Clinical trial NCT02508207
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2016-02-01; Completion date: 2017-06-01
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the clinical mechanisms of action in lung and extrapulmonary systems of VX-661 (tezacaftor; TEZ) in combination with ivacaftor (IVA) (TEZ/IVA) in participants with cystic fibrosis (CF) who are homozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene.

Detailed description:

Arms: arm 1: Participants received placebo matched to tezacaftor (TEZ)/ivacaftor (IVA) fixed dose combination (FDC) tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 29 days. arm 2: Participants received 100 milligram (mg) TEZ/150 mg IVA FDC tablet orally once daily in the morning followed by 150 mg IVA tablet orally once daily in the evening for 29 days.
Interventions: intervention 1: Tezacaftor/Ivacaftor intervention 2: Ivacaftor intervention 3: Tezacaftor/Ivacaftor matching placebo intervention 4: Ivacaftor matching placebo
Intervention descriptions: intervention 1: Tezacaftor/Ivacaftor FDC intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_000.pdf: 




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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Exploratory Study to Evaluate Effects of VX-661 in Combination With Ivacaftor 
on Lung and Extrapulmonary Systems in Subjects Aged 18 Years and Older With 
Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation 
 
 
Clinical Phase and 
Clinical Study Type 
Phase 2, efficacy and safety 
 
 
Objective 
To evaluate the clinical mechanisms of action in lung and extrapulmonary systems 
of VX-661 in combination with ivacaftor (IVA) (VX-661/IVA) in subjects with 
cystic fibrosis (CF) who are homozygous for the F508del mutation on the CF 
transmembrane conductance regulator (CFTR) gene. 
 
 
Endpoints 
Key Endpoints: 
• Absolute change in percent predicted forced expiratory volume in 1 second 
(ppFEV1) from baseline at Day 28 
• Absolute change in mucociliary clearance (MCC) from baseline at Day 28 
• Absolute change in gastrointestinal pH from baseline at Day 29 
• Absolute change in sweat chloride from baseline at Day 29 
Other Endpoints: 
 
 
 
 
• Safety and tolerability assessments based on adverse events (AEs), clinical 
laboratory values (i.e., serum chemistry, vitamin levels, lipid panel, 
hematology, coagulation studies, and urinalysis), standard 12-lead 
electrocardiograms (ECGs), vital signs, and pulse oximetry 
 
 
Number of Subjects 
A target of approximately 35 subjects and up to approximately 45 subjects  
 
 
Study Population 
Male and female subjects aged 18 years and older with CF, homozygous for the 
F508del-CFTR mutation 
Investigational Drug 
Active substances: VX-661/IVA (fixed-dose combination [FDC] with VX-661 
and IVA) 
 
Activity: CFTR corrector (VX-661) and potentiator (IVA) (increased chloride ion 
[Cl−] secretion) 
 
Strength and Route of Administration: 100-mg VX-661/150-mg IVA FDC 
film-coated tablet for oral administration 
 
Dose Administered: 100-mg VX-661/150-mg IVA daily (qd) 
(1 × 100-mg/150-mg FDC tablet qd) in the morning 
 
Active substance: IVA 


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Activity: CFTR potentiator (increased Cl− secretion) 
 
Strength and Route of Administration: 150-mg IVA film-coated tablet for oral 
administration 
 
Dose Administered: 150-mg IVA qd (1 × 150-mg tablet qd) in the evening 
 
 
 
VX-661/IVA FDC placebo and IVA placebo  
 
Strength and Route of Administration: 0-mg, film-coated, matching placebo 
tablets for oral administration 
 
 
Study Duration 
Excluding the Screening Period (up to 28 days in duration), subjects will 
participate in this study for up to 57 ± 7 days. 
During the Treatment Period, study drug (VX-661/IVA or placebo) will be 
administered for 29 ± 3 days. A Safety Follow-Up Visit is required for all subjects 
28 ± 7 days after the last dose of study drug. 
 
 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter, exploratory study in subjects with CF who are homozygous for the 
F508del-CFTR mutation. 
This study includes a Screening Period, a Treatment Period, and a Safety Follow-
up Visit. 
Screening Period (Day −28 through Day −1): 
The Screening Period will occur between 1 and 28 days before the first dose of 
study drug to confirm that the subjects meet the eligibility criteria. 
 
During the Screening Period, a patency capsule and a wireless motility capsule 
(WMC) will be administered. The patency capsule will be administered at the 
Day -28 to Day -13 Clinic Visit. A telephone contact will occur 2 days after 
administration of the patency capsule to confirm the passage of the capsule in the 
stool (unless the subject confirms the passage of the capsule prior to the scheduled 
telephone contact). Subjects who are unable to successfully pass the patency 
capsule test will not be randomized. 
 
The WMC will be administered at the Day -23 to Day -10 Clinic Visit after 
confirmation that the patency capsule has passed. A telephone contact will occur 5 
days after administration of the WMC to confirm the passage of the capsule 
(unless the subject confirms the passage of the capsule prior to the scheduled 
telephone contact). The subject will not be randomized in the study until passage 
of the WMC has been confirmed by the central reader or X-ray, regardless of 
confirmation of passage by the subject at the telephone contact. 
Treatment Period (Day 1 through Day 29 ± 3 days): 
On Day 1, subjects will be randomized (4:1) to VX-661/IVA combination therapy 
(100-mg VX-661 qd/150-mg IVA every 12 hours [q12h]) or placebo 
Safety Follow-up Visit (28 ± 7 days after the last dose of study drug) 
The Safety Follow-up Visit is required for all subjects 28 ± 7 days after the last 
dose of study drug. Subjects who complete the Day 29 Visit and subsequently the 
Safety Follow-up Visit will be offered the opportunity to enroll into an extension 
study of VX-661/IVA combination therapy if they meet eligibility requirements 
for the extension study. 




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3 
SCHEDULE OF ASSESSMENTS 
Schedules of Assessments are shown in Table 3-1 (Screening Period) and Table 3-2 (Treatment Period through the Safety Follow-up 
Visit). 
All visits are to be scheduled relative to the Day 1 Visit (first dose of study drug). 
Table 3-1 
Study VX14-661-111: Screening Period 
Assessment 
Screening Period 
Day -28 through Day -1 
Screening Visit 
Day -28 to Day -13 
Telephone Contact 
2 Days After Patency 
Capsule Administration 
Clinic Visit 
Day -23 to -10a 
Telephone Contact 5 Days 
After WMC Administration 
Clinic visit 
X 
 
Xb 
 
Informed consent  
X 
 
 
 
Inclusion/exclusion criteria review 
Continuous from signing of informed consent form (ICF) before randomizationa 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Ophthalmologic history 
X 
 
 
 
CF genotypec 
X 
 
 
 
Weight, heightd 
X 
 
 
 
Complete physical examination 
X 
 
 
 
Ophthalmologic examinatione 
Between signing of ICF and randomization 
Standard 12-lead ECGf 
X 
 
 
 
Vital signsg 
X 
 
 
 
 a 
Clinic Visit Day -23 through Day -10 will take place only if a subject passes the patency capsule test. Select baseline assessments are performed on Day -23 through Day -10 
(Table 3-1), and the remaining are performed on Day 1 (Table 3-2). Before any baseline assessments are performed, eligibility for enrollment based on all available screening 
assessment results must be verified by the investigator.  
b 
This visit may occur on 1 day or on 2 separate days (see Section 8.1.1). 
c 
All subjects will be tested for CFTR genotype regardless of availability of a previous CFTR genotype laboratory report. Refer to the Laboratory Manual for specific 
instructions. 
d 
Weight and height will be measured with shoes off. 
e 
One ophthalmologic examination will be conducted by a licensed ophthalmologist during the Screening Period. The ophthalmologic examination does not need to be repeated 
if there is documentation of an examination that met the protocol criteria and that was conducted within 3 months before the Screening Period (see Section 11.7.7). Subjects 
with clinically significant cataracts, lens opacity, Y-suture, or lamellar rings will be excluded. 
f 
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes. ECGs will be performed before vital signs, pulse oximetry, and any other 
procedures that may affect heart rate (e.g., blood sampling). 


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Table 3-1 
Study VX14-661-111: Screening Period 
Assessment 
Screening Period 
Day -28 through Day -1 
Screening Visit 
Day -28 to Day -13 
Telephone Contact 
2 Days After Patency 
Capsule Administration 
Clinic Visit 
Day -23 to -10a 
Telephone Contact 5 Days 
After WMC Administration 
Pulse oximetryg 
X 
 
 
 
Spirometry 
Xh 
 
Xi 
 
Urinalysis 
X 
 
 
 
Serum FSHj (postmenopausal female 
subjects only) 
X 
 
 
 
Pregnancy testk 
Serum 
 
Urinel  
 
Sweat chloridem 
X 
 
 
 
Hematology 
X 
 
 
 
Coagulation 
X 
 
 
 
Serum chemistry 
X 
 
 
 
Patency capsule 
Xn 
Confirm passageo 
 
 
Meal or snack at site 
 
 
Xp 
 
WMCq 
 
 
Xr 
confirm passages 
 g 
Vital signs and pulse oximetry will be collected after the subject has been at rest (seated or supine) for 5 minutes. Vital signs will be performed after ECGs and before blood 
sampling. 
h 
Spirometry may be performed pre- or postbronchodilator (see Section 11.4.1).  
i 
Spirometry should be performed prebronchodilator, on the same day as the MCC assessment, and prior to both WMC and MCC if both are done on the same day. Spirometry 
values must be ≥30 percent predicted FEV1 before MCC (see Section 11.4.2). 
j 
FSH will be measured for any suspected postmenopausal female with at least 12 months of continuous spontaneous amenorrhea. Serum FSH levels must be ≥40 mIU/mL to 
be considered postmenopausal. 
k 
Pregnancy tests will be performed for all female subjects of childbearing potential (see Section 11.7.5). 
l 
Pregnancy test results will be obtained before administration of WMC and the MCC assessment. If the Clinic Visit Day -23 to -10 occurs on 2 separate days, pregnancy 
testing will occur before the procedures on each day.  
m 
Sweat chloride test is not required if the subject has a documented sweat chloride test result in the medical records. 
n 
All subjects will be administered a patency capsule test at the Day -28 to Day -13 Screening Visit after all other assessments have been completed. Subjects will stay under 
observation in the clinic for 2 hours after administration of the patency capsule. 
o 
Telephone contact will occur 2 days after administration of the patency capsule to confirm passage of the patency capsule in the stool (unless the subject confirms passage of 
the capsule prior to the scheduled telephone contact [Section 11.4.3]). A subject must pass the patency capsule test to continue the Screening Period assessments. If passage of 
the patency capsule is not confirmed during the telephone contact, the medical monitor must be contacted immediately to confirm further course of action (see the Study 
Reference Manual for additional information). 
p 
Subjects must adhere to study restrictions in Table 9-2 regarding meals. During the Clinic Visit(s) on Day -23 to Day -10, subjects will fast for 8 hours (water is permitted) 
before administration of a snack bar (in place of the morning meal), and for an additional 4 hours immediately following administration of the WMC. ). If  the Day -23 to – 10 
Visit occurs on 2 separate days, a meal or snack bar will be provided at the clinic on both days. 


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Table 3-1 
Study VX14-661-111: Screening Period 
Assessment 
Screening Period 
Day -28 through Day -1 
Screening Visit 
Day -28 to Day -13 
Telephone Contact 
2 Days After Patency 
Capsule Administration 
Clinic Visit 
Day -23 to -10a 
Telephone Contact 5 Days 
After WMC Administration 
MCCt 
 
 
X 
 
 
 
Prior and concomitant medications 
Continuous from signing of ICF through Safety Follow-up Visit 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
CF: cystic fibrosis; ECG: electrocardiogram; FSH: follicle-stimulating hormone; MCC: mucociliary clearance; WMC: wireless motility capsule 
 q 
If MCC and WMC administration occur on a single day, WMC administration should be completed before the MCC assessment.  
r 
Subjects must pass the patency capsule test and adhere to WMC restrictions in Table 9-1 before administration of the WMC (see Section 11.4.3). Subjects will fast for 8 hours 
(water is permitted) before administration of a snack bar (in place of the morning meal) with the WMC, and will fast for an additional 4 hours immediately following 
administration of the WMC. All screening assessments, except for the ophthalmologic examination 
, must be completed before the WMC. 
s 
Telephone contact will occur 5 days after the administration of the WMC to evaluate passage of the capsule (unless the subject confirms the passage of the capsule prior to the 
scheduled contact). If passage of the WMC is not confirmed during the telephone contact, the medical monitor must be contacted immediately to confirm further course of 
action. Subjects will not be randomized in the study until passage of the WMC has been confirmed by the central reader or X-ray, regardless of confirmation of passage by 
subject at telephone contact (see Section 11.4.3 and the Study Reference Manual for additional information). 
t 
Bronchodilator usage is restricted for 12 hours before the MCC assessment. The first MCC scan will be immediately following radiolabeled aerosol inhalation, and the second 
scan 6 hours (± 30 minutes) after inhalation. Subjects will adhere to study restrictions in Table 9-1 related to MCC (see the Study Reference Manual for additional 
information).  
 
 


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Table 3-2 
Study VX14-661-111: Treatment Period and Safety Follow-Up Visit 
Event/Assessmenta 
 Treatment Period 
Telephone Contact 
5 Days After WMC 
Administration 
Early  
Treatment 
Terminationb 
Visit 
Safety Follow-up Visit 
28 (± 7) Days 
After Last Dose of 
Study Drug 
Day 1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days)c 
Day 29 
(± 3 days) 
Clinic visit 
X 
  
Xd 
X 
 
 X 
X 
Telephone contact 
 
Xe 
 
 
X 
 
 
Inclusion and exclusion criteria reviewf 
X 
 
 
 
 
 
 
Weight and Heightg 
X 
 
X 
 
 
X (weight) 
X 
Complete physical examinationh 
X 
 
 
  
 
  
X 
Standard 12-lead ECGi 
Xj 
 
 
Xj 
 
Xj 
Xj 
Vital signsk 
X 
 
X 
X 
 
X 
X 
Pulse oximetryk 
X 
 
X 
X 
 
X 
X 
Spirometryl 
X 
 
X 
 
 
X 
X 
 a 
All assessments will be performed before administration of study drug unless noted otherwise. 
b 
If the subject prematurely discontinues study treatment, an Early Treatment Termination (ETT) Visit should be scheduled as soon as possible after the last dose of study drug. 
Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit, approximately 28 (± 7) days after their last dose of study drug. 
If the ETT Visit occurs 3  weeks or later following the last dose of study drug, then the ETT will not be required (see Section 8.1.4). 
c 
This visit may occur on 1 day or on 2 separate days (see Section 8.1.2). All assessments of the Day 28 Visit must be completed before the Day 29 Visit assessments.  
d 
Subjects will be offered the option of an overnight stay in proximity to the clinic between Days 28 and 29. 
e 
A telephone contact will occur on Day 14 to review adverse events (AEs) and concomitant medications. 
f 
Confirmation of subject eligibility will occur before randomization. 
g 
Weight and height will be measured before dosing with shoes off. Height will be collected only for subjects 21 years of age or younger at the Day 1, Day 28, and Safety 
Follow-up Visits. 
h 
A complete physical examination will occur on Day 1 and at the Safety Follow-up Visit. Symptom-targeted physical examinations will occur at any time during the study if 
triggered by AEs or if deemed necessary by the investigator. 
i 
All ECGs will be performed before vital signs, pulse oximetry, and any other procedures that may affect heart rate (e.g., blood sampling). Subjects must be supine for at least 
5 minutes before the start of the ECG.  
j 
At the Day 1 and Day 29 Visits, ECGs will be collected before dosing and at 1.5 (approximately ± 15 minutes) and 3 hours (approximately ± 15 minutes) after the morning 
dose of study drug. ECGs collected on Day 1 before dosing will be performed in triplicate. If study drug is not administered on the Day of the visit (i.e., because of study drug 
interruption or permanent discontinuation of study drug), only 1 ECG will be collected. 
k 
Vital signs and pulse oximetry will be collected before dosing and after the subject has been at rest (seated or supine) for at least 5 minutes. Vital signs will be performed after 
ECGs and before blood sampling. In cases where Day 28 Visit assessments occur on 2 separate days, vital signs and pulse oximetry will be collected on both days.  
l 
Spirometry will be performed before study drug dosing and should be performed prebronchodilator (see Section 11.4.1). At the Day 28 Visit, bronchodilator usage is 
restricted for 12 hours before the MCC assessment. If the Day 28 Visit assessments occur on 2 separate days, spirometry should be performed on the same day as and 
preceding the MCC assessment. 


