Conditions: Cystic Fibrosis
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 83
Healthy volunteers: no

Brief summary:
This is a Phase 3, 2-part (Part A and Part B), open label, multicenter study evaluating the pharmacokinetic (PK), safety, and tolerability of multiple doses of tezacaftor (TEZ) in combination with ivacaftor (IVA) in subjects 6 through 11 years of age with CF who are homozygous or heterozygous for the F508del- CF transmembrane conductance regulator protein (CFTR) mutation.

Detailed description:

Arms:
arm 1: Participants weighing \<25 kg received TEZ 50 mg once daily/IVA 75 mg q12h orally for 14 days.

Participants weighing ≥25 kg received TEZ 50 mg once daily/IVA 150 mg q12h orally for 14 days. arm 2: Participants weighing \<40 kg received TEZ 50 mg/IVA 75 mg as fixed dose combination orally once daily in the morning and IVA 75 mg orally once daily in the evening for 24 weeks.

Participants weighing ≥40 kg received TEZ 100 mg/IVA 150 mg as fixed dose combination orally once daily in the morning and IVA 150 mg orally once daily in the evening for 24 weeks.

Interventions: intervention 1: TEZ intervention 2: TEZ/IVA intervention 3: IVA
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_000.pdf: 




Protocol VX15-661-113, Version 3.0 
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2 
PROTOCOL SYNOPSIS 
Title A Phase 3, Open-label Study to Evaluate the Pharmacokinetics, Safety, and 
Tolerability of VX-661 in Combination With Ivacaftor in Subjects 6 Through 
11 Years of Age With Cystic Fibrosis, Homozygous or Heterozygous for the 
F508del-CFTR Mutation 
Brief Title A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of 
VX-661/Ivacaftor in Pediatric Subjects With Cystic Fibrosis  
  
Clinical Phase and 
Clinical Study Type  
Phase 3, pharmacokinetic (PK), safety, and tolerability (pediatric population) 
  
Objectives Part A  
Primary Objective 
To evaluate the PK of VX-661 and ivacaftor after administration of multiple doses 
of VX-661 in combination with ivacaftor 
Secondary Objectives 
• 
To evaluate the PK of VX-661 metabolites, M1-661 and M2-661, and 
ivacaftor metabolites, M1-ivacaftor and M6-ivacaftor, after administration of 
multiple doses of VX-661 in combination with ivacaftor 
• 
To evaluate the safety and tolerability of multiple doses of VX-661 in 
combination with ivacaftor  
Part B 
Primary Objective 
To evaluate the safety and tolerability of VX-661 in combination with ivacaftor 
through Week 24 
Secondary Objectives 
• 
To evaluate the PK of VX-661, M1-661, M2-661, ivacaftor, M1-ivacaftor, 
and M6-ivacaftor after administration of multiple doses of VX-661 in 
combination with ivacaftor 
• 
To evaluate the efficacy of VX-661 in combination with ivacaftor through 
Week 24 
  
Endpoints Part A  
Primary Endpoint 
VX-661 and ivacaftor PK parameters, including maximum observed concentration 
(Cmax), area under the concentration versus time curve during a dosing interval 
(AUCτ), and other PK parameters as appropriate 
Secondary Endpoints 
• 
M1-661, M2-661, M1-ivacaftor, and M6-ivacaftor PK parameters, including 
Cmax, AUCτ, and other PK parameters as appropriate 
• 
Safety and tolerability of VX-661 in combination with ivacaftor as 
determined by adverse events (AEs), clinical laboratory values (serum 
chemistry, hematology, coagulation studies, lipids, vitamins, and urinalysis), 
standard 12-lead electrocardiogram (ECGs), vital signs, pulse oximetry, and 
spirometry 
 


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Part B 
Primary Endpoint 
Safety and tolerability of VX-661 in combination with ivacaftor as determined by 
AEs, clinical laboratory values (serum chemistry, hematology, coagulation 
studies, lipids, vitamins, and urinalysis), standard 12-lead ECGs, vital signs, pulse 
oximetry, ophthalmologic examinations, and spirometry 
Secondary Endpoints  
• 
VX-661, M1-661, M2-661, ivacaftor, M1-ivacaftor, and M6-ivacaftor PK 
parameters, including Cmax, AUCτ, and other PK parameters as appropriate 
• 
Absolute change in ppFEV1 from baseline through Week 24 
• 
Relative change in ppFEV1 from baseline through Week 24 
• 
Absolute change in weight and weight-for-age z-score from baseline at 
Week 24 
• 
Absolute change in height and height-for-age z-score from baseline at 
Week 24 
• 
Absolute change in body mass index (BMI) and BMI-for-age z-score from 
baseline at Week 24  
• 
Absolute change in sweat chloride from baseline through Week 4 
• 
Absolute change in sweat chloride from baseline through Week 24  
• 
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
respiratory domain score from baseline through Week 24 
 
Number of Subjects Part A  
Up to approximately 16 subjects total are planned for enrollment across Cohort 1 
(subjects weighing <25 kg at baseline) and Cohort 2 (subjects weighing ≥25 kg at 
baseline). Subjects who participate in Part A may participate in Part B if Part B 
eligibility criteria are met. 
Part B 
Approximately 56 subjects are planned for enrollment. Assuming a 10% dropout 
rate, approximately 50 subjects are expected to complete Part B.  
  
Study Population Part A and Part B 
Male and female subjects 6 through 11 years of age with cystic fibrosis (CF), 
homozygous or heterozygous for the F508del-CFTR Mutation. Subjects in Part A 
may participate in Part B if Part B eligibility criteria are met. 
  


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Investigational Drug Part A  
Active substance: VX-661 
 Activity: CFTR corrector (increased chloride ion [Cl−] secretion) 
 Strength and Route of Administration: VX-661 50-mg tablets for oral 
administration  
  
 Active substance: Ivacaftor 
 Activity: CFTR potentiator (increased Cl− secretion) 
 Strength and Route of Administration: Ivacaftor 75-mg granules or 150-mg tablet 
for oral administration 
  
 Part B 
Active substances: VX-661 and ivacaftor 
 Activity: CFTR corrector and potentiator (increased Cl− secretion) 
 Strength and Route of Administration:  
VX-661 50-mg/ivacaftor 75-mg fixed-dose combination (FDC) tablet or VX-661 
100-mg/ivacaftor 150-mg FDC tablet for oral administration  
  
 Active substance: Ivacaftor 
 Activity: CFTR potentiator (increased Cl− secretion) 
 Strength and Route of Administration: Ivacaftor 75-mg tablet or 150-mg tablet for 
oral administration 
  
Study Duration Part A 
Excluding the Screening Period, subject participation will be up to 31 days (Day 1 
through the Safety Follow-up Visit). The planned treatment duration of VX-661 in 
combination with ivacaftor is 14 days.  
Part B 
Excluding the Screening Period, subject participation will be up to 29 weeks 
(Day 1 through the Safety Follow-up Visit). The planned treatment duration of 
VX-661 in combination with ivacaftor is 24 weeks. 
  
Study Design This is a Phase 3, 2-part (Part A and Part B), open-label, multicenter study 
evaluating the PK, safety, and tolerability of multiple doses of VX-661 in 
combination with ivacaftor in subjects 6 through 11 years of age with CF who are 
homozygous or heterozygous for the F508del-CFTR mutation. Efficacy will also 
be evaluated in Part B. Part A is composed of 2 weight-based cohorts, which will 
be enrolled simultaneously, and Part B is composed of a single cohort. 
Part A 
Part A includes the following: 
• 
Screening Period (Day -28 through Day -1) 
• 
Treatment Period (Day 1 through Day 14) 
• 
Washout Period (Day 14 to Day 28 [± 3 days]) 
• 
Safety Follow-up Visit (14 [± 3] days after the last dose of study drug) 
 


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Screening Period  
After obtaining written informed consent (and assent, if applicable), Screening 
Visit assessments will be completed at any time during the period of 4 weeks 
(Day -28 through Day -1) before the first dose of the study drug (Day 1).  
Treatment Period  
During the Treatment Period, subjects will be administered VX-661 50 mg daily 
(qd) in combination with ivacaftor, either 75 mg (subjects <25 kg at baseline) or 
150 mg (subjects ≥25 kg baseline), every 12 hours (q12h) for 14 days. On Day 14, 
only the morning dose of study drug will be administered. 
Washout Period 
A 2-week Washout Period (Day 14 to Day 28 [± 3 days]) will be included in order 
to evaluate the off-drug response. 
Safety Follow-up Visit  
A Safety Follow-up Visit is scheduled to occur 14 (± 3) days after the last dose of 
study drug for all subjects, including subjects who permanently discontinue from 
study treatment for any reason. 
A review of safety, tolerability, and PK data will be completed by an internal 
Vertex team after Part A to select the VX-661 dose for Part B. 
Part B 
Part B includes the following: 
• 
Screening Period (Day -28 through Day -1) 
• 
Treatment Period (Day 1 through Week 24 [± 5 days]) 
• 
Safety Follow-up Visit (4 weeks [± 7 days] after the last dose of study drug) 
Screening Period 
After obtaining written informed consent (and assent, if applicable), Screening 
Visit assessments will be completed at any time during the period of 4 weeks 
(Day -28 through Day -1) before the first dose of study drug (Day 1). 
Treatment Period 
During the Treatment Period, subjects will be administered VX-661 50 mg qd in 
combination with ivacaftor 75 mg q12h (subjects <40 kg at baseline) or VX-661 
100 mg qd in combination with ivacaftor 150 mg q12h (subjects ≥40 kg at 
baseline) for 24 weeks. No dose adjustments will be made throughout the duration 
of treatment in this study. 
Safety Follow-up Visit  
A Safety Follow-up Visit is scheduled to occur 4 weeks (± 7 days) after the last 
dose of study drug. The Safety Follow-up Visit is not required for subjects who 
have enrolled in the extension study (see below) within 28 days after the last dose 
of study drug. Subjects who permanently discontinue study drug treatment will 
have an Early Treatment Termination (ETT) Visit and a Safety Follow-up Visit. 
Extension Study 
At the Week 24 Visit in Part B, subjects who complete study drug treatment will 
be offered the opportunity to enroll in an extension study evaluating VX-661 in 
combination with ivacaftor (enrollment will be based on the eligibility criteria 
specified within the extension study). Subjects who prematurely discontinue study 
drug treatment are not eligible to rollover into the extension study. 
  
 
 


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Assessments PK Assessments 
Part A and Part B 
VX-661, M1-661, M2-661, ivacaftor, M1-ivacaftor, and M6-ivacaftor plasma PK 
parameters 
Safety Assessments 
Part A and Part B 
Adverse events, clinical laboratory assessments (serum chemistry, hematology, 
coagulation studies, lipids, vitamins, and urinalysis), standard 12-lead ECGs, vital 
signs, pulse oximetry, spirometry, and physical examinations (PEs) 
Part B will also include ophthalmologic examinations. 
Efficacy Assessments  
Part A 
Spirometry 
Part B 
Spirometry, weight, height, BMI, sweat chloride, and CFQ-R 
  
  
Statistical Analyses Part A 
Sample size calculations conducted using noncompartmental analysis-based PK 
parameters, such as clearance and volume, in adults indicate that data from 
8 subjects will allow 80% power to target a 95% CI within 60% and 140% of the 
geometric mean estimate of clearance for VX-661 in each pediatric subgroup 
(cohort). 
There will be no statistical analyses for the safety variables in Part A. All safety 
analyses will be performed descriptively.  
Part B 
An important safety endpoint is the incidence of AEs. With 50 subjects 
completing the study, there is a 92.3% chance of observing AEs in at least 
1 subject if the true incidence rate is 5%, and a 99.5% chance of observing AEs in 
at least 1 subject if the true incidence rate is 10%.  
For the primary endpoints, summary statistics will be provided for 
treatment-emergent adverse events (TEAEs), clinical laboratory assessments 
(serum chemistry, hematology, lipids, vitamins, and coagulation studies), standard 
12-lead ECGs, vital signs, pulse oximetry, and spirometry during the 
treatment-emergent period. 


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IDMC Reviews Part A 
An independent data monitoring committee (IDMC) will be formed. The IDMC 
objectives and operational details will be defined in a separate document (the 
IDMC Charter), which will be finalized before the first subject is screened in 
Part B. The IDMC will conduct a planned review of study data for the purpose of 
safety monitoring as outlined in the IDMC Charter.  
Part B 
The IDMC objectives and operational details will be defined in a separate 
document (IDMC Charter), which will be finalized before the first subject is 
screened. The IDMC will conduct regular planned reviews of study data for the 
purpose of safety monitoring as outlined in the IDMC Charter. 


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3 
SCHEDULE OF ASSESSMENTS 
The schedules of assessments for Study VX15-661-113 (Study 113) are shown in Table 3-1 
(Part A Screening), Table 3-2 (Part A Treatment Period and Safety Follow-up Visit), Table 3-3 
(Part B Screening), and Table 3-4 (Part B Treatment Period and Safety Follow-up Visit).  
Table 3-1 
Study VX15-661-113: Part A Screening 
Assessment 
Screening Visit (Day -28 to Day -1) 
Informed consent (and assent, if applicable) 
X 
Demographics 
X 
Medical history 
X 
Ophthalmological historya 
X 
Weight, height, and vital signsb,c 
X 
Pulse oximetryc 
X 
Ophthalmologic examinationa,d 
X 
Full physical examinatione 
X 
Standard 12-lead ECGf 
X 
Spirometryg 
X 
Sweat chlorideh 
X 
CFTR genotypei,j 
X 
Serum pregnancy test (female subjects of childbearing potential)i,k 
X 
Serum chemistryi 
X 
Vitamin levelsi 
X 
Hematology and coagulation studiesi 
X 
Urinalysisi 
X 
Inclusion/exclusion criteria review  
X 
Prior and concomitant medications 
Continuous from signing of ICF (and assent form, if 
applicable) through Safety Follow-up Visit 
AEs and SAEs 
Continuous from signing of ICF (and assent form, if 
applicable) through Safety Follow-up Visit 
AE: adverse event; BMI: body mass index; CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; 
ECG: electrocardiogram; ICF: informed consent form; SAE: serious adverse event 
 
a 
Refer to Section 11.7.6 for details. 
b 
Weight and height will be measured with shoes off. BMI will be derived from assessment of height and weight. 
c 
Vital signs and pulse oximetry will be collected after the subject has been seated or supine for at least 5 minutes (see Section 11.7.4). 
d 
An ophthalmologic examination will be conducted by a licensed ophthalmologist. The examination does not need to be repeated if 
there is documentation of an examination meeting protocol criteria that was conducted within 3 months before the start of the 
Screening Period. Subjects with documentation of bilateral lens removal do not need the ophthalmologic examination. Subjects with 
clinically significant cataracts, lens opacity, Y suture, or lamellar rings will be excluded (refer to Section 9.2). 
e 
Refer to Section 11.7.4 for details. 
f 
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes (refer to Section 11.7.5). The ECG 
will be performed before any other procedures that may affect heart rate. 
g 
Spirometry may be performed pre- or post-bronchodilator (refer to Section 11.6.1).  
h  
A sweat chloride test must be performed if an eligible sweat chloride value is not available in the subject’s medical records (refer to 
Section 11.6.2). For subjects using a sweat chloride value documented in their medical record to establish eligibility, the sweat 
chloride test at the Screening Visit is optional.  
i  
Refer to Section 11.7.2 for details.  
j  
All subjects will be tested to assess CFTR genotype, regardless of availability of a previous CFTR genotype lab report. In subjects 
with the R117H mutation, linkage to poly-T tract polymorphisms will also be determined from a second specimen. Specific 
instructions will be provided in the Laboratory Manual. 
k  
Any female subject who does not meet the criteria for non-childbearing potential (refer to Section 11.7.8.1) is considered to be of 
 
childbearing potential and must have a serum pregnancy test. 


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Table 3-2 
Study VX15-661-113: Part A Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Day 1 
 
Day 2 
 
Day 4 
(± 1 day) 
Day 7 
(± 1 day) 
Day 14 
 
Day 21 
(± 1 day) 
Day 28 
Safety Follow-up Visit 
(14 [± 3] days after the 
last dose) 
Clinic visit 
X 
X 
 
X 
X 
X 
X 
Telephone contactb 
 
 
X 
 
 
 
 
Safety Assessments 
Weight and heightc 
X 
 
 
 
X 
 
X 
Vital signsd 
X 
X 
 
X 
X 
 
X 
Pulse oximetryd 
X 
X 
 
X 
X 
 
X 
Full physical examinatione 
X 
 
 
 
X 
 
X 
Standard 12-lead ECGf 
Xg 
X 
 
X 
X 
 
X 
Spirometryh 
X 
X 
 
X 
X 
 
X 
Pregnancy test (female subjects of childbearing potential)i,j 
X 
(urine) 
 
 
 
 
 
X 
(serum) 
Serum chemistryj 
X 
 
 
X 
X 
 
X 
Lipid panelj,k 
X 
 
 
 
X 
 
 
Vitamin levelsj 
 
 
 
 
X 
 
 
Hematologyj 
X 
 
 
X 
X 
 
X 
 
a 
All assessments will be performed before study drug dosing unless noted otherwise (refer to Section 11.1). When repeats of an assessment are required postdose at a given 
 
visit, the assessment will be collected only once if study drug is not administered on the day of the visit (i.e., study drug interruption or permanent discontinuation of study 
 
drug). 
b  
Telephone contact will be made to assess the subject's status, any AEs, concomitant medications, treatments, and procedures. 
c 
Weight and height will be measured with shoes off. BMI will be derived from assessment of height and weight. 
d 
Vital signs and pulse oximetry will be collected after the subject has been seated or supine for at least 5 minutes (refer to Section 11.7.4). 
e 
At other visits, symptom-directed physical examinations will occur if triggered by AEs or if deemed necessary by the investigator (refer to Section 11.7.4). 
f 
Standard 12-lead ECGs will be performed before study drug dosing (unless noted otherwise) after the subject has been supine for at least 5 minutes (refer to Section 11.7.5). 
g 
ECGs collected on Day 1 before study drug dosing will be performed in triplicate.  
h 
Spirometry must be performed for all subjects before dosing and should be performed pre-bronchodilator (refer to Section 11.6.1). 
i  
Any female subject who does not meet the criteria for non-childbearing potential (refer to Section 11.7.8.1) is considered to be of childbearing potential and must have a 
 
pregnancy test.  
j  
Refer to Section 11.7.2 for details. 
k  
Blood samples will be collected for the lipid panel following at least a 4-hour fast.  


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Table 3-2 
Study VX15-661-113: Part A Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Day 1 
 
Day 2 
 
Day 4 
(± 1 day) 
Day 7 
(± 1 day) 
Day 14 
 
Day 21 
(± 1 day) 
Day 28 
Safety Follow-up Visit 
(14 [± 3] days after the 
last dose) 
Coagulation studiesj 
 
 
 
 
 
X 
 
Urinalysisj 
X 
 
 
 
X 
 
 
Concomitant medications, treatments, and procedures 
Continuous from signing of ICF (and assent form, if applicable) through Safety Follow-up Visit 
AEs and SAEs 
Continuous from signing of ICF (and assent form, if applicable) through Safety Follow-up Visit 
PK Assessments 
PK Sampling 
Xl 
Xl 
 
 
Xm 
Xm 
Xm 
Study Drug Administration 
VX-661 + IVAn 
VX-661 qd + IVA q12h 
Day 1 through Day 14 (morning dose only on Day 14) 
 
 
AE: adverse event; BMI: body mass index; CF: cystic fibrosis; ECG: electrocardiogram; ICF: informed consent form; IVA: ivacaftor; PK: pharmacokinetic; q12h: every 12 hours; 
qd: daily; SAE: serious adverse event 
 
l 
PK blood samples will be collected on Day 1 at 1, 2, 4, 5, and 24 hours (i.e., predose on Day 2) after the morning dose of study drug on Day 1. Acceptable windows for 
 
sampling times are shown in Table 11-1. 
m 
PK blood samples will be collected before the morning dose of study drug on Day 14 and at 1, 2, 4, and 5 hours after the morning dose of study drug on Day 14. A PK blood 
sample will also be collected at 168 hours (i.e., Day 21) after the morning dose of study drug on Day 14 and at the Safety Follow-up Visit. Acceptable windows for sampling 
times are shown in Table 11-1.  
n 
The study drug should be administered approximately 30 minutes after the start of consuming a fat-containing meal or snack. Refer to Section 9.3 for details on study 
restrictions and Section 10.2 for details on study drug administration (e.g., fasting requirements). On days of scheduled visits, the dose of study drug will be administered at 
the clinical site after predose assessments have been completed. The last dose of study drug will be the morning dose on Day 14. 


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Table 3-3 
Study VX15-661-113: Part B Screening 
Assessment 
Screening Visit 
(Day -28 through Day -1) 
Informed consent (and assent, if applicable) 
X 
Demographics 
X 
Medical history  
X 
Ophthalmological historya 
X 
Weight, height, and vital signsb,c 
X 
Pulse oximetryc 
X 
Ophthalmologic examinationa,d 
X 
Full physical examinatione 
X 
Standard 12-lead ECGf 
X 
Spirometryg 
X 
Sweat chlorideh 
X 
CFTR genotypei,j 
X 
Serum pregnancy test (female subjects of childbearing potential)i,k 
X 
Serum chemistryi 
X 
Hematologyi 
X 
Coagulation studiesi 
X 
Urinalysisi 
X 
Inclusion/exclusion criteria review 
X 
Prior and concomitant medications 
Continuous from signing of ICF (and assent form, if 
applicable) through Safety Follow-up Visit 
AEs and SAEs 
Continuous from signing of ICF (and assent form, if 
applicable) through Safety Follow-up Visit 
AE: adverse event; BMI: body mass index; CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; 
ECG: electrocardiogram; ICF: informed consent form; SAE: serious adverse event 
 
 
a 
Refer to Section 11.7.6 for details. 
b 
Weight and height will be measured with shoes off. BMI will be derived from assessment of height and weight. 
c 
Vital signs and pulse oximetry will be collected after the subject has been seated or supine for at least 5 minutes (refer 
to Section 11.7.4). 
d 
An ophthalmologic examination will be conducted by a licensed ophthalmologist. The examination does not need to be 
repeated if there is documentation of an examination meeting protocol criteria that was conducted within 3 months 
before the start of the Screening Period. Subjects with documentation of bilateral lens removal do not need the 
ophthalmologic examination. Subjects with clinically significant cataracts, lens opacity, Y suture, or lamellar rings will 
be excluded (refer to Section 9.2). 
e 
Refer to Section 11.7.4 for details. 
f 
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes (refer to 
Section 11.7.5). The ECG will be performed before any other procedures that may affect heart rate (e.g., blood draws). 
g 
Spirometry may be performed pre- or post-bronchodilator (refer to Section 11.6.1).  
h  
A sweat chloride test must be performed if an eligible sweat chloride value is not available in the subject’s medical 
 
records (refer to Section 11.6.2). For subjects using a sweat chloride value documented in their medical record to 
 
establish eligibility, the sweat chloride test at the Screening Visit is optional. 
i  
Refer to Section 11.7.2 for details.  
j  
All subjects will be tested to assess CFTR genotype, regardless of availability of a previous CFTR genotype lab report. 
In subjects with the R117H mutation, linkage to poly-T tract polymorphisms will also be determined from a second 
specimen. Specific instructions will be provided in the Laboratory Manual. 
k  
Any female subject who does not meet the criteria for non-childbearing potential (refer to Section 11.7.8.1) is 
 
considered to be of childbearing potential and must have a serum pregnancy test. 


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Table 3-4 
Study VX15-661-113: Part B Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Day 1 
 
Day 15 
(± 3 days) 
Week 4 
(± 5 days) 
Week 8 
(± 5 days) 
Week 12 
(± 5 days) 
Week 16 
(± 5 days) 
Week 20 
(± 5 days) 
Week 24 
(± 5 days)b 
ETT Visitc 
Safety Follow-up 
Visit 
(4 weeks [± 7 days] 
after last dose)d 
Clinic visit 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Telephone contacte 
 
 
 
 
X 
 
X 
 
 
 
Inclusion and exclusion criteria 
review 
X 
 
 
 
 
 
 
 
 
 
CFQ-Rf 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Weight, height, and vital signsg,h 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Pulse oximetryh 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Ophthalmologic examination 
 
 
 
 
 
 
 
Xi 
Xi 
Xi 
Full physical examinationj 
X 
 
 
 
 
 
 
X 
 
 
 
a 
All assessments will be performed before study drug dosing unless noted otherwise (refer to Section 11.1). When repeats of an assessment are required postdose at a given 
visit, the assessment will be collected only once if study drug is not administered on the day of the visit (i.e., study drug interruption or permanent discontinuation of study 
drug). 
b  
At the Week 24 Visit, subjects who complete study drug treatment will be offered the opportunity to enroll in an extension study evaluating VX-661 in combination with 
 
ivacaftor. Subjects who prematurely discontinue study drug treatment are not eligible to rollover into the extension study. 
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 (refer to 
Section 8.1.5). Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit, approximately 4 weeks (± 7 days) after their last 
dose of study drug. If the ETT Visit occurs 3 weeks or later after 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 
The Safety Follow-up Visit is not required for subjects who have enrolled in the extension study within 28 days after the last dose of study drug. 
e 
Telephone contacts will be made to assess the subject's status, any AEs, concomitant medications, treatments, and procedures.  
f 
The CFQ-R should be completed before the start of any other assessments (refer to Section 11.1).  
g 
Weight and height will be measured with shoes off. BMI will be derived from assessment of height and weight. 
h 
Vital signs and pulse oximetry will be collected after the subject has been seated or supine for at least 5 minutes (refer to Section 11.7.4). 
i 
An ophthalmologic examination will be conducted by a licensed ophthalmologist at or within 28 days before the Week 24 Visit OR at or within 35 days before the Safety 
Follow-up Visit (refer to Section 11.7.6). For subjects who discontinue treatment after receiving at least 1 dose of study drug, this examination may be completed at the ETT 
Visit OR at or within 35 days before the Safety Follow-Up Visit (if applicable [refer to Section 8.1.5]). Subjects who have documentation of bilateral lens removal are not 
required to complete the eye examination at the Week 24 Visit, the ETT Visit, or Safety Follow-up Visit. 
j 
At other visits, symptom-directed physical examinations will occur if triggered by AEs or if deemed necessary by the investigator (refer to Section 11.7.4). 


