Clinical trial NCT02565914
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2015-08-01; Completion date: 2022-12-05
Enrollment: 1131 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 3, multicenter, open-label, 3-part rollover study in subjects with CF who are homozygous or heterozygous for the F508del-CFTR mutation and who participated in studies VX13-661-103 (Study 103, NCT02070744), VX14-661-106 (Study 106, NCT02347657), VX14-661-107 (Study 107, NCT02516410), VX14-661-108 (Study 108, NCT02392234), VX14-661-109 (Study 109, NCT02412111), VX14-661-111 (Study 111, NCT02508207), VX15-661-112 (NCT02730208), and VX16-661-114 (NCT03150719). The study is designed to evaluate the safety and efficacy of long-term treatment of VX-661 in combination with ivacaftor.

Detailed description:

Arms: arm 1: Part A: Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 milligram (mg)/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.

Part B: Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 106,108,109,112 and 114 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.

Part C: Participants who received TEZ/IVA, IVA monotherapy or Placebo in parent studies 106,108, and 114 were administered TEZ 100 mg/IVA 150 mg fixed dose tablet in the morning and IVA 150 mg mono tablet in the evening for 192 weeks.
Interventions: intervention 1: TEZ/IVA intervention 2: IVA
Intervention descriptions: intervention 1: Fixed dose tablet for oral administration. intervention 2: Tablet for oral administration.

Protocol documents:
Prot_000.pdf: 






Protocol VX14-661-110, Version 3.4 IRE, ESP, ISR, US 
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2 
PROTOCOL SYNOPSIS  
Title A Phase 3, Open-label, Rollover Study to Evaluate the Safety and Efficacy of 
Long-term Treatment With VX-661 in Combination With Ivacaftor in Subjects 
Aged 12 Years and Older With Cystic Fibrosis, Homozygous or Heterozygous for 
the F508del-CFTR Mutation 
Brief Title A Study to Evaluate the Safety and Efficacy of Long-term Treatment With 
VX-661 in Combination With Ivacaftor in Subjects With Cystic Fibrosis Who 
Have an F508del-CFTR Mutation 
  
Clinical Phase and 
Clinical Study Type  
Phase 3, safety and efficacy 
  
Objectives Primary Objective 
Treatment Cohort 
• 
To evaluate the long-term safety and tolerability of VX-661 in combination 
with ivacaftor in subjects with CF, homozygous or heterozygous for the 
F508del-CFTR mutation who are in the Treatment Cohort 
 
Secondary Objectives 
Treatment Cohort 
• 
To evaluate the long-term efficacy of VX-661 in combination with ivacaftor 
for subjects in the Treatment Cohort 
Observational Cohort 
• 
To evaluate the post-treatment safety of VX-661 in combination with 
ivacaftor for subjects in the Observational Cohort 
  
Endpoints Primary Endpoints  
Treatment Cohort 
Safety and tolerability of long-term treatment of VX-661 in combination with 
ivacaftor based on adverse events (AEs), ophthalmologic exams (subjects 
<18 years of age [age on the date of informed consent/assent in the parent study]), 
clinical laboratory values (serum chemistry, hematology, coagulation, lipids, 
vitamins, and urinalysis), standard digital electrocardiograms (ECGs), vital signs, 
and pulse oximetry 
Observational Cohort  
Not applicable 
Secondary Endpoints  
Treatment Cohort 
The following efficacy endpoints will be analyzed: 
• 
Absolute change from baseline in percent predicted forced expiratory volume 
in 1 second (ppFEV1) 
• 
Relative change from baseline in ppFEV1 
• 
Number of pulmonary exacerbations 
• 
Absolute change from baseline in body mass index (BMI) 
• 
Absolute change from baseline in BMI z-score for subjects aged <20 years 
• 
Absolute change from baseline in Cystic Fibrosis Questionnaire–Revised 


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(CFQ-R) respiratory domain score 
• 
Absolute change from baseline in body weight 
• 
Absolute change from baseline in body weight z-score for subjects aged 
<20 years 
• 
Absolute change from baseline in height z-score for subjects aged <20 years 
• 
Time-to-first pulmonary exacerbation  
• 
Pharmacokinetic (PK) parameters of VX-661, a VX-661 metabolite 
(M1-661), ivacaftor, and an ivacaftor metabolite (M1-ivacaftor)  
Observational Cohort  
• 
Safety, as determined by related serious adverse events (SAEs) 
  
Number of Subjects Study VX14-661-110 is a rollover study that plans to enroll subjects from 
Studies VX13-661-103, VX14-661-106, VX14-661-107, VX14-661-108, 
VX14-661-109, VX14-661-111, and other eligible Vertex studies investigating 
VX-661 in combination with ivacaftor who meet the eligibility criteria for this 
study. Approximately up to 1375 subjects are potentially eligible to be enrolled 
from the following parent studies: 40 subjects from Study VX13-661-103, 490 
subjects from Study VX14-661-106, 300 subjects from Study VX14-661-107, up 
to 300 subjects from Study VX14-661-108, up to 200 subjects from 
Study VX14-661-109, and 45 subjects from Study VX14-661-111.  
  
Study Population Treatment Cohort 
Male and female subjects 12 years of age and older with CF who are homozygous 
or heterozygous for the F508del-CFTR mutation 
Observational Cohort 
Male and female subjects <18 years of age (age on the date of informed 
consent/assent in the parent study) with CF who are homozygous or heterozygous 
for the F508del-CFTR mutation 
  
Investigational Drug Treatment Cohort 
 Active substance: VX-661 and ivacaftor 
 Activity: CFTR corrector and potentiator (increased chloride ion [Cl−] secretion) 
 Strength and Route of Administration: VX-661 100 mg/ivacaftor 150-mg 
fixed-dose combination (FDC) film-coated tablet for oral administration 
  
 Active substance: ivacaftor 
 Activity: CFTR potentiator (increased Cl− secretion) 


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 Strength and Route of Administration: ivacaftor 150-mg film-coated tablet for oral 
administration 
  
Study Duration Treatment Cohort 
Study drug will be administered for approximately 96 weeks [with a Safety 
Follow-up Visit 28 days (± 7 days) after the last dose. 
Observational Cohort 
For the Observational Cohort, maximum subject participation will be 
approximately 2 years.  
  
Study Design This is a Phase 3, multicenter, open-label, rollover study in subjects with CF who 
are homozygous or heterozygous for the F508del-CFTR mutation and who 
participated in Studies VX13-661-103, VX14-661-106, VX14-661-107, 
VX14-661-108, VX14-661-109, VX14-661-111, VX15-661-112, VX16-661-114, 
or other Vertex studies investigating VX-661 in combination with ivacaftor. The 
study is designed to evaluate the safety and efficacy of long-term treatment of 
VX-661 in combination with ivacaftor.  
Subjects in the Treatment Cohort will receive VX-661 100 mg/ivacaftor 150-mg 
FDC tablet daily (qd) in the morning and ivacaftor 150-mg tablet qd in the 
evening. The Treatment Period will be approximately 96 weeks. 
While participating in the Treatment Cohort, if allowed by another Vertex study 
protocol, subjects may screen for the other Vertex study of investigational CFTR 
modulators (including clinical studies of Next Generation CFTR modulators, 
hereafter referred to as “another qualified Vertex study”), but are not permitted to 
screen for studies of lumacaftor in combination with ivacaftor and ivacaftor 
monotherapy. 
Subjects who completed at least 4 weeks of treatment before discontinuing 
Study VX14-661-110 to participate in another qualified Vertex study, and who 
meet the eligibility criteria (Sections 9.1 and 9.2) will be offered the opportunity 
to re-enroll once in the Study VX14-661-110 Treatment Cohort. Subjects who 
re-enroll will resume treatment with VX-661/ivacaftor at the next study day after 
their previous treatment discontinuation in Study VX14-661-110. Subjects who 
discontinue Study VX14-661-110 more than once to participate in another 
qualified Vertex study may not re-enroll in Study VX14-661-110 a second time.  
During the course of study conduct, if VX-661 in combination with ivacaftor is 
approved and available for the treatment of CF in populations enrolled in 
Study VX14-661-110, subjects with the approved CFTR genotypes may be 
discontinued from this rollover study at the discretion of the sponsor. If a subject 
is continuing onto commercially available VX-661/ivacaftor, the Early Treatment 
Termination Visit will be completed before dosing with commercial drug begins, 
and the Safety Follow-up Visit will not be required. Alternatively, if local health 
authorities decline to approve, or if clinical benefit is not demonstrated for the use 
of VX-661 in combination with ivacaftor for the treatment of CF in populations 
enrolled in Study VX14-661-110, 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 subset of subjects. 
If subjects are discontinued from the study, an Early Treatment Termination Visit 
should occur within 7 days of the last dose of study drug. 
Observational Cohort  
Subjects <18 years of age (age on the date of informed consent/assent in the 
parent study) who received at least 4 weeks of study drug in the parent study, who 
are not eligible for the Treatment Cohort or who elect not to enroll in the 


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Treatment Cohort, and meet eligibility criteria will be offered the opportunity to 
enroll in the Observational Cohort.  
Subjects in the Observational Cohort will not receive study drug and will have 
regularly scheduled telephone calls for approximately 2 years after their last dose 
of study drug in the parent study to assess post-treatment safety of 
VX-661/ivacaftor combination therapy. 
  
Assessments Treatment Cohort 
Safety Assessments 
AEs, ophthalmologic examinations (subjects <18 years of age [age on the date of 
informed consent/assent in the parent study]), clinical laboratory values (serum 
chemistry, hematology, coagulation, lipids, vitamins, and urinalysis), standard 
digital ECGs, vital signs, and pulse oximetry 
Efficacy Assessments 
Spirometry, weight, height, BMI, CFQ-R, 
 and documentation of other 
events related to outcomes (e.g., pulmonary exacerbations) 
Pharmacokinetic Assessments 
VX-661, M1-661, ivacaftor, and M1-ivacaftor 
Observational Cohort  
Related SAEs 
  
  
Statistical Analyses Statistical analysis details will be provided in the Statistical Analysis Plan (SAP), 
which will be finalized before the clinical data lock for the study. 
The safety analysis will be performed on all subjects pooled together irrespective 
of their CFTR mutations. The efficacy analysis will be the secondary analysis and 
will be performed on each of the CFTR mutation groups separately 
(F508del/F508del, F508del/Residual Function, and F508del/Gating). The 
methods used for the efficacy analyses will be similar for those used in the parent 
studies. For example, the analysis for absolute change from baseline in ppFEV1 
will be based on a mixed-effect repeated-measure model (MMRM). Descriptive 
summary statistics will be provided for relevant safety and efficacy parameters. In 
addition, the least square (LS) mean and the associated 95% CI at each defined 
analysis visit will be provided for the efficacy parameters. 
 


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3 
SCHEDULE OF ASSESSMENTS 
The schedules of assessments are provided in Table 3-1 (Treatment Cohort) and Table 3-2 
(Observational Cohort). Subjects who received at least 4 weeks of study drug in the Treatment 
Cohort, discontinued Study VX14-661-110 to participate in another Vertex study of 
investigational CFTR modulators that allows participation of subjects in Study VX14-661-110 
(hereafter referred to as “another qualified Vertex study”), and who meet the eligibility criteria 
(Sections 9.1 and 9.2) will be offered the opportunity to re-enroll once in the Treatment Cohort 
of Study VX14-661-110.  


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3.1 
Treatment Cohort 
Table 3-1 
Study VX14-661-110: Treatment Cohort 
Event/Assessmenta 
Day –28 to 
Day -1 
Treatment Periodb 
ETT 
Visit/ 
Departing 
Visit 
(Within 
7 Days of Last 
Dose of Study 
Drug)b,c,d,e 
Safety 
Follow-up 
Visit 
28 (± 7) Days 
After Last 
Dosec,d,e 
Day 1f/ 
Returning 
Visitb,g 
Day 15 
(± 3 days) 
Weeks 8, 
16, 24, 36 
(± 5 days) 
Week 48 
(± 5 days) 
Weeks 60, 
72, 84 
(± 5 days) 
Week 96 
(± 5 days) 
Clinic visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
 a 
All assessments will be performed before dosing unless noted otherwise. 
b 
Selected visits may overlap with visits in the other qualified Vertex study: the Screening Visit of the other qualified Vertex study and a scheduled Treatment Period visit; the 
last required visit of the other qualified Vertex study and the Returning Visit; and the visit with the first dose of study drug in the other qualified Vertex study and the ETT 
Visit (refer to Section 8.1.1.1 and Section 8.1.1.3 for the timing/order of assessments in these cases). 
c 
If the subject prematurely discontinues study treatment, an ETT Visit should be scheduled as soon as possible after the subject decides to terminate study treatment 
(Section 8.1.1.3). Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit, approximately 28 (± 7) days after their last 
dose of study drug. 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.  
d 
If a subject is continuing onto commercially available VX-661/ivacaftor, the ETT Visit (Section 8.1.1.3) will be completed before dosing with commercial drug begins, and 
the Safety Follow-up Visit (Section 8.1.1.2) will not be required.  
e 
If a subject discontinues treatment to participate in another qualified Vertex study, the ETT Visit (Section 8.1.1.3) will be completed, and the Safety Follow-up Visit 
(Section 8.1.1.2) will not be required if the subject enrolls in the other study within 28 (± 7 days) days of the last dose of study drug in Study VX14-661-110.  
f 
Initial enrollment: The Day 1 Visit of Study VX14-661-110 will be on the same day as the last scheduled visit of the parent study for subjects at Study VX14-661-110 sites 
that have been activated by the time the subject has completed the last scheduled visit in the parent study. Subjects at these active sites will NOT have to repeat any 
Study VX14-661-110 Day 1 assessments that were specified to be performed at the last scheduled visit in the parent study. Subjects who were enrolled but had Day 1 study 
drug administration procedures (Section 10.2) delayed will have to repeat the safety (Section 11.8) and spirometry (Section 11.7.1) assessments that were specified to be 
performed at the Day 1 Visit before receiving their first dose of study drug. However, the Day 1 Visit of Study VX14-661-110 will NOT coincide with the last scheduled visit 
of the parent study for subjects at Study VX14-661-110 sites that have NOT been activated by the time the subject has completed the last scheduled visit in the parent study. 
Subjects at these nonactive sites will have to repeat any Study VX14-661-110 Day 1 assessments that were specified to be performed at the last scheduled visit in the parent 
study. 
g 
Re-enrollment: Subjects who re-enroll in the Treatment Cohort will complete the Returning Visit and will resume treatment with VX-661/ivacaftor at the next study day after 
their previous treatment discontinuation from Study VX14-661-110. If the timepoint coincides with a scheduled Study VX14-661-110 visit (± 5 days), only the Returning 
Visit assessments will be completed. Subjects who were re-enrolled but had their Returning Visit study drug administration procedures (Section 10.2) delayed will have to 
repeat the safety (Section 11.8) and spirometry (Section 11.7.1) assessments that were specified to be performed at the Returning Visit before receiving their first dose of 
study drug. 


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Table 3-1 
Study VX14-661-110: Treatment Cohort 
Event/Assessmenta 
Day –28 to 
Day -1 
Treatment Periodb 
ETT 
Visit/ 
Departing 
Visit 
(Within 
7 Days of Last 
Dose of Study 
Drug)b,c,d,e 
Safety 
Follow-up 
Visit 
28 (± 7) Days 
After Last 
Dosec,d,e 
Day 1f/ 
Returning 
Visitb,g 
Day 15 
(± 3 days) 
Weeks 8, 
16, 24, 36 
(± 5 days) 
Week 48 
(± 5 days) 
Weeks 60, 
72, 84 
(± 5 days) 
Week 96 
(± 5 days) 
Informed consent/assent 
Xh 
Xh 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria review 
 
X 
 
 
 
 
 
 
 
CFQ-Ri 
 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and heightj 
 
X 
 
X 
X 
X 
X 
X 
X 
Ophthalmological 
historyk 
 
Day 1 
 
 
 
 
 
 
 
Ophthalmologic 
examinationl 
Xh,m 
Xn 
 
 
X 
 
X 
Xo 
Xp 
Complete physical 
examinationp 
 
X 
 
 
X 
 
X 
X 
 
Pregnancy testq 
 
urine 
 
urine 
urine 
urine 
serum 
serum 
serum 
 h  
If the baseline ophthalmologic examination (see Footnote m) is not conducted as a parent study assessment but is conducted during the Day -28 to Day -1 period of 
Study VX14-661-110, informed consent/assent will be obtained before this examination and will not be obtained again on Day 1 of Study VX14-661-110. 
i 
Questionnaires must be completed before the start of any other assessments scheduled at that visit (Section 11.1). The CFQ-R must be completed first,
  
j 
Weight and height will be measured before dosing with shoes off (Section 11.7.2). Height will be collected only for subjects ≤21 years of age (age on the date of informed 
consent/assent in the parent study).  
k 
Required on Day 1 for all subjects without a documented ophthalmological history from the parent study. Not required at the Returning Visit. 
l 
Ophthalmologic examinations will be conducted on subjects < 18 years of age (age on the date of informed consent/assent in the parent study) by a licensed ophthalmologist. 
m 
An ophthalmologic examination will be conducted on subjects < 18 years of age (age on the date of informed consent/assent in the parent study) by a licensed 
ophthalmologist within 28 days before enrollment on Day 1 (Section 11.8.7). This examination may be conducted while the subject is participating in the parent study. If this 
examination is not conducted during the Day -28 to Day -1 period, subjects are required to complete the Day 1 ophthalmologic examination.  
n 
The Day 1 ophthalmologic examination is not required for subjects who complete the baseline ophthalmologic examination during the Day -28 to Day -1 period (this 
examination may be conducted while the subject is participating in the parent study). 
o 
Subjects <18 years of age (age on the date of informed consent/assent in the parent study) who discontinue treatment after receiving at least 1 dose of study drug will have an 
ophthalmologic examination conducted by a licensed ophthalmologist (Section 8.1.1.3). The examination may be completed at either the ETT or Safety Follow-Up Visit, but 
must be completed by the date of the Safety Follow-Up Visit. 
p 
Symptom-targeted physical examinations will occur at any time during the study if triggered by AEs or if deemed necessary by the investigator (Section 11.8.3). 
q 
Pregnancy tests will be performed for all female subjects of childbearing potential. All urine pregnancy tests will be performed at the site.  


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Table 3-1 
Study VX14-661-110: Treatment Cohort 
Event/Assessmenta 
Day –28 to 
Day -1 
Treatment Periodb 
ETT 
Visit/ 
Departing 
Visit 
(Within 
7 Days of Last 
Dose of Study 
Drug)b,c,d,e 
Safety 
Follow-up 
Visit 
28 (± 7) Days 
After Last 
Dosec,d,e 
Day 1f/ 
Returning 
Visitb,g 
Day 15 
(± 3 days) 
Weeks 8, 
16, 24, 36 
(± 5 days) 
Week 48 
(± 5 days) 
Weeks 60, 
72, 84 
(± 5 days) 
Week 96 
(± 5 days) 
Standard 12-lead ECGr 
 
X 
X 
Weeks 8, 
16, 24 
X 
Week 72 
X 
X 
X 
Vital signss 
 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetrys 
 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometryt 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyu 
 
Xv 
X 
X 
X 
X 
X 
X 
X 
Coagulationu 
 
Xv 
 
X 
X 
X 
X 
X 
X 
Serum chemistryu 
 
Xv 
X 
X 
X 
X 
X 
X 
X 
Lipid panelu 
 
Xv 
 
X 
X 
X 
X 
X 
X 
Vitamin levelsu 
 
Xv 
 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
 
X 
X 
X 
X 
X 
X 
PK sampling 
 
 
 
Week 24w 
 
 
 
X 
 
Other events related to 
outcomex 
 
X 
X 
X 
X 
X 
X 
X 
X 
Meal(s) or snack(s) at 
sitey 
 
X 
X 
X 
X 
X 
 
 
 
Study drug count 
 
 
X 
X 
X 
X 
X 
X 
 
 r 
All standard 12-lead ECGs will be performed before dosing and after the subject has been supine for at least 5 minutes (Section 11.8.4). At the Day 1 and 15 Visits, ECGs 
will be collected before dosing and at 1.5 and 4 hours after the morning dose. A window of ± 15 minutes will be allowed around the nominal times for all postdose ECG 
assessments. ECGs collected on Day 1 before dosing will be performed in triplicate. If study drug is not administered on the day of the visit (i.e., because of study drug 
interruption), only 1 ECG will be collected. 
s 
Vital signs and pulse oximetry will be collected before dosing and after the subject has been at rest (seated or supine) for at least 5 minutes (Sections 11.8.3 and 11.8.5). 
t 
Spirometry must be performed for all subjects before dosing and should be performed pre-bronchodilator (Section 11.7.1). 
u 
With the exception of Day 15, all blood samples will require a 4-hour fast before collection.  
v 
Blood samples will be collected before the first dose of study drug. 
w 
A single blood sample for PK will be collected within 60 minutes before dosing (Section 11.5.1).  
x 
Other events related to outcome include assessments relating to pulmonary exacerbations, administration of antibiotic therapy for sinopulmonary signs or symptoms, and 
hospitalizations (Section 11.7.5). 
y 
Fat-containing food such as a standard CF high-fat, high-calorie meal or snack will be provided at the site to subjects after all predose assessments have occurred. 


