Conditions: Cystic Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 156
Healthy volunteers: no

Brief summary:
This is a Phase 3, randomized, double-blind, ivacaftor-controlled, parallel-group, multicenter study of tezacaftor in combination with ivacaftor in subjects aged 12 years and older with CF who are heterozygous for the F508del-CFTR mutation and a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive.

Detailed description:

Arms:
arm 1: Ivacaftor 150 milligram (mg) tablet orally every 12 hours for 4 weeks. arm 2: VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks. arm 3: Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks.

Interventions: intervention 1: Ivacaftor intervention 2: Tezacaftor/Ivacaftor
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 








Protocol VX14-661-109, Version 4.0
Page 5 of 81
Vertex Pharmaceuticals Incorporated
Number of Subjects
Approximately 160 subjects will be randomized (1:1) to the VX-661/ivacaftor 
combination therapy arm or ivacaftor monotherapy arm. Of the randomized 
subjects, approximately 15% will carry an R117H mutation on the second CFTR
allele.
Study Population
Male and female subjects aged 12 years or older with CF who are heterozygous
for the F508del-CFTR mutation and a second CFTR allele with a gating defect 
that is clinically demonstrated to be ivacaftor responsive
Investigational Drug
Active substances: VX-661 and ivacaftor 
Activities: CFTR corrector and potentiator (increased chloride ion [Clí] secretion)
Strength and Route of Administration: 100-mg VX-661/150-mg ivacaftor 
fixed-dose combination (light yellow) film-coated tablet for oral administration
Active substance: ivacaftor 
Activity: CF transmembrane potentiator (increased Clí secretion)
Strength and Route of Administration: 150-mg ivacaftor (light blue) 
film-coated tablet for oral administration
Active substance: not applicable
Activity: placebo
Strength and Route of Administration: 0-mg film-coated placebo tablets for 
oral administration visually matching the 100-mg VX-661/150-mg ivacaftor 
fixed-dose combination tablet and the 150-mg ivacaftor tablet.
Study Duration
Excluding the Screening Period (approximately 28 days in duration) and Ivacaftor 
Run-in Period (approximately 4 weeks in duration), subjects who complete the 
Active Comparator Treatment Period (including those who prematurely 
discontinue study treatment) will participate in this study for up to 13 weeks. 
During the Active Comparator Treatment Period, study drug (VX-661/ivacaftor or 
ivacaftor only) will be administered up to 8 weeks. 
A Safety Follow-up Visit will occur 28 days ± 7 days after the final dose of study 
drug. A Safety Follow-Up Visit is not required for subjects who have completed 
the Week 8 Visit and have enrolled in the extension study of VX-661 in 
combination with ivacaftor within 28 days after the last dose of study drug.
Study Design
This is a Phase 3, randomized, double-blind, ivacaftor-controlled, parallel-group, 
multicenter study in subjects aged 12 years and older with CF who are 
heterozygous for the F508del-CFTR mutation and a second CFTR allele with a 
gating defect that is clinically demonstrated to be ivacaftor responsive.
This study includes the following:
x
Screening Period (Week -8 to Week -4)
x
Ivacaftor Run-in Period where all subjects will receive ivacaftor (Week -4 to 
Day -1)
x
Active Comparator Treatment Period (Day 1 through Week 8 ± 5 days)
x
Safety Follow-up Visit (28 days ± 7 days after the final dose of study drug)






Protocol VX14-661-109, Version 4.0
Page 8 of 81
Vertex Pharmaceuticals Incorporated
3 
SCHEDULE OF ASSESSMENTS
Table 3-1 and Table 3-2 provide the schedule of assessments during the study from the 
Screening Period through the Safety Follow-up Visit.
All visits are to be scheduled relative to the Day 1 Visit (first dose of randomized study 
drug). For example, the Week 8 (± 5 days) Visit would occur after 8 weeks of study drug 
administration in the Active Comparator Treatment Period has been completed (i.e., Day 57, 
first day of Week 9).
Table 3-1 
Screening Period Assessments – Study VX14-661-109 
Event/Assessment
Screening Period
(Week -8 Through Week -4)
ICF and assent (when applicable)
X
Demographics
X
Medical history 
X
Ophthalmological history 
X
CFQ-Ra
X
CFTR genotypeb
X
Height and weightc
X
Ophthalmologic examinationd
X
Complete PE
X
FSHe
X
Serum pregnancy test (all females of childbearing potential)f
X
Standard digital ECGg
X
Vital signsh
X
Pulse oximetryh
X
Spirometryi
X
a
The CFQ-R, 
 must be completed prior to the start of any other assessments scheduled at that visit.
b
All subjects will be tested for CFTR genotype. The results of the confirmatory genotype sample obtained at the 
Screening Visit must be reviewed before enrollment. In subjects with confirmed R117H mutation, linkage to poly-T
track polymorphisms will also be determined. Specific instructions will be provided in the Laboratory Manual. 
c
Weight and height will be measured with shoes off.
d
An ophthalmologic examination will be conducted on subjects of all ages by an ophthalmologist. 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 or if there is documentation of bilateral lens removal 
(Section 11.7.8). Subjects with clinically significant cataracts, lens opacity, Y-suture, or lamellar rings will be excluded 
from the study.
e
FSH will be measured for any potentially postmenopausal female with at least 12 months of continuous spontaneous 
DPHQRUUKHD6HUXP)6+OHYHOVPXVWEH mIU/mL to be considered postmenopausal.
f
Any female subject who does not meet the criteria for non-childbearing potential is considered to be of childbearing 
potential and must have a serum pregnancy test.
g
A standard digital ECG will be performed after the subject has been supine for at least 5 minutes.
h
Vital signs and pulse oximetry will be collected after the subject has been at rest (seated or supine) for 5 minutes. 
i
Spirometry may be performed pre- or postbronchodilator (Section 11.6.1). Screening spirometry evaluation may be 
repeated, as specified in Section 8.1.1.1.


Protocol VX14-661-109, Version 4.0
Page 9 of 81
Vertex Pharmaceuticals Incorporated
Table 3-1 
Screening Period Assessments – Study VX14-661-109 
Sweat chloridej
X
Urinalysis
X
Hematology
X 
Coagulation
X
Serum chemistry
X
Inclusion/exclusion criteria review
X
Prior and concomitant medications
X
AEs and SAEs
Continuous from signing of ICF and assent (where 
applicable) through Safety Follow-up Visitk
AE: adverse event; CFTR: cystic fibrosis transmembrane conductance regulator; CFQ-R: Cystic Fibrosis Questionnaire-
Revised; ECG: electrocardiogram; FSH: follicle-stimulating hormone; ICF: informed consent form; PE: physical 
examination; 
SAE: serious adverse event; 
j  
A sweat chloride test must be performed at the Screening Visit if an eligible sweat chloride value is not available in the 
subject’s medical records and the Screening Visit value is needed to establish eligibility. For subjects using sweat 
chloride values documented in their medical records to establish eligibility, the sweat chloride test at the Screening 
Visit is optional.
k
For enrolled subjects who do not have a Safety Follow-up Visit, AEs and SAEs will be collected through the earliest of 
the following: 28 days after the last dose of study drug; the ETT Visit, if that visit is 3 weeks or later following the last 
dose of study drug (Section 8.1.5); or prior to the first dose of study drug in the extension study.