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Table 3-2 
Study VX14-661-111: Treatment Period and Safety Follow-Up Visit 
Event/Assessmenta 
 Treatment Period 
Telephone Contact 
5 Days After WMC 
Administration 
Early  
Treatment 
Terminationb 
Visit 
Safety Follow-up Visit 
28 (± 7) Days 
After Last Dose of 
Study Drug 
Day 1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days)c 
Day 29 
(± 3 days) 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
X 
 
X 
X 
Sweat chloriden 
X 
 
 
X 
 
 
 
Pregnancy testo 
Urine 
 
Urine 
Serum 
 
Serum 
Xp 
VX-661 and M1-661 PKq 
 
 
X 
X 
 
X 
X 
IVA and M1-IVA PKq 
 
 
X 
X 
 
X  
X 
Hematology 
X 
 
 
X 
 
X 
X 
Coagulation 
X 
 
 
X 
 
X 
X 
Serum chemistry 
X 
 
 
X 
 
X 
X 
Lipid panelr 
X 
 
 
X 
 
X 
X 
Vitamin levels 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
n 
Sweat collection will occur before the morning dose and no more than 1 hour before the predose PK sample collection. Sweat chloride assessments will not overlap with the 
collection of other assessments (see the Laboratory Manual for additional information). 
o 
Pregnancy tests will be performed for all female subjects of childbearing potential. On Day 1, pregnancy test results must be obtained before randomization. On Day 28, 
pregnancy test results must be obtained before the MCC assessment.  
p 
Serum pregnancy test must be performed at the ETT Visit for subjects who discontinue the study and at the Safety Follow-up Visit for subjects who complete the study and 
chose not to enroll in the extension study. Urine pregnancy test must be performed for subjects who complete Day 29 and choose to enroll in the extension study or for 
subjects who discontinue the study and complete both ETT and Safety Follow-up Visits.  
q 
Single PK blood samples will be collected within 60 minutes before the morning dose of study drug at Day 28 and Day 29. If study drug is not administered at the visit (i.e., 
study drug interruption or permanent discontinuation of study drug), a PK blood sample will still be collected. At the ETT (as applicable) and the Safety Follow-up Visit, a 
single PK blood sample will also be collected. 
r 
Blood samples for lipid panel tests will be collected after fasting for a minimum of 4 hours (see Section 11.7.2).  


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Table 3-2 
Study VX14-661-111: Treatment Period and Safety Follow-Up Visit 
Event/Assessmenta 
 Treatment Period 
Telephone Contact 
5 Days After WMC 
Administration 
Early  
Treatment 
Terminationb 
Visit 
Safety Follow-up Visit 
28 (± 7) Days 
After Last Dose of 
Study Drug 
Day 1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days)c 
Day 29 
(± 3 days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wireless motility capsule (WMC) 
 
 
 
Xs 
Confirm passaget 
 
 
Mucociliary clearance assessment (MCC)u 
 
 
X 
 
 
 
 
Adverse events and concomitant 
medications 
Continuous from signing of ICF through Safety Follow-up Visit 
Randomizationv 
X 
 
 
 
 
 
 
Meal(s) or snack(s) at sitew 
X 
 
X 
Xx 
 
 
 
Study drug dosingy 
X 
 
 
 
Study drug count 
X 
 
X 
X 
 
X 
Xz 
CF: cystic fibrosis; ECG: electrocardiogram; FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; 
; MCC: mucociliary 
clearance; PK: pharmacokinetics; WMC: wireless motility capsule 
 s 
Subjects will adhere to study restrictions in Table 9-1 related to WMC. During the Day 29 Visit, subjects will fast for 8 hours (water is permitted) before administration of a 
snack bar (in place of the morning meal) with the WMC and the morning dose of study drug , and will fast for an additional 4 hours immediately following administration of 
the WMC. 
t 
Telephone contact will occur 5 days after the administration of the WMC to confirm passage of the capsule (unless the subject confirms passage of the capsule before the 
scheduled telephone contact). If passage of the WMC is not confirmed by the telephone contact, the medical monitor must be contacted immediately to confirm further course 
of action. Passage of the WMC must be confirmed by the central reader or X-ray, regardless of confirmation of passage by subject at telephone contact (see Section 11.4.3 and 
the Study Reference Manual for additional information). 
u 
On Day 28, radiolabeled aerosol inhalation will occur after the dose of study drug. One MCC scan will occur immediately following radiolabeled aerosol inhalation and a 
second scan approximately 6 hours (± 30 minutes) after inhalation. Subjects will adhere to study restrictions in Table 9-1 related to MCC (see the Study Reference Manual for 
additional information). Refer to Section 8.1.2 for the Day 28 Visit assessments. 
v 
Randomization must occur after all inclusion and exclusion criteria are met and before the first dose of study drug. Randomization may occur on Day -1. 
w 
Fat-containing food such as a “standard CF” high-fat, high-calorie meal or snack will be provided at the site to subjects after all predose assessments have occurred (if the 
Day 28 assessments occur on 2 separate days, a meal or snack will be provided for each clinic visit.).  
x 
Administration of a snack bar (in place of the morning meal). 
y 
Study drug will be administered as described in Section 10.2. On Day 1 through the morning of the Day 29 Clinic Visit, study drug will be administered within 30 minutes of 
starting a meal with fat-containing food such as a “standard CF” high-fat, high-calorie meal or snack. At the Day 29 Visit, subjects will receive a snack bar in place of the 
morning meal. On days of scheduled visits, the morning dose of study drug will be administered at the site after the last predose assessment has been completed. 
z 
Study drug count will occur at the Safety Follow-up Visit for all subjects who discontinue the study and for whom the Safety Follow-up Visit replaces the ETT. 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 6 
4 
Table of Contents ................................................................................................................. 12 
List of Tables............................................................................................................................ 16 
List of Figures .......................................................................................................................... 16 
5 
Introduction.......................................................................................................................... 17 
6 
Study Objective .................................................................................................................... 18 
7 
Study Endpoints ................................................................................................................... 18 
7.1 
Key Endpoints ................................................................................................................ 18 
 
 
8 
Study Design ......................................................................................................................... 19 
8.1 
Overview of Study Design ............................................................................................. 19 
8.1.1 
Screening ................................................................................................................ 20 
8.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 21 
8.1.1.2 
Rescreening ...................................................................................................... 21 
8.1.1.3 
Extension of Screening Period Window .......................................................... 22 
8.1.2 
Treatment Period .................................................................................................... 22 
8.1.3 
Safety Follow-up Visit............................................................................................ 23 
8.1.4 
Early Treatment Termination ................................................................................. 23 
8.2 
Rationale for Study Design and Study Drug Regimens ................................................. 23 
8.2.1 
Study Design........................................................................................................... 23 
8.2.2 
Study Drug Dose and Duration .............................................................................. 23 
8.2.3 
Rationale for Study Population............................................................................... 23 
8.2.4 
Rationale for Study Assessments ........................................................................... 24 
9 
Study Population .................................................................................................................. 25 
9.1 
Inclusion Criteria ............................................................................................................ 25 
9.2 
Exclusion Criteria ........................................................................................................... 26 
9.3 
Study Restrictions ........................................................................................................... 29 
9.3.1 
Additional Dietary Restrictions/Prohibited Medications ....................................... 29 
9.4 
Prior and Concomitant Medications ............................................................................... 30 
9.5 
Removal of Subjects ....................................................................................................... 31 
9.6 
Replacement of Subjects ................................................................................................ 32 
10 Study Drug Administration and Management ................................................................. 32 
10.1 Preparation and Dispensing ............................................................................................ 32 
10.2 Administration ................................................................................................................ 32 
10.3 Method of Assigning Subjects to Treatment Groups ..................................................... 33 
10.4 Missed Doses .................................................................................................................. 33 
10.5 Dose Modification for Toxicity ...................................................................................... 33 
10.6 Packaging and Labeling ................................................................................................. 34 
10.7 Study Drug Supply, Storage, and Handling ................................................................... 34 
10.8 Drug Accountability ....................................................................................................... 34 
10.9 Disposal, Return, or Retention of Unused Drug ............................................................. 34 






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15.2 Investigator Signature Page ............................................................................................ 69 
 


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List of Tables 
Table 3-1 
Study VX14-661-111: Screening Period ................................................................ 6 
Table 3-2 
Study VX14-661-111: Treatment Period and Safety Follow-Up Visit .................. 9 
Table 9-1 
Study Restrictions ................................................................................................. 29 
Table 9-2 
Additional Study Restrictions ............................................................................... 30 
Table 10-1 
Study Drug Administration - Treatment Period.................................................... 32 
Table 10-2 
Identity of Study Drugs, Dosage, and Storage ...................................................... 34 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 42 
Table 12-1 
Power for Within-Group Comparison (100 mg VX-661 qd + 150 mg IVA q12h) 
for ppFEV1 With N = 36 and ∆ = 4.5% ................................................................ 50 
Table 12-2 
Power for Within-Group Comparison (100 mg VX-661 qd + 150 mg IVA q12h) 
for Average % Whole Lung Clearance Through 60 Minutes With N = 36 and 
∆ = 6% .................................................................................................................. 50 
Table 12-3 
Power for Within-Group Comparison (100 mg VX-661 qd + 150 mg IVA q12h) 
for Small Bowel AUC Over 1-minute Mean pH Increments Through 30 Minutes 
After Gastric Emptying With N = 36 and ∆ = 22 pH Minutes (or Equivalently, 
0.73 pH) ................................................................................................................ 50 
Table 12-4 
Power for Within-Group Comparison (100 mg VX-661 qd + 150 mg IVA q12h) 
for Sweat Chloride With N = 36 and ∆ = -5 mmol/L ........................................... 50 
Table 13-1 
Grading of AE Severity ........................................................................................ 58 
Table 13-2 
Classifications for AE Causality ........................................................................... 58 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 59 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 59 
List of Figures 
Figure 8-1 
Schematic of the Study Design ............................................................................. 20 


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5 
INTRODUCTION 
Cystic fibrosis (CF) is an orphan disease1,2 that affects an estimated 70,000 children and adults 
worldwide,3 and is the most common fatal genetic disease in persons of European descent.4 
Despite progress in the treatment of CF with antibiotics and mucolytics, the predicted median 
age of survival for a person with CF is in the mid-30s.4,5 Although most morbidity and mortality 
are caused by progressive loss of lung function, the disease affects multiple organs.6 
CF is an autosomal recessive genetic disease caused by defects in the gene encoding the CF 
transmembrane conductance regulator (CFTR), an epithelial chloride ion channel activated by 
cyclic adenosine monophosphate-dependent protein kinase A that is responsible for aiding in the 
regulation of salt and water absorption and secretion in various tissues.4 This function is 
defective in patients with CF due to a loss of either cell surface expression and/or function. 
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). The proportion of patients 
with CF who are homozygous for the F508del-CFTR mutation is similar across geographic 
regions: approximately 47% in the US,7 44% in the European Union (EU),8 49% in Canada,9 and 
52% in Australia.10 
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 chloride and bicarbonate 
transport,11,12,13 which impairs fluid regulation and promotes accumulation of thick, sticky 
mucus in the airway. The mucus build-up obstructs the airways and interferes with the activity of 
defensins, which contributes to dysbiosis and predisposes the patient to chronic lung 
infections.14,15 
In addition to pulmonary disease, multiple other organ systems are impacted in patients with CF. 
One key extrapulmonary manifestation of CF is pancreatic disease, which results in 
pathophysiologic changes in both endocrine and exocrine pancreatic function. CFTR-mediated 
transport of both chloride and bicarbonate ions plays an important role in maintaining optimal 
solubility of intraluminal fluid and facilitating flow of alkaline fluid from acinar cells into the 
pancreatic and bile ducts. Alkaline fluid enters the duodenum of the small intestine and rapidly 
neutralizes the acidic pH of chyme entering the small intestine from the stomach, thus creating 
an optimal pH for digestive enzyme activity and micelle formation. Decreased CFTR function 
results in pancreatic duct blockages and decreased secretion of bicarbonate-rich fluids and 
enzymes from the exocrine pancreas into the small intestine.16 The role of CFTR as a 
bicarbonate channel will be explored in this study by examining the change in pH from the 
stomach to the proximal small intestine. 
Two complementary approaches to increase CFTR-mediated chloride secretion in the airway 
epithelia have been studied.17 One approach is to treat with a compound (CFTR “correctors”) 
that will modify the cellular processing and trafficking of the CFTR protein to increase the 
amount of functional CFTR at the cell surface. Another approach is to treat with compounds 
(“potentiators”) that increase the channel gating activity of protein kinase A-activated CFTR at 
the cell surface to enhance ion transport. Depending on the amount of residual CFTR channel 
activity in the membrane and the pathophysiology of that activity (reflecting the CFTR genotype 
of the patient and possibly other factors), both approaches may be required to ameliorate lung 
disease in patients with CF. A modest restoration of chloride secretion through the action of a 


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potentiator and/or corrector could prevent the hyperabsorption of water across the apical surface 
of epithelial cells, allowing proper maintenance of airway hydration. Restoration of 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 compound developed by Vertex Pharmaceuticals Incorporated (Vertex) that has 
been shown to have CFTR corrector properties. Several lines of in vitro evidence suggest that 
VX-661 works by promoting the proper cellular processing and trafficking of a fraction of 
F508del-CFTR protein during its biogenesis and processing in the endoplasmic reticulum, 
allowing it to exit the endoplasmic reticulum and traffic to the cell surface.18 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 substantial increase in Cl− secretion.18 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).19 
Ivacaftor (IVA, VX-770; Kalydeco [150-mg tablets]) is a compound developed by Vertex that 
has been shown to have CFTR potentiator properties. Proof of concept that pharmacologic 
modulation of CFTR function can result in clinical benefit in patients with CF was observed in 
subjects with CF and the G551D-CFTR mutation who had robust clinical improvement following 
administration of IVA.20 Kalydeco is currently indicated for treatment of CF in a subset of 
patients with Class III or “gating” CFTR mutations, including the G551D-CFTR mutation. 
Details about the VX-661 and IVA development programs can be found in the Investigator's 
Brochures.21,22 
6 
STUDY OBJECTIVE 
To evaluate the clinical mechanisms of action in lung function and extrapulmonary systems of 
VX-661 in combination with IVA (VX-661/IVA) in subjects with CF who are homozygous for 
the F508del-CFTR mutation 
7 
STUDY ENDPOINTS 
7.1 
Key Endpoints 
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
from baseline at Day 28 
• Absolute change in mucociliary clearance (MCC) from baseline at Day 28 
• Absolute change in gastrointestinal pH from baseline at Day 29 
• Absolute change in sweat chloride from baseline at Day 29 
 


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7.2 
Other Endpoints 
 
 
 
 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory 
values (i.e., serum chemistry, vitamin levels, lipid panel, hematology, coagulation 
studies, and urinalysis), standard 12-lead electrocardiograms (ECGs), vital signs, and 
pulse oximetry 
8 
STUDY DESIGN 
8.1 
Overview of Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter, 
exploratory study in subjects with CF who are homozygous for the F508del-CFTR mutation. 
This study is designed to evaluate the lung function and extrapulmonary responses of subjects 
receiving VX-661/IVA combination therapy. 
This study includes a Screening Period, Treatment Period, and a Safety Follow-up Visit. The 
study plans to randomize approximately 35 subjects and up to approximately 45 subjects. 
Subjects will be randomized (4:1) to VX-661/IVA or placebo, respectively, as shown in Figure 
8-1.  
Subjects who prematurely discontinue study drug treatment will be asked to complete 
assessments as described in Section 8.1.4. 
Subjects who complete the Treatment Period and are eligible and elect to roll into an extension 
study will be required to have a Safety Follow-up visit 28 ± 7 days after the last dose of study 
drug. 


