z-score)4 
Parent Study 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 Week 108 
OL Week 120 
OL Week 132 
OL Week 144 
OL Week 156 
OL Week 168 
OL Week 180 
OL Week 192 
OL Safety Follow-up 
-- 
 
15 
29 
57 
113 
169 
253 
337 
421 
505 
589 
673 
757 
841 
925 
1009 
1093 
1177 
1261 
1345 
Not applicable 
≤1 corresponding to the first 
dose date of parent study 
(1, 22] 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 211] 
(211, 295] 
(295, 379] 
(379, 463] 
(463, 547] 
(547, 631] 
(631, 715] 
(715, 799] 
(799, 883] 
(883, 967] 
(967, 1051] 
(1051, 1135] 
(1135, 1219] 
(1219, 1303] 
(1303, 1401] 
Use nominal visit 
SwCl 
 
Parent study baseline 
 
OL Day 15 
OL Week 4 
OL Week 8 
OL Week 16 
OL Week 24 
OL Week 72 
OL Week 96 
OL Week 120 
OL Week 144 
OL Week 168 
OL Week 192 
-- 
 
15 
29 
57 
113 
169 
505 
673 
841 
1009 
1177 
1345 
 
1 corresponding to the first 
dose date of parent study 
 (1, 22] 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 337] 
(337, 589] 
(589, 757] 
(757, 925] 
(925, 1093] 
(1093, 1261] 
(1261, 1401] 
Notes: 
1 Visit name for analysis purpose is used to report data in tables and figures. 
 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
1. If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
2. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. 


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Table 12-1 
Analysis Visit Windows for Efficacy and Safety Assessments in Study 105  
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2 
3 For unscheduled vital signs measurements collected at Study Day 1, if any, they will be treated as post-dose 
observations. 
4 Weight 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. 
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. 
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 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: 
TC safety Baseline is defined in Section 9.1. If multiple ECG measurements are obtained on the same calendar 
day during the analysis period, 
o 
For summary purpose, the average value will be used as the ECG on that day; 
o 
For threshold analysis purpose, all ECG values will be used 
 
 




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12.3 
Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date in study 105 database are defined below. If 
the imputed AE start date is before the informed consent date for the Treatment Period 
(Extension Period) OLS, the AE start date will be imputed using the informed consent date 
(Extension Period enrollment date). Ongoing events from the parent studies will follow the 
imputation rule described in the SAP for parent studies. 
• If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period (Extension Period) OLS or AE end date is missing, then  
▪ if AE start year and month are equal to the month and year of first dose date 
of the Treatment Period (Extension Period) OLS, then impute the AE start day 
as the day of first dose date of the Treatment Period (Extension Period) OLS;  
▪ else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period (Extension Period) OLS or AE end date is missing, then  
▪ if AE start year is equal to the year of first dose date of the Treatment Period 
(Extension Period) OLS, then impute the AE start month and day as the month 
and day of first dose date of the Treatment Period (Extension Period) 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.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing, then query site.  
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the first dose date 
of the Treatment Period (Extension Period) OLS.  
o else impute the AE start date as the informed consent date. 
 
Imputation rules for partial AE end date in study 105 database 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 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20xULN 
>20xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20xULN 
>20xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤ 3xULN) or 
(AST>ULN - ≤ 3xULN) 
(ALT>3x - ≤ 5xULN) or (AST>3x - 
≤ 5xULN) 
(ALT>5x- ≤ 8xULN) or (AST>5x - 
≤    8xULN) 
(ALT>8x - ≤ 20xULN) or (AST>8x 
- ≤ 20xULN) 
ALT>20xULN or AST> 20xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5xULN 
>2.5 – ≤ 5.0xULN 
>5.0 – ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Indirect Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 


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


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Table 12-3 
Threshold Analysis Criteria for Laboratory Tests 
Parameter 
Threshold Analysis 
Comments 
Platelets 
Platelet decreased 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L  
<50.0 – ≥ 25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 
Reticulocytes/Erythrocytes (%)   
<LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated partial thromboplastin 
time (PTT)  
 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5xULN 
>2.5xULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5xULN 
>2.5xULN 
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 
>3xULN 
>5xULN 
>8xULN 
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 
 
 


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Table 12-5 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
QTc 
 
>450 to <500ms (Male) or >470 to <500ms 
(Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
 
To be applied to any kind of QT correction 
formula.  
 
