A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of VX-659/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 Through 11 Years of Age
Phase: PHASE3
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated



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2 
PROTOCOL SYNOPSIS 
Title A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of 
VX-659/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 Through 
11 Years of Age 
  
Brief Title Evaluation of VX-659/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years  
  
Clinical Phase 
and Clinical 
Study Type  
Phase 3, pharmacokinetic (PK), safety, and tolerability 
  
Objectives Part A 
Primary Objective 
To evaluate the PK of VX-659, tezacaftor (TEZ), and ivacaftor (IVA) when dosed in triple 
combination (TC) 
Secondary Objectives 
 To evaluate the PK of TEZ and IVA metabolites  
 To evaluate the safety and tolerability of VX-659/TEZ/IVA  
  
Endpoints Part A  
Primary Endpoint 
PK parameters of VX-659, TEZ, and IVA, including Cmax, C
trough, and AUC
0-τ 
Secondary Endpoints 
 PK parameters of TEZ and IVA metabolites, including Cmax, C
trough, and AUC
0-τ 
 Safety and tolerability as determined by adverse events (AEs), clinical laboratory values, 
standard 12-lead ECGs, vital signs, and pulse oximetry 

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Number of 
Subjects 
Part A  
Approximately 12 subjects are planned for enrollment. 
 
  
 
Study 
Population 
Male and female cystic fibrosis (CF) subjects 6 through 11 years of age who are homozygous 
for F508del (F/F genotype) or heterozygous for F508del and a minimal function mutation that 
is not responsive to TEZ, IVA, or TEZ/IVA (F/MF genotypes). 
 
 
  
Investigational 
Drug 
 
Part A 
Active substance: VX-659/TEZ/IVA  
Activity: CFTR correctors (VX-659 and TEZ) and CFTR potentiator (IVA) (increased 
chloride ion secretion) 
Strength and route of administration: 120-mg VX-659/50-mg TEZ/75-mg IVA fixed-dose 
combination (FDC) tablet for oral administration AND 75-mg IVA tablet for oral 
administration 
Dose administered:  
 VX-659 120 mg qd/TEZ 50 mg qd/IVA 75 mg q12h; 1 × VX-659/TEZ/IVA FDC tablet 
in the morning and 1 × IVA tablet in the evening 

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Statistical 
Analyses 
Data from Parts A 
 will be analyzed separately. 
Part A 
Approximately 12 subjects will be enrolled in Part A. Sample size calculations were 
determined based on VX-659 PK using noncompartmental analysis-based parameters, such as 
clearance and volume of distribution. Based on the variability observed in adults, data from 
12 subjects will allow 80% power to target a 95% CI within 60% and 140% of the geometric 
mean estimate of clearance for VX-659.  
  

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4 
TABLE OF CONTENTS 
1 Title Page 
................................................................................................................................ 1 
2 Protocol Synopsis 
................................................................................................................... 2 
3 Schedule of Assessments........................................................................................................ 7 
4 Table of Contents 
................................................................................................................. 15 
List of Tables............................................................................................................................ 18
 
List of Figures 
.......................................................................................................................... 18 
List of Abbreviations................................................................................................................ 19 
5 Introduction.......................................................................................................................... 22 
5.1 Background 
..................................................................................................................... 22 
5.2 Study Rationale .............................................................................................................. 22 
6 Study Objectives 
.................................................................................................................. 23 
6.1 Primary Objectives 
......................................................................................................... 23 
6.2 Secondary Objectives 
..................................................................................................... 23 
7 Study Endpoints 
................................................................................................................... 23 
7.1 Primary Endpoints 
.......................................................................................................... 23 
7.2 Secondary Endpoints 
...................................................................................................... 23 
 
 
8 Study Population 
.................................................................................................................. 24 
8.1 Inclusion Criteria 
............................................................................................................ 24 
8.2 Exclusion Criteria 
........................................................................................................... 25 
9 Study Implementation 
......................................................................................................... 27 
9.1 Study Design .................................................................................................................. 27 
9.1.1 Screening 
................................................................................................................ 28 
9.1.1.1 Repetition of Screening Assessments 
.............................................................. 29 
9.1.1.2 Rescreening 
...................................................................................................... 29 
9.1.1.3 Extension of Screening Period Window 
.......................................................... 29 
9.1.2 Treatment Period 
.................................................................................................... 29 
9.1.3 Follow-up................................................................................................................ 30 
9.1.4 Early Termination of Treatment 
............................................................................. 30 
9.1.5 Lost to Follow-up 
................................................................................................... 30 
9.1.6 Completion of Study Participation 
......................................................................... 31 
9.1.7 Independent Data Monitoring Committee 
.............................................................. 31 
9.2 Method of Assigning Subjects to Treatment Groups 
..................................................... 31 
9.3 Rationale for Study Elements 
......................................................................................... 32 
9.3.1 Study Design........................................................................................................... 32 
9.3.2 Study Population..................................................................................................... 32 
9.3.3 Study Drug Dose and Duration .............................................................................. 32 
9.3.4 Rationale for Study Assessments ........................................................................... 33
 
9.4 Study Restrictions 
........................................................................................................... 34 
9.4.1 Prohibited Medications 
........................................................................................... 34 
9.4.2 Exposure to Sunlight .............................................................................................. 35 
9.5 Prior and Concomitant Medications 
............................................................................... 35 
9.6 Administration 
................................................................................................................ 36 
9.6.1 Dosing 
..................................................................................................................... 36 

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List of Abbreviations 
Abbreviation Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
AUC 
area under the concentration versus time curve 
BMI 
body mass index 
CF 
cystic fibrosis 
 