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inconclusive, an X-ray will be required to confirm the WMC passage. The subject will not be 
randomized in the study until passage of the WMC has been confirmed by the central reader or 
X-ray, regardless of confirmation of passage by the subject at the telephone contact (see the 
Study Reference Manual for additional information). 
To allow flexibility, the Clinic Visit Day -23 to Day -10 may occur on 1 day or on 2 separate 
days as follows (see Table 3-1):  
• Spirometry and MCC should be performed on the same day and spirometry should 
precede MCC.  
• If WMC administration and MCC occur on a single day, spirometry should occur before 
WMC administration, and WMC administration should occur before MCC.  
• A urine pregnancy test will be completed before WMC administration and the MCC; if 
WMC administration and MCC occur on 2 separate days, pregnancy testing will occur 
before the procedures on each day.  
• If assessments occur on 2 separate days, a meal or snack bar will be provided at the clinic 
on both days. 
• Fasting will occur only on the day of WMC administration. 
Subjects will be outpatients during the Screening Period. 
8.1.1.1 
Repetition of Screening Assessment(s) 
Repetition of individual screening assessment(s) that did 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 or assessment 
may be permitted with the approval of the medical monitor. 
• Exclusionary liver function test (LFT) levels, which may be retested within 14 days of the 
original screening date. 
• If screening spirometry measurements fail to meet acceptability and repeatability criteria as 
specified by American Thoracic Society/European Respiratory Society guidelines,23 repeat 
spirometry evaluation may be performed once, after discussion with the medical monitor. 
If repeat values of the individual assessment(s) described above are within the eligibility criteria 
and completed within the screening window, then the subject will be eligible for the study, 
provided they meet all eligibility criteria. 
8.1.1.2 
Rescreening 
Subjects may only be rescreened with the approval of the medical monitor. If a subject is 
rescreened, all Screening Visit (Day -28 to Day -13) assessments will be repeated except for the 
following: 
• Patency capsule assessment 
• Ophthalmology examination (if performed within the last 3 months) 
• CF genotyping 




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8.1.3 
Safety Follow-up Visit 
The Safety Follow-up Visit assessments are listed in Table 3-2. The Safety Follow-up Visit will 
occur approximately 28 (± 7) days after the last dose of study drug for all subjects, including 
subjects who discontinue treatment (see Section 8.1.4). 
Subjects who complete the Day 29 Visit and subsequently the Safety Follow-up Visit will be 
offered the opportunity to enroll into an extension study of VX-661/IVA combination therapy if 
they meet eligibility requirements for the extension study. 
8.1.4 
Early Treatment Termination 
If a subject prematurely discontinues study treatment, an Early Treatment Termination Visit 
(ETT) should be scheduled as soon as possible after the last dose of study drug. Subjects who 
prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit, 
approximately 28 (± 7) days after their last dose of study drug. The assessments performed at the 
ETT and Safety Follow-up Visit are listed in Table 3-2. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the Safety 
Follow-up Visit will be completed in place of the ETT. 
8.2 
Rationale for Study Design and Study Drug Regimens 
8.2.1 
Study Design 
A randomized, double-blind, placebo-controlled study design will avoid measurement bias by 
the investigator and will reduce reporting bias of symptoms or outcomes by subject. 
This study is designed to observe the effects of VX-661 (100 mg daily [qd]) and IVA 
(150 mg every 12 hours [q12h]) combination therapy on lung function (measured by ppFEV1 and 
MCC), gastrointestinal pH, and CFTR modulation (sweat chloride). These data will be 
informative for understanding the underlying clinical mechanisms of physiological 
improvements derived from CFTR modulation. 
8.2.2 
Study Drug Dose and Duration 
The dose regimen of VX-661 for this study is equivalent to the dose evaluating VX-661/IVA 
combination therapy in a Phase 2 study, Study VX11-661-101 (Study 101), and is the same dose 
selected for the Phase 3 studies.21 The dose regimen of 100-mg VX-661 qd/ 150 mg IVA q12h 
provided clinically meaningful and statistically significant improvements in ppFEV1 in 
Study 101 with 28 days of treatment in subjects homozygous for the F508del-CFTR mutation. In 
addition, a trend of decreased sweat chloride levels was observed with VX-661/IVA combination 
therapy at multiple dose levels investigated in Study 101 in subjects heterozygous and 
homozygous for the F508del-CFTR mutation.21Finally, in a separate study evaluating IVA 
monotherapy in patients with the G551D-CFTR mutation, improvements were observed within 1 
month in both ppFEV1 and MCC, as well as in gastrointestinal pH as measured by WMC.24 
Based on the timing of these treatment effects in those studies, a 4-week placebo-controlled 
duration was considered adequate. 
8.2.3 
Rationale for Study Population 
The study population will be subjects with CF who are 18 years of age and older and are 
homozygous for the F508del-CFTR mutation. The F508del-CFTR mutation interferes with the 
processing and trafficking of the CFTR protein, resulting in decreased chloride transport.18,19 In 


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Study 101, subjects homozygous for F508del-CFTR who were treated with VX-661/IVA 
combination therapy had statistically significant and clinically meaningful improvements in 
ppFEV1, supporting the further development of VX-661/IVA combination therapy.21 The 
baseline characteristics of the population to be enrolled in this study are anticipated to be similar 
to the subset of subjects aged 18 years and older in the Phase 3 study (Study VX14-661-106) of 
VX-661/IVA combination therapy in subjects homozygous for F508del-CFTR. 
8.2.4 
Rationale for Study Assessments 
The rationale for all efficacy assessments, including those related to lung function (ppFEV1), 
MCC, gastrointestinal pH, and sweat chloride, is provided below. Given the complexity and 
duration required to complete these assessments, clinical visits have been extended over multiple 
days within the screening and treatment periods. The safety assessments are standard parameters 
for clinical studies in drug development. The pharmacokinetics (PK) assessment (Section 11.3) is 
included to assess exposure to study drug. 
Spirometry 
To study the effect of VX-661/IVA combination therapy on lung function, ppFEV1 will be 
assessed as a measure of air flow in the lungs. 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/IVA 
combination therapy. Spirometry is the most widely implemented standardized assessment to 
evaluate lung function. 
MCC 
Mucus clearance is an innate airway defense mechanism for clearing bacteria and viruses, which 
is dependent on adequate airway surface hydration. It is hypothesized that patients with CF have 
defects in airway hydration, which in turn slows mucus clearance and promotes airway 
obstruction and subsequent infection. In a study evaluating IVA monotherapy in patients with the 
G551D-CFTR mutation, improvements were observed in both ppFEV1 and MCC. These results 
provide evidence for the underlying mechanism of action of IVA monotherapy and the observed 
clinical benefit in these patients.24 Therefore, the effect of VX-661/IVA combination therapy on 
MCC will also be assessed in this study using an imaging technique that enables the tracking of 
mucus within the airways. 
Gastrointestinal pH 
In addition to studying effects in the pulmonary system, and given that CFTR transports 
bicarbonate and chloride, the effect of VX-661/IVA combination therapy on gastrointestinal pH 
will be assessed. Efficient neutralization of gastric acid in the proximal portion of the small 
intestine is an important factor in optimal nutrient absorption and digestion. Patients with CF 
have reduced bicarbonate secretion from the pancreas and gastrointestinal mucosa,25, 26,27 and a 
more acidic small intestinal milieu as compared with healthy controls,28 resulting in increased 
mucus viscosity, inefficient pancreatic enzyme activity and malnutrition. In a study evaluating 
IVA monotherapy in patients with the G551D-CFTR mutation, IVA treatment results in 
improvement in the pH of the small bowel, as measured using an ingested capsule device (a 
WMC).24 Therefore, the effect of VX-661/IVA combination therapy on bicarbonate secretion 
will also be assessed in this study using gastrointestinal pH as determined by a WMC. 
 




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received before randomization, a previous CFTR genotype laboratory report may be used to 
establish eligibility. Note: Subjects who have been randomized and whose screening 
genotype results do not confirm study eligibility must be discontinued from the study as 
described in Section 9.5. 
4. Confirmed diagnosis of CF32 defined as a sweat chloride value ≥60 mmol/L by quantitative 
pilocarpine iontophoresis (as documented in the subject's medical record OR from sweat 
chloride test result obtained during screening, if subject does not have a sweat chloride test 
result in the medical record). 
5. FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height (equation of Hankinson 
et al.)33 during the Day -28 to Day -13 Screening Visit (Section 11.4.1). Spirometry 
measurements must meet American Thoracic Society/European Respiratory Society criteria23 
for acceptability and repeatability (Section 8.1.1.1). 
6. Stable CF disease as judged by the investigator. 
7. Willing to remain on a stable CF medication regimen as described in Section 9.4 from 
screening through the Safety Follow-up Visit. 
8. All subjects must agree to undergo a patency capsule test and WMC assessment during 
screening. Subjects will not be randomized if they have not passed the patency capsule 
and WMC. 
9.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible for this study: 
1. History of any comorbidity that, in the opinion of the investigator, might confound the results 
of the study or pose an additional risk in administering study drug to the subject. For 
example: 
• History of cirrhosis with portal hypertension, and/or history of risk factors for Torsade de 
Pointes (e.g., familial long QT syndrome, hypokalemia, heart failure, left ventricular 
hypertrophy, bradycardia, myocardial infarction, cardiomyopathy, history of arrhythmia 
[ventricular and atrial fibrillation], obesity, acute neurologic events [subarachnoid 
hemorrhage, intracranial hemorrhage, cerebrovascular accident, and intracranial trauma], 
and autonomic neuropathy) 
2. Any of the following abnormal laboratory values at screening: 
• Hemoglobin <10 g/dL 
• Abnormal liver function defined as any 2 or more of the following: ≥3 × upper limit of 
normal (ULN) aspartate aminotransferase (AST), ≥3 × ULN alanine aminotransferase 
(ALT), ≥3 × ULN gamma-glutamyl transpeptidase (GGT), ≥3 × ULN alkaline 
phosphatase (ALP), or ≥2 × ULN total bilirubin 
• Abnormal liver function defined as any increase of ≥5 × ULN AST or ALT 
• Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 
(calculated by the Modification of Diet in Renal Disease Study Equation)34,35 


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3. 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) 
4. A standard 12-lead ECG demonstrating QTc >450 msec at Screening. If QTc exceeds 
450 msec for the screening ECG, 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 
5. History or evidence of cataract, lens opacity, Y-suture, or lamellar rings determined to be 
clinically significant by the ophthalmologist during the ophthalmologic examination during 
the Screening Period. The ophthalmologic 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 Screening Period (Section 11.7.7). 
6. History of solid organ or hematological transplantation 
7. History of alcohol or drug abuse, as deemed by the investigator, in the past year, including 
but not limited to cannabis, cocaine, and opiates 
8. Ongoing or prior participation in an investigational drug study as follows: 
• A washout period of 5 terminal half-lives of the previous investigational study drug (i.e., 
non-CFTR modulators) or 30 days, whichever is longer, must elapse before screening. 
The duration of the elapsed time may be longer if required by local regulations. 
• Subjects with previous participation in an investigational study of VX-661, lumacaftor, or 
another CFTR modulator within 90 days of screening or a washout period of 5 terminal 
half-lives of the previous investigational drug, whichever is longer, are not eligible. 
Eligibility of subjects enrolled in previous CFTR modulator studies must be confirmed by 
the medical monitor. 
• Ongoing participation in any observational (noninterventional) study, including studies 
requiring assessment without administration of study drug, is permitted. 
9. Use of restricted medications or foods within the specified window before the first dose of 
study drug and before specific assessments as defined in Section 9.3. 
10. Pregnant or nursing females (females of childbearing potential must have negative pregnancy 
test in the Screening Period and at the Day 1 Visit) 
11. Sexually active subjects of reproductive potential who are not willing to follow the 
contraception requirements outlined in Section 11.7.5.1 
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. An adult (aged 18 years or older) who is a relative of a study staff member may be 
randomized in the study provided that 
• the adult lives independently of and does not reside with the study staff member 
• the adult participates in the study at a site other than the site at which the family member 
is employed 


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13. Colonization with organisms associated with a more rapid decline in pulmonary status (e.g., 
Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). For 
subjects who have had a history of a positive culture in the past, the investigator could be 
guided by the following suggested criteria for a subject to be considered free of colonization: 
• The subject should have had 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. 
14. Subjects who have had radiation exposure within 1 year before the first MCC procedure that 
would cause them to exceed federal regulations by participating in this study (whole body 
exposure >5 Rem [50 mSv] for adults) 
15. In the opinion of the investigator, unable to adequately perform inhalation maneuvers needed 
for isotope deposition during the MCC procedures 
16. Additional exclusion criteria related to administration of WMCs include: 
• History of any intraperitoneal abdominal or pelvic surgery (cesarean section, 
cholecystectomy and appendectomy are permitted if performed >3 months before the patency 
assessment during screening) or surgery involving the luminal gastrointestinal tract. The 
Vertex medical monitor should be contacted in case of questions. 
(Note: A percutaneous endoscopic gastrostomy [PEG] tube in the past or present or an 
extraperitoneal abdominal surgery, such as an inguinal hernia or umbilical hernia repair, are 
not exclusionary.) 
• Clinical or radiographic evidence of bowel obstruction or stricture within the last 12 months 
• Prior intestinal resection 
• Previous history of bezoars (the presence of retained liquid, bile, or small amounts of poorly 
organized food residue is permitted) 
• Presence or history of extensive intestinal diverticulosis, diverticular stricture, and other 
intestinal strictures 
• History of inflammatory bowel disease, with or without strictures 
• Presence or history of fibrosing colonopathy 
• Dysphagia to solid food or pills (unable to swallow a 13 mm × 26 mm capsule) 
• Use of cardiac medical devices such as pacemakers and defibrillators (gastric stimulators, 
bladder stimulators, spinal stimulators, medication infusion devices, insulin pumps, and 
continuous glucose monitors are permitted) 


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9.3 
Study Restrictions 
Study restrictions related to the biomarker assessments are summarized in Table 9-1. 
Table 9-1 
Study Restrictions 
Restricted Medication/Food/Activity a 
Timing of Restriction 
MCC 
 
No hypertonic saline, bronchodilator, or dornase alfa usage 
12 hours before MCC procedures 
WMC 
 
Food or drink (water permitted) 
 
8 hours before WMC administration AND for 4 
hours immediately after WMC administration 
with a snack bar 
Proton-pump inhibitorsb 
1 week before WMC administration until 
capsule has passed 
Calcium, aluminum, or magnesium antacidsb 
24 hours before WMC administration until 
capsule has passed 
Histamine 2 blockersb 
48 hours before WMC administration until 
capsule has passed 
Narcotic medicationsb 
48 hours before WMC administration until 
capsule has passed 
Chronic laxatives changes 
From Screening until the last WMC has passed 
Tobacco 
8 hours before WMC administration and for 6 
hours immediately after WMC administration 
Alcohol 
24 hours before WMC administration until 
capsule has passed 
Rigorous exercise 
From WMC administration until capsule has 
passed 
MRI 
No MRI from patency capsule or WMC 
administration until capsule has passed  
MCC: mucociliary clearance; MRI: magnetic resonance imaging; WMC: wireless motility capsule 
a 
See Section 9.4 for guidance for concomitant medications. 
b 
A nonexhaustive list of medications is included in the Study Reference Manual. For questions, contact the 
Vertex medical monitor. 
9.3.1 
Additional Dietary Restrictions/Prohibited Medications 
Prohibited medications and certain foods are not allowed in this study (Screening Period through 
Safety Follow-up Visit) (Table 9-2). Known CYP3A4 inducers and inhibitors are restricted 
because VX-661 and IVA are metabolized at least in part via the hepatic enzymatic pathway 
using CYP3A4. 
A nonexhaustive list of study prohibitions and cautions for food and medication will be provided 
in the Study Reference Manual. 


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Table 9-2 
Additional Study Restrictions 
Restricted Medication/Food 
Study Period 
Screening Period 
Treatment Period Through Safety 
Follow-up Visit 
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 
Moderate and strong CYP3A 
inhibitors (except for 
ciprofloxacin) 
None allowed within 14 days before 
the first dose of the study drug 
None allowed through the Safety 
Follow-up Visit 
Commercially available CFTR-
modulators (e.g., Kalydeco, 
lumacaftor) 
None allowed during Screening 
Period 
None allowed through the Safety 
Follow-up Visit 
CYP: cytochrome P450; IVA: ivacaftor. 
Note: The use of restricted medication by subjects with medical needs will be addressed on a case-by-case basis 
with the medical monitor. 
9.4 
Prior and Concomitant Medications 
Information regarding all prior and concomitant medications, including the subject's CF 
medications, other medications, and herbal and naturopathic remedies administered from at least 
28 days before the Screening Period through the Safety Follow-up Visit, if applicable, will be 
recorded in each subject's source documents. For subjects who are screened but are not 
subsequently randomized into the study, details of prior medication will only be documented in 
the subjects' source documents. 
• Subjects must remain on a stable medication (and supplement) regimen for their CF from at 
least 28 days before Day 1 through the Safety Follow-up Visit. Stable medication regimen is 
defined as the current medication regimen for CF that subjects have been following for at 
least 28 days before Day 1. Guidelines for stable medication regimens for CF are as follows: 
o Subjects who are taking daily inhaled tobramycin or other chronically inhaled 
antibiotics should remain on that regimen throughout the study. 
o Subjects who 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 of up to 10 mg/day (chronically) or prednisone 
60 mg qd for up to 5 days 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 and MCC assessments 
performed according to the guidelines provided in Section 11.4.1. and Section 11.4.2. 
• Concomitant use of medications known to prolong the QT interval should be used with 
caution during the study, as the effect of VX-661/IVA combination therapy on the QT 
interval has not been evaluated in a thorough QT study. Consideration should be given to 


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obtaining an ECG when concomitant medication known to prolong the QT interval is 
administered. 
9.5 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons. If a subject 
has been withdrawn from study drug treatment, the subject should continue to be followed, 
provided the subject has not withdrawn consent. Subjects will be continued to be followed for 
safety for 28 days ± 7 days after the last dose of study drug (see Table 3-2). 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact 
the subject. In any circumstance, reasonable effort will be made to document subject outcome. 
The investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a Safety Follow-up Visit, if 
applicable (Section 8.1.4), and follow up with the subject regarding any unresolved AEs. 
If the subject withdraws consent, 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. 
The investigator should inquire about the reason for withdrawal of consent. 
Subjects must return all unused study drug. 
A subject will be withdrawn from study drug treatment for any of the following reasons: 
• A female subject or a female partner of a male subject has a confirmed pregnancy. 
• A subject’s treatment is unblinded by the investigator. 
A subject may be withdrawn from study drug treatment after a discussion between the 
investigator and the medical monitor for any of the following reasons: 
• A subject develops a medical condition that requires prolonged concomitant therapy with a 
prohibited medication or prolonged interruption of the study drug. 
• A subject develops a life-threatening AE or a serious AE (SAE) that places him/her at 
immediate risk, and discontinuation of study drug treatment and withdrawal from the study 
are deemed necessary. 
• A subject is noncompliant with study requirements. 
• A subject has an increase in transaminases (ALT or AST) according to evaluations and 
management described in Section 11.7.8. 
• A subject has an increase in QTc according to evaluations and management described in 
Section 11.7.4.1. 
• A subject develops a cataract or lens opacity. 
Subjects who discontinue study treatment early should complete the assessments of the ETT 
and/or Safety Follow-up Visit, as noted in Section 8.1.4. 