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Table 3-4 
Study VX15-661-113: Part B Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Day 1 
 
Day 15 
(± 3 days) 
Week 4 
(± 5 days) 
Week 8 
(± 5 days) 
Week 12 
(± 5 days) 
Week 16 
(± 5 days) 
Week 20 
(± 5 days) 
Week 24 
(± 5 days)b 
ETT Visitc 
Safety Follow-up 
Visit 
(4 weeks [± 7 days] 
after last dose)d 
Standard 12-lead ECGk 
Xl 
X 
X 
X 
 
X 
 
X 
X 
X 
Spirometryn 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Sweat chlorideo 
X 
 
X 
 
 
 
 
X 
 
 
Pregnancy test (female subjects of 
childbearing potential)p,q 
X 
(urine) 
X 
(serum) 
X 
(serum) 
X 
(serum) 
 
X 
(serum) 
 
X 
(serum) 
X 
(serum) 
X 
(serum) 
Serum chemistryq 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Lipid panelq 
X 
 
 
X 
 
X 
 
X 
X 
 
Vitamin levelsq 
X 
 
 
X 
 
 
 
X 
X 
 
Hematologyq 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Coagulation studiesq 
X 
 
 
 
 
 
 
X 
X 
X 
Urinalysisq 
X 
 
 
 
 
 
 
X 
X 
X 
 
k 
All standard 12-lead ECGs will be performed before study drug dosing (unless noted otherwise) and after the subject has been supine for at least 5 minutes (refer to 
Section 11.7.5). ECGs will be performed before any other procedures that may affect heart rate (e.g., blood draws). 
l  
ECGs collected on Day 1 before study drug dosing will be performed in triplicate.  
n 
Spirometry must be performed for all subjects before dosing and should be performed pre-bronchodilator (refer to Section 11.6.1). 
o 
Sweat collection will be done approximately at the same time as predose blood collections (refer to Section 11.1 and Section 11.6.2). 
p 
Any female subject who does not meet the criteria for non-childbearing potential (refer to Section 11.7.8.1) is considered to be of childbearing potential and must have a 
pregnancy test.  
q  
Refer to Section 11.7.2 for details.  


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Table 3-4 
Study VX15-661-113: Part B Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Day 1 
 
Day 15 
(± 3 days) 
Week 4 
(± 5 days) 
Week 8 
(± 5 days) 
Week 12 
(± 5 days) 
Week 16 
(± 5 days) 
Week 20 
(± 5 days) 
Week 24 
(± 5 days)b 
ETT Visitc 
Safety Follow-up 
Visit 
(4 weeks [± 7 days] 
after last dose)d 
Single PK samplingr 
 
 
Xs 
Xs 
 
 
 
 
 
 
Serial PK samplingt 
 
 
 
 
 
Xs 
 
 
 
 
Study drug count 
 
X 
X 
X 
 
X 
 
X 
 
 
Concomitant medications, treatments, 
and procedures 
Continuous from signing of ICF (and assent form, if applicable) through Safety Follow-up Visit 
AEs and SAEs 
Continuous from signing of ICF (and assent form, if applicable) through Safety Follow-up Visit 
Study Drug Administration 
VX-661 + IVAu 
VX-661 qd + IVA q12h 
 
 
 
AE: adverse event; BMI: body mass index; CF: cystic fibrosis; CFQ-R: CF Questionnaire-Revised; ECG: electrocardiogram; ETT: Early Treatment Termination; ICF: informed 
consent form; IVA: ivacaftor; 
; PK: pharmacokinetic; q12h: every 12 hours; SAE: serious adverse event 
 
r 
At the Week 4 and Week 8 Visits, PK blood samples will be collected before dosing. Blood samples collected before dosing must be collected within 60 minutes before 
dosing. 
s  
At the Week 16 Visit, subjects will fast for at least 2 hours after administration of the morning dose of study drug.  
t 
At the Week 16 Visit, PK blood samples will be collected before the morning dose and at 1, 2, 4, and 5 hours after the morning dose. Acceptable windows for sampling times 
are shown in Table 11-1. If study drug is not administered on the day of the visit (i.e., study drug interruption or permanent discontinuation of study drug), only 1 PK blood 
sample will be collected. 
u 
The study drug should be administered within 30 minutes after consuming a fat-containing meal or snack. Refer to Section 9.3 for details on study restrictions and 
Section 10.2 for details on study drug administration. On days of scheduled visits, the dose of study drug will be administered at the site after predose assessments have been 
completed. At the Week 24 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 24 Visit. 


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4 
TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
 
2 
Protocol Synopsis ............................................................................................................. 3 
3 
Schedule of Assessments.................................................................................................. 9 
4 
Table of Contents ........................................................................................................... 16 
List of Tables...................................................................................................................... 19 
List of Figures .................................................................................................................... 19 
5 
Introduction.................................................................................................................... 20 
5.1 
Background ............................................................................................................... 20 
5.2 
Study Rationale ........................................................................................................ 21 
6 
Study Objectives ............................................................................................................ 22 
6.1 
Primary Objectives ................................................................................................... 22 
6.2 
Secondary Objectives ............................................................................................... 22 
7 
Study Endpoints ............................................................................................................. 22 
7.1 
Primary Endpoints .................................................................................................... 22 
7.2 
Secondary Endpoints ................................................................................................ 23 
 
 
8 
Study Design ................................................................................................................... 24 
8.1 
Overview of Study Design ....................................................................................... 24 
8.1.1 
Screening .......................................................................................................... 26 
8.1.1.1 
Repetition of Screening Period Assessments ............................................. 26 
8.1.1.2 
Rescreening ................................................................................................ 27 
8.1.1.3 
Extension of Screening Period Window .................................................... 27 
8.1.2 
Treatment Period .............................................................................................. 27 
8.1.3 
Washout Period................................................................................................. 28 
8.1.4 
Safety Follow-up .............................................................................................. 28 
8.1.5 
Early Discontinuation/Early Treatment Termination ....................................... 28 
8.1.6 
Lost to Follow-up ............................................................................................. 29 
8.1.7 
Independent Data Monitoring Committee ........................................................ 29 
8.2 
Rationale for Study Design and Study Drug Regimens ........................................... 30 
8.2.1 
Study Design..................................................................................................... 30 
8.2.2 
Study Drug Dose and Duration ........................................................................ 30 
8.2.2.1 
VX-661 Dose ............................................................................................. 30 
8.2.2.2 
Ivacaftor Dose ............................................................................................ 31 
8.2.2.3 
Study Drug Duration .................................................................................. 31 
8.2.3 
Rationale for Study Assessments ..................................................................... 31 
9 
Study Population ............................................................................................................ 33 
9.1 
Inclusion Criteria ...................................................................................................... 33 
9.2 
Exclusion Criteria ..................................................................................................... 36 
9.3 
Study Restrictions ..................................................................................................... 38 
9.4 
Prior and Concomitant Medications ......................................................................... 40 
9.5 
Removal of Subjects ................................................................................................. 41 
9.6 
Replacement of Subjects .......................................................................................... 42 




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12.3.2 
Background Characteristics .............................................................................. 66 
12.3.2.1 Subject Disposition .................................................................................... 66 
12.3.2.2 Demographics and Baseline Characteristics .............................................. 67 
12.3.2.3 Prior and Concomitant Medications........................................................... 67 
12.3.2.4 Study Drug Exposure and Compliance ...................................................... 68 
12.3.3 
Efficacy Analysis .............................................................................................. 68 
12.3.3.1 Analysis of Primary Efficacy Variables ..................................................... 69 
12.3.3.2 Analysis of Secondary Efficacy Variables ................................................. 69 
12.3.4 
Safety Analysis ................................................................................................. 70 
12.3.4.1 Adverse Events........................................................................................... 71 
12.3.4.2 Clinical Laboratory Assessments ............................................................... 72 
12.3.4.3 Electrocardiogram ...................................................................................... 72 
12.3.4.4 Vital Signs .................................................................................................. 72 
12.3.4.5 Physical Examination ................................................................................. 73 
12.3.4.6 Other Safety Analysis ................................................................................ 73 
12.3.4.6.1 Pulse Oximetry .................................................................................... 73 
12.3.4.6.2 Ophthalmologic Examinations ............................................................ 73 
12.3.4.6.3 Spirometry ........................................................................................... 73 
12.3.5 
Interim and IDMC Analyses ............................................................................. 73 
12.3.5.1 Interim Analysis ......................................................................................... 73 
12.3.5.2 IDMC Analysis .......................................................................................... 74 
12.4 Clinical Pharmacology Analysis .............................................................................. 74 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ..................... 74 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting .................................................................................................................. 74 
13.1.1 
Adverse Events ................................................................................................. 74 
13.1.1.1 Definition of an Adverse Event.................................................................. 74 
13.1.1.2 Clinically Significant Assessments ............................................................ 74 
13.1.1.3 Documentation of Adverse Events............................................................. 75 
13.1.1.4 Adverse Event Severity .............................................................................. 75 
13.1.1.5 Adverse Event Causality ............................................................................ 76 
13.1.1.6 Study Drug Action Taken .......................................................................... 76 
13.1.1.7 Adverse Event Outcome ............................................................................ 77 
13.1.1.8 Treatment Given......................................................................................... 77 
13.1.2 
Serious Adverse Events .................................................................................... 77 
13.1.2.1 Definition of a Serious Adverse Event....................................................... 77 
13.1.2.2 Documentation of Serious Adverse Events................................................ 78 
13.1.2.3 Reporting Serious Adverse Events............................................................. 79 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ................................ 79 
13.2 Administrative Requirements ................................................................................... 79 
13.2.1 
Ethical Considerations ...................................................................................... 79 
13.2.2 
Subject Information and Informed Consent ..................................................... 79 
13.2.3 
Investigator Compliance ................................................................................... 79 
13.2.4 
Access to Records ............................................................................................. 80 
13.2.5 
Subject Privacy ................................................................................................. 80 


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13.2.6 
Record Retention .............................................................................................. 80 
13.2.7 
Study Termination ............................................................................................ 81 
13.3 Data Quality Assurance ............................................................................................ 81 
13.4 Monitoring ................................................................................................................ 81 
13.5 Electronic Data Capture ........................................................................................... 82 
13.6 Publications and Clinical Study Report .................................................................... 82 
 
 
13.6.2 
Clinical Study Report ....................................................................................... 83 
14 References ....................................................................................................................... 84 
15 Protocol Signature Pages .............................................................................................. 88 
15.1 Sponsor Signature Page ............................................................................................ 88 
15.2 Investigator Signature Page ...................................................................................... 89 
16 Appendix A: CFTR Allele Mutations .......................................................................... 90 
 
List of Tables 
Table 3-1 
Study VX15-661-113: Part A Screening .......................................................... 9 
Table 3-2 
Study VX15-661-113: Part A Treatment Period and Safety Follow-up Visit 10 
Table 3-3 
Study VX15-661-113: Part B Screening......................................................... 12 
Table 3-4 
Study VX15-661-113: Part B Treatment Period and Safety Follow-up Visit 13 
Table 9-1 
Lifestyle Guidelines and Study Restrictions (Part A) ..................................... 38 
Table 9-2 
Lifestyle Guidelines and Study Restrictions (Part B) ..................................... 40 
Table 10-1 
Study Drug Administration ............................................................................. 43 
Table 10-2 
Study Drug Administration ............................................................................. 44 
Table 10-3 
Study Drug ...................................................................................................... 46 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows .......................................... 49 
Table 11-2 
Safety Laboratory Test Panels ........................................................................ 55 
Table 11-3 
Acceptable Methods of Contraception............................................................ 63 
Table 12-1 
Probability of Observing At Least 1 Subject With an AE in the Study if the 
AE Incidence (θ) is 5% and 10% .................................................................... 65 
Table 13-1 
Grading of AE Severity .................................................................................. 76 
Table 13-2 
Classifications for AE Causality ..................................................................... 76 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE ............ 77 
Table 13-4 
Classifications for Outcome of an AE ............................................................ 77 
List of Figures 
Figure 8-1 
Schematic of Study Design for Part A ............................................................ 25 
Figure 8-2 
Schematic of Study Design for Part B ............................................................ 26 
 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) affects an estimated 70,000 children and adults worldwide2 and is the 
most common fatal genetic disease in persons of European descent.3 Based on the size of the 
population, CF qualifies as an orphan disease.4,5 Despite progress in the treatment of CF with 
antibiotics and mucolytics, the predicted median age of survival for a person with CF is 
approximately 40 years.3,6 Although the disease affects multiple organs, most morbidity and 
mortality are caused by progressive loss of lung function.7 
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.3 This function is 
defective in patients with CF due to a loss of either cell surface expression and/or function. 
More than 1900 mutations in the CFTR gene have been identified.8 Mutations in the CFTR 
gene have been classified based on the molecular and functional consequence of the mutation 
on the CFTR protein9,10,11 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).11 In the US, almost 87% 
of patients with CF have at least 1 copy of the F508del-CFTR mutation and about 47% have 
2 copies.12 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.13 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.14,15 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.16 


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Two complementary approaches to increase CFTR-mediated Cl- secretion in the airway 
epithelia have been studied.10 One approach is to treat with a compound that will modify the 
cellular processing and trafficking of the CFTR protein to increase the amount of functional 
CFTR at the cell surface. This kind of compound has been termed a CFTR corrector. Another 
approach is to treat with a compound that increases the 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 proper maintenance of airway hydration. Adequate 
airway hydration could alleviate the cycle of mucus plugging, infection, and inflammation, 
which leads to irreversible structural changes in the lungs and, eventually, respiratory failure 
for patients with CF. 
VX-661 is a CFTR corrector that works by facilitating the processing and trafficking of 
F508del-CFTR and other mutant CFTR forms, thereby increasing the amount of functional 
CFTR protein at the cell surface, resulting in enhanced chloride transport.17 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.17 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).18 
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.  
Kalydeco (ivacaftor) is indicated for the treatment of CF in patients as young as 2 years of 
age who have 1 of the following mutations in the CFTR gene: G551D, G1244E, G1349D, 
G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H. Please refer to the ivacaftor 
Investigator's Brochure19 and local prescribing information or summary of product 
characteristics for your region for the current approved use of Kalydeco. 
Details about the VX-661 and ivacaftor development programs can be found in the 
Investigator's Brochures.19,2021,22  
5.2 
Study Rationale  
Vertex is currently evaluating VX-661 and ivacaftor combination therapy in subjects aged 
12 years and older with CF who are homozygous or heterozygous for the F508del-CFTR 


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mutation in 4 Phase 3 studies (Studies VX14-661-106, VX14-661-107, VX14-661-108, and 
VX14-661-109). The present study is designed to obtain pharmacokinetic (PK), safety, and 
tolerability information in the pediatric population (subjects 6 through 11 years of age) to 
expand the evaluation of VX-661 and ivacaftor combination therapy in subjects 6 through 
11 years of age who are homozygous or heterozygous for the F508del-CFTR mutation. 
Efficacy will also be evaluated in Part B of this study. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
Part A  
To evaluate the PK of VX-661 and ivacaftor after administration of multiple doses of 
VX-661 in combination with ivacaftor 
Part B 
To evaluate the safety and tolerability of VX-661 in combination with ivacaftor through 
Week 24 
6.2 
Secondary Objectives 
Part A  
• To evaluate the PK of VX-661 metabolites, M1-661 and M2-661, and ivacaftor 
metabolites, M1-ivacaftor and M6-ivacaftor, after administration of multiple doses of 
VX-661 in combination with ivacaftor 
• To evaluate the safety and tolerability of multiple doses of VX-661 in combination with 
ivacaftor  
Part B 
• To evaluate the PK of VX-661, M1-661, M2-661, ivacaftor, M1-ivacaftor, and 
M6-ivacaftor after administration of multiple doses of VX-661 in combination with 
ivacaftor 
• To evaluate the efficacy of VX-661 in combination with ivacaftor through Week 24 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoints 
Part A  
VX-661 and ivacaftor PK parameters, including maximum observed concentration (Cmax), 
area under the concentration versus time curve during a dosing interval (AUCτ), and other 
PK parameters as appropriate 


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Part B 
Safety and tolerability of VX-661 in combination with ivacaftor as determined by adverse 
events (AEs), clinical laboratory values (serum chemistry, hematology, coagulation studies, 
lipids, vitamins, and urinalysis), standard 12-lead electrocardiograms (ECGs), vital signs, 
pulse oximetry, ophthalmologic examinations, and spirometry 
7.2 
Secondary Endpoints 
Part A  
• M1-661, M2-661, M1-ivacaftor, and M6-ivacaftor PK parameters, including Cmax, AUCτ, 
and other PK parameters as appropriate 
• Safety and tolerability of VX-661 in combination with ivacaftor as determined by AEs, 
clinical laboratory values (serum chemistry, hematology, coagulation studies, lipids, 
vitamins, and urinalysis), standard 12-lead ECGs, vital signs, pulse oximetry, and 
spirometry 
Part B  
• VX-661, M1-661, M2-661, ivacaftor, M1-ivacaftor, and M6-ivacaftor PK parameters, 
including Cmax, AUCτ, and other PK parameters as appropriate 
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
from baseline through Week 24 
• Relative change in ppFEV1 from baseline through Week 24 
• Absolute change in weight and weight-for-age z-score from baseline at Week 24 
• Absolute change in height and height-for-age z-score from baseline at Week 24 
• Absolute change in body mass index (BMI) and BMI-for-age z-score from baseline at 
Week 24 
• Absolute change in sweat chloride from baseline through Week 4 
• Absolute change in sweat chloride from baseline through Week 24  
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain 
score from baseline through Week 24 


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8 
STUDY DESIGN 
8.1 
Overview of Study Design 
This is a Phase 3, 2-part (Part A and Part B), open-label, multicenter study evaluating the PK, 
safety, and tolerability of multiple doses of VX-661 in combination with ivacaftor in subjects 
6 through 11 years of age with CF who are homozygous or heterozygous for the 
F508del-CFTR mutation. Efficacy will also be evaluated in Part B. Part A is composed of 
2 weight-based cohorts, which will be enrolled simultaneously, and Part B is composed of a 
single cohort. Subjects who participate in Part A may participate in Part B if Part B eligibility 
criteria are met. 
Part A 
Up to approximately 16 subjects total are planned for enrollment across Cohort 1 (subjects 
weighing <25 kg at baseline) and Cohort 2 (subjects weighing ≥25 kg at baseline).  
Part A includes the following: 
• Screening Period (Day -28 through Day -1) 
• Treatment Period (Day 1 through Day 14) 
• Washout Period (Day 14 to Day 28 [± 3 days]) 
• Safety Follow-up Visit (14 [± 3] days after the last dose of study drug) 
Figure 8-1 depicts the schematic for the Part A study design. After obtaining written 
informed consent (and assent, if applicable), Screening Visit assessments will be completed 
at any time during the period of 4 weeks (Day -28 through Day -1) before the first dose of the 
study drug (Day 1). During the Treatment Period, subjects will be administered VX-661 
50 mg daily (qd) in combination with ivacaftor, either 75 mg (subjects <25 kg at baseline) or 
150 mg (subjects ≥25 kg at baseline), every 12 hours (q12h) for 14 days. A 2-week Washout 
Period (Day 14 to Day 28 [± 3 days]) will be included in order to evaluate the off-drug 
response. A Safety Follow-up Visit is scheduled to occur 14 (± 3) days after the last dose of 
study drug for all subjects, including subjects who permanently discontinue from study 
treatment for any reason. 
A review of safety, tolerability, and PK data will be completed by an internal Vertex team 
after Part A to select the VX-661 dose for Part B.  


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Figure 8-1 
Schematic of Study Design for Part A 
 
Part B 
Approximately 56 subjects are planned for enrollment. Assuming a 10% dropout rate, 
approximately 50 subjects are expected to complete Part B.  
Part B includes the following: 
• Screening Period (Day -28 through Day -1) 
• Treatment Period (Day 1 through Week 24 [± 5 days]) 
• Safety Follow-up Visit (4 weeks [± 7 days] after the last dose of study drug) 
Figure 8-2 depicts the schematic for the Part B study design. After obtaining written 
informed consent (and assent, if applicable), Screening Visit assessments will be completed 
at any time during the period of 4 weeks (Day -28 through Day -1) before the first dose of 
study drug (Day 1). During the Treatment Period, subjects will be administered VX-661 
50 mg qd in combination with ivacaftor 75 mg q12h (subjects <40 kg at baseline) or VX-661 
100 mg qd in combination with ivacaftor 150 mg q12h (subjects ≥40 kg at baseline) for 
24 weeks. No dose adjustments will be made throughout the duration of treatment in this 
study. At the Week 24 Visit, subjects who complete study drug treatment will be offered the 
opportunity to enroll in an extension study evaluating VX-661 in combination with ivacaftor 
(enrollment will be based on the eligibility criteria specified within the extension study). 
Subjects who prematurely discontinue study drug treatment are not eligible to rollover into 
the extension study. 
A Safety Follow-up Visit is scheduled to occur 4 weeks (± 7 days) after the last dose of study 
drug. The Safety Follow-up Visit is not required for subjects who have enrolled in the 


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extension study within 28 days after the last dose of study drug. Subjects who permanently 
discontinue study drug treatment will have an Early Treatment Termination (ETT) Visit and 
a Safety Follow-up Visit. 
Figure 8-2 
Schematic of Study Design for Part B 
 
8.1.1 
Screening 
Part A and Part B 
Screening Visit assessments are listed in Table 3-1 (Part A) and Table 3-3 (Part B). 
The Screening Period will occur within 28 days before the first dose of study drug to confirm 
that subjects meet the selection criteria for the study. To participate in the study, the subject's 
parent or legal guardian must sign and date a study-specific informed consent form (ICF) and 
the subject must sign an assent form (if applicable) before any study-specific procedures can 
be performed. The ICF (and assent form, if applicable) will comply with all applicable 
regulations governing the protection of human subjects and will be approved by Vertex and 
the site's institutional review board (IRB). 
To prepare for study participation, subjects will be instructed on the Study Restrictions 
(Section 9.3) and use of concomitant medications (Section 9.4). 
8.1.1.1 
Repetition of Screening Period Assessments 
Part A and Part B  
Repetition of any individual Screening Visit assessment(s) that do not meet eligibility criteria 
is not permitted, with the following exceptions:  
• If there is clear evidence of a laboratory error (e.g., hemolyzed sample) or equipment 
malfunction, collection of a repeat sample for the appropriate laboratory test may be 
permitted after discussion with the Vertex medical monitor or authorized designee. 


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• If a convincing alternative etiology is identified for elevated transaminases, exclusionary 
liver function test (LFT) levels may be retested within 14 days of the original Screening 
Visit date. 
If repeat values of the individual assessment(s) are within the eligibility criteria and 
completed within the Screening Period window, then the subject is eligible for the study. 
8.1.1.2 
Rescreening 
Part A and Part B  
Subjects may be rescreened after discussion with, and approval from, the Vertex medical 
monitor or authorized designee to account for exclusionary events that may not reflect the 
subject’s true baseline due to an acute event, which may resolve. Subjects who complete 
Part A or who discontinue treatment for other reasons than safety reasons and wish to 
participate in Part B, must be rescreened and meet all eligibility criteria before enrolling in 
Part B. Subjects who were not eligible to participate in Part A may be rescreened for Part B 
after discussion with, and approval from, the Vertex medical monitor or authorized designee. 
If a subject is rescreened, all Screening Visit assessments will be repeated except for CF 
genotyping and the ophthalmologic examination (if the ophthalmologic examination was 
performed within 3 months before the Rescreening Visit). If a subject is rescreened, the 
screening window will begin after the first rescreening assessment has been initiated. 
8.1.1.3 
Extension of Screening Period Window 
Part A and Part B 
A subject may have the Screening Period window extended by 2 weeks after approval by the 
medical monitor or authorized designee for the following reasons: 
• Repetition of the Screening Period assessments (Section 8.1.1.1) 
• Unexpected operational or logistic delays, or to meet the eligibility criteria 
• Scheduling of the ophthalmologic examination (Section 11.7.6) 
8.1.2 
Treatment Period 
Part A and Part B  
Study drug will be dispensed to the subject’s legally appointed and authorized representative 
(e.g., parent or legal guardian) for administration to the study subjects on study days where a 
clinic visit is not scheduled, as described in Section 10.1. 
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled visit, the Vertex medical monitor or authorized designee will be notified, and the 
investigator will make every effort to arrange follow-up evaluations at appropriate intervals 
to document the course of the abnormalities. 
Part A  
Table 3-2 lists the Treatment Period Visits and assessments for Part A. Subjects will be 
outpatients during the Treatment Period. All visits should occur within the windows 
specified. 


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The duration of the Treatment Period is 14 days. The first dose of the study drug will be 
administered on Day 1, and the last dose of study drug will be the morning dose administered 
on Day 14 (Figure 8-1). Dosing details are given in Section 10.2. Subjects must return to the 
clinical site on Day 21 for PK assessments (Table 3-2). 
Subjects who prematurely discontinue study drug dosing will be asked to return to the 
clinical site for a Safety Follow-up Visit (Section 8.1.5). 
Part B 
Table 3-4 lists the Treatment Period visits and assessments for Part B. Subjects will be 
outpatients during the Treatment Period. All visits should occur within the windows 
specified. 
The planned duration of the Treatment Period is 24 weeks. The first dose of the study drug 
will be administered on Day 1 and the last dose of study drug will be the evening dose 
administered the day before the Week 24 Visit. Dosing details are given in Section 10.2. 
8.1.3 
Washout Period 
Part A 
A 2-week Washout Period (Day 14 to Day 28 ± 3 days) will be included in order to evaluate 
the off-drug response. 
Part B 
Not applicable  
8.1.4 
Safety Follow-up 
Part A  
Table 3-2 lists the Safety Follow-up Visit assessments for Part A. Subjects will have a Safety 
Follow-up Visit 14 (± 3) days after the last dose of study drug.  
Part B 
Table 3-4 lists the Safety Follow-up Visit assessments for Part B. Subjects will have a Safety 
Follow-up Visit 4 weeks (± 7 days) after the last dose of study drug. The Safety Follow-up 
Visit is not required for subjects who have enrolled in the extension study within 28 days 
after the last dose of study drug.  
8.1.5 
Early Discontinuation/Early Treatment Termination  
Part A  
Subjects who prematurely discontinue study drug dosing will be asked to return to the 
clinical site 14 (± 3) days after their last dose of study drug for a Safety Follow-up Visit. 
Safety Follow-up Visit assessments are listed in Table 3-2. 
Part B 
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. Subjects who 
prematurely discontinue treatment will also be required to complete the Safety Follow-up 


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Visit, approximately 4 weeks ± 7 days after their last dose of study drug. The assessments 
performed at the Safety Follow-up Visit are listed in Table 3-4. 
If the ETT Visit occurs 3 weeks or later after the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required.  
During the course of study conduct, if local health authorities decline to approve, or if 
clinical benefit is not demonstrated for the use of VX-661 in combination with ivacaftor for 
the treatment of CF in a corresponding adult population, pediatric subjects with the relevant 
CFTR genotypes may be discontinued after communication to investigators and IRBs/ 
independent ethics committees (IECs) of the risks/benefits related to the safety and efficacy 
observed for the subset of adult subjects. If subjects are discontinued from the study, an ETT 
Visit should occur as soon as possible after the last dose of study drug and a Safety 
Follow-up Visit should occur approximately 4 weeks ± 7 days after the last dose of study 
drug. 
If the subject withdraws consent for the study no further evaluations should be performed, 
and no additional data should be collected. Vertex may retain and continue to use any data 
collected before such withdrawal of consent. 
8.1.6 
Lost to Follow-up 
Part A and Part B 
A subject will be considered lost to follow-up if both of the following occur: 
• 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 after the second missed visit). 
• Subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 
8.1.7 
Independent Data Monitoring Committee 
Part A 
An independent data monitoring committee (IDMC) will be formed using the 
 
 (Section 12.3.5.2). The IDMC objectives and 
operational details will be defined in a separate document (the IDMC Charter), which will be 
finalized before the first subject is screened in Part B. The IDMC will conduct a planned 
review of study data for the purpose of safety monitoring as outlined in the IDMC Charter. 
Part B 
The IDMC objectives and operational details will be defined in a separate document (IDMC 
Charter), which will be finalized before the first subject is screened. The IDMC will conduct 
regular planned reviews of study data for the purpose of safety monitoring as outlined in the 
IDMC Charter. 