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Table 3-1 
Study VX14-661-110: Treatment Cohort 
Event/Assessmenta 
Day –28 to 
Day -1 
Treatment Periodb 
ETT 
Visit/ 
Departing 
Visit 
(Within 
7 Days of Last 
Dose of Study 
Drug)b,c,d,e 
Safety 
Follow-up 
Visit 
28 (± 7) Days 
After Last 
Dosec,d,e 
Day 1f/ 
Returning 
Visitb,g 
Day 15 
(± 3 days) 
Weeks 8, 
16, 24, 36 
(± 5 days) 
Week 48 
(± 5 days) 
Weeks 60, 
72, 84 
(± 5 days) 
Week 96 
(± 5 days) 
Study drug dosingz 
 
Day 1 to Week 96 
 
 
Concomitant 
medications 
 
Continuous from signing of the ICF and Assent (where applicable) through the Safety Follow-up Visit 
Concomitant treatments 
and procedures 
 
Continuous from signing of the ICF and Assent (where applicable) through the Safety Follow-up Visit 
AEs and SAEsbb 
 
Continuous from signing of the ICF and Assent (where applicable) through the Safety Follow-up Visit 
AE: adverse event; CF: cystic fibrosis; CFQ-R: CF Questionnaire–Revised; ECG: electrocardiogram; ETT: Early Treatment Termination; ICF: informed consent form; 
PK: pharmacokinetic; SAE: serious adverse event; 
 
 z 
The study drug should be administered every 12 hours (± 2 hours) within 30 minutes of starting a meal with fat-containing food such as a standard CF high-fat, high-calorie 
meal or snack (Section 10.2). On days of scheduled visits, the morning dose of study drug will be administered at the site after predose assessments have been completed. The 
final dose of study drug will be administered the evening before the Week 96 Visit. If the Returning Visit coincides with the last Visit of the other Vertex study, the morning 
dose of VX-661/ivacaftor may be supplied by the other Vertex study. 
bb 
SAEs that occur after the Safety Follow-Up Visit and are considered related to study drug(s) will be reported to Vertex GPS within 24 hours as described in Section 13.1.2.2. 


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3.2 
Observational Cohort 
Table 3-2 
Study VX14-661-110: Observational Cohort  
Event/Assessment 
Day 1a 
Long-term Follow-up 
Approx. Every 3 to 
4 Months for the First 
Year 
Approx. 2 Years 
(± 4 weeks) 
Clinic visit 
X 
 
 
Telephone contact 
 
X 
X 
Informed consent/assent 
X 
 
 
Inclusion criteria reviewb 
X 
 
 
Related serious adverse events 
Continuous from signing of ICF and Assent through last telephone contact 
ICF: informed consent form. 
 
 a 
The Day 1 Visit of Study VX14-661-110 will be on the same day as the last scheduled visit of the parent study for subjects 
at Study VX14-661-110 sites that have been activated by the time the subject has completed the last visit in the parent study. 
Subjects at these active sites will NOT have to repeat any Study VX14-661-110 Day 1 assessments that were specified to be 
performed at the last scheduled visit of the parent study. However, the Day 1 Visit of Study VX14-661-110 will NOT 
coincide with the last scheduled visit of the parent study for subjects at Study VX14-661-110 sites that have NOT been 
activated by the time the subject has completed the last scheduled visit in the parent study. Subjects at these nonactive sites 
will have to repeat any Study VX14-661-110 Day 1 assessments that were specified to be performed at the last scheduled 
visit in the parent study. 
b 
Subjects must be < 18 years of age (age on the date of informed consent/assent in the parent study) and meet the other 
inclusion criteria (Section 9.1) to be eligible for the Observational Cohort. 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 4 
Primary Endpoints ...................................................................................................................... 4 
Secondary Endpoints .................................................................................................................. 4 
 
3 
Schedule of Assessments........................................................................................................ 8 
3.1 
Treatment Cohort .............................................................................................................. 9 
3.2 
Observational Cohort ...................................................................................................... 13 
4 
Table of Contents ................................................................................................................. 14 
List of Tables............................................................................................................................ 18 
List of Figures .......................................................................................................................... 18 
5 
Introduction.......................................................................................................................... 19 
5.1 
Background ..................................................................................................................... 19 
5.2 
Study Rationale .............................................................................................................. 21 
6 
Study Objectives .................................................................................................................. 21 
6.1 
Primary Objective ........................................................................................................... 21 
6.2 
Secondary Objectives ..................................................................................................... 21 
7 
Study Endpoints ................................................................................................................... 21 
7.1 
Primary Endpoints .......................................................................................................... 21 
7.2 
Secondary Endpoints ...................................................................................................... 21 
 
 
8 
Study Design ......................................................................................................................... 22 
8.1 
Overview of Study Design ............................................................................................. 22 
8.1.1 
Treatment Cohort (Eligible Subjects 12 Years of Age and Older) ......................... 25 
8.1.1.1 
Treatment Period .............................................................................................. 25 
8.1.1.2 
Safety Follow-up .............................................................................................. 26 
8.1.1.3 
Early Treatment Termination ........................................................................... 26 
8.1.2 
Observational Cohort (Eligible Subjects <18 Years of Age) ................................. 27 
8.1.2.1 
Day 1 ................................................................................................................ 27 
8.1.2.2 
Long-term Follow-up ....................................................................................... 28 
8.1.3 
Lost to Follow-up ................................................................................................... 28 
8.2 
Rationale for Study Design and Study Drug Regimens ................................................. 28 
8.2.1 
Study Design........................................................................................................... 28 
8.2.2 
Study Drug Dose and Duration .............................................................................. 29 
8.2.3 
Rationale for Study Assessments ........................................................................... 29 
9 
Study Population .................................................................................................................. 31 
9.1 
Inclusion Criteria ............................................................................................................ 31 
9.2 
Exclusion Criteria ........................................................................................................... 33 
9.3 
Study Restrictions (Treatment Cohort) .......................................................................... 34 
9.4 
Prior and Concomitant Medications (Treatment Cohort) ............................................... 34 
9.5 
Removal of Subjects (Treatment Cohort) ....................................................................... 35 
9.6 
Replacement of Subjects (Treatment Cohort) ................................................................ 36 
10 Study Drug Administration and Management (Treatment Cohort) .............................. 36 






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13.2.3 
Investigator Compliance ......................................................................................... 67 
13.2.4 
Access to Records ................................................................................................... 67 
13.2.5 
Subject Privacy ....................................................................................................... 67 
13.2.6 
Record Retention .................................................................................................... 68 
13.2.7 
Study Termination .................................................................................................. 68 
13.3 Data Quality Assurance .................................................................................................. 68 
13.4 Monitoring ...................................................................................................................... 69 
13.5 Electronic Data Capture ................................................................................................. 69 
13.6 Publications and Clinical Study Report .......................................................................... 69 
 
 
13.6.2 
Clinical Study Report ............................................................................................. 70 
14 References ............................................................................................................................. 71 
15 Protocol Signature Pages .................................................................................................... 74 
15.1 Sponsor Signature Page .................................................................................................. 74 
15.2 Investigator Signature Page ............................................................................................ 75 
 


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List of Tables 
Table 3-1 
Study VX14-661-110: Treatment Cohort ............................................................... 9 
Table 3-2 
Study VX14-661-110: Observational Cohort ....................................................... 13 
Table 9-1 
Study Restrictions in Treatment Cohort of Study VX14-661-110 ....................... 34 
Table 10-1 
Study Drug Administration – Treatment Period ................................................... 36 
Table 10-2 
Dosing Recommendations for Subjects Taking Concomitant CYP3A Inhibitors 37 
Table 10-3 
Identity of Study Drugs, Dosage, and Storage ...................................................... 39 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 46 
Table 11-2 
Acceptable Methods of Contraception.................................................................. 51 
Table 13-1 
Grading of AE Severity ........................................................................................ 63 
Table 13-2 
Classifications for AE Causality ........................................................................... 64 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 64 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 64 
List of Figures 
Figure 8-1 
Study Design ......................................................................................................... 24 
 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) affects an estimated 70,000 children and adults worldwide1 and is the most 
common fatal genetic disease in persons of European descent.2 Based on the size of the 
population, CF qualifies as an orphan disease.3,4 Despite progress in the treatment of CF with 
antibiotics and mucolytics, the predicted median age of survival for a person with CF is in the 
mid-40s.2,5 Although the disease affects multiple organs, most morbidity and mortality is caused 
by progressive loss of lung function.6 
CF is an autosomal recessive genetic disease caused by a defect in the gene encoding the cystic 
fibrosis transmembrane conductance regulator (CFTR), an epithelial chloride ion (Cl-) channel 
activated by cyclic AMP-dependent protein kinase A 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. 
More than 1900 mutations in the CFTR gene have been identified.7 Mutations in the CFTR gene 
have been classified based on the molecular and functional consequence of the mutation on the 
CFTR protein8,9,10 and can be generally considered to reduce the quantity of functional CFTR 
protein that reaches the epithelial cell surface or reduce the function of CFTR protein located at 
the cell surface. CFTR gene mutations that affect the quantity of functional cell surface CFTR 
protein include defects that reduce CFTR protein synthesis and defects that impede the cellular 
processing and delivery of CFTR proteins to the cell surface. 
CFTR gene mutations associated with minimal CFTR function include 
• mutations associated with severe defects in ability of the CFTR channel to open and close, 
known as defective channel gating or “gating mutations”; 
• severe defects in the cellular processing of CFTR and its delivery to the cell surface; 
• no (or minimal) CFTR synthesis; and 
• severe defects in channel conductance. 
The most prevalent mutation is an in-frame deletion in the CFTR gene resulting in a loss of 
phenylalanine at position 508 in the CFTR protein (F508del-CFTR).10 In the USA, almost 87% 
of patients with CF have at least 1 copy of the F508del-CFTR mutation, and approximately 47% 
have 2 copies.11 In the European Union, approximately 83% of patients with CF have 1 or 
2 copies of the F508del-CFTR mutation, and approximately 38.7% of patients with CF in the 
United Kingdom have 2 copies.12 The F508del-CFTR mutation interferes with the ability of the 
CFTR protein to reach and remain at the cell surface, as well as to open and close, resulting in 
decreased Cl- transport.13,14 The combined effect is a marked reduction in 
F508del-CFTR-mediated Cl- secretion that impairs fluid regulation and promotes accumulation 
of thick sticky mucus in the airway. The mucus build-up obstructs the airways and predisposes 
the patient to chronic lung infections.15 


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Two complementary approaches to increase CFTR-mediated Cl- secretion in airway epithelia 
have been studied.9 One approach is to treat with a compound that will modify the cellular 
processing and delivery of CFTR protein to the cell surface. This kind of compound has been 
termed a CFTR corrector. Another approach is to treat with a compound that increases channel 
gating activity of protein kinase A-activated CFTR at the cell surface to enhance ion transport. 
This kind of compound has been termed a potentiator. 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 to 
ameliorate lung disease in patients with CF. A modest restoration of Cl- secretion through the 
action of a potentiator and/or corrector could prevent the hyperabsorption of water across the 
apical surface of epithelial cells, allowing for proper maintenance of airway hydration. Adequate 
airway hydration could alleviate the cycle of mucus plugging, infection, and inflammation that 
leads to irreversible structural changes in the lungs, and eventually respiratory failure for patients 
with CF. 
VX-661 is a compound developed by Vertex Pharmaceuticals Incorporated (Vertex) that has 
been shown to have CFTR corrector properties. Several lines of in vitro evidence suggest that 
VX-661 works by promoting the proper folding of a fraction of F508del-CFTR protein during its 
biogenesis and processing in the endoplasmic reticulum, allowing it to exit the endoplasmic 
reticulum and traffic to the cell surface.16 When added for more than 24 hours to human 
bronchial epithelial (HBE) cells isolated and cultured from lung explants obtained from donors 
with CF (CF-HBE cells) who are homozygous for the F508del-CFTR mutation, a 
concentration-dependent increase in levels of mature (i.e., plasma membrane) F508del-CFTR 
was observed. The increased trafficking of F508del-CFTR to the cell surface resulted in a 
significant increase in Cl− secretion.16 VX-661 did not correct the processing and localization of 
other misfolded or normally folded proteins other than CFTR, suggesting that the mechanism of 
VX-661 action is selective for CFTR (CFTR corrector).17 
Ivacaftor (also known as VX-770) is the first CFTR modulator to show an improvement in 
CFTR function and clinical benefit in patients with CF. Results from several Phase 3 studies 
showed that ivacaftor is effective in the treatment of patients with CF who have mutations that 
result in gating defects as evidenced by sustained improvements in CFTR channel function 
(measured by reduction in sweat chloride concentration) and corresponding substantial, durable 
improvements in lung function, respiratory symptoms, and weight gain. Ivacaftor was also well 
tolerated, as evidenced by the rates and reasons for premature discontinuation and results of 
safety assessments.  
In the US, ivacaftor (150-mg tablets; trade name Kalydeco) is indicated for the treatment of CF 
in patients aged 2 years and older who have 1 of the following mutations in 
the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, 
S549R, or R117H. In the EU, Kalydeco is indicated for the treatment of CF in patients aged 
6 years and older who have 1 of the following mutations in the CFTR gene: G551D, G1244E, 
G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R. In Canada, Kalydeco is indicated 
for the treatment of CF in patients aged 6 years and older who have 1 of the following mutations 
in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, 
S549R, or G970R. It is also indicated for the treatment of CF in patients aged 18 years and older 
who have the R117H mutation in the CFTR gene. In Australia, Kalydeco is indicated for the 
treatment of CF in patients aged 6 years and older who have a G551D or other gating (class III) 


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mutation in the CFTR gene. In New Zealand, Switzerland, and Liechtenstein, Kalydeco is 
currently indicated for the treatment of CF in patients 6 years of age and older who have 
the G551D mutation. 
Details about the VX-661 and ivacaftor development programs can be found in the Investigator's 
Brochures.18,19 
5.2 
Study Rationale  
To date, the long-term safety of VX-661 in combination with ivacaftor has not yet been 
evaluated. Therefore, the primary objective of this study is to evaluate the long-term safety and 
tolerability of VX-661 in combination with ivacaftor in subjects with CF, homozygous or 
heterozygous for the F508del-CFTR mutation. In addition, a secondary objective of this study is 
to evaluate the long-term efficacy and durability of treatment with VX-661 in combination with 
ivacaftor in the same subjects.  
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the long-term safety and tolerability of VX-661 in combination with ivacaftor in 
subjects with CF, homozygous or heterozygous for the F508del-CFTR mutation who are in the 
Treatment Cohort 
6.2 
Secondary Objectives 
Treatment Cohort 
To evaluate the long-term efficacy of VX-661 in combination with ivacaftor for subjects in the 
Treatment Cohort 
Observational Cohort 
To evaluate the post-treatment safety of VX-661 in combination with ivacaftor for subjects in the 
Observational Cohort 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoints 
Treatment Cohort 
Safety and tolerability of long-term treatment of VX-661 in combination with ivacaftor based on 
adverse events (AEs), ophthalmologic exams (subjects <18 years of age [age on the date of 
informed consent/assent in the parent study]), clinical laboratory values (serum chemistry, 
hematology, coagulation, lipids, vitamins, and urinalysis), standard digital electrocardiograms 
(ECGs), vital signs, and pulse oximetry. 
7.2 
Secondary Endpoints  
Treatment Cohort 
The following efficacy endpoints will be analyzed: 


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• Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) 
• Relative change from baseline in ppFEV1 
• Number of pulmonary exacerbations 
• Absolute change from baseline in body mass index (BMI) 
• Absolute change from baseline in BMI z-score for subjects aged <20 years 
• Absolute change from baseline in Cystic Fibrosis Questionnaire–Revised (CFQ-R) 
respiratory domain score 
• Absolute change from baseline in body weight 
• Absolute change from baseline in body weight z-score for subjects aged <20 years 
• Absolute change from baseline in height z-score for subjects aged <20 years 
• Time-to-first pulmonary exacerbation  
• Pharmacokinetic (PK) parameters of VX-661, a VX-661 metabolite (M1-661), ivacaftor, and 
an ivacaftor metabolite (M1-ivacaftor)  
Observational Cohort  
• Safety, as determined by related serious adverse events (SAEs) 
8 
STUDY DESIGN 
8.1 
Overview of Study Design 
This is a Phase 3, multicenter, open-label, rollover study in subjects with CF who are 
homozygous or heterozygous for the F508del-CFTR mutation and who participated in 
Studies VX13-661-103, VX14-661-106, VX14-661-107, VX14-661-108, VX14-661-109, 
VX14-661-111, or other Vertex studies investigating VX-661 in combination with ivacaftor. The 
study is designed to evaluate the safety and efficacy of long-term treatment of VX-661 in 
combination with ivacaftor. 
A schematic of the study design is shown in Figure 8-1. 
This study consists of a Treatment Cohort (eligible subjects 12 years of age and older) and an 
Observational Cohort (eligible subjects <18 years of age [age on the date of informed 
consent/assent in the parent study]), which will enroll subjects from Studies VX13-661-103, 


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VX14-661-106, VX14-661-107, VX14-661-108, VX14-661-109, VX14-661-111, and other 
Vertex studies investigating VX-661 in combination with ivacaftor. The Treatment Cohort and 
the Observational Cohort will be open to enrollment in parallel.  
Treatment Cohort 
Subjects who completed study drug treatment (i.e., VX-661/ivacaftor, ivacaftor monotherapy, or 
placebo) during the Treatment Period in the parent study who meet the eligibility criteria 
(Sections 9.1 and 9.2) will be offered the opportunity to enroll in Study VX14-661-110. Subjects 
who permanently discontinue study drug treatment or who withdrew consent during the parent 
study are not eligible for enrollment in the Treatment Cohort.  
Subjects in the Treatment Cohort will receive VX-661 100 mg/ivacaftor 150-mg fixed-dose 
combination (FDC) tablet daily (qd) in the morning and ivacaftor 150-mg tablet qd in the 
evening. The Treatment Period will be approximately 96 weeks. 
Subjects may screen for another qualified Vertex study while participating in the Treatment 
Cohort.  
Subjects who completed at least 4 weeks of treatment before discontinuing Study VX14-661-110 
to participate in another qualified Vertex study, and who meet the eligibility criteria (Sections 9.1 
and 9.2), will be offered the opportunity to re-enroll in the Treatment Cohort of 
Study VX14-661-110. Subjects who re-enroll will resume treatment with VX-661/ivacaftor at 
the next study day after their previous treatment discontinuation from Study VX14-661-110 
(e.g., a subject who discontinued at Study Day 50 would resume treatment at Study Day 51). 
Subjects who discontinue Study VX14-661-110 more than once to participate in another 
qualified Vertex study may not re-enroll in Study VX14-661-110 a second time.   
During the course of study conduct, if VX-661 in combination with ivacaftor is approved and 
available for the treatment of CF in populations enrolled in Study VX14-661-110, subjects with 
the approved CFTR genotypes may be discontinued from this rollover study at the discretion of 
the sponsor (Section 10.6). If a subject is continuing onto commercially available 
VX-661/ivacaftor, the Early Treatment Termination Visit (Section 8.1.1.3) will be completed 
before dosing with commercial drug begins, and the Safety Follow-up Visit (Section 8.1.1.2) will 
not be required. Alternatively, if local health authorities decline to approve, or if clinical benefit 
is not demonstrated for the use of VX-661 in combination with ivacaftor for the treatment of CF 
in populations enrolled in Study VX14-661-110, 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 subset of subjects. If subjects are discontinued from 
the study, an Early Treatment Termination Visit should occur within 7 days of the last dose of 
study drug and a Safety Follow-up Visit should occur within 28 (± 7) days after the last dose of 
study drug. 
Observational Cohort  
Subjects <18 years of age (age on the date of informed consent/assent in the parent study) who 
received at least 4 weeks of study drug in the parent study, who are not eligible for the Treatment 
Cohort or who elect not to enroll in the Treatment Cohort, and meet eligibility criteria (Section 
9.1) will be offered the opportunity to enroll in the Observational Cohort.  