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Subjects who are randomized and whose screening CFTR genotype results do not confirm study 
eligibility must be discontinued from study drug treatment, will undergo ETT and/or Safety 
Follow-up Visits per Section 8.1.3 and Section 8.1.4, 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 
Subjects who withdraw or are withdrawn for nonsafety reasons during the Treatment Period may 
be replaced in order to have approximately 35 subjects completing the study. 
10 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
Study drug refers to VX-661/IVA, IVA, and their matching placebos. 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
10.2 
Administration 
Study drug tablets will be administered orally during the Treatment Period as shown in 
Table 10-1. 
Table 10-1 
Study Drug Administration - Treatment Period  
Treatment Arm 
Time 
Drug(s) and Dose(s) Administered 
Route of Administration 
VX-661/IVA 
 
AM 
100-mg VX-661 / 150-mg IVA FDC tablet, 
oral 
PM 
150-mg IVA tablet, 
oral 
Placebo 
 
AM 
VX-661/IVA-matching placebo FDC tablet, 
oral 
PM 
IVA-matching placebo tablet, 
oral 
AM: morning; FDC: fixed dose combination; IVA: ivacaftor; PM: evening. 
Study drug should be administered within 30 minutes of starting a meal with fat-containing food 
such as a “standard CF” high-fat, high-calorie meal or snack according to the following 
guidelines: 
1. Throughout the Treatment Period, study drugs will be administered after the start and before 
the end of a meal. It is recommended that the duration of each meal associated with study 
drug intake (i.e., breakfast and dinner/snack, as applicable) should not exceed 30 minutes. 
2. 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. 
3. On days of WMC administration, subjects will fast overnight and will ingest a snack bar 
provided at the site in place of the morning high-fat meal immediately before ingesting the 
WMC. Subjects will fast for 4 hours after the capsule is taken and snack bar is consumed. 


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4. At the Day 1 Visit, all subjects will be observed for 6 hours after the morning dose of the 
study drug.  
5. 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. 
6. On days of scheduled visits, the morning dose of study drug will be administered at the site 
after predose assessments have been completed. The meal or snack will be provided by the 
site for the morning dose of study drug. 
7. If a subject's scheduled visit is to occur in the afternoon, the following guidelines must be 
used: 
• If the dose in the clinic will be within 6 hours of the subject's scheduled morning dose, 
the subject should withhold their morning dose of 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. 
8. For visits after the Day 1 Visit, subjects will be instructed to bring all used and unused study 
drug to the site. 
10.3 
Method of Assigning Subjects to Treatment Groups 
A target of approximately 35 subjects, with up to approximately 45, who meet the eligibility criteria 
will be randomized in a ratio of 4:1 (active study drug:placebo). An interactive web response 
system (IWRS) will be used to assign subjects to treatment. Detailed instructions for 
randomization will be provided separately.  
10.4 
Missed Doses 
If a subject misses a dose and recalls the missed dose within 6 hours, the subject should take 
his/her dose with food. If more than 6 hours have elapsed after his/her usual dosing time, the 
subject should skip that dose and resume his/her normal schedule for the following dose. For 
example, 
• If the morning dose of study drug should have been taken at approximately 08:00, and the 
subject remembers at 12:00 that he/she forgot to take that dose, he/she should take the dose 
with food as soon as possible. 
• If the morning dose of study drug should have been taken at approximately 08:00, and more 
than 6 hours have elapsed beyond the scheduled dosing time (i.e., the time is past 14:00), the 
subject would resume dosing with the evening dose at approximately 20:00. 
10.5 
Dose Modification for Toxicity 
The dosage of VX-661 or ivacaftor cannot be altered, but the investigator can stop treatment 
(Section 9.5). 


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10.6 
Packaging and Labeling 
Vertex will supply the 100-mg VX-661 / 150-mg IVA FDC tablets, VX661/IVA-matching 
placebo FDC tablets, 150-mg IVA tablets, and IVA-matching placebo tablets. Study drug 
labeling will be in compliance with applicable local and national regulations. Additional details 
regarding packaging, labeling, and dispensing for the study drugs will be included in the 
Pharmacy Manual. 
10.7 
Study Drug Supply, Storage, and Handling 
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 detailed in Section 10.8 or via the drug accountability forms as 
instructed by Vertex. 
Table 10-2 
Identity of Study Drugs, Dosage, and Storage 
Drug Name 
Strength/Formulation/Route 
Dosage 
Storage Condition 
VX-661/IVA FDC 
tablet 
100 mg/150 mg tablet; oral 
100 mg/150 mg, 
1 tablet morning dose 
≤25°C (77°F) with excursions 
to 30°C (86°F) 
IVA 
150 mg tablet, oral 
150 mg, 1 tablet 
evening dose 
≤25°C (77°F) with excursions 
to 30°C (86°F) 
VX-661/IVA FDC-
matching placebo 
0 mg/0 mg tablet; oral 
0 mg/0 mg, 1 tablet 
morning dose 
≤25°C (77°F) with excursions 
to 30°C (86°F) 
IVA-matching 
placebo 
0 mg tablet, oral 
0 mg, 1 tablet evening 
dose 
≤25°C (77°F) with excursions 
to 30°C (86°F) 
FDC: fixed dose combination; IVA: ivacaftor 
10.8 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received, (2) study drug dispensed to the subjects, and (3) study drug 
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. 
10.9 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. 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. 
10.10 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 


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study drug dosing and remind the subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should contact the medical monitor to discuss discontinuation of the 
subject from the study. 
10.11 
Blinding and Unblinding 
This is a double-blind study. 
10.11.1 
Blinding  
Blinding of treatment codes and applicable study data will be maintained until the database is 
locked for the final analysis.  
The subjects and all site personnel, including the investigator, the site monitor, and the study 
team, will be blinded with the exception of the following: 
• Any site personnel for whom this information is important to ensure the safety of the subject 
in the event of a life-threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of the subject 
and her fetus in the event of a pregnancy 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy SAE 
processing and reporting regulations 
• Unblinded statistician preparing the final (production) randomization list, who is not part of 
the study team 
• Vertex Clinical Operations IWRS management 
• Vertex Clinical Supply Chain 
• Vendor analyzing PK samples 
• Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time 
Vertex Drug Metabolism and Pharmacokinetics laboratory personnel will not be involved in the 
conduct of the study and will be unblinded to the bioanalysis results but will remain blinded to 
subject number and treatment assignment. 
Spirometry Data Blinding 
Despite treatment blinding, knowledge of the spirometry results has the potential to suggest 
whether a subject has been administered active study drug or placebo. Therefore, during the 
conduct of the study, the Vertex study team will have no access to the postdose spirometry 
results data. The vendor for central reading of the spirometry data will only send the blinded 
spirometry files (blinded treatment group, with real values for screening and baseline, but with 
dummy values for all the spirometry results data after baseline) to Vertex to be used for 
developing the statistical programs. Furthermore, subjects and their caregiver should not be 
informed of their study-related spirometry results during the Treatment Period regardless of 
whether the subject has prematurely discontinued treatment. 


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Sweat Chloride Data Blinding 
Despite treatment blinding, knowledge of the sweat chloride data has the potential to suggest 
whether a subject has been administered active study drug or placebo. Therefore, during the 
conduct of the study, the Vertex study team will not have access to the sweat chloride data; 
dummy data will be used to develop statistical programs. During the process of locking the 
clinical database, after all study visits have been completed, access to treatment-blinded sweat 
chloride data will be provided to a small group of individuals who are not part of the Vertex 
study team. This group, which will consist of a biostatistician, a statistical programmer, a 
validation statistical programmer, and a clinical reviewer, will review the sweat chloride data to 
ensure there are no significant data issues and will use the blinded data set to refine the statistical 
programs. 
MCC Blinding 
Despite treatment blinding, knowledge of the MCC data has the potential to suggest whether a 
subject has been administered active study drug or placebo. Therefore, during the conduct of the 
study, the Vertex study team will have no access to the MCC data. Results data will be submitted 
to a central reader. These individuals, including site staff performing the MCC assessment, will 
otherwise not be involved in any other aspects of study conduct or subject interaction. 
WMC Blinding 
Despite treatment blinding, knowledge of the WMC data has the potential to suggest whether a 
subject has been administered active study drug or placebo. Therefore, during the conduct of the 
study, the Vertex study team will have no access to the WMC data, except confirmation that the 
WMC has passed. Results data will be submitted to the central reader, who will otherwise not be 
involved in any other aspects of study conduct or subject interaction. 
10.11.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the medical monitor, they will use their best 
judgment, based on the nature and urgency of the clinical situation, and may proceed with 
unblinding without having successfully reached and discussed the situation with the medical 
monitor. 
In addition, the Vertex Medical Information Call Center (MICC) 
will answer 
calls 24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. Contact information for the Vertex medical monitor and 
MICC will be provided in the Study Reference Manual. 
If a subject's treatment assignment has been unblinded for a medical emergency or urgent clinical 
situation, the medical monitor will be notified within 24 hours of the unblinding event. The 




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Samples from the PK sampling will be kept frozen by a designee until all analyses have been 
completed and then disposed of according to Vertex or designee standard operating procedures 
(SOPs). 
For each visit with a PK blood draw, a record of study drug administration will be collected as 
described in Section 10.2. The collection date and time that each PK blood sample is drawn will 
also be recorded. 
Details on sample collection, processing, and shipping will be provided in a separate 
protocol-specific Laboratory Manual. 
11.3.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood and urine 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. 
11.3.3 
Bioanalysis 
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee SOPs. A description of the assay and validation data will be provided in separate 
reports. 
If appropriate, these samples may also be used for evaluations of metabolites of VX-661 and 
IVA during treatment. These samples may also be used for further evaluation of the bioanalytical 
method and for analyses that provide information on the metabolic pathways used or impacted 
by VX-661 and IVA. These data will be used for exploratory purposes and may not be included 
in the clinical study report. 
11.4 
Key Efficacy Assessments 
11.4.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines23 at the 
time points noted in Table 3-1 and Table 3-2 according to the additional guidelines that follow. 
Prebronchodilator spirometry is defined as spirometry testing performed for subjects who have: 
• withheld their short-acting bronchodilators (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) for more than 12 hours before the 
spirometry assessment; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 
During the Screening Visit, spirometry assessments may be performed pre- or 
postbronchodilators. At all other visits (including the Clinic Visit on Day -23 to Day -10), all 
spirometry assessments should be performed prebronchodilator. During the Treatment Period, 
spirometry assessments must be performed before administration of study drug. 


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In the event that a subject forgets to withhold bronchodilator(s), spirometry should be performed 
according to the following: 
• If a subject's Clinic Visit Day -23 to -10 spirometry is prebronchodilator, but, on a 
subsequent visit, the subject forgets to withhold bronchodilator use, a postbronchodilator 
spirometry will be obtained for that visit only, and the visit will not be rescheduled. 
• If, on Clinic Visit Day -23 to -10, the subject forgets to withhold his/her dose of 
bronchodilator, then spirometry and MCC should be performed post-bronchodilator, and all 
subsequent spirometric measurements (according to the schedule of assessments detailed in 
Table 3-2), and the MCC assessment at Day 28, should be performed post-bronchodilator. 
• Each spirometry assessment will be recorded in the source documents as prebronchodilator 
or postbronchodilator. 
If more than 1 spirometry assessment is required at a visit, bronchodilators will be withheld until 
completion of the last scheduled spirometry assessment is completed. 
All sites will be provided with spirometers to be used for all study assessments. Spirometry data 
will be transmitted to a centralized spirometry service for quality review. 
Subjects should not be informed of their study-related spirometry results during the Treatment 
Period. 
The following parameters will be determined as part of the spirometry assessment: 
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 
• Forced expiratory flow (FEF25%-75%) (L/s) 
11.4.2 
Mucociliary Clearance 
MCC will be assessed as indicated in Table 3-1 and Table 3-2. 
All bronchodilators usage is restricted for 12 hours before the MCC assessments at the Day -23 
to Day -10 Visit and the Day 28 Visit. 
On Day 28, MCC will occur after the dose of study drug. MCC assessments will be performed 
according to an SOP in the Study Manual. 
Subjects with less than 30 percent predicted FEV1 on day of MCC, or with acute upper or lower 
respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for 
pulmonary disease within 14 days before scheduled MCC procedures, should not have the 
assessment performed. 
Sites that perform MCC assessments will be expected to procure the MCC equipment as 
described in the SOP. During the MCC assessment, a series of images will be collected 
immediately following inhalation of a radiolabeled aerosol and again approximately 6 hours 
later. Specific instructions for the conduct of MCC testing and submission of results to the 
central reading center are provided in the Study Reference Manual. 






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documenting, grading, and reporting AEs. A separate document that details AE case report form 
(CRF) completion guidelines for investigators as well as training will be provided. 
11.7.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory. Blood samples requiring a 4-
hour fast will be collected predose on Day 1 and Day 29, and at the ETT and Safety Follow-Up 
Visit. Fasting is not required at other time points unless specified in Table 3-1 and Table 3-2. 
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table 3-1 and Table 3-2. 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 11-1. 
Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose 
Blood urea nitrogen 
Creatinine 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate 
Inorganic phosphate  
Total bilirubin, direct bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase  
Alanine aminotransferase 
Lactate dehydrogenase 
Gamma-glutamyl transpeptidase 
Total protein 
Albumin 
Creatine kinase 
Amylase 
Lipase 
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 
Reticulocytes 
Platelets 
Leukocytes 
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes  
Monocytes 
Coagulation Studies 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio 
Leukocyte esterase  
Nitrite  
Urobilinogen  
Urine protein  
pH 
Urine blood  
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose  
Note: Day 1, Day 29, ETT, and Safety Follow-up blood draws will be done after a minimum 4-hour fast. All other 
blood draws do not require fasting. 
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be performed and results for provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 


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Additional tests at screening: The following additional tests will be performed during screening 
to assess eligibility:  
Clinical laboratory assessments from screening will have no clinically significant findings that 
preclude participation in the study, as judged by the investigator, for a subject to receive study 
drug on Day 1. 
Pregnancy (β-human chorionic gonadotropin) Tests for Females of Childbearing Potential: 
Serum samples will be obtained as specified in Table 3-1 and Table 3-2 and analyzed at the 
central laboratory. Urine pregnancy tests will be performed at the site as specified in Table 3-1 
and Table 3-2. 
FSH (Screening Period only): Blood sample for FSH will be measured for any suspected 
postmenopausal female with at least 12 months of continuous spontaneous amenorrhea. Serum 
FSH levels must be ≥40 mIU/mL to be considered postmenopausal. 
CF Genotype (Screening Period only): CFTR genotyping will be performed on all subjects to 
confirm the genotype documented in the subject's medical record (if available). Refer to the 
Laboratory Manual for details. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate. 
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
At the discretion of the local investigator, local laboratories may be used for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it should be verified by the central laboratory as soon as possible after the 
investigator becomes aware of the abnormal result. If it is not possible to send a timely specimen 
to the central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base 
the assessment of an AE on the local laboratory value. 
11.7.3 
Physical Examinations and Vital Signs 
A physical examination (PE) of all body systems and vital signs assessment will be performed at 
visits noted in Table 3-1 and Table 3-2. 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 PEs will be reported as 
AEs. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. These will be assessed following a 5-minute rest in the supine position. 
11.7.4 
Electrocardiograms 
11.7.4.1 
Standard 12-Lead Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Schedule of Assessments (Table 3-1 and Table 3-2). A window of approximately ± 15 minutes 
will be allowed around the nominal times for all ECG assessments. Additional standard 12-lead 


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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 QTc 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 QTc, 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. 
11.7.5 
Contraception and Pregnancy 
11.7.5.1 
Contraception 
The effects of VX-661 monotherapy or in combination with IVA on conception, pregnancy, and 
lactation in humans are not known. Neither VX-661 nor IVA 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 IVA were each found to be 
nonteratogenic in reproductive toxicology studies in rats and rabbits.21,22 Subjects should follow 
the contraception requirements outlined in this study protocol. The effects of VX-661 
monotherapy or in combination with IVA on the PK of hormonal contraceptives are not known. 
Thus, 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/IVA combination therapy, 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 and until 90 days following the last dose of study drug. 
Contraception for the couple is waived for the following: 


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• 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. 
• The male subject 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: 
• Postmenopausal: spontaneous amenorrhea for at least 12 consecutive months and serum 
FSH level ≥40 mIU/mL at screening 
• Documented hysterectomy or a bilateral oophorectomy/salpingo-oophorectomy 
• NOTE: All other female subjects who have had their first menstrual period will be 
considered to be of childbearing potential. 
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. 
• 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. 


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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. 
• 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. 