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8.2 
Rationale for Study Design and Study Drug Regimens 
8.2.1 
Study Design 
This is a Phase 3, 2-part (Part A and Part B), open-label, multicenter study evaluating the PK, 
safety, and tolerability of multiple doses of VX-661 in combination with ivacaftor in subjects 
6 through 11 years of age with CF who are homozygous or heterozygous for the 
F508del-CFTR mutation. Efficacy will also be evaluated in Part B. Part A is composed of 
2 cohorts and Part B is composed of a single cohort. The open-label design is considered 
adequate to evaluate the PK and safety of VX-661 in combination with ivacaftor in this 
pediatric population. Subjects will be divided into 2 weight-based cohorts in Part A so that 
the relationship between VX-661 PK and body weight can be explored across the entire 
weight range expected in the 6 to 11 year old population.  
The subjects studied are from the population that is expected to benefit from VX-661 in 
combination with ivacaftor. Part B is designed to evaluate the long term safety, tolerability, 
and PK, as well as efficacy, of VX-661 in combination with ivacaftor in the pediatric CF 
population. This design is in harmony with guidelines for the study of human subjects, 
especially children, and balances safety concerns with potential benefits for the individual. 
8.2.2 
Study Drug Dose and Duration 
8.2.2.1 
VX-661 Dose 
Part A 
The 50 mg qd dose of VX-661 has been selected for evaluation in pediatric subjects 
6 through 11 years of age in Part A of this study. A population PK model was used to 
simulate VX-661 exposure in subjects weighing 15 to 40 kg to represent the pediatric 
population in this study. The simulations indicate that a 50 mg qd dose in subjects weighing 
15 to 25 kg and 25 to 40 kg will yield exposures comparable or lower to those observed at 
the 100 mg qd dose in adults, which has been demonstrated to be safe and efficacious. 
Therefore, the dose selected for Part A is expected to be safe in pediatric subjects 6 through 
11 years of age. 
Part B 
A review of safety, tolerability, and PK data was completed by an internal Vertex team after 
Part A to select the VX-661 dose for Part B. The PK data in Part A were consistent with the 
predictions from the population PK model. Consequently, this model was used to simulate 
exposures for different VX-661 doses in weight ranges expected for subjects 6 through 
11 years of age. Based on these simulations, VX-661 doses of 50 mg qd in subjects weighing 
<40 kg and 100 mg qd in subjects weighing >40 kg were selected for Part B to match the 
exposures observed at the dose of 100 mg qd in subjects 12 years and older. These exposures 
were shown to be safe and efficacious in Phase 2 and Phase 3 clinical studies 
(VX11-661-101, VX13-661-103, VX14-661-106, and VX14-661-108). 


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8.2.2.2 
Ivacaftor Dose 
Part A  
Ivacaftor doses have been selected to provide similar exposures to those observed at the 
efficacious dose in adults. Based on population PK simulations, an ivacaftor dose of 
75 mg q12h in subjects 6 through 11 years of age weighing <25 kg and a dose of 
150 mg q12h in subjects 6 through 11 years of age weighing ≥25 kg is expected to yield 
similar exposures to those observed in adults administered 150 mg q12h.  
Therefore, the ivacaftor doses chosen for the pediatric population in this study (6 through 
11 years of age) are: 
• 75 mg q12h in subjects <25 kg at baseline 
• 150 mg q12h in subjects ≥25 kg at baseline 
Part B 
For Part B, it was desired to provide similar IVA exposures to those observed at the 
efficacious dose in adults while maintaining the same TEZ:IVA ratio in adult and pediatric 
populations. Following review of the safety, tolerability, and PK data from Part A, additional 
population PK simulations of IVA were performed to evaluate the impact on IVA exposures 
of increasing the weight cutoff from 25 kg to 40 kg to maintain consistency with TEZ dosing 
and the adult TEZ:IVA ratio. As expected, these simulations demonstrated that lowering the 
IVA dose from 150 mg q12h to 75 mg q12h in subjects weighing between 25 kg and 40 kg 
lowered predicted IVA exposures. However, IVA exposures were similar to those observed 
at the efficacious dose in adults. Additionally, the majority of subjects still achieved IVA 
exposures exceeding the model-predicted EC90 calculated for ppFEV1 in the G551D gating 
population. 23  Given that the IVA EC90 for G551D exceeds that for F508del and other 
mutations that are responsive to IVA in vitro (that is, these same exposures are predicted to 
exceed the EC90 for these mutations by even more than for G551D) 24, increasing the IVA 
weight cut off from 25 kg to 40 kg is not predicted to  impact efficacy. 
8.2.2.3 
Study Drug Duration 
Part A 
Based on the PK of VX-661 and ivacaftor in adults, dosing for 14 days in Part A is 
considered sufficient to achieve steady-state exposures of VX-661, ivacaftor, and their 
metabolites. 
Part B 
The 24-week duration of dosing in Part B was chosen to provide an adequate assessment of 
long-term safety. 
8.2.3 
Rationale for Study Assessments 
The safety and PK assessments are standard parameters for clinical studies in drug 
development and are generally recognized as reliable, accurate, and relevant to the study of 
subjects with CF. Ophthalmologic examinations were added to the standard safety 
assessments. 


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Ophthalmologic Examinations: A juvenile rat toxicity study performed to support dosing of 
ivacaftor in subjects <2 years of age demonstrated lens opacities in some animals.19 Prior 
studies in rats and dogs of older age did not demonstrate similar findings. Given substantial 
differences between human and rat lens development, the finding is of unlikely relevance to 
humans. Periodic ophthalmologic examinations for children aged 11 years and younger 
receiving ivacaftor are being performed to confirm this interpretation. The overall data 
acquired to-date does not suggest an association between ivacaftor treatment and cataract 
development; however, a potential association has not been fully excluded. 
Spirometry: Since 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 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 
determined. 
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.  
Sweat Chloride: In patients with CF, the underlying CFTR ion transport defect results in 
elevated sweat electrolyte levels.25,26 The sweat chloride test (quantitative pilocarpine 
iontophoresis) is the most common diagnostic tool for CF. A sweat chloride concentration of 
≥60 mmol/L is considered to be diagnostic of CF, whereas <40 mmol/L is considered 
normal. Based on the mechanisms of action of VX-661 and ivacaftor, the sweat chloride test 
was included in this study as a measure of the effect of VX-661 in combination with 
ivacaftor on CFTR activity. 
CFQ-R: The CFQ-R is a frequently used CF-specific instrument that measures the 
health-related quality of life of patients with CF.27,28,29 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-R30,31 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. 


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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 Part A and 
Part B. Subjects who participate in Part A may participate in Part B if Part B eligibility 
criteria are met. 
1. Subject (or his or her legally appointed and authorized representative) will sign and date 
an ICF and the subject will sign and date an assent form (if applicable) (separately for 
Part A and Part B). 
2. Subjects (male and female) will be between the ages of 6 and 11 years, inclusive, on the 
date(s) of informed consent (and assent, if applicable) for each relevant part of the study 
(Part A and/or Part B, as applicable). 
3. Subjects who weigh ≥15 kg without shoes at the Screening Visit.  
4. All genotypes listed in Section 16 are eligible in Part A. Each genotype for which 
clinical benefit has been demonstrated in the corresponding adult population will be 
eligible in Part B. Genotype is to be confirmed at the Screening Visit. If the CFTR 
screening genotype result is not received before enrollment, a previous CFTR genotype 
lab report may be used to establish eligibility. Subjects who have been enrolled and 
whose screening genotype does not confirm study eligibility must be discontinued from 
the study as described in Section 9.5. 
Subjects with a confirmed diagnosis of CF37 (as determined by meeting 1 of the following 
criteria [5 through 8]): 
5. For subjects who are homozygous for the F508del-CFTR mutation 
a. Confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by 
quantitative pilocarpine iontophoresis (as documented in the subject’s medical record 
OR from the sweat chloride test result obtained at the Screening Visit). 
6. For subjects who are heterozygous for the F508del-CFTR mutation and with a second 
CFTR mutation that is not likely to respond to VX-661 and/or ivacaftor therapy (refer to 
Section 16). Subjects with these mutations are not eligible for Part B. 


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a. Confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by 
quantitative pilocarpine iontophoresis (as documented in the subject’s medical record 
OR from the sweat chloride test result obtained at the Screening Visit). 
7. For subjects who are heterozygous for the F508del-CFTR mutation and with a second 
allele with a CFTR mutation predicted to have residual function (refer to Section 16)  
a. Confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by 
quantitative pilocarpine iontophoresis (as documented in the subject’s medical record 
OR from the sweat chloride test result obtained at the Screening Visit). 
b. If the sweat chloride value is <60 mmol/L, there must be documented evidence of 
chronic sinopulmonary disease37 and/or gastrointestinal disease consistent with a 
diagnosis of CF as judged by the principal investigator, manifest by at least 1 of the 
following: 
• Persistent colonization/infection, defined as ≥2 positive respiratory cultures 
within a 6 month period, with 1 or more typical CF pathogens 
(e.g., Staphylococcus aureus, Haemophilus influenzae, mucoid and nonmucoid 
Pseudomonas aeruginosa) 
• Chronic cough and sputum production 
• Persistent chest radiograph abnormalities consistent with CF pulmonary disease 
(e.g., bronchiectasis, atelectasis, infiltrates, hyperinflation) 
• Nasal polyps, chronic sinusitis as manifest by radiographic or computed 
tomographic abnormalities of the paranasal sinuses 
• Evidence of gastrointestinal disease consistent with the diagnosis of CF 
• Significant delays in growth and/or weight gain consistent with the diagnosis of 
CF 
If it is unclear whether a subject meets this criterion, please consult with the medical 
monitor prior to enrollment. 
8. For subjects who are heterozygous for the F508del-CFTR mutation and with a second 
CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive 
(refer to Section 16) 


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a. Confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by 
quantitative pilocarpine iontophoresis (as documented in the subject’s medical record 
[this value may be obtained from a record collected prior to use of Kalydeco] OR 
from the sweat chloride test result obtained at the Screening Visit). 
b. If the sweat chloride value is <60 mmol/L, there must be documented evidence of 
chronic sinopulmonary disease37 and/or gastrointestinal disease consistent with a 
diagnosis of CF as judged by the principal investigator, manifest by at least 1 of the 
following: 
• Persistent colonization/infection, defined as ≥2 positive respiratory cultures 
within a 6 month period, with 1 or more typical CF pathogens 
(e.g., Staphylococcus aureus, Haemophilus influenzae, mucoid and nonmucoid 
Pseudomonas aeruginosa) 
• Chronic cough and sputum production 
• Persistent chest radiograph abnormalities consistent with CF pulmonary disease 
(e.g., bronchiectasis, atelectasis, infiltrates, hyperinflation) 
• Nasal polyps, chronic sinusitis as manifest by radiographic or computed 
tomographic abnormalities of the paranasal sinuses 
• Evidence of gastrointestinal disease consistent with the diagnosis of CF 
• Significant delays in growth and/or weight gain consistent with the diagnosis of 
CF 
If it is unclear whether a subject meets this criterion, please consult with the medical 
monitor prior to enrollment. 
9. Subjects with ppFEV1 of ≥40 percentage points adjusted for age, sex, height, and 
ethnicity using the Global Lung Initiative (GLI) equation38 at the Screening Visit 
(Section 11.6.1).  
10. Subjects with stable CF disease as deemed by the investigator at the Screening Visit. 
11. Subjects who are willing to remain on their stable CF medication regimen through 
Day 14 (Part A) or through Week 24 (Part B) or, if applicable, through the Safety 
Follow-up Visit. 
12. Subjects who are able to swallow tablets.  
13. Female subjects of childbearing potential must have a negative serum pregnancy test at 
the Screening Visit and a negative urine pregnancy test at the Day 1 Visit before 
receiving the first dose of study drug. 
14. Subjects of childbearing potential who are sexually active must meet the contraception 
requirements outlined in Section 11.7.8.1.  
15. As deemed by the investigator, the subject’s legally appointed and authorized 
representative (e.g., parent or legal guardian) must be able to understand protocol 
requirements, restrictions, and instructions. The subject’s legally appointed and 


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authorized representative should be able to ensure that the subject will comply with and is 
likely to complete the study as planned. 
9.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible for Part A and 
Part B. 
1. History of any comorbidity reviewed at the Screening Visit 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 
• history of risk factors for Torsades de Pointes 
ο 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, 
intracranial trauma), and autonomic neuropathy 
2. Any clinically significant laboratory abnormalities at the Screening Visit that would 
interfere with the study assessments or pose an undue risk for the subject (as deemed by 
the investigator). 
3. Any of the following abnormal laboratory values at the Screening Visit: 
• Hemoglobin <10 g/dL 
• Abnormal liver function defined as any 2 or more of the following:  
o ≥3 × upper limit of normal (ULN) aspartate aminotransferase (AST)  
o ≥3 × ULN alanine aminotransferase (ALT)  
o ≥3 × ULN gamma-glutamyl transpeptidase (GGT) 
o ≥3 × ULN alkaline phosphatase  
o ≥2 × ULN total bilirubin 
• Abnormal liver function defined as any increase of ≥5 × ULN ALT or AST 
• Abnormal renal function defined as glomerular filtration rate ≤45 mL/min/1.73 m2 
(calculated by the Counahan-Barratt equation)39  
4. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in 
therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first 
dose of study drug). 
5. Colonization with organisms associated with a more rapid decline in pulmonary status 
(e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus) at 
the Screening Visit. The investigator could be guided by the following suggested criteria 
for a subject to be considered free of colonization:  


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• The subject should have had at least 2 respiratory tract cultures negative for these 
organisms within the past 12 months, with no subsequent positive cultures. 
• These 2 respiratory tract cultures should have been separated by at least 3 months. 
• One of these 2 respiratory tract cultures should have been obtained within the past 
6 months. 
6. A standard 12-lead ECG demonstrating QTc >450 msec at the Screening Visit. If QTc 
exceeds 450 msec at the Screening Visit, the ECG should be repeated 2 more times 
during the Screening Period, and the average of the 3 QTc values should be used to 
determine the subject's eligibility. 
7. History of solid organ or hematological transplantation at the Screening Visit. 
8. Ongoing or prior participation in an investigational drug study or use of commercially 
available CFTR modulator that does not align with the following requirements: 
• A washout period of 30 days or 5 terminal half-lives of the previous investigational 
study drug, whichever is longer, must elapse before screening. 
o The duration of the elapsed time may be longer if required by local regulations.  
• A washout period of 28 days for investigational lumacaftor/ivacaftor or 
physician-prescribed Orkambi must elapse before the Day 1 Visit.  
• Investigational ivacaftor or physician-prescribed Kalydeco can be taken until the 
Day 1 Visit, at which time ivacaftor will be dispensed from the investigational study 
drug supply. 
Note: Ongoing participation in a noninterventional study (including observational 
studies) is permitted. 
9. Use of restricted medication or food within a specified duration before the Screening 
Visit or first dose of study drug and/or unwillingness to maintain the restrictions as 
defined in Table 9-1 (Part A) or Table 9-2 (Part B).  
10. History or evidence of cataract, lens opacity, Y-suture, or lamellar rings determined to be 
clinically significant by the ophthalmologist during the ophthalmologic examination at 
the Screening Visit. The Screening Visit ophthalmologic examination does not need to be 
repeated if there is documentation of an examination meeting protocol criteria 
(Section 11.7.6) that was conducted within 3 months before the start of the Screening 
Period. If the subject has documentation of bilateral lens removal, an ophthalmologic 
examination is not required and this criterion is not applicable.  
11. Pregnant and nursing females. 
12. The subject or a close relative of the subject is the investigator or a subinvestigator, 
research assistant, pharmacist, study coordinator, or other staff directly involved with the 
conduct of the study. 


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9.3 
Study Restrictions 
Part A 
To avoid variable PK results because of uncontrolled use of dietary/nutritional supplements, 
tobacco, juices, or other foods that may affect drug metabolizing enzymes and transporters, it 
is important to exclude subjects who do not meet or cannot comply with the lifestyle 
guidelines and study restrictions summarized in Table 9-1. 
Table 9-1 
Lifestyle Guidelines and Study Restrictions (Part A) 
Restricted 
Medication/Food/ 
Activitya 
Timing of Restriction 
From (Minimum) 
To 
Investigational (from 
another study) or 
physician-prescribed 
Kalydeco 
Day 1 
Until last dose of study drug  
Investigational or 
physician-prescribed 
Orkambi (LUM/IVA) 
None allowed within 28 days before 
the Day 1 Visit 
Completion of Safety Follow-up 
assessments 
Other investigational 
drugs or devices  
30 days or 5 half-lives before 
screening, or time determined by local 
requirements; whichever is longer 
Completion of Safety Follow-up 
assessments 
Moderate and strong 
CYP3A inducers 
None allowed within 14 days before 
the first dose of the study drug 
Until last PK sample is taken 
Strong and moderate 
CYP3A inhibitors (except 
Ciprofloxacin) 
None allowed within 14 days before 
the first dose of the study drug 
Until last PK sample is taken 
Nonprescription 
medications 
14 days or 5 half-lives (whichever is 
longer) before first study drug dose  
 
Occasional, limited ibuprofen 
(≤1200 mg/day) and acetaminophen at 
doses of ≤2 g/day is allowed for pain. 
Completion of Safety Follow-up 
assessments 
Herbal and dietary 
supplements  
14 days before first study drug dose 
Completion of Safety Follow-up 
assessments 
Tobacco or 
nicotine-containing 
product 
45 days before first study drug dose 
Until last PK sample is taken 
Grapefruit or grapefruit 
juice, pomelos, star fruit, 
Seville oranges or Seville 
orange juice 
7 days before first study drug dose 
Until last PK sample is taken 
Orange juice, vegetables 
from the mustard green 
family (e.g., kale, 
broccoli, watercress, 
collard greens, kohlrabi, 
brussels sprouts, mustard), 
and charbroiled meats 
7 days before first study drug dose  
Until last PK sample is taken 


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Table 9-1 
Lifestyle Guidelines and Study Restrictions (Part A) 
Restricted 
Medication/Food/ 
Activitya 
Timing of Restriction 
From (Minimum) 
To 
Alcoholb 
Not more than 2 drinks/day before 
screening AND none 48 hours before 
first study drug dosec 
Completion of Safety Follow-Up 
assessments 
Caffeine 
An average of no more than five 
240 mL servings per day of coffee or 
other caffeinated beverages per day 
beginning at screening AND none 
24 hours before first study drug dose 
Until last PK sample is taken  
Strenuous exercise 
(e.g., heavy lifting, weight 
training, and aerobics)d 
• 
24 hours before the Screening 
Visit 
• 
24 hours before Day 1 
• 
24 hours before Day 7 
• 
24 hours before Day 14 
• 
24 hours before Safety Follow-up 
Visit 
• 
Not applicable 
• 
After end of the Day 2 Visit 
• 
After end of the Day 7 Visit 
• 
After end of the Day 14 Visit 
• 
After the Safety Follow-up Visit 
CFTR: cystic fibrosis transmembrane conductance regulator; CYP: cytochrome P450; IVA: ivacaftor; 
LUM: lumacaftor; PK: pharmacokinetic. 
Note: The use of restricted medication in subjects with a medical need will be addressed on a case-by-case basis 
with the medical monitor or authorized designee. See the Study Reference Manual for a more complete list of 
medications prohibited/restricted in the study. 
a 
Refer Section 9.4 for guidance for concomitant medications. 
b 
Subjects may undergo alcohol testing if deemed appropriate by the investigator (Section 11.7.2). 
c 
One drink equals 5 ounces/150 mL of wine, 12 ounces/360 mL of beer, or 1.5 ounces/45 mL of hard liquor. 
d 
Walking at a normal pace will be permitted. 
Detailed restrictions for fluid and food intake during study drug administration are presented 
in Section 10.2. 
Part B 
Prohibited medications and certain foods are not allowed in Part B (Screening Period through 
Week 24) as summarized in Table 9-2. Both VX-661 and ivacaftor are metabolized 
predominantly via the hepatic enzymatic pathway using CYP3A4. Therefore, the use of 
known inducers and inhibitors of CYP3A, which have the potential to significantly alter the 
exposure of VX-661 and ivacaftor, will be restricted in this study. 


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Table 9-2 
Lifestyle Guidelines and Study Restrictions (Part B) 
Restricted Medication/Food 
Study Period 
Screening Period 
Treatment 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 
None allowed through the Safety 
Follow-up Visit 
Moderate and strong CYP3A 
inducers 
None allowed within 14 days before 
the first dose of the study drug 
None allowed through the Safety 
Follow-up Visit 
Strong and moderate CYP3A 
inhibitors (except Ciprofloxacin) 
None allowed within 14 days before 
the first dose of the study drug 
None allowed through the Safety 
Follow-up Visit 
Investigational (from another 
study) or physician-prescribed 
Kalydeco 
None allowed after the first dose of 
the study drug (no restriction during 
the Screening Period) 
Last dose of study drug  
Investigational or 
physician-prescribed Orkambi 
(LUM/IVA) 
None allowed within 28 days before 
the Day 1 Visit 
None allowed through the Safety 
Follow-up Visit 
Other investigational drugs or 
devices  
None allowed within 30 days or 
5 half-lives before screening, or 
time determined by local 
requirements; whichever is longer 
None allowed through the Safety 
Follow-up Visit 
CFTR: cystic fibrosis transmembrane conductance regulator; CYP: cytochrome P450; IVA: ivacaftor; 
LUM: lumacaftor. 
Note: The use of restricted medication in subjects with a medical need will be addressed on a case-by-case basis 
with the medical monitor or authorized designee. See the Study Reference Manual for a more complete list of 
medications prohibited/restricted in the study. 
Detailed restrictions for fluid and food intake during study drug administration are presented 
in Section 10.2. 
9.4 
Prior and Concomitant Medications  
Part A and Part B 
Subjects will abstain from all restricted concomitant medications as described in the 
exclusion criteria (Section 9.3). 
Information regarding all prior and concomitant medications, including the subject's CF 
medications, other medications, and herbal and naturopathic remedies administered from 
4 weeks before the Screening Period through the Safety Follow-up Visit will be recorded in 
each subject's source documents and electronic case report form (eCRF).  
• It is recommended that subjects remain on their stable medication regimen for CF from 
4 weeks before Day 1 through Day 14 (Part A) or through Week 24 (Part B) or, if 
applicable, through the Safety Follow-up Visit. Stable medication regimen is defined as 
the current medication regimen for CF (except for commercially available CFTR 
modulators) that subjects have been following for at least 4 weeks 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 discussed and approved by the Vertex medical 
monitor. Guidelines for stable medication regimens for CF are as follows: 


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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. 
• Subjects may receive doses of prednisone (or prednisolone) of up to 10 mg/day 
(chronically), or prednisone (or prednisolone) 60 mg qd for up to 5 days with tapering 
down to 10 mg/day within 2 weeks, without prior approval of the medical monitor. 
• Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments 
performed according to the guidelines provided in Section 11.6.1. 
• Concomitant use of medications known to prolong the QT interval should be used with 
caution during the study, even though the effect of VX-661 in combination with ivacaftor 
on the QT interval has been evaluated in a thorough QT study, which demonstrated no 
prolongation of the QT interval. Consideration should be given to obtaining an ECG 
when concomitant medication known to prolong the QT interval is administered. 
9.5 
Removal of Subjects  
Part A 
Subjects may withdraw from the study at any time at their own request, and subjects may be 
withdrawn at any time at the discretion of the investigator or Vertex for safety, behavior, 
noncompliance (study drug dosing or study procedures), or administrative reasons. 
Part B 
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.  
Part A and Part B 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. 
The investigator will inquire about the reason for withdrawal, request that the subject return 
all unused investigational product(s), request that the subject return for an ETT Visit, if 
applicable (see Section 8.1.5 [Part B]), and a Safety Follow-up Visit, if applicable (see 
Section 8.1.5), 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. 
Subjects who are enrolled on the basis of a historical genotype result and whose screening 
genotype does not confirm study eligibility will be discontinued from study drug treatment, 
will undergo ETT and/or Safety Follow-up Visits per Section 8.1.5, and will then be 
discontinued from the study. After discontinuation of study drug treatment, these subjects 
will not undergo any further assessments other than those performed at the ETT and/or 
Safety Follow-up Visits. 
9.6 
Replacement of Subjects 
Part A and Part B 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug 
treatment period(s) may be replaced at Vertex's discretion. 
10 
STUDY DRUG ADMINISTRATION AND MANAGEMENT  
10.1 
Preparation and Dispensing 
Part A and Part B 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee to the subject’s legally appointed and authorized representative (e.g., parent or legal 
guardian) for administration to the study subject. 
VX-661 and ivacaftor tablets and ivacaftor capsules containing granules will be dispensed at 
the clinical site to individual dosing containers by 2 operators, 1 of whom is a qualified 
pharmacist, and following national and local laws and regulations. 
10.2 
Administration 
Part A  
On Day 1 through the morning dose on Day 14 (last dose of study drug), study drug tablets 
and granules will be orally administered with water (tablets and granules) and applesauce or 
other appropriate food listed in the study manual (granules) (see details below) as shown in 
Table 10-1.  


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Table 10-1 
Study Drug Administration 
Subjects 
Treatment Arm 
Time 
VX-661 
IVA 
Subjects <25 kg at 
baseline 
VX-661 50 mg qd +  
IVA 75 mg q12h 
AM 
1 × 50-mg tablet 
1 capsule containing 
75-mg of granules 
PM 
none 
1 capsule containing 
75-mg of granules 
Subjects ≥25 kg at 
baseline 
VX-661 50 mg qd +  
IVA 150 mg q12h 
AM 
1 × 50-mg tablet 
1 × 150-mg tablet 
PM 
none 
1 × 150-mg tablet 
IVA: ivacaftor; q12h: every 12 hours; qd: daily. 
The granule formulation will be dispensed by opening the capsules containing the granules 
and mixing the granules in applesauce (or other appropriate food listed in the study manual). 
Each dose will comprise 10 mL of applesauce in which the granules from 1 capsule are 
mixed. The subject will consume the applesauce and granule mixture followed by 240 mL 
ambient temperature water. Details on preparing the study drug will be provided in the 
Pharmacy Manual. 
Study drug should be administered approximately 30 minutes after the start of consuming a 
fat-containing meal or snack according to the following guidelines:  
1. The morning dose of study drug will be administered at the clinical site on Days 1, 2, 7, 
and 14. In the event a subject’s scheduled visit occurs in the afternoon, all assessments 
will be collected relative to the evening dose. 
2. Study drug will be administered after all predose safety and PK assessments have been 
performed. 
3. VX-661 doses should be administered every 24 hours (± 1 hour) and ivacaftor should be 
administered every 12 hours (± 1 hour). For each subject, all doses (morning and 
evening) of study drugs should be administered at approximately the same time each day. 
For example, if the morning doses of study drug are administered at 08:00 hour on Day 1, 
all subsequent morning doses should be administered between 07:00 hour and 
09:00 hour. 
4. Study drug tablets (or tablets and granules, if applicable) will be administered within 
5 minutes of each other. 
5. On Day 1 and Day 14, subjects will fast for at least 4 hours before and 2 hours after 
administration of the morning dose of study drug (except for meal or snack given with 
study drug administration). 
6. Study drug will be administered with approximately 240 mL (approximately 1 cup, 
8 ounces, or half a pint) of water (tablets and granules) and 10 mL applesauce or other 
appropriate food listed in the study manual (granules).   
7. The date, amount taken, and time of study drug administration, including whether food 
was taken with each dose, will be recorded for 2 days before PK sample collection and on 
the days of PK sample collection. 