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8.1.1 
Treatment Cohort (Eligible Subjects 12 Years of Age and Older) 
8.1.1.1 
Treatment Period 
After obtaining informed consent and assent (where applicable), and eligibility has been 
confirmed, subjects will receive VX-661 100 mg/ivacaftor 150-mg FDC tablet qd in the morning 
and ivacaftor 150-mg tablet qd in the evening. Study drug will be administered for 
approximately 96 weeks.  
Initial Enrollment 
Timing of Treatment Cohort Day 1 Visit in Study VX14-661-110 Active Sites 
The Day 1 Visit of Study VX14-661-110 will be on the same day as the last scheduled visit of 
the parent study for subjects at Study VX14-661-110 sites that have been activated by the time 
the last scheduled visit of the parent study has been completed. Subjects at these active sites 
MAY have to repeat any Day 1 assessments of Study VX14-661-110 that were specified to be 
performed at the last scheduled study visit of the parent study. Assessments for the Treatment 
Cohort are listed in Table 3-1. 
Subjects who were enrolled but had Day 1 study drug administration procedures (Section 10.2) 
delayed will have to repeat the safety (Section 11.8) and spirometry (Section 11.7.1) assessments 
that were specified to be performed at the Day 1 Visit before receiving their first dose of study 
drug. 
Timing of Day 1 Visit in Study VX14-661-110 Nonactive Sites 
The Day 1 Visit of Study VX14-661-110 will NOT coincide with the last scheduled visit of the 
parent study for subjects at Study VX14-661-110 sites that have NOT been activated by the time 
the last scheduled visit of the parent study has been completed. Subjects at these nonactive sites 
will have to repeat any Study VX14-661-110 Day 1 assessments that were specified to be 
performed at the last scheduled visit of the parent study. Assessments for the Treatment Cohort 
are listed in Table 3-1.  
Re-enrollment  
Subjects who re-enroll in the Treatment Cohort will complete the Returning Visit and resume 
treatment with VX-661/ivacaftor at the next study day after their previous treatment 
discontinuation from Study VX14-661-110. If the timepoint coincides with a scheduled 
Study VX14-661-110 visit (± 5 days), only the Returning Visit assessments will be completed. 
Assessments for the Treatment Cohort are listed in Table 3-1. 
Subjects who re-enroll in the Treatment Cohort but have a delay in their Returning Visit study 
drug administration procedures (Section 10.2) will have to repeat the safety (Section 11.8) and 
spirometry (Section 11.7.1) assessments that are specified to be performed at the Returning Visit 
before receiving their first dose of study drug. 
Timing of Overlapping Visits With Another Qualified Vertex Study 
The Returning Visit in Study VX14-661-110 may be on the same day as the last required visit of 
the other qualified Vertex study. If completed on the same day, the order/timing in the Schedule 
of Assessments in the other qualified Vertex study should be followed and subjects MAY have 
to repeat Study VX14-661-110 assessments that were specified to be performed at the last 


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required visit of the other qualified Vertex study. Assessments for the Treatment Cohort are 
listed in Table 3-1.  
Screening for Another Qualified Vertex Study 
Timing of Overlapping Visits With Another Qualified Vertex Study  
Subjects may screen for another qualified Vertex study while participating in the Treatment 
Cohort. The Screening Visit of the other qualified Vertex study may be on the same day as a 
scheduled Treatment Period visit in Study VX14-661-110. If completed on the same day, the 
order/timing in the VX14-661-110 Schedule of Assessments should be followed and subjects 
MAY have to repeat any Screening Visit assessments that were specified in the other qualified 
Vertex study in order to maintain the integrity of the data for the other qualified Vertex study. 
8.1.1.2 
Safety Follow-up 
Treatment Cohort 
Subjects who do not complete the Day 1 Visit in Study VX14-661-110 within 28 days after the 
last dose of study drug in the parent study are to complete the Safety Follow-Up Visit in the 
parent study before receiving the first dose of study drug in Study VX14-661-110.  
The Safety Follow-up Visit is scheduled to occur 28 (± 7) days after the last dose of study drug. 
The Safety Follow-up Visit assessments are listed in Table 3-1.  
If a subject is continuing onto commercially available VX-661/ivacaftor, the Early Treatment 
Termination Visit (Section 8.1.1.3) will be completed before dosing with commercial drug 
begins, and the Safety Follow-up Visit will not be required. 
If a subject discontinues treatment to participate in another qualified Vertex study, the Early 
Treatment Termination Visit (Section 8.1.1.3) will be completed, and the Safety Follow-up Visit 
will not be required if the subjects enrolls in the other study within 28 (±7) days of the last dose 
of study drug in Study VX14-661-110. 
8.1.1.3 
Early Treatment Termination 
Treatment Cohort  
If a subject prematurely discontinues study treatment, an Early Treatment Termination Visit 
should be scheduled as soon as possible after the subject decides to terminate study treatment 
and should occur within 7 days after the last dose of study drug. Subjects who prematurely 
discontinue treatment will also be required to complete the Safety Follow-up Visit, 
approximately 28 (± 7) days after their last dose of study drug as described in Section 8.1.1.2. 
The assessments performed at the Safety Follow-up Visit are listed in Table 3-1.  
If the Early Treatment Termination Visit occurs 3 weeks or later following the last dose of study 
drug, then the Early Treatment Termination Visit will replace the Safety Follow-up Visit, and a 
separate Safety Follow-up Visit will not be required. If a subject discontinues 
Study VX14-661-110 to participate in another qualified Vertex study, and the subject does not 
re-enroll in Study VX14-661-110, the Early Treatment Termination 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 VX-661 in combination with ivacaftor is approved and 
available for the treatment of CF in populations enrolled in Study VX14-661-110, subjects with 


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the approved CFTR genotypes may be discontinued from this rollover study at the discretion of 
the sponsor (Section 10.6). If a subject is continuing onto commercially available 
VX-661/ivacaftor, the Early Treatment Termination Visit will be completed before dosing with 
commercial drug begins, and the Safety Follow-up Visit (Section 8.1.1.2) will not be required. 
Alternatively, if local health authorities decline to approve, or if clinical benefit is not 
demonstrated for the use of VX-661 in combination with ivacaftor for the treatment of CF in 
populations enrolled in Study VX14-661-110, 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 subset of subjects. If subjects are discontinued from 
the study, an Early Treatment Termination Visit should occur within 7 days of the last dose of 
study drug and a Safety Follow-up Visit should occur within 28 (± 7) days after the last dose of 
study drug. 
If a subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations will be performed and no additional data will be collected. 
Vertex may retain and continue to use any data collected before such withdrawal of consent. 
Timing of Overlapping Visits With Another Qualified Vertex Study 
If a subject enrolls in another qualified Vertex study and is discontinued from 
Study VX14-661-110, the Early Treatment Termination Visit in Study VX14-661-110 may be on 
the same day as the visit with the first dose of study drug in the other qualified Vertex study. If 
completed on the same day, the order/timing in the Schedule of Assessments in the other 
qualified Vertex study should be followed and subjects MAY have to repeat any 
Study VX14-661-110 assessments that were specified to be performed at the visit with the first 
dose of study drug in the other qualified Vertex study. 
8.1.2 
Observational Cohort (Eligible Subjects <18 Years of Age)  
8.1.2.1 
Day 1 
Following consent and assent (where applicable) and confirmation of eligibility, subjects will 
undergo the Day 1 assessments as shown in Table 3-2.  
Timing of Day 1 Visit in Study VX14-661-110 Active Sites 
The Day 1 Visit of the Observational Cohort will be on the same day as the last scheduled visit 
of the parent study for subjects at Study VX14-661-110 sites that have been activated by the time 
the last scheduled visit of the parent study has been completed. Subjects at these active sites 
MAY have to repeat any Study VX14-661-110 Day 1 assessments that were specified to be 
performed at the last scheduled study visit of the parent study. Assessments for the Observational 
Cohort are listed in Table 3-2. 
Timing of Day 1 Visit in Study VX14-661-110 Nonactive Sites 
The Day 1 Visit of the Observational Cohort of Study VX14-661-110 will NOT coincide with 
the last scheduled visit of the parent study for subjects at Study VX14-661-110 sites that have 
NOT been activated by the time the last scheduled visit of the parent study has been completed. 
Subjects at these nonactive sites will have to repeat any Study VX14-661-110 Day 1 assessments 
that were specified to be performed at the last scheduled visit of the parent study. Assessments 
for the Observational Cohort are listed in Table 3-2. 


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8.1.2.2 
Long-term Follow-up 
Subjects will be followed for approximately 2 years. A telephone contact will be made 
approximately every 3 to 4 months during the first year and at approximately 2 years (± 4 weeks) 
as shown in Table 3-2. 
8.1.3 
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. 
8.2 
Rationale for Study Design and Study Drug Regimens 
8.2.1 
Study Design 
The F508del-CFTR mutation is the most prevalent of the CFTR mutations. In vitro studies in 
primary cultures of HBE from subjects with CF who are homozygous for the F508del-CFTR 
mutation have demonstrated significant increases in CFTR activity with the addition of VX-661 
in combination with ivacaftor when compared to no treatment, VX-661 alone, or ivacaftor alone. 
Clinical studies of subjects with CF have demonstrated significant increases in lung function 
(FEV1) in subjects with CF who are homozygous or heterozygous for the F508del-CFTR 
mutation when treated with VX-661 in combination with ivacaftor when compared to placebo 
(Study VX11-661-101).18 Four Phase 3 studies are investigating the efficacy and safety of 
VX-661 in combination with ivacaftor in subjects with CF who are homozygous 
(Study VX14-661-106) or heterozygous (Studies VX14-661-107, VX14-661-108, and 
VX14-661-109) with F508del-CFTR mutation. Study VX14-661-107 was terminated early 
because the study met the prespecified futility criteria. In addition, 3 Phase 2 studies are 
investigating the safety and efficacy of VX-661 in combination with ivacaftor in subjects with 
CF who are homozygous for F508del-CFTR (Study VX13-661-103, Study VX14-661-111, and 
Study VX15-661-112). Study VX16-661-114 is a Phase 3b study being conducted in subjects 
with CF who are homozygous for F508del. 
Study VX14-661-110 will enroll subjects with CF who participated in a qualifying parent study 
of VX-661 in combination with ivacaftor (Studies VX13-661-103, VX14-661-106, 
VX14-661-107, VX14-661-108, VX14-661-109, VX14-661-111, and other eligible Vertex 
studies investigating VX-661 in combination with ivacaftor). Study VX14-661-110 will enroll 
subjects with CF who participated in a qualifying parent study (Studies VX15-661-112, 
VX16-661-114, and other eligible Vertex studies investigating VX-661 in combination with 
ivacaftor) or who completed study drug treatment. 
Results from Study VX14-661-110 will provide information on the safety and efficacy of long-
term treatment with VX-661 in combination ivacaftor in subjects with CF who are aged 12 years 
and older and homozygous or heterozygous for the F508del-CFTR mutation. Study VX14-661-
110 offers an opportunity to continue treatment with VX-661 in combination with ivacaftor for 
subjects in qualifying parent studies who had completed their assigned treatment with 
combination therapy. For subjects who received placebo in their qualifying parent study, 


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Study VX14-661-110 offers the opportunity to receive treatment with VX-661 in combination 
with ivacaftor. For subjects <18 years of age (age on the date of informed consent/assent in the 
parent study) not eligible for further treatment with VX-661 and ivacaftor or who choose not to 
continue treatment, participation in the Observational Cohort of this study provides an 
opportunity for long-term safety data collection after subjects discontinue VX-661 in 
combination with ivacaftor in an eligible parent study.  
If an evaluation of the efficacy data from the Phase 3 studies suggests that the VX-661/ivacaftor 
treatment does not provide clinically meaningful benefit for subsets of subjects included in these 
studies, Vertex may recommend that subjects with relevant genotypes discontinue from the 
Treatment Cohort. In addition, if local health authorities decline to approve, or if clinical benefit 
is not demonstrated for the use of VX-661 in combination with ivacaftor for the treatment of CF 
in populations enrolled in Study VX14-661-110, 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 subset of subjects. 
8.2.2 
Study Drug Dose and Duration 
All subjects enrolled in the Treatment Cohort will receive the same regimen of study drug that is 
being administered in the Phase 3 studies of VX-661 in combination with ivacaftor in subjects 
with CF who are 12 years of age or older. Subjects will receive a morning dose of VX-661 
100 mg/ivacaftor 150 mg (FDC tablet) and an evening dose of ivacaftor 150 mg. These dosages 
were selected based on efficacy, safety, and tolerability results from Study VX11-661-101.18 The 
dose regimen of ivacaftor planned for this study (150 mg q12h) is the current labeled dose 
regimen for patients with CF with gating mutations who are 12 years of age and older. Dosages 
for subjects 12 to 17 years of age (same as the adult dosage) were determined based on the 
historical data on weight as a function of age in patients with CF from the ivacaftor Phase 3 
program and the US CF Foundation Registry, weights in the 12- to 17-year old population are 
expected to be only slightly lower than those of the adult CF population.20  
All subjects in the Treatment Cohort will receive VX-661 in combination with ivacaftor. 
Subjects who received VX-661 in combination with ivacaftor in the parent study and continue to 
receive this combination in Study VX14-661-110 may receive treatment for up to approximately 
2.5 years, providing further information on the safety and efficacy of long-term treatment with 
VX-661 in combination with ivacaftor.  
8.2.3 
Rationale for Study Assessments 
The safety and PK assessments are standard parameters for clinical studies in drug development. 
The efficacy assessments are widely accepted and generally recognized as reliable, accurate, and 
relevant to the study of patients with CF. 
Spirometry: As lung disease is the major cause of morbidity and mortality for patients with CF, 
CF lung disease is the desired primary target of VX-661/ivacaftor combination therapy. 
Spirometry (as measured by FEV1) is the most widely implemented standardized assessment to 
evaluate lung function. 
Nutritional Status (measured by weight and BMI): Malnutrition is common in patients with CF 
because of increased energy expenditures due to lung disease and fat malabsorption. Given that 
VX-661 in combination with ivacaftor is a systemic therapy, it has the potential to improve 
extrapulmonary manifestations of CF, including those in the gastrointestinal system. Improved 


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nutritional status, defined as an increase in weight and/or BMI, is considered an appropriate 
endpoint for therapies targeting CFTR and was used in previous clinical studies of 
CFTR-targeted therapies (Studies VX08-770-102 and VX08-770-103). To evaluate the effect of 
VX-661 in combination with ivacaftor on growth, change in weight and BMI will be measured. 
As children gain weight and height as part of normal growth, adjustment for age and sex is 
necessary to assess changes in nutritional status in a population of boys and girls in varying 
stages of growth. To evaluate the effect of VX-661 in combination with ivacaftor on growth and 
nutrition adjusted for age and sex, weight-for-age, height-for-age, BMI-for-age, and the 
respective z-scores will be determined. Height and weight will be collected at the study visits 
indicated in the schedule of assessments. 
CFQ-R: The CFQ-R is a frequently used CF-specific instrument that measures the health-related 
quality of life of patients with CF.21,22,23 As VX-661 in combination with ivacaftor is a systemic 
therapy, it has the potential to improve respiratory symptoms as well as other extrapulmonary 
manifestations of CF. These improvements can be captured by the non-respiratory symptoms 
domains of the CFQ-R. Linguistically validated versions of the CFQ-R24,25 are available, thereby 
allowing consistent interpretation of the results in this global study. The CFQ-R will be used to 
capture and evaluate the impact of VX-661 in combination with ivacaftor on patient report of 
respiratory symptoms and other aspects of health-related quality of life. 
Other Events Related to Outcome: Pulmonary exacerbations, administration of antibiotic therapy 
for sinopulmonary signs and symptoms, and hospitalizations are other outcomes used to assess 
efficacy in therapies targeting improvement in CF disease. CF pulmonary exacerbations are a 
compilation of patient signs and symptoms that often result in the need for aggressive treatment, 
including the use of intravenous (IV) antibiotics administered at home, at the site, or in the 
hospital and/or pulmonary exacerbations that may require hospitalization. To date, there is no 
generally accepted objective definition of a pulmonary exacerbation,26 and large multicenter CF 
clinical studies have used many variations of physician-derived definitions.27,28,29,30 Despite the 
lack of a standard definition, reduction in pulmonary exacerbation rate has served as a key 
clinical efficacy measure in definitive CF clinical studies, supporting the registration of 2 chronic 
CF pulmonary therapies (inhaled recombinant human DNase and inhaled tobramycin).26 To 
evaluate the potential effect of VX-661 in combination with ivacaftor on pulmonary 
exacerbations, count, duration, and time-to-first event of hospitalizations and count and 
time-to-first event of IV courses of antibiotics for pulmonary exacerbations will be derived. For 
data consistency, this protocol specifies 1 definition of pulmonary exacerbation which is based 
on the definition used for the other studies including the ivacaftor monotherapy initial 
registration studies (Section 11.7.5.1). Because signs and symptoms in the definition may occur 
without meeting the overall definition of a pulmonary exacerbation, the number and timing of 


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outpatient sick visits to the clinic or hospital for CF that are unrelated to the study protocol will 
also be collected. 
9 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
9.1 
Inclusion Criteria 
Subjects who meet all of the following inclusion criteria will be eligible for this study. 
1. Signed and dated an informed consent form (ICF), and where appropriate, signed and dated 
an assent form. 
2. Did not withdraw consent from the parent study. 
3. Able to understand and comply with protocol requirements, restrictions, and instructions, and 
likely to complete the study as planned, as judged by the investigator and Vertex, based in 
part on study compliance in Studies VX13-661-103, VX14-661-106, VX14-661-107, 
VX14-661-108, VX14-661-109, VX14-661-111, or other Vertex studies investigating 
VX-661 in combination with ivacaftor. 
4. The following criteria apply to the Treatment and Observational Cohorts: 
• Subjects entering the Treatment Cohort must meet all of the following criteria:  
1. Elect to enroll in the Treatment Cohort 
2. Completed study drug treatment during the Treatment Period in a parent study 
(Studies VX13-661-103, VX14-661-106, VX14-661-107, VX14-661-108, or 
VX14-661-109), study drug treatment and the Safety Follow-up Visit for subjects 
from Study VX14-661-111, or study drug treatment and follow-up as specified in 
other Vertex studies investigating VX-661 in combination with ivacaftor. (Note: 
studies VX11-661-101 and VX15-661-113 are not eligible parent studies.)  
o Subjects who had study drug interruptions, but completed study visits up to the 
last scheduled visit of the Treatment Period of the parent study (and the Safety 
Follow-up Visit for subjects from Study VX14-661-111 or study drug treatment 
and follow-up as specified in other parent Vertex studies investigating VX-661 in 
combination with ivacaftor) are eligible.  
o Subjects who had a study drug interruption at the last scheduled visit of the 
Treatment Period of the parent study, subjects who required interruption to be 
continued or initiated at Day 1 in Study VX14-661-110, or subjects who resumed 
study drug in the parent study after a study drug interruption due to elevated 
transaminases but who did not complete at least 4 weeks of rechallenge with 
study drug (due to the timing of the rechallenge versus the time remaining in the 
Treatment Period of the parent study) must meet eligibility criteria and have 
received approval from the Vertex medical monitor in order to be enrolled into 
the Treatment Cohort of Study VX14-661-110. 


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Note: Subjects who permanently discontinue study drug treatment during the parent 
study, including at the last visit of the Treatment Period are not eligible to enroll into 
the Treatment Cohort. 
3. Willing to remain on a stable CF medication (and supplement) regimen through the 
Safety Follow-up Visit of Study VX14-661-110. 
• Subjects re-enrolling in the Treatment Cohort must meet all of the following criteria:  
1. Previously received at least 4 weeks of study drug before discontinuing 
Study VX14-661-110 to participate in another qualified Vertex study, which is 
defined as a Vertex study of investigational CFTR modulators that allows 
participation of subjects in Study VX14-661-110. Note: other qualified Vertex studies 
do not include studies of lumacaftor in combination with ivacaftor or ivacaftor 
monotherapy. 
2. Completed the last required visit of another qualified Vertex study before or during 
the Returning Visit in Study VX14-661-110. (If the last required visit of the other 
qualified Vertex study is more than 60 days from the Returning Visit in Study VX14-
661-110, approval of the medical monitor is required.) Subjects who discontinue 
Study VX14-661-110 to screen for another qualified Vertex study, and do not enroll 
into the other study, are eligible to re-enroll in Study VX14-661-110. 
3. Willing to remain on a stable CF medication (and supplement) regimen through the 
Safety Follow-up Visit of Study VX14-661-110. 
4. Subjects who discontinue Study VX14-661-110 more than once to participate in 
another qualified Vertex study may not re-enroll in Study VX14-661-110 a second 
time.   
• Subjects entering the Observational Cohort must meet the following criteria: 
1. <18 years of age (age on the date of informed consent/assent in the parent study) 
2. Completed study drug treatment during the Treatment Period in a parent study 
(Studies VX13-661-103, VX14-661-106, VX14-661-107, VX14-661-108, or 
VX14-661-109), study drug treatment and the Safety Follow-up Visit for subjects 
from Study VX14-661-111, or study drug treatment and follow-up as specified in 
other parent Vertex studies investigating VX-661 in combination with ivacaftor, but 
do not elect to enroll in the Study VX14-661-110 Treatment Cohort (note: Studies 
VX11-661-101, and VX15-661-113 are not eligible parent studies); or 
3. Received at least 4 weeks of study drug treatment and completed visits up to the last 
scheduled visit of the Treatment Period of a parent study (and the Safety Follow-up 
Visit for subjects from Study VX14-661-111 or study drug treatment and follow-up 
as specified in other parent Vertex studies investigating VX-661 in combination with 
ivacaftor), but do not meet eligibility criteria for enrollment into the Treatment 
Cohort 
Note: Subjects who permanently discontinued study drug in the parent study must 
have completed the last scheduled study visit of the Treatment Period (and the Safety 
Follow-up Visit for subjects from Study VX14-661-111 or study drug treatment and 


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follow-up as specified in other parent Vertex studies investigating VX-661 in 
combination with ivacaftor).  
9.2 
Exclusion Criteria  
Treatment Cohort 
Subjects who meet any of the following exclusion criteria will NOT be eligible for this study. 
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. For 
example: 
History of cirrhosis with portal hypertension, and/or history of risk factors for Torsade de 
Pointes (e.g., familial long QT syndrome, hypokalemia, heart failure, left ventricular 
hypertrophy, bradycardia, myocardial infarction, cardiomyopathy, history of arrhythmia 
[ventricular and atrial fibrillation], obesity, acute neurologic events [subarachnoid 
hemorrhage, intracranial hemorrhage, cerebrovascular accident, and intracranial trauma], and 
autonomic neuropathy) 
2. Pregnant and nursing females. Females of childbearing potential must have a negative urine 
pregnancy test at the Day 1 Visit (and the Returning Visit for subjects who re-enroll) and 
before receiving the first dose of study drug. 
3. Sexually active subjects of reproductive potential who are not willing to follow the 
contraception requirements outlined in Section 11.8.8.1. 
4. History of drug intolerance in the parent study or other qualified Vertex study that would 
pose an additional risk to the subject in the opinion of investigator or Vertex. Examples of 
subjects who may not be eligible for the Treatment Cohort include the following:  
• Subjects with a history of allergy or hypersensitivity to the study drug 
• Liver function test (LFT) abnormality during study drug treatment in the parent study or 
other qualified Vertex study that required permanent study drug discontinuation  
• ECG abnormality (e.g., persistent QTc >450 msec) during study drug treatment in the 
parent study or other qualified Vertex study that required permanent study drug 
discontinuation 
• Other severe or life-threatening reactions to the study drug in the parent study or other 
qualified Vertex study. 
5. History of poor compliance with study drug and/or procedures in the parent study or other 
qualified Vertex study as deemed by the investigator. 
6. Participation in an investigational drug trial (other than Studies VX13-661-103, 
VX14-661-106, VX14-661-107, VX14-661-108, VX14-661-109, VX14-661-111, other 
Vertex studies investigating VX-661 in combination with ivacaftor, or other qualified Vertex 
study) or use of a commercially available CFTR modulator (e.g., Kalydeco) as defined in 
Table 9-1. NOTE: participation in a noninterventional study (including observational studies, 
registry studies, and studies requiring blood collections without administration of study 
drug), and screening for other qualified Vertex studies is permitted.  