 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
CI 
confidence interval 
Cl− 
chloride ion 
Cmax 
maximum observed concentration 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
predose concentration 
CYP 
cytochrome P450 
 
 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ETT 
Early Termination of Treatment 
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 
F/MF 
heterozygous for F508del and a minimal CFTR function mutation 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
 
 
 
 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
 
 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
HBE 
human bronchial epithelial (cells) 
HIPAA 
Health Insurance Portability and Accountability Act  

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Abbreviation Definition 
SI 
SI units (International System of Units) 
SUSAR 
suspected, unexpected, serious adverse reaction 
SwCl 
sweat chloride 
TC 
triple combination 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
ULN 
upper limit of normal 
US 
United States 
 

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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive disease with serious, chronically debilitating 
morbidities and high premature mortality and, at present, has no cure. CF affects approximately 
70,000 individuals worldwide.
1  
CF is caused by a defect in the gene encoding the CFTR protein, an epithelial chloride (Cl-) ion 
channel that is responsible for aiding in the regulation of salt and water absorption and secretion 
in various tissues.
2 This function is defective in patients with CF due to a loss of cell surface 
expression and/or function of CFTR. 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.
3, 4 
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 (Kalydeco
® and Orkambi
®). 
Tezacaftor (TEZ; VX-661) is a first-generation CFTR corrector that improves the processing and 
trafficking of the F508del-CFTR protein, resulting in an increase in the quantity of 
F508del-CFTR protein at the cell surface. Ivacaftor (IVA) increases the open-channel probability 
of the F508del-CFTR protein that has been delivered to the cell surface by TEZ, thereby 
enhancing total chloride transport. The combined effect of TEZ and IVA is increased quantity 
and function of F508del-CFTR at the cell surface. 
VX-659 is a next-generation CFTR corrector. In vitro, the triple combination (TC) of VX-659, 
TEZ, and IVA (VX-659/TEZ/IVA) increased CFTR chloride transport in F508del/F508del-
human bronchial epithelial (HBE) cells more than any of the dual combinations (VX-659/TEZ, 
VX-659/IVA, and TEZ/IVA) or individual components (VX-659, TEZ, and IVA) under most 
conditions studied.
5  
5.2 
Study Rationale 
Given the progressive nature of CF, there is a strong rationale for treating patients earlier in life. 
Vertex is currently evaluating VX-659/TEZ/IVA TC therapy in Phase 3 studies in adult and 
adolescent CF subjects who are heterozygous for F508del with a second CFTR allele carrying a 
minimal function (MF) mutation that is not responsive to TEZ, IVA, or TEZ/IVA (F/MF 
genotypes; Appendix A) and subjects homozygous for F508del (F/F genotype). Given the 
clinical benefit seen in a Phase 2 study of adults with CF with VX-659/TEZ/IVA, the present 
study is designed to obtain pharmacokinetic (PK), safety, tolerability, and pharmacodynamic 
(PD) information to expand the evaluation of this study drug in the pediatric population 
6 through 11 years of age with F/F or F/MF genotypes (refer to VX-659 Investigator’s 
Brochure). 

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6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
Part A 
To evaluate the PK of VX-659, TEZ, and IVA when dosed in TC 
6.2 
Secondary Objectives 
Part A 
 To evaluate the PK of TEZ and IVA metabolites  
 To evaluate the safety and tolerability of VX-659/TEZ/IVA  
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoints 
Part A  
PK parameters of VX-659, TEZ, and IVA, including Cmax, C
trough, and AUC
0-τ 
7.2 
Secondary Endpoints 
Part A  
 PK parameters of TEZ and IVA metabolites, including Cmax, C
trough, and AUC
0-τ 
 Safety and tolerability as determined by AEs, clinical laboratory values, standard 12-lead 
ECGs, vital signs, and pulse oximetry 

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8 
STUDY POPULATION 
Eligibility will be reviewed and documented by a qualified member of the investigator’s team 
before enrollment. 
8.1 
Inclusion Criteria 
Parts A 
 
Subjects who meet all of the following inclusion criteria will be eligible for Part A  
 
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
informed consent form (ICF), and an assent form. 
2. Subjects (males and/or females), 6 through 11 years of age, inclusive, on the date of informed 
consent. 
3. Subjects who weigh 15 kg without shoes at the Screening Visit. 

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 Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical 
carcinoma in situ (all 3 with no recurrence for the last 5 years).  
2. Any clinically significant laboratory abnormalities at the Screening Visit that would interfere 
with the study assessments or pose an undue risk for the subject (as deemed by the 
investigator). 
3. Any of the following abnormal laboratory values at screening: 
 Hemoglobin <10 g/dL 
 Total bilirubin ≥2 × upper limit of normal (ULN) 
 Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase 
(GGT), or alkaline phosphatase (ALP) ≥3 × ULN 
 Abnormal renal function defined as glomerular filtration rate ≤45 mL/min/1.73 m2 
(calculated by the Counahan-Barratt equation)
7 
4. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy 
(including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study 
drug). 
5. Lung infection with organisms associated with a more rapid decline in pulmonary status 
(including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and 
Mycobacterium abscessus). For subjects who have had a history of a positive culture, the 
investigator will apply the following criteria to establish whether the subject is free of 
infection with such organisms:  
 The subject has not had a respiratory tract culture positive for these organisms within the 
12 months before the date of informed consent and assent. 
 The subject has had at least 2 respiratory tract cultures negative for such organisms 
within the 12 months before the date of informed consent, with the first and last of these 
separated by at least 3 months, and the most recent one within the 6 months before the 
date of informed consent and assent. 
6. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of 
study drug (Day 1).  
7. A screen positive for drugs of abuse or alcohol, as defined in Section 11.5.2, at the Screening 
Visit. 
8. Ongoing or prior participation in an investigational drug study (including studies 
investigating VX-659 with or without coadminstration with other study drugs) within 30 days 
of the Screening Visit.  
 A washout period of 5 terminal half-lives of the previous investigational study drug, or 
30 days, whichever is longer, must elapse before the Screening Visit.  
 The duration of the elapsed time may be longer if required by local regulations.  
Note: Ongoing participation in a noninterventional study (including observational 
studies) is permitted. 