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11.7.5.2 
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 study drug(s). 
If a female subject or the female partner of a male subject becomes pregnant while participating 
in the study, study drug will 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 11.7.5.1). 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 active drug, the subject or partner will be followed until the 
end of the pregnancy and the infant will be followed for 1 year after the birth, provided informed 
consent is obtained. A separate ICF will be provided to explain these follow-up activities. 
Pregnancy itself does not constitute an AE. 
11.7.6 
Pulse Oximetry 
Arterial oxygen saturation by pulse oximetry will be measured at visits noted in Table 3-1 and 
Table 3-2. This will be assessed following a 5-minute rest (seated or supine) and before study 
drug dosing. At visits when study drug is taken at the site, pulse oximetry will be collected 
before the morning dose. This is a noninvasive measure of oxygen delivery to the tissues and has 
been correlated with clinical status and lung function. 
11.7.7 
Ophthalmologic Examination 
Subjects will undergo an ophthalmologic examination performed by a licensed ophthalmologist 
at screening, which includes 
• measurement of best corrected distance visual acuity of each eye 
• measurement of lens refracting power following cycloplegia (e.g., autorefractor or 
ophthalmoscopy streak) 
• pharmacologically dilated examination of the lens with a slit lamp 
The screening ophthalmologic examination must be completed and the results reviewed before 
randomization. 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. 
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). 
Additional ophthalmologic examinations may be conducted at the discretion of the investigator. 
The medical monitor should be notified of any additional ophthalmologic examinations. 
In addition, at screening, the following history will be obtained for all subjects: 
• history of steroid use 
• history or presence of diabetes 


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• any prior ophthalmologic or optometric examinations 
• history of trauma to the eye 
• any family history of glaucoma, congenital cataracts, or cataracts arising later in life 
• use of corrective lenses (contact lenses or eyeglasses) 
• history of prolonged exposure to sunlight or ultraviolet light and use of sunglasses 
• history of exposure to secondhand smoke 
11.7.8 
Liver Function Test Parameters 
Liver function testing (ALT, AST, GGT, ALP, and total bilirubin) must be performed as noted in 
Table 3-2. 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, follow-up 
levels must be obtained within 7 ± 2 days. 
If a subject cannot return to the site for liver function testing, a local laboratory may be used. 
Elevations in LFTs at the local laboratory must be reported immediately to the medical monitor, 
and the subject must have the tests repeated and sent to the central laboratory as soon as possible 
(ideally within 48 to 72 hours). 
Study drug administration must be interrupted immediately (before confirmatory testing), and 
the medical monitor must be notified, if any of the following criteria is met: 
• ALT or AST >8 × ULN 
• ALT or AST >5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical 
jaundice 
A thorough investigation of potential causes should be conducted and the subject should be 
followed closely for clinical progression. 
If no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, or alcohol 
ingestion) for the confirmed elevated transaminases is identified, regardless of whether ALT or 
AST levels have improved, study drug treatment must be permanently discontinued if repeat 
testing within 48 to 72 hours confirms the initial elevation. Subjects in whom treatment is 
discontinued for elevated transaminases should have their transaminases monitored closely until 
levels normalize or return to baseline. 
Resumption of Study Drug 
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 while the subject remains on study drug 
and during the followup. If a protocol-defined transaminase elevation occurs within 4 weeks of 


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rechallenge with the study drug, then the study drug must be permanently discontinued, 
regardless of the presumed etiology. 
12 
STATISTICAL AND ANALYTICAL PLANS 
This study is planned as an exploratory study. No type I error control for hypothesis testing will 
be applied, and each of the key endpoints will be assessed individually using a significance level 
α of 0.05. 
Analysis of all data will be performed by Vertex or its designee(s). Before the database is locked 
for analysis, a detailed plan for the analysis of efficacy and safety data will be presented in a 
statistical analysis plan (SAP), and a detailed plan for PK analysis will be presented in a clinical 
pharmacology analysis plan (CPAP). 
12.1 
Sample Size and Power 
A target of approximately 35 subjects, with up to approximately 45, who meet the eligibility 
criteria will be randomized in a ratio of 4:1 to active study drug or placebo to maximize power 
across the endpoints. 
The objective of the study is to evaluate the clinical mechanisms of VX-661/IVA combination 
therapy in both lung function and extrapulmonary systems in subjects with CF who are 
homozygous for the F508del mutation on the CFTR gene. For a subset of the key endpoints 
(specifically, MCC and gastrointestinal pH, as captured in Table 12-2 and Table 12-3), no data 
are available for the F508del homozygous population. Therefore, data for both gastrointestinal 
pH and MCC were compiled from a study evaluating IVA monotherapy in patients with the 
G551D-CFTR mutation for the purpose of sample size calculation.24 Mean changes from 
baseline for gastrointestinal pH and MCC endpoints in the combination group were derived 
assuming approximately 50% of those observed for the active group in the observational study. 
Standard deviations were assumed to be similar to those observed in the reference studies. For 
ppFEV1 and sweat chloride endpoints, sample size assumptions were based on observed data 
from the VX11-661-101 study.23 
Based on these assumptions, a sample size of 36 subjects in the combination group (based on 45 
subjects randomized 4:1) will provide adequate power to detect a statistically significant 
difference from baseline at Day 28 or 29 for the key endpoints, even after assuming that 10 to 
30% subjects may not have complete data through Day 29 (depending on the endpoint). 
Table 12-1 through Table 12-4 display power estimates to detect an expected mean change from 
baseline (∆) for key endpoint measures in the VX-661/IVA combination therapy based on a 
sample size of 36 subjects in the VX-661/IVA group using a 2-sided paired t-test at a 
significance level of α = 0.05. More specifically, the endpoint measures include ppFEV1 at 
Day 28 (Table 12-1), percent whole lung mucus clearance through 60 minutes at Day 28 (Table 
12-2), small bowel area under the curve (AUC) over 1-minute mean pH increments through 30 
minutes after gastric emptying at Day 29 (Table 12-3), and sweat chloride at Day 29 (Table 
12-4). Further, a sample size of 28 subjects in the VX661/IVA group (resulting in a total of 35 
subjects including 7 subjects in the placebo group) will provide at least 80% power to detect the 
expected mean change from baseline with the expected standard deviation. Sample size 
calculations were performed using PASS 11 software, Version 11.0.2. Given the exploratory 


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nature of this study, no multiplicity adjustment of type I error will be conducted for the analysis 
of key endpoints. 
 
Table 12-1 
Power for Within-Group Comparison (100 mg VX-661 qd + 150 mg IVA 
q12h) for ppFEV1 With N = 36 and ∆ = 4.5% 
Standard deviation 
σ = 7% (expected) 
σ = 8% 
σ = 9% 
σ = 10% 
Power 
96% 
91% 
83% 
75% 
Power (10% missing data) 
95% 
88% 
80% 
71% 
 
 
 
 
 
N for 80% power 
21 
27 
34 
41 
ppFEV1: percent predicted forced expiratory volume in 1 second; IVA: ivacaftor 
 
 
Table 12-2 
Power for Within-Group Comparison (100 mg VX-661 qd + 150 mg IVA 
q12h) for Average % Whole Lung Clearance Through 60 Minutes With 
N = 36 and ∆ = 6% 
Standard deviation 
σ = 6% 
σ = 8% (expected) 
σ = 10% 
σ = 12% 
Power 
>99% 
99% 
94% 
83% 
Power (20% missing data) 
>99% 
97% 
88% 
74% 
 
 
 
 
 
N for 80% power 
10 
16 
24 
34 
ppFEV1: percent predicted forced expiratory volume in 1 second; IVA: ivacaftor 
 
Table 12-3 
Power for Within-Group Comparison (100 mg VX-661 qd + 150 mg IVA 
q12h) for Small Bowel AUC Over 1-minute Mean pH Increments Through 
30 Minutes After Gastric Emptying With N = 36 and ∆ = 22 pH Minutes (or 
Equivalently, 0.73 pH) 
Standard deviation (pH mins) 
σ = 20 
σ = 24 (expected) 
σ = 28 
σ = 32  
Power 
>99% 
>99% 
>99% 
98% 
Power (30% missing data) 
>99% 
>99% 
97% 
92% 
 
 
 
 
 
N for 80% power 
9 
12 
15 
19 
ppFEV1: percent predicted forced expiratory volume in 1 second; IVA: ivacaftor 
 
Table 12-4 
Power for Within-Group Comparison (100 mg VX-661 qd + 150 mg IVA 
q12h) for Sweat Chloride With N = 36 and ∆ = -5 mmol/L 
Standard deviation (mmol/L) 
σ = 5 
σ = 6 
σ = 7 (expected)  
σ = 8  
Power 
>99% 
>99% 
99% 
95% 
Power (10% missing data) 
>99% 
>99% 
98% 
94% 
 
 
 
 
 
N for 80% power 
10 
14 
18 
23 
ppFEV1: percent predicted forced expiratory volume in 1 second; IVA: ivacaftor 


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12.2 
Analysis Sets 
The All Subjects Set will include all subjects who were randomized or received at least 1 dose 
of study drug. This analysis set will be used for all individual subject data listings and the 
disposition summary table, unless otherwise specified. 
The Full Analysis Set (FAS) will include all randomized subjects who were F508del 
homozygous and received at least 1 dose of study drug. The FAS will be used for all efficacy 
analyses. 
The Safety Set will include all subjects who received at least 1 dose of study drug. The Safety 
Set will be used for all safety analyses. 
12.3 
Statistical Analysis 
This section presents a summary of the planned statistical analyses of efficacy and safety. 
Analysis details will be provided in the SAP. 
12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: the 
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. Unless otherwise specified, minimum and maximum 
values will be reported with the same precision as the units of the raw data. The mean and 
median will be reported to 1 additional decimal place, and the SD and SE will be reported to 
2 additional decimal places. Any values that require a transformation to standard units (metric or 
International System [SI]) will be converted with the appropriate precision. 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug. For ECG, 
the baseline will be defined as the average of the most recent triplicate pretreatment 
measurements before the first dose of study drug. 
Change (absolute change) from baseline will be calculated as postbaseline value – baseline 
value. 
Relative change from baseline will be calculated as (postbaseline value – baseline 
value)/baseline value. 
The treatment-emergent (TE) period will include the time from the first dose to the Safety 
Follow-up Visit or 28 days after the last dose of the study drug for subjects who did not complete 
the Safety Follow-up Visit. 
Rules for handling missing data will be described in the SAP. 


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12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
The number and percentage of subjects in each disposition category (e.g., randomized, dosed, 
included in the FAS, included in the Safety Set, completed Treatment Period, completed 
study/Safety Follow-up Visit, and discontinued treatment or study with a breakdown of the 
reasons for discontinuation for treatment or study, respectively) will be summarized overall and 
by treatment group. 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized using descriptive summary statistics. Protocol deviations/violations will be provided 
in an individual subject data listings.  
The following demographics and baseline characteristics will be summarized overall and by 
treatment group for the FAS and will include (but are not limited to): sex, race, age, baseline 
weight, baseline height, baseline body mass index (BMI), baseline ppFEV1, baseline whole lung 
mucus clearance through 60 minutes, and baseline small bowel AUC over 1-minute mean pH 
increments through 30 minutes after gastric emptying.  
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 using the World Health Organization Drug 
Dictionary Enhanced and categorized as the following: 
• Prior medication: any medication that started before initial dosing of study drug, regardless 
of when it ended 
• Concomitant medication: medication continued or newly received during the TE period 
• Post-treatment medication: medication continued or newly received after the TE period 
A given medication may be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; or 
prior, concomitant, and post-treatment. If a medication has a missing or partially missing 
start/end date or time and if it cannot be determined whether it was taken before the first dose of 
study drug, concomitantly during the TE period, or after the TE period, it will be considered in 
all 3 categories of prior, concomitant, and post-treatment medication. 
Prior medications and concomitant medications will be summarized descriptively based on the 
FAS. Post-treatment medications will be provided separately in an individual subject data listing. 
12.3.2.4 
Study Drug Exposure and Compliance 
Exposure to study drug will be summarized for the FAS in terms of duration of treatment a 
subject received (in days), defined as the last day minus the first day of study drug plus 1. 
Dosing compliance will be summarized for the FAS, and will be derived as 100 × [(total number 
of pills dispensed) – ( total number of pills returned)]/( total number of pills planned to be taken 
per day × duration of study drug exposure in days). 






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• All TEAEs 
• TEAEs by strongest relationship  
• TEAEs by maximum 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 relationship level in 
the relationship summaries. In addition, a listing containing individual subject level AE data for 
all deaths and other serious and significant AEs will be provided separately. All AEs, including 
pre- and post-treatment AEs, will be presented in individual subject data listings. 
12.4.3.2 
Clinical Laboratory Assessments 
For the treatment-emergent laboratory measurements, the observed values and change from 
baseline values of the continuous hematology and chemistry results will be summarized in SI 
units overall and by treatment group at each scheduled time point. 
The number and percentage of subjects with at least 1 potentially clinically significant (PCS) 
event during the TE period will be summarized overall and by treatment group. The PCS 
(postbaseline) shift from baseline will also be summarized for selected laboratory parameters. 
The PCS criteria and the parameter selection criteria will be provided in the SAP. 
Results of urinalysis and the serum pregnancy test will be listed in individual subject data listings 
only. In addition, a listing containing individual subject hematology, chemistry, and coagulation 
values outside the reference ranges will be provided. This listing will include data from 
scheduled and unscheduled time points. 
12.4.3.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided overall and by treatment group at each scheduled time point for 
the following ECG measurements: RR, PR, QT, and QT corrected for HR intervals (QTcF), QRS 
duration, and HR. 
The number and percentage of subjects with at least 1 PCS event during the TE period will be 
summarized overall and by treatment group. The PCS (postbaseline) shift from baseline will also 
be summarized. The PCS criteria will be provided in the SAP. 
Additional ECG analyses will be described in the SAP. 
12.4.3.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized overall and by treatment group at each scheduled time point. 


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The following vital signs parameters will be summarized: systolic and diastolic blood pressure 
(mm Hg), body temperature (°C), HR (beats per minute), and respiratory rate (breaths per 
minute). 
The number and percentage of subjects with at least 1 PCS event during the TE period will be 
summarized overall and by treatment group. The PCS (postbaseline) shift from baseline will also 
be summarized. The PCS criteria will be provided in the SAP. 
Additional vital sign analyses will be described in the SAP. 
12.4.3.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided overall and by treatment group at each scheduled 
time point for the percent of oxygen saturation by pulse oximetry. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
period will be summarized overall and by treatment group. 
12.4.3.6 
Physical Examination 
PE findings will be presented in an individual subject data listing only. 
12.4.3.7 
Other Safety Analysis 
Not applicable. 
12.4.4 
Interim and IDMC Analyses 
Not applicable. 
12.5 
Clinical Pharmacology Analysis 
12.5.1 
Pharmacokinetic Analysis 
A detailed description of the clinical pharmacology analyses will be provided in a CPAP. 
Listings of plasma concentration data of VX-661, IVA, and their metabolites (M1-661 and 
M1-IVA) will be provided in the clinical study report. A population approach may be used to 
analyze the time-versus-plasma concentration data of VX-661, IVA, and their metabolites. The 
PK/PD relationship between concentrations of VX-661 and IVA 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 


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occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed. 
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs, will be assessed and 
those deemed a clinically significant worsening from baseline documented as an AE. When 
possible, a clinical diagnosis for the study assessment will be provided, rather than the abnormal 
test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, the 
abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the clinical status of the subject indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
 All AEs will be collected from the time the 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: through the Safety Follow-up Visit 
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 electronic CRF 
(eCRF) 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 “non-serious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity 
• Causal relationship to study drug(s) 
• Action taken  


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• Outcome  
• Concomitant medication or other treatment given 
• Indication of dose limiting toxicity 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and non-serious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed February 
2015). 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  
AE: adverse event. 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories 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). 
AE: adverse event. 
13.1.1.6 
Study Drug Action Taken 


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The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories shown in Table 13-3. 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
AE: adverse event. 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories 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) 
AE: adverse event. 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, hospitalization, 
surgery, or physical therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation in the study and is suspected of being a delayed toxicity due to administration of 
the study drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  


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• 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 should 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) should 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. 
13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. The Vertex Clinical 
Trial SAE Form will be completed for new/initial events as well as to report follow-up 




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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, all eCRFs, study reports, and communications relating to the 
study will identify subjects by assigned subject numbers. As required by federal regulations, the 
investigator will allow Vertex and/or its representatives access to all pertinent medical records to 
allow for the verification of data gathered in the eCRFs/SAE Forms and the review of the data 
collection process. The FDA (or other regulatory authority) may also request access to all study 
records, including source documentation, for inspection. 
As applicable, in accordance with the Health Insurance Portability and Accountability Act 
(HIPAA) and associated privacy regulations, a subject authorization to use personally 
identifiable health information may be required from each subject before research activities 
begin. This authorization document will clearly specify which parties will have access to a 
subject's personal health information, for what purpose, and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs 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 


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• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into an eCRF by study site 
personnel using a secure, validated web-based electronic data capture (EDC) application. Vertex 
will have read-only access to site-entered clinical data in the EDC application. 
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the eCRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the eCRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 
eCRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the eCRFs on the 
subjects for which they are responsible. 
An eCRF will be completed for each enrolled study subject. It is the investigator's responsibility 
to ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject's 
eCRF. Source documentation supporting the eCRF data will indicate the subject's participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the eCRF as soon as possible after 
information is collected. 
The audit trail entry will show the user's identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the eCRFs, 
including any changes made to the eCRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible. 
Vertex will retain the eCRF data and corresponding audit trails. A copy of the final archival 
eCRF in the form of a CD or other electronic media will be placed in the investigator's study file. 




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14 
REFERENCES 
 
 
1  
FDA Office of Orphan Products Development (OOPD). Available from: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.
htm. Accessed 18 February 2015. 
2  
The Committee for Orphan Medicinal Products (COMP). Available from: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_
000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30. 
Accessed 18 February 2015 
3 
Cystic Fibrosis Foundation Web Site [Internet]. Available from: 
http://www.cff.org/AboutCF/. Accessed 18 February 2015. 
4 
Kriendler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125:219-29. 
5 
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2009 Annual 
Data Report. Bethesda (MD): 2011. 
6  
Flume PA, Van Devanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012:10(1):88. 
7  
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry: 2012 Annual 
Data Report. Bethesda (MD): 2013. 
8  
European Cystic Fibrosis Society. ECFS Patient Registry: 2010 Annual Report. Karup, 
Denmark: 2014. 
9  
Cystic Fibrosis Canada. The Canadian Cystic Fibrosis Registry: 2012 Annual Report. 
Toronto, Canada: 2014. 
10  
Cystic Fibrosis Australia. Cystic Fibrosis in Australia 2012: 15th Annual Report From 
the Australian Cystic Fibrosis Data Registry. Baulkham Hills, Australia: 2013. 
11 
Cheng SH, Gregory RJ, Marshall J, Sucharita P, Souza DW, White GA, et al. Defective 
intracellular transport and processing of CFTR is the molecular basis of most cystic 
fibrosis. Cell. 1990;63:827-34. 
12 
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. 
13  
Quinton PM. Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis. Lancet 
2008;372:416-7. 
14 
Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352:1992-2001. 
15  
Pezzulo AA et al, Reduced airway surface pH impairs bacterial killing in the porcine 
cystic fibrosis lung. Nature 2012;487:109-113. 