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7. Subjects who are enrolled in a qualified Vertex parent study with more than 
1 blinded-treatment periods but who have not completed treatment in all blinded-treatment 
periods are not eligible to enroll in the Treatment Cohort but may be eligible to enroll in the 
Observational Cohort if inclusion criteria are met. 
8. Previous re-enrollment in the Treatment Cohort of Study VX14-661-110, after participating 
in other qualified Vertex studies.  
9.3 
Study Restrictions (Treatment Cohort) 
For subjects enrolled in the Treatment Cohort, prohibited medications and certain foods are not 
allowed in this study while subjects are receiving study drug (Table 9-1). Both VX-661 and 
ivacaftor are metabolized predominantly via the hepatic enzymatic pathway utilizing CYP3A4. 
Co-administration of VX-661 and ivacaftor with moderate and strong CYP3A inducers such as 
rifampin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum) 
has the potential to significantly reduce VX-661 and ivacaftor exposure and is restricted in this 
study. Case-by-case exceptions for concomitant use of a moderate CYP3A inducer with 
VX-661/ivacaftor may be granted by the Vertex MM if it is the PI's opinion that the benefits 
outweigh the risks for the subject in question. 
A more detailed but nonexhaustive list of study prohibitions and cautions for food and 
medication will be provided in the Study Reference Manual. 
Table 9-1 
Study Restrictions in Treatment Cohort of Study VX14-661-110 
Restricted Medication/Food 
Study Period 
Certain fruits and fruit juices 
(grapefruit, grapefruit juice, 
Seville oranges, marmalade) 
None allowed within 14 days before the first dose of the study drug through 
the Safety Follow-up Visit 
Moderate and strong CYP3A 
inducers 
None allowed within 14 days before the first dose of the study drug through 
the Safety Follow-up Visit 
Commercially available CFTR 
modulators (e.g., ivacaftor 
[Kalydeco]) 
None allowed within 30 days before the first dose of the study drug through 
the Safety Follow-up Visit 
CFTR: cystic fibrosis transmembrane conductance regulator; CYP: cytochrome P450. 
9.4 
Prior and Concomitant Medications (Treatment Cohort) 
Medicinal products affected by VX-661/ivacaftor 
CYP3A, P-gp, or CYP2C9 substrates 
Co-administration with (oral) midazolam, a sensitive CYP3A substrate, did not affect midazolam 
exposure. No dose adjustment is required when co-administered with CYP3A substrates. 
Based on in vitro data, ivacaftor and its M1 metabolite have the potential to inhibit 
P-glycoprotein (P-gp). Co-administration of VX-661/ivacaftor with digoxin, a sensitive P-gp 
substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by 
ivacaftor. Administration of VX-661/ivacaftor 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. Use with caution and appropriate monitoring when using 
concomitant digoxin or other substrates of P-gp with a narrow therapeutic index. Ivacaftor may 


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inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during 
co-administration of VX-661/ivacaftor with warfarin is recommended. 
Information regarding all prior and concomitant medications, including the subject's CF 
medications, other medications, and herbal and naturopathic remedies administered at or after 
completion of treatment in the parent study through the Safety Follow-up Visit, if applicable, 
will be recorded in each subject's source documents.  
• Subjects must remain on a stable CF medication (and supplement) regimen through the 
Safety Follow-up Visit. Stable medication regimen is defined as the current medication 
regimen for CF that subjects have been following for at least 28 days before Day 1. Subjects 
must not initiate long-term treatment with new medication from 28 days before Day 1 
through the Safety Follow-up Visit unless it is discussed and approved by the Vertex 
medical monitor.  Guidelines for stable medication regimens for CF are as follows: 
o Subjects who are taking daily inhaled tobramycin or other chronically inhaled antibiotics 
should remain on that regimen throughout the study. 
o Subjects who are on inhaled cycling antibiotics should continue on their prior schedule. 
The timing of the first dose of study drug should be synchronized as closely as possible to 
the first day of inhaled cycling antibiotics in the cycle. 
o Subjects who alternate 2 different antibiotics monthly should remain on the same 
schedule during the study. The timing of the first dose of study drug should be 
synchronized as closely as possible to the first day of 1 of the inhaled alternating 
antibiotics. 
• There are no restrictions on the concomitant use of corticosteroids. 
For subjects in the Treatment Cohort, information on 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 11.7.1. 
9.5 
Removal of Subjects (Treatment Cohort) 
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 the subject has not withdrawn consent.  
Subjects who discontinue study treatment early should continue to return for study assessments 
at the Early Treatment Termination Visit and/or the Safety Follow-up Visit, as noted in 
Section 8.1.1.3.  
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a Safety Follow-up Visit, if 
applicable (see Section 8.1.1.2), and follow up with the subject regarding any unresolved AEs. 


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If the subject withdraws consent for the study, no further evaluations will be performed and no 
additional data will be collected. Vertex may retain and continue to use any data collected before 
such withdrawal of consent. 
9.6 
Replacement of Subjects (Treatment Cohort) 
Subjects who withdraw or are withdrawn during the study drug Treatment Period will not be 
replaced. 
10 
STUDY DRUG ADMINISTRATION AND MANAGEMENT (TREATMENT 
COHORT) 
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 
Administration 
Study drug tablets will be administered orally as shown in Table 10-1. Subjects in the 
Observational Cohort will not receive study drug. 
Table 10-1 
Study Drug Administration – Treatment Period 
Treatment Cohort 
Time 
Drug(s) and Dose(s) Administered 
Route of Administration 
VX-661/ivacaftor 
AM 
VX-661 100-mg/IVA 150-mg fixed-dose tablet 
oral 
PM 
IVA 150-mg tablet 
oral 
AM: morning; IVA: ivacaftor; PM: evening. 
Treatment Cohort 
Study drug should be administered within 30 minutes of starting a meal with fat-containing food, 
such as a standard CF high-fat, high-calorie meal or snack, according to the following guidelines: 
1. Study drug should be administered q12h (± 2 hours). For each subject, all doses (morning 
and evening) of study drugs will be taken at approximately the same time each day. For 
example, the morning dose could be taken at 08:00 every morning and the evening dose 
could be taken at 20:00 every evening throughout the study. 
2. On days of scheduled visits, the morning dose of study drug will be administered at the site 
after predose assessments have been completed.  A meal or snack will be provided by the site 
for the morning dose of study drug.  
3. If a subject's scheduled visit is to occur in the afternoon, the following guidelines must be 
used for administering either the morning or evening dose: 
• If the dose in the clinic will be within 6 hours of the subject's scheduled morning dose, 
the subject should withhold their morning dose of study drug, and the morning dose will 
be administered in the clinic. 


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• If the dose in the clinic will be more than 6 hours after the subject's scheduled morning 
dose, the subject should take the morning dose at home, and the evening dose will be 
administered in the clinic. In this event, all assessments will be collected relative to the 
evening dose. 
4. For visits after the Day 1 Visit, subjects will be instructed to bring all used and unused study 
drug to the site; study drug will be dispensed at each visit, as appropriate. 
5. At the Week 96 Visit, the morning dose of study drug will NOT be administered. The last 
dose of study drug will be the evening dose administered the day before the Week 96 Visit. 
Treatment Cohort Only: 
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.  
10.3 
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 the Treatment Cohort. 
Subjects in the Observational Cohort will not receive study drug.  
10.4 
Dose Modification for Use With Concomitant CYP3A Inhibitors 
(Treatment Cohort) 
The dosage of VX-661/ivacaftor can be altered only when co-administered with moderate or 
strong inhibitors of CYP3A.  
Table 10-2 
Dosing Recommendations for Subjects Taking Concomitant CYP3A 
Inhibitors 
Type of 
Inhibitor 
Example of Inhibitor 
VX-661 100 mg/Ivacaftor 150 mg 
Ivacaftor 
150 mg 
Strong 
CYP3A 
inhibitor 
ketoconazole, itraconazole, 
posaconazole, voriconazole, 
telithromycin, and clarithromycina  
One tablet twice a week in the morning 
(3 to 4 days between doses) 
No evening dose  
Moderate 
CYP3A 
inhibitor 
fluconazole, erythromycin 
One tablet of VX-661 100 mg/ivacaftor 150 mg or one 
ivacaftor 150 mg in the morning, taken on alternate days. 
No evening dose. 
a 
A more detailed but nonexhaustive list of study prohibitions and cautions for food and medication will be 
provided in the Study Reference Manual. 
The dosage of VX-661/ivacaftor cannot be otherwise altered, but the investigator can interrupt or 
stop treatment (Sections 10.5 and 10.6). 
10.5 
Study Drug Interruption (Treatment Cohort) 
If study drug dosing must be interrupted for more than 72 hours, the medical monitor must be 
notified. In these instances, study drug dosing may only resume after approval by the medical 
monitor. Specific instructions for interruption for elevated LFT levels and increased QTc 
intervals are provided in Section 11.8.6 and Section 11.8.4, respectively. 


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Missed Doses 
If a subject misses a dose and recalls the missed dose 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. For 
example, 
• if the morning dose of study drug should have been taken at approximately 08:00, and the 
subject remembers at 12:00 that he/she forgot to take his/her dose, he/she should take the 
dose with food as soon as possible. 
• if the morning dose of study drug should have been taken at approximately 08:00, and more 
than 6 hours have elapsed beyond the scheduled dosing time (i.e., the time is past 14:00), the 
subject would resume dosing with the evening dose at approximately 20:00. 
10.6 
Discontinuation of Study Participation (Treatment Cohort)  
If after review of a marketing application, local health authorities decline to approve, or if 
clinical benefit is not demonstrated for the use of VX-661 in combination with ivacaftor for the 
treatment of CF in populations enrolled in Study VX14-661-110, 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 subset of subjects. In 
addition, if evaluation of efficacy data from the Phase 3 studies suggests that the 
VX-661/ivacaftor treatment does not provide clinically meaningful benefit for a population 
enrolled in Study VX14-661-110, Vertex may recommend that subjects with relevant CFTR 
genotypes discontinue from the Treatment Cohort of the study. 
Subjects who become eligible to receive commercially-available VX-661/ivacaftor by 
prescription of a physician may be discontinued from this rollover study at the discretion of the 
sponsor. If a subject is continuing onto commercially available VX-661/ivacaftor, the Early 
Treatment Termination Visit (Section 8.1.1.3) will be completed before dosing with commercial 
drug begins, and the Safety Follow-up Visit (Section 8.1.1.2) will not be required. 
Subjects may be discontinued from the Treatment Cohort at any time due to safety reasons. If a 
cataract or lens opacity is identified and determined to be clinically significant by the 
ophthalmologist after dosing, the subject will be notified. After discussion with the site principal 
investigator and in collaboration with the Vertex medical monitor, the subject may elect to 
continue or discontinue the study. If the subject discontinues study drug, they should complete 
the Early Treatment Termination Visit and Safety Follow-up Visit (see Section 8.1.1.3 for Early 
Treatment Termination). If the subject continues, more frequent ophthalmologic monitoring 
should be considered. 
10.7 
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 VX-661 and ivacaftor will be included in the Pharmacy 
Manual. 
10.8 
Study Drug Supply, Storage, and Handling 
Blister cards must be stored at room temperature according to Table 10-3 and to the instructions 
provided in the Pharmacy Manual. While at the clinical site, the investigator, or an authorized 


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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 in 
Section 10.9. 
Instructions regarding the storage and handling of study drug after dispensation to subjects will 
be provided to sites in the Pharmacy Manual. 
Table 10-3 
Identity of Study Drugs, Dosage, and Storage 
Drug Name 
Strength/Formulation/Route 
Dosage 
Storage Condition 
VX-661/ivacaftor 
fixed-dose tablet 
100-mg/150-mg tablet; oral 
100 mg/ 
150 mg, morning dose 
≤25°C (77°F) with excursions 
to 30°C (86°F) 
Ivacaftor 
150-mg tablet, oral 
150 mg, evening dose 
≤25°C (77°F) with excursions 
to 30°C (86°F) 
 
10.9 
Drug Accountability (Treatment Cohort) 
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 until inventoried by the study monitor. The study 
monitor will review study drug records and inventory throughout the study. 
10.10 
Disposal, Return, or Retention of Unused Drug (Treatment Cohort) 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The site monitor will instruct the site when 
it is appropriate to return or destroy study drug. If the site monitor authorizes destruction at the 
study site, the investigator, or designee, must 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. 
10.11 
Compliance (Treatment Cohort) 
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 contact the medical monitor to discuss discontinuation of the 
subject from the study 
10.12 
Blinding and Unblinding 
This will be an open-label study. However, subjects should not be informed of their study-related 
spirometry results during the study regardless if the subject has prematurely discontinued 
treatment. 


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11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments is shown in Table 3-1 (Treatment Cohort) and Table 3-2 
(Observational Cohort). 
If study drug is not administered on the day of the visit (i.e., study drug interruption), 
assessments will still be collected unless otherwise noted. 
The CFQ-R questionnaire must be completed before any other assessment at the clinic visits. For 
the remaining assessments, the following assessments must be performed in the following order 
when more than 1 assessment is required at a particular time point. 
2. standard 12-lead ECG recording 
3. vital signs and pulse oximetry (interchangeable order is acceptable) 
4. spirometry 
5. safety laboratory assessments and PK sampling (i.e., blood draws) 
All other assessments may be completed in any order as shown in Table 3-1 and Table 3-2.  
11.2 
Informed Consent/Assent 
Each subject of age of consent (per local requirements) must sign and date a study-specific ICF 
before any study-specific procedures can be performed and before the subject receives the first 
dose of study drug. Subjects not of age of consent must assent, if applicable per local 
requirements, to participate in the study, and the subject's parent or legal guardian must sign and 
date a study-specific ICF before any study-specific procedures can be performed, and before 
the subject receives the first dose of the study drug. The consent/assent forms will comply 
with all applicable regulations governing the protection of human subjects. An ICF and Assent 
Form, approved by Vertex and the site's institutional review board (IRB) or independent ethics 
committee (IEC), must be used. 
Subjects who re-enroll in the Treatment Cohort must re-consent/assent (Table 3-1) before any 
study-specific procedures can be performed and before the subject receives the first dose of 
the study drug. 
11.3 
Assigning Subject Number 
All subjects will retain their subject number from the parent study. 
11.4 
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. 
Age, sex, race, and ethnicity will be derived from the parent study because these data are 
required for the normalization of spirometry values using either the Wang or Hankinson methods 
(Section 11.7.1).  


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11.5 
Pharmacokinetics (Treatment Cohort Only) 
11.5.1 
Blood Sampling 
Blood samples will be collected as shown in Table 3-1 for the determination of the plasma 
concentrations of VX-661, M1-661, ivacaftor, and M1-ivacaftor. Blood samples must be 
collected within 60 minutes before dosing.  
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. 
For each visit with a PK blood draw, a record of study drug administration will be collected as 
described in Section 10.2. The collection date and time that each PK blood sample is drawn will 
also be recorded. 
Details on sample collection, processing, and shipping will be provided in a separate 
protocol-specific Laboratory Manual. 
11.5.2 
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 Laboratory Manual. The 
shipment address and assay laboratory contact information will be provided to the investigational 
site before initiation of the study. 
11.5.3 
Bioanalysis 
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee standard operating procedures. A description of the assay and validation data will be 
provided in separate reports. 


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11.7 
Efficacy 
11.7.1 
Spirometry (Treatment Cohort) 
Spirometry will be performed according to the American Thoracic Society Guidelines32, 
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 dosing. 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 is pre-bronchodilator, but, on a subsequent visit, 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, the subject forgets to withhold his/her dose of bronchodilator, spirometry 
should be performed post-bronchodilator, and all subsequent spirometric measurements  
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. 
The parameters listed below will be normalized using the standards of Wang et al.33 (for female 
subjects aged 12 to 15 years [inclusive] and male subjects aged 12 to 17 years [inclusive]) or 
Hankinson et al.34 (for female subjects aged 16 years and older and male subjects aged 18 years 
and older).  
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 
• Forced expiratory flow (FEF25%-75%) (L/s) 


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11.7.2 
Height and Weight (Treatment Cohort) 
Height and weight will be measured with shoes off. Height and weight will be measured before 
the morning dose of the study drug during the Treatment Period. During the Treatment Period 
and at the Safety Follow-up Visit, height will be collected only for subjects ≤ 21 years of age 
(age on the date of informed consent/assent in the parent study). 
11.7.3 
Cystic Fibrosis Questionnaire-Revised (Treatment Cohort) 
Subjects will be asked to complete the CFQ-R in their native language. The CFQ-R will be 
completed before the start of any other assessments, as noted in Table 3-1.  
• Subjects who are 12 and 13 years of age at Day 1 will complete the CFQ-R Child version 
themselves, and their parents/caregivers will complete the CFQ-R Parent version, on all 
visits, regardless of whether the subject subsequently turns 14 years of age during the study.  
• Subjects who have turned 14 years of age during their participation in the parent study and 
have their Day 1 Visit for Study VX14-661-110 on the same day as the last parent study visit 
will complete the CFQ-R per the parent protocol requirement. At Day 15 and all subsequent 
visits, these subjects will complete the CFQ-R Adolescent/Adult version themselves.  
• Subjects 14 years of age and older at Day 1 who do not have their Day 1 Visit for Study 
VX14-661-110 on the same day as the last parent study visit will complete the 
Adolescent/Adult version of the questionnaire themselves at all visits.  
The questionnaires provide information about demographics; general quality of life, school, 
work, or daily activities; and symptom difficulties (pertaining to CF). Copies of the CFQ-R used 
in this study will be provided in the Study Reference Manual. Validated translations24,25 of the 
CFQ-R, if available, will be provided for participating centers in non-English-speaking countries.  
11.7.5 
Other Events Related to Outcome (Treatment Cohort)  
11.7.5.1 
Antibiotic Therapy for Sinopulmonary Sign/Symptoms (Treatment 
Cohort) 
New or changed antibiotic therapy (IV, inhaled, or oral) for the following sinopulmonary 
signs/symptoms will be determined and documented at visits: 
• Change in sputum 
• New or increased hemoptysis 
• Increased cough 
• Increased dyspnea 
• Malaise, fatigue, or lethargy 


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• 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, a pulmonary exacerbation is defined as a 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 pulmonary exacerbation used in the parent clinical studies including those 
investigating ivacaftor and VX-661/ivacaftor.35,36 
It is recommended that the study drug should not be interrupted during a pulmonary exacerbation 
unless, in the opinion of the investigator, it would be in the best interest of the subject. 
The following information will be determined for protocol-defined pulmonary exacerbations: 
• Number of pulmonary exacerbations 
• Number of days with pulmonary exacerbations 
• Time-to-first pulmonary exacerbation 
• Number of pulmonary exacerbations requiring hospitalizations 
• Number of days hospitalized for pulmonary exacerbations* 
• Time-to-first hospitalization for pulmonary exacerbation 
• Number of pulmonary exacerbations requiring IV antibiotic therapy 
• Number of days on IV antibiotic therapy for pulmonary exacerbations 
• Time-to-first IV antibiotic therapy for pulmonary exacerbations 
*For each treatment group, the number of days hospitalized for pulmonary exacerbations will be 
analyzed as 48 weeks times the total numbers of days in hospital for pulmonary exacerbation, 
divided by the total number of weeks on treatment, for all subjects in the same treatment group.  
11.7.5.2 
Hospitalization for CF (Treatment Cohort) 
At the visits indicated in Table 3-1, subjects will be queried about planned and unplanned 
hospitalizations lasting ≥24 hours. The dates of hospitalizations and the reasons for 
hospitalizations will be documented. 
For any hospitalization (unplanned and planned), the procedures for safety reporting should be 
followed (see Section 13.1.2.3). 
The following information will be determined: 
• Number of planned hospitalizations for CF (i.e., prophylactic antibiotic therapy) 


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• Number of all unplanned hospitalizations 
• Number of days of all unplanned hospitalizations 
• Time-to-first unplanned hospitalization 
11.8 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, pulse oximetry, ophthalmologic examinations (subjects <18 years of age [age on 
the date of informed consent/assent in the parent study]), and PEs. 
11.8.1 
Adverse Events (Treatment Cohort) 
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 eCRF 
completion guidelines for investigators as well as training will be provided. 
11.8.2 
Clinical Laboratory Assessments (Treatment Cohort) 
Blood and urine samples will be analyzed at a central laboratory. With the exception of Day 15 
(when a lipid panel is not required), all blood samples will require a 4-hour fast before collection 
(at least a 4-hour fast is needed for the lipid panel). Fasting is not required at other time points 
unless specified in the assessment table. On Day 1/Returning Visit, blood samples will be 
collected before the first dose of the study drug. At all other scheduled visits, these samples will 
be collected at any time during the visit. Although blood samples are to be collected and 
analyzed at a central laboratory, a local laboratory may be used if a subject cannot return to the 
clinical study site for the mandatory liver function testing (Section 11.8.6). All urine pregnancy 
tests will be performed at the site. 
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table 3-1. Laboratory test results that are abnormal and considered clinically significant will be 
reported as AEs (see Section 13.1.1).   


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Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose 
Blood urea nitrogen 
Creatinine 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate 
Inorganic phosphate  
Total bilirubin, direct bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase  
Alanine aminotransferase 
Lactate dehydrogenase 
Gamma-glutamyl transpeptidase 
Total protein 
Albumin 
Creatine kinase 
Amylase 
Lipase 
Hemoglobin 
Erythrocytes 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration  
Mean corpuscular volume 
Reticulocytes 
Platelets 
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  
Vitamin Levels 
Vitamins A, D, E, K, and B12 
Lipid Panel 
Total cholesterol, triglycerides 
Low-density lipoprotein (LDL) 
High-density lipoprotein (HDL) 
a 
If urine is positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of urine will be 
performed for leukocytes, erythrocytes, crystals, bacteria, and casts. 
The safety laboratory test panels are shown in Table 11-1. 
Pregnancy (β-human chorionic gonadotropin) testing for female subjects who are of childbearing 
potential from the time of the Day 1 Visit or at any point through the Safety Follow-up Visit (as 
defined in Section 11.8.8.1): Serum samples will be obtained as specified and analyzed at the 
central laboratory. Urine samples will be obtained as specified and all urine pregnancy tests will 
be performed at the site. The urine pregnancy test on Day 1 (and the Returning Visit for 
subjects who re-enroll) must be negative before the first dose of study drug.  
Additional evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
At the discretion of the local investigator, local laboratories may be used for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it should 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 


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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. 
11.8.3 
Physical Examinations and Vital Signs (Treatment Cohort) 
A PE of all body systems and vital signs assessment will be performed at Day 1 and select study 
visits. At other visits, symptom-directed PEs and symptom-directed vital sign assessments can be 
performed at the discretion of the investigator or healthcare provider. 
A PE includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/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 physical examinations will be reported 
as AEs. 
Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse rate, and 
respiration rate. These will be assessed following a 5-minute rest in the seated or supine position. 
11.8.4 
Electrocardiograms (Treatment Cohort) 
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. A window of ± 15 minutes will be allowed around the 
nominal times for all postdose ECG assessments. 
The performance of all ECGs will adhere to the following guidelines: 
• The subject will be instructed to rest in the supine position for at least 5 minutes before 
having an ECG performed. 
• The ECG will be performed before any other procedures that may affect heart rate, such as 
blood draws. 
The ECG traces will be manually read at the study site at the Day 1 and Safety Follow-up Visits. 
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 the Safety Follow-up Visit 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 >45 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 (>45 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.  
If the QTcF value remains above the threshold value (>45 msec from the average of the 
3 predose values on Day 1 or ≥500 msec) on repeated measurement or is noted on >2 occasions 
with no identified alternative etiology for the increased QTcF study drug, then discontinuation 
from study drug treatment may be required after discussion with the medical monitor. Subjects in 
whom treatment is discontinued for increased QTc should have their QTc monitored closely until 
it normalizes or returns to baseline. 