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screening data from these subjects must be obtained within 28 days before administration of 
study drug. 
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.4) and concomitant medications (Section 9.5). 
9.1.1.1 
Repetition of Screening Assessments 
Parts A 
  
Screening assessments may be repeated once to establish study eligibility. If repeat values of the 
individual assessment(s) are within the eligibility criteria and completed within the screening 
window, then the subject is eligible for the study. 
9.1.1.2 
Rescreening 
Parts A  
 
Subjects may be rescreened once. If a subject is rescreened, all screening assessments will be 
repeated, except for:  
 CFTR genotyping 
 Ophthalmologic examination (if performed within 3 months of the date of informed consent) 
If a subject is rescreened, a new screening window will begin when the first rescreening 
assessment has been initiated. 
9.1.1.3 
Extension of Screening Period Window 
Parts A 
  
A subject may have the Screening Period window extended by 2 weeks for the following 
reasons: 
 Repetition of the Screening Period assessments (Section 9.1.1.1) 
 Unexpected operational or logistic delays, or to meet the eligibility criteria 
 Scheduling of ophthalmologic examination (Section 11.5.5) 
9.1.2 
Treatment Period 
Parts A 
  
The Treatment Period will last approximately 15 days in Part A 
 Study 
drug administration details are provided in Section 9.6. 
Subjects who prematurely discontinue study drug treatment will remain in the study from the 
time of discontinuation of study drug treatment through the last scheduled study visit and 
complete the assessments for all study visits, as described in Section 9.1.4. 

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9.1.3 
Follow-up 
Part A  
Subjects will have a Safety Follow-up Visit 28 (± 7) days after the last dose of study drug.  
9.1.4 
Early Termination of Treatment 
Parts A 
  
If a subject prematurely discontinues study drug treatment, an Early Termination of Treatment 
(ETT) Visit should be scheduled as soon as possible after the decision to discontinue treatment. 
Subjects who prematurely discontinue treatment will also be required to complete the Safety 
Follow-up Visit (Table 3-2 for Part A 
 if applicable (Section 9.1.3).  
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.  

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9.1.6 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as 1 of the following: 
Part A 
 For subjects who complete the Treatment Period: the Safety Follow-up Visit 
 For subjects who prematurely discontinue study drug treatment but do not withdraw consent 
(and assent, as applicable): the latest of the Day 15 Visit, ETT Visit, or Safety Follow-up 
Visit 
 For subjects who withdraw consent or assent: date of withdrawal of consent or assent, 
whichever is earlier (Section 9.9) 
9.2 
Method of Assigning Subjects to Treatment Groups 
An interactive web response system (IWRS) will be used.  

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Table 9-2 
Prohibited Medications 
Medication 
Timing of Restriction 
Rationale 
Start of 
Restriction 
End of 
Restriction 
Moderate and strong 
CYP3A or CYP2C9 
inducers 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
through 
completion of 
study 
participation 
VX-659, TEZ, and IVA are metabolized 
extensively via CYP3A4. VX-659 is also 
metabolized by CYP2C9. Therefore, use of 
moderate and strong inducers of CYP3A or 
CYP2C9 and moderate and strong inhibitors of 
CYP3A, which have the potential to alter the 
exposure of VX-659, TEZ, or IVA, will be 
prohibited. 
 
Moderate and strong 
CYP3A inhibitors 
(except 
ciprofloxacin)
a 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
through 
completion of 
study 
participation 
Sensitive OATP1B1 
substrates 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
through 
completion of 
study 
participation 
VX-659 is a potential inhibitor of the hepatic 
transporter OATP1B1. Therefore, sensitive 
substrates of OATP1B1, such as HMG-CoA 
reductase inhibitors ("statins") are prohibited 
during treatment. 
CFTR modulators 
(investigational or 
approved), except for 
study drugs 
None allowed 
within 28 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
until after the last 
dose of study 
drug 
These agents may confound the results of this 
study. 
Herbal and dietary 
supplements 
None allowed 
within 14 days 
before the first 
dose of the study 
drug on Day 1 
None allowed 
through 
completion of 
study 
participation 
These agents may confound the results of this 
study. 
CYP: cytochrome P450; IVA: ivacaftor; OATP1B1: organic anion transporting polypeptide 1B1; 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). 
9.4.2 
Exposure to Sunlight 
Parts A  
 
Subjects will take appropriate measures to minimize exposure to ultraviolet radiation 
(e.g., prolonged sunlight, tanning booths) from Day 1 through completion of study participation. 
9.5 
Prior and Concomitant Medications 
Parts A  
 
Prohibited medications as described in Section 9.4.1 are not allowed in this study while subjects 
are receiving study drug. A nonexhaustive study prohibitions and cautions list for food and 
medications will be provided in the Study Reference Manual. 