Protocol VX14-661-109, Version 4.0
Page 11 of 81
Vertex Pharmaceuticals Incorporated
Table 3-2 
Ivacaftor Run-in Period, Active Comparator Treatment Period, ETT, and Safety Follow-up Visit Assessments –
Study VX14-661-109 
Event/Assessmenta
Ivacaftor Run-in Periodb
Active Comparator Treatment Period
ETT
Visitc
Safety 
Follow-up Visit
28 days 
(± 7 Days)
After Last Dosed
Week -4 
(Day -28
± 2 Days)
Week -2 
(Day -14)
(± 2 Days)
Day 1
Week 2
(Day 15)
(± 2 Days)
Week 4
(Day 29)
(± 5 Days)
Week 8
(Day 57)
(± 5 Days)
Complete PEh
X
Pregnancy testi
X
X
X
X
X
X
Standard digital ECGj
X
X
X
X
X
X
X
X
Vital signsk
X
X
X
X
X
X
X
X
Pulse oximetryk
X
X
X
X
X
X
X
X
Spirometryl
X
X
X
X
X
X
X
X
Sweat chloridem
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Hematology
X
X
X
X
X
X
Coagulation
X
X
X
X
X
Serum chemistry
Xn
X
Xn
X
X
X
X
X
Lipid panelo
X
X
X
X
h
Symptom-targeted PEs will occur at any time during the study if triggered by AEs or if deemed necessary by the investigator.
i
Pregnancy tests will be performed for all female subjects RIFKLOGEHDULQJSRWHQWLDO$XULQHȕ-hCG test will be performed at the Week -4 (before first dose of study drug), 
Day 1, and Week 4 Visits. A serum pregnancy test will be performed at the Week 8 Visit, at the ETT, and the Safety Follow-up Visit.  
j
All standard digital ECGs will be performed before dosing and after the subject has been supine for at least 5 minutes. At the Day 1 and Week 2 Visits, ECGs will be 
collected before dosing and at 1.5, 3, 4, and 6 hours after the morning dose. The ECG will be performed before the morning dose of study drug at Week -4, Week -2, and 
Week 4. Single ECGs will be performed at Week 8, ETT, and Safety Follow-up Visits. ECGs collected on Week -4 and Day 1 before dosing will be performed in triplicate. 
Where repeats of the same assessment are required at a given visit, if study drug is not administered on the day of the visit (i.e., study drug interruption or permanent 
discontinuation of study drug), only 1 ECG will be collected.  
k
Vital signs and pulse oximetry will be collected before dosing after the subject has been at rest (seated or supine) for at least 5 minutes.
l
At all visits, spirometry will be performed for all subjects pre-bronchodilator and before dosing (Section 11.6.1). On Days 1 and 15, subjects <18 years of age at the Screening 
Visit will have additional spirometry assessments performed at 2 and 4 hours postdose. If more than 1 spirometry assessment is required at a visit, bronchodilators will be 
withheld until the last scheduled spirometry assessment is completed.
m  
The sweat chloride collection on dosing days should occur before the morning dose of the study drugs. At each time point, 2 samples will be collected, 1 from each arm (left 
and right). Collection of sweat chloride will not overlap with any other study assessments.
n  
Blood samples will be collected before the first dose of study drug.
o 
Subjects will require 4 hours of fasting before the blood sample for the lipid panel is obtained. 


Protocol VX14-661-109, Version 4.0
Page 12 of 81
Vertex Pharmaceuticals Incorporated
Table 3-2 
Ivacaftor Run-in Period, Active Comparator Treatment Period, ETT, and Safety Follow-up Visit Assessments –
Study VX14-661-109 
Event/Assessmenta
Ivacaftor Run-in Periodb
Active Comparator Treatment Period
ETT
Visitc
Safety 
Follow-up Visit
28 days 
(± 7 Days)
After Last Dosed
Week -4 
(Day -28
± 2 Days)
Week -2 
(Day -14)
(± 2 Days)
Day 1
Week 2
(Day 15)
(± 2 Days)
Week 4
(Day 29)
(± 5 Days)
Week 8
(Day 57)
(± 5 Days)
Vitamin levels
X
X
X
X
PK samplingp
X
X
X
X
Randomizationr
X
Meal(s) or snack(s) at sites
X
X
X
X
X
Ivacaftor dosingt
X
Randomized treatment dosingu
X
X
X
Study drug count
X
X
X
X
X
X
Concomitant medicationsv
X 
X 
X 
X 
X 
X 
X 
X 
p
PK blood samples will be collected at Week -2 (before the morning dose and at 2 and 6 hours after the morning dose) and Week 2 (before the morning dose and at 3 and 
8 hours after the morning dose). If study drug is not administered at the Week -2 Visit or Week 2 Visit (i.e., study drug interruption or permanent discontinuation of study 
drug), a single PK blood sample will still be collected. At the ETT and the Safety Follow-up Visits (as applicable), a PK blood sample will also be collected.
Randomization must occur after all inclusion and exclusion criteria are met, after the 4 weeks Ivacaftor Run-in Period, and before the first dose of study drug on Day 1 of the 
Active Comparator Treatment Period. Randomization will be done through IWRS. 
s
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 been completed.
t
Subjects will receive ivacaftor 150 mg q12h from the Week -4 Visit through the evening of Day -1 (1 day prior to the Day 1 Visit). The study drug should be administered 
every 12 hours (± 2 hours) within 30 minutes after starting a meal with fat-containing food such as a “standard CF” high-fat, high-calorie meal or snack. On days of scheduled 
visits, the morning dose of study drug will be administered at the site after predose assessments have been completed. 
u
Subjects will receive randomized study treatment from randomization through the evening of the day before the Week 8 Visit. The study drug should be administered every 
12 hours (± 2 hours) within 30 minutes after starting a meal with fat-containing food such as a “standard CF” high-fat, high-calorie meal or snack. On days of scheduled visits, 
the morning dose of study drug will be administered at the site after predose assessments have been completed. 
v 
Information on concomitant medications is collected through the Safety Follow-up Visit for all subjects. For subjects who discontinue treatment and are followed for certain 
efficacy assessments after the ETT Visit (see Section 8.1.5), information on concomitant antibiotic therapy for “sinopulmonary signs/symptoms” are collected through the 
Week 8 Visit, as described in Section 11.6.4.1.1