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Further details pertaining to ECGs will be provided to sites in a separate document (ECG 
Manual). 
11.8.5 
Pulse Oximetry (Treatment Cohort) 
Arterial oxygen saturation by pulse oximetry will be measured at visits noted in Table 3-1. This 
will be assessed following a 5-minute rest (seated or supine) and before study drug dosing. At 
visits when study drug is taken at the site, pulse oximetry will be collected before the morning 
dose. This is a noninvasive measure of oxygen delivery to the tissues and has been correlated 
with clinical status and lung function. 
11.8.6 
Liver Function Test Parameters (Treatment Cohort) 
Liver Function Testing 
Liver function testing (ALT, AST, GGT, ALP, direct bilirubin, and total bilirubin) must be 
performed as noted for serum chemistry, while subjects are receiving study drug treatment and at 
the Early Treatment Termination Visit and the Safety Follow-up Visit. These blood samples 
should be processed and shipped immediately per the Laboratory Manual. 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN and clinical 
symptoms must be followed closely, including repeat confirmatory testing performed by the 
central laboratory within 48 to 72 hours of the initial finding and subsequent close monitoring of 
ALT and AST levels, as clinically indicated. In addition, if ALT or AST is >5 × ULN, repeat 
follow-up levels must be obtained within 7 ± 2 days. 
If a subject cannot return to the site for liver function testing, a local laboratory may be used. 
Elevations in LFTs at the local laboratory 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 Interruption 
Study drug administration must be interrupted immediately (prior to confirmatory testing), and 
the medical monitor must be notified, if any of the following criteria is 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. 
If no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, or alcohol 
ingestion) for the confirmed elevated transaminases is identified, regardless of whether ALT or 
AST levels have improved, study drug treatment must be permanently discontinued if repeat 
testing within 48 to 72 hours confirms the initial elevation. Subjects in whom treatment is 
discontinued for elevated transaminases should have their transaminases monitored closely until 
levels normalize or return to baseline. 
Resumption of Study Drug 


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If an alternative, reversible cause of transaminase elevation has been identified, study drug may 
be resumed once transaminases return to baseline or are ≤2 × ULN, whichever is higher. 
Approval of the medical monitor is required before resumption of study drug. Upon resumption 
of study drug, transaminases should be assessed weekly for 4 weeks. If a protocol-defined 
transaminase elevation occurs 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. 
11.8.7 
Ophthalmologic Examination (Treatment Cohort) 
Subjects <18 years of age (age on the date of informed consent/assent in the parent study) will 
undergo a baseline ophthalmologic examination performed by a licensed ophthalmologist within 
28 days before enrollment on Day 1 of Study VX14-661-110, which includes: 
• measurement of best corrected distance visual acuity of each eye, 
• measurement of lens refracting power following cycloplegia (e.g., autorefractor or 
ophthalmoscopy streak), and 
• pharmacologically dilated examination of the lens with a slit lamp. 
The baseline ophthalmologic examination must be completed and the results reviewed before 
enrollment. This examination may be conducted while the subject is participating in the parent 
study.  
If a cataract or lens opacity is identified and determined to be clinically significant by the 
ophthalmologist at the baseline examination, the subject will be notified. After discussion with 
the site principal investigator and in collaboration with the Vertex medical monitor, the subject 
may elect to participate or not to participate in the study. If the subject elects to participate, more 
frequent ophthalmologic monitoring should be considered. 
Subjects who are enrolled in the Treatment Cohort will have ophthalmologic exams as noted in 
Table 3-1. If a cataract or lens opacity is identified and determined to be clinically significant by 
the ophthalmologist after dosing, the subject will be notified. After discussion with the site 
principal investigator and in collaboration with the Vertex medical monitor, the subject may elect 
to continue or discontinue the study. If the subject discontinues study drug, they should complete 
the Early Treatment Termination Visit and Safety Follow-up Visit (Sections 8.1.1.3 and 8.1.1.2). 
If the subject continues, more frequent ophthalmologic monitoring should be considered. 
In addition to the baseline examination, an ophthalmologic examination will be performed by a 
licensed ophthalmologist at the Early Treatment Termination or Safety Follow-Up Visit for 
subjects < 18 years of age (age on the date of informed consent/assent in the parent study) who 
discontinue treatment after receiving at least 1 dose of study drug. This examination may be 
completed at either the Early Treatment Termination or Safety Follow-Up Visit, but must be 
completed by the date of the Safety Follow-Up Visit.  
In addition, on Day 1 of Study VX14-661-110, the following history will be obtained for all 
subjects, if it was not documented in the parent study: 
• history of steroid use 
• history or presence of diabetes 


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• any prior ophthalmologic or optometric examinations 
• history of trauma to the eye 
• any family history of glaucoma, congenital cataracts, or cataracts arising later in life 
• use of corrective lenses (contact lenses or eyeglasses) 
• history of prolonged exposure to sunlight or ultraviolet light and use of sunglasses 
• history of exposure to secondhand smoke. 
11.8.8 
Contraception and Pregnancy (Treatment Cohort) 
11.8.8.1 
Contraception 
Participation in this study requires a commitment from the subject and his/her partner to use at 
least 1 acceptable method of contraception, which must be used correctly with every act of 
sexual intercourse. Methods of contraception should be in successful use from at least 14 days 
before the first dose of study drug (unless otherwise noted) and until 90 days following the last 
dose of study drug.  
For female subjects using oral hormonal contraceptives: 
1. The oral hormonal contraceptives should be in successful use from at least 60 days before the 
first dose of study drug (unless otherwise noted) and until 90 days following the last dose of 
study drug. 
2. Female subjects who change their method of contraception to hormonal contraceptive during 
Study VX14-661-110 must use a second form of approved contraception for at least 60 days 
after beginning oral contraceptives. 
Contraception for the 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. 
• If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented through 
examination of a semen specimen or by demonstration of the absence of the vas deferens by 
ultrasound before the first dose of the study drug. 
• If the female is of non-childbearing potential, per the following: 
o Documented hysterectomy or a bilateral oophorectomy/salpingo-oophorectomy. 
o Postmenopausal: continuous amenorrhea for at least 12 months and serum FSH levels ≥ 
40 mIU/mL.  
o Has not achieved menarche (has not had her first menstrual period). If a female achieves 
menarche during the study, she will need to follow acceptable methods of contraception 
or abstinence. 
For subjects for whom contraception methods are not waived due to at least 1 of the reasons 
cited above, the following are acceptable contraceptive methods for male subjects and their 
female (non-study) partners, and for female subjects and their male (non-study) partners: 


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Table 11-2 
Acceptable Methods of Contraception 
• Male vasectomy 6 months or more previously, with a documented negative post-vasectomy semen analysis for 
sperm. 
• Male or female condom with or without spermicide (either as a single product if commercially available and/or as 
allowed according to local regulations; otherwise condom and spermicide as separate products). 
• Female bilateral tubal ligation performed at least 6 months previously. 
• Female diaphragm, cervical cap, or vaginal sponge, each with spermicide (where available). 
• Female continuous use of an intrauterine device (non-hormone releasing or hormone releasing) for at least 90 days 
before the first dose of study drug 
• Female combined (estrogen and progestogen-containing) or progestogen-only oral hormonal contraception 
associated with inhibition of ovulation if successfully used for at least 60 days before the first dose of study drug 
or with a second form of approved contraception for at least 60 days after beginning hormonal contraception. 
 
Important notes: 
• Local requirements may prohibit the use of some of these acceptable methods listed above. 
Please contact the medical monitor with any questions. 
• If applicable, additional contraception requirements may need to be followed according to 
local regulations and/or requirements. 
• Male and female subjects who are not sexually active at the time of screening must agree to 
follow the contraceptive requirements of this study if they become sexually active. 
• Female condom used with male condom (as a double method of contraception) is not an 
acceptable method of contraception due to risk of tearing; a different acceptable method of 
birth control must be used as described in Table 11-2.  
• Male subjects must not donate sperm after the first dose of study drug, throughout the study, 
and for 90 days following the last dose of study drug. 
• Female subjects and female partners of male subjects should not plan to become pregnant 
during the study through 90 days following the last dose of study drug. 
• Female subjects should not nurse a child from the start of study drug dosing through 90 days 
following the last dose of study drug. 
Other situations that do not fall within the above specifications may be discussed with the Vertex 
medical monitor on an individual basis. 
11.8.8.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and within 90 days after the last dose of the study drug. 
If a female subject or the female partner of a male subject becomes pregnant while participating 
in the study, study drug must be permanently discontinued immediately. For male subjects, study 
drug does not need to be permanently discontinued if the female partner's pregnancy resulted 
from donated sperm or sperm banked before study drug exposure (Section 11.8.8.1). The 
investigator must 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. 


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If the subject is confirmed to be on study 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/assent 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 the Treatment Cohort in this 
protocol. Statistical analysis details for the Treatment Cohort will be provided in the Statistical 
Analysis Plan (SAP) will be finalized before the clinical data lock for the study. 
No analysis will be performed for the Observational Cohort.  
12.1 
Sample Size and Power 
Study VX14-661-110 is a rollover study that plans to enroll subjects from 
Studies VX13-661-103, VX14-661-106, VX14-661-108, VX14-661-109, VX14-661-111, and 
other eligible Vertex studies investigating VX-661 in combination with ivacaftor who meet the 
eligibility criteria for this study. Approximately up to 1375 subjects are potentially eligible to be 
enrolled from the following parent studies: 40 subjects from Study VX13-661-103, 490 subjects 
from Study VX14-661-106, up to 300 subjects from Study VX14-661-108, up to 200 subjects 
from Study VX14-661-109, and 45 subjects from Study VX14-661-111, if eligible.  
12.2 
Analysis Sets 
For subjects in the Treatment Cohort, the assignment to analysis sets will be done before the 
clinical data lock for the study.  
The All Subjects Set is defined as all subjects who signed inform consent (enrolled) and have 
received at least 1 dose of study drug in Study VX14-661-110. This analysis set will be used in 
subject listings and disposition summary tables unless otherwise specified.  
The Full Analysis Set (FAS) is defined as all enrolled subjects who have received at least 1 dose 
of study drug in Study VX14-661-110 and have one of the following mutations: 
F508del/F508del, F508del/Residual function, and F508del/Gating. The FAS is to be used in the 
efficacy analyses unless otherwise specified.  
The Safety Set is defined as all subjects who received at least 1 dose of study drug in 
Study VX14-661-110. The Safety Set is to be used for the 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). 
Categorical variables will be summarized using counts and percentages.  
Baseline value, unless otherwise specified, for efficacy and safety analyses, will be defined as 
the most recent non-missing measurement (scheduled or unscheduled) collected before the first 
dose of VX-661/ivacaftor or ivacaftor alone (in the parent study or Study VX14-661-110, but 


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after the washout period, if applicable). For subjects who received VX-661 and ivacaftor 
combination therapy in the parent study, the baseline will be the same as the baseline in the 
parent study. For subjects who received placebo or ivacaftor in the parent study and transitioned 
to VX-661/ivacaftor in Study VX14-661-110, the baseline will be the baseline in Study 
VX14-661-110. For subjects from Study VX14-661-108, the parent study baseline will be the 
baseline for Treatment Period 2 in Study VX14-661-108. For subjects from 
Study VX13-661-103, the parent study baseline will be the baseline in the Open-label Phase of 
Study VX13-661-103 for subjects who participated in the Open-label Phase or the baseline in 
Study VX14-661-110 for subjects who did not participate in the Open-label Phase of Study 
VX13-661-103.  
Change (absolute change) from baseline will be calculated as postbaseline value - baseline 
value. 
Relative change from baseline will be calculated as (postbaseline value - baseline 
value)/baseline value. 
Efficacy Analysis Period will include the time from the first dose of VX-661/ivacaftor or 
ivacaftor alone (in the parent study or Study VX14-661-110, but after the washout period, if 
applicable) to the last scheduled efficacy visit in Part of Study VX14-661-110. For subjects who 
participate in another qualified Vertex study before completing Study VX14-661-110 
assessments and re-enroll in Study VX14-661-110, the Efficacy Analysis Period will exclude the 
time between the last dose before the discontinuation from Study VX14-661-110 and the first 
dose after re-enrollment in Study VX14-661-110.  
Treatment-emergent (TE) Period will include the time from the first active dose of 
VX-661/ivacaftor or ivacaftor alone (in the parent study or Study VX14-661-110, but after the 
washout period, if applicable) to the Safety Follow-up Visit or 28 days after the last dose of the 
study drug for subjects who do not have a Safety Follow-up Visit or who have their Safety 
Follow-up Visit more than 35 days after the last dose of Study VX14-661-110. For subjects who 
participate in another qualified Vertex study before completing Study VX14-661-110 (96 weeks) 
and re-enroll in Study VX14-661-110, the TE Period will exclude the time spent in the other 
study. Specifically, the TE Period will be interrupted 28 days after the last dose of study drug in 
Study VX14-661-110 and will restart with re-enrollment into Study VX14-661-110 when the 
subject takes the first dose of study drug.  
Note, in the Efficacy Analysis and TE Periods, for subjects who received the active study drugs 
in Study VX14-661-108, the first active dose will be the first dose of VX-661/ivacaftor or 
ivacaftor monotherapy in the Treatment Period 2 of Study VX14-661-108. For subjects who 
received the active study drug from Study VX13-661-103, the first active dose will be the first 
active dose of study drug in the Open-label Phase of Study VX13-661-103. 
12.3.2 
Overview of Analysis Strategies 
• Study VX14-661-110 data will not be analyzed in isolation as patients received different 
durations of treatment in the parent studies. Study VX14-661-110 data will be integrated with 
the parent study data for each subject from the first active dose of VX-661/ivacaftor or 
ivacaftor alone (after the washout period, if applicable).  
• The analysis baseline will be the last non-missing measurement prior to the first active dose 
of VX-661/ivacaftor or ivacaftor alone [in the parent study (after the washout period, if 


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applicable) or Study VX14-661-110]. All post-baseline measurements will be mapped to the 
uniform analysis visit windows based on the study days counted from the first active dose of 
VX-661/ivacaftor or ivacaftor alone (after the washout period in the parent study, if 
applicable) to make the results more comparable and interpretable.  
• For subjects in Study VX14-661-110, the safety analyses will be performed on all of the 
subjects pooled together. The efficacy analysis will be performed on each CFTR mutation 
group separately (F508del/F508del, F508del/Residual Function, and F508del/Gating). 
12.3.3 
Background Characteristics 
Subject disposition, demographic and baseline characteristics, prior and concomitant 
medications, study drug exposure and compliance, and other background characteristics will be 
summarized. Additionally, all subject data will be presented in subject data listings.  
12.3.3.1 
Subject Disposition 
All summaries in this section will be performed on all subjects pooled together based on the 
Safety Set, and performed on each CFTR mutation group separately (F508del/F508del, 
F508del/Residual Function, and F508del/Gating) based on the FAS, unless otherwise specified 
in the SAP. No statistical hypothesis testing will be performed. 
Subject disposition analysis will be performed. The number and percentage of subjects in the 
following categories will be summarized as appropriate: 
• All Subjects Set  
• Safety Set 
• FAS 
• Completed study drug treatment 
• Prematurely discontinued treatment and the reasons for discontinuation 
• Prematurely discontinued the study during the Safety Follow-up and the reasons for 
discontinuations 
12.3.3.2 
Demographics and Baseline Characteristics 
All summaries in this section will be performed on all subjects pooled together based on the 
Safety Set, and performed on each CFTR mutation group separately (F508del/F508del, 
F508del/Residual Function, and F508del/Gating) based on the FAS, unless otherwise specified 
in the SAP. No statistical hypothesis testing will be performed. Demographics and baseline 
characteristics of Study VX14-661-110 will be based on the demographics and baseline 
characteristics in the parent studies. 
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized. Baseline characteristics will be the based on the parent study baseline 
characteristics. Protocol deviations/violations will be provided as a subject data listing only. 
Important protocol deviations/violations will be listed or summarized. 
The following demographics and baseline characteristics will be summarized for the FAS: sex, 
race, ethnicity, age, weight, height, BMI, region, baseline ppFEV1, and baseline score of CFQ-R 
respiratory domain.  


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12.3.3.3 
Prior and Concomitant Medications 
All summaries in this section will be performed on all subjects pooled together based on the 
Safety Set, unless otherwise specified in the SAP. No statistical hypothesis testing will be 
performed. 
Medications used in this study will be coded by using the World Health Organization-Drug 
Dictionary Enhanced and categorized as the following:  
• Prior medication: any medication that started before the first active dose of study drug (in 
the parent study or in Study VX14-661-110, after the washout period, if applicable), 
regardless of when it ended. In addition, for subjects who participate in another qualified 
Vertex study before completing Study VX14-661-110 assessments and re-enroll in 
Study VX14-661-110, any medication that was collected with a start date after the informed 
consent/assent for re-enrollment is signed and before the first dose of VX-661/ivacaftor after 
re-enrollment in Study VX14-661-110 will also be considered as prior medication, regardless 
of when medication was discontinued. 
• Concomitant medication: medication continued or newly received at, or after, initial dosing 
of study drug through the end of the TE Period. 
• Post-treatment medication: medication continued or newly received beyond the TE Period. 
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 it was taken before initial dosing, 
concomitantly, or beyond the TE Period, it will be considered as prior, concomitant, and 
post-treatment. 
Concomitant medications will be summarized descriptively for the Safety Set by: 1) preferred 
name; and 2) anatomic class (ATC) level 1, ATC level 2, and preferred name.  
The medications (prior, concomitant, post-treatment) will be listed. 
12.3.3.4 
Study Drug Exposure and Compliance 
All summaries in this section will be performed on all subjects pooled together based on the 
Safety Set, and performed on  each CFTR mutation group separately (F508del/F508del, 
F508del/Residual Function, and F508del/Gating) based on the FAS, unless otherwise specified 
in the SAP. No statistical hypothesis testing will be performed. 
Treatment Cohort 
Exposure to study drug (i.e., duration of treatment) will be summarized for the FAS in terms of 
duration of treatment a subject received (in days), defined as the last day minus the first day of 
dosing with VX-661/ivacaftor or ivacaftor monotherapy in the parent study (but after the 
washout period, if applicable) or VX-661/ivacaftor in Study VX14-661-110, plus 1.  
Dosing compliance will be summarized for the FAS and is calculated as the actual number of 
days at which study drug was administered, as a percentage of the duration of study drug 
exposure. 


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Duration of treatment and dosing compliance will be summarized by descriptive summary 
statistics. 
12.3.4 
Efficacy Analysis 
Treatment Cohort 
Assessment of the long-term efficacy and tolerability of VX-661 /ivacaftor for subjects in the 
Treatment Cohort is a secondary or other objective of this study. The efficacy analysis will be 
performed on each CFTR mutation group separately (F508del/F508del, F508del/Residual 
function, and F508del/Gating). All data collected during the efficacy analysis period through the 
end of Study VX14-661-110 will be summarized.  
12.3.4.1 
Analysis of Primary Efficacy Variables 
Not applicable since efficacy is not a primary objective. 
12.3.4.2 
Analysis of Secondary 
 Efficacy Variables (Treatment 
Cohort) 
• Absolute change from baseline in ppFEV1 
One of the secondary efficacy endpoints is the absolute change from baseline in ppFEV1. The 
primary analysis for this secondary endpoint will be based on a mixed-effect repeated-measure 
model (MMRM), as applicable. The model will include the absolute change from baseline in 
ppFEV1 as the dependent variable; treatment group, visit, and treatment-by-visit interaction as 
fixed effects; and subject as a random effect with or without adjustment for sex, age, baseline 
ppFEV1. 
In the model, visit will be treated as a class variable, assuming an unstructured covariance matrix 
to model the within-subject variability. This model imposes no assumptions on the correlational 
structure and is considered robust. Denominator degrees of freedom for the F test for fixed 
effects will be estimated using the Kenward-Roger approximation. If there is a convergence 
problem due to the use of an unstructured covariance matrix, a compound symmetry covariance 
structure will be used to model the within-subject errors. With a mixed-effects model based on a 
restricted maximum likelihood estimation used for the primary analysis and assuming that, 
conditional on fixed and random effects, data are missing at random, no imputation of missing 
data will be performed. 
Descriptive summary statistics including number of subjects, mean, standard error, and least 
square mean (LS mean), along with the associated 95% CI will be provided for each visit. 
• Relative change from baseline in ppFEV1  
Analysis of this variable will be performed using the same MMRM model as described for the 
absolute change from baseline in ppFEV1. 
• Number of pulmonary exacerbations 
The number of pulmonary exacerbations will be analyzed using a negative binomial regression 
model as applicable. The independent variables will include visit, sex, age, baseline ppFEV1. The 
event rate and 95% CI will be reported. 