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9.6 
Administration 
9.6.1 
Dosing 
Part A  
On Day 1 through Day 15, VX-659/TEZ/IVA will be orally administered with water. On Day 15, 
only the morning dose of VX-659/TEZ/IVA will be administered. 
Study drug should be administered within approximately 30 minutes of the start of a 
fat-containing snack or meal, such as a standard "CF" meal or snack according to the following 
guidelines:  
1. Morning dose of study drug will be administered at the site on Days 1, 2, 8, and 15. 
2. Study drug will be administered after all predose assessments have been performed. 
3. All doses of study drug (morning and evening, as applicable) should be administered at 
approximately every 12 hours (± 1 hour) on each dosing occasion (e.g., if the morning doses 
of study drug are administered at 08:00 hour on Day 1, all subsequent morning doses should 
be administered between 07:00 hour and 09:00 hour). 
4. Study drug tablets will be administered within 5 minutes of each other. 
5. Study drug will be administered with approximately 240 mL (approximately 1 cup, 8 ounces, 
or half a pint) of water.   
6. At the Day 1 Visit, all subjects will be observed for 4 hours after the morning dose of the 
study drug. 
7. The date, amount taken, and time of study drug administration including whether food was 
taken with each dose, will be recorded for 2 days before PK sample collection and on the 
days of PK sample collection. 

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9.6.2 
Missed Doses 
9.6.2.1 
Morning Dose of Study Drug 
Parts A 
  
If a subject misses the morning dose of study drug and recalls within 6 hours, the subject should 
take his/her dose with food. If more than 6 hours but fewer than 12 hours have elapsed after 
his/her usual dosing time, the subject should take the morning dose of study drug but skip the 
evening dose of study drug. If more than 12 hours have elapsed after his/her usual dosing time, 
the subject should skip the morning dose of study drug and take the evening dose of study drug.  

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9.6.2.2 
Evening Dose of Study Drug 
Parts A 
  
If a subject misses the evening dose of IVA and recalls within 6 hours, the subject should take 
his/her dose with food. If more than 6 hours have elapsed after his/her usual dosing time, the 
subject should skip that dose and resume his/her normal schedule for the following dose.  
9.7 
Dose Modification for Toxicity 
Parts A 
  
Modifications of the study drug dose are prohibited. Should any unacceptable toxicity arise, 
individual subjects will be withdrawn from the study and dosing will cease. 
9.8 
Study Drug Interruption and Stopping Rules 
9.8.1 
Liver Function Tests 
Parts A 
 
The central laboratory will notify the medical monitor of ALT or AST >3 × 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 criteria are met: 
 Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, 
alcohol ingestion) is identified, regardless of whether transaminase levels have improved 
All subjects in whom treatment is discontinued for elevated transaminases (and bilirubin, as 
applicable) should have these levels monitored closely until levels normalize or return to 
baseline. 

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If an alternative, reversible cause of transaminase elevation with or without increased bilirubin or 
clinical jaundice has been identified, study drug administration may be resumed once 
transaminases return to baseline or are ≤2 × ULN, whichever is higher. Regardless of the 
duration of interruption, the medical monitor should be notified prior to resumption of study 
drug. Upon resumption of study drug, transaminases and bilirubin should be assessed weekly for 
4 weeks. If a protocol-defined transaminase elevation interruption threshold recurs within 
4 weeks of rechallenge with the study drug (with confirmation of the initial elevation by repeat 
testing within 48 to 72 hours), then the study drug must be permanently discontinued, regardless 
of the presumed etiology. 
9.8.2 
Rash 
Parts A 
  
Individuals who develop a generalized rash will be monitored closely. Study drug dosing should 
be interrupted if a subject develops a generalized rash of Grade 3 or higher, or a rash that is 
considered a serious adverse event (SAE). The investigator will notify the medical monitor of 
any rash that results in interruption of study drug, is Grade 3 or higher (Section 13.1.1.4), or is an 
SAE. Investigators should consider additional evaluation including laboratory testing (e.g., 
complete blood count with differential, liver function tests), photographs of the rash, and 
dermatology consultation. The investigator may consider resumption of study drug if considered 
clinically appropriate. 
9.9 
Removal of Subjects  
Parts A 
  
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: 
 Has a screening CFTR genotype that does not confirm study eligibility if a previous CFTR 
genotype laboratory report was used to establish eligibility. These subjects must be 
discontinued from the study (Section 8.1) 
 Meets any of the stopping (discontinuation) criteria (Section 9.8) 
 Has a QTcF value above the threshold for repeat measurement (Section 11.5.4) 
 Becomes pregnant (Section 11.5.6.2)  
Subjects who discontinue study drug treatment should return for study assessments, as noted in 
Section 9.1.4. 
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 

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Follow-up Visit, if applicable (see Section 9.1.4), 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. 
9.10 
Replacement of Subjects 
Part A Only 
Subjects who withdraw or are withdrawn for nonsafety reasons during the Treatment Period may 
be replaced as needed in Part A, 
 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
Parts A 
 
Study drug refers to VX-659/TEZ/IVA. 
10.1 
Preparation and Dispensing 
Parts A 
  
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 
Parts A 
  
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 
Parts A 
 
Table 10-1 provides the study drug information. The investigator, or an authorized designee 
(e.g., a licensed pharmacist), will ensure that all investigational product is stored in a secured 
area, under recommended storage conditions, and in accordance with applicable regulatory 
requirements. Detailed instructions regarding the storage, handling, and dispensation of the study 
drug will be provided in the Pharmacy Manual. 