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8. On Day 1 and Day 14, subjects will be instructed not to drink fluids from 1 hour before to 
1 hour after administration of the morning dose of study drug, except for approximately 
240 mL (approximately 1 cup, 8 ounces, or half a pint) of water that will be used for the 
administration of study drug, or the beverage provided with the standard meal or snack. 
Outside of this time window, fluids may be taken ad libitum.  
9. The last dose of study drug will be the morning dose on Day 14. 
Part B 
A review of safety, tolerability, and PK data was completed by an internal Vertex team after 
Part A to select the VX-661 dose for Part B (Section 8.1). 
On Day 1 through the evening dose administered the day before the Week 24 Visit (last dose 
of study drug), study drug tablets will be orally administered with water as shown in 
Table 10-2.  
Table 10-2 
Study Drug Administration 
Subjects 
Treatment Arm 
Time 
VX-661/IVA 
IVA 
Subjects <40 kg at 
baseline 
VX-661 50 mg qd +  
IVA 75 mg q12h 
AM 
1 × 50-mg VX-661/ 
75-mg IVA tablet 
none 
PM 
none 
1 × 75-mg tablet 
Subjects ≥40 kg at 
baseline 
VX-661 100 mg qd +  
IVA 150 mg q12h 
AM 
1 × 100-mg VX-661/ 
150-mg IVA tablet 
none 
PM 
none 
1 × 150-mg tablet 
IVA: ivacaftor; q12h: every 12 hours; qd: daily. 
Note: No dose adjustments will be made throughout the duration of treatment in this study. Additional details regarding study 
drug administration for VX-661 and ivacaftor will be included in the Pharmacy Manual. 
Study drug should be administered within 30 minutes after consuming a fat-containing 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. At Week 16, subjects will fast for at least 2 hours after administration of the morning 
dose of study drug.  
3. Study drug will be administered with approximately 240 mL (approximately 1 cup, 
8 ounces, or half a pint) of water. 
4. 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. 
5. On days of scheduled visits (Day 1, Day 15, Weeks 4, 8, and 16), with the exception of 
afternoon visits addressed below, the morning dose of study drug will be administered at 
the site after predose assessments have been completed.  


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6. 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. 
• 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. 
7. 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. 
8. At the Week 24 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 24 
Visit.  
10.3 
Dose Modification for Toxicity 
Part A and Part B 
The dosage of individual study drugs or the regimen cannot be altered, but the investigator 
can interrupt or stop treatment with all study drugs. 
10.4 
Study Drug Interruption 
Part A and Part B 
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 elevated QTc 
levels are provided in Section 11.7.3 and Section 11.7.5, respectively. 
10.5 
Missed Doses 
Part A and Part B 
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 hour, 
and the subject remembers at 12:00 hour 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 hour, 
and greater than 6 hours have elapsed beyond the scheduled dosing time (i.e., the time 
is past 14:00 hour), the subject would resume dosing with the evening dose at 
approximately 20:00 hour. 


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10.6 
Method of Assigning Subjects to Treatment Groups 
Part A and Part B  
This is an open-label study. Randomization is not required because all subjects will be 
treated identically (i.e., dosage is based on weight at baseline). 
10.7 
Packaging and Labeling 
Part A and Part B  
Vertex will supply the VX-661 and ivacaftor tablets and ivacaftor granules. The tablets will 
be supplied in child-resistant weekly blister cards and the granule formulation will be 
supplied in capsules in bottles. 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 
Part A and Part B  
The investigator, or an authorized designee (e.g., a licensed pharmacist), will ensure that all 
investigational product is stored in a secured area, under recommended storage conditions, 
and in accordance with applicable regulatory requirements. To ensure adequate records, all 
study drugs will be accounted for as described in Section 10.9. 
Table 10-3 
Study Drug  
Drug Name 
Formulation/ 
Route 
Dosage 
Packaging 
(Formulation 
Strength) 
Storage 
Condition 
Part A 
 
 
 
 
VX-661 
Tablet/Oral 
VX-661 50 mg 
Supplied as 50-mg 
VX-661 tablets 
Store at ≤25ºC (77ºF) with 
excursions to 30ºC (86ºF) 
IVA 
Tablet/Oral 
IVA 150 mg  
Supplied as 150-mg 
IVA tablets 
Store at ≤30ºC 
IVA 
Granule/Oral 
IVA 75 mg 
Supplied as 75-mg 
IVA granules in 
capsules 
Store at ≤30ºC 


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Table 10-3 
Study Drug  
Drug Name 
Formulation/ 
Route 
Dosage 
Packaging 
(Formulation 
Strength) 
Storage 
Condition 
Part B 
 
 
 
 
VX-661/IVA 
Fixed-dose 
tablet/Oral 
VX-661 100 mg/ 
IVA 150 mg 
Supplied as 100 mg 
VX-661/150 mg 
IVA tablets 
≤25°C (77°F) with 
excursions to 30°C (86°F) 
VX-661/IVA 
Fixed-dose 
tablet/Oral  
VX-661 50 mg/ 
IVA 75 mg 
Supplied as 50 mg 
VX-661/75 mg IVA 
tablets 
≤25°C (77°F) with 
excursions to 30°C (86°F) 
IVA 
Tablet/Oral 
IVA 150 mg  
Supplied as 150-mg 
IVA tablets 
≤25°C (77°F) with 
excursions to 30°C (86°F) 
IVA 
Tablet/Oral 
IVA 75 mg 
Supplied as 75 mg 
IVA tablets 
≤25°C (77°F) with 
excursions to 30°C (86°F) 
IVA: ivacaftor. 
Note: Additional details regarding packaging, labeling, and dispensing for VX-661 and ivacaftor will be 
included in the Pharmacy Manual. 
10.9 
Drug Accountability 
Part A and Part B  
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 
Part A and Part B  
The study site staff or pharmacy personnel will retain all materials returned by the subjects 
until the study monitor has performed drug accountability. At the end of the study, the study 
monitor will provide instructions as to the disposition of any unused investigational product. 
If the study monitor authorizes destruction at the study site, the investigator will ensure that 
the materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Vertex. Destruction will be 
adequately documented. 
10.11 
Compliance  
Part A and Part B  
For study drug doses administered at study visits, doses will be administered under the direct 
supervision of the investigator or designee.  


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For study drug doses administered during the outpatient periods of the study, drug 
accountability will be assessed at each visit by counting returned dosage units. Discrepancies 
will be discussed with the subject and recorded in the source documents. If subjects 
demonstrate continued noncompliance of study drug dosing despite educational efforts, the 
investigator will contact the medical monitor to discuss discontinuing the subject from the 
study.  
10.12 
Blinding and Unblinding 
Part A and Part B  
This will be an open-label study; however, subjects and their legally appointed and 
authorized representative (e.g., parent or legal guardian) should not be informed of their 
study-related spirometry (Part A and Part B), sweat chloride (Part B) 
 
results during the Treatment Period. 
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments is shown in Table 3-1 through Table 3-4.  
The following assessments must be performed in the order specified below when more than 
1 assessment is required at a particular time point: 
Part A 
1. Vital signs 
2. Pulse oximetry  
3. Standard 12-lead ECG recordings 
4. Spirometry 
5. PK sampling and safety laboratory assessments (i.e., blood draws). PK blood samples 
collected before dosing must be collected within 60 minutes before dosing as described in 
Section 11.4. 
Part B 
1. The CFQ-R should be completed before the start of any other assessments scheduled at 
that visit.  
2. ECGs will be performed before dosing and before any other procedures that may affect 
heart rate (e.g., blood draws). 
4. PK blood samples collected before dosing must be collected within 60 minutes before 
dosing as described in Section 11.4.1. 




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Samples from the PK sampling will be stored by Vertex or its designee until all analyses 
have been completed and then disposed of according to Vertex or designee standard 
operating procedures. 
Details on sample collection, processing, and shipping will be provided in a separate 
Laboratory Manual. 
11.4.2 
Processing and Handling of Pharmacokinetic Samples 
Part A and Part B  
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. 
11.4.3 
Bioanalysis 
Part A and Part B  
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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11.6 
Efficacy 
Part B 
The assessments described in Section 11.6.1 through Section 11.6.4 will be performed in 
Part B. 


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11.6.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines40 at 
the time points noted in Table 3-1, Table 3-2, Table 3-3, and Table 3-4 according to the 
additional guidelines that follow. 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who 
have 
• withheld their short-acting bronchodilator (e.g., albuterol) or anticholinergic 
(e.g., Atrovent) for more than 4 hours before the spirometry assessment; 
• withheld their long-acting bronchodilator (e.g., salmeterol) 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. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilator. At all other visits, all spirometry assessments should be performed 
“pre-bronchodilator.” During the Treatment Period, spirometry assessments must be 
performed before dosing, unless noted otherwise. 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 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 
(according to the Schedule of Assessments detailed in Table 3-4) should be performed 
post-bronchodilator. 
• Each spirometry assessment will be recorded in the source documents as 
pre-bronchodilator or post-bronchodilator. 
The parameters listed below will be normalized using the standards of GLI.38  
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 
• Forced expiratory flow (FEF25%-75%) (L/s) 
All sites will be provided with spirometers and associated materials to be used for all study 
assessment by the central spirometry service. Spirometry data will be transmitted to a 
centralized spirometry service for quality review. 
Subjects and their parent/caregiver should not be informed of their study-related spirometry 
results during the Treatment Period. 


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11.6.2 
Sweat Chloride  
The sweat chloride test is a standard diagnostic tool for CF, serving as a biomarker of CFTR 
activity. Collection of sweat samples will be performed at visits specified in Table 3-4 using 
an approved collection device (Part B). Sweat samples will be sent to a central laboratory for 
testing and interpretation of results. Individual sweat chloride test results will not be 
disclosed to the study sites. Specific instructions for collection, handling, processing, and 
shipping of sweat chloride samples to the central laboratory will be provided separately.  
The sweat chloride test must be conducted predose relative to the morning dose of study drug 
during the Treatment Period. At each time point, 2 samples will be collected, 1 sample from 
each arm (left and right).  
In addition, sweat collection must be performed at the Screening Visit (Table 3-1 [Part A] 
and Table 3-3 [Part B]) if an eligible sweat chloride value is not available in the subject’s 
medical record (NOTE: for subjects who are heterozygous for the F508del-CFTR mutation 
and with a second CFTR allele with a gating defect that is clinically demonstrated to be 
ivacaftor responsive, this value may be obtained from a record collected prior to use of 
Kalydeco). For subjects using a sweat chloride value documented in their medical record to 
establish eligibility, the sweat chloride test at the Screening Visit is optional.  
Collection of sweat chloride will not overlap with any other study assessments. 
Subjects and their parent/caregiver should not be informed of their study-related sweat 
chloride results during the Treatment Period. 
11.6.3 
Weight, Height, and BMI 
Weight, height, and BMI (derived) will be assessed. Weight and height will be measured 
with shoes off at time points noted in Table 3-2 and Table 3-4. Weight and height will be 
measured before the dose of the study drug during the Treatment Period. 
In addition, weight, height, and BMI (derived) will be assessed at the Screening Visit 
(Table 3-1 [Part A] and Table 3-3 [Part B]). 
11.6.4 
Cystic Fibrosis Questionnaire-Revised  
Subjects will be asked to complete the CFQ-R in their native language. The CFQ-R will be 
completed before dosing at visits noted in Table 3-4. The version and format of CFQ-R will 
be based on age at baseline, regardless of whether the subject changes age during the study. 
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 translations of 
the CFQ-R, if available, will be provided for participating centers in non-English-speaking 
countries (if applicable).30,31 The CFQ-R should be completed before the start of any 
assessments scheduled at that visit. 
11.7 
Safety 
Part A and Part B  
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of 
vital signs, ECGs, and physical examinations (PEs). 


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11.7.1 
Adverse Events 
Part A and Part B  
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF 
completion guidelines for investigators as well as training will be provided. 
11.7.2 
Clinical Laboratory Assessments  
Part A and Part B  
Blood and urine samples will be analyzed at a central laboratory with the exception of urine 
pregnancy tests, which will be analyzed at the clinical site. Blood samples requiring a 4-hour 
fast for clinical laboratory assessments will be collected on Day 1 and Day 14 in Part A. 
Fasting is not required at other time points unless specified otherwise (see Section 10.2). All 
blood samples will be collected while subjects are in a seated or supine position. Specific 
instructions for the collection, processing, and shipment of samples will be provided in a 
separate Laboratory Manual. 
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table 3-1, Table 3-2, Table 3-3, and Table 3-4. Laboratory test results that are abnormal and 
considered clinically significant will be reported as AEs (see Section 13.1).  
The safety laboratory test panels are shown in Table 11-2.  


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Table 11-2 
Safety Laboratory Test Panels  
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogen   
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate aminotransferase (=SGOT)  
Alanine aminotransferase (=SGPT)  
Lactate dehydrogenase 
Amylase  
Lipase  
Gamma glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Vitamin Levels 
Vitamins A, D, E, K, and B12 
Lipid Panel 
Total cholesterol, triglycerides 
Low-density lipoprotein (LDL) 
High-density lipoprotein (HDL) 
Hemoglobin  
Erythrocytes:  
Mean corpuscular hemoglobin  
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelets  
Reticulocytes  
Leukocytes  
Differential (absolute and percent): 
Eosinophils  
Basophils  
Neutrophils  
Lymphocytes  
Monocytes  
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
Leukocyte esterase  
Nitrite  
Urobilinogen  
Urine protein  
pH 
Urine blood  
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose  
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination 
of urine will be performed and results provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
Clinical laboratory assessments from screening will have no clinically significant findings 
that preclude participation in the study, as deemed by the investigator, for a subject to receive 
study drug on Day 1. 
Pregnancy testing for female subjects of childbearing potential who are not abstinent 
(Section 11.7.8.1): 
Part A 
Female subjects of childbearing potential must have a negative pregnancy test at the 
Screening Visit (serum test), on Day 1 (urine test), and at the Safety Follow-up Visit (serum 
test). 
Part B 
Female subjects of childbearing potential must have a negative pregnancy test at the 
Screening Visit (serum test), on Day 1 (urine test), and every study visit thereafter (serum 
test). 


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Part A and Part B 
If a urine pregnancy test is positive on Day 1, study drug will not be administered and the 
pregnancy will be confirmed with a serum beta-human chorionic gonadotropin test. If 
confirmed, the subject is not eligible for the study.  
For pregnancy tests conducted after dosing, if a serum beta-human chorionic gonadotropin 
test is positive, the pregnancy will be reported and the subject will be permanently withdrawn 
from study drug dosing as discussed in Section 11.7.8.2. If a pregnancy test is positive, the 
procedures outlined in Section 11.7.8.2 will be followed. 
CF genotype (Screening Period only): CF genotyping will be performed on all subjects to 
confirm the genotype documented in the subject's medical record. This assessment does not 
need to be repeated in the case of rescreening or for confirmed subjects in Part A who wish to 
participate in Part B. In subjects with the R117H mutation, linkage to poly-T tract 
polymorphisms will also be determined from a second specimen. Specific instructions will be 
provided in the Laboratory Manual. 
Alcohol Screening (Part A Only): Subjects may undergo random urine alcohol testing if 
deemed appropriate by the investigator.  
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged by the investigator to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be 
used. Local laboratories may be used at the discretion of the local investigator for 
management of urgent medical issues. If a local laboratory test value is found to be abnormal 
and clinically significant, it will be verified by the central laboratory as soon as possible after 
the investigator becomes aware of the abnormal result. If it is not possible to send a timely 
specimen to the central laboratory (e.g., the subject was hospitalized elsewhere), the 
investigator may base the assessment of an AE on the local laboratory value. 
11.7.3 
Liver Function Test Parameters 
Part A and Part B  
Liver Function Testing 
Liver function testing (ALT, AST, GGT, ALP, direct bilirubin, and total bilirubin) must be 
performed as noted in Table 3-2 and Table 3-4 for serum chemistry while subjects are 
receiving study drug treatment and at 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 confirmatory liver function testing, a local laboratory 
may be used. Elevations in LFTs at the local laboratory must be reported immediately to the 


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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 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 
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. 
11.7.4 
Physical Examinations, Vital Signs, and Pulse Oximetry 
Part A and Part B  
A PE of all body systems and vital signs assessment will be performed at screening and 
select study visits (Table 3-1, Table 3-2, Table 3-3, and Table 3-4). 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. After screening, 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. 


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Arterial oxygen saturation by pulse oximetry is a noninvasive measure of oxygen delivery to 
the tissues and has been correlated with clinical status and lung function. These will be 
assessed following at least a 5-minute rest in the seated or supine position. 
11.7.5 
Electrocardiograms 
Part A and Part B  
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Schedule of Assessments (Table 3-1, Table 3-2, Table 3-3, and Table 3-4). Additional 
standard 12-lead ECGs will be performed at any other time if clinically indicated.  
The performance of all ECGs will adhere to the following guidelines: 
• The subject will be instructed to rest 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 Screening 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. 
Further details pertaining to ECGs will be provided to sites in a separate document (ECG 
Manual). 
11.7.6 
Ophthalmologic Examination 
Part A and Part B  
Subjects will undergo an ophthalmologic examination performed by a licensed 
ophthalmologist at the Screening Visit (Part A and Part B) and at the Week 24 Visit OR the 
Safety Follow-up Visit (Part B only), which includes 
• measurement of best corrected distance visual acuity of each eye 


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• pharmacologically dilated examination of the lens with a slit lamp 
The screening ophthalmologic examination must be completed and the results reviewed to 
determine subject eligibility. This examination does not have to be repeated if there is 
documentation of an examination that met protocol criteria and that was within 3 months 
before the start of the Screening Period. Subjects with documentation of bilateral lens 
removal do not need the ophthalmologic examination. 
If a cataract, lens opacity, Y-suture, or lamellar rings are identified and determined to be 
clinically significant by the ophthalmologist at the Screening examination, the subject is 
ineligible for study entry (see Section 9.2). If a cataract or lens opacity is identified and 
determined to be clinically significant by the ophthalmologist after dosing, the subject and 
Vertex medical monitor will be notified. After discussion with the principal investigator who 
collaborates with the Vertex medical monitor, the subject may elect to continue or 
discontinue study drug treatment. If the subject discontinues study drug treatment, the subject 
should complete the ETT and Safety Follow-up Visits (see Section 8.1.5). If the subject 
continues study drug treatment, more frequent ophthalmologic monitoring should be 
considered. 
In addition to the Screening Visit examination, an ophthalmologic examination will be 
performed by a licensed ophthalmologist at or within 28 days before the Week 24 Visit OR at 
or within 35 days before the Safety Follow-up Visit (Part B only). For subjects who 
discontinue treatment after receiving at least 1 dose of study drug, the ophthalmologic 
examination may be completed at the ETT Visit OR at or within 35 days before the Safety 
Follow-Up Visit (if applicable [Section 8.1.5]). Subjects who have documentation of bilateral 
lens removal are not required to complete the eye examination at the Week 24 Visit, the ETT 
Visit, or Safety Follow-up Visit. 
Additional ophthalmologic examinations may be conducted at the discretion of the 
investigator. The medical monitor should be notified of the results of any additional 
ophthalmologic examinations. 
In addition, at screening, the following history will be obtained for all subjects: 
• history of steroid use 
• history of trauma to the eye 
• any family history of glaucoma, congenital cataracts, or cataracts arising later in life 
11.7.7 
Spirometry 
Refer to Section 11.6.1 for the spirometry assessment. 
11.7.8 
Contraception and Pregnancy  
Standard contraception- and pregnancy-related information and requirements are provided 
below. It should be noted that some of this information and requirements may have limited 
applicability in this pediatric population. 


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11.7.8.1 
Contraception 
Part A 
The effects of VX-661 monotherapy or in combination with ivacaftor on conception, 
pregnancy, and lactation in humans are not known. Neither VX-661 nor ivacaftor showed 
any genotoxic potential in a standard battery of in vitro (Ames test, Chinese hamster ovary 
cell chromosomal aberration) and in vivo (mouse micronucleus) studies. VX-661 and 
ivacaftor were each found to be nonteratogenic in reproductive toxicology studies in rats and 
rabbits.19,20 Subjects should follow the contraception requirements outlined in this study 
protocol. Hormonal contraception is not an acceptable method of contraception for female 
subjects though it is acceptable for the female partners of male subjects. 
At this stage in the development of VX-661 in combination with ivacaftor, participation in 
this study requires a commitment from the research subject and his/her partner to use at least 
1 effective method of birth control. Acceptable methods of contraception for participants of 
this study and their partners are listed below. Methods of contraception should be in 
successful use from signing of consent, approximately 28 days before the first dose of study 
drug (unless otherwise noted), and until 90 days following the last dose of study drug. 
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, and 
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 or medical record 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 Has not achieved menarche (has not had her first menstrual period). Females who fall 
into this category are considered not to be of childbearing potential only as long as 
they have not had their first menstrual period. If a female achieves menarche during 
the study, she will need to provide consent for compliance (proper method of 
contraception or abstinence).  
o NOTE: All other female subjects who have had their first menstrual period will be 
considered to be of childbearing potential. 
• Same sex relationships. 
Acceptable contraceptive methods: 
Acceptable contraceptive methods for male subjects or male partners of female subjects 
include the following: 
• Vasectomy 6 months or more previously, with a documented negative postvasectomy 
semen analysis for sperm. 


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• Condom and spermicide.  
• In countries where spermicide is not available, condom without spermicide will be 
considered acceptable. 
• Local regulations may require use of an additional acceptable method of contraception.  
Acceptable contraceptive methods for female subjects include the following: 
• Bilateral tubal ligation performed at least 6 months previously. 
• Continuous use of an intrauterine device (non-hormone-releasing) for at least 90 days 
before the first dose of study drug. 
• Barrier contraception (such as diaphragm, cervical cap, or female condom) and 
spermicide.  
• In countries where spermicide is not available, barrier contraception without spermicide 
will be considered acceptable. 
• Local regulations may require use of an additional acceptable method of contraception.  
• NOTE: Hormonal contraceptives will not be considered as an effective method; however, 
female subjects are not required to discontinue hormonal contraceptives. 
Acceptable contraceptive methods for female partners of male subjects:  
• Bilateral tubal ligation performed at least 6 months previously. 
• Continuous use of an intrauterine device for at least 90 days before first dose of study 
drug. 
• Barrier contraception (such as diaphragm, cervical cap, or female condom) and 
spermicide. 
• In countries where spermicide is not available, condom without spermicide will be 
considered acceptable.  
• Local regulations may require use of an additional acceptable method of contraception. 
• Hormonal contraceptives, if successfully used for at least 60 days before first dose of 
study drug.  
Additional notes: 
• Acceptable methods of contraception listed above are examples. Local requirements may 
prohibit the use of some of these examples. Please contact the medical monitor with any 
questions. 
• A female condom cannot be used with male condom (as a double method of 
contraception) due to risk of tearing. 
• 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 with 
a partner of the opposite sex. 


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• If applicable, additional contraception requirements may need to be followed according 
to local regulations and/or requirements. 
• 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. 
• Male subjects whose female partner becomes pregnant through well-documented in vitro 
fertilization (donated sperm) or banked sperm (collected before the subject received study 
drug) must be compliant with the contraception requirements. In this scenario, the male 
subject and his female partner must commit to using barrier methods of contraception (to 
ensure there is no exposure of the fetus to study drug) for the duration of the study and 
until 90 days after 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. 
• Unique situations that may not fall within the above specifications should be discussed 
with the medical monitor. 
Part B 
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 113 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. 


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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: 
Table 11-3 
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 11-3.  
• 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.  


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11.7.8.2 
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 11.7.8.1). 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. 
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 is obtained. A separate ICF will be provided to explain these follow-up 
activities. Pregnancy itself does not constitute an AE. 
12 
STATISTICAL AND ANALYTICAL PLANS  
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the Statistical Analysis Plan (SAP), and PK data analysis details 
will be provided in the Clinical Pharmacology Analysis Plan (CPAP), both of which will be 
finalized before the clinical data lock for the study. 
12.1 
Sample Size and Power 
Part A 
Sample size calculations were conducted to estimate the precision in determining VX-661 
clearance in pediatric subjects in the 2 weight-based cohorts. The method used 
noncompartmental analysis-based PK parameters, such as clearance and volume, in adults 
with the assumption that there is similar variability in clearance in adults and pediatric 
subjects 6 through 11 years of age within each weight group. The calculations indicate that 
data from 8 subjects will allow 80% power to target a 95% CI within 60% and 140% of the 
geometric mean estimate of clearance for VX-661 in each pediatric subgroup (cohort).  
Part B 
Planned enrollment is approximately 56 subjects. Assuming a 10% dropout rate, 
approximately 50 subjects are expected to complete Part B. An important safety endpoint is 
the incidence of AEs. Table 12-1 presents estimates of the probability for observing at least 
1 subject with an AE for the given incidence (θ) and sample size. With a total sample size of 
50 subjects (completer), there is a 92.3% chance of observing AEs in at least 1 subject if the 
true incidence rate is 5%, and a 99.5% chance of observing AEs in at least 1 subject if the 
true incidence rate is 10%. The probabilities have been calculated by assuming a binomial 
distribution for the number of AEs using SAS®.  