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• Absolute change from baseline in body mass index (BMI) 
Analysis of this variable will be similar to the model as described for the absolute change in 
ppFEV1 from baseline, with the addition of baseline BMI as the covariate. 
• Absolute change from baseline in BMI z-score 
Analysis of this variable will be similar to the model as described for the absolute change in 
ppFEV1 from baseline, with the addition of the BMI z-score at baseline as a covariate for 
subjects <20 years old at the time of the Screening Visit in the parent study. 
• Absolute change from baseline in CFQ-R respiratory domain score 
Analysis of this domain will be similar to the model as described for the absolute change in 
ppFEV1 from baseline, with the addition of the CFQ-R respiratory domain score at baseline as 
the covariate.  
• Absolute change from baseline in body weight 
Analysis for this variable will be similar to the model as described for the absolute change in 
ppFEV1 from baseline, with the addition of the body weight at baseline as a covariate. 
• Absolute change from baseline in body weight z-score for subjects aged <20 years at 
screening in the parent study 
Analysis of this variable will be similar to the model as described for the absolute change in 
ppFEV1 from baseline, with the addition of the body weight z-score at baseline as a covariate for 
subjects <20 years old at the time of the Screening Visit in the parent study. 
• Absolute change from baseline in height z-score for subjects aged <20 years at 
screening in the parent study 
Analysis of this variable will be similar to the model as described for the absolute change in 
ppFEV1 from baseline, with the addition of the height z-score at baseline as a covariate for 
subjects <20 years old at the time of the Screening Visit in the parent study. 
• Time-to-first pulmonary exacerbation 
Time-to-first pulmonary exacerbation is defined as days starting from the first dose of VX-661 
and ivacaftor combination therapy to the first event of pulmonary exacerbation. A subject 
without exacerbation before the end of the Efficacy Analysis Period of Study VX14-661-110 
will be considered censored at the end of the Efficacy Analysis Period. Kaplan-Meier method 
will be used to produce graphical presentation of the survival distribution (exacerbation-free 
survival) and to estimate cumulative survival rates by the CFTR mutation groups. 


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• Absolute change in Brody/CF-CT scores from baseline using LDCT scans for subjects 
enrolling from Study VX15-661-112 
Only applicable for the subjects enrolling from Study VX15-661-112. The absolute values and 
changes from baseline of the Total Brody/CF-CT scores 
 will be summarized 
descriptively. 
12.3.5 
Safety Analysis (Treatment Cohort) 
Evaluating the long-term safety and tolerability of VX-661 in combination with ivacaftor 
treatment in the Treatment Cohort is the primary objective of this study. All safety analyses will 
be based on TE Period for subjects in the Safety Set.  
The overall safety profile of the combination treatment will be assessed in terms of the following 
safety and tolerability endpoints: 
• Treatment-emergent adverse events (TEAEs), SAEs, TEAEs leading to treatment 
discontinuations, TEAEs leading to treatment interruptions, deaths. 
• Clinical laboratory results (i.e., hematology, serum chemistry, coagulation studies, vitamin 
levels, lipid panel, and urinalysis) 
• Standard 12-lead ECGs  
• Vital signs 
• Pulse oximetry 
• Pregnancy test 
Descriptive analysis of safety will be performed for subjects in the Safety Set of 
Study VX14-661-110.  
12.3.5.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs.  
• Pretreatment AE: any AE that increased in severity or newly developed before the first 
active dose of VX-661/ivacaftor or ivacaftor alone in the TE Period. For subjects who 
participate in another qualified Vertex study before completing Study VX14-661-110 
assessments and re-enroll in Study VX14-661-110, pretreatment AEs include any AE that 
increased in severity or began before the first dose of VX-661/ivacaftor in the TE Period, and 
any AE that increased in severity or began after signing informed consent/assent for re-


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enrollment and before the first dose of VX-661/ivacaftor after re-enrollment in Study 
VX14-661-110. 
• TEAE: any AE that increased in severity or began at, or after, the first active dose of 
VX-661/ivacaftor or ivacaftor alone in the TE Period.  
• Post-treatment AE: any AE that increased in severity or began beyond 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 treatment, then the AEs will be classified as TEAEs. 
An overview of AEs table will include the following. 
• All TEAEs 
• TEAEs by strongest relationship 
• Related TEAEs 
• TEAEs by maximum severity 
• Grade 3/4 TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• TEAEs leading to death 
The following summary tables of TEAEs will also be provided:  
• All TEAEs by PT and by SOC/PT 
• Related TEAEs by SOC/PT 
• Serious TEAEs by PT and by SOC/PT 
• Related serious TEAEs by SOC/PT  
• Grade 3/4 TEAEs by SOC/PT 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption  
• TEAEs leading to death 
• Treatment-emergent elevated transaminases events by PT 
• Treatment-emergent respiratory events or symptoms by PT 
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 as well 
as total number of events). 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 


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worst/highest relationship level in the relationship summaries. An AE overview table will be 
provided. A separate table will summarize all TEAEs when each of them is considered unique, 
hereafter referred to as an AE count table. In addition, a listing containing individual subject 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. 
12.3.5.2 
Clinical Laboratory Assessments 
For the treatment-emergent laboratory measurements, the raw values and change from baseline 
values of the continuous laboratory parameters will be summarized in SI units at each scheduled 
time point during the TE Period. Mean value at each visit will be plotted for each of the liver 
function parameters. In addition, a listing containing individual subject laboratory assessment 
values outside the reference ranges will be provided. 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period will be summarized for selected laboratory parameters. The shift of the threshold 
analysis criteria from baseline to postbaseline will also be summarized for selected laboratory 
parameters. The threshold analysis and parameter-selection criteria will be provided in the SAP. 
Results of abnormal urinalysis and positive serum/urine pregnancy tests will be listed in 
individual subject data listings only.  
12.3.5.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of raw values and change from 
baseline values will be provided at each scheduled time point during the TE Period for the 
following standard digital ECG measurements: PR, QT, and QTc for HR interval (QTcF), QRS 
duration, and HR. In addition, the mean value at each visit will be plotted by treatment groups 
for QTc. 
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period will be summarized by treatment group. The threshold analysis criteria will be 
provided in the SAP.  
12.3.5.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the raw values and change from baseline 
values will be summarized at each scheduled time point during the TE Period: systolic and 
diastolic blood pressure (mm Hg), body temperature (°C), HR (beats per minute [bpm]), and 
respiratory rate (breaths per minute).  
The number and percentage of subjects with at least 1 threshold analysis event during the 
TE Period will be summarized. The threshold analysis criteria will be provided in SAP.  
12.3.5.5 
Physical Examination 
No tables/figures/listings will be provided for physical examination. 
12.3.5.6 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of raw values and change 
from baseline values will be provided at each scheduled time point during the TE Period for the 
percent of oxygen saturation by pulse oximetry. In addition, the mean value at each visit will be 
plotted by treatment groups for the percent of oxygen saturation.  


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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 tabulated. 
12.3.5.7 
Ophthalmologic Examination 
Ophthalmologic examination results will be listed for subjects < 18 years old (age on the date of 
informed consent/assent in the parent study) with cataracts anytime during the TE period. 
12.3.5.8 
Pregnancy Tests 
Positive urine and serum pregnancy test results during baseline and TE period will be listed. 
12.3.6 
Interim Analyses, DMC Analyses, and Data Monitoring 
12.3.6.1 
Interim Analysis  
Interim analyses may occur at any time during the study as determined by Vertex. During any 
interim analysis time, if any parent study is still not completely unblinded to the relevant study 
personnel, the analysis will be performed according to the relevant unblinding plans. In general, 
Vertex Biometrics will use blinded data to program tables, figures, and listings (TFLs) based on 
the relevant SAP for the interim analysis. An independent biometrics team (internal or external 
as defined in the Unblinding Plan) will then rely on the programs to prepare unblinded TFLs 
using unblinded data. The details of the unblinding process will be provided in the Unblinding 
Plan. 
12.3.6.2 
DMC Analysis 
A DMC (Data Monitoring Committee) will be formed. The DMC’s objectives and operational 
details will be defined in a separate document (the DMC Charter). The DMC will conduct 
regular planned safety reviews of study data as outlined in the DMC Charter. 
12.3.6.3 
Data Monitoring 
Vertex will continuously monitor unblinded safety data. If in the course of evaluating safety 
events from other blinded studies, data from the open-label study may be shared with an external 
data monitoring committee in order to better understand any potential safety signals.  
12.4 
Clinical Pharmacology Analysis  
12.4.1 
Pharmacokinetic Analysis (Treatment Cohort) 
A detailed description of the clinical pharmacology analyses will be provided in the CPAP. 
Listings of plasma concentration data of VX-661, ivacaftor, and their metabolites will be 
provided in the clinical study report. A population approach may be used to analyze the 
time-versus-plasma concentration data of VX-661, ivacaftor, and their metabolites. The 
PK/pharmacodynamic (PD) relationship between concentrations of VX-661 and ivacaftor (and 
their metabolites as appropriate) and efficacy and safety measurements may be investigated. The 
results of the PK and PK/PD analyses using a population approach will be presented in a separate 
report, if applicable.  


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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 preexisting 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 a clinically significant worsening from baseline 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 clinical status of the subject indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF is signed, or assent, if applicable, until the following 
time points: 
• Until time of withdrawal of consent 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up Visit 
• For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of: 
o 28 days after the last dose of study drug, or 
o the Early Treatment Termination Visit, if that visit is 3 weeks or later following the last 
dose of study drug (see Section 8.1.1.3), or 


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o the Early Treatment Termination Visit, or until the time of enrollment in another 
qualified Vertex study 
All subjects will be queried, using non-leading 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 eCRF and 
source document. The following data will be documented for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity 
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity  
The investigator will determine and record the severity of all serious and non-serious 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 August 
2012). 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 experience 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 re-appeared 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. 
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) 


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13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, hospitalization, 
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. 
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.  




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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. 
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 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 eCRFs, 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 doctor 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 eCRFs/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.  


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For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act and associated regulations (“HIPAA”) 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. 
13.3 
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 an eCRF 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.  


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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 eCRF 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 eCRFs/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 
eCRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture 
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 eCRFs on the 
subjects for which they are responsible.  
An eCRF 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 
eCRF. Source documentation supporting the eCRF 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 eCRF 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 eCRFs, 
including any changes made to the eCRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the eCRF data and corresponding audit trails. A copy of the final archival 
eCRF in the form of a CD 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 clinical study report, 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 Web Site [Internet]. Available from: 
http://www.cff.org/AboutCF/. Accessed 24 September 2014. 
2 
Kriendler JL. Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010 Feb;125:219-29. 
3 
FDA Office of Orphan Products Development (OOPD). Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.
htm. Accessed 24 September 2014. 
4 
The Committee for Orphan Medicinal Products (COMP). Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_
000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30. 
Accessed 24 September 2014. 
5 
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2012 Annual 
Data Report. Bethesda, Maryland. 2013. 
6 
Flume PA and Van Devanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Medicine. 2012:10(1):88. 
7 
Cystic Fibrosis Mutation Database (CFTR1). Cystic Fibrosis Centre at the Hospital for 
Sick Children in Toronto Web site. Available at: 
http://www.genet.sickkids.on.ca/cftr/StatisticsPage.html. Accessed 24 September 2014.  
8 
Castellani C, Bonizzato A, Cabrini G, Mastella G. Newborn screening strategy for cystic 
fibrosis: a field study in an area with high allelic heterogeneity. Acta Paediatr. 
1997;86(5):497-502. 
9 
Van Goor F, Hadida S, Grootenhuis P. Pharmacological rescue of mutant CFTR function 
for the treatment of cystic fibrosis. Top Med Chem. 2008;3:91-120. 
10 
McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of genotype on phenotype 
and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 
2003;361(9370):1671-6. 
11 
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2011 Annual 
Data Report. Bethesda, Maryland. 2012. 
12 
European Cystic Fibrosis Society. European Cystic Fibrosis Society Patient Registry 
2008-2009. Karup, Denmark, 2012. Available from: 
http://www.ecfs.eu/files/webfm/webfiles/File/ecfs_registry/ECFSPR_Report0809_v3201
2.pdf 
13 
Cheng SH, Gregory RJ, Marshall J, Sucharita P, Souza DW, White GA, et al. Defective 
intracellular transport and processing of CFTR is the molecular basis of most Cystic 
Fibrosis. Cell. 1990;63:827-34. 
 


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14 
Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, et al. Altered chloride 
ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature. 
1991;354:526-28. 
15 
Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. NEJM. 2005;352:1992-2001. 
16 
Vertex Pharmaceuticals Incorporated. Report G016. Effects of VRT-893661 on 
CFTR-mediated chloride secretion in human bronchial epithelia isolated from cystic 
fibrosis subjects. Report date: 17 February 2010. 
17 
Lukacs GL, Chang XB, Bear C, Kartner N, Mohamed A, Riordan JR, et. al. The delta 
F508 mutation decreases the stability of cystic fibrosis transmembrane conductance 
regulator in the plasma membrane. Determination of functional half-lives on transfected 
cells. J Biol Chem 1993;268:21592-98. 
18 
Vertex Pharmaceuticals Incorporated. VX-661 Investigator's Brochure. Version 7.0. 
Report date: 08 May 2015. 
19 
Vertex Pharmaceuticals Incorporated. Ivacaftor (VX-770) Investigator’s Brochure. 
Version 13.0, 16 May 2016. 
20 
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry: 2012 Annual 
Data Report. Bethesda, MD. Report date: 2013. 
21 
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. 
22 
Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
23 
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. 
24 
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-relate quality of life instrument. Qual Life Res. 2003;12(1):77-85. 
25 
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. 
26 
Mayer-Hamblett N, Ramsey BW, Kronmal RA. Advancing outcome measures for the 
new era of drug development in cystic fibrosis. Proc Am Thorac Soc. 2007;4(4):370-7. 
27 
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;331:637-42. 
28 
Rosenfeld M, Emerson J, Williams-Warren J, Pepe M, Smith A, Montgomery AB, et al. 
Defining a pulmonary exacerbation in cystic fibrosis. J Pediatr. 2001;139(3):359-65. 
29 
Rabin HR, Butler SM, Johnson CA, Colin AA, FitzSimmons SC, Geller DE, et al. 
Pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol. 2004;37(5):400-6. 
 


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30 
Blumer, JL, Saiman L, Konstan MW, Melnick D. The efficacy and safety of meropenem 
and tobramycin vs. ceftazidime and tobramycin in the treatment of acute pulmonary 
exacerbations in patients with cystic fibrosis. Chest. 2005;128(4):2336-46. 
32 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
33 
Wang X, Dockery DQ, Wypij D, Fay ME, Ferris BG. Pulmonary function between 6 and 
18 years of age. Pediatr Pulmonol. 1993;15:75-88. 
34 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general US population. Am J Respir Crit Care Med. 1999;159:179-87. 
35 
Mayer-Hamblett N, Ramsey BW, Kronmal RA. Advancing outcome measures for the 
new era of drug development in cystic fibrosis. Proc Am Thorac Soc. 2007;4(4):370-7. 
36 
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;365:1663-72. 




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15.2 
Investigator Signature Page 
Protocol #: 
VX14-661-110 
Version #: 
3.4 IRE, ESP, 
ISR, US 
Version 
Date: 
09 June 2017 
Study Title: A Phase 3, Open-label, Rollover Study to Evaluate the Safety and Efficacy of 
Long-term Treatment With VX-661 in Combination With Ivacaftor in Subjects Aged 
12 Years and Older With Cystic Fibrosis, Homozygous or Heterozygous for the 
F508del-CFTR Mutation 
 
 
I have read Protocol VX14-661-110, Version 3.4 IRE, ESP, ISR, US and agree to conduct the 
study according to its terms. I understand that all information concerning VX-661 and ivacaftor 
and this protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is 
confidential.   
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 

SAP_001.pdf: 
VERTEX PHARMACEUTICALS INCORPORATED 
 Statistical Analysis Plan for Part A
(Methods) 
Protocol Number VX14-661-110 Version 3.0 
A Phase 3, Open-label, Rollover Study to Evaluate the Safety and 
Efficacy of Long-term Treatment With VX-661 in Combination With 
IVA in Subjects Aged 12 Years and Older With Cystic Fibrosis, 
Homozygous or Heterozygous for the F508del-CFTR Mutation 
Authors of SAP: 
 
Version: Version 1.0 
Version Date of SAP: 20-Mar-2019 
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) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
3 
INTRODUCTION 
Study VX14-661-110 (Study 110) is a Phase 3, Open-label, rollover study to evaluate the safety 
and efficacy of long-term treatment with VX-661 in combination with ivacaftor (IVA) in subjects 
aged 12 years and older with cystic fibrosis, homozygous or heterozygous for the F508del-CFTR 
mutation.  
This SAP will focus on the safety and efficacy analysis for all the subjects enrolled in Part A. As 
there is no subject enrolled in Part A Observational Cohort, the methods pertain to Part A 
Treatment Cohort, unless specified otherwise. 
The Vertex Biometrics department or a designated Contract Research Organization (CRO) will 
perform the statistical analysis of the safety and efficacy data. SAS® Version 9.4 Software (SAS 
Institute, Cary, North Carolina, USA) or higher will be used to generate all statistical outputs 
(tables, figures, listings, and datasets).  This SAP will be finalized and approved prior to the final 
clinical data lock. 
4 
STUDY OBJECTIVES 
4.1 
Primary Objective 
Part A  
To evaluate the long-term safety and tolerability of VX-661/IVA in subjects with CF, 
homozygous or heterozygous for the F508del-CFTR mutation who are in the Treatment Cohort 
4.2 
Secondary Objectives 
Part A  
Treatment Cohort  
To evaluate the long-term efficacy of VX-661/IVA for subjects in the Treatment Cohort  
Observational Cohort  
To evaluate the post-treatment safety of VX-661/IVA for subjects in the Observational Cohort  
5 
STUDY ENDPOINTS 
5.1 
Primary Endpoints 
Part A  
Treatment Cohort  
Safety and tolerability of long-term treatment of VX-661/IVA based on adverse events (AEs), 
ophthalmologic exams (subjects <18 years of age [age on the date of informed consent/assent 
in the parent study]), clinical laboratory values (serum chemistry, hematology, coagulation, 
lipids, vitamins, and urinalysis), standard digital electrocardiograms (ECGs), vital signs, and 
pulse oximetry. 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
5.2 
Secondary Endpoints 
Part A  
Treatment Cohort  
 Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1)  
 Relative change from baseline in ppFEV1  
 Number of pulmonary exacerbations (PEx) 
 Absolute change from baseline in body mass index (BMI)  
 Absolute change from baseline in BMI z-score for subjects aged <20 years  
 Absolute change from baseline in Cystic Fibrosis Questionnaire–Revised (CFQ-R) respiratory 
domain score  
 Absolute change from baseline in body weight  
 Absolute change from baseline in body weight z-score for subjects aged <20 years  
 Absolute change from baseline in height z-score for subjects aged <20 years  
 Time-to-first PEx 
 Pharmacokinetic (PK) parameters of VX-661, a VX-661 metabolite (M1-661), IVA, and an IVA 
metabolite (M1-IVA)  
Observational Cohort  
 Safety, as determined by related serious adverse events (SAEs)  
6 
STUDY DESIGN  
6.1 
Overall Design  
This is a Phase 3, multicenter, open-label, rollover study in subjects with CF who are 
homozygous or heterozygous for the F508del-CFTR mutation and who participated in Studies 
VX13-661-103 (Study 103), VX14-661-106 (Study 106), VX14-661-107 (Study 107), VX14-661-
108 (Study 108), VX14-661-109 (Study 109), VX14-661-111 (Study 111), Study 112, VX16-661-
114 (Study 114), or other Vertex studies investigating VX-661/IVA. The study is designed to 
evaluate the safety and efficacy of long term treatment of VX-661/IVA. 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
A schematic of the study design is shown in Figure 6-1 Study Design. 
Part A 
Part A consists of a Treatment Cohort and an Observational Cohort (see definitions below). 
Subjects from Studies 103, 106, 107, 108, 109, 111, and other eligible Vertex studies 
investigating VX-661/IVA, may enroll in Part A.  The Treatment Cohort and the Observational 
Cohort will be open to enrollment in parallel. The analyses specified in this SAP focus on the 
Part A Treatment Cohort only. 
Treatment Cohort 
Subjects who completed study drug treatment (i.e., VX-661/IVA, IVA monotherapy, or placebo) 
during the Treatment Period in the parent study who meet the eligibility criteria (Study Protocol 
Sections 9.1 and 9.2) will be offered the opportunity to enroll in Study 110. Subjects who 
permanently discontinue study drug treatment or who withdrew consent during the parent 
studies are not eligible for enrollment in the Treatment Cohort.  
Subjects in the Treatment Cohort will receive VX-661 100 mg/IVA 150-mg fixed-dose 
combination (FDC) tablet daily (qd) in the morning and IVA 150-mg tablet qd in the evening. 
The Treatment Period will be approximately 96 weeks. 
Subjects may screen for another qualified Vertex study while participating in the Treatment 
Cohort.  Subjects who completed at least 4 weeks of treatment before discontinuing Study 110 
to participate in another qualified Vertex study, and who meet the eligibility criteria (Study 
Protocol Sections 9.1 and 9.2), will be offered the opportunity to re-enroll in the Treatment 
Cohort of Study 110. Subjects who re-enroll will resume treatment with VX-661/IVA at the next 
study day after their previous treatment discontinuation from Study 110 (e.g., a subject who 
discontinued at Study Day 50 would resume treatment at Study Day 51). Subjects who 
discontinue Study 110 more than once to participate in another qualified Vertex study may not 
re-enroll in Study 110 a second time.   
Observational Cohort  
Subjects <18 years of age (age on the date of informed consent/assent in the parent study) who 
received at least 4 weeks of study drug in the parent study, who are not eligible for the 
Treatment Cohort or who elect not to enroll in the Treatment Cohort, and meet eligibility 
criteria (Study Protocol Section 9.1) will be offered the opportunity to enroll in the 
Observational Cohort.  
Subjects in the Observational Cohort will not receive study drug and will have regularly 
scheduled telephone calls for approximately 2 years after their last dose of study drug in the 
parent study to assess post-treatment safety of VX-661/IVA combination therapy. 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
Figure 6-1 Study Design 
 
ivacaftor; q12h: every 12 hours; qd: daily.  
Notes: All subjects will receive a VX-661 100 mg/ivacaftor 150-mg fixed dose combination tablet qd in the morning and an 
ivacaftor 150-mg tablet qd in the evening. 
a 
Subjects enrolled in parent studies may be eligible to enroll in the Part A Treatment Cohort or Part B if they completed study 
drug treatment in the parent study and meet the eligibility criteria for the Part A Treatment Cohort or Part B. Subjects who 
complete Part A of Study VX14-661-110 may continue into Part B of the study.  
b 
Subjects may be eligible to re-enroll in the Part A Treatment Cohort or Part B if they completed the last required visit of 
another qualified Vertex study and meet eligibility criteria for re-enrollment. 
c 
Subjects who re-enroll in the Part A Treatment Cohort or in Part B will complete the Returning Visit and resume treatment 
with VX-661/IVA on the next study day after their previous treatment discontinuation from Study VX14-661-110. 
d 
The Safety Follow-up Visit in the Part A Treatment Cohort is scheduled to occur 28 (± 7 days) after the last dose of study 
drug in Part A (Section 8.1.1.2) for subjects who do not enroll in Part B. The Safety Follow-up Visit in Part B is scheduled 
to occur 28 (± 7 days) after the last dose of study drug in Part B. Exceptions are explained elsewhere in the protocol. 
e 
During the course of study conduct, if VX-661 in combination with ivacaftor is approved and available for the treatment of 
CF in populations enrolled in Study VX-661-110, subjects with the approved CFTR genotypes may be discontinued from 
this rollover study at the discretion of the sponsor. If a subject is continuing onto commercially available VX-661/ivacaftor, 
the Early Treatment Termination Visit will be completed before dosing with commercial drug begins, and the Safety 
Follow-up Visit will not be required. Alternatively, if local health authorities decline to approve, or if clinical benefit is not 
demonstrated for the use of VX-661 in combination with ivacaftor for the treatment of CF in populations enrolled in Study 
VX-661-110, 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 subset of subjects. If subjects are 
discontinued from the study, an Early Treatment Termination Visit should occur within 7 days of the last dose of study drug 
and a Safety Follow-up Visit should occur within 28 (± 7) days after the last dose of study drug. 
f 
Subjects <18 years of age (age on the date of informed consent/assent in the parent study) who are not eligible for the 
Treatment Cohort, or elect not to enroll in the Treatment Cohort, may be eligible for the Observational Cohort. 
g 
A telephone contact will be made every 3 to 4 months during the first year and at approximately 2 years (± 4 weeks). 
6.2 
Sample Size and Power 
Part A  
Treatment Cohort  
1,044 eligible subjects are enrolled from the following parent studies:  
 
23 subjects from Study 103. 
 