Protocol VX14-661-109, Version 4.0
Page 13 of 81
Vertex Pharmaceuticals Incorporated
Table 3-2 
Ivacaftor Run-in Period, Active Comparator Treatment Period, ETT, and Safety Follow-up Visit Assessments –
Study VX14-661-109 
Event/Assessmenta
Ivacaftor Run-in Periodb
Active Comparator Treatment Period
ETT
Visitc
Safety 
Follow-up Visit
28 days 
(± 7 Days)
After Last Dosed
Week -4 
(Day -28
± 2 Days)
Week -2 
(Day -14)
(± 2 Days)
Day 1
Week 2
(Day 15)
(± 2 Days)
Week 4
(Day 29)
(± 5 Days)
Week 8
(Day 57)
(± 5 Days)
Concomitant treatments and 
procedures
X
X
X
X
X
X
X
X
AEs and SAEs
Continuous from signing of ICF and assent (where applicable) through Safety Follow-up Visitw
$(DGYHUVHHYHQWȕ-hCG: beta-human chorionic gonadotropin; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire–Revised; ECG: electrocardiogram; ETT: Early Treatment 
Termination; IWRS: interactive web response system; PE: physical examination; PK: pharmacokinetic; 
; SAE: serious adverse event; 
w
For enrolled subjects who do not have a Safety Follow-up Visit, AEs and SAEs will be collected through the earliest of the following: 28 days after the last dose of study 
drug; the ETT Visit, if that visit is 3 weeks or later following the last dose of study drug (Section 8.1.5); or prior to the first dose of study drug in the extension study.


Protocol VX14-661-109, Version 4.0
Page 14 of 81
Vertex Pharmaceuticals Incorporated
4 
TABLE OF CONTENTS
1 
Title Page .......................................................................................................................... 1 
2 
Protocol Synopsis ............................................................................................................. 4 
3 
Schedule of Assessments.................................................................................................. 8 
4 
Table of Contents ........................................................................................................... 14 
List of Tables...................................................................................................................... 18 
List of Figures .................................................................................................................... 18 
5 
Introduction.................................................................................................................... 19 
6 
Study Objectives ............................................................................................................ 21 
6.1 
Primary Objective ..................................................................................................... 21 
6.2 
Secondary Objectives ............................................................................................... 21 
7 
Study Endpoints ............................................................................................................. 21 
7.1 
Primary Endpoints .................................................................................................... 21 
7.2 
Key Secondary Endpoints ........................................................................................ 21 
7.3 
Secondary Endpoints ................................................................................................ 21 
8 
Study Design ................................................................................................................... 22 
8.1 
Overview of Study Design ....................................................................................... 22 
8.1.1 
Screening .......................................................................................................... 23 
8.1.1.1 
Repetition of Screening Assessment(s) ...................................................... 24 
8.1.1.2 
Rescreening ................................................................................................ 24 
8.1.1.3 
Extension of the Screening Period Window .............................................. 24 
8.1.2 
Ivacaftor Run-in Period (4 Weeks) ................................................................... 24 
8.1.3 
Active Comparator Treatment Period (8 Weeks) ............................................. 25 
8.1.4 
Safety Follow-up .............................................................................................. 25 
8.1.5 
Early Treatment Termination ........................................................................... 25 
8.1.6 
Independent Data Monitoring Committee ........................................................ 26 
8.2 
Rationale for Study Design and Study Drug Regimens ........................................... 26 
8.2.1 
Study Design..................................................................................................... 26 
8.2.2 
Study Drug Dose and Duration ........................................................................ 27 
8.2.3 
Rationale for Study Population......................................................................... 27 
8.2.4 
Rationale for Study Assessments ..................................................................... 28 
9 
Study Population ............................................................................................................ 29 
9.1 
Inclusion Criteria ...................................................................................................... 29 
9.2 
Exclusion Criteria ..................................................................................................... 30 
9.3 
Study Restrictions ..................................................................................................... 32 
9.3.1 
Dietary Restrictions/Prohibited Medications .................................................... 32 
9.4 
Prior and Concomitant Medications ......................................................................... 33 
9.5 
Removal of Subjects ................................................................................................. 34 
9.6 
Replacement of Subjects .......................................................................................... 35 
10 Study Drug Administration and management ............................................................ 35 
10.1 Preparation and Dispensing ...................................................................................... 35 
10.2 Administration .......................................................................................................... 35 


Protocol VX14-661-109, Version 4.0
Page 15 of 81
Vertex Pharmaceuticals Incorporated
10.3 Method of Assigning Subjects to Treatment Groups ............................................... 37 
10.4 Dose Modification for Toxicity ................................................................................ 37 
10.5 Study Drug Interruption ........................................................................................... 37 
10.6 Missed Doses ............................................................................................................ 37 
10.7 Packaging and Labeling ........................................................................................... 38 
10.8 Study Drug Supply, Storage, and Handling ............................................................. 38 
10.9 Drug Accountability ................................................................................................. 38 
10.10 Disposal, Return, or Retention of Unused Drug ....................................................... 39 
10.11 Compliance ............................................................................................................... 39 
10.12 Blinding and Unblinding .......................................................................................... 39 
10.12.1 Blinding ............................................................................................................ 39 
10.12.2 Unblinding ........................................................................................................ 40 
11 Assessments .................................................................................................................... 41 
11.1 Timing of Assessments ............................................................................................. 41 
11.1.1 
Informed Consent/Assent ................................................................................. 42 
11.1.2 
Assigning Subject Number ............................................................................... 42 
11.2 Subject and Disease Characteristics ......................................................................... 42 
11.3 Total Blood Volume ................................................................................................. 42 
11.4 Pharmacokinetics ...................................................................................................... 42 
11.4.1 
Blood Sampling ................................................................................................ 42 
11.4.2 
Processing and Handling of Pharmacokinetic Samples ................................... 43 
11.4.3 
Bioanalysis........................................................................................................ 43 
11.6 Efficacy ..................................................................................................................... 44 
11.6.1 
Spirometry ........................................................................................................ 44 
11.6.2 
Sweat Chloride Testing .................................................................................... 45 
11.6.3 
Cystic Fibrosis Questionnaire-Revised ............................................................ 46 
11.7 Safety ........................................................................................................................ 47 
11.7.1 
Adverse Events ................................................................................................. 47 
11.7.2 
Clinical Laboratory Assessments ..................................................................... 47 
11.7.3 
Physical Examinations and Vital Signs ............................................................ 49 
11.7.4 
Electrocardiograms ........................................................................................... 50 
11.7.5 
Contraception and Pregnancy ........................................................................... 50 
11.7.5.1 Contraception ............................................................................................. 50 
11.7.5.2 Pregnancy ................................................................................................... 53 
11.7.6 
Pulse Oximetry ................................................................................................. 53 
11.7.7 
Liver Function Test Parameters ........................................................................ 54 
11.7.8 
Ophthalmologic Examination ........................................................................... 55 