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Table 12-1 
Probability of Observing At Least 1 Subject With an AE in the Study if 
the AE Incidence (θ) is 5% and 10% 
Treatment 
Sample Size 
θ = 5% 
θ = 10% 
VX-661 50 mg qd + IVA 75 mg q12h  
OR  
VX-661 100 mg qd + IVA 150 mg q12h 
50 
92.3% 
99.5% 
IVA: ivacaftor; q12h: every 12 hours; qd: daily. 
12.2 
Analysis Sets 
Assignment of subjects to analysis sets will be done before the clinical data lock for the 
study. The analysis set will be defined separately for Part A and Part B. 
Safety Set (Part A and Part B) 
The Safety Set will include all subjects who received at least 1 dose of study drug. 
Full Analysis Set (Part B Only) 
Full Analysis Set (FAS) will include subjects who carry the intended CFTR mutations (see 
Section 16) and received at least 1 dose of study drug. The FAS will be used for all efficacy 
analyses. 
PK Set (Part A and Part B) 
The PK Set is defined as subjects who received at least 1 dose of study drug and for whom 
the primary PK data are considered to be sufficient and interpretable. 
All Subjects Set (Part A and Part B) 
The All Subjects Set is defined as subjects who are eligible for study enrollment and received 
a subject identification number, or were dosed. All subject data listings will be presented 
using the All Subjects Set, unless otherwise specified. 
12.3 
Statistical Analysis 
This section presents a summary of the planned statistical analyses of safety and efficacy 
data. The Vertex Biometrics department or a designated contract research organization 
(CRO) will analyze the data derived from this study. SAS Version 9.2 or higher will be used 
to generate all statistical outputs (tables, figures, listings, and data sets). 
Statistical analysis and presentation details will be provided in the SAP for the study. Details 
of additional supportive efficacy and safety analyses not included in the protocol may be 
provided in the SAP. 
12.3.1 
General Considerations 
Data from Part A and Part B will be analyzed separately. 
All individual subject data for those who were eligible for study enrollment and received a 
subject identification number, or were dosed, will be presented in data listings. 


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Continuous variables will be summarized by the treatment group (VX-661 50 mg qd 
+ ivacaftor 75 mg q12h, VX-661 50 mg qd + ivacaftor 150 mg q12h) and overall for Part A 
and by treatment group (VX-661 50 mg qd + ivacaftor 75 mg q12h, VX-661 100 mg qd 
+ ivacaftor 150 mg q12h) and overall for Part B using the following descriptive summary 
statistics: number of subjects (n), mean, standard deviation (SD), standard error (SE), 
median, minimum value (min), and maximum value (max). The precision of the 
measurement for each continuous variable will be specified in the SAP. 
Categorical variables will be summarized by the treatment group (VX-661 50 mg qd 
+ ivacaftor 75 mg q12h, VX-661 50 mg qd + ivacaftor 150 mg q12h) and overall for Part A 
and by treatment group (VX-661 50 mg qd + ivacaftor 75 mg q12h, VX-661 100 mg qd 
+ ivacaftor 150 mg q12h) and overall for Part B using counts and percentages. Percentages 
will be presented to 1 decimal place. 
Treatment emergent (TE) period for Part A will correspond to data from the first dose of 
study drug in Part A to the Safety Follow-up Visit or 14 days after the last dose in Part A for 
subjects who do not have a Safety Follow-up Visit. Similarly, the TE period for Part B will 
correspond to data from first dose of study drug in Part B through the Safety Follow-up Visit 
or 28 days after the last dose in Part B for subjects who do not have an Safety Follow-up 
Visit. 
Baseline for Part A is defined as the most recent nonmissing measurement (scheduled or 
unscheduled) collected prior to the first dose of study drug in Part A. For ECGs, baseline will 
be the average of the 3 pretreatment measurements on Day 1. For sweat chloride, the baseline 
value will be the mean of assessment values on the left and the right arm at the most recent 
time point prior to the first dose of study drug. The measurement end time should also be 
before dosing to be considered in the calculation for baseline sweat chloride. Baseline for 
Part B will be similarly defined. 
Absolute change from baseline will be calculated as post-baseline value – baseline value.   
Relative change from baseline will be calculated as 100 x (post-baseline value – baseline 
value)/ baseline value.   
12.3.2 
Background Characteristics 
Subject disposition, demographic and baseline characteristics, prior and concomitant 
medications, study drug exposure, and other background characteristics will be summarized 
by the treatment group (VX-661 50 mg qd + ivacaftor 75 mg q12h, VX-661 50 mg qd 
+ ivacaftor 150 mg q12h) and overall for Part A and by treatment group (VX-661 50 mg qd + 
ivacaftor 75 mg q12h, VX-661 100 mg qd + ivacaftor 150 mg q12h) and overall for Part B. 
All summaries described above will be based on the Safety Set for Part A and the FAS for 
Part B, unless otherwise specified. 
12.3.2.1 
Subject Disposition 
Part A 
The number and percentage of subjects in the following categories: All Subjects Set and 
Safety Set will be summarized. In addition, the number and percentage (based on Safety Set) 
of subjects in each disposition category (e.g., completed treatment, completed study; with a 


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breakdown of the reason for study discontinuation or treatment discontinuation) will be 
summarized. 
Part B 
The number and percentage of subjects in the following categories: All Subjects Set, FAS, 
and Safety Set will be summarized. In addition, the number and percentage (based on FAS) 
of subjects in each disposition category (e.g., completed treatment, completed study; with a 
breakdown of the reason for study discontinuation or treatment discontinuation) will be 
summarized. 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized separately for Part A and Part B. Important Protocol deviations will be provided 
as a subject data listing.  
The following demographics and baseline characteristics will be summarized: sex, race, 
ethnicity, age, weight, height, BMI, region, ppFEV1, sweat chloride, and score of CFQ-R 
respiratory domain.  
No statistical tests will be carried out to evaluate any baseline imbalance between treatment 
groups. 
12.3.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced. 
Part A 
Medications in Part A will be categorized as the following:  
• Prior medication: any medication that started before the first dose of study drug in 
Part A, regardless of when it ended. 
• Concomitant medication: medication continued or newly received during the TE period 
for Part A. 
• Post-treatment medication: medication continued or newly received after the TE period 
for Part A. For those subjects from Part A who enrolled in Part B, medications that 
continued or were newly received on or after the first dose of study drug in Part B will 
not be considered as post-treatment medication. 
A given medication can be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; 
or prior, concomitant, and post-treatment. If a medication has a missing or partial missing 
start/end date or time and it cannot be determined whether the medication was taken before 
first dose, concomitantly, or post-treatment, it will be considered as prior, concomitant, and 
post-treatment. 
Prior and post-treatment medications will only be listed and not summarized. The 
concomitant medications will be summarized descriptively based on the Safety Set.   




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For Part B, assessment of efficacy is a secondary objective. The rest of the section will 
describe efficacy analysis of data from Part B.  
12.3.3.1 
Analysis of Primary Efficacy Variables 
Not Applicable 
12.3.3.2 
Analysis of Secondary Efficacy Variables 
Part A 
Not applicable 
Part B 
A summary of observed values and change from baseline by treatment group (VX-661 
50 mg qd + ivacaftor 75 mg q12h, VX-661 100 mg qd + ivacaftor 150 mg q12h) and overall 
will be provided for all secondary efficacy variables based on FAS.  
Absolute change in ppFEV1 from baseline through Week 24:  
Absolute change from baseline in ppFEV1 will be analyzed using a restricted maximum 
likelihood (REML)-based mixed effect model repeated measures (MMRM) approach that 
would include 'treatment', 'visit', and 'treatment by visit' interaction as fixed, categorical 
effects and 'baseline ppFEV1' as continuous, fixed covariate. An unstructured (co)variance 
structure will be used to model the within-subject errors. If the model fails to converge, a 
compound symmetry covariance structure will be considered. The degrees of freedom of the 
denominator will be approximated by the Kenward-Roger’s method.41 The estimated mean 
change from baseline through Week 24 within each treatment group and the overall treatment 
will be calculated using appropriate contrasts. The corresponding LS means, P value and the 
95% CI will be calculated and presented in a table. The primary assessment of efficacy will 
be based on these estimates. 
The estimated mean changes at post-baseline visits within each treatment group and the 
overall treatment will also be presented. The least squares (LS) means, P values and the 95% 
CIs will be presented in a table. The LS means (95% CI) for change from baseline at each 
visit will be plotted for the individual treatment groups and the overall treatment group. 
Additional supportive analysis and sensitivity analysis may be described in the SAP. 
Relative change in ppFEV1 from baseline through Week 24: Analysis of this variable will 
be performed using the same approach as described for the absolute change in ppFEV1 from 
baseline.  
Absolute change in weight (/weight-for-age z-score) from baseline at Week 24: Analysis 
of this variable will be similar to that for the absolute change in ppFEV1 from baseline. The 
MMRM will use baseline weight (/weight-for-age z-score) as covariate instead of baseline 
ppFEV1. For this variable, the assessment of efficacy will be primarily based on Week 24.  
Absolute change in height (/height-for-age z-score) from baseline at Week 24: Analysis 
of this variable will be similar to that for the absolute change in ppFEV1 from baseline. The 
MMRM will use baseline height (/height-for-age z-score) as covariate instead of baseline 
ppFEV1. For this variable, the assessment of efficacy will be primarily based on Week 24. 


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Absolute change in BMI (/BMI-for-age z-score) from baseline at Week 24: Analysis of 
this variable will be similar to that for the absolute change in ppFEV1 from baseline. The 
MMRM will use baseline BMI (/BMI-age z-score) as covariate instead of baseline ppFEV1. 
For this variable, the assessment of efficacy will be primarily based on Week 24.  
Absolute changes in sweat chloride from baseline through Week 4 and through 
Week 24: Analysis of this variable will be performed using the same approach as described 
for the absolute change in ppFEV1 from baseline. The MMRM will use baseline sweat 
chloride value as covariate instead of baseline ppFEV1. The estimated mean change from 
baseline through Week 4 and Week 24 within each treatment group and the overall treatment 
will be calculated using appropriate contrasts. The corresponding LS means, P value, and the 
95% CI will be calculated and presented in a table. For this variable, the assessment of 
efficacy will be primarily based on the estimates for mean change from baseline through 
Week 24. Note that for each scheduled sampling time point, 1 sample from each arm would 
be obtained. The data analysis will use the average of the results from the 2 samples. 
Absolute change in the CFQ-R respiratory domain score from baseline through 
Week 24: Analysis of this domain will be similar to that for the absolute change in ppFEV1 
from baseline. The MMRM will use the baseline CFQ-R respiratory domain score as a 
covariate instead of baseline ppFEV1.  
12.3.4 
Safety Analysis 
Safety is a secondary objective of Part A, and the primary objective of Part B. The safety 
endpoints included for analyses are as follows: 
Part A and Part B 
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (serum chemistry, hematology, coagulation studies, lipids, 
vitamins, and urinalysis) 
• Standard 12-lead ECGs 
• Vital signs 
• Pulse oximetry 
• Ophthalmologic examinations (Part B) 
• Spirometry 
Safety analyses will use the Safety Set. All safety analyses will be based on the set of data 
associated with the TE period for Part A and Part B. The data will be summarized by the 
treatment group (VX-661 50 mg qd + ivacaftor 75 mg q12h, VX-661 50 mg qd + ivacaftor 
150 mg q12h) and overall for Part A and by treatment group (VX-661 50 mg qd + ivacaftor 
75 mg q12h, VX-661 100 mg qd + ivacaftor 150 mg q12h) and overall for Part B.  


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12.3.4.1 
Adverse Events 
Part A 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
• 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 during the TE 
period for Part A.  
• Post-treatment AE: any AE that increased in severity or that was newly developed after 
the TE period for Part A. For subjects from Part A who enrolled in Part B, an AE that 
increased in severity on or after the first dose of study drug in Part B will not be 
considered as a post-treatment AE. 
Part B 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
• Pretreatment AE: any AE that started before the first dose of study drug in Part B.  
• TEAE: any AE that increased in severity or that was newly developed during the TE 
period for Part B.  
• Post-treatment AE: any AE that increased in severity or that was newly developed after 
the TE period for Part B.  
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. 
Part A and Part B 
AE summary tables will be presented for TEAE only and will include the following: 
• All TEAEs  
• TEAEs by strongest relationship  
• TEAEs by maximal severity 
• TEAEs leading to treatment discontinuation 
• Serious TEAEs 
• TEAEs leading to death 
• Frequently reported TEAEs 
Summaries will be presented by MedDRA system organ class and preferred term using 
frequency counts and percentages (i.e., number and percentage of subjects with an event). 
When summarizing the number and percentage of subjects with an event, subjects with 
multiple occurrences of the same AE or a continuing AE will be counted once, only the 
maximum severity level will be presented in the severity summaries, and the strongest 


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relationship level in the relationship summaries. An AE overview table will be provided. 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 pretreatment and 
post-treatment AEs, will be presented in individual subject data listings. 
12.3.4.2 
Clinical Laboratory Assessments 
Part A and Part B 
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. In addition for 
Part B, the mean value of liver function parameters at each visit will be plotted by the 
treatment group (VX-661 50 mg qd + ivacaftor 75 mg q12h, VX-661 100 mg qd + ivacaftor 
150 mg q12h) and overall. 
The number and percentage of subjects with at least 1 threshold analysis event during the TE 
period will be summarized. The shift of the threshold analysis criteria from baseline to 
postbaseline will also be summarized for selected laboratory parameters. The threshold 
analysis criteria and the parameter selection criteria will be provided in the SAP.   
Results of urinalysis will be presented in individual subject data listings only. Additionally, a 
listing containing individual subject laboratory measurements outside the reference ranges 
will be provided. This listing will include data from scheduled and unscheduled time points. 
12.3.4.3 
Electrocardiogram 
Part A and Part B 
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 
for Part B, the mean QTcF value at each visit will be plotted by treatment group (VX-661 
50 mg qd + ivacaftor 75 mg q12h, VX-661 100 mg qd + ivacaftor 150 mg q12h) and overall. 
The number and percentage of subjects with at least 1 threshold analysis event during the TE 
period will be tabulated. The threshold analysis criteria for ECG data will be provided in the 
SAP.  
Additional ECG analyses may be described in the SAP. 
12.3.4.4 
Vital Signs 
Part A and Part B 
The raw values and change from baseline values during the TE period will be summarized at 
each scheduled time point: systolic and diastolic blood pressure (mm Hg), body temperature 
(°C), heart rate (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 tabulated. The threshold analysis criteria for vital signs data will be provided 
in the SAP.  
Additional vital sign analyses may be described in the SAP. 


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12.3.4.5 
Physical Examination 
Part A and Part B 
PE findings will be presented as a data listing only. Clinically relevant results identified after 
screening will be reported as AEs. 
12.3.4.6 
Other Safety Analysis 
12.3.4.6.1 
Pulse Oximetry 
Part A and Part B 
A summary of raw values and change from baseline values during the TE period will be 
provided at each scheduled time point for the percent of oxygen saturation by pulse oximetry. 
In addition for Part B, the mean percent of oxygen saturation at each visit will be plotted by 
treatment group (VX-661 50 mg qd + ivacaftor 75 mg q12h, VX-661 100 mg qd + ivacaftor 
150 mg q12h) and overall. 
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. 
12.3.4.6.2 
Ophthalmologic Examinations 
Part A and Part B 
The ophthalmologic examination results will be presented in individual subject data listings. 
12.3.4.6.3 
Spirometry  
Part A 
Spirometry data will be listed and descriptively summarized.  
Part B 
The following summary regarding the decline in spirometry will be provided: 
• Number and percentage of subjects with ≥10 or ≥20 percentage points decrease in 
average absolute change from baseline through Week 24 for ppFEV1. 
• Number and percentage of subjects with ≥0.10 L or ≥0.20 L decrease in average absolute 
change from baseline through Week 24 for FEV1. 
Subjects with ≥10 percentage points decrease in average absolute change from baseline 
through Week 24 for ppFEV1 or ≥0.10 L decrease in the average absolute change from 
baseline through Week 24 for FEV1 will be listed.  
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analysis 
Part A 
Not applicable 


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Part B 
Interim analyses may take place at any time during the study if warranted by the ongoing 
data, and/or deemed necessary by the internal Vertex team. 
12.3.5.2 
IDMC Analysis 
Part A and Part B 
Details of the IDMC (Section 8.1.7) analysis will be provided in the IDMC analysis plan.  
12.4 
Clinical Pharmacology Analysis 
A detailed description of the clinical pharmacology analyses will be provided in the CPAP.  
PK parameters of VX-661, M1-661, M2-661, ivacaftor, M1-ivacaftor, and M6-ivacaftor will 
be estimated using standard noncompartmental methods. The key PK parameters are Cmax 
and AUCτ. All PK parameters will be summarized using descriptive statistics for each group. 
Further details of the planned PK analysis will be provided in the CPAP.  
A population approach will be used to analyze the time versus-plasma concentration data of 
VX-661, ivacaftor, and their metabolites. The PK/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. 
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: 


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• 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 until the following time points: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, 
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 prior to the first dose of study drug in the extension study (Part B). 
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 CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the 
study will be recorded only in the subject's source documents. The following data will be 
documented for each AE: 
• Description of the event 
• 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 


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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. 
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.  


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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) 
 
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) 


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• Life-threatening, such that the subject was at immediate risk of death from the reaction as 
it occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person's ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize 
the subject or may require medical or surgical intervention to prevent 1 of the outcomes 
listed above (e.g., an allergic bronchospasm requiring intensive treatment in an 
emergency room or at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled 
sooner or to be prolonged relative to what was planned. In addition, hospitalizations clearly 
not associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and "severe,” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may 
be of relatively minor medical significance, such as a severe headache. This is not the same 
as “serious,” which is based on subject/event outcome or action described above, and is 
usually associated with events that pose a threat to a subject's life or functioning. 
Seriousness, not severity, serves as a guide for defining expedited regulatory reporting 
obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through 
the Safety Follow-up Visit, regardless of causality, will be reported by the investigator to 
Vertex GPS. In addition, all SAEs that occur after the Safety Follow-up Visit and are 
considered related to study drug(s) will be reported to Vertex GPS within 24 hours. 
SAEs will be recorded on the Vertex Organized Safety Information Collection Form 
(hereafter referred to as the “SAE Form”) using a recognized medical term or diagnosis that 
accurately reflects the event. SAEs will be assessed by the investigator for relationship to the 
investigational study drug(s) and possible etiologies. On the Clinical Trials SAE Form, 
relationship to study drug(s) will be assessed only as related (includes possibly related) or not 
related (includes unlikely related), and severity assessment will not be required. For the 
purposes of study analysis, if the event has not resolved at the end of the study reporting 
period, it will be documented as ongoing. For purposes of regulatory safety monitoring, the 
investigator is required to follow the event to resolution and report to Vertex the outcome of 
the event using the Vertex Clinical Trials SAE Form. 




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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 CRFs, study reports, and communications relating to the 
study will identify subjects by assigned subject numbers and access to subject names linked 
to such numbers shall be limited to the site and the study 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 CRFs/SAE 
forms and the review of the data collection process. The FDA and regulatory authorities in 
other jurisdictions, including the IRB/IEC, may also request access to all study records, 
including source documentation, for inspection. 
For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act 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 


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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 a CRF by study site 
personnel using a secure, validated web-based electronic data capture (EDC) application. 
Vertex will have read-only access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator 
for resolution. Any changes to study data will be made to the CRF and documented in an 
audit trail, which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness 
and clarity, cross-checking with source documents, and clarification of administrative matters 
will be performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 


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CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator's 
responsibility to ensure the accuracy, completeness, clarity, and timeliness of the data 
reported in the subject's CRF. Source documentation supporting the CRF data will indicate 
the subject's participation in the study and will document the dates and details of study 
procedures, AEs, other observations, and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible 
after information is collected.  
The audit trail entry will show the user's identification information and the date and time of 
any correction. The investigator will provide formal approval of all the information in the 
CRFs, including any changes made to the CRFs, to endorse the final submitted data for the 
subjects for whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival 
CRF in the form of a 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  
Nordestgaard BG, Langsted A, Mora S, Kolovou G, Baum H, Bruckert E, et al. 
Fasting is not routinely required for determination of a lipid profile: clinical and 
laboratory implications including flagging at desirable concentration cut-points—a 
joint consensus statement from the European Atherosclerosis Society and European 
Federation of Clinical Chemistry and Laboratory Medicine. European Heart Journal. 
2016;37:1944–58. 
2 
Cystic Fibrosis Foundation Web Site [Internet]. Available from: 
http://www.cff.org/AboutCF/. Accessed 25 August 2015. 
3 
Kriendler JL. Cystic fibrosis: Exploiting its genetic basis in the hunt for new 
therapies. Pharmacol Ther. 2010 Feb;125:219-29. 
4 
FDA Office of Orphan Products Development (OOPD). Available from: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/defa
ult.htm. Accessed 25 August 2015. 
5 
The Committee for Orphan Medicinal Products (COMP). Available from: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_conte
nt_000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30. 
Accessed 25 August 2015. 
6 
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2012 Annual 
Data Report. Bethesda, Maryland; 2013. 
7 
Flume PA, Van Devanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012:10(1):88. 
8 
Cystic Fibrosis Mutation Database (CFTR1). Cystic Fibrosis Centre at the Hospital 
for Sick Children in Toronto Web site. Available from: 
http://www.genet.sickkids.on.ca/cftr/StatisticsPage.html. Accessed 25 August 2015.  
9 
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. 
10 
Van Goor F, Hadida S, Grootenhuis P. Pharmacological rescue of mutant CFTR 
function for the treatment of cystic fibrosis. Ion Channels. 2008;3:91-120. 
11 
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. 
12 
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2011 Annual 
Data Report. Bethesda, Maryland; 2012. 


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13 
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_v3
2012.pdf. Accessed 25 August 2015. 
14 
Cheng SH, Gregory RJ, Marshall J, Paul S, 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. 
15 
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;354:526-8. 
16 
Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 
2005;352:1992-2001. 
17 
Vertex Pharmaceuticals Incorporated. Effects of VRT-893661 on CFTR-mediated 
chloride secretion in human bronchial epithelia isolated from cystic fibrosis subjects. 
Report G016. Report date: 17 Feb 2010. 
18 
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;268:21592-8. 
19 
Vertex Pharmaceuticals Incorporated. Ivacaftor (VX-770) Investigator’s Brochure. 
Version 13.0. Report date: 16 May 2016. 
20  
Vertex Pharmaceuticals Incorporated. Ivacaftor (VX-770) Investigator’s Brochure. 
Version 13.0, Addendum 1. Report date: 23 June 2016. 
21 
Vertex Pharmaceuticals Incorporated. VX-661 Investigator's Brochure. Version 8.0. 
Report date: 07 November 2016. 
22  
Vertex Pharmaceuticals Incorporated. VX-661 Investigator's Brochure. Version 8.0, 
Addendum 1. Report date: 20 April 2017. 
23  
Vertex Pharmaceuticals Incorporated. Ivacaftor population pharmacokinetic/ 
pharmacodynamic analysis of percent predicted forced exhaled volume in 1 second 
(ppFEV1) in cystic fibrosis subjects with the G551D gating mutation Report N020. 
Report date: 20 March 2017. 
24  
Vertex Pharmaceuticals Incorporated. Assessment of the combination of TEZ/IVA 
compared to TEZ or IVA alone across CFTR residual function mutations expressed in 
Fischer Rat Thyroid cells; effects on processing and trafficking and chloride 
transport. Report M078. 12 June 2017. 
25 
Wilschanski M, Zielenski J, Markiewicz D, Tsui LC, Corey M, Levison H, et al. 
Correlation of sweat chloride concentration with classes of the cystic fibrosis 
transmembrane conductance regulator gene mutations. J Pediatr. 1995;127:705-10. 


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26 
Rowe SM, Accurso F, Clancy JP. Detection of cystic fibrosis transmembrane 
conductance regulator activity in early-phase clinical trials. Proc Am Thorac Soc. 
2007;4:387-98. 
27 
Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life 
measures for children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32. 
28 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4:378-86. 
29 
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):535-46. 
30 
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. 
31 
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. 
37  
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. 
Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998;132(4):589-95. 
38  
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 
2012 equations. Eur Respir J. 2012;40(6):1324-43. 
39 
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51:875-8. 


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40 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
41  
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics. 1997;53:983-97. 




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15.2 
Investigator Signature Page 
Protocol #: 
VX15-661-113 
Version #: 
3.0 
Version Date 
19 July 2017 
Study Title: A Phase 3, Open-label Study to Evaluate the Pharmacokinetics, Safety, and 
Tolerability of VX-661 in Combination With Ivacaftor in Subjects 6 Through 11 Years of 
Age With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation 
 
 
I have read Protocol VX15-661-113, Version 3.0 and agree to conduct the study according to 
its terms. I understand that all information concerning VX-661/ivacaftor and this protocol 
supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential.   
 
 
Printed Name 
 
 
Signature 
 
Date 
 


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16 
APPENDIX A: CFTR ALLELE MUTATIONS 
Subjects can either be homozygous for the F508del-CFTR mutation, or heterozygous for the 
F508del-CFTR mutation.  
Heterozygous subjects must have F508del on 1 allele and a second CFTR allele that meets at 
least 1 of the following criteria:  
• Encodes a mutation predicted to have residual function  
• Encodes a mutation with a gating defect clinically demonstrated to be 
ivacaftor-responsive (subjects are eligible for Part A and may be eligible for Part B if 
clinical benefit has been demonstrated in the corresponding adult population) 
• Encodes a mutation that is not likely to respond to VX-661 and/or ivacaftor therapy 
(subjects are not eligible for Part B)  
The lists below represent acceptable mutations for the second CFTR allele for heterozygous 
subjects. 
CFTR Mutations Predicted to Have Residual Function 
2789+5G→A 
D110E 
A455E 
F1074L 
3849+10kbC→T 
D110H 
D579G 
D1152H 
3272-26A→G 
R117C 
S945L 
D1270N 
711+3A→G 
E193K 
S977F 
E831X 
E56K 
L206W 
F1052V 
 
P67L 
A1067T 
K1060T 
 
R74W 
R352Q 
R1070W 
 
Note: Characteristics of residual function mutations: population-level average sweat chloride <86 mmol/L 
(1 standard deviation from the average sweat chloride for the most common processing and trafficking mutation 
based on CFTR2, F508del-CFTR), incidence of pancreatic insufficiency ≤50% based on subjects with at least 
1 copy of the mutation from epidemiologic data(CFTR2) or published literature42-49 and in vitro response to 
ivacaftor, defined as an increase in percent normal chloride transport of ≥10 percentage points in transfected 
FRT cells expressing the CFTR form produced by the mutation. 
 