464 subjects from Study 106.  
 
159 subjects from Study 107. 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
 
227 subjects from Study 108.  
 
138 subjects from Study 109. 
 
33 subjects from Study 111.  
Observational Cohort  
No patient enrolled in observational cohort. 
6.3 
Randomization 
Randomization is not required because all subjects will receive the same open-label active 
study drug in the Treatment Cohort. 
6.4 
Blinding and Unblinding 
This will be an open-label study. However, subjects should not be informed of their 
study-related spirometry results during the study regardless of whether the subject has 
prematurely discontinued treatment. 
7 
ANALYSIS SETS  
The All Subjects Set is defined as all subjects who have signed inform consent (enrolled) or 
have received at least 1 dose of study drug in Part A. This analysis set will be used in subject 
data listings and disposition summary tables, unless otherwise specified.  
7.1 
Efficacy Analysis Sets 
The Full Analysis Set (FAS) is defined as all enrolled subjects who have received at least 1 dose 
of study drug in Part A and have one of the following mutations: F508del/F508del (F/F) and 
F508del/Residual function (F/RF). The FAS is to be used in the efficacy analyses unless otherwise 
specified.  
Study 106 and 108 were the basis for the approval of TEZ/IVA.  Although Study 107 and 109 
subjects were rolled over to FAS in Study 110, after the study results were available, subjects 
from Study 107 and 109 were early discontinued from Study 110.  Thus, the efficacy analysis 
will focus on the 106/110 Efficacy Set (ES) and 108/110 ES, defined as all the FAS subjects 
rolling over from Study 106 and 108 respectively.  
As shown in Table 7-1, treatment group assignment is based on the randomized treatment in 
parent study. For 108/110 ES, the randomized treatment assignment in Period 2 will be used to 
assign subjects to a treatment group in Study 110. 
Table 7-1 Treatment Group for Efficacy Analysis Sets 
Treatment Group 
Description 
TEZ/IVA 
Subjects randomized to TEZ/IVA in parent study  
PBO-TEZ/IVA 
Subjects randomized to placebo in parent study 
IVA-TEZ/IVA 
Subjects randomized to IVA in parent study 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
7.2 
Pulmonary Exacerbation Analysis Sets 
106/110 PEx Analysis Set and 108/110 PEx Analysis Set are defined in Error! Reference source 
not found.. They include the subjects who received TEZ/IVA in parent study or Part A. 
Table 7-2 Treatment Group for PEx Analysis Sets 
Analysis 
Population Name 
Treatment Group 
Description 
106/110 PE 
Analysis Set 
TEZ/IVA 
Subjects randomized to TEZ/IVA in Study 106 
and received treatment 
PBO-TEZ/IVA 
Subjects randomized to placebo in Study 106 
and  who received TEZ/IVA in Study 110 
108/110 PE 
Analysis Set 
TEZ/IVA 
Subjects randomized to IVA-TEZ/IVA sequence 
or PBO-TEZ/IVA sequence in Study 108 and who 
received treatment in Period 2 of Study 108 
IVA-TEZ/IVA 
Subjects randomized to TEZ/IVA-IVA sequence 
or PBO-IVA sequence in Study 108 and who 
received treatment in Period 2 of Study 108 and 
who received TEZ/IVA in Study 110. Subjects in 
TEZ/IVA-IVA sequence who did not enroll in 
Study 110 treatment cohort will also be 
included in this group if they received 
treatment in Period 1. 
PBO-TEZ/IVA 
Subjects randomized to TEZ/IVA-PBO sequence 
or IVA-PBO sequence in Study 108 and who 
received treatment in Period 2 of Study 108 and 
who received TEZ/IVA in Study 110. Subjects in 
TEZ/IVA-PBO sequence who did not enroll in 
Study 110 treatment cohort will also be 
included in this group if they received 
treatment in Period 1. 
7.3 
Safety Analysis Set 
The Safety Set is defined as all subjects who have received at least 1 dose of study drug in Part 
A irrespective of their genotype. The Safety Set is to be used for the safety analyses unless 
otherwise specified. 
7.4 
Parent Study Safety Analysis Set 
The safety results from Study 106 will be presented along with Part A results. The definition of 
106 Safety Set is the same as defined in the SAP/CSR for Study 106, i.e., subjects who received 
at least 1 dose of study drug in Study 106. 
The treatment group assignment is the same as in Study 106, as illustrated in Table 7-3.  






Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
 Assessments at the Early Treatment Termination (ETT) Visit will follow the windowing rules 
for regular visits.  
 Assessments at SFU Visit will follow the windowing rules for regular visits if they fall within 
the upper boundary of the window for the last scheduled visit. If assessments occur after 
the upper boundary of the window for the last scheduled visit, they will be still considered 
as the SFU Visit.  
Incomplete/Missing data will not be imputed, unless otherwise specified.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless otherwise specified. 
Unscheduled Visits: Unscheduled visit measurements will be included in the following: 
 Derivations of measurements at scheduled visits per specified visit windowing rules; 
 Derivations of baseline/last on-treatment measurements; 
 Derivations of the maximum/minimum on-treatment values and maximum/minimum 
changes from baseline values for safety analyses; 
 Data listings where appropriate. 
Treatment-emergent (TE) Period will include the time from the first active dose of 
VX-661/ivacaftor or ivacaftor alone (in the parent study or Study VX14-661-110, but after the 
washout period, if applicable) to the Safety Follow-up Visit in Part A or 28 days after the last 
dose of the study drug for subjects who do not have a Safety Follow-up Visit or who have their  
Safety Follow-up Visit more than 35 days after the last dose in Part A of Study VX14-661-110. 
For subjects who participate in another qualified Vertex study before completing Part A of 
Study VX14-661-110 (96 weeks) and re-enroll in Study VX14-661-110, the TE Period will exclude 
the time spent in the other study.  
110 Treatment-Emergent (TE) Period is defined as the time from 1st dose of study drug in Part 
A to SFU in Part A or 28 days after the last dose of the study drug for subjects who do not have 
a SFU Visit or who have their SFU Visit more than 35 days after the last dose in Part A.  
For subjects who participate in another qualified Vertex study before completing Part A (96 
weeks) and re-enroll in Study 110, the TE Period will exclude the time spent in the other study.  
The efficacy analysis baseline is defined as the most recent non-missing measurement 
(scheduled or unscheduled) collected prior to the first dose of study drug in the parent studies 
for all subjects, except for subjects randomized to the placebo arm in Study 106.  
The efficacy analysis baseline for subjects randomized to the Study 106 placebo arm is defined 
as the most recent non-missing measurement (scheduled or unscheduled) collected prior to the 
first dose of study drug in Study 110. 
The safety analysis baseline, unless otherwise specified, is defined as the last non-missing 
assessment prior to the first dose of active treatment (TEZ/IVA or IVA) from the parent study 
(after the wash-out period, where applicable) or Study 110, whichever is earlier.  


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
9.2 
Subject Disposition 
The number and percentage (based on All Subjects Set) of subjects in the following categories 
will be presented:  
 
All Subjects Set  
 
Safety Set 
 
FAS 
 
Completed treatment regimen 
 
Prematurely discontinued treatment  and the reason for discontinuation 
 
Completed study  
 
Prematurely discontinued study and the reason for discontinuation 
 
Subjects from each of the parent studies 
 
Subjects rolling over to Part B 
The summary tables for these categories (except “Subjects from each of the parent studies”) 
based on 106/110 ES and 108/110 ES will be provided separately. 
A listing of subjects who discontinued treatment or who discontinued study will be provided.  
9.3 
Demographics and Baseline Characteristics 
The following demographic data from parent studies will be summarized separately for 106/110 
ES and 108/110 ES: 
 
Age at screening 
 
Age groups (< 18, and >=18 years) 
 
Sex  
 
Ethnicity  
 
Race  
 
Geographic region by North America, Europe (including Australia and Israel) 
The following baseline characteristics from parent studies will be summarized separately for 
106/110 ES and 108/110 ES: 
 
Weight (kg) 
 
Height (cm) 
 
BMI (kg/m2) 
 
Weight z-score (subjects <20 years old at screening) 
 
Height z-score (subjects <20 years old at screening) 
 
BMI z-score (subjects <20 years old at screening) 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
 
Percent predicted FEV1  
 
Percent predicted FEV1 categories (<40,  ≥40 to <70,  ≥70 to ≤90,  >90) 
 
FEV1 (L)  
 
CFQ-R Respiratory  
Listings of informed consent, of important protocol deviations/violations will be provided.  
Medical history, coded by using the Medical Dictionary for Regulatory Activities (MedDRA), will 
not be summarized because most data were already collected in the parent studies. Only a 
listing will be presented for the medical history data collected in Part A. 
9.4 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary (WHO-DD) and categorized as: 
 Prior medication: any medication that started before the first dose of study drug in Study 
Part A, regardless of when the medication ended.  
 Concomitant medication: medication continued or newly received at, or after, initial dosing 
of study drug through the end of 110 TE Period.  
 Post-treatment medication: medication continued or newly received after 110 TE Period. 
A given medication can be classified as a prior, a concomitant, 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 and it cannot 
be determined whether it was taken before the first dose, concomitantly, or beyond the TE 
period, it will be considered as prior, concomitant, and post-treatment. 
Medications with missing or partially missing start dates will impute 2000 for the missing year, 
January for the missing month, and 1 for the missing day. Medications with missing or partially 
missing stop dates will impute 2050 for the missing year, December for the missing month, and 
the last day of the month for the missing day. The logic to decide the category of a medication 
is presented in Table 9-1: 
Table 9-1 Logic for Determining the Category of a Medication 
Medication start 
date 
Medication end date 
< first dose date 
of 110 study drug 
≥ first dose date of 110 study 
drug and ≤ End date of 110 TE 
period 
> End date of 
110 TE period 
< first dose date of 
study drug 
P 
PC 
PCA 
≥ first dose date 
and  
≤ End date of TE 
period 
- 
C 
CA 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
> End date of TE 
period 
- 
- 
A 
P: Prior; C: Concomitant; A: Post  
Concomitant medications will be summarized descriptively for Safety Set by: 1) preferred name; 
and 2) anatomic class (ATC) level 1, ATC level 2, and preferred name.  
The medications (prior, concomitant, post-treatment) will be listed. 
9.5 
Study Drug Exposure and Compliance 
The cumulative duration of TEZ/IVA exposure based on 110 TE Period is defined as: last dose 
date on TEZ/IVA – first dose date on TEZ/IVA + 1 day, regardless of any interruption between 
the first and last dose. If the last dose date is missing, the subject’s last ETT date (for early 
treatment discontinuations) will be used as a substitute for analysis purposes.  
Study drug compliance rate will be calculated as follows:  
100 × [1 - (Total number of days study drug interrupted) / (Duration of study drug exposure)], 
The total number of days 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.  
Duration of treatment and dosing compliance for Safety Set will be summarized by descriptive 
summary statistics: the number of subjects (n), mean, SD, median, min, and max. 
Listings of study drug administration, of study drug compliance rates, and of study drug 
interruptions will be provided. 
9.6 
Efficacy Analysis 
9.6.1 
Definitions of Efficacy Endpoints  
9.6.1.1 
Absolute Change in Percent Predicted FEV1 from Baseline 
ppFEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a percentage and will be 
calculated using the Hankinson ([1]) and Wang ([2]) standards with details in Section 11.2. 
9.6.1.2 
Number of Pulmonary Exacerbations 
The definition of a PEx is based on the definition in the individual CSP/CSR. A PEx is defined as a 
new 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 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
 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 of the chest 
 Decrease in pulmonary function by 10% 
 Radiographic changes indicative of pulmonary infection 
The number of PEx is defined as the total number of PEx during the PEx Analysis Period.  
9.6.1.3 
Absolute Change in BMI from Baseline 
BMI will be calculated as: 
BMI = Weight (kg)/(height (m)2) 
9.6.1.4 
Absolute Change in CFQ-R Respiratory Domain from Baseline 
The CFQ-R is a validated CF-specific instrument that measures quality-of-life domains. Three 
different versions of CFQ-R forms have been used in the VX-661 program:  
 CFQ-R for Children Ages 12 and 13 has a total of 35 questions to form 8 domains. All 
questions are scored 1, 2, 3, or 4. 
 CFQ-R for Adolescents and Adult (subjects 14 years and older) has a total of 50 questions to 
form 12 domains. Question 43, which is scored 1, 2, 3, 4, or 5, is not used in calculating any 
domain; all the other 49 questions are scored 1, 2, 3, or 4. 
 CFQ-R for Parents/Caregivers (subjects 13 years and younger) has a total of 44 questions to 
form 11 domains. Question 37, which is scored 1, 2, 3, 4, or 5, is not used in calculating any 
domains; all the other 43 questions are scored 1, 2, 3, or 4. 
For all three CFQ-R versions, to calculate the score for each domain, the response scores on the 
negatively phrased questions are reversed (reversed scores = 5 – response scores) so that 1 
always represents the worst condition and 4 always represents the best condition.  
The scaled score for each domain ranges from 0 (worst condition) to 100 (best condition). It is 
calculated as follows: 
Scaled score for a domain = 100 × (mean(scores of all questions in that domain) - 1)/3 
The scaled score for a specific domain will not be calculated if more than half of the questions 
in the domain have missing scores. 
 
Scaled scores will be used in the efficacy analysis. 
9.6.1.5 
Time to First Pulmonary Exacerbation on TEZ/IVA 
The time to first PEx is defined as the number of days from the first dose of TEZ/IVA to the first 
PEx event during the PEx Analysis Period. 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
9.6.2 
Analysis of Efficacy Endpoints 
Most continuous endpoints during 110 Efficacy Analysis Period will be analyzed for subjects in 
106/110 ES and 108/110 ES using a mixed-effects model for repeated measures (MMRM) with 
similar specification as in the parent study SAP/CSR, if applicable. However, these MMRM 
analysis will be restricted to the last visit at which the total number of subjects is approximately 
70% of subjects from the respective parent study.  
These continuous endpoints during 110 Efficacy Analysis Period will also be descriptively 
summarized for subjects in FAS who roll over from Study 103 and 111, where the patients carry 
F/F mutation.  
No hypothesis testing will be done for between-group comparisons. 
9.6.2.1 
Absolute Change in Percent Predicted FEV1 from Baseline 
9.6.2.1.1 
Subjects in 106/110 ES 
The MMRM for 106/110 ES during 110 Efficacy Analysis Period will have the absolute change in 
ppFEV1 from baseline (including all measurements up to Week 96 [inclusive], both on-
treatment measurements and measurements after treatment discontinuation) as the 
dependent variable and the following fixed effects: treatment (PBO-TEZ/IVA, TEZ/IVA), visit, and 
treatment-by-visit interaction, sex and age group at screening (<18, ≥18 years old), parent study 
baseline ppFEV1, and parent study baseline ppFEV1-by-visit interaction.  
The repeated-measures analysis will be based on the restricted maximum likelihood (REML) 
method assuming an unstructured (UN) covariance structure to model the within-subject 
errors. The denominator degrees of freedom will be based on the method proposed by 
Kenward-Roger. If the model fails to converge due to the UN covariance assumption, a 
compound symmetry (CS) covariance structure will be used to model the within-subject errors. 
In the MMRM approach, assuming that the data are missing at random, no imputation of 
missing data will be performed. 
The number of subjects, least-squares (LS) means 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 (±95% CI) for absolute change from baseline at each visit will also be plotted by 
treatment group.  
In addition, the descriptive statistics for observed values and absolute changes from baseline in 
ppFEV1 by treatment group will be presented at scheduled visits during 110 Efficacy Analysis 
Period.  
9.6.2.1.2 
Subjects in 108/110 ES 
The analysis for 108/110 ES during 110 Efficacy Analysis Period will be similar to that for 
106/110 ES with the exception of different fixed effects: treatment (PBO-TEZ/IVA, IVA-TEZ/IVA, 
TEZ/IVA), visit, treatment-by-visit interaction and parent study baseline ppFEV1.  
Similarly, the results from this MMRM along with descriptive statistics for observed values and 
absolute changes from baseline will be presented at scheduled visits within each treatment 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
group, and LS means (±95% CI) for absolute change from baseline at each visit will also be 
plotted by treatment group.   
9.6.2.1.3 
Subjects in FAS Who Roll Over from Study 103 
For FAS patients rolling over from Study 103, descriptive statistics will be summarized for 
observed values and absolute changes from baseline in ppFEV1 by treatment group at 
scheduled visit during 110 Efficacy Analysis Period. 
9.6.2.1.4 
Subjects in FAS Who Roll Over from Study 111 
The analysis for FAS patients rolling over from Study 111 will be similar to that for FAS patients 
rolling over from Study 103. 
9.6.2.2 
Number of Pulmonary Exacerbations 
9.6.2.2.1 
Subjects in 106/110 PEx Analysis Set  
The number of PEx during the PEx Analysis Period will be analyzed for 106/110 PEx Analysis Set 
using a negative binomial regression model and reported as event rate along with the 95% CI. 
The model will include: treatment (TEZ/IVA, PBO-TEZ/IVA), sex, age group at screening (<18, 
≥18 years old), and parent study baseline ppFEV1. The logarithm of PEx analysis period duration 
will be treated as the offset in this 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. 
9.6.2.2.2 
Subjects in 108/110 PEx Analysis Set  
The analysis for 108/110 PEx Analysis Set will be similar to 106/110 PE Analysis Set, with the 
exception of different fixed effects: treatment (TEZ/IVA, IVA-TEZ/IVA, and PBO-TEZ/IVA), 
residual function mutation (Class V non-canonical splice and Classes II to IV residual function), 
age group at screening (<18, ≥18 years old), and parent study baseline ppFEV1. 
Similarly the number of PEx (i) requiring hospitalization, and (ii) requiring IV antibiotic therapy 
will be analyzed. 
9.6.2.3 
Time to First Pulmonary Exacerbation  
9.6.2.3.1 
Subjects in 106/110 PEx Analysis Set  
Time-to-first PEx on TEZ/IVA during PEx Analysis Period will be analyzed and plotted by 
treatment group using the Kaplan-Meier approach.  
Subjects without a PEx by the end of PEx Analysis Period will be censored at the time-point 
corresponding to the end of PEx Analysis Period.  
9.6.2.3.2 
Subjects in 108/110 PEx Analysis Set  
The analysis of time-to-first PEx for 108/110 PEx Analysis Set will be similar to that for 106/110 
PEx Analysis Set.  


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
9.6.2.4 
Other Efficacy Endpoints 
For all the other efficacy endpoints (including relative change in ppFEV1 from baseline, absolute 
change in BMI from baseline, absolute change in BMI z- score from baseline, absolute change in 
CFQ-R Respiratory Domain Score from baseline, absolute change in weight from baseline, 
absolute change in weight z-score from baseline, absolute change in height z-score from 
baseline), the analysis will be similar to the analysis of absolute change in ppFEV1 from baseline. 
Note that for CFQ-R Respiratory Domain Score, the Pooled 'Children Ages 12 and 13' Version 
and 'Adolescents and Adults' Version is used for MMRM based approach and descriptive 
summary, ‘Parents/Caregivers’ Version is also used for descriptive summary. 
 
 
 
9.6.2.4.1 
Subjects in 106/110 ES and 108/110 ES 
The similar analysis will be performed as the analysis of absolute change in ppFEV1 from 
baseline for 106/110 ES or 108/110 ES during 110 Efficacy Analysis Period. However, in the 
MMRM models of all other efficacy endpoints, the terms involving parent study baseline 
ppFEV1 will be replaced by similar terms involving the corresponding endpoint in parent study.  
Similarly, the results based on MMRM along with descriptive statistics for observed values and 
absolute changes from baseline will be presented at scheduled visits within each treatment 
group, and LS means (±95% CI) for absolute change from baseline at each visit will also be 
plotted by treatment groups.   
9.6.2.4.2 
Subjects in FAS Who Roll Over from Study 103 and 111 
For subjects in FAS who rolled over from Study 103 and 111 respectively, descriptive summary 
statistics of observed values and absolute or relative changes from baseline in these efficacy 
endpoints will be provided at scheduled visit during 110 Efficacy Analysis Period. 
9.7 
Safety Analysis 
9.7.1 
Adverse Events  
For each individual parent study, summary table of treatment emergent AEs during the 
respective parent study will be included in the Study 110 CSR. The parent studies are 103, 111, 
106, 108, 107 and 109. 
The analysis of Adverse Events in the rest of section 9.7.1 will be based on the Safety Set during 
110 TE Period.  
For analysis purposes, AEs will be categorized as pre-treatment AEs, treatment-emergent 
adverse events (TEAEs), or post-treatment AEs: 
 
Pretreatment AE: any AE that started before the first dose of study drug in Part A. 
 