 
 
 
Note: Based on CPMP 1997 guideline. 
 


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Table 12-6 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Pulse Rate 
Same as above in ECG category 
 
 
SBP increased 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg and >10 mmHg increase from 
baseline 
>140 mmHg and >20 mmHg increase from 
baseline 
>160 mmHg and >10 mmHg increase from 
baseline 
>160 mmHg and >20 mmHg increase from 
baseline 
 
809/770 analyses 
SBP decrease 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from 
baseline 
<90 mmHg and >20 mmHg decrease from 
baseline 
<80 mmHg and >10 mmHg decrease from 
baseline 
<80 mmHg and >20 mmHg decrease from 
baseline 
 
Per HV grade 1, 3, plus shift change 


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


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12.5 
Adverse Events of Special Interest  
Table 12-4 
MedDRA Preferred Terms for Event of Special Interest 
Adverse event of special interest 
MedDRA preferred terms 
Elevated transaminases 
Alanine aminotransferase abnormal, Alanine aminotransferase 
increased, Aspartate aminotransferase abnormal, Aspartate 
aminotransferase increased, Transaminases abnormal, 
Transaminases increased, Liver function test abnormal, Liver 
function test increased, Hypertransaminasaemia, Hepatic 
enzyme abnormal, Hepatic enzyme increased 
Rash 
Acute generalised exanthematous pustulosis, Anal rash, 
Cutaneous vasculitis, Dermatitis, Dermatitis 
allergic, Dermatitis atopic, Dermatitis bullous, Dermatitis 
exfoliative, Dermatitis exfoliative 
generalised, Drug eruption, Drug hypersensitivity, Drug reaction 
with eosinophilia and systemic 
symptoms, Epidermal necrosis, Epidermolysis, Erythema 
multiforme, Erythrodermic atopic dermatitis, 
Exfoliative rash, Fixed eruption, Generalised bullous fixed drug 
eruption, Immune-mediated 
dermatitis, Mucocutaneous rash, Nodular rash, 
Oculomucocutaneous syndrome, Penile rash, Perioral 
dermatitis, Rash, Rash erythematous, Rash follicular, Rash 
macular, Rash maculo-papular, Rash 
maculovesicular, Rash morbilliform, Rash papular, Rash 
papulosquamous, Rash pruritic, Rash 
pustular, Rash rubelliform, Rash scarlatiniform, Rash vesicular, 
SJS-TEN overlap, Scrotal 
dermatitis, Skin exfoliation, Skin necrosis, Skin toxicity, 
Stevens-Johnson syndrome, Toxic 
epidermal necrolysis, Toxic skin eruption, Type IV 
hypersensitivity reaction, Urticaria, Urticaria 
papular, Urticaria vesiculosa, Urticarial dermatitis, Urticarial 
vasculitis, Vasculitic rash 
 
 
 
Note: The preferred terms listed in the table is based on the MedDRA version 24.1 applicable at 
the time of finalization of the SAP. If the MedDRA version is upgraded at the time of the final 
analysis, the corresponding preferred terms based on the upgraded version will be used in the 
analysis of adverse events of special interest. 
 
 
 


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12.6 
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: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138978 
[Accessed April 9, 2018]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] Available 
at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138979 [Accessed 
April 9, 2018].   
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: http://www.ers-education.org/home/browse-all-
content.aspx?idParent=138988 [Accessed  April 9, 2018]. 
Data handling rule for spirometry is as follows:  
• Input age with at least 2 decimal places 
• Use height at screening of the parent study regardless if height is collected at other study 
visits for subjects whose age at informed consent of the parent study is >21 years. For 
subjects with age <=21 years, height collected at the respective visit should be used; If 
the height at the respective visit is not available, the last non-missing record will be used  
• For race, map CRF black or AA to black, all other races in CRF (except white) are 
mapped to 'other'; multiple checks for race in CRF are also mapped to 'other'; white is a 
reference race in the equations and assumes 0 values for all race coefficients in the       
GLI equations. 
 
 


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