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16  
Gelfond D, Changxing M, Semler J, Borowitz D. Intestinal pH and gastrointestinal transit 
profiles in cystic fibrosis patients measured by wireless motility capsule. Dig Dis Sci 
2013;58:2275-2281. 
17  
Van Goor F, Hadida S, Grootenhuis P. Pharmacological rescue of mutant CFTR function 
for the treatment of cystic fibrosis. Top Med Chem. 2008;3:91-120. 
18 
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. 
19 
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;268:21592-21598. 
20 
Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, et al. Effect of 
VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 
2010;363:1991-2003. 
21 
Vertex Pharmaceuticals Incorporated. VX-661 Investigator's Brochure. Version 7.0. 
Report date: 08 May 2015. 
22 
Vertex Pharmaceuticals Incorporated. Ivacaftor (VX-770) Investigator's Brochure. 
Version 13.0, Addendum 1. Report date: 23 June 2016. 
23 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
24 
Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, et al. Clinical 
mechanism of the cystic fibrosis transmembrane conductance regulator potentiator 
ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 
2014;190(2):175–184. 
25  
Couper RT, Corey M, Moore DJ, Fisher LJ, Forstner GG, Durie PR. Decline of exocrine 
pancreatic function in cystic fibrosis patients with pancreatic sufficiency. Pediatr Res. 
1992;32:179–182. 
26  
Clarke LL, Harline MC. Dual role of CFTR in cAMP-stimulated HCO3- secretion across 
murine duodenum. Am J Physiol. 1998;274:G718–G726. 
27  
Pratha VS, Hogan DL, Martensson BA, Bernard J, Zhou R, Isenberg JI. Identification of 
transport abnormalities in duodenal mucosa and duodenal enterocytes from patients with 
cystic fibrosis. Gastroenterology. 2000;118:1051–1060. 
28  
Gelfond D, Ma C, Semler J, Borowitz D. Intestinal pH and gastrointestinal transit profiles 
in cystic fibrosis patients measured by wireless motility capsule. Dig Dis Sci. 
2013;58(8):2275-81. 
29 
Wilcschanski 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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30 
Rowe S, 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. 
31  
Hisert KB, Cooke JP, Garudathri J, Wu X, Pope C, Grogan B, et al. The 28th Annual 
North American Cystic Fibrosis Conference, Georgia World Congress Center, Atlanta, 
Georgia, Conference Supplement: Volume: 49 DOI: 10.1002/ppul.v49.S38/issuetoc.  
32 
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. 
Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998;132(4):589-95. 
33  
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general US population. Am J Respir Crit Care Med. 1999;159:179-87. 
34 
Levey AS, Bosch JP, Breyer Lewis J, Greene T, Rogers N, Roth D. A more accurate 
method to estimate glomerular filtration rate from serum creatinine: a new prediction 
equation. Ann Intern Med. 1999;130:461-70. 
35 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang Y, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247-54. 




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15.2 
Investigator Signature Page 
Protocol #: 
VX14-661-111 Version #: 4.0 
Version Date 
19 Sep 2016 
Study Title: A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Exploratory Study to Evaluate Effects of VX-661 in Combination With Ivacaftor on Lung 
and Extrapulmonary Systems in Subjects Aged 18 Years and Older With Cystic Fibrosis, 
Homozygous for the F508del-CFTR Mutation 
 
 
I have read Protocol VX14-661-111, Version 4.0 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 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods)  
Page 1 of 58 
Protocol Number: VX14-661-111 
 
 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan (Final Analysis)  
Methods 
Protocol Number VX14-661-111, Version 4.0 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Exploratory Study 
to Evaluate Effects of VX-661 in Combination With Ivacaftor on Lung and Extrapulmonary 
Systems in Subjects Aged 18 Years and Older With Cystic Fibrosis, Homozygous for the 
F508del-CFTR Mutation 
 
Author of SAP Methods: 
 
Version: 1.0  
Version Date of SAP: 27 July 2017 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, MA 02210-1862 
 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the 
prior written consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent 
required under applicable laws or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them. 






Statistical Analysis Plan (Methods)  
Page 4 of 58 
Protocol Number: VX14-661-111 
 
 
 
Vertex Pharmaceuticals Incorporated 
 
Gastric Emptying With N (VX-661/ivacaftor combination therapy) = 36 and ∆ = 22 pH 
Minutes (or Equivalently, 0.73 pH) .................................................................................. 9 
Table 6-4 Power for Within-Group Comparison (VX-661/ivacaftor combination therapy) for 
Sweat Chloride With N (VX-661/ivacaftor combination therapy) = 36 and ∆ = -5 
mmol/L .............................................................................................................................. 9 




Statistical Analysis Plan (Methods)  
Page 6 of 58 
Protocol Number: VX14-661-111 
 
 
 
Vertex Pharmaceuticals Incorporated 
 
As all endpoints in this study are considered exploratory, statistical significance on every endpoint is 
not required for study success. 
5 
STUDY ENDPOINTS 
5.1 
Efficacy Endpoints 
5.1.1 
Key Efficacy Endpoints 
• 
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline at Day 28 
• 
Absolute change in mucociliary clearance (MCC) from baseline at Day 28 
• 
Absolute change in gastrointestinal pH from baseline at Day 29 
• 
Absolute change in sweat chloride from baseline at Day 29 
 
 
 
 
 
 
5.2 
Safety Endpoint 
Safety and tolerability will be evaluated via the following assessments: 
• 
Adverse events (AEs)  
• 
Clinical laboratory values (hematology, serum chemistry, coagulation studies, vitamin levels, 
lipid panel, and urinalysis) 
• 
Standard digital electrocardiograms (ECGs) 
• 
Vital signs 
• 
Pulse oximetry 
6 
STUDY DESIGN  
6.1 
Overview of Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter, 
exploratory study in subjects with CF who are homozygous for the F508del-CFTR mutation. This 
study is designed to evaluate the lung function and extrapulmonary responses of subjects receiving 
VX-661/ivacaftor combination therapy. 
This study includes a Screening Period, Treatment Period, and a Safety Follow-up Visit. The study 
plans to randomize a target of 35 subjects and up to approximately 45 subjects. Subjects will be 
randomized (4:1) to VX-661/ivacaftor or placebo, respectively, as shown in Figure 7-1.  


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study. Standard deviations were assumed to be similar to those observed in the reference studies. For 
ppFEV1 and sweat chloride endpoints, sample size assumptions were based on observed data from the 
Vertex VX11-661-101 study.  
Based on these assumptions, a sample size of 36 subjects in the VX-661/ivacaftor combination 
therapy group (based on 45 subjects randomized 4:1) will provide adequate power to detect a 
statistically significant difference from baseline at Day 28 or 29 for the key endpoints, even after 
assuming that 10 % to 30% subjects may not have complete data through Day 29 (depending on the 
endpoint, based on estimates obtained from the GOAL study). 
Table 6-1 through Table 6-4 display power estimates to detect an expected mean change from 
baseline (∆) for key endpoint measures in the VX-661/ivacaftor combination therapy group based on 
a sample size of 36 subjects in the VX-661/ivacaftor group using a 2-sided paired t-test at a 
significance level of α = 0.05. More specifically, the endpoint measures include ppFEV1 at Day 28 
(Table 6-1), percent whole lung mucus clearance through 60 minutes at Day 28 (Table 6-2), small 
bowel area under the curve (AUC) over 1-minute mean pH increments through 30 minutes after 
gastric emptying at Day 29 (Table 6-3), and sweat chloride at Day 29 (Table 6-4). Further, a sample 
size of 28 subjects in the VX661/ivacaftor combination therapy group (resulting in a total of 35 
subjects including 7 subjects in the placebo group to achieve a 4:1 randomization ratio) will provide 
at least 80% power for each of the endpoints to detect the expected mean change from baseline with 
the expected standard deviation. Thus 35 to 45 subjects will be required to obtain a minimum of 80% 
to a maximum of >99% power across endpoints. Sample size calculations were performed using 
PASS 11 software, Version 11.0.2. Given the exploratory nature of this study, no multiplicity 
adjustment of type I error will be conducted for the analysis of key endpoints. 
Table 6-1 Power for Within-Group Comparison  (VX-661/ivacaftor combination therapy) for 
ppFEV1 With N (VX-661/ivacaftor combination therapy) = 36 and ∆ = 4.5% 
Standard deviation 
σ = 7% 
(expected) 
σ = 8% 
σ = 9% 
σ = 10% 
Power 
96% 
91% 
83% 
75% 
Power (10% missing data) 
95% 
88% 
80% 
71% 
 
 
 
 
 
N (VX-661/ivacaftor 
combination therapy) for 
80% power 
21 
27 
34 
41 
 
 


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Table 6-2 Power for Within-Group Comparison (VX-661/ivacaftor combination therapy) for Average 
% Whole Lung Clearance Through 60 Minutes With N (VX-661/ivacaftor combination therapy) = 36 
and ∆ = 6% 
Standard deviation 
σ = 6% 
σ = 8% 
(expected) 
σ = 10% 
σ = 12% 
Power 
>99% 
99% 
94% 
83% 
Power (20% missing data) 
>99% 
97% 
88% 
74% 
 
 
 
 
 
N (VX-661/ivacaftor 
combination therapy) for 
80% power 
10 
16 
24 
34 
 
Table 6-3 Power for Within-Group Comparison (VX-661/ivacaftor combination therapy) for Small 
Bowel AUC Over 1-minute Mean pH Increments Through 30 Minutes After Gastric Emptying With 
N (VX-661/ivacaftor combination therapy) = 36 and ∆ = 22 pH Minutes (or Equivalently, 0.73 pH) 
Standard deviation (pH 
mins) 
σ = 20 
σ = 24 (expected) 
σ = 28 
σ = 32  
Power 
>99% 
>99% 
>99% 
98% 
Power (30% missing data) 
>99% 
>99% 
97% 
92% 
 
 
 
 
 
N (VX-661/ivacaftor 
combination therapy) for 
80% power 
9 
12 
15 
19 
 
Table 6-4 Power for Within-Group Comparison (VX-661/ivacaftor combination therapy) for Sweat 
Chloride With N (VX-661/ivacaftor combination therapy) = 36 and ∆ = -5 mmol/L 
Standard deviation 
(mmol/L) 
σ = 5 
σ = 6 
σ = 7 
(expected)  
σ = 8  
Power 
>99% 
>99% 
99% 
95% 
Power (10% missing data) 
>99% 
>99% 
98% 
94% 
 
 
 
 
 
N (VX-661/ivacaftor 
combination therapy) for 
80% power 
10 
14 
18 
23 
 
6.3 
Randomization 
A target of at least 35 subjects, with up to approximately 45, who meet the eligibility criteria will be 
randomized in a ratio of 4:1 (active study drug:placebo). An interactive web response system (IWRS) 
will be used to assign subjects to treatment using a list of randomization codes generated by a 
designated vendor 
. The only Vertex personnel involved in developing the randomization 


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specifications and reviewing the dummy randomization code list was the Study Biostatistician (SB).  
The SB was blinded to the final randomization code list and the actual treatment assignments. 
6.4 
Blinding and Unblinding 
This is a double-blind study. 
6.4.1 
Blinding 
Blinding of treatment codes and applicable study data will be maintained until the database is locked 
for the final analysis.  
The subjects and all site personnel, including the investigator, the site monitor, and the study team, 
will be blinded with the exception of the following: 
• 
Any site personnel for whom this information is important to ensure the safety of the subject in 
the event of a life-threatening medical emergency 
• 
Any site personnel for whom this information is important to ensure the safety of the subject and 
her fetus in the event of a pregnancy 
• 
Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy SAE processing 
and reporting regulations 
• 
Unblinded statistician preparing the final (production) randomization list, who is not part of the 
study team 
• 
Vertex Clinical Operations IWRS management 
• 
Vertex Clinical Supply Chain 
• 
Vendor analyzing PK samples 
• 
Vertex medical monitor may, for matters relating to safety concerns, unblind individual subjects 
at any time 
Vertex Drug Metabolism and Pharmacokinetics laboratory personnel will not be involved in the 
conduct of the study and will be unblinded to the bioanalysis results but will remain blinded to 
subject number and treatment assignment. 
Spirometry Data Blinding 
Despite treatment blinding, knowledge of the spirometry results has the potential to suggest whether a 
subject has been administered active study drug or placebo. Therefore, during the conduct of the 
study, the Vertex study team will have no access to the postdose spirometry results data. The vendor 
for central reading of the spirometry data will only send the blinded spirometry files (blinded 
treatment group, with real values for screening and baseline, but with dummy values for all the 
spirometry results data after baseline) to Vertex to be used for developing the statistical programs. 
Furthermore, subjects and their caregiver should not be informed of their study-related spirometry 
results during the Treatment Period regardless of whether the subject has prematurely discontinued 
treatment. 
 
 


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Sweat Chloride Data Blinding 
Despite treatment blinding, knowledge of the sweat chloride data has the potential to suggest whether 
a subject has been administered active study drug or placebo. Therefore, during the conduct of the 
study, the Vertex study team will not have access to the sweat chloride data; dummy data will be used 
to develop statistical programs. During the process of locking the clinical database, after all study 
visits have been completed, access to treatment-blinded sweat chloride data will be provided to a 
small group of individuals who are not part of the Vertex study team. This group, which will consist 
of a biostatistician, a statistical programmer, a validation statistical programmer, and a clinical 
reviewer, will review the sweat chloride data to ensure there are no significant data issues and will 
use the blinded data set to refine the statistical programs. 
MCC Blinding 
Despite treatment blinding, knowledge of the MCC data has the potential to suggest whether a subject 
has been administered active study drug or placebo. Therefore, during the conduct of the study, the 
Vertex study team will have no access to the MCC data. Results data will be submitted to a central 
reader. These individuals, including site staff performing the MCC assessment, will otherwise not be 
involved in any other aspects of study conduct or subject interaction. 
WMC Blinding 
Despite treatment blinding, knowledge of the WMC data has the potential to suggest whether a 
subject has been administered active study drug or placebo. Therefore, during the conduct of the 
study, the Vertex study team will have no access to the WMC data, except confirmation that the 
WMC has passed. Results data will be submitted to the central reader, who will otherwise not be 
involved in any other aspects of study conduct or subject interaction. 
6.4.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the blind. 
The unblinding method will be either a manual or electronic process. 
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree to the 
need for unblinding. If investigators deem it not necessary to unblind immediately, they will first 
attempt to contact the medical monitor to discuss and agree to the need for unblinding. If investigators 
have tried but are unable to reach the medical monitor, they will use their best judgment, based on the 
nature and urgency of the clinical situation, and may proceed with unblinding without having 
successfully reached and discussed the situation with the medical monitor. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory reporting 
requirements. In addition, Vertex may, for matters relating to safety concerns, unblind individual 
subjects at any time. 
7 
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), and Safety Set.  


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The All Subjects Set will include all subjects who were randomized or dosed. This analysis set will 
be used for all individual subject data listings and the disposition summary table, unless specified 
otherwise. 
The Full Analysis Set (FAS) will include all randomized subjects who carry the intended CFTR 
allele mutation and have received at least 1 dose of study drug. The FAS will be used to summarize 
subject demographics and baseline characteristics, and for all efficacy analyses, unless specified 
otherwise. 
The Safety Set will include all subjects who received at least 1 dose of study drug. The Safety Set 
will be used for all safety analyses, with subjects analyzed according to the treatment they received, 
unless specified otherwise. If a subject received at least 1 dose of VX-661/IVA, the subject will be 
analyzed in the VX-661/IVA treatment group. 
8 
STATISTICAL ANALYSIS 
8.1 
General Considerations 
The Schedule of Assessments is provided in Appendix A. The precision standards for reporting safety 
and efficacy variables are provided in an internal Biometrics document that specifies the 
programming rules including the precision for derived variables.  
All individual subject data for subjects who were randomized or received at least 1 dose of study drug 
will be presented in individual subject data listings. 
Continuous variables will be summarized using the following descriptive summary statistics: the 
number of subjects (n), mean, standard deviation (SD), standard error (SE), median, minimum value 
(min), and maximum value (max).   
Categorical variables will be summarized using counts and percentages.  
Baseline Value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected prior to the first dose of study drug. For ECGs, the 
baseline value will be defined as the average of the non-missing pretreatment measurements 
(triplicate) on Day 1. For sweat chloride, the baseline value will be the mean of non-missing 
assessment values on the left and the right arms at the same time point that is the most recent time 
prior to the first dose of the study drug. 
Change (Absolute Change) from baseline will be calculated as Postbaseline value - Baseline value.  
Relative change from baseline will be calculated and expressed in percentage as 
100%×(Postbaseline value - Baseline value)/Baseline value. 
Treatment Emergent (TE) Period will include the time period starting from the first dose date of 
the study drug to the Safety Follow-up Visit. For subjects who do not have a Safety Follow-up Visit, 
the TE period will start from the first dose date of the study drug to 28 days after the last dose date of 
the study drug. The TE period will be used for safety analyses unless specified otherwise.  
Unscheduled Visits: Unscheduled visit measurements will be included in analysis as follows: 
• In scheduled visit windows per specified visit windowing rules.  
• In the derivation of baseline/last on-treatment measurements. 