Protocol VX14-661-109, Version 4.0
Page 16 of 81
Vertex Pharmaceuticals Incorporated
12 Statistical and Analytical Plans .................................................................................... 56 
12.1 Sample Size and Power ............................................................................................ 56 
12.2 Analysis Sets ............................................................................................................ 57 
12.3 Statistical Analysis ................................................................................................... 57 
12.3.1 
General Considerations ..................................................................................... 57 
12.3.2 
Background Characteristics .............................................................................. 58 
12.3.2.1 Subject Disposition .................................................................................... 59 
12.3.2.2 Demographics and Baseline Characteristics .............................................. 59 
12.3.2.3 Prior and Concomitant Medications........................................................... 60 
12.3.2.4 Study Drug Exposure and Compliance ...................................................... 60 
12.3.3 
Efficacy Analysis .............................................................................................. 61 
12.3.3.1 Analysis of Primary Variables ................................................................... 61 
12.3.3.2 Analysis of Key Secondary Efficacy Variables ......................................... 61 
12.3.3.3 Analysis of Secondary Efficacy Variables ................................................. 62 
12.3.4 
Safety Analysis ................................................................................................. 62 
12.3.4.1 Adverse Events........................................................................................... 62 
12.3.4.2 Clinical Laboratory Assessments ............................................................... 63 
12.3.4.3 Electrocardiogram ...................................................................................... 64 
12.3.4.4 Vital Signs .................................................................................................. 64 
12.3.4.5 Physical Examination ................................................................................. 65 
12.3.4.6 Other Safety Analysis ................................................................................ 65 
12.3.4.6.1 Pulse Oximetry .................................................................................... 65 
12.3.4.6.2 Postdose Spirometry ............................................................................ 65 
12.3.5 
Interim and IDMC Analyses ............................................................................. 65 
12.3.5.1 Interim Analysis ......................................................................................... 65 
12.3.5.2 IDMC Analysis .......................................................................................... 65 
12.4 Clinical Pharmacology Analysis .............................................................................. 65 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ..................... 66 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting .................................................................................................................. 66 
13.1.1 
Adverse Events ................................................................................................. 66 
13.1.1.1 Definition of an Adverse Event.................................................................. 66 
13.1.1.2 Clinically Significant Assessments ............................................................ 66 
13.1.1.3 Documentation of Adverse Events............................................................. 66 
13.1.1.4 Adverse Event Severity .............................................................................. 67 
13.1.1.5 Adverse Event Causality ............................................................................ 68 
13.1.1.6 Study Drug Action Taken .......................................................................... 68 
13.1.1.7 Adverse Event Outcome ............................................................................ 69 
13.1.1.8 Treatment Given......................................................................................... 69 
13.1.2 
Serious Adverse Events .................................................................................... 70 
13.1.2.1 Definition of a Serious Adverse Event....................................................... 70 
13.1.2.2 Documentation of Serious Adverse Events................................................ 70 
13.1.2.3 Reporting Serious Adverse Events............................................................. 71 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ................................ 71 
13.2 Administrative Requirements ................................................................................... 71 


Protocol VX14-661-109, Version 4.0
Page 17 of 81
Vertex Pharmaceuticals Incorporated
13.2.1 
Ethical Considerations ...................................................................................... 71 
13.2.2 
Subject Information and Informed Consent and Assent ................................... 71 
13.2.3 
Investigator Compliance ................................................................................... 72 
13.2.4 
Access to Records ............................................................................................. 72 
13.2.5 
Subject Privacy ................................................................................................. 72 
13.2.6 
Record Retention .............................................................................................. 72 
13.2.7 
Study Termination ............................................................................................ 73 
13.3 Data Quality Assurance ............................................................................................ 73 
13.4 Monitoring ................................................................................................................ 73 
13.5 Electronic Data Capture ........................................................................................... 74 
14 References ....................................................................................................................... 76 
15 Protocol Signature Pages .............................................................................................. 79 
15.1 Sponsor Signature Page ............................................................................................ 79 
15.2 Investigator Signature Page ...................................................................................... 80 
16 Appendix A: Second CFTR Allele Mutations Included for Subjects who are 
Heterozygous for the F508del-CFTR Mutation .......................................................... 81 


Protocol VX14-661-109, Version 4.0
Page 18 of 81
Vertex Pharmaceuticals Incorporated
List of Tables
Table 3-1 
Screening Period Assessments – Study VX14-661-109 ................................... 8 
Table 3-2 
Ivacaftor Run-in Period, Active Comparator Treatment Period, ETT, and 
Safety Follow-up Visit Assessments – Study VX14-661-109 ........................ 10 
Table 9-1 
Study Restrictions ........................................................................................... 33 
Table 10-1 
Study Drug Administration – Ivacaftor Run-in Period ................................... 35 
Table 10-2 
Study Drug Administration - Active Comparator Treatment Period .............. 36 
Table 10-3 
Identity of Study Drugs, Dosage, and Storage ................................................ 38 
Table 11-1 
Acceptable PK Sampling Windows ................................................................ 43 
Table 11-2 
Safety Laboratory Test Panels ........................................................................ 48 
Table 13-1 
Grading of AE Severity .................................................................................. 68 
Table 13-2 
Classifications for AE Causality ..................................................................... 68 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE ............ 69 
Table 13-4 
Classifications for Outcome of an AE ............................................................ 69 
List of Figures
Figure 8-1 
Schematic View of the Study Design ............................................................. 23 