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Table 10-1 Study Drug: Strength/Dosing Form/Route 
Drug Name, Dosing Form, Route 
Strength 
Part A:  
All Subjects 
VX-659/TEZ/IVA, FDC tablet, oral 
 
VX-659 
120 mg  
TEZ 
50 mg 
IVA 
75 mg 
IVA, tablet, oral 
75 mg 
FDC: fixed-dose combination; IVA: ivacaftor; TEZ: tezacaftor 
10.4 
Drug Accountability 
Parts A 
 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee. The study monitor will review study drug 
records and inventory throughout the study. 
If a site uses a site-specific drug accountability system and/or process, including processes 
associated with the destruction of returned materials, the process must be documented and 
approved by Vertex. The study monitor must review the drug accountability documentation on a 
regular basis. The study monitor will promptly communicate to Vertex any discrepancies he/she 
is unable to resolve with the site.  
10.5 
Disposal, Return, or Retention of Unused Drug 
Parts A 
 
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  
Parts A 
 
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. 

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10.7 
Blinding and Unblinding 
Parts A 
  
This will be an open-label study; however, subjects and their legally appointed and authorized 
representative (e.g., parent or legal guardian) should not be informed of their 
 
 results during the Treatment Period, 
regardless if the subject permanently discontinues treatment. 
11 
ASSESSMENTS 
The timing of assessments is shown in Table 3-1 through Table 3-4.  
The following assessments must be performed in the order specified below when more than 
1 assessment is required at a particular time point: 
Parts A  
 
1. Vital signs 
2. Pulse oximetry  
3. Standard 12-lead ECG recordings 
4. Safety laboratory assessments  
5. PK sampling 
 may be performed in either order when occurring at the same 
time point. PK blood samples collected before dosing must be collected within 60 minutes 
before dosing as described in Section 11.2.1. 
11.1 
Subject and Disease Characteristics 
Parts A 
  
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 
Medical history will be elicited from each subject and extracted from medical records during 
screening. Based on the medical history, the subject will be assessed for any disqualifying 
medical conditions as specified in the inclusion and exclusion criteria. The medical history will 
include a complete review of systems, medical and surgical histories, and any allergies. 

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11.4 
Efficacy 
11.4.1 
Spirometry 
Parts A 
  
Spirometry will be performed according to the American Thoracic Society Guidelines
13 and 
according to the additional guidelines that follow. 

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11.4.4 
Height and Weight 
Parts A 
  
Height and weight will be measured with shoes off and before the dose of the study drug during 
the Treatment Period. 
11.5 
Safety 
Parts A 
  
Safety evaluations will include reporting of AEs, clinical laboratory assessments, physical 
examinations (PEs), clinical evaluation of vital signs, pulse oximetry, standard 12-lead ECGs, 
and ophthalmologic examinations. 
Medical history and PE information will be collected during the course of the study and will be 
captured in the source documentation. Physical examinations post-baseline will not be captured 
for inclusion into the study database. However, any untoward findings identified on PEs 
conducted after the administration of the first dose of study drug will be captured as an AE if 

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those findings meet the definition of an AE. Demographic data collected at the Screening Visit 
will be included in the study database. 
11.5.1 
Adverse Events 
Parts A 
  
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. Electronic AE case report form (CRF) completion 
guidelines for investigators as well as training will be provided. 
11.5.2 
Clinical Laboratory Assessments 
Parts A 
  
Blood and urine samples will be analyzed at a central laboratory with the exception of urine 
pregnancy tests, which will be analyzed locally. All blood samples will be collected while 
subjects are in a seated or supine position. Specific instructions for the collection, processing, 
and shipment of samples will be provided in a separate Laboratory Manual. Laboratory test 
results that are abnormal and considered clinically significant must be reported as AEs (see 
Section 13.1.1.2).  
Blood and urine samples for clinical laboratory assessments will be collected according to the 
schedule of assessments (Table 3-1 
). 

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Table 11-2 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. 
Clinical laboratory assessments from screening will have no clinically significant findings that 
preclude participation in the study, as deemed by the investigator, for a subject to receive study 
drug on Day 1.  
Liver function testing (ALT, AST, GGT, ALP, and total bilirubin) must be performed at the 
scheduled visits and Week 20 (a minimum of every 4 weeks after Week 4). A local laboratory 
may be used for the Week 20 sample if a subject cannot return to the site for the blood draw; 
confirmatory testing by the central lab must be performed as soon as possible if liver function 
tests are determined to be abnormal.  
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 serum pregnancy test at screening. A definition of 
non-childbearing potential is provided in Section 11.5.6.1. 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, when there is no clinic visit scheduled, at home 
by using a home kit provided by the site. Results 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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CF genotype (Screening Period only): CF genotyping will be performed on all subjects to 
confirm the genotype documented in the subject
's medical record. This assessment does not need 
to be repeated in the case of rescreening 
 
 
Drug and Alcohol Screening (Screening Period [Parts A  
 and Day 1 [Part A Only]): 
opiates, methadone, cannabinoids, cocaine, amphetamines/methamphetamines, barbiturates, 
benzodiazepines, cotinine, and alcohol will be assessed by a urine test. Subjects may undergo 
random urine drug screen and alcohol testing if deemed appropriate by the investigator. Drug 
screen result will be negative for all subjects to receive study drug. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged by the investigator to be clinically appropriate.  
For the purposes of study conduct and unless noted otherwise, only laboratory tests done in the 
central laboratory may be used. Local laboratories may be used at the discretion of the local 
investigator for management of urgent medical issues. If a local laboratory test value is found to 
be abnormal and clinically significant, it will be verified by the central laboratory as soon as 
possible after the investigator becomes aware of the abnormal result. If it is not possible to send a 
timely specimen to the central laboratory (e.g., the subject was hospitalized elsewhere), the 
investigator may base the assessment of an AE on the local laboratory value. 
11.5.3 
Physical Examinations and Vital Signs 
Parts A 
  
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits. At other visits, symptom-directed PEs and symptom-directed vital signs assessments 
can be performed at the discretion of the investigator or healthcare provider
. 
A PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, nose, and 
throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs. 
Symptom-directed PEs and symptom-directed vital signs assessment may be performed if 
appropriate. 
Weight, height, and BMI (derived) will also be assessed (Section 11.4.4). 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. These will be assessed following at least a 5-minute rest in the seated or supine 
position. 
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. 