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• In the derivation of maximum/minimum on-treatment values and maximum/minimum 
change from baseline values for safety analyses. 
• In individual subject data listings as appropriate. 
Visit Windowing Rules:  The analysis visit windows for protocol-defined visits are provided in 
Appendix B.  
Incomplete/Missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
Multiplicity: No multiplicity adjustment will be performed for hypothesis testing. 
8.2 
Background Characteristics  
8.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized overall and by treatment 
group:  
• 
All Subjects   
• 
Randomized 
• 
Full Analysis Set (FAS) 
• 
Safety Set 
The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized overall and by treatment group: 
• 
Completed treatment period  
• 
Prematurely discontinued the treatment and the reason for discontinuation  
• 
Completed study (i.e., completed Safety Follow-up Visit) 
• 
Prematurely discontinued the study and the reason for discontinuation  
• 
Enrolled in a rollover extension study 
A listing will be provided for subjects who discontinued treatment or who discontinued study with 
reasons for discontinuation. A randomization listing of subjects will be provided. 
8.2.2 
Demographics and Baseline Characteristics 
Demographics, medical history and baseline characteristics will be summarized overall and by 
treatment group based on the FAS. 
Demographic data will include the following: 
• 
Age (in years) 
• 
Sex (female and male) 


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• 
Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Not collected per local regulations, and Other) 
Baseline characteristics will include the following: 
• 
Weight (kg) 
• 
Height (cm) 
• 
BMI (kg/m2) 
Disease characteristics will include the following: 
• 
Percent predicted FEV1 at baseline 
• 
Sweat chloride at baseline 
• 
Whole  lung mucus clearance through 60 minutes at baseline 
• 
Small bowel AUC over one-minute mean pH increments through 30 minutes after gastric 
emptying at baseline 
• 
Use of dornase alfa (Yes, No) 
• 
Use of inhaled antibiotic (Yes, No) 
• 
Use of any bronchodilator (Yes, No)  
• 
Use of any inhaled bronchodilator (Yes, No)  
• 
Use of any inhaled hypertonic saline (Yes, No) 
• 
Use of any inhaled corticosteroids (Yes, No) 
 
 
 
 
 
 
 
 
 
 
A summary of medical history will be provided. In addition, the number of subjects reported to have 
had positive cultures for respiratory pathogens in 2 years prior to screening will be summarized by 
test and categories. 
8.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced (WHODDE) and categorized as the following: 
• 
Prior medication: any medication that started before the first dose date of study drug, regardless 
of when the medication ended. 


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• 
Concomitant medication: medication continued or newly received on or after the first dose date of 
study drug through the end of TE period. 
• 
Post-treatment medication: medication continued or newly received after the TE period. 
A given medication may be classified as follows: prior, concomitant, post-treatment, both prior and 
concomitant, both concomitant and post-treatment, or prior, concomitant, and post-treatment.  
If a medication has a completely missing or partially missing start/stop date and it cannot be 
determined whether it was taken before the first dose date, concomitantly, or after the TE period, it 
will be classified as prior, concomitant, and post-treatment. 
Prior medications and concomitant medications will be summarized descriptively using frequency 
tables by preferred name.  
Summaries of medications will be based on the FAS.  
Post-treatment medications will be listed by subject.  
Details for imputing missing or partial start and/or stop dates of medication are described in Appendix 
C. 
8.2.4 
Study Drug Exposure  
Duration of study drug exposure (in days) will be calculated as follows: last dose date – first dose 
date + 1 day, regardless of any study drug interruption  
Exposure summaries will be based on the FAS. 
8.2.5 
Study Drug Compliance 
Study drug compliance based on number of tablets taken will be calculated as: 100 × [(total number 
of tablets dispensed) – (total number of tablets returned)]/( total number of tablets planned to be taken 
per day × duration of study drug exposure in days). The maximum percentage of tablets taken will be 
100%  
Study drug compliance based on study drug exposure will be calculated as: 100 × [1 - (total number 
of days of study drug interruption) / (duration of study drug exposure in days)].  A study drug 
interruption on a given day will be determined by an interruption of both VX-661/ivacaftor and 
Ivacaftor doses on that day. 
Study drug compliance will be summarized descriptively by the number of subjects (n), mean, SD, 
SE, median, min, and max. They will also be summarized in categories: <80% and ≥80% using 
frequency tables. 
Study drug compliance summaries will be based on the FAS. 
8.2.6 
Important Protocol Deviations  
An important protocol deviation (IPD) is a deviation that has the potential to affect the interpretation 
of study results. All IPDs will be derived from a subset of major and minor deviations and will be 
identified from the clinical database and/or site deviation log. The rules for identifying IPDs will be 
included in an internal Biometrics document.  




















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• 
Vital signs  
• 
Pulse oximetry 
Safety endpoints will be analyzed based on the Safety Set. Only a descriptive analysis of safety will 
be performed. 
All safety data will be presented in individual subject data listings. 
8.4.1 
Adverse Events  
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 date of study drug 
• 
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed at or 
after the first dose date of study drug through the end of the TE period  
• 
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was newly 
developed beyond the TE period 
For AEs with completely missing or partially missing start dates, if there is no clear evidence that the 
AEs started before or after study treatment, the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of adverse events are described in Appendix H.   
AE summary tables will be presented for TEAEs only, overall and by treatment group, and will 
include the following: 
• 
All TEAEs 
• 
TEAEs by strongest relationship  
• 
TEAEs by maximum severity 
• 
TEAEs leading to treatment discontinuation 
• 
Serious TEAEs 
• 
TEAEs leading to death 
Summaries will be presented by MedDRA system organ class and preferred term using frequency 
counts and percentages (i.e., number and percentage of subjects with an event). When summarizing 
the number and percentage of subjects with an event, subjects with multiple occurrences of the same 
AE or a continuing AE will be counted once. Only the maximum severity level will be presented in 
the severity summaries, and the strongest relationship level will be presented in the relationship 
summaries.  
In addition, a listing containing individual subject adverse event data for TEAEs leading to treatment 
discontinuation, SAEs and deaths will be provided separately. All AEs, including pre- and post-
treatment AEs, will be presented in an individual subject data listing. 


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8.4.2 
Clinical Laboratory 
For treatment emergent laboratory measurements, the raw values and change from baseline values of 
the continuous hematology, chemistry, and coagulation studies will be summarized in SI units by 
treatment group at each scheduled visit.  
The number and percentage of subjects with at least one threshold analysis laboratory event during 
the TE period will be summarized overall and by treatment group, including the shift of the threshold 
analysis event from baseline to post baseline. The threshold analysis criteria are provided in Appendix 
H. 
For each LFT laboratory test (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
alkaline phosphatase [ALP], and total bilirubin), a scatter plot of the maximum treatment-emergent 
value versus the baseline value corresponding to xULN will be presented. Further, a scatter plot of the 
maximum treatment-emergent value of ALT and AST, separately, versus the maximum treatment-
emergent value of total bilirubin corresponding to xULN will also be presented. 
A listing of subjects with elevated LFT results during the TE period will be presented based on any of 
the following: AST>3 × ULN, ALT>3 × ULN, ALP >1.5 × ULN, or total bilirubin >2 × ULN. For 
each subject in the listing, LFT assessments at all time points will be included (scheduled and 
unscheduled). 
Results of vitamin levels and lipid panel will be summarized by treatment group and visit. 
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, coagulation values, vitamin 
levels, and lipid values outside the normal reference ranges will be provided. This listing will include 
data from both scheduled and unscheduled visits. 
8.4.3 
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 and visit for the following standard 12-lead ECG  
measurements: RR (ms), HR (beats per minute), PR (ms), QRS duration (ms), QRX axis (degrees), 
QT (ms), and QT corrected for HR [QTcF (ms)].  
The number and percentage of subjects with at least one threshold analysis ECG event during the TE 
period will be summarized overall and by treatment group. The threshold analysis criteria are 
provided in Appendix H. 
8.4.4 
Vital Signs 
For treatment-emergent vital signs measurements, the raw values and change from baseline values 
will be summarized by treatment group and visit: 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 with at least one threshold analysis vital signs event during 
the TE period will be summarized overall and by treatment group. The threshold analysis criteria are 
provided in Appendix H. 


Statistical Analysis Plan (Methods)  
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8.4.5 
Pulse Oximetry 
For treatment-emergent pulse oximetry measurements, a summary of raw values and change from 
baseline values will be provided by treatment group and visit for the percent of oxygen saturation.  
The number and percentage of subjects with shift changes from baseline (normal/missing and low 
according to the reference range) to the lowest percent of oxygen saturation during the TE period will 
be summarized overall and by treatment group. 
8.4.6 
Physical Examination 
PE findings will be presented as a data listing only. 
9 
INTERIM AND DMC ANALYSES 
9.1 
Interim Analysis 
Not applicable. 
9.2 
DMC Analysis 
Not applicable. 
 
 
 


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10 REFERENCES 
 
1 Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general U.S. population. Am J Respir Crit Care Med. 1999; 159:179-87. 
2 Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, et al. Clinical 
mechanism of the cystic fibrosis transmembrane conductance regulator potentiator 
ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 
2014;190(2):175–184. 


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11 APPENDICES 
Appendix A 
Schedule of Assessments 
Schedules of Assessments are shown in Table 12-1 (Screening Period) and Table 12-2 (Treatment Period through the Safety Follow-up Visit). 
All visits are to be scheduled relative to the Day 1 Visit (first dose of study drug). 
Table 11-1  Study VX14-661-111: Screening Period 
Assessment 
Screening Period 
Day -28 through Day -1 
Screening Visit 
Day -28 to Day -13 
Telephone Contact 
2 Days After Patency 
Capsule 
Administration 
Clinic Visit 
Day -23 to -10a 
Telephone Contact 5 Days 
After WMC 
Administration 
Clinic visit 
X 
 
Xb 
 
Informed consent  
X 
 
 
 
Inclusion/exclusion criteria review 
Continuous from signing of informed consent form (ICF) before randomizationa 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Ophthalmologic history 
X 
 
 
 
CF genotypec 
X 
 
 
 
Weight, heightd 
X 
 
 
 
                                                 
 
a  
Clinic Visit Day -23 through Day -10 will take place only if a subject passes the patency capsule test. Select baseline assessments are performed on Day -23 through Day -10, 
and the remaining are performed on Day 1. Before any baseline assessments are performed, eligibility for enrollment based on all available screening assessment results must 
be verified by the investigator. 
b  
This visit may occur on 1 day or on 2 separate days. 
c 
All subjects will be tested for CF genotype. The CF genotype sample will be taken during the Day -28 to Day -13 Visit. Confirmation of the genotype will be required before 
randomization. 
d 
 Weight and height will be measured with shoes off. 


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Table 11-1  Study VX14-661-111: Screening Period 
Assessment 
Screening Period 
Day -28 through Day -1 
Screening Visit 
Day -28 to Day -13 
Telephone Contact 
2 Days After Patency 
Capsule 
Administration 
Clinic Visit 
Day -23 to -10a 
Telephone Contact 5 Days 
After WMC 
Administration 
Complete physical examination 
X 
 
 
 
Ophthalmologic examinatione 
Between signing of ICF and randomization 
Standard 12-lead ECGf 
X 
 
 
 
Vital signsg 
X 
 
 
 
Pulse oximetryg 
X 
 
 
 
Spirometry 
Xh 
 
Xi 
 
Urinalysis 
X 
 
 
 
Serum FSHj (postmenopausal 
female subjects only) 
X 
 
 
 
Pregnancy testk 
Serum 
 
Urinel  
 
                                                 
 
e 
One ophthalmologic examination will be conducted by a licensed ophthalmologist during the Screening Period. The ophthalmologic examination does not need to be repeated 
if there is documentation of an examination that met the protocol criteria and that was conducted within 3 months before the Screening Period. Subjects with clinically 
significant cataracts, lens opacity, Y-suture, or lamellar rings will be excluded. 
f 
 A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes. ECGs will be performed before vital signs, pulse oximetry, and any other 
procedures that may affect heart rate (e.g., blood sampling). 
g 
 Vital signs and pulse oximetry will be collected after the subject has been at rest (seated or supine) for 5 minutes. Vital signs will be performed after ECGs and before blood 
sampling. 
h 
Spirometry may be performed pre- or postbronchodilator. 
i 
Spirometry should be performed prebronchodilator, on the same day as the MCC assessment, and prior to both WMC and MCC if both are done on the same day.. Spirometry 
values must be ≥30 percent predicted FEV1 before MCC. 
j 
 FSH will be measured for any suspected postmenopausal female with at least 12 months of continuous spontaneous amenorrhea. Serum FSH levels must be ≥40 mIU/mL to 
be considered postmenopausal. 
k 
Pregnancy tests will be performed for all female subjects of childbearing potential. 


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Table 11-1  Study VX14-661-111: Screening Period 
Assessment 
Screening Period 
Day -28 through Day -1 
Screening Visit 
Day -28 to Day -13 
Telephone Contact 
2 Days After Patency 
Capsule 
Administration 
Clinic Visit 
Day -23 to -10a 
Telephone Contact 5 Days 
After WMC 
Administration 
Sweat chloridem 
X 
 
 
 
Hematology 
X 
 
 
 
Coagulation 
X 
 
 
 
Serum chemistry 
X 
 
 
 
Patency capsule 
Xn 
Confirm passageo 
 
 
Meal or snack at site 
 
 
Xp 
 
WMCq 
 
 
Xr 
confirm passages 
                                                                                                                                                                                                                         
 
l 
 Pregnancy test results will be obtained before administration of WMC and the MCC assessment. If the Clinic Visit Day -23 to -10 occurs on 2 separate days, pregnancy testing 
will occur before the procedures on each day. 
m 
Sweat chloride test is not required if the subject has a documented sweat chloride test result in the medical records. 
n 
All subjects will be administered a patency capsule test at the Day -28 to Day -13 Screening Visit after all other assessments have been completed. Subjects will stay under 
observation in the clinic for 2 hours after administration of the patency capsule. 
o 
Telephone contact will occur 2 days after administration of the patency capsule to confirm passage of the patency capsule in the stool (unless the subject confirms passage of 
the capsule prior to the scheduled telephone contact). A subject must pass the patency capsule test to continue the Screening Period assessments. If passage of the patency 
capsule is not confirmed during the telephone contact, the subjects must return to the clinic and the medical monitor must be contacted immediately (see the Study Reference 
Manual for additional information). 
p 
Subjects must adhere to study restrictions in the CSP regarding meals. During the Clinic Visit on Day -23 to Day -10, subjects will fast for 8 hours (water is permitted) before 
administration of a snack bar (in place of the morning meal), and for an additional 4 hours immediately following administration of the WMC. If the Day -23 to – 10 Visit 
occurs on 2 separate days, a meal or snack bar will be provided at the clinic on both days. 
q   If MCC and WMC administration occur on a single day, WMC administration should be completed before the MCC assessment. 
r 
Subjects must pass the patency capsule test and adhere to WMC restrictions in the CSP before administration of the WMC. Subjects will fast for 8 hours (water is permitted) 
before administration of a snack bar (in place of the morning meal) with the WMC, and will fast for an additional 4 hours immediately following administration of the WMC. 
All screening assessments, except for the ophthalmologic examination 
, must be completed before the WMC. 


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Table 11-1  Study VX14-661-111: Screening Period 
Assessment 
Screening Period 
Day -28 through Day -1 
Screening Visit 
Day -28 to Day -13 
Telephone Contact 
2 Days After Patency 
Capsule 
Administration 
Clinic Visit 
Day -23 to -10a 
Telephone Contact 5 Days 
After WMC 
Administration 
MCCt 
 
 
X 
 
 
 
Prior and concomitant medications 
Continuous from signing of ICF through Safety Follow-up Visit 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
CF: cystic fibrosis; ECG: electrocardiogram; FSH: follicle-stimulating hormone; MCC: mucociliary clearance; WMC: wireless motility capsule 
                                                                                                                                                                                                                         
 
s  
Telephone contact will occur 5 days after the administration of the WMC to evaluate passage of the capsule (unless the subject confirms the passage of the capsule prior to the 
scheduled contact). If passage of the WMC is not confirmed during the telephone contact, the medical monitor must be contacted immediately to confirm further course of 
action. Subjects will not be randomized in the study until passage of the WMC has been confirmed by the central reader or X-ray, regardless of confirmation of passage by 
subject at telephone contact. 
t  
Bronchodilator usage is restricted for 12 hours before the MCC assessment. The first MCC scan will be immediately following radiolabeled aerosol inhalation, and the second 
scan 6 hours (± 30 minutes) after inhalation. Subjects will adhere to study restrictions in the CSP related to MCC (see the Study Reference Manual for additional information). 
  