Protocol VX14-661-109, Version 4.0
Page 19 of 81
Vertex Pharmaceuticals Incorporated
5 
INTRODUCTION
Cystic fibrosis (CF) affects an estimated 70,000 children and adults worldwide1 and is the 
most common fatal genetic disease in persons of European descent.2 Based on the size of the 
population, CF qualifies as an orphan disease.3,4 Despite progress in the treatment of CF with 
antibiotics and mucolytics, the predicted median age of survival for a person with CF is in 
the mid-30s.2,5 Although the disease affects multiple organs, most morbidity and mortality 
are caused by progressive loss of lung function.6
CF is an autosomal recessive genetic disease caused by a defect in the gene encoding the CF 
transmembrane conductance regulator protein (CFTR), an epithelial chloride ion (Clí)
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.2 This function is defective in patients with CF due to a loss of either cell surface 
expression and/or function. 
More than 1900 mutations in the CFTR gene have been identified.7 Mutations in the CFTR
gene have been classified based on the molecular and functional consequence of the mutation 
on the CFTR protein8,9,10 and can be generally considered to reduce the quantity of 
functional CFTR protein that reaches the epithelial cell surface or reduce the function of 
CFTR protein located at the cell surface. CFTR gene mutations that affect the quantity of 
functional cell surface CFTR protein include defects that reduce CFTR protein synthesis and 
defects that impede the cellular processing and delivery of CFTR proteins to the cell surface.
CFTR gene mutations associated with minimal CFTR function include
x
mutations associated with severe defects in ability of the CFTR channel to open and 
close, known as defective channel gating or “gating mutations”; 
x
severe defects in the cellular processing of CFTR and its delivery to the cell surface;
x
no (or minimal) CFTR synthesis; and
x
severe defects in channel conductance.
The most prevalent mutation is an in-frame deletion in the CFTR gene resulting in a loss of 
phenylalanine at position 508 in the CFTR protein (F508del-CFTR).10 In the United States 
(US), almost 87% of patients with CF have at least 1 copy of the F508del-CFTR mutation 
and about 47% have 2 copies.11 In the European Union (EU), approximately 83% of patients 
with CF have 1 or 2 copies of the F508del-CFTR mutation, and approximately 38.7% of 
patients with CF in the United Kingdom have 2 copies.12 The F508del-CFTR mutation 
interferes with the ability of the CFTR protein to reach and remain at the cell surface, as well 
as to open and close, resulting in decreased Clí transport.13,14 The combined effect is a 
marked reduction in F508del-CFTR-mediated Clí secretion that impairs fluid regulation and 
promotes accumulation of thick, sticky mucus in the airway. The mucus build-up obstructs 
the airways and predisposes the patient to chronic lung infections.15


Protocol VX14-661-109, Version 4.0
Page 20 of 81
Vertex Pharmaceuticals Incorporated
Two complementary approaches to increase CFTR-mediated Clí secretion in the airway 
epithelia have been studied.9 One approach is to treat with a compound that will modify the 
cellular processing and trafficking of the CFTR protein to increase the amount of functional 
CFTR at the cell surface. This kind of compound has been termed a CFTR corrector. Another 
approach is to treat with a compound that increases the channel gating activity of protein 
kinase A-activated CFTR at the cell surface to enhance ion transport. This kind of compound 
has been termed a potentiator. Depending on the amount of residual CFTR channel activity 
in the membrane and the pathophysiology of that activity (reflecting the CFTR genotype of 
the patient and possibly other factors), both approaches may be required to ameliorate lung 
disease in patients with CF. A modest restoration of Clí secretion through the action of a 
potentiator and/or corrector could prevent the hyperabsorption of water across the apical 
surface of epithelial cells, allowing proper maintenance of airway hydration. Adequate 
airway hydration could alleviate the cycle of mucus plugging, infection, and inflammation, 
which leads to irreversible structural changes in the lungs and, eventually, respiratory failure 
for patients with CF.
VX-661 is a 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 
the F508del-CFTR protein during its biogenesis and processing in the endoplasmic 
reticulum, allowing it to exit the endoplasmic reticulum and traffic the cell surface.16 When 
added for more than 24 hours to human bronchial epithelial (HBE) cells isolated and cultured 
from lung explants obtained from donors with CF (CF-HBE cells) who are homozygous for 
the F508del-CFTR mutation, a concentration-dependent increase in levels of mature 
(i.e., plasma membrane) F508del-CFTR was observed. The increased trafficking of 
F508del-CFTR to the cell surface resulted in a significant increase in Clí secretion.16 VX-661 
did not correct the processing and localization of other misfolded or normally folded proteins 
other than CFTR, suggesting that the mechanism of VX-661 action is selective for CFTR 
(CFTR corrector).17
Ivacaftor (also known as VX-770) is the first CFTR modulator to show an improvement in 
CFTR function and clinical benefit in patients with CF. Results from several Phase 3 studies 
showed that ivacaftor is effective in the treatment of patients with CF who have mutations 
that result in gating defects as evidenced by sustained improvements in CFTR channel 
function (measured by reduction in sweat chloride concentration) and corresponding 
substantial, durable improvements in lung function, respiratory symptoms, and weight gain. 
Ivacaftor was also well tolerated, as evidenced by the rates and reasons for premature 
discontinuation and results of safety assessments. 
Kalydeco (ivacaftor) is indicated for the treatment of CF in patients as young as 2 years of 
age who have 1 of the following mutations in the CFTR gene: G551D, G1244E, G1349D, 
G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H. Please refer to the ivacaftor IB 
and local prescribing information or summary of product characteristics for your region for 
the current approved use of Kalydeco. 
Details about the VX-661 and ivacaftor development programs can be found in the 
Investigator's Brochures.18,19




Protocol VX14-661-109, Version 4.0
Page 22 of 81
Vertex Pharmaceuticals Incorporated
8
STUDY DESIGN
8.1
Overview of Study Design
This is a Phase 3, randomized, double-blind, ivacaftor-controlled, parallel-group, multicenter 
study in subjects aged 12 years and older with CF who are heterozygous for the 
F508del-CFTR mutation and a second CFTR allele with a gating defect that is clinically 
demonstrated to be ivacaftor responsive (Section 16). 
This study is designed to compare active treatment of VX-661 (100 mg daily [qd]) and 
ivacaftor (150 mg every 12 hours [q12h]) combination therapy with ivacaftor monotherapy 
(150 mg q12h).  
The treatment regimens will be as follows:
x
VX-661/ivacaftor combination therapy 
o
Morning dose: 1 tablet of fixed-dose combination of VX-661 100 mg/ivacaftor 
150 mg and 1 tablet of placebo visually matched to ivacaftor 
o
Evening dose: 1 tablet of ivacaftor 150 mg 
x
Ivacaftor monotherapy 
o
Morning dose: 1 tablet of placebo visually matched to the fixed-dose combination 
tablet and 1 tablet of ivacaftor 150 mg 
o
Evening dose: 1 tablet of ivacaftor 150 mg 
This study includes a Screening Period (approximately 28 days), an Ivacaftor Run-in Period 
(approximately 4 weeks), an Active Comparator Treatment Period (up to 8 weeks), and a 
Safety Follow-up Visit (approximately 28 days after last dose). Following the Ivacaftor 
Run-in Period, approximately 160 subjects will be randomized in a ratio of 1:1 to receive 
either VX-661/ivacaftor combination therapy or ivacaftor monotherapy for 8 weeks during 
the Active Comparator Treatment Period. The randomization will be stratified by age at the 
6FUHHQLQJ9LVLWYHUVXV years of age), type of mutation on the second CFTR allele 
(R117H versus other allowed mutations; Section 16), and percent predicted FEV1 severity 
determined at the end of the Ivacaftor Run-in Period (<70 versus t70; see Figure 8-1). Of the 
randomized subjects, approximately 15% will carry an R117H mutation on the second CFTR
allele (Section 16). Week 8 is the conclusion of the Active Comparator Treatment Period of 
the study. 
Subjects who complete the Week 8 Visit, regardless of whether they have prematurely 
discontinued study drug treatment, will be offered the opportunity to enroll in an extension 
study, if they meet the eligibility criteria. 
All subjects randomized in the Active Comparator Treatment Period will be required to 
complete study assessments for all scheduled visits through Week 8, regardless of whether 
they have prematurely discontinued study treatment (Section 8.1.5).