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CFTR Mutations With a Gating Defect Clinically Demonstrated to Be 
Ivacaftor-Responsive 
R117H 
G178R 
S549N 
S549R 
G551D 
G551S 
G1244E 
S1251N 
S1255P 
G1349D 
Source: CFTR2.org [Internet]. Baltimore (MD): Clinical and functional translation of CFTR. The Clinical and 
Functional Translation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins University, the 
Hospital for Sick Children. Available at: http://www.cftr2.org/. Accessed 15 September 2014. 
The list below represents acceptable mutations for CFTR mutations that are not likely to 
respond to VX-661 and/or ivacaftor therapy; however, this list is non-exhaustive and 
investigators should contact the medical monitor regarding other mutations that may also 
meet study eligibility criteria. Subjects with these mutations are not eligible for Part B. 
CFTR Mutations That Are Not Likely to Respond to VX-661 and/or Ivacaftor Therapy 
(Not eligible for Part B) 
Criteria 
Mutation 
 
 
 
 
Truncation mutations  
• %PI >50% and/or SwCl- 
>86 mmol/L 
• no full-length protein  
Q39X 
Q290X 
G542X 
R792X 
R1162X 
W57X 
G330X 
Q552X 
E822X 
S1196X 
E60X 
W401X 
R553X 
W846X 
W1204X 
R75X 
Q414X 
E585X 
R851X 
S1255X 
E92X 
S434X 
G673X 
Q890X 
W1282X 
Q98X 
S466X 
R709X 
S912X 
Q1313X 
Y122X 
S489X 
K710X 
W1089X 
 
L218X 
Q493X 
L732X 
Y1092X 
 
Q220X 
W496X 
R764X 
E1104X 
 
C276X 
Q525X 
R785X 
R1158X 
 
Canonical splice mutations  
• %PI >50% and/or SwCl- 
>86 mmol/L 
• no or little mature mRNA   
621+1G→T 
405+3A→C 
1717-1G→A 
2622+1G→A 
4374+1G→T 
711+1G→T 
406-1G→A 
1811+1.6kbA→G 
3120+1G→A 
 
711+5G→A 
621+1G→T 
1811+1G→C 
3120G→A 
 
712-1G→T 
1248+1G→A 
1812-1G→A 
3850-1G→A 
 
405+1G→A 
1341+1G→A 
1898+1G→A 
4005+1G→A 
 
Frameshift mutations  
• %PI >50% and/or SwCl- 
>86 mmol/L 
• garbled or truncated 
protein 
663delT 
3905insT 
1677delTA 
3007delG 
2043delG 
2183AA→G 
2184delA 
3876delA 
574delA 
2869insG 
CFTRdele2,3 
1078delT 
2307insA 
2711delT 
3600+2insT 
3659delC 
1154insTC 
4382delAa 
3791delC 
3737delA 
394delTT 
2183delAA 
4016insT 
CFTRdele22,23 4040delA 
2184insA 
2143delT 
2347delG 
457TAT→G 
541delC 


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CFTR Mutations That Are Not Likely to Respond to VX-661 and/or Ivacaftor Therapy 
(Not eligible for Part B) 
Criteria 
Mutation 
 
 
 
 
Class II, III, IV mutations not 
responsive to ivacaftor or 
VX-661  
• %PI >50% and/or SwCl- 
>86 mmol/L,  
OR  
• not responsive in vitro to 
ivacaftor and VX-661) 
A46Db 
S341Pb 
R560T 
R1066C 
N1303K 
T338Ic 
L467Pb 
R560S 
R1066M 
R347H 
R347P 
I507del 
A561E 
L1077Pb 
 
L927P 
V520F 
Y569Db 
H1085Rb 
 
G85E 
A559Tb 
L1065P 
M1101K 
 
%PI: percentage of subjects who are pancreatic insufficient; SwCl-: sweat chloride. 
Notes: CFTR mutations that are not likely to respond to VX-661 and/or ivacaftor therapy were defined using 
3 major sources: biological plausibility for the mutation to respond (i.e., class), evidence of clinical severity on 
a population basis based on the patient registry CFTR2 (average sweat chloride >86 mmol/L, percentage of 
patients with pancreatic insufficiency [%] is >50%), and in vitro testing (mutations that responded with chloride 
transport <10% of wild-type CFTR were considered minimal function and nonresponsive). The clinical severity 
criteria (average sweat chloride >86 mmol/L, %PI >50%) do not specifically apply to the individual subjects to 
be enrolled in this study, but were used to classify the mutation status. 
a 
PI frequency is consistent with a residual function mutation, but this mutation is included because of SwCl- 
data and biological rationale, which suggests that this type of mutation should be severe and not responsive. 
b 
Unpublished data. 
c 
PI frequency is consistent with a residual function mutation, but this mutation is included because of SwCl- 
 
data, low baseline in vitro conductance, and failure for ivacaftor to improve conductance by at least 10% 
 
over baseline. 


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References 
 
42  
Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N et al. Defining the 
disease liability of variants in the cystic fibrosis transmembrane conductance 
regulator gene. Nature Gen 2013; published online 25 August 2013; 
doi:10.1038/ng.274. 
43 
Ren HY, Grove DE, De La Rosa O, Houck SA, Sopha P, Van Goor F, et al. VX-809 
corrects folding defects in cystic fibrosis transmembrane conductance regulator 
protein through action on membrane-spanning domain 1. Mol Biol Cell. 
2013;24(19):3016-24. 
44 
Cebotaru L, Rapino D, Cebotaru V, Guggino WB. Correcting the cystic fibrosis 
 
disease mutant, A455E CFTR. PLoS One. 2014;9[1]:e85183. 
45 
Okiyoneda T, Veit G, Dekkers JF, Bagdany M, Soya N, Xu H, et al. Mechanism-
 
based corrector combination restores ΔF508-CFTR folding and function. Nat Chem 
 
Biol. 2013;9[7]:444-54. 
46 
Padoan R, Bassotti A, Seia M, Ambrosioni A, Fiori S, Prandoni S, et al. Mutation and 
polymorphism report. Human Mutation, Mutation and Polymorphism Report #111. 
2000. Online. Available at: http://journals.wiley.com/1059-
7794/pdf/mutation/mpr111.pdf. 
47 
Padoan R, Genoni S, Moretti E, Seia M, Giunta A, Corbetta C. Genetic and clinical 
 
features of false-negative infants in a neonatal screening programme for cystic 
 
fibrosis. Acta Paediatr 2002; 91:82-7. 
48  
Mercier B, Verlingue C, Lissens W, Silber SJ, Novelli G, Bonduelle M, et al. Is 
Congenital Bilateral Absence of Vas Deferens a Primary Form of Cystic Fibrosis? 
Analyses of the CFTR Gene in 67 Patients. Am J Hum Genet. 1995; 56:272-7. 
49  
Casals T, Bassas L, Ruiz-Romero J, Chillón M, Giménez J, Ramos MD, et al. 
Extensive analysis of 40 infertile patients with congenital absence of the vas deferens: 
in 50% of cases only one CFTR allele could be detected. Hum Genet. 
1995;95(2):205-11. 

SAP_001.pdf: 
SAP VX15-661-113, Version 1.0 
Page 1 of 25 
Vertex Pharmaceuticals Incorporated 
 
 
 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan (Interim Analysis #1):  (Methods) 
Protocol Number VX15-661-113, Version 1.2 
 
A Phase 3, Open-label Study to Evaluate the Pharmacokinetics, Safety, and 
Tolerability of VX-661 in Combination With Ivacaftor in Subjects 6 Through 
11 Years of Age With Cystic Fibrosis, Homozygous or Heterozygous for the 
F508del-CFTR Mutation  
 
Author of SAP:  
 
Version: 1.0  
Version Date of SAP: 11 January 2017 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, MA 02210, USA 
 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 




SAP VX15-661-113, Version 1.0 
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Vertex Pharmaceuticals Incorporated 
 
10.4 Imputation Rules for Missing AE dates ................................................................... 25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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List of Tables 
Table 8-1 
Summaries Planned for Safety Data ................................................................. 14 
Table 10-1 
Study VX15-661-113: Part A Screening .......................................................... 19 
Table 10-2 
Study VX15-661-113: Part A Treatment Period and Safety Follow-up Visit .. 21 
 
List of Figures 
Figure 6-1 
Schematic of Study Design for Part A................................................................ 7 
Figure 6-2 
Schematic of Study Design for Part B ................................................................ 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 
INTRODUCTION 
This SAP is for the interim analysis (IA) following completion of the Part A of the study and 
is based on the following: 
• approved clinical study protocol (CSP) (Version 1.2, dated 26 May 2016), 
• approved electronic case report form (eCRF) (Version 2.0, dated 11 Oct 2016). 
The protocol states that a review of the safety, tolerability, and pharmacokinetic (PK) data 
will be completed by an internal Vertex team after Part A. The objective of this IA is the 
same as the objective for Part A, as listed in Section 4. 
Study VX15-661-113 is a Phase 3, 2-part (Part A and Part B), open-label, multicenter study 
evaluating the PK, safety, and tolerability of multiple doses of tezacaftor (TEZ; VX-661) in 
combination with ivacaftor (IVA; VX-770) in subjects 6 through 11 years of age with CF 
who are homozygous or heterozygous for the F508del-CFTR mutation.  
This SAP (Methods) documents the safety objective of Part A and describes the planned 
statistical analyses and data presentations for the same. Analysis addressing the clinical 
pharmacology objective (i.e., the primary objective of Part A) is described in the interim 
version of the Clinical Pharmacology Data Analysis Plan (CPAP), which will be developed 
separately.  
The Vertex Biometrics Department will perform the analysis of Part A safety data as defined 
in this plan; SAS (Version 9.2 or higher) will be used to generate all statistical outputs 
(tables, figures, listings, and datasets). The SAP will be finalized and approved prior to the 
data cut for the IA and if the methods in this SAP differ from the methods described in the 
protocol, the SAP prevails.  
4 
STUDY OBJECTIVES FOR PART A 
4.1 
Primary Objective 
To evaluate the PK of TEZ and IVA after administration of multiple doses of TEZ in 
combination with IVA 


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4.2 
 Secondary Objectives 
• To evaluate the PK of TEZ metabolites, M1-TEZ and M2-TEZ, and IVA metabolites, 
M1-IVA and M6-IVA, after administration of multiple doses of TEZ in combination 
with IVA 
• To evaluate the safety and tolerability of multiple doses of TEZ in combination with 
IVA  
5 
STUDY ENDPOINTS FOR PART A 
5.1 
Primary Endpoints 
TEZ and IVA PK parameters, including maximum observed concentration (Cmax), area under 
the concentration versus time curve during a dosing interval (AUCτ), and other PK 
parameters as appropriate 
5.2 
Secondary Endpoints 
• M1-TEZ, M2-TEZ, M1-IVA, and M6-IVA PK parameters, including Cmax, AUCτ, 
and other PK parameters as appropriate 
• 
Safety and tolerability of TEZ in combination with IVA as determined by adverse 
events (AEs), clinical laboratory values (serum chemistry, hematology, coagulation 
studies, lipids, vitamins, and urinalysis), standard 12-lead electrocardiograms (ECGs), 
vital signs, pulse oximetry, and spirometry 
 
6 
STUDY DESIGN  
6.1 
Overview of Study Design 
This is a Phase 3, 2-part (Part A and Part B), open-label, multicenter study evaluating the PK, 
safety, and tolerability of multiple doses of TEZ in combination with IVA in subjects 
6 through 11 years of age with CF who are homozygous or heterozygous for the 
F508del-CFTR mutation. Efficacy will also be evaluated in Part B. Part A is composed of 
2 weight-based cohorts, which will be enrolled simultaneously, and Part B is composed of a 
single cohort. Subjects who participate in Part A may participate in Part B. 


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Part A 
Approximately 16 subjects total, approximately 8 subjects in each cohort (Cohort 1 [subjects 
weighing <25 kg at baseline] and Cohort 2 [subjects weighing ≥25 kg at baseline]), are 
planned for enrollment. 
Part A includes the following: 
• Screening Period (Day -28 through Day -1) 
• Treatment Period (Day 1 through Day 14) 
• Washout Period (Day 14 to Day 28 [± 3 days]) 
• Safety Follow-up Visit (14 [± 3] days after the last dose of study drug) 
Figure 6-1 depicts the schematic for the Part A study design. After obtaining written 
informed consent (and assent, if applicable), Screening Visit assessments will be completed 
at any time during the period of 4 weeks (Day -28 through Day -1) before the first dose of the 
study drug (Day 1). During the Treatment Period, subjects will be administered TEZ 50 mg 
daily (qd) in combination with IVA, either 75 mg (subjects <25 kg at baseline) or 150 mg 
(subjects ≥25 kg at baseline), every 12 hours (q12h) for 14 days. A 2-week Washout Period 
(Day 14 to Day 28 [± 3 days]) will be included in order to evaluate the off-drug response. A 
Safety Follow-up Visit (SFUV) is scheduled to occur 14 (± 3) days after the last dose of 
study drug for all subjects, including subjects who permanently discontinue from study 
treatment for any reason. 
A review of safety, tolerability, and PK data will be completed by an internal Vertex team 
after Part A to select the TEZ dose for Part B.  
Figure 6-1 
Schematic of Study Design for Part A 
 


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Part B 
Approximately 56 subjects are planned for enrollment. Assuming a 10% dropout rate, 
approximately 50 subjects are expected to complete Part B.  
Part B includes the following: 
• Screening Period (Day -28 through Day -1) 
• Treatment Period (Day 1 through Week 24 [± 5 days]) 
• SFUV (4 weeks [± 7 days] after the last dose of study drug) 
Figure 6-2 depicts the schematic for the Part B study design. After obtaining written 
informed consent (and assent, if applicable), Screening Visit assessments will be completed 
at any time during the period of 4 weeks (Day -28 through Day -1) before the first dose of 
study drug (Day 1). During the Treatment Period, subjects will be administered TEZ (dose to 
be determined in Part A) in combination with ivacaftor, either 75 mg (subjects <25 kg at 
baseline) or 150 mg (subjects ≥25 kg at baseline), q12h for 24 weeks. At the Week 24 Visit, 
subjects who complete study drug treatment will be offered the opportunity to enroll in an 
extension study evaluating TEZ in combination with IVA (enrollment will be based on the 
eligibility criteria specified within the extension study). Subjects who prematurely 
discontinue study drug treatment are not eligible to rollover into the extension study. 
A SFUV is scheduled to occur 4 weeks (± 7 days) after the last dose of study drug. The 
SFUV is not required for subjects who have enrolled in the extension study within 28 days 
after the last dose of study drug. Subjects who permanently discontinue study drug treatment 
will have an Early Treatment Termination (ETT) Visit and a SFUV. 
Figure 6-2 
Schematic of Study Design for Part B 
 


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6.2 
Sample Size and Power for Part A 
Sample size calculations were conducted to estimate the precision in determining TEZ 
clearance in pediatric subjects in the 2 weight-based cohorts. The method used 
noncompartmental analysis-based PK parameters, such as clearance and volume, in adults 
with the assumption that there is similar variability in clearance in adults and pediatric 
subjects 6 through 11 years of age within each weight group. The calculations indicate that 
data from 8 subjects will allow 80% power to target a 95% CI within 60% and 140% of the 
geometric mean estimate of clearance for TEZ in each pediatric subgroup (cohort). 
Therefore, approximately 16 subjects (approximately 8 subjects in each cohort) are planned 
for enrollment in Part A.  
6.3 
Randomization for Part A 
Not applicable because subjects will receive treatment based on weight at baseline. 
6.4 
 Blinding and Unblinding for Part A 
Not applicable because this is an open-label study. 
 
7 
ANALYSIS SETS FOR PART A 
The following analysis sets are defined: Part A - All Subjects Set and Part A - Safety Set. 
Assignment of subjects to analysis sets will be done prior to the data-cut for the IA following 
completion of Part A.  
The Part A - All Subjects Set is defined as subjects who consented to Part A of the study or 
received at least 1 dose of study drug in Part A of the study.  
The Part A - Safety Set is defined as all subjects who received at least 1 dose of study drug 
in Part A of the study.  
8 
STATISTICAL ANALYSIS FOR PART A 
8.1 
General Considerations  
The IA will be restricted to data only from Part A (includes the off-treatment period between 
the Day 14 Visit and SFUV).  
All individual subject data for those who consented to Part A or were dosed in Part A will be 
presented in data listings. The Schedule of Assessments is provided in Section 10.1. The 
precision standards are provided in Section 10.3. 
Continuous variables will be summarized by treatment (TEZ 50 mg qd + IVA 75 mg q12h, 
TEZ 50 mg qd + IVA 150 mg q12h) and overall using the following descriptive summary 
statistics: number of subjects (n), mean, standard deviation (SD), median, minimum value 
(min), and maximum value (max).  


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Categorical variables will be summarized by treatment (TEZ 50 mg qd + IVA 75 mg q12h, 
TEZ 50 mg qd + IVA 150 mg q12h) and overall using counts and percentages.  
Treatment-emergent (TE) period will correspond to data from the first dose of study drug 
in Part A to the SFUV in Part A or 14 days after the last dose in Part A for subjects who do 
not have a SFUV.  
Baseline for Part A is defined as the most recent non-missing measurement (scheduled or 
unscheduled) collected prior to the first dose of study drug in Part A. For ECGs, baseline will 
be the average of the 3 pretreatment measurements on Day 1 of Part A.  
Absolute change from baseline will be calculated as post-baseline value – baseline value.   
Relative change from baseline will be calculated as 100 x (post-baseline value – baseline 
value)/ baseline value.   
Unscheduled Visits: Subject data obtained during unscheduled visits will not be summarized 
but will be included in subject data listings only, except for the analysis of the maximum 
value during TE period and maximum changes from baseline during TE period (see Section 
8.3.3). Unscheduled visit values will not be used to impute missing scheduled visit values, 
except for the baseline calculation. 
 
Visit Windowing Rules: Due to the short duration of the Treatment Period, visit windowing 
will not add significant value to the analysis and therefore will not be applied. 
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. 
8.2 
Background Characteristics for Part A 
8.2.1 Subject Disposition 
The number of subjects in the following categories will be presented by treatment group:  
• Part A - All Subjects Set  
• Part A - Safety Set 
In the same table, the number and percentage (based on Part A - Safety Set) of subjects in 
each of the following disposition categories will be presented by treatment group: 
• Completed study drug treatment  
• Prematurely discontinued the treatment (TEZ or IVA) and the reasons for 
discontinuations  
• Completed study 
• Prematurely discontinued study and the reasons for discontinuations 


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A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuations.  
8.2.2 Demographics and Baseline Characteristics 
Demographic and baseline characteristics data will be summarized by treatment group based 
on the Part A - Safety Set. 
Demographic data will include the following: 
• Age at screening 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and Other) 
Baseline characteristics will include the following: 
• Weight (kg)  
• Height (cm)  
• BMI (kg/m2)  
• FEV1 
• ppFEV1  
8.2.3 Medical History 
Medical history in this study will be coded by using the Medical Dictionary for Regulatory 
Activities (MedDRA). 
For the Part A - Safety Set, medical history will be summarized descriptively by treatment 
group, system organ class (SOC) and preferred term (PT). The corresponding data listing will 
also be provided. 
In addition, a listing of subjects reported to have had positive cultures for respiratory 
pathogens in 2 years prior to screening (i.e., answered yes on the respiratory microbiology 
form) will be presented. A listing of ophthalmology history will also be presented. 
8.2.4 Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced (WHO-DDE) and categorized as follows:  
• Prior medication: any medication that started before the first dose of study drug in 
Part A, regardless of when it ended. 


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• Concomitant medication: medication continued or newly received during the TE 
period for Part A.  
• Post-treatment medication: medication continued or newly received after the TE 
period for Part A. For those subjects from Part A who enrolled in Part B, medications 
that continued or were newly received on or after the first dose of study drug in Part 
B will not be considered as post-treatment medication. 
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 partially missing 
start/end date or time and it cannot be determined whether the medication was taken before 
initial dosing, concomitantly, or post-treatment, it will be considered as prior, concomitant, 
and post-treatment. 
For the Part A - Safety Set, concomitant medications will be summarized descriptively by 1) 
treatment group, preferred name (PN); and 2) treatment group, anatomic class (ATC) level 1, 
ATC level 2, and PN. Prior medications and post-treatment medications will be listed for 
each subject.  
As an intermediate step for programming purposes, medications with missing or partially 
missing start dates will use 2000 to impute for the missing year, January for the missing 
month, and 1 for the missing day. Medications with missing or partially missing stop dates 
will use 2050 to impute for the missing year, December for the missing month, and the last 
day of the month for the missing day.  
8.2.5 Study Drug Exposure 
Exposure summaries will be based on the Part A - Safety Set and presented by treatment 
group. 
Duration of study drug exposure is defined as follows: last dose date in Part A – first dose 
date in Part A + 1 day, regardless of any interruption in dosing between the first and the last 
dose.  
Duration of study drug exposure will be summarized descriptively (number, mean, SD, 
median, minimum, and maximum).  
8.2.6 Important Protocol Deviations 
An important protocol deviation (IPD) is any PD that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a 
subject’s rights, safety or well-being. The rules for identifying IPDs will be finalized prior to 
the data-cut for the IA following completion of Part A. The rules will be developed by a team 
consisting of, at a minimum, the Medical Monitor, the Study Biostatistician, the Clinical 
Data Manager, and the Clinical Operations Study Lead. This team will review the list of 
protocol deviations, to develop rules for identifying IPDs.   


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The protocol deviations that should be considered as potential IPDs include, but are not 
limited to: 
• Violation of subjects rights, safety or well-being 
• Subject entered the study despite violation of an inclusion or exclusion criteria 
• Subject received the wrong treatment or incorrect doses  
Occurrence of any of these events should be considered as potential IPDs, but the team 
should categorize them as IPDs only if they have the potential to significantly affect 
interpretation of study results or significantly affects the subject’s rights, safety or well-
being. The team should construct rules for identifying IPDs rather than identifying individual 
subjects with IPDs.  
IPDs (from the site deviation log) will be provided as a subject data listing. 
8.3 
Safety Analysis for Part A 
Safety is a secondary objective of this study, and the safety endpoints included for analyses 
are as follows: 
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory measurements (chemistry, hematology, coagulation, lipids, 
vitamins, and urinalysis) 
• Standard 12-lead ECG 
• Vital signs 
• Pulse oximetry 
• Spirometry 
Safety analyses will be performed by treatment group. Safety analysis will be conducted for 
the Part A - Safety Set and subjects analyzed according to the treatment they received. Only 
descriptive analysis of safety will be performed (i.e., no statistical hypothesis testing will be 
performed). 
Table 8-1 shows the safety summaries (e.g., raw value, change from baseline, incidence, and 
clinical abnormalities) that will be summarized for TEAEs, clinical laboratory values, 
12-lead ECG, vital signs, pulse oximetry, spirometry and physical examination.  
The incidence of TEAEs will be summarized. For the non-AE safety evaluations (clinical 
laboratory, ECGs, vital signs, pulse oximetry and spirometry), raw values, and changes from 
baseline will be summarized as indicated in Table 8-1. For example, an “X” under the raw 
value column (second column) means that the raw values for the safety evaluation will be 
summarized; an “X” under the Change column (third column) means that change will be 
summarized.  
Throughout this section, “change” refers to absolute change from baseline. 


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Table 8-1 
Summaries Planned for Safety Data 
Safety Assessment 
Incidence 
Raw Value 
Change 
Clinical 
Abnormalities 
TEAEs 
X 
 
 
Present in listing only 
Chemistry/Hematology/ 
Coagulation/Vitamins/ 
Lipids 
 
X 
X 
Present in listing only 
Urinalysis 
 
Present in listing only 
 
Present in listing only 
12-lead ECG 
 
X 
X 
Present in listing only 
Vital signs 
 
X 
X 
Not applicable 
Pulse oximetry 
 
X 
X 
Not applicable 
Spirometry 
 
X 
X 
Not applicable 
Physical Examination 
 
Present in listing only 
 
Not applicable 
TEAE: Treatment-emergent adverse event; ECG: electrocardiogram; X: safety assessment will be summarized 
in tables. 
8.3.1 Adverse Events  
AEs will be coded according to MedDRA and categorized as pretreatment AEs, 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 during the TE 
period for Part A.  
• Post-treatment AE: any AE that increased in severity or that was newly developed 
beyond the TE period for Part A. For subjects from Part A who enrolled in Part B, an AE 
that increased in severity on or after the first dose of study drug in Part B will not be 
considered as a post-treatment AE. 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study treatment for Part A, then the AEs will be classified as TEAEs. As an 
intermediate step for programming purposes, imputation rules for missing or partially 
missing AE start/end dates are defined in Section 10.4. 
AE summary tables will be presented for TEAEs only and will include the following: 
(1) all TEAEs  
(2) related (defined as possibly related, related, or missing) TEAEs 
(3)  serious TEAEs  
(4) Grade 3/4 TEAEs  
(5) TEAEs leading to treatment discontinuation  


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Summaries will be presented by MedDRA SOC and PT using frequency counts and 
percentages by treatment group. A subject with multiple occurrences of the same TEAE or a 
continuing TEAE will be counted only once.  
An overview of all TEAEs will be summarized in the following categories: 
• Any TEAEs  
• TEAEs by relationship 
• Related TEAEs 
• TEAEs by severity 
• Grade 3/4 TEAEs 
• Serious TEAEs 
• Related Serious TEAEs 
• TEAEs leading to treatment discontinuation (this will include TEAEs leading to 
discontinuation of either TEZ tablet or the IVA tablet) 
• TEAEs leading to treatment interruption (this will include TEAEs leading to 
interruption of either TEZ tablet or the IVA tablet) 
• TEAEs leading to death 
In addition, a listing containing individual subject adverse event data for TEAEs leading to 
treatment discontinuation, treatment interruptions, SAEs and all deaths will be provided 
separately, with a flag indicating the TEAE status for SAEs and deaths. 
For all AEs, the action taken on the CRF for TEZ is collected separately from the AE action 
taken for IVA. As a result, it is possible that in the AE dataset, the AE actions taken for the 
two agents are different. The summary of “TEAE Leading to Treatment Discontinuation” 
and listings of "TEAE Leading to Treatment Discontinuation", "TEAE Leading to Treatment 
Interruption" account for discontinuation and interruptions for either agent.  
8.3.2 Clinical Laboratory 
For treatment-emergent laboratory measurements, the raw values and change from baseline 
values of the continuous hematology, chemistry, vitamin, lipids and coagulation results will 
be summarized in SI units by treatment group at each scheduled time point.  
Results of urinalysis and the urine/serum pregnancy test will be listed in individual subject 
data listings only.  
In addition, a listing containing individual subject hematology, chemistry, vitamin, lipids and 
coagulation results outside the reference ranges will be provided. This listing will include 
data from scheduled and unscheduled visits. 


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8.3.3 Standard 12-Lead Electrocardiogram 
For treatment-emergent ECG measurements, a summary of raw values and change from 
baseline values will be provided by treatment group at each scheduled time point for the 
following standard 12-lead ECG measurements: PR, QTc for HR intervals (QTcF), QRS 
duration, and HR.  
In addition, the number and percentage of subjects by maximum value of QT/QTcF intervals 
during TE period, categorized as ≤450 msec, >450 msec and ≤480 msec, >480 msec and 
≤500 msec, and >500 msec, as well as maximum change from baseline value of QT/QTcF 
intervals during TE period, categorized as ≤0 msec, >0 and ≤30 msec, >30 msec and 
≤60 msec, and >60 msec, will be provided. 
8.3.4 Vital Signs 
For treatment-emergent vital signs measurements, the raw values and change from baseline 
values will be summarized by treatment group at each scheduled time point for the following: 
systolic and diastolic blood pressure (mm Hg), body temperature (oC), HR (beats per 
minute), and respiratory rate (breaths per minute).  
8.3.5 Pulse Oximetry 
For treatment-emergent percent of oxygen saturation by pulse oximetry, a summary of raw 
values and change from baseline values will be provided by treatment group at each 
scheduled time point.  
8.3.6 Spirometry 
For spirometry measurements, a summary of raw values, absolute and relative change from 
baseline values will be provided by treatment group at each scheduled time point for the 
following parameters: FEV1 (L), forced vital capacity (FVC) (L), FEV1/FVC (ratio), forced 
expiratory flow (FEF25%-75%) (L/s), ppFEV1, percent predicted FVC, percent predicted FEF, 
and percent predicted FEV1/FVC. The predicted values for spirometry will be calculated 
using the Global Lung Initiative (GLI) equation1. See section 10.2 for details on GLI 
equation. 
8.3.7 Physical Examination 
Physical examination findings will be presented as a data listing only. 
8.3.8 Other Safety Analyses 
Not Applicable. 