 


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Table 11-2 Study VX14-661-111: Treatment Period and Safety Follow-Up Visit 
Event/Assessmenta 
 Treatment Period 
Telephone Contact 
5 Days After WMC 
Administration 
Early  
Treatment 
Terminationb 
Visit 
Safety Follow-up 
Visit 
28 (± 7) Days 
After Last Dose of 
Study Drug 
Day 1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days)c 
Day 29 
(± 3 days) 
Clinic visit 
X 
  
Xd 
X 
 
 X 
X 
Telephone contact 
 
Xe 
 
 
X 
 
 
Inclusion and exclusion criteria 
reviewf 
X 
 
 
 
 
 
 
Weight and Heightg 
X 
 
X 
 
 
X (weight) 
X 
Complete physical examinationh 
X 
 
 
  
 
  
X 
Standard 12-lead ECG i 
Xj 
 
 
Xj 
 
Xj 
Xj 
Vital signsk 
X 
 
X 
X 
 
X 
X 
                                                 
 
a 
All assessments will be performed before administration of study drug unless noted otherwise. 
b 
If the subject prematurely discontinues study treatment, an Early Treatment Termination (ETT) Visit should be scheduled as soon as possible after the last dose of study drug. 
Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit, approximately 28 (± 7) days after their last dose of study drug. 
If the ETT Visit occurs 3  weeks or later following the last dose of study drug, then the ETT will not be required. 
c 
This visit may occur on 1 day or on 2 separate days. All assessments of the Day 28 Visit must be completed before the Day 29 Visit assessments. 
d 
Subjects will be offered the option of an overnight stay in proximity to the clinic between Days 28 and 29. 
e 
A telephone contact will occur on Day 14 to review adverse events (AEs) and concomitant medications. 
f 
Confirmation of subject eligibility will occur before randomization. 
g 
Weight and height will be measured before dosing with shoes off. Height will be collected only for subjects 21 years of age or younger at the Day 1, Day 28, and Safety 
Follow-up Visits. 
h 
A complete physical examination will occur on Day 1 and at the Safety Follow-up Visit. Symptom-targeted physical examinations will occur at any time during the study if 
triggered by AEs or if deemed necessary by the investigator. 
i 
  All ECGs will be performed before vital signs, pulse oximetry, and any other procedures that may affect heart rate (e.g., blood sampling). Subjects must be supine for at least 
5 minutes before the start of the ECG.  
j 
At the Day 1 and Day 29 Visits, ECGs will be collected before dosing and at 1.5 and 3 hours after the morning dose of study drug. ECGs collected on Day 1 before dosing 
will be performed in triplicate. If study drug is not administered on the Day of the visit (i.e., because of study drug interruption or permanent discontinuation of study drug), 
only 1 ECG will be collected. 




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Event/Assessmenta 
 Treatment Period 
Telephone Contact 
5 Days After WMC 
Administration 
Early  
Treatment 
Terminationb 
Visit 
Safety Follow-up 
Visit 
28 (± 7) Days 
After Last Dose of 
Study Drug 
Day 1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days)c 
Day 29 
(± 3 days) 
Serum chemistry 
X 
 
 
X 
 
X 
X 
Lipid panelr 
X 
 
 
X 
 
X 
X 
Vitamin levels 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wireless motility capsule (WMC) 
 
 
 
Xs 
Confirm passaget 
 
 
Mucociliary clearance assessment 
(MCC)u 
 
 
X 
 
 
 
 
Adverse events and concomitant 
medications 
Continuous from signing of ICF through Safety Follow-up Visit 
                                                 
 
r 
Blood samples for lipid panel tests will be collected after fasting for a minimum of 4 hours.  
s 
Subjects will adhere to study restrictions in the CSP related to WMC. During the Day 29 Visit, subjects will fast for 8 hours (water is permitted) before administration of a 
snack bar (in place of the morning meal) with the WMC and the morning dose of study drug , and will fast for an additional 4 hours immediately following administration of 
the WMC. 
t 
Telephone contact will occur 5 days after the administration of the WMC to confirm passage of the capsule. If passage of the WMC is not confirmed by the telephone contact, 
the medical monitor must be contacted immediately to confirm further course of action. Passage of the WMC must be confirmed by the central reader or X-ray, regardless of 
confirmation of passage by subject at telephone contact. 
u 
On Day 28, radiolabeled aerosol inhalation will occur after the dose of study drug. One MCC scan will occur immediately following radiolabeled aerosol inhalation and a 
second scan approximately 6 hours (± 30 minutes) after inhalation. Subjects will adhere to study restrictions in the CSP related to MCC (see the Study Reference Manual for 
additional information). 


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Event/Assessmenta 
 Treatment Period 
Telephone Contact 
5 Days After WMC 
Administration 
Early  
Treatment 
Terminationb 
Visit 
Safety Follow-up 
Visit 
28 (± 7) Days 
After Last Dose of 
Study Drug 
Day 1 
 
Day 14 
(± 3 days) 
Day 28 
(± 3 days)c 
Day 29 
(± 3 days) 
Randomizationv 
X 
 
 
 
 
 
 
Meal(s) or snack(s) at sitew 
X 
 
X 
Xx 
 
 
 
Study drug dosingy 
X 
 
 
 
Study drug count 
X 
 
X 
X 
 
X 
Xz 
CF: cystic fibrosis; ECG: electrocardiogram; FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; 
 
; MCC: mucociliary clearance; PK: pharmacokinetics; WMC: wireless motility capsule 
                                                 
 
v 
Randomization must occur after all inclusion and exclusion criteria are met and before the first dose of study drug. Randomization may occur on Day -1. 
w 
Fat-containing food such as a “standard CF” high-fat, high-calorie meal or snack will be provided at the site to subjects after all predose assessments have occurred (if the Day 
28 assessments occur on 2 separate days, a meal or snack will be provided for each clinic visit.). 
x 
Administration of a snack bar (in place of the morning meal). 
y 
Study drug will be administered as described in the CSP. On Day 1 through the morning of the Day 29 Clinic Visit, study drug will be administered within 30 minutes of 
starting a meal with fat-containing food such as a “standard CF” high-fat, high-calorie meal or snack. At the Day 29 Visit, subjects will receive a snack bar in place of the 
morning meal. On days of scheduled visits, the morning dose of study drug will be administered at the site after the last predose assessment has been completed. 
z 
Study drug count will occur at the Safety Follow-up Visit for all subjects who discontinue the study and for whom the Safety Follow-up Visit replaces the ETT. 


Statistical Analysis Plan (Methods) 
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Appendix B 
Analysis Visit Window Mapping Rules for Safety and Efficacy Assessments 
Table 11-3 Analysis Visit Windows for Safety and Efficacy Assessments 
Safety Assessment 
Visita 
Target Study Dayb 
Analysis Visit 
Windowc 
(in study days) 
Hematology 
Serum Chemistry 
Coagulation 
Urinalysis 
Lipids  
Vitamin Levels 
Baseline 
1 
≤ 1 
Day 29 
29 
[2, 43] 
 
Safety Follow-up 
57 
Use nominal visit 
Standard 12-Lead ECG 
Baseline 
Day 1 
1 
Day 1 (1.5 hours and 
3 hours post morning 
dose) 
Day 1 (1.5 hours and 3 
hours post morning dose)  
Use nominal visit 
Day 29 (before, 1.5 
hours and 3 hours 
post morning dose) 
Day 29 (before, 1.5 hours 
and 3 hours post morning 
dose) 
Use nominal visit 
 
Safety Follow-up 
57 
Use nominal visit 
Vital Signs  
Pulse Oximetry  
 
Baseline 
1 
≤ 1   
Day 28 
28 
 Use nominal visit 
 
 
Day 29 
29 
 Use nominal visit 
Safety Follow-up 
57 
Use nominal visit 
Weight and Height 
Baseline 
1 
≤ 1 
Day 28 
28 
[2, 42] 
Safety Follow-up 
57 
Use nominal visit 
When a subject is lost to follow up and last dose date is unknown, impute last dose date of all study drugs as last 
on-treatment visit date. 
 
aVisit name is used to report data in tables, listings and figures.  
bTarget day time point per protocol is predose, except for ECG measurements.  
cFor an early treatment discontinuation, Day 28 is last dose date -1, and Day 29 = last dose date of all study 
drugs. 
 
 
 




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ii. 
If there are multiple measurements with the same distance to the target day, the latest 
measurement will be used.   
b) For safety parameters: if there are multiple measurements within a visit window,   
i. 
The measurement closest to the target day will be used; or  
ii. 
If there are multiple measurements within the same distance from the target day, the 
latest measurement will be used. 
iii. 
For tables of the extreme lab measurement based on ULN or LLN, convert the lab 
measurements into times of ULN or LLN first, and then select the extreme measurement. 
Derived Variables 
1. Age (in years) at first dose date  
Obtain age at screening (in days) in yy mm format (e.g., 24 years, 6 months) from screening vital 
signs page, and add 0.5 month to convert to days. 
Obtain screening date from Date of Visit (DOV) page. 
Then age (in years) at first dose date = integer part of {[(first dose date-screening date) in days + age 
at screening (in days)]/365.25}. 
Correspondingly, age (in months) at first dose date = integer part of 12*{[(first dose date-screening 
date) in days + age at screening (in days)]/365.25}. 
2. Age (in years) at post-baseline visit (for use in calculation of percent predicted 
spirometry variables) 
Age (in years) at post-baseline visit = integer part of {[(post-baseline visit date – screening date) in 
days + age at screening (in days)]/365.25} 
3. Missing First Dose Date or Last Dose Date 
If the first dose date is missing, use Day 1 visit date. 
If the last dose date is missing at final analysis, use maximum (Early Treatment Termination visit 
date, last study drug administration date from EX SDTM domain, excluding PK dosing dates). 
 
 


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Appendix C 
Imputation Rules for Missing or Partial Start/Stop Dates of Concomitant 
Medications 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1) Missing or partial medication start date: 
a) If only Day is missing, use the first day of the month.  
b) If Day and Month are both missing, use the first day of the year.  
c) If Day, Month and Year are all missing, use a date prior to the first dose date. 
2) Missing or partial medication stop date: 
a) If only Day is missing, use the last day of the month. 
b) If Day and Month are both missing, use the last day of the year. 
c) If Day, Month and year are all missing, assign ‘continuing’ status to stop date. 
In summary, the prior, concomitant or post categorization of a medication is described in Table 12-10 
below. 
Table 11-4   Prior, Concomitant and Post Categorization of a Medication  
Medication start date 
Medication stop 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 
> End date of TE period 
- 
- 
A 
P: Prior; C: Concomitant; A: Post  
 
 
 






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Appendix E 
Coefficients for Hankinson Method for Calculating Predicted Spirometry 
Parameters 
Percent predicted FEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a percentage. 
The predicted FEV1 (L) will be calculated using the Hankinson1 standard.  
The Hankinson standard is designed for application to male subjects 18 years and older and female 
subjects 16 years and older.  In this study, the standard will be applied for males and females aged 18 
years and older per the study eligibility criteria.  
Hankinson Normal Values (HNVs) will be calculated for FEV1, forced vital capacity (FVC), forced 
expiratory flow mid expiratory phase (FEF25-75%), and FEV1/FVC% using the Hankinson equation:  
Predicted lung function parameter = b0+b1 × age+b2 × age2+ b3 × height2 
In the equation, height is given in centimeters, age is given in years, and the coefficients b0, b1, b2, 
and b3 are determined based on subject’s sex, race, and age group as shown in Table 12-5. The 
‘White’ race is handled as ‘Caucasian’ and all non-White race categories including ‘Asian’, 
‘American Indian or Alaska Native’, ‘Native Hawaiian or Other Pacific Islander’, ‘Not collected per 
local regulations’, and ‘Other’, are handled as ‘African American’. 
If either height or age is missing, and the spirometry measurement is non-missing, the last non-
missing value of height and age will be used in the calculation of predicted values. 
 
 


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Table 11-5   HNVs Equation Coefficients by Sex, Race, and Age 
Parameter 
Sex 
Race 
Age 
(years) 
bo 
b1 
b2 
b3 
HNVFEV1 
Male 
Caucasian 
<20 
-0.7453 
-0.04106 
0.004477 0.00014098 
≥20 
0.5536 
-0.01303 -0.000172 0.00014098 
African 
American 
<20 
-0.7048 
-0.05711 
0.004316 0.00013194 
≥20 
0.3411 
-0.02309 
 0.00013194 
Mexican 
American 
<20 
-0.8218 
-0.04248 
0.004291 0.00015104 
≥20 
0.6306 
-0.02928 
 0.00015104 
Female 
Caucasian 
<18 
-0.8710 
0.06537 
 0.00011496 
≥18 
0.4333 
-0.00361 -0.000194 0.00011496 
African 
American 
<18 
-0.9630 
0.05799 
 0.00010846 
≥18 
0.3433 
-0.01283 -0.000097 0.00010846 
Mexican 
American 
<18 
-0.9641 
0.06490 
 0.00012154 
≥18 
0.4529 
-0.01178 -0.000113 0.00012154 
HNVFVC 
Male 
Caucasian 
<20 
-0.2584 
-0.20415 
0.010133 0.00018642 
≥20 
-0.1933 
0.00064 -0.000269 0.00018642 
African 
American 
<20 
-0.4971 
-0.15497 
0.007701 0.00016643 
≥20 
-0.1517 
-0.01821 
 0.00016643 
Mexican 
American 
<20 
-0.7571 
-0.09520 
0.006619 0.00017823 
≥20 
0.2376 
-0.00891 -0.000182 0.00017823 
Female 
Caucasian 
<18 
-1.2082 
0.05916 
 0.00014815 
≥18 
-0.3560 
0.01870 -0.000382 0.00014815 
African 
American 
<18 
-0.6166 
-0.04687 
0.003602 0.00013606 
≥18 
-0.3039 
0.00536 -0.000265 0.00013606 
Mexican 
American 
<18 
-1.2507 
0.07501 
 0.00014246 
≥18 
0.1210 
0.00307 -0.000237 0.00014246 
HNVFEF25-75% 
Male 
Caucasian 
<20 
-1.0863 
0.13939 
 0.00010345 
≥20 
2.7006 
-0.04995 
 0.00010345 
African 
American 
<20 
-1.1627 
0.12314 
 0.00010461 
≥20 
2.1477 
-0.04238 
 0.00010461 
Mexican 
American 
<20 
-1.3592 
0.10529 
 0.00014473 
≥20 
1.7503 
-0.05018 
 0.00014473 
Female 
Caucasian 
<18 
-2.5284 
0.52490 -0.015309 0.00006982 
≥18 
2.3670 
-0.01904 -0.000200 0.00006982 
African 
American 
<18 
-2.5379 
0.43755 -0.012154 0.00008572 
≥18 
2.0828 
-0.03793 
 0.00008572 
Mexican 
American 
<18 
-2.1825 
0.42451 -0.012415 0.00009610 
≥18 
1.7456 
-0.01195 -0.000291 0.00009610 
HNVFEV1/FVC% Male 
Caucasian 
 
88.066 
-0.2066 
 
 


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Source: Reference: Hankinson (Tables 4, 5 and 6). 
African 
American 
 
89.239 
-0.1828 
 
 
Mexican 
American 
 
90.024 
-0.2186 
 
 
Female 
Caucasian 
 
90.809 
-0.2125 
 
 
African 
American 
 
91.655 
-0.2039 
 
 
 
 
Mexican 
American 
 
92.360 
-0.2248 
 
 










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Appendix H 
Imputation Rules for Missing or Partial AE Start Date  
Imputation rules for missing or partial AE start date are defined below: 
1) 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 prior to 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 pre-treatment AE, 
TEAE or post-treatment AE. 
2) 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 prior to 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 pre-treatment AE, 
TEAE or post-treatment AE. 
3) 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 prior to the first dose date then the AE should be considered as a pre-treatment 
AE. Otherwise, the AE will be considered as TEAE. 
 
 


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Appendix I 
Criteria for Threshold Analysis Events 
Table 11-6 
Threshold Criteria for Laboratory Tests (as applicable) 
Parameter 
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 
<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  
CTCAE grade 1-4 


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>27.8 mmol/L 
Albumin 
<35 - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L  
CTCAE grade 1-3 
 
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 
<0.74 – ≥ 0.6mmol/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 
FDA DILI Guidance and CTCAE 
 


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>5 – ≤  8 xULN 
>8 – ≤  20.0 xULN 
>20.0 x ULN 
ALT or AST 
(ALT>ULN and ALT ≤  3 xULN) or 
(AST>ULN and AST≤  3 xULN) 
(ALT>3 xULN and ALT ≤  5 xULN) or 
(AST>3xULN and AST≤  5 xULN) 
(ALT>5 xULN and ALT ≤  8 xULN) or 
(AST>5xULN and AST≤  8 xULN) 
(ALT>8 xULN and ALT ≤  20 xULN) or 
(AST>8xULN and AST≤  20 xULN) 
ALT>20 xULN or AST> 20 xULN 
FDA DILI Guidance  
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 


Statistical Analysis Plan (Methods)  
 
  
   
 
 
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Protocol Number: VX14-661-111 
 
 
 
Vertex Pharmaceuticals Incorporated 
 
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 
 


Statistical Analysis Plan (Methods)  
 
  
   
 
 
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Protocol Number: VX14-661-111 
 
 
 
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Table 11-7 
Threshold Criteria for Coagulation 
Parameter 
Criteria 
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 
 


Statistical Analysis Plan (Methods)  
 
  
   
 
 
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Protocol Number: VX14-661-111 
 
 
 
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Table 11-8 
Threshold Criteria for ECGs 
Parameter 
Criteria 
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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Table 11-9 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 
 


Statistical Analysis Plan (Methods)  
 
  
   
 
 
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Weight 
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
CTCAE grade 1-3 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
CTCAE grade 1-3