Protocol VX14-661-109, Version 4.0
Page 24 of 81
Vertex Pharmaceuticals Incorporated
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: 
x
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.
x
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 (ATS)/European Respiratory Society (ERS) 
guidelines,20 repeat spirometry evaluation may be performed once.
If repeat values of the individual assessment(s) are within the eligibility criteria and 
completed within the screening window, then the subject is eligible for the study.
8.1.1.2
Rescreening
Subjects may only be rescreened with the approval of the medical monitor. If a subject is 
rescreened, all screening assessments will be repeated except for CF genotyping, 
follicle-VWLPXODWLQJKRUPRQH)6+OHYHOLIVHUXP)6+OHYHOZDV mIU/mL during prior 
screening), sweat chloride, and the ophthalmologic examination (if performed within the last 
3 months). If a subject is rescreened, the screening window will begin once the first 
rescreening assessment has been initiated.
8.1.1.3
Extension of the Screening Period Window
A subject may have the Screening Period window extended by 2 weeks for the following 
reasons:
x
Unexpected operational or logistic delays, or to meet the eligibility criteria
x
Repetition of the Screening Period assessments (Section 8.1.1.1)
x
Additional time to conduct ophthalmologic examinations (Section 11.7.8) 
8.1.2
Ivacaftor Run-in Period (4 Weeks)
The Ivacaftor Run-in Period will have a total duration of 4 weeks and is designed to establish 
a reliable on-treatment (ivacaftor monotherapy) baseline for the Active Comparator 
Treatment Period. The first dose of open-label ivacaftor will be administered at the Week -4 
Visit. The last dose of open-label ivacaftor will be administered in the evening on Day -1 
(1 day prior to the Day 1 Visit). With prior approval of the medical monitor, the Ivacaftor 
Run-in Period may be extended if the subject does not meet criteria for entry into the Active 
Comparator Treatment Period (Section 8.1.3).
Study visits during the Ivacaftor Run-in Period will occur as shown in Table 3-2. Subjects 
will be outpatients during the Ivacaftor Run-in Period. All visits should occur within the 
windows specified. 


Protocol VX14-661-109, Version 4.0
Page 25 of 81
Vertex Pharmaceuticals Incorporated
Subjects who prematurely discontinue study drug treatment during the Ivacaftor Run-in 
Period will not be randomized or participate in the Active Comparator Treatment Period. 
These subjects will complete an ETT Visit and Safety Follow-up Visit. The Safety Follow-up 
Visit will be their last visit in the study.
8.1.3
Active Comparator Treatment Period (8 Weeks)
The Active Comparator Treatment Period will last approximately 8 weeks. Subjects will be 
randomized to 1 of 2 treatment arms (VX-661/ivacaftor or ivacaftor alone) as shown in 
Figure 8-1.  
The first dose of the randomized study drug will be administered after randomization on 
Day 1. Dosing details are given in Section 10.2.
In order to continue into the Active Comparator Treatment Period, subjects must have stable 
CF disease (as judged by the investigator) and have remained on a stable CF medication 
regimen during the run-in period. If these criteria are not met (for example, if the subject has
an acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy 
[including antibiotics] for pulmonary disease within 28 days before the Day 1 Visit [first 
dose of study drugs in the Active Comparator Treatment Period]), possible extension of the 
Ivacaftor Run-in Period should be discussed with the medical monitor. 
Study visits during the Active Comparator Treatment Period will occur as shown in 
Table 3-2. Subjects will be outpatients during the Active Comparator Treatment Period. All 
visits should occur within the windows specified. 
Subjects who prematurely discontinue study treatment during the Active Comparator 
Treatment Period will remain in the study from the time of discontinuation of study treatment 
through the Week 8 Visit and complete assessments for all study visits, as described in 
Section 8.1.5.
8.1.4
Safety Follow-up
The Safety Follow-up Visit assessments are listed in Table 3-2. There will be an outpatient 
Safety Follow-up Visit 28 days ± 7 days after the last dose of study drug for subjects who 
complete study drug dosing and for subjects who prematurely discontinue study drug dosing. 
If the Early Treatment Termination (ETT) Visit occurs 3 weeks or later following the last 
dose of study drug, then the ETT Visit will replace the Safety Follow-up Visit, and a separate 
Safety Follow-up Visit will not be required. 
The Safety Follow-up Visit is not required for subjects who complete the Week 8 Visit and 
have enrolled in the extension study of VX-661 in combination with ivacaftor within 28 days 
after the last dose of study drug. 
8.1.5
Early Treatment Termination
If the subject prematurely discontinues study treatment, an ETT Visit should be scheduled as 
soon as possible after the subject decides to terminate study treatment. Subjects who 
prematurely discontinue treatment will also be required to complete the Safety Follow-up 
Visit, approximately 28 (± 7) days after their last dose of study drug. The assessments 
performed at the Safety Follow-up Visit are listed in Table 3-2. 