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11.5.4 
Electrocardiograms 
Parts A 
  
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines: 
 The ECG will be done before any other procedures that may affect heart rate, such as blood 
draws. 
 The subject will be instructed to rest for at least 5 minutes before having an ECG. 
 ECGs will be performed in triplicate at the Day 1 Visit. 
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 safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. A subject with a 
QTcF value above the threshold value will discontinue dosing. 
11.5.5 
Ophthalmologic Examination 
Parts A
  
Ophthalmologic examinations do not need to be completed if there is documentation of bilateral 
lens removal for the subject. 
All examinations will be conducted by a licensed ophthalmologist or optometrist and will 
include: 
 measurement of best-corrected distance visual acuity of each eye; and 
 pharmacologically dilated examination of the lens with a slit lamp. 
The screening examination does not need to be conducted if there is documentation of an 
examination meeting the protocol requirements that was conducted within 3 months before the 
date of informed consent. 
Any clinically significant abnormal findings will be reported as AEs. 

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11.5.6 
Contraception and Pregnancy 
Parts A 
  
The effects of VX-659 monotherapy or in TC with TEZ and IVA on conception, pregnancy, and 
lactation in humans are not known. VX-659, 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-659, TEZ, and IVA have not shown teratogenicity in rats and rabbits. 
11.5.6.1 
Contraception 
Parts A  
  
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 Screening Visit through 90 days after the last dose of study drug. 
 If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the first 
dose of study drug (e.g., examination of a semen specimen or by demonstration of the 
absence of the vas deferens by ultrasound). 
 If the female is of non-childbearing potential. To be considered of non-childbearing potential, 
the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum 
follicle-stimulating hormone (FSH) level within the laboratory’s reference range for 
postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
Note: All other females 10 years of age and older (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 11-3. 

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Table 11-3 Acceptable Methods of Contraception 
 
Male Subjects and Their 
Female (Non-study) 
Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy performed at least 6 months previously, 
with a documented negative postvasectomy semen 
analysis for sperm 
Yes 
Yes 
Bilateral tubal occlusion (e.g., ligation) performed at 
least 6 months previously 
Yes 
Yes 
Male or female condom with or without spermicidea 
Yes 
Yes 
Female barrier contraception (such as diaphragm, 
cervical cap, or sponge) with spermicide 
Yes 
Yes 
Continuous use of an intrauterine device for at least 
90 days before the first dose of study drug 
 
 
 Hormone-releasing 
Yes 
Nob 
 Non-hormone releasing 
Yes 
Yes 
Hormonal contraceptives, if successfully used for at 
least 60 days before the first dose of study drug 
 
Yes 
 
Nob 
 
a A female condom cannot be used with a male condom due to risk of tearing.  
b 
Hormone-releasing intrauterine devices and hormonal contraceptives are not considered an acceptable method 
in female study subjects due to potential induction of metabolism by VX-659; however, female subjects are not 
required to discontinue their use of hormone-releasing intrauterine devices or hormonal contraceptives.
 
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 11-3.  
 Male subjects must not donate sperm during the period starting from the first dose of study 
drug until 90 days after the last dose of study drug. 
 Female subjects should not nurse a child during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
 For male subjects with a female partner of childbearing potential, the couple should not plan 
to become pregnant during the study or within 90 days after the last dose of study drug, with 
the exception of couples who plan to become pregnant by artificial insemination using sperm 
banked by the male subject before the first dose of study drug or sperm from another source. 
11.5.6.2 
Pregnancy 
Parts A
  
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a female subject becomes pregnant during study participation, study drug will be permanently 
discontinued immediately. The investigator will notify the medical monitor and Vertex Global 
Patient Safety (GPS) within 24 hours of the site’s knowledge of the subject’s (or partner’s) 
pregnancy using the Pregnancy Information Collection Form. Male subjects with female partners 

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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. 
If confirmed to be on active drug, 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 
Parts A 
  
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 
Part A 
Approximately 12 subjects will be enrolled in Part A. Sample size calculations were determined 
based on VX-659 PK, using noncompartmental analysis (NCA)-based parameters, such as 
clearance and volume of distribution. Based on the variability observed in adults, data from 
12 subjects will allow 80% power to target a 95% CI within 60% and 140% of the geometric 
mean estimate of clearance for VX-659.  

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A given medication can 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 partial missing start/end date 
or time and it cannot be determined whether the medication was taken before first dose, 
concomitantly, or post-treatment, it will be considered as prior, concomitant, and post-treatment. 
Prior and post-treatment medications will only be listed and not summarized. The concomitant 
medications will be summarized descriptively based on the FAS.  
12.3.2.4 
Study Drug Exposure and Compliance 
Parts A  
 
Study drug compliance will be measured by the exposure ratio, which is calculated as: 100 × [1 - 
(Total number of days study drug interruption) / (Duration of study drug exposure in days)]. The 
total number of days of study drug interrupted is defined as the sum of (number of days of study 
drug interrupted in each interruption interval); where number of days of study drug interrupted in 
each interval is defined as the interruption end date - the corresponding interruption start date + 
1. 
Study drug exposure will be summarized based on the Safety Set in terms of the duration of 
treatment a subject received (in days), defined as the last day – the first day of study drug plus 1, 
regardless of study drug interruption. 
In addition, percentage of tablets taken will also be summarized based on the FAS, and will be 
calculated as 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). 
Duration of treatment and exposure ratio will be summarized using descriptive statistics.   