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9 
REFERENCES 
1. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 
2012 equations. Eur Respir J. 2012;40(6):1324-43. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10 APPENDICES 
10.1 
Schedule of Assessments 
Table 10-1 
Study VX15-661-113: Part A Screening 
Assessment 
Screening Visit (Day -28 to Day -1) 
Informed consent (and assent, if applicable) 
X 
Demographics 
X 
Medical history 
X 
Ophthalmological historya 
X 
Weight, height, and vital signsb,c 
X 
Pulse oximetryc 
X 
Ophthalmologic examinationa,d 
X 
Full physical examinatione 
X 
Standard 12-lead ECGf 
X 
Spirometryg 
X 
Sweat chlorideh 
X 
CFTR genotypei,j 
X 
Serum pregnancy test (female subjects of childbearing potential)i,k 
X 
Serum chemistryi 
X 
Vitamin levelsi 
X 
Hematology and coagulation studiesi 
X 
Urinalysisi 
X 
Inclusion/exclusion criteria review  
X 
Prior and concomitant medications 
Continuous from signing of ICF (and assent form, if 
applicable) through Safety Follow-up Visit 
AEs and SAEs 
Continuous from signing of ICF (and assent form, if 
applicable) through Safety Follow-up Visit 
                                                 
 
a 
Refer to Section 11.7.6 of CSP for details. 
b 
Weight and height will be measured with shoes off. BMI will be derived from assessment of height and weight. 
c 
Vital signs and pulse oximetry will be collected after the subject has been seated or supine for at least 5 minutes (see 
Section 11.7.4 of CSP). 
d 
An ophthalmologic examination will be conducted by a licensed ophthalmologist. The examination does not need to be 
repeated if there is documentation of an examination meeting protocol criteria that was conducted within 3 months 
before the start of the Screening Period. Subjects with documentation of bilateral lens removal do not need the 
ophthalmologic examination. Subjects with clinically significant cataracts, lens opacity, Y suture, or lamellar rings will 
be excluded (refer to Section 9.2 of CSP). 
e 
Refer to Section 11.7.4 of CSP for details. 
f 
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes (refer to 
Section 11.7.5 of CSP). The ECG will be performed before any other procedures that may affect heart rate. 
g 
Spirometry may be performed pre- or post-bronchodilator (refer to Section 11.6.1 of CSP).  
h  
A sweat chloride test must be performed if an eligible sweat chloride value is not available in the subject’s medical 
records (refer to Section 11.6.2 of CSP). For subjects using a sweat chloride value documented in their medical record 
to establish eligibility, the sweat chloride test at the Screening Visit is optional.  
i  
Refer to Section 11.7.2 of CSP for details.  
j  
All subjects will be tested to assess CFTR genotype, regardless of availability of a previous CFTR genotype lab report. 
In subjects with confirmed R117H mutation, linkage to poly-T track polymorphisms will also be determined from a 
second specimen. Specific instructions will be provided in the Laboratory Manual. 
k  
Any female subject who does not meet the criteria for non-childbearing potential (refer to Section 11.7.8.1 of CSP)  is 
considered to be of  childbearing potential and must have a serum pregnancy test. 


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Table 10-1 
Study VX15-661-113: Part A Screening 
Assessment 
Screening Visit (Day -28 to Day -1) 
AE: adverse event; BMI: body mass index; CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; 
ECG: electrocardiogram; ICF: informed consent form; SAE: serious adverse event 


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Table 10-2 
Study VX15-661-113: Part A Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Day 1 
 
Day 2 
 
Day 4 
(± 1 day) 
Day 7 
(± 1 day) 
Day 14 
 
Day 21 
(± 1 day) 
Day 28 
Safety Follow-up Visit 
(14 [± 3] days after the last 
dose) 
Clinic visit 
X 
X 
 
X 
X 
X 
X 
Telephone contactb 
 
 
X 
 
 
 
 
Safety Assessments 
Weight and heightc 
X 
 
 
 
X 
 
X 
Vital signsd 
X 
X 
 
X 
X 
 
X 
Pulse oximetryd 
X 
X 
 
X 
X 
 
X 
Full physical examinatione 
X 
 
 
 
X 
 
X 
Standard 12-lead ECGf 
Xg 
X 
 
X 
Xg 
 
X 
Spirometryh 
X 
X 
 
X 
X 
 
X 
Pregnancy test (female subjects of childbearing potential)i,j 
X 
(urine) 
 
 
 
 
 
X 
(serum) 
Serum chemistryj 
X 
 
 
X 
X 
 
X 
Lipid panelj,k 
X 
 
 
 
X 
 
 
Vitamin levelsj 
 
 
 
 
X 
 
 
Hematologyj 
X 
 
 
X 
X 
 
X 
Coagulation studiesj 
 
 
 
 
 
X 
 
                                                 
 
a 
All assessments will be performed before study drug dosing unless noted otherwise (refer to Section 11.1 of CSP). When repeats of an assessment are required postdose at a given 
 
visit, the assessment will be collected only once if study drug is not administered on the day of the visit (i.e., study drug interruption or permanent discontinuation of study drug). 
b  
Telephone contact will be made to assess the subject's status, any AEs, concomitant medications, treatments, and procedures. 
c 
Weight and height will be measured with shoes off. BMI will be derived from assessment of height and weight. 
d 
Vital signs and pulse oximetry will be collected after the subject has been seated or supine for at least 5 minutes (refer to Section 11.7.4 of CSP). 
e 
At other visits, symptom-directed physical examinations will occur if triggered by AEs or if deemed necessary by the investigator (refer to Section 11.7.4 of CSP). 
f 
Standard 12-lead ECGs will be performed before study drug dosing (unless noted otherwise) after the subject has been supine for at least 5 minutes (refer to Section 11.7.5 of CSP). 
g 
At the Day 1 and Day 14 Visits, standard 12-lead ECGs will be performed after the subject has been supine for at least 5 minutes at the following times: before the morning dose of study 
drug, and at 1.5, 3, 4, and 6 hours after the morning dose of study drug. ECGs collected on Day 1 before study drug dosing will be performed in triplicate. A window of ±15 minutes will 
be allowed around the nominal times for all postdose ECG assessments.  
h 
Spirometry must be performed for all subjects before dosing and should be performed pre-bronchodilator (refer to Section 11.6.1 of CSP). 
i  
Any female subject who does not meet the criteria for non-childbearing potential (refer to Section 11.7.8.1 of  CSP) is considered to be of childbearing potential and must have a 
 
pregnancy test.  
j  
Refer to Section 11.7.2 of CSP for details. 
k  
Blood samples will be collected for the lipid panel following at least a 4-hour fast.  


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Table 10-2 
Study VX15-661-113: Part A Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Day 1 
 
Day 2 
 
Day 4 
(± 1 day) 
Day 7 
(± 1 day) 
Day 14 
 
Day 21 
(± 1 day) 
Day 28 
Safety Follow-up Visit 
(14 [± 3] days after the last 
dose) 
Urinalysisj 
X 
 
 
 
X 
 
 
Concomitant medications, treatments, and procedures 
Continuous from signing of ICF (and assent form, if applicable) through Safety Follow-up Visit 
AEs and SAEs 
Continuous from signing of ICF (and assent form, if applicable) through Safety Follow-up Visit 
PK Assessments 
PK Sampling 
Xl 
Xl 
 
 
Xm 
Xm 
Xm 
Study Drug Administration 
VX-661 + IVAn 
VX-661 qd + IVA q12h 
Day 1 through Day 14 (morning dose only on Day 14) 
 
 
AE: adverse event; BMI: body mass index; CF: cystic fibrosis; ECG: electrocardiogram; ICF: informed consent form; IVA: ivacaftor; PK: pharmacokinetic; q12h: every 12 hours; qd: daily; 
SAE: serious adverse event 
 
                                                 
 
l 
PK blood samples will be collected on Day 1 at 1, 2, 4, 5, and 24 hours (i.e., predose on Day 2) after the morning dose of study drug on Day 1. Acceptable windows for sampling times 
are shown in Table 11-1 of CSP. 
m 
PK blood samples will be collected before the morning dose of study drug on Day 14 and at 1, 2, 4, and 5 hours after the morning dose of study drug on Day 14. A PK blood sample will 
also be collected at 168 hours (i.e., Day 21) after the morning dose of study drug on Day 14 and at the Safety Follow-up Visit. Acceptable windows for sampling times are shown in Table 
11-1 of CSP.  
n 
The study drug should be administered approximately 30 minutes after the start of consuming fat-containing food (e.g., standard “CF” high-fat, high-calorie meal or snack). Refer to 
Section 9.3 of CSP for details on study restrictions and Section 10.2 of CSP for details on study drug administration (e.g., fasting requirements). On days of scheduled visits, the dose of 
study drug will be administered at the clinical site after predose assessments have been completed. The last dose of study drug will be the morning dose on Day 14. 


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10.2 
GLI Regression Equation and Implementation 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Quanjer GLI-2012 Regression Equations and Lookup Tables. Philip H. Quanjer, Sanja 
Stanojevic, Tim J. Cole, Janet Stocks. Version 7 April 2013. Available at: http://www.ers-
education.org/guidelines/global-lung-function-initiative/tools/quanjer-gli-2012-regression-
equations-and-lookup-tables.aspx. Accessed 08 December 2015.  
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Implementing GLI-2012 regression equations. Philip H. Quanjer, Sanja Stanojevic, Tim J. 
Cole, Janet Stocks. Version 19 July 2015. Available at: http://www.ers-
education.org/guidelines/global-lung-function-initiative/gli-2012-explained.aspx. Accessed 
08 December 2015.   
GLI-2012 - SAS Macro. Sanja Stanojevic. Version 2, 7 April 2013. Available at: 
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/sas-macro.aspx. 
Accessed 08 December 2015.  
 
 
 
 
 
 
 


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10.3 
Standards for Safety Variable Display in TFLs 
Continuous Variables 
 
The precision for continuous variables has been specified in the Vertex Standard 
Programming Rules document (Version 1.0, December 2015): 
Categorical Variables: Percentages will be presented to 1 decimal place. 


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10.4 
Imputation Rules for Missing AE dates 
 
Imputation rules for missing or partial AE start date are defined below: 
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. 
 


  
 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
Methods 
Part B 
Protocol Number VX15-661-113, Version 3.0 
 
A Phase 3, Open-label Study to Evaluate the Pharmacokinetics, Safety, and 
Tolerability of VX-661 in Combination With Ivacaftor in Subjects 6 Through 
11 Years of Age With Cystic Fibrosis, Homozygous or Heterozygous for the 
F508del-CFTR Mutation  
 
Author of SAP:  
 
Version: 1.0  
Version Date of SAP: 22 June 2018 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, MA 02210, USA 
 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations.  Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 




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9.4.6.3 
Spirometry .......................................................................................................... 21 
10 Summary of Planned Interim Analysis................................................................................ 21 
11 REFERENCES ...................................................................................................................... 22 
12 APPENDICES ........................................................................................................................ 23 
12.1 Schedule of Assessments .................................................................................................. 23 
12.2 Analysis Visit Window Mapping Rules for Efficacy and Safety Measurement .............. 23 
12.3 Standards for Safety and Efficacy Variable Display in TFLs .......................................... 25 
12.4 BMI-for-age z-score ......................................................................................................... 25 
12.5 Imputation Rules for Missing AE dates ........................................................................... 25 
12.6 Details of GLI Equations for Calculating ppFEV1 ........................................................... 27 
12.7 Threshold Analysis Criteria .............................................................................................. 28 
 
 
 
List of Tables 
Table 9-1 
Logic for Determining the Category of a Medication .............................................. 14 
List of Figures 
Figure 7-1 
Schematic of Study Design for Part A........................................................................ 9 
Figure 7-2 
Schematic of Study Design for Part B ...................................................................... 10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
bpm 
beats per minute 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire – Revised 
CFTR 
cystic fibrosis transmembrane conductance regulator  
CI 
confidence interval 
CRF 
case report form 
CRO 
contract research organization 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDC 
VX-661 100-mg/IVA 150-mg fixed-dose tablet 
FEF25-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity  
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
IVA 
ivacaftor 
LS means 
Least squares means 
LFT 
liver function test 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum value 
MMRM 
mixed model repeated measure 
N 
number of subjects 
PD 
pharmacodynamic/pharmacodynamics  
PK 
pharmacokinetic/pharmacokinetics 
ppFEV1 
percent predicted FEV1 
PT 
preferred term 
q12h 
every 12 hours 
QRS 
Q, R, and S-wave define the QRS-complex in an ECG 
QT 
QT interval: The duration of ventricular depolarization and subsequent 
repolarization; it is measured from the beginning of the QRS complex to the end 
of the T wave 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate with Fridericia’s correction  
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 


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Abbreviation 
Term 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHODD 
World Health Organization Drug Dictionary Enhanced 
 
 
 
 
 


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4 
INTRODUCTION 
This statistical analysis plan (SAP) Methods, which describes the planned analyses for Study 
VX15-661-113 Part B, is based on the following: 
• approved clinical study protocol (CSP) (Version 3.0, dated 19 July 2017), 
• approved electronic case report form (eCRF) (Version 3.0, dated 25 Sep 2017). 
Study VX15-661-113 is a Phase 3, 2-part (Part A and Part B), open-label, multicenter study 
evaluating the PK, safety, and tolerability of multiple doses of tezacaftor (TEZ; VX-661) in 
combination with ivacaftor (IVA; VX-770) in subjects 6 through 11 years of age with CF who are 
homozygous or heterozygous for the F508del-CFTR mutation.  
Part A has been completed before initiation of Part B, and the data have been analyzed based on a 
separate SAP for Part A (version 1.0, dated 11 January 2017).  
The pharmacokinetic (PK) of TEZ/IVA also will be evaluated in the study. The relevant PK 
analyses will be documented separately in the clinical pharmacology analysis plan (CPAP) for the 
study. 
The Vertex Biometrics Department or designee will perform the analysis of Part B safety and 
efficacy data as defined in this plan; SAS (Version 9.4 or higher) will be used to generate all 
statistical outputs (tables, figures, listings, and datasets). The SAP will be finalized and approved 
prior to the final clinical data lock.  If the methods in this SAP differ from the methods described 
in the protocol, the SAP prevails. Unless otherwise specified, Study VX15-661-113 in the rest of 
this document pertains to Study VX15-661-113 Part B.  
5 
STUDY OBJECTIVES FOR PART B 
5.1 
Primary Objective 
To evaluate the safety and tolerability of VX-661 in combination with ivacaftor through Week 24 
5.2 
Secondary Objectives 
• To evaluate the PK of VX-661, M1-661, M2-661, ivacaftor, M1-ivacaftor, and M6-ivacaftor 
after administration of multiple doses of VX-661 in combination with ivacaftor 
• To evaluate the efficacy of VX-661 in combination with ivacaftor through Week 24 
 
6 
STUDY ENDPOINTS FOR PART B 
6.1 
Primary Endpoints 
Safety and tolerability of VX-661 in combination with ivacaftor as determined by adverse events 
(AEs), clinical laboratory values (serum chemistry, hematology, coagulation studies, lipids, 
vitamins, and urinalysis), standard 12-lead electrocardiograms (ECGs), vital signs, pulse 
oximetry, ophthalmologic examinations, and spirometry 


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6.2 
Secondary Endpoints 
• VX-661, M1-661, M2-661, ivacaftor, M1-ivacaftor, and M6-ivacaftor PK parameters, 
including Cmax, AUCτ, and other PK parameters as appropriate 
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline through Week 24 
• Relative change in ppFEV1 from baseline through Week 24 
• Absolute change in weight and weight-for-age z-score from baseline at Week 24 
• Absolute change in height and height-for-age z-score from baseline at Week 24 
• Absolute change in body mass index (BMI) and BMI-for-age z-score from baseline at 
Week 24 
• Absolute change in sweat chloride from baseline through Week 4 
• Absolute change in sweat chloride from baseline through Week 24  
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score 
from baseline through Week 24 
7 
STUDY DESIGN  
7.1 
Overview of Study Design 
This is a Phase 3, 2-part (Part A and Part B), open-label, multicenter study evaluating the PK, 
safety, and tolerability of multiple doses of VX-661 in combination with ivacaftor in subjects 
6 through 11 years of age with CF who are homozygous or heterozygous for the F508del-CFTR 
mutation. Efficacy will also be evaluated in Part B.  This SAP describes the analysis plan for Part 
B, but a description of Part A study design is included below for reference. 
Part A is composed of 2 weight-based cohorts, which will be enrolled simultaneously, and Part B 
is composed of a single cohort. Subjects who participated in Part A and are eligible to  participate 
in Part B if Part B eligibility criteria are met. All genotypes listed in Section 16 of the protocol are 
eligible in Part A. Each genotype for which clinical benefit has been demonstrated in the 
corresponding adult population are eligible in Part B, please see details in the protocol. 
Part A (Completed) 
Up to approximately 16 subjects total were planned for enrollment across Cohort 1 (subjects 
weighing <25 kg at baseline) and Cohort 2 (subjects weighing ≥25 kg at baseline).  
Part A included the following: 
• Screening Period (Day -28 through Day -1) 
• Treatment Period (Day 1 through Day 14) 


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• Washout Period (Day 14 to Day 28 [± 3 days]) 
• Safety Follow-up Visit (14 [± 3] days after the last dose of study drug) 
Figure 7-1 depicts the schematic for the Part A study design. After obtaining written informed 
consent (and assent, if applicable), Screening Visit assessments were completed at any time 
during the period of 4 weeks (Day -28 through Day -1) before the first dose of the study drug 
(Day 1). During the Treatment Period, subjects were administered VX-661 50 mg daily (qd) in 
combination with ivacaftor, either 75 mg (subjects <25 kg at baseline) or 150 mg (subjects ≥25 kg 
at baseline), every 12 hours (q12h) for 14 days. A 2-week Washout Period (Day 14 to Day 28 
[± 3 days]) were included in order to evaluate the off-drug response. A Safety Follow-up Visit is 
scheduled to occur 14 (± 3) days after the last dose of study drug for all subjects, including 
subjects who permanently discontinue from study treatment for any reason. 
A review of safety, tolerability, and PK data has been completed by an internal Vertex team after 
Part A to select the VX-661 dose for Part B.   
Figure 7-1 
Schematic of Study Design for Part A 
 
Part B 
Approximately 56 subjects are planned for enrollment. Assuming a 10% dropout rate, 
approximately 50 subjects are expected to complete Part B.  
Part B includes the following: 
• Screening Period (Day -28 through Day -1) 
• Treatment Period (Day 1 through Week 24 [± 5 days]) 
• Safety Follow-up Visit (4 weeks [± 7 days] after the last dose of study drug) 
Figure 7-2 of protocol depicts the schematic for the Part B study design. After obtaining written 
informed consent (and assent, if applicable), Screening Visit assessments will be completed at 
any time during the period of 4 weeks (Day -28 through Day -1) before the first dose of study 


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drug (Day 1). During the Treatment Period, subjects will be administered VX-661 50 mg qd in 
combination with ivacaftor 75 mg q12h (subjects <40 kg at baseline) or VX-661 100 mg qd in 
combination with ivacaftor 150 mg q12h (subjects ≥40 kg at baseline) for 24 weeks. No dose 
adjustments will be made throughout the duration of treatment in this study. At the Week 24 
Visit, subjects who complete study drug treatment will be offered the opportunity to enroll in an 
extension study evaluating VX-661 in combination with ivacaftor (enrollment will be based on 
the eligibility criteria specified within the extension study). Subjects who prematurely discontinue 
study drug treatment are not eligible to rollover into the extension study. 
A Safety Follow-up Visit is scheduled to occur 4 weeks (± 7 days) after the last dose of study 
drug. The Safety Follow-up Visit is not required for subjects who have enrolled in the extension 
study within 28 days after the last dose of study drug. Subjects who permanently discontinue 
study drug treatment will have an Early Treatment Termination (ETT) Visit and a Safety Follow-
up Visit. 
Figure 7-2 
Schematic of Study Design for Part B 
 
7.2 
Sample Size and Power for Part B 
Planned enrollment is approximately 56 subjects. Assuming a 10% dropout rate, approximately 
50 subjects are expected to complete Part B. An important safety endpoint is the incidence of 
AEs. With a total sample size of 50 subjects (completer), there is a 92.3% chance of observing 
AEs in at least 1 subject if the true incidence rate is 5%, and a 99.5% chance of observing AEs in 
at least 1 subject if the true incidence rate is 10%. The probabilities have been calculated by 
assuming a binomial distribution for the number of AEs using SAS®.  
7.3 
Randomization for Part B 
Not applicable. 


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7.4 
 Blinding and Unblinding for Part B 
Not applicable because this is an open-label study. 
8 
ANALYSIS SETS FOR PART B 
The following analysis sets are defined: Safety Set, Full Analysis Set, 
 
  
The Safety Set is defined as all subjects who received at least 1 dose of study drug in Part B of 
the study.  
The Full Analysis Set is defined as all subjects who carry the intended CFTR mutations and 
received at least 1 dose of study drug in Part B of the study. 
 
 
9 
STATISTICAL ANALYSIS FOR PART B 
9.1 
General Considerations  
All individual subject data for those who enrolled or received at least one dose of study drug in 
Part B, will be presented in data listings. The Schedule of Assessments is provided in Section 3 of 
the protocol. The precision standards are provided in Section 12.3. 
Continuous variables will be summarized using the following descriptive summary statistics: 
number of subjects (n), mean, standard deviation (SD), median, minimum value (min), and 
maximum value (max).  
Categorical variables will be summarized using counts and percentages.  
Treatment-emergent (TE) period will correspond to data from the first dose of study drug to 28 
days after the last dose of the study drug or to the completion of study participation date, 
whichever occurs first. Completion of study participation is defined as one of the following: 
• For subjects who complete Part B and enroll in the extension study within 28 days of the 
Week 24 Visit: the last participation date  
• For subjects who complete Part B and do not enroll in the extension study within 28 days of 
the Week 24 Visit: the Safety Follow-up Visit 
• For subjects who prematurely discontinue study drug treatment but do not withdraw consent: 
the latest of ETT Visit, or Safety Follow-up Visit (if required) 
• For subjects who withdraw consent: date of withdrawal of consent 
Baseline for Part B is defined as the most recent non-missing measurement (scheduled or 
unscheduled) collected prior to the first dose of study drug in Part B. For ECGs, baseline will be 
the average of the 3 pretreatment measurements on Day 1 of Part B. For sweat chloride, the 
baseline value will be the mean of the last values on the left and the right arm prior to the first 
dose of the study.   


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Absolute change from baseline will be calculated as post-baseline value – baseline value.   
Relative change from baseline will be calculated and expressed in percentage as 100 × (post-
baseline value – baseline value)/ baseline value.   
Unscheduled Visits: Subject data obtained during unscheduled visits will not be summarized but 
will be included in subject data listings only, except for the analysis of the maximum value during 
TE period and maximum changes from baseline during TE period (see Section 9.4.3).  
 
Visit Windowing Rules: Section 12.2 defines the windows for protocol-defined visits. The 
windows will be applied using the following rules for both scheduled and unscheduled visits: 
1. If no measurement is available within a visit window, the assessment will be considered 
missing for the visit; 
2. If there is more than one measurement available within the same visit window, use the 
following rules:  
o For all efficacy parameters, if there are multiple measurements within a visit window, the 
record at the scheduled visit will be used. Otherwise, 
• 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 early treatment termination (ETT) visit will follow the windowing 
rules for regular visits up to Week 24.  
• 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 Week 24, or 
remain as SFU if they go beyond the upper boundary of the window for Week 24. 
o For all safety parameters, if there are multiple measurements within a visit window, then 
• the record closest to the target day will be used;  
• if there are multiple records within the same distance from the target day, the latest 
record will be used; or 
• SFU visit will not be windowed; instead, it will be used according to the nominal 
visit in relevant analyses. 
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 parameters. 
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. 
9.2 
Background Characteristics for Part B 
9.2.1 Subject Disposition 
In the summary table of subject disposition, the number of subjects in the following categories 
will be presented:  


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• Safety Set 
• Full Analysis Set 
In the same table, the number and percentage (based on FAS) of subjects in each of the following 
disposition categories will be presented: 
• Completed study drug treatment  
• Prematurely discontinued the treatment (TEZ or IVA) and the reasons for discontinuations  
• Completed study 
• Prematurely discontinued study and the reasons for discontinuations 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuations.  
9.2.2 Demographics and Baseline Characteristics 
Demographic and baseline characteristics data will be summarized based on the Safety Set. 
Demographic data will include the following: 
• Age at screening 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and Other) 
Baseline characteristics will include the following, all at baseline unless otherwise specified: 
• Type of mutation (F508del/F508del; F508del/Residual Function) 
• Weight (kg) at baseline and weight group at enrollment 
• Weight z-score  
• Height (cm)  
• Height z-score 
• BMI (kg/m2)  
• BMI z-Score 
• FEV1 
• ppFEV1  
• Sweat Chloride 
• CFQ-R respiratory domain score 


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9.2.3 Medical History 
Medical history in this study will be coded by using the Medical Dictionary for Regulatory 
Activities (MedDRA). 
Based on the Safety Set, medical history will be summarized descriptively by system organ class 
(SOC) and preferred term (PT). The corresponding data listing will also be provided. 
In addition, a listing of subjects reported to have had positive cultures for respiratory pathogens in 
2 years prior to screening (i.e., answered yes on the respiratory microbiology form) will be 
presented. A listing of ophthalmology history will also be presented. 
9.2.4 Prior and Concomitant Medications 
Medications used in this study will be coded using the World Health Organization Drug 
Dictionary Enhanced (WHODD) and categorized as follows:  
• Prior medication: any medication that started before the first dose of study drug in Part 
B, regardless of when it ended.  
• Concomitant medication: medication continued or newly received during the TE period 
for Part B.  
• Post-treatment medication: medication continued or newly received after the TE period 
for Part B. For those subjects from Part A who enrolled in Part B, medications that 
continued or were newly received on or after the first dose of study drug in Part B will not 
be considered as post-treatment medication. 
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 partially missing start/end date 
or time and it cannot be determined whether the medication was taken before initial dosing, 
concomitantly, or post-treatment, it will be considered as prior, concomitant, and post-treatment. 
Based on the Safety Set, concomitant medications will be summarized descriptively by: 1) 
preferred name (PN); and 2) anatomic class (ATC) level 1, ATC level 2, and preferred name. 
Prior medications and post-treatment medications will be listed for each subject.  
As an intermediate step for programming purposes, medications with missing or partially missing 
start dates will use 2000 to impute for the missing year, January for the missing month, and 1 for 
the missing day. Medications with missing or partially missing stop dates will use 2050 to impute 
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 
study drug 
≥ first dose date and ≤ 
End date of TE period 
> End date of TE 
period 
< first dose date of study drug 
P 
PC 
PCA 
≥ first dose date and  
≤ End date of TE period 
- 
C 
CA 


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> End date of TE period 
- 
- 
A 
P: Prior; C: Concomitant; A: Post  
9.2.5 Study Drug Exposure 
Exposure summaries will be presented based on the Safety Set. 
Duration of study drug exposure is defined as follows: last dose date in Part B – first dose date in 
Part B + 1 day, regardless of any interruption in dosing between the first and the last dose.  
Duration of study drug exposure will be summarized descriptively (number, mean, SD, median, 
minimum, and maximum).  
9.2.6 Study Drug Compliance  
Study drug compliance based on study drug exposure will be calculated as: 100 × [1 − (total 
number of days of any study drug interruption) / (duration of study drug exposure in days)].  
Study drug compliance will be summarized descriptively by the number of subjects (n), mean, 
SD, median, min, and max. Compliance also will be summarized in categories: <80% and ≥80% 
using frequency tables. 
Study drug compliance will be summarized based on the Safety Set. 
9.2.7 Important Protocol Deviations  
Important protocol deviations (IPD) are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of the study data or that may significantly 
affect a subject's rights, safety, or well-being. IPD rules will be developed and finalized before 
database lock. 
The protocol deviations that should be considered as potential IPDs include, but are not limited 
to: 
• Violation of subjects rights, safety or well-being 
• Subject entered the study despite violation of any inclusion or exclusion criteria 
• Subject was less than 80% compliant with study medications 
• Subject received excluded concomitant medications 
• Subject received the wrong treatment or incorrect doses 
• Subject remained in study despite meeting withdrawal criteria 
Occurrence of any of these events should be considered as potential IPDs.  
IPDs (from the clinical database or from the site deviation log) will be presented in an individual 
subject data listing. 
9.3 
Efficacy Analysis for Part B 
There is no multiplicity adjustment in this study; p-values provided for the secondary and other 
endpoints are considered nominal. 