Protocol VX14-661-109, Version 4.0
Page 27 of 81
Vertex Pharmaceuticals Incorporated
endpoint was selected in order to obtain a more robust assessment of the durability of 
response that is less affected by short-term variability in FEV1. The Week 8 Visit is the 
conclusion of the Active Comparator Treatment Period in this study.
8.2.2
Study Drug Dose and Duration
The dose regimen of VX-661 chosen for continued development in Phase 3 was studied in 
Study 101 in 2 CF populations: F508del-CFTR homozygous subjects (Group 4) and 
F508del-CFTR heterozygous subjects who had G551D-CFTR on the other allele (Group 7). 
The dose regimen of VX-661 100 mg qd in combination with ivacaftor 150 mg q12h 
provided clinically meaningful and statistically significant improvements in percent predicted 
FEV1 in both populations, as well as a signal of CFTR modulation as assessed by the change 
in sweat chloride.
The dose regimen of ivacaftor planned for this study (150 mg q12h) is the current approved 
dose regimen for patients with CF with gating mutations who are aged 6 years and older. 
8.2.3
Rationale for Study Population
The study population will be subjects with CF 12 years of age and older who are 
heterozygous for the F508del-CFTR mutation and a second CFTR allele with a gating defect 
that is clinically demonstrated to be ivacaftor responsive. Based on the results from 
Study 101 (Section 8.2.1), subjects with the F508del-CFTR mutation on only 1 allele may 
respond to VX-661/ivacaftor combination therapy when the second allele is also responsive 
to potentiator modulation. 
Patients with CF who have CFTR alleles that qualify them for inclusion in this study may 
live in a region where ivacaftor (Kalydeco) is already approved for patients with their 
mutations and is available for use by prescription. Because of this, it is anticipated that this 
study will enroll both subjects who have been exposed to ivacaftor within 28 days prior to the 
Screening Visit and subjects who have not. The intent of this study is to determine if 
VX-661/ivacaftor combination therapy has additional benefit over ivacaftor monotherapy in 
this population. Subjects who have been exposed to ivacaftor within 28 days prior to the 
Screening Visit must have an FEV1 DQG90% of predicted normal for age, sex, and 
height at the Screening Visit. Those who have not been exposed to ivacaftor within 28 days 
prior to the Screening Visit must have an FEV1 DQGRISUHGLFWHGQRUPDOIRUDJH
sex, and height at the Screening Visit.
The inclusion of subjects with CF who are 12 to 17 years of age is justified based on severity 
of disease and allometric scaling. The overall disease status for the adolescent and adult 
populations to be enrolled in this study is anticipated to be similar based on the identical 
enrollment criteria, particularly the FEV1 and the requirement for clinical stability. Both 
VX-661 and ivacaftor are predominantly eliminated by metabolism via the cytochrome P450 
(CYP) 3A4 enzymatic pathway. The maturity of the CYP enzymes in adolescents is expected 
to be similar to adults.21 Therefore, the low likelihood of differences in PK of VX-661 and 
ivacaftor between adolescents and adults further supports the inclusion of adolescents in this 
study. The dose regimen of ivacaftor planned for this study (150 mg q12h) is the current 
labeled dose regimen for patients with CF with gating mutations who are aged 6 years and 
older. Based on the historical data from the ivacaftor Phase 3 program and the US CF 






Protocol VX14-661-109, Version 4.0
Page 30 of 81
Vertex Pharmaceuticals Incorporated
x
Chronic cough and sputum production 
x
Persistent chest radiograph abnormalities (e.g., bronchiectasis, atelectasis, infiltrates, 
hyperinflation) 
x
Nasal polyps, chronic sinusitis; radiographic or computed tomographic abnormalities 
of the paranasal sinuses 
If it is unclear whether a subject meets this criterion, please consult with the medical 
monitor prior to enrollment.  
8. Stable CF disease as judged by the investigator.
9. Willing to remain on a stable CF medication regimen from Week -4 through the last day 
of dosing (Week 8) or, if applicable, the Safety Follow-up Visit.
10. Willing to discontinue use of physician-prescribed ivacaftor (Kalydeco) from Week -4 to 
the last day of dosing (Week 8). Beginning Week -4, subjects will receive ivacaftor 
(Kalydeco) as the study drug. 
9.2
Exclusion Criteria
Subjects who meet any of the following exclusion criteria will not be eligible.
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, a
x
history of cirrhosis with portal hypertension and/or 
x
history of risk factors for Torsades 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, or intracranial trauma], and autonomic neuropathy). 
2. Any of the following abnormal laboratory values at the Screening Visit:
x
Hemoglobin <10 g/dL
x
Abnormal liver function defined as any 2 or more of the following:  
o
 × upper limit of normal (ULN) aspartate aminotransferase (AST), 
o
 × ULN alanine aminotransferase (ALT), 
o
 × ULN gamma-glutamyl transpeptidase (GGT),  
o
 × ULN alkaline phosphatase, or  
o
 × ULN total bilirubin
x
$EQRUPDOOLYHUIXQFWLRQGHILQHGDVDQ\LQFUHDVHRI× ULN AST or ALT
x
Abnormal renal function defined as JORPHUXODUILOWUDWLRQUDWH mL/min/1.73 m2
(calculated by the Modification of Diet in Renal Disease Study Equation)32,33 for 


Protocol VX14-661-109, Version 4.0
Page 31 of 81
Vertex Pharmaceuticals Incorporated
VXEMHFWV years of age DQG mL/min/1.73 m2 (calculated by the 
Counahan-Barratt equation)34 for subjects aged 12 to 17 years (inclusive). 
3. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in 
therapy (including antibiotics) for pulmonary disease within 4 weeks before Week -4 
(first dose of study drug for the Ivacaftor Run-in Period). 
4. A 12-lead ECG demonstrating QTc >450 msec at the Screening Visit. 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 of solid organ or hematological transplantation. 
6. 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 or if there is documentation of 
bilateral lens removal (Section 11.7.8).
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 study drug (including studies 
investigating lumacaftor [VX-809] or VX-661) within 30 days of the Screening Visit. 
x
A washout period of 5 terminal half-lives of the previous investigational study drug 
or 30 days, whichever is longer, must elapse before the Screening Visit. The duration 
of the elapsed time may be longer if required by local regulations.  
x
Subjects enrolled in open-label extension studies of ivacaftor are not excluded from 
enrollment.
x
Ongoing participation in a noninterventional study (including observational studies 
and studies requiring assessments 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 as defined in Table 9-1.
10. Pregnant and nursing females (females of childbearing potential must have a negative 
pregnancy test at Screening and Week -4 Visits).
11. 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 enrolled in the study provided that 
x
the adult lives independently of and does not reside with the study staff member. 
x
the adult participates in the study at a site other than the site at which the family 
member is employed.


Protocol VX14-661-109, Version 4.0
Page 32 of 81
Vertex Pharmaceuticals Incorporated
12. 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:  
x
The subject should have had 2 respiratory tract cultures negative for these organisms 
within the past 12 months, with no subsequent positive cultures. 
x
These 2 respiratory tract cultures should have been separated by at least 3 months. 
x
One of these 2 respiratory tract cultures should have been obtained within the past 
6 months. 
9.3
Study Restrictions
9.3.1
Dietary Restrictions/Prohibited Medications
Prohibited medications and certain foods are not allowed in this study (Screening Period 
through Safety Follow-up Visit) while subjects are receiving study drug (Table 9-1). Both 
ivacaftor and VX-661 are metabolized predominantly via the hepatic enzymatic pathway 
utilizing CYP3A4. Therefore, the use of known inducers and inhibitors of CYP3A, which 
have the potential to significantly alter the exposure of VX-661 and ivacaftor, will be 
restricted in this study. 
A nonexhaustive list of study prohibitions and cautions for food and medication will be 
provided in the Study Reference Manual. 