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 Treatment-emergent adverse events (TEAEs) 
 Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis as 
applicable) 
 Standard 12-lead ECGs 
 Vital signs 
 Pulse oximetry 
 Ophthalmological examinations 
12.3.5.1 
Adverse Events 
Parts A  
 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
 Pretreatment AE: any AE that occurred before the first dose of study drug 
 TEAE: any AE that is worsened (either in severity or seriousness) or that was newly 
developed at or after the first dose of study drug through the end of the TE Period 
 Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed after the TE Period 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study drug treatment, then the AEs will be classified as TEAEs. 
AE summary tables will be presented for TEAEs only, overall and by treatment group, 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 
Summaries will be presented by MedDRA System Organ Class and Preferred Term 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 

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will be provided separately. All AEs, including pre- and post-treatment AEs, will be presented in 
individual subject data listings. 
12.3.5.2 
Clinical Laboratory Assessments 
Parts A  
 
For the treatment-emergent laboratory measurements, the observed values and change from 
baseline values of the continuous hematology, serum chemistry, and coagulation results will be 
summarized in SI units at each scheduled visit. 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized overall and by treatment group. The threshold analysis criterion shift 
from baseline will also be summarized for select laboratory parameters. The threshold analysis 
criteria and the parameter selection criteria will be provided in the SAP. 
Results of urinalysis and the serum pregnancy test will be listed in individual subject data listings 
only. In addition, a listing containing individual subject hematology, chemistry, and coagulation 
values outside the reference ranges will be provided. This listing will include data from 
scheduled and unscheduled visits. 
12.3.5.3 
Electrocardiogram 
Parts A 
 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided, at each scheduled visit and time point, as applicable, for the 
following ECG interval measurements (in msec): RR, PR, QT, and QT corrected for HR (QTcF), 
QRS duration, and heart rate (HR) (beats per minute). 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized. The threshold analysis criteria will be provided in the SAP. 
12.3.5.4 
Vital Signs 
Parts A 
  
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each scheduled visit. The following vital signs parameters 
will be summarized: systolic and diastolic blood pressure (mm Hg), body temperature (C), pulse 
rate (heart rate, beats per minute), and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized. The threshold analysis criteria will be provided in the SAP. 
12.3.5.5 
Pulse Oximetry 
Parts A 
  
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each scheduled visit 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. 

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13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
All subsections below apply to Parts A  
 
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 9.1.6. 
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: 

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 Description of the event 
 Classification of "serious" or "nonserious" 
 Date of first occurrence and date of resolution (if applicable) 
 Severity 
 Causal relationship to study drug(s)  
 Action taken  
 Outcome  
 Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology 
Criteria for Adverse Events (CTCAE), Version 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. 
 

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13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4. 
Table 13-4 Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. "Fatal" will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
 
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)  

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If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms "serious" and "severe" because they are not 
synonymous. The term "severe" is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
"serious," which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
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: 
 (preferred choice) 
Fax: 
  
For questions, contact telephone: 
 

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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. 
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 and Assent 
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.  

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13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers and access to subject names linked to such 
numbers 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. 

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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. 
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. 

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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. 
13.6 
Publications and Clinical Study Report 

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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 
REFERENCE 
1  
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 03 September 2015. 
2  
Kreindler JL. Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
3  
Stern M, Wiedemann B, Wenzlaff P. From registry to quality management: the German 
Cystic Fibrosis Quality Assessment project 1995 - 2006. Eur Respir J. 2008;31(1):29-35. 
4  
Cystic Fibrosis Trust. UK Cystic Fibrosis Trust Annual Review 2010. Bromley, Kent, 
UK: Cystic Fibrosis Trust; 2012. 
6  
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. 
7  
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51(11):875-78. 
8  
Konstan M, McKone EF, Moss RB, Marigowda G, Cooke J, Huang X, et al. Evidence for 
reduced rate of lung function decline and sustained benefit with combination lumacaftor 
and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR 
mutation Lancet Haematol 2016; 
13  
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. 
 

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APPENDIX A   
Eligible MF CFTR Mutations 
"MF" mutations are a subset of minimal function mutations that are non-responsive to TEZ, 
IVA, or TEZ/IVA. A mutation is considered an MF mutation if it meets at least 1 of the 
following 2 criteria: 
(1) biological plausibility of no translated protein (genetic sequence predicts the complete 
absence of CFTR protein), or 
(2) in vitro testing that supports lack of responsiveness to TEZ, IVA, or TEZ/IVA, and evidence 
of clinical severity on a population basis (as reported in large patient registries). 
Inclusion of MF Mutations Based on In Vitro Testing 
Mutations that were considered to be MF mutations based on in vitro testing met the following 
criteria in in vitro experiments: 
 baseline chloride transport that was <10% of wildtype CFTR 
 an increase in chloride transport of <10% over baseline following the addition of TEZ, 
IVA, or TEZ/IVA in the assay 
These mutations also had evidence of clinical severity on a population basis (per CFTR2 patient 
registry; accessed on 15 February 2016). Patients with these mutations on one allele and F508del 
on the other allele exhibited evidence of clinical severity as defined as: 
 average sweat chloride >86 mmol/L, and 
 prevalence of pancreatic insufficiency (PI) >50% 
These clinical severity criteria do not apply to the individual subjects to be enrolled in the study, 
but were used to categorize each mutation on a population level. 
Eligible MF Mutations 
The list below represents acceptable mutations, which are detectable by an FDA-cleared 
genotyping assay or other method (e.g., sequencing); however, this list may not include every 
eligible mutation, and investigators should contact the medical monitor regarding other 
mutations that may also meet study eligibility criteria. 
 