TEAE: any AE that increased in severity or that was newly developed at or after the first 
dose of study drug in Study Part A through the end of 110 TE Period. 
 
Post-treatment AE: any AE that increased in severity or that was newly developed after 
110 TE Period. 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
For AEs with missing or partial start date, if there is no clear evidence that the AEs started (or 
increased in severity) before the first dose, the start date will be imputed to the first dosing 
date and the AE will be considered as TEAE. As an intermediate step for programming purposes, 
imputation rules for missing or partially missing AE start/end dates are defined in Section 11.4. 
TEAEs will be classified into 4 categories of relationship to the study drugs: not related, unlikely 
related, possibly related, related. 
TEAEs will be classified into 4 categories of severity: 
 
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 and 5): Any adverse drug experience that places the subject, 
in the view of the investigator, at immediate risk of death. 
All the summary tables of TEAEs display counts and exposure-adjusted event rates for the 
Safety Set in Study 110.  
9.7.1.1 
Overview of TEAEs 
An overview of all TEAEs will be summarized the following categories: 
 
Any TEAEs  
 
TEAEs by strongest relationship 
 
Related TEAEs 
 
TEAEs by maximum severity 
 
Grade 3/4 TEAEs 
 
Serious TEAEs 
 
Related serious TEAEs 
 
TEAEs leading to treatment discontinuation (this will capture TEAEs leading to 
discontinuation to either the morning or the evening tablets) 
 
TEAEs leading to treatment interruption (this will capture TEAEs leading to interruption 
to either the morning or the evening tablets) 
 
TEAE leading to death  
9.7.1.2 
TEAEs, Related TEAEs, Serious TEAEs, Related Serious TEAEs, 
Grade 3/4 TEAEs  
Using MedDRA System Organ Class (SOC) and Preferred Term (PT), the number of subjects and 
exposure-adjusted event rates for the following TEAEs are summarized based on the Safety Set 
during 110 TE Period: 
 
TEAEs by PT and by SOC/PT 




Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
9.7.2 
Clinical Laboratory Values 
With the threshold criteria for abnormal high/abnormal low listed in Section 11.3, the following 
summaries for chemistry, LFT, hematology, coagulation, vitamin levels, and lipid panel 
assessments will be presented for Safety Set during 110 TE Period: 
 
Raw values and change from baseline will be summarized using SI units by visit. 
 
Number and percentage of subjects with abnormal assessments meeting the threshold 
criteria will be summarized during the entire 110 TE Period.  
 
A summary table for the shift from baseline to post-baseline will be summarized by visit. 
Mean value at each visit will be plotted for each LFT parameter.  
A listing containing individual subject laboratory assessment values outside the reference 
ranges will be provided.  
Listings of abnormal urinalysis and positive serum/urine pregnancy tests will be provided. 
9.7.3 
Electrocardiogram  
The raw values and change from baseline values will be summarized at each scheduled visit for 
Safety Set during 110 TE Period: PR, QT, and QTc for HR interval (QTcF), QRS duration, and HR. 
The number and percentage of subjects with at least 1 threshold analysis event during the 
entire 110 TE Period will be summarized by treatment group. The threshold analysis criteria are 
listed in Section 11.3.  
9.7.4 
Vital Signs 
The raw values and change from baseline values will be summarized at each scheduled visit for 
Safety Set during 110 TE Period: systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), HR (beats per minute [bpm]), and respiratory rate (breaths per minute).  
The number and percentage of subjects with at least 1 threshold analysis event during the 
entire 110 TE Period will be summarized. The threshold analysis criteria are provided in Section 
11.3. 
9.7.5 
Pulse Oximetry 
The raw values and change from baseline values will be summarized at each scheduled visit for 
Safety Set during 110 TE Period 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 
entire 110 TE Period will be tabulated. 
 
9.7.6 
Ophthalmologic Examination 
The ophthalmologic examination results may be listed for subjects < 18 years old (age on the 
date of informed consent/assent in the parent study) with cataracts anytime during 110 TE 
Period. 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
9.7.7 
Pregnancy Tests  
Positive urine and serum pregnancy test results during baseline and TE period will be listed. 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
10 
REFERENCES 
[1] Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general U.S. population. Am J Respir Crit Care Med. 1999; 159:179-87. 
[2] Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG. Pulmonary function between 6 and 18 
years of age. Pediatr Pulmonol. 1993; 15:75-88. 
[3] Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics. 1997;53:983-97. 
[4] Rubin, DB. and Schenker, N.. Interval estimation from multiply-imputed data: a case 
study using agriculture industry codes. Journal of the American Statistical Association. 
1987; 81: 366–374. 
[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] Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
[7] 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. 
[8] Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
[9] FDA, Center for Drug Evaluation and Research (CDER) and Center for Biologics 
Evaluation and Research (CBER). Guidance for Industry Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation. July 2009. 
 
 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
11 
APPENDICES 
11.1 
Analysis Visit Window Mapping Rules  
 
Table 11-1 Visit Window Mapping Rules for Safety Measurements 
Assessments 
Visit 
Target Study Day 
Visit Window  
(in study days) 
 Standard 12-lead 
ECG 
 Vital signs 
 Pulse oximetry 
 Labs 
o Chemistry 
o Hematology 
Day 1 
1 
[1, 1] 
Day 15  
15 
[2, 36] 
Week 8  
57 
[37, 85] 
Week 16  
113 
[86, 141] 
Week 24 
169 
[142, 211] 
Week 36  
253 
[212, 295] 
Week 48  
337 
[296, 379] 
Week 60  
421 
[380, 463] 
Week 72  
505 
[464, 547] 
Week 84  
589 
[548, 631] 
Week 96  
673 
[632, 687] 
ETT 
N/A 
Follow the individual 
visit window to be 
mapped to individual 
visits 
Safety Follow-up Visit  
N/A 
Nominal (remain as 
SFU) 
 Coagulation 
 Lipid Panel 
 Labs 
o Vitamin Level 
o Urinalysis 
Day 1 
1 
[1, 1] 
Week 8  
57 
[2, 85] 
Week 16  
113 
[86, 141] 
Week 24 
169 
[142, 211] 
Week 36  
253 
[212, 295] 
Week 48  
337 
[296, 379] 
Week 60  
421 
[380, 463] 
Week 72  
505 
[464, 547] 
Week 84  
589 
[548, 631] 
Week 96  
673 
[632, 687] 
ETT 
N/A 
Follow the individual 
visit window to be 
mapped to individual 
visits 
Safety Follow-up Visit  
N/A 
Nominal (remain as 
SFU) 
Note: spirometry assessments, BMI, weight, and height will be used for both efficacy and safety purposes. Their 
measurements will follow the visit windowing rules for efficacy measurements. 
 
 
 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
Table 11-2 Visit Window Mapping Rules for Efficacy Measurements 
Assessments 
Visit 
Analysis Visit 
Target 
Study 
Day 
Visit Window  
(in study days) 
 Spiromtery 
 CFQ-R 
 
Day 15  
Study 110 Day 15  
15 
[2, 36] 
Week 8  
Study 110 Week 8  
57  
[37, 85] 
Week 16 
Study 110 Week 16 
113 
[86, 141] 
Week 24  
Study 110 Week 24  
169 
[142, 211] 
Week 36 
Study 110 Week 36 
253 
[212, 295] 
Week 48 
Study 110 Week 48 
337 
[296, 379] 
Week 60  
Study 110 Week 60  
421 
[380, 463] 
Week 72 
Study 110 Week 72 
505 
[464, 547] 
Week 84 
Study 110 Week 84 
589 
[548, 631] 
Week 96 
Study 110 Week 96 
673 
[632, 687] 
ETT 
 
N/A 
Follow the individual 
visit window to be 
mapped to individual 
visits 
Safety Follow-up Visit 
Safety Follow-up Visit 
N/A 
Follow the individual 
visit window to be 
mapped to individual 
visits if fall within the 
upper boundary of the 
window for the last 
scheduled visit (Day 
687); or remain as SFU 
if otherwise.  
 Weight and 
height 
 BMI 
 
Week 8 
Study 110 Week 8 
57 
[2, 85] 
Week 16 
Study 110 Week 16 
113 
[86, 141] 
Week 24  
Study 110 Week 24  
169 
[142, 211] 
Week 36 
Study 110 Week 36 
253 
[212, 295] 
Week 48 
Study 110 Week 48 
337 
[296, 379] 
Week 60 
Study 110 Week 60 
421 
[380, 463] 
Week 72 
Study 110 Week 72 
505 
[464, 547] 
Week 84 
Study 110 Week 84 
589 
[548, 631] 
Week 96 
Study 110 Week 96 
673 
[632, 687] 
ETT 
ETT 
N/A 
Follow the individual 
visit window to be 
mapped to individual 
visits 
Safety Follow-up Visit 
Safety Follow-up Visit 
N/A 
Follow the individual 
visit window to be 
mapped to individual 
visits if fall within the 
upper boundary of the 
window for the last 
scheduled visit (Day 
687); or remain as SFU 
if otherwise. 
 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
Note:  
1. 
To apply the above visit windows, please first label Day 1 for the date of the first dose in 
Study 110 drug, and use the nominal visit names to label SFU (for safety). 
2. 
After the SFU (for safety) measurements are determined; the above visit windows will be 
applied to determine the analysis visit names for all remaining measures at scheduled or 
unscheduled visits.  
3. 
For all efficacy parameters, if there are multiple measurements within a visit window, the 
record at the scheduled visit will be used. Otherwise, 
 If there are no measurements at the scheduled visit, then the record closest to the target 
day will be used;  
 If there are multiple records with the same distance to the target day, the latest record will 
be used.   
 Assessments at the early treatment termination (ETT) visit will follow the windowing 
rules for regular visits.  
 Assessments at safety follow-up (SFU) visit will follow the windowing rules for regular 
visits if they fall within the upper boundary of the window for the last scheduled visit; it 
will remain as the SFU if it goes beyond the upper boundary of the window for the last 
scheduled visit. 
4. 
For all safety parameters, if there are multiple measurements within a visit window, then 1) 
the record closest to the target day will be used, with the exception of the threshold analysis 
in which the worst record will be used; 2) if there are multiple records within the same 
distance of the target day, the latest record will be used; or 3) the SFU visit will not be 
windowed; instead, the nominal visit will be used in relevant analysis. 
 
Special handling for ECG: 
 On Day 1 & Day 15, ECGs will be collected before dosing and at 1.5 and 4 hours after the 
morning dose. None of the measures on Day 1 or Day 15 will be mapped into other visits. 
o Day 1 post-dose and Day 15 pre-/post-dose measurements will be analyzed based on 
nominal visit names.  
o On Day 1, the pre-dose measurements will be performed in triplicate, the average of the 
triplicate will be used as pre-dose measurement on Day 1. Only pre-dose measurement 
with nominal visit names related to the triplicate shall be used in this average.  
 The visit window in the above table will still apply for the ECG data after Day 15.


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
11.2 
Coefficients for Hankinson and Wang Methods for Calculating 
Predicted Spirometry Parameters  
Percent predicted FEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a 
percentage. The predicted FEV1 (L) will be calculated using the Hankinson1 and Wang2 
standards.  
The Hankinson standard will be applied to male subjects 18 years and older and female subjects 
16 years and older; the Wang standard will be applied to male subjects 6 to 17 years and 
female subjects 6 to 15 years of age. During the study, the subjects who have a birthday that 
would move them from Wang to Hankinson will use the Wang standard before that birthday 
and the Hankinson standard at or after that birthday. 
Hankinson Normal Values (HNVs) will be calculated for FEV1, forced vital capacity (FVC), forced 
expiratory flow mid expiratory phase (FEF25-75%), and FEV1/FVC% using the Hankinson equation:  
Predicted lung function parameter = b0+b1 × age+b2 × age2+ b3 × height2 
In the equation, height is given in centimeters, age is given in years, and the coefficients b0, b1, 
b2, and b3 are determined based on subject’s sex, race, and age group as provided in [1]. 
Wang Normal Values (WNVs) will be calculated for FEV1, FVC, FEF25-75%, and FEV1/FVC using the 
Wang equation:  
ln(Predicted lung function parameter) = α+ βln (height) 
Wang Normal Values (WNVs) will be calculated for FEV1, FVC, FEF25-75%, and FEV1/FVC using the 
Wang equation. In the equation, height is given in meters, and the coefficients α and β are 
determined based on subject’s sex, race, and age as provided in [2]. 
If either height or age is missing, and the spirometry measurement is non-missing, the last non-
missing value of height and age will be used in the calculation of predicted values. 
  


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
 
11.3 
Threshold Analysis Criteria 
Table 11-3 Threshold Criteria for Clinical Chemistry and Hematology 
Parameter 
Threshold Criteria 
 
Clinical Chemistry 
CPK 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
Creatinine 
>ULN - ≤ 1.5 x ULN 
>1.5 - ≤ 3.0 x ULN 
>3.0 - ≤ 6.0 x ULN 
>6.0 x ULN 
Blood Urea 
Nitrogen 
>ULN - ≤ 1.5 x ULN 
>1.5 - ≤ 3.0 x ULN 
>3.0 - ≤ 6.0 x ULN 
>6.0 x ULN 
Sodium 
Hyponatremia 
<LLN - ≥130 mmol/L 
<130 – ≥120 mmol/L  
<120 mmol/L  
Hypernatremia 
>ULN - ≤ 150 mmol/L 
>150 mmol/L- ≤155 mmol/L  
>155 mmol/L - ≤ 160 mmol/L 
>160 mmol/L 
Potassium 
Hypokalemia 
 <LLN – ≥ 3.0 mmol/L 
 <3.0 – ≥ 2.5 mmol/L 
 <2.5 mmol/L 
Hyperkalemia 
>ULN – ≤ 5.5 mmol/L 
>5.5 –  ≤ 6.0 mmol/L  
>6.0 – ≤ 7.0 mmol/L  
>7.0 mmol/L 
Total 
Cholesterol 
>ULN – ≤ 7.75 mmol/L 
>7.75 – ≤ 10.34 mmol/L  
>10.34 – ≤ 12.92 mmol/L 
>12.92 mmol/L 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
Triglycerides 
>1.71 – ≤ 3.42 mmol/L  
>3.42 – ≤ 5.7 mmol/L  
>5.7 – ≤ 11.4 mmol/L  
>11.4 mmol/L 
Glucose 
 
 
 
 
 
 
Hypoglycemia 
<3.0 – ≥ 2.2 mmol/L  
<2.2 - ≥ 1.7 mmol/L 
<1.7 mmol/L 
Hyperglycemia  
>ULN - ≤ 8.9 mmol/L 
>8.9 – ≤ 13.9 mmol/L 
>13.9 – ≤ 27.8 mmol/L  
>27.8 mmol/L 
Albumin 
<35 - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L  
Amylase 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.0 x ULN  
>2.0 – ≤ 5.0 x ULN 
>5.0 x ULN 
Lipase 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.0 x ULN  
>2.0 – ≤ 5.0 x ULN 
>5.0 x ULN 
Direct 
bilirubin 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2 x ULN 
>2 – ≤ 3 x ULN  
>3 – ≤ 10 x ULN 
>10 x ULN 
GGT  
>ULN - ≤ 2.5 x ULN 
>2.5 –  ≤ 5.0 x ULN 
>5.0 –  ≤ 20.0 x ULN  
>20.0 x ULN 
Calcium 
Hypercalcemia 
>ULN - ≤ 2.9 mmol/L  
>2.9 – ≤ 3.1 mmol/L  
>3.1 – ≤ 3.4 mmol/L  
>3.4 mmol/L 
Hypocalcemia 
<LLN - ≥ 2.0 mmol/L 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
<2.0 – ≥1.75 mmol/L  
<1.75 – ≥ 1.5 mmol/L  
<1.5 mmol/L  
Magnesium 
 
Hypermagnesemia 
>ULN - ≤ 1.23 mmol/L 
>1.23 – ≤ 3.30 mmol/L 
>3.30 mmol/L 
Hypomagnesemia 
<LLN - ≥ 0.5 mmol/L 
<0.5 – ≥ 0.4 mmol/L 
<0.4 – ≥ 0.3 mmol/L  
<0.3 mmol/L  
Inorganic 
phosphate 
Hypophosphatemia 
<0.74 – ≥ 0.6mmol/L 
<0.6 – ≥ 0.3 mmol/L 
<0.3 mmol/L 
ALT 
>ULN - ≤  3 xULN 
>3 – ≤  5 xULN 
>5 – ≤  8 xULN 
>8 – ≤  20.0 xULN 
>20.0 x ULN 
AST 
>ULN - ≤  3 xULN 
>3 – ≤  5 xULN 
>5 – ≤  8 xULN 
>8 – ≤  20.0 xULN 
>20.0 x ULN 
ALT or AST 
(ALT>ULN and ALT ≤  3 xULN) or (AST>ULN and AST≤  3 xULN); 
(ALT>3 xULN and ALT ≤  5 xULN) or (AST>3xULN and AST≤  5 xULN); 
(ALT>5 xULN and ALT ≤  8 xULN) or (AST>5xULN and AST≤  8 xULN); 
(ALT>8 xULN and ALT ≤  20 xULN) or (AST>8xULN and AST≤  20 xULN); 
ALT>20 xULN or AST> 20 xULN 
Alkaline 
Phosphatase 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5 xULN 
>2.5 – ≤ 5.0 x ULN 
>5.0 – ≤ 20.0 x ULN  
>20.0 x ULN  
Total Bilirubin 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2 x ULN 
>2 – ≤ 3 x ULN  
>3 – ≤ 10 x ULN 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
>10 x ULN 
ALT and Total 
Bilirubin 
ALT>3xULN and TBILI>2xULN 
AST and Total 
Bilirubin 
AST>3xULN and TBILI>2xULN 
(ALT or AST) 
and Total 
Bilirubin  
(ALT>3xULN or AST>3xULN) and TBILI>2×ULN 
Hematology 
WBC 
WBC decreased 
<LLN - ≥ 3.0 x 10e9 /L 
<3.0 – ≥ 2.0 x 10e9 /L  
<2.0 – ≥ 1.0 x 10e9 /L  
<1.0 x 10e9 /L 
Leukocytosis 
>100 x 10e9 /L 
Lymphocytes 
Lymphocyte decreased 
<LLN - ≥ 0.8 x10e9 /L 
<0.8 – ≥ 0.5 x10e9 /L  
<0.5 – ≥ 0.2 x10e9 /L  
<0.2 x10e9 /L 
Lymphocyte increased 
>4 – ≤ 20 x10e9/L  
>20 x10e9/L  
Neutrophils 
Neutrophil decreased 
<LLN - ≥ 1.5 x10e9 /L 
<1.5 –  ≥ 1.0 x10e9 /L  
<1.0 –  ≥ 0.5 x10e9 /L  
<0.5 x10e9 /L 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L  
< 80 g/L 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L above ULN 
>40 g/L above ULN  
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 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
Note: Sources utilized for threshold analyses:  
- NCI CTC-AE v4.03;  
- FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical trials;  
- FDA Guidance for Industry – DILI: Premarketing Clinical Evaluation. 
 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
Table 11-4 Threshold Criteria for Coagulation 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ECGs 
Ref.: CPMP 1997 guideline. 
Parameter 
Threshold 
 
Activated 
partial 
thromboplas
tin time  
(PTT)  
 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
 
 
Prothrombin 
time (PT) 
International 
Normalized 
Ratio (INR) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
 
 
Note: Sources utilized for threshold analyses:  
- NCI CTC-AE v4.03;  
- FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical trials;  
- FDA Guidance for Industry – DILI: Premarketing Clinical Evaluation. 
 
 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
 Table 11-5 Threshold Criteria for ECGs 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ECGs 
Ref.: CPMP 1997 guideline. 
Parameter 
Threshold 
 
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 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
 
QTc 
 
>450 ms (Male)  
>470 ms (Female) 
≥500 ms 
 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
 
 
 
Note: Sources utilized for threshold analyses:  
- NCI CTC-AE v4.03;  


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
- FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical trials;  
- FDA Guidance for Industry – DILI: Premarketing Clinical Evaluation. 
 
 
 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
Table 11-6 Threshold Criteria for Vital Signs 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT VITAL SIGNS 
Parameter 
Threshold Criteria 
 
HR 
 
Same PCS as above in ECG category 
 
SBP 
SBP increased 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from baseline 
>140 mmHg & >20 mmHg increase from baseline 
>160 mmHg & >10 mmHg increase from baseline 
>160 mmHg & >20 mmHg increase from baseline 
 
 
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 
 
DBP 
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 
 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
 
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  
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
 
Note: Sources utilized for threshold analyses:  
- NCI CTC-AE v4.03;  
- FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical trials;  
- FDA Guidance for Industry – DILI: Premarketing Clinical Evaluation 


Statistical Analysis Plan (Methods) 
Vertex Study: VX14-661-110 
Vertex Pharmaceuticals Incorporated 
11.4 
Imputation Rules for Missing or Partial AE Date 
For missing or partial AE start date, use the imputation rules below for the purpose of 
determining whether an AE is treatment-emergent. The imputed dates will not be displayed in 
the listing outputs. 
If only Day of AE start date is missing:  
If the AE start year and month are the same as that for the first dose date, then: 
 
If the full (or  partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start day as the day of first dose date; otherwise, impute the AE 
start day as 1. 
 
Otherwise, 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: 
If AE start year = first dose year, then: 
 
If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start Month and Day as the Month and Day of first dose date; 
otherwise, impute the AE start Month as January and the Day as 1. 
 
Otherwise, impute the AE start MONTH as January and the 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 with no 
imputation. Also compare the full (or partial) AE end date to the first dose date. If the AE end 
date is before the first dose date then the AE should be considered as a pretreatment AE. 
Otherwise, the AE will be considered as TEAE. 
Missing or partially missing AE end date will not be imputed.