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All efficacy analyses described in this section will be based on the Full Analysis Set, unless 
specified otherwise. The analysis will include all available measurements through the last 
assessment, including measurements after treatment discontinuation.  
9.3.1 Analysis of Secondary Efficacy Variables 
Absolute change from baseline in percent predicted FEV1 through Week 24 
This endpoint is the average absolute change from baseline in percent predicted FEV1 (with a unit 
of percentage points) through Week 24, which is defined as the average of absolute changes from 
baseline in ppFEV1 at each post-baseline scheduled visits.  
Percent predicted FEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a 
percentage. The predicted FEV1 will be calculated using the Quanjer GLI-2012 Regression 
Equations and Lookup Tables1, adjusting for age, height, sex and ethnicity. Details are provided 
in Appendix 12.6. 
Absolute change from baseline in ppFEV1 will be analyzed using a restricted maximum 
likelihood (REML)-based mixed effect model repeated measures (MMRM) approach that would 
include visit and baseline ppFEV1(continuous) as fixed effects, and subject as random effect. An 
unstructured (co)variance structure will be used to model the within-subject errors. If the model 
fails to converge, a compound symmetry covariance structure will be considered. The degrees of 
freedom of the denominator will be approximated by the Kenward-Roger’s method.2  
The primary result obtained from the model will be the average treatment effect through Week 
24. The corresponding LS means, standard error (SE), the 95% CI, and p-value will be provided. 
Furthermore, absolute change from baseline in percent predicted FEV1 at each post-baseline will 
be estimated from the main model above. The LS means with the corresponding 2-sided 95% CIs 
and p-value will be provided at Week 24; LS means and the corresponding 2-sided 95% CIs will 
be provided for other post-baseline scheduled visits.  
Relative change in percent predicted FEV1 from baseline through Week 24 
A similar MMRM model as that for absolute change in ppFEV1 from baseline through Week 24 
will be used for this variable using the same approach as described for the absolute change in 
ppFEV1 from baseline.  
Absolute change in weight (/weight-for-age z-score) from baseline at Week 24  
Absolute change in height (/height-for-age z-score) from baseline at Week 24 
Absolute change in BMI (/BMI-for-age z-score) from baseline at Week 24 (details of BMI-
for-age z-score in section 12.4) 
A similar MMRM model will be used for the above variables using the same approach as 
described for the absolute change in ppFEV1 from baseline through Week 24.  The MMRM will 
include corresponding baseline values (continuous) as covariate instead of baseline ppFEV1. For 
these variables, the assessment of efficacy will be primarily based on the estimated mean change 
from baseline at Week 24.  
Absolute change in sweat chloride from baseline through Week 4 and through Week 24 
A similar MMRM model will be used for this variable using the same approach as described for 
the absolute change in ppFEV1 from baseline.  The MMRM will include baseline sweat chloride 
value as covariate instead of baseline ppFEV1. Please note that the first post-baseline assessment 


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of sweat chloride is at Week 4, thus, the estimated mean change at Week 4 will be used to assess 
absolute change in sweat chloride from baseline through Week 4.  
Absolute change in Cystic Fibrosis Questionnaire–Revised (CFQ-R) respiratory domain 
score from baseline through Week 24 
A similar MMRM model will be used for this variable using the same approach as described for 
the absolute change in ppFEV1 from baseline.   The MMRM will include the baseline CFQ-R 
respiratory domain score as a covariate instead of baseline ppFEV1. 
9.4 
Safety Analysis for Part B 
Safety is a primary objective of this study. Safety analysis will be based on the Safety Set. Only 
descriptive analysis of safety will be performed (i.e., no statistical hypothesis testing will be 
performed). The safety endpoints will be summarized using descriptive summary statistics.  The 
primary analysis of safety will be based on the overall, in addition, by-dose level summary is 
provided. Due to the small sample size, the by-dose level summary should be interpreted with 
caution. 
 
The safety endpoints included for analyses are as follows: 
• Treatment-emergent adverse events (TEAEs) 


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• Clinical laboratory measurements (chemistry, hematology, coagulation, lipids, vitamins, 
and urinalysis) 
• Standard 12-lead ECG 
• Vital signs 
• Pulse oximetry  
• Ophthalmologic examinations 
• Spirometry 
Throughout this section, “change” refers to absolute change from baseline. 
9.4.1 Adverse Events  
AEs will be coded according to MedDRA and categorized as pretreatment AEs, TEAEs, or post-
treatment AEs: 
• Pretreatment AE: any AE that started before the first dose of study drug in Part B. 
• TEAE: any AE that increased in severity or that was newly developed during the TE period 
for Part B.  
• Post-treatment AE: any AE that increased in severity or that was newly developed beyond 
the TE period for Part B.  
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started  (or 
increased in severity) before or after study treatment for Part B, then the AEs will be classified as 
TEAEs. As an intermediate step for programming purposes, imputation rules for missing or 
partially missing AE start/end dates are defined in Section 12.5. 
AE summary tables will be presented for TEAEs only and will include the following: 
(1) all TEAEs  
(2) related (defined as possibly related, related, or missing) TEAEs 
(3) serious TEAEs  
(4) Grade 3/4 TEAEs  
(5) TEAEs leading to treatment discontinuation  
(6) TEAEs leading to treatment interruption  
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages. 
A subject with multiple occurrences of the same TEAE or a continuing TEAE will be counted 
only once.  
9.4.1.1 
Overview of TEAEs  
An overview of all TEAEs will be provided for the total number of TEAEs, and with number and 
percent of subjects including the following categories: 
• Any TEAEs  
• TEAEs by strongest relationship 


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• Related TEAEs 
• TEAEs by maximal severity 
• Grade 3/4 TEAEs 
• Serious TEAEs 
• Related Serious TEAEs (possibly related, related or missing) 
• TEAEs leading to treatment discontinuation (this will include TEAEs leading to 
discontinuation of either TEZ tablet or the IVA tablet) 
• TEAEs leading to treatment interruption (this will include TEAEs leading to interruption 
of either TEZ tablet or the IVA tablet) 
• TEAEs leading to death 
In addition, a listing containing individual subject adverse event data for TEAEs leading to 
treatment discontinuation, treatment interruptions, SAEs and all deaths will be provided 
separately, with a flag indicating the TEAE status for SAEs and deaths. 
For all AEs, the action taken on the CRF for TEZ/IVA (AM dose) is collected separately from the 
AE action taken for IVA (PM dose). As a result, it is possible that in the AE dataset, the AE 
actions taken for the two agents are different. The summary of TEAE Leading to Treatment 
Discontinuation or Interruptions account for discontinuation and interruptions for either agent.  
9.4.1.2 
TEAEs by System Organ Class (SOC) and Preferred Term (PT) 
Summaries will be presented by MedDRA system organ class (SOC) and preferred term using 
frequency counts and percentages (i.e., number and percentage of subjects with an event). When 
summarizing the number and percentage of subjects with an event, subjects with multiple 
occurrences of the same AE or a continuing AE will be counted once. Only the maximum 
severity level will be presented in the severity summaries, and the strongest relationship level will 
be presented in the relationship summaries.  
9.4.1.3 
Respiratory Events and Symptoms 
Respiratory symptoms are defined as any TEAEs for the following 3 PTs: 
• Chest discomfort 
• Dyspnoea 
• Respiration abnormal 
Respiratory events are defined as any of the afore-mentioned respiratory symptoms, or any 
TEAEs for the following 4 additional PTs: 
• Asthma 
• Bronchial hyperreactivity 
• Bronchospasm 
• Wheezing 
A summary of respiratory symptoms and events will be presented by preferred term. 


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9.4.2 Clinical Laboratory  
For treatment-emergent laboratory measurements, the raw values and change from baseline 
values of the continuous hematology, chemistry, vitamin, lipids and coagulation results will be 
summarized in SI units at each scheduled time point.  
The number and percentage of subjects with events meeting threshold criteria laboratory event 
during the TE period will be summarized, including the shift of the event meeting threshold 
criteria from baseline to post-baseline. The threshold criteria are provided in section12.6.  
Results of urinalysis and the urine/serum pregnancy test will be listed in individual subject data 
listings only.  
In addition, a listing containing individual subject hematology, chemistry, vitamin, lipids and 
coagulation results outside the reference ranges will be provided. This listing will include data 
from scheduled and unscheduled visits. 
For each liver function test (LFT) laboratory test (i.e. alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP], and total bilirubin), the following 
additional analyses will be presented: 
• A listing of subjects with elevated LFT results during the TE period will be presented. For 
each subject in the listing, LFT assessments at all time points will be included (scheduled 
and unscheduled).  
• For each of the LFTs, mean values (±SD) will be plotted by visit, and a box plot of the 
LFT value/ULN will be plotted by visit.  
• The incidence of LFTs meeting threshold criteria 
• For each of the LFTs, mean values (±SD) will be plotted by visit, and a box plot of the 
LFT value/ULN will be plotted by visit.  
• The incidence of LFTs meeting threshold criteria against the baseline threshold criteria 
also will be summarized by LFT parameters and visit (only shifts to values worse than 
baseline will be presented). 
 
A summary table for the shift from baseline to the value at Week 24 will be provided for vitamin 
levels and lipid panel. A box plot of vitamin levels and lipid panel also will be plotted against 
visit.  
9.4.3 Standard 12-Lead Electrocardiogram 
For treatment-emergent ECG measurements, a summary of raw values and change from baseline 
values will be provided at each scheduled time point for the following standard 12-lead ECG 
measurements: PR, QTc for HR intervals (QTcF), QRS duration, and HR.  
The number and percentage of subjects with at least 1 ECG event meeting threshold criteria 
during the TE period will be summarized by ECG parameters. The threshold criteria are provided 
in Appendix 12.6. 
For QTcF and HR, mean values (±SD) will be plotted by scheduled visit.  


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9.4.4 Vital Signs 
For treatment-emergent vital signs measurements, the raw values and change from baseline 
values will be summarized at each scheduled time point for the following: systolic and diastolic 
blood pressure (mm Hg), body temperature (oC), HR (beats per minute), and respiratory rate 
(breaths per minute).  
The number and percentage of subjects meeting threshold criteria during the TE period will be 
summarized by vital signs parameters. The threshold criteria are provided in Appendix 12.6. 
For SBP and DBP, mean values (±SD) will be plotted by scheduled visit.   
9.4.5 Physical Examination 
Physical examination findings will be presented as a data listing only. 
9.4.6 Other Safety Analyses 
9.4.6.1 Pulse Oximetry 
For treatment-emergent percent of oxygen saturation by pulse oximetry, a summary of raw values 
and change from baseline values will be provided at each scheduled time point.  In addition, the 
mean value of percent of oxygen saturation at each visit during the TE Period will be plotted. 
9.4.6.2 Ophthalmologic Examination 
Ophthalmologic examination findings will be presented as a data listing. 
9.4.6.3 Spirometry 
The number and percentage of subjects with percent predicted FEV1 decline ≥10, ≥15, and ≥20 
percentage points in the absolute change from baseline in predose value will be summarized for 
scheduled visits.   
In addition, the number and percentage of subjects with ≥0.10 L or ≥0.20 L decrease in the 
absolute change from baseline through Week 24 for FEV1 will also be summarized for scheduled 
visit. 
Subjects with ≥10 percentage points decrease in absolute change from baseline through Week 24 
for ppFEV1 or ≥0.10 L decrease in the absolute change from baseline through Week 24 for FEV1 
will be listed.  
10 SUMMARY OF PLANNED INTERIM ANALYSIS 
Not Applicable.  
 
 


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11 REFERENCES 
1Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 
2 Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 
3 Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12 APPENDICES 
12.1 
Schedule of Assessments 
Please see Section 3.0 Schedule of Assessments of the protocol. 
12.2 
Analysis Visit Window Mapping Rules for Efficacy and Safety 
Measurement 
Table 12-3 
Visit Window Mapping Rules  
Assessments 
Visit 
Target Study Day 
Visit Window  
(in study days) 
• Weight and height 
• Pregnancy test 
• Standard 12-lead 
ECG 
• Vital signs 
• Pulse oximetry 
• Spirometry 
• Labs 
o Chemistry 
o Hematology 
• CFQ-R 
 
 
Day 1 
1 
[1, 1] 
Day 15  
15 
[2, 22] 
Week 4 
29 
[23, 43] 
Week 8  
57 
[44, 85] 
Week 16  
113 
[86, 141] 
Week 24  
169 
[142, 183] 
ETT 
N/A 
Follow the individual 
visit window to be 
mapped to individual 
visits 
Safety Follow-up Visit (no CFR-Q) 
N/A 
Nominal 
• Lipid panel 
 
 
 
Day 1  
1 
[1,1] 
Week 8 
57 
[2, 85] 
Week 16 
113 
[86, 141] 
Week 24  
169 
[142, 183] 
ETT 
N/A 
Follow the individual 
visit window to be 
mapped to individual 
visits 
• Sweat chloride 
Day 1 
1 
[1, 1] 
Week 4 
29 
[2, 99] 
Week 24  
169 
[100, 183] 
• Vitamin levels 
 
Day 1 
1 
[1, 1] 
Week 8 
57 
[2, 113] 
Week 24 
169 
[114, 183] 
ETT 
NA 
Follow the individual 
visit window to be 
mapped to individual 
visits 
• Labs 
o Coagulation 
o Urinalysis 
 
Day 1 
1 
[1, 1] 
Week 24 
169 
[2, 183] 
ETT  
NA 
Follow the individual 
visit window to be 
mapped to individual 
visits 


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Safety Follow-up Visit  
N/A 
Nominal 
Note:  
1. 
To apply the above visit windows, please first determine the baseline measurements based on 
the first dose of study medication and then label Day 1 for the date of the first dose of study 
drug, and use the nominal visit names to label SFU (for safety). 
2. 
After baseline, and 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. 
If there is no scheduled Day 1 post dose visit, any assessments on Day 1 after the first dose 
will be considered for the window of next visit. 
4. 
For all efficacy parameters, if there are multiple measurements within a visit window, the 
record at the scheduled visit will be used.  
• 
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.   
5. 
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; or 2) if there are multiple records within the 
same distance from the target day, the latest record will be used. 
6. 
FEV1, ppFEV1, BMI, Weight and Height are following the efficacy windowing rules. 
Special handling for ECG: 
• On Day 1, the pre-dose measurements will be collected as triplets, 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 triplets shall be used in this average.  
For other post-dose visits, the visit window in the above table will apply. 
 
 
 


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12.3 
Standards for Safety and Efficacy Variable Display in TFLs 
Continuous Variables 
 
The precision for continuous variables has been specified in the Vertex Standard Programming 
Rules document (Version 1.0, December 2015): 
 
Categorical Variables: Percentages will be presented to 1 decimal place. 
 
 
12.4 
BMI-for-age z-score 
BMI z-score will be calculated by using Centers for Disease Control and Prevention (CDC) 
growth charts3. The BMI z-score will be calculated as follows: 










=






≠
−






=
0
,
ln
0
,
1
L
S
M
X
L
LS
M
X
z
L
 
where X is the derived BMI value in kg/m2 based on the raw weight and raw height and L, M, and 
S are selected from the CDC BMI-for-age chart by subject sex and age. The BMIAGE file 
contains these parameters by sex (1=male, 2=female) and age; it is available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. SAS code for calculating percentiles 
and z-scores is available at:   http://www.cdc.gov/growthcharts/computer_programs.htm. 
NOTE: The CDC BMI-for-age charts are designed for use in pediatric populations (2 to 20 years 
of age); in this analysis plan, BMI z-score will be calculated only for subjects between 2 and <20 
years of age at screening. 
12.5 
Imputation Rules for Missing AE dates 
Imputation rules for missing or partial AE start date are defined below: 
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. 


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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. 
 


12.6 
Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Quanjer GLI-2012 Regression Equations and Lookup Tables. Philip H. Quanjer, Sanja 
Stanojevic, Tim J. Cole, Janet Stocks. Version 7 April 2013. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/quanjer-gli-2012-
regression-equations-and-lookup-tables.aspx 
Accessed Sep 11, 2017.  
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Implementing GLI-2012 regression equations. Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, 
Janet Stocks. Version 19 July 2015. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/spirometry-tools/it-
engineers-and-manufacturers.aspx 
Accessed Sep 11, 2017.   
GLI-2012 - SAS Macro. Sanja Stanojevic. Version 2, 7 April 2013. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/sas-macro.aspx 
Accessed  Sep 11, 2017. 
Data handling rule for spirometry is as follows:  
• Input age with at least 2 decimal places, and height with 1 decimal place. 
• For race, map CRF black or AA to black, all other races in CRF (except white) are 
mapped to 'other'; white is a reference race in the equations and assumes 0 values for all 
race coeffiecients in the       GLI  equations. 
 
 
 


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12.7 
Threshold Analysis Criteria  
Threshold Criteria for Clinical Chemistry and Hematology 
Parameter 
Threshold Criteria 
Comments 
Clinical Chemistry 
CPK 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
CTCAE grades 1-4 
Creatinine 
>ULN - ≤ 1.5 x ULN 
>1.5 - ≤ 3.0 x ULN 
>3.0 - ≤ 6.0 x ULN 
>6.0 x ULN 
CTCAE grades 1-4 
Blood Urea 
Nitrogen 
>ULN - ≤ 1.5 x ULN 
>1.5 - ≤ 3.0 x ULN 
>3.0 - ≤ 6.0 x ULN 
>6.0 x ULN 
Same criteria as creatinine  
 
No CTCAE  
Sodium 
Hyponatremia 
<LLN - ≥130 mmol/L 
<130 – ≥120 mmol/L  
<120 mmol/L  
CTCAE grade 1, 3, 4 
 
(No CTCAE grade 2) 
Hypernatremia 
>ULN - ≤ 150 mmol/L 
>150 mmol/L- ≤155 mmol/L  
>155 mmol/L - ≤ 160 mmol/L 
>160 mmol/L 
CTCAE grade 1-4 
Potassium 
Hypokalemia 
 <LLN – ≥ 3.0 mmol/L 
 <3.0 – ≥ 2.5 mmol/L 
 <2.5 mmol/L 
CTCAE grade 1&2, 3, 4 
  
(Grade 1 and 2 are the same) 
Hyperkalemia 
>ULN – ≤ 5.5 mmol/L 
>5.5 –  ≤ 6.0 mmol/L  
>6.0 – ≤ 7.0 mmol/L  
>7.0 mmol/L 
CTCAE grade 1-4 
Total Cholesterol 
>ULN – ≤ 7.75 mmol/L 
>7.75 – ≤ 10.34 mmol/L  
>10.34 – ≤ 12.92 mmol/L 
>12.92 mmol/L 
CTCAE grade 1-4 
Triglycerides 
>1.71 – ≤ 3.42 mmol/L  
>3.42 – ≤ 5.7 mmol/L  
>5.7 – ≤ 11.4 mmol/L  
>11.4 mmol/L 
CTCAE grade 1-4 
Glucose 
 
 
 
 
 
 
Hypoglycemia 
<LLN – ≥ 3.0 mmol/L  
<3.0 – ≥ 2.2 mmol/L  
<2.2 - ≥ 1.7 mmol/L 
<1.7 mmol/L 
CTCAE grade 1-4 
Hyperglycemia  
>ULN - ≤ 8.9 mmol/L 
>8.9 – ≤ 13.9 mmol/L 
>13.9 – ≤ 27.8 mmol/L  
>27.8 mmol/L 
CTCAE grade 1-4 
Albumin 
<35 - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L  
CTCAE grade 1-3 
 


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Amylase 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.0 x ULN  
>2.0 – ≤ 5.0 x ULN 
>5.0 x ULN 
CTCAE grade 1-4 
Lipase 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.0 x ULN  
>2.0 – ≤ 5.0 x ULN 
>5.0 x ULN 
CTCAE grade 1-4 
Direct bilirubin 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2 x ULN 
>2 – ≤ 3 x ULN  
>3 – ≤ 10 x ULN 
>10 x ULN 
Same Criteria as Total Bilirubin 
 
No CTCAE  
Not in DILI Guidance 
 
GGT  
>ULN - ≤ 2.5 x ULN 
>2.5 –  ≤ 5.0 x ULN 
>5.0 –  ≤ 20.0 x ULN  
>20.0 x ULN 
CTCAE grade 1-4 
Calcium 
Hypercalcemia 
>ULN - ≤ 2.9 mmol/L  
>2.9 – ≤ 3.1 mmol/L  
>3.1 – ≤ 3.4 mmol/L  
>3.4 mmol/L 
CTCAE grade 1-4 
Hypocalcemia 
<LLN - ≥ 2.0 mmol/L 
<2.0 – ≥1.75 mmol/L  
<1.75 – ≥ 1.5 mmol/L  
<1.5 mmol/L  
CTCAE grade 1-4 
Magnesium 
 
Hypermagnesemia 
>ULN - ≤ 1.23 mmol/L 
>1.23 – ≤ 3.30 mmol/L 
>3.30 mmol/L 
CTCAE grade 1, 3, 4 
 
No CTCAE grade 2 
Hypomagnesemia 
<LLN - ≥ 0.5 mmol/L 
<0.5 – ≥ 0.4 mmol/L 
<0.4 – ≥ 0.3 mmol/L  
<0.3 mmol/L  
CTCAE grade 1-4 
 
 
 
Inorganic 
phosphate 
Hypophosphatemia 
 
<LLN - ≥ 0.8 mmol/L 
<0.8 –≥.6mmol/L 
<0.6 – ≥ 0.3 mmol/L 
<0.3 mmol/L 
CTCAE grade 1-4 
ALT 
>ULN - ≤  3 xULN 
>3 – ≤  5 xULN 
>5 – ≤  8 xULN 
>8 – ≤  20.0 xULN 
>20.0 x ULN 
Per FDA DILI Guidance Jul 2009 and 
CTCAE 
 
AST 
>ULN - ≤  3 xULN 
>3 – ≤  5 xULN 
>5 – ≤  8 xULN 
>8 – ≤  20.0 xULN 
>20.0 x ULN 
FDA DILI Guidance and CTCAE 
 
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) 
FDA DILI Guidance  


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(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  
FDA DILI Guidance and CTCAE 
 
Total Bilirubin 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2 x ULN 
>2 – ≤ 3 x ULN  
>3 – ≤ 10 x ULN 
>10 x ULN 
FDA DILI Guidance and CTCAE 
 
 
ALT and Total 
Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009  
 
AST and Total 
Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009 
 
(ALT or AST) and 
Total Bilirubin  
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009  
 
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 
CTCAE grade 1-4 
Leukocytosis 
>100 x 10e9 /L 
CTCAE grade 3 (only Grade available)  
Lymphocytes 
Lymphocyte decreased 
<LLN - ≥ 0.8 x10e9 /L 
<0.8 – ≥ 0.5 x10e9 /L  
<0.5 – ≥ 0.2 x10e9 /L  
<0.2 x10e9 /L 
CTCAE grade 1-4 
Lymphocyte increased 
>4 – ≤ 20 x10e9/L  
>20 x10e9/L  
CTCAE grade 2, 3 (only Grades available) 
Neutrophils 
Neutrophil decreased 
<LLN - ≥ 1.5 x10e9 /L 
<1.5 –  ≥ 1.0 x10e9 /L  
<1.0 –  ≥ 0.5 x10e9 /L  
<0.5 x10e9 /L 
CTCAE grade 1-4 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L  
< 80 g/L 
CTCAE grade 1-3 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L above ULN 
>40 g/L above ULN  
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L  
<50.0 – ≥ 25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 


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Threshold Criteria for Coagulation 
Parameter 
Threshold 
Comments 
Activated partial 
thromboplastin 
time  (PTT)  
 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
 
CTCAE grade 1-3 
Prothrombin time 
(PT) International 
Normalized Ratio 
(INR) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
 
CTCAE grade 1-3 
 
 


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Threshold Criteria for ECGs 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ECGs 
Ref.: CPMP 1997 guideline. 
Parameter 
Threshold 
Comments 
HR 
 
 
Bradycardia 
 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
Per HV grade 2, 3, plus shift change 
 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
 
QTc 
 
>450 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 
 


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Threshold Criteria for Vital Signs 
Parameter 
Threshold Criteria 
Comments 
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 
809/770 analyses 
 
SBP decrease 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from baseline 
<90 mmHg and >20 mmHg decrease from baseline 
<80 mmHg and >10 mmHg decrease from baseline 
<80 mmHg and >20 mmHg decrease from baseline 
Per HV grade 1, 3, plus shift change 
 
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 
809/770 analyses 
 
DBP decreased 
  
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from baseline 
<60 mmHg and >10 mmHg decrease from baseline 
<45 mmHg and >5 mmHg decrease from baseline 
<45 mmHg and >10 mmHg decrease from baseline 
 
Weight 
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
CTCAE grade 1-3 
 


SAP VX15-661-113, Version 1.0                                                                                                     Page 34 of 34 
 
 
Vertex Pharmaceuticals Incorporated 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
CTCAE grade 1-3