Protocol VX14-661-109, Version 4.0
Page 33 of 81
Vertex Pharmaceuticals Incorporated
Table 9-1 
Study Restrictions
Restricted Medication/Food
Study Period
Screening Period
Ivacaftor Run-in and Active 
Comparator Treatment Period
Certain fruits and fruit juices 
(Grapefruit, grapefruit juice, 
Seville oranges, marmalade)
None allowed within 14 days before 
the first dose of the study drug 
(Week -4)
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 
(Week -4)
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 
(Week -4)
None allowed through the Safety 
Follow-up Visit
Commercially available ivacaftor 
(Kalydeco)
Permitted during the Screening 
Period but none allowed after the 
first dose of the study drug 
(Week -4)
None allowed through the Safety 
Follow-up Visit
Commercially available CFTR 
modulators other than ivacaftor 
(Kalydeco)
None allowed within 30 days before 
the Screening Visit.
None allowed through the Safety 
Follow-up Visit
CYP: cytochrome P450.
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 
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 enrolled into the study, details of prior medication will only be documented in 
the subjects' source documents.
x
Subjects must remain on a stable medication (and supplement) regimen for their CF from 
28 days before Week -4 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 Week -4. Subjects must not initiate long-term treatment with new 
medication from 28 days before Week -4 through the Safety Follow-up Visit unless it is 
discussed and approved by the Vertex medical monitor. Guidelines for stable medication 
regimens for CF are as follows:
o
Subjects who are taking daily inhaled tobramycin or other chronically inhaled 
antibiotics should remain on that regimen throughout the study. 
o
Subjects who are on inhaled cycling antibiotics should continue on their prior 
schedule. The timing of the first dose of study drug should be synchronized as closely 
as possible to the first day of inhaled cycling antibiotics in the cycle.


Protocol VX14-661-109, Version 4.0
Page 34 of 81
Vertex Pharmaceuticals Incorporated
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.
x
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.
x
Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments 
performed according to the guidelines provided in Section 11.6.1.
x
Concomitant use of medications known to prolong the QT interval should be used with 
caution during the study, as the effect of VX-661 in combination with ivacaftor on the 
QT interval has not been evaluated in a thorough QT study. Consideration should be 
given to 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 as outlined in Section 8.1.5, provided the subject has not withdrawn consent.  
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 and return for all scheduled visits. 
A subject will be withdrawn from study treatment for any of the following reasons: 
x
A female subject or a female partner of a male subject has a confirmed pregnancy.
x
A subject’s treatment is unblinded by the investigator.
A subject may be withdrawn from study treatment after a discussion between the investigator 
and the medical monitor for any of the following reasons: 
x
A subject develops a medical condition that requires prolonged concomitant therapy with 
a prohibited medication or prolonged interruption of the study drug. 


Protocol VX14-661-109, Version 4.0
Page 35 of 81
Vertex Pharmaceuticals Incorporated
x
A subject develops a life-threatening AE or a serious adverse event (SAE) that places 
him/her at immediate risk, and discontinuation of study treatment deemed necessary.
x
A subject is noncompliant with study requirements. 
x
A subject has an increase in transaminases (ALT or AST) according to evaluations and 
management described in Section 11.7.7.
x
A subject has an increase in QTc according to evaluations and management described in 
Section 11.7.4.
x
A subject develops a cataract or lens opacity.
Subjects who discontinue study treatment early should continue to return for assessments, as 
described in Section 8.1.5.
9.6
Replacement of Subjects
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug 
treatment periods (Ivacaftor Run-in Period and Active Comparator Treatment Period) may be 
replaced at Vertex's discretion.
10
STUDY DRUG ADMINISTRATION AND MANAGEMENT
Study drug refers to VX-661/ivacaftor, ivacaftor, and placebo tablets visually matching the 
VX-661/ivacaftor and ivacaftor tablets.
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 Ivacaftor Run-in Period, subjects 
will receive ivacaftor 150 mg q12h from the Week -4 Visit through the evening of Day -1 
(1 day prior to the Day 1 Visit) (Table 10-1). During the Active Comparator Treatment 
Period, subjects will receive randomized study treatment from randomization through the 
evening of the day before the Week 8 Visit. Subjects will receive the same number of tablets 
each day to maintain the blind during the Active Comparator Treatment Period (Table 10-2). 
Table 10-1 
Study Drug Administration – Ivacaftor Run-in Period
Treatment Arm
Time
Drug(s) and Dose(s) Administered
Route of Administration
ivacaftor
AM
IVA 150-mg tablet
oral
PM
IVA 150-mg tablet
oral
AM: morning; IVA: ivacaftor; PM: evening. 


Protocol VX14-661-109, Version 4.0
Page 36 of 81
Vertex Pharmaceuticals Incorporated
Table 10-2 
Study Drug Administration - Active Comparator Treatment Period
Treatment Arm
Time
Drug(s) and Dose(s) Administered
Route of Administration
VX-661/ivacaftor
AM
VX-661 100-mg/IVA 150-mg fixed-dose tablet
IVA matching placebo tablet
oral
PM
IVA 150-mg tablet
oral
ivacaftor
AM
VX-661/IVA matching placebo tablet
IVA 150-mg tablet
oral
PM
IVA 150-mg tablet
oral
AM: morning; IVA: ivacaftor; PM: evening.
Study drug should be administered within 30 minutes before 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 Ivacaftor Run-in Period and the Active Treatment Comparator 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. At the Week -4 Visit, all subjects will be observed for 1 hour after the morning dose of 
study drug. At the Day 1 Visit, all subjects will be observed for 6 hours after the morning 
dose of study drug. 
4. The date, amount taken, and time of study drug administration, including whether food 
was taken with each dose, will be recorded for 2 days before PK sample collection and on 
the days of PK sample collection.
5. On days of scheduled visits, 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.  
6. If a subject's scheduled visit is to occur in the afternoon, the following guidelines must be 
used: 
x
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.


Protocol VX14-661-109, Version 4.0
Page 37 of 81
Vertex Pharmaceuticals Incorporated
x
If the dose in the clinic will be more than 6 hours after the subject's scheduled 
morning dose, the subject should take the morning dose at home and the evening dose 
will be