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Non-exhaustive List of Minimal Function CFTR Mutations Eligible for VX17-659-106 
MF Mutation Category 
Mutation 
 
 
 
 
Nonsense mutations 
Q2X 
L218X 
Q525X 
R792X 
E1104X 
S4X 
Q220X 
G542X 
E822X 
W1145X 
W19X 
Y275X 
G550X 
W882X 
R1158X 
G27X 
C276X 
Q552X 
W846X 
R1162X 
Q39X 
Q290X 
R553X 
Y849X 
S1196X 
W57X 
G330X 
E585X 
R851X 
W1204X 
E60X 
W401X 
G673X 
Q890X 
L1254X 
R75X 
Q414X 
Q685X 
S912X 
S1255X 
L88X 
S434X 
R709X 
Y913X 
W1282X 
E92X 
S466X 
K710X 
Q1042X 
Q1313X 
 
Q98X 
S489X 
Q715X 
W1089X 
Q1330X 
 
Y122X 
Q493X 
L732X 
Y1092X 
E1371X 
 
E193X 
W496X 
R764X 
W1098X 
Q1382X 
 
W216X 
C524X 
R785X 
R1102X 
Q1411X 
Canonical splice mutations  185+1G→T 711+5G→A 1717-8G→A 
2622+1G→A 
3121-1G→A 
296+1G→A 712-1G→T 
1717-1G→A 
2790-1G→C 
3500-2A→G 
296+1G→T 1248+1G→A 1811+1G→C 
3040G→C 
 (G970R) 
3600+2insT 
405+1G→A 1249-1G→A 1811+1.6kbA→G 
3850-1G→A 
405+3A→C 1341+1G→A 1811+1643G→T  3120G→A 
4005+1G→A 
406-1G→A 1525-2A→G 1812-1G→A 
3120+1G→A 
4374+1G→T 
621+1G→T 1525-1G→A 1898+1G→A 
3121-2A→G 
 
 
711+1G→T  
1898+1G→C 
 
 
Small (≤3 nucleotide) 
insertion/deletion (ins/del) 
frameshift mutations 
182delT 
1078delT 
1677delTA 
2711delT 
3737delA 
306insA 
1119delA 
1782delA 
2732insA 
3791delC 
306delTAGA 1138insG 
1824delA 
2869insG 
3821delT 
365-366insT 1154insTC 
1833delT 
2896insAG 
3876delA 
394delTT 
1161delC 
2043delG 
2942insT 
3878delG 
442delA 
1213delT 
2143delT 
2957delT 
3905insT 
444delA 
1259insA 
2183AA→G a 
3007delG 
4016insT 
 
457TAT→G 1288insTA 
2184delA 
3028delA 
4021dupT 
 
541delC 
1343delG 
2184insA 
3171delC 
4022insT 
 
574delA 
1471delA 
2307insA 
3171insC 
4040delA 
 
663delT 
1497delGG 
2347delG 
3271delGG 
4279insA 
 
849delG  
1548delG 
2585delT 
3349insT 
4326delTC 
 
935delA 
1609del CA 
2594delGT 
3659delC 
 
Non-small (>3 nucleotide) 
insertion/deletion (ins/del) 
frameshift mutations 
CFTRdele1 
CFTRdele16-17b 
1461ins4 
CFTRdele2 
CFTRdele17a,17b 
1924del7 
CFTRdele2,3 
CFTRdele17a-18 
2055del9→A 
CFTRdele2-4 
CFTRdele19 
2105-2117del13insAGAAA 
CFTRdele3-10,14b-16 CFTRdele19-21 
2372del8 
CFTRdele4-7 
CFTRdele21 
2721del11 
CFTRdele4-11 
CFTRdele22-24 
2991del32 
CFTR50kbdel 
CFTRdele22,23 
3121-977_3499+248del2515 
CFTRdup6b-10 
124del23bp 
3667ins4 
CFTRdele11 
602del14  
4010del4 
 
CFTRdele13,14a 
852del22 
4209TGTT→AA 
 
CFTRdele14b-17b 
991del5 
 

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Non-exhaustive List of Minimal Function CFTR Mutations Eligible for VX17-659-106 
MF Mutation Category 
Mutation 
 
 
 
 
Missense mutations that   
 Are not responsive in 
vitro to TEZ, IVA, or 
TEZ/IVA 
and 
 %PI>50% and SwCl- 
>86 mmol/L 
A46Db 
V520F 
Y569Db 
N1303K 
  
G85E 
A559Tb 
L1065P 
 
 
R347P 
R560T 
R1066C 
 
 
L467Pb 
R560S 
L1077Pb 
 
 
I507del 
A561E 
M1101K 
 
 
 
 
 
 
 
CFTR: cystic fibrosis transmembrane conductance regulator; IVA: ivacaftor; SwCl: sweat chloride; TEZ: tezacaftor 
Source: CFTR2.org [Internet]. Baltimore (MD): 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 15 February 2016. 
Notes: %PI: percentage of F508del-CFTR heterozygous patients in the CFTR2 patient registry who are pancreatic 
insufficient; SwCl: mean sweat chloride of F508del-CFTR heterozygous patients in the CFTR2 patient registry. 
a Also known as 2183delAA→G.  
b Unpublished data. 
 

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15.2 
Investigator Signature Page 
Protocol #:  VX18-659-106 Version #: 1.0 
Version Date: 14 May 2018 
Study Title: A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of 
VX-659/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 Through 11 Years 
of Age 
 
 
I have read Protocol VX18-659-106, Version 1.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-659, tezacaftor, and ivacaftor and this 
protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
  
Signature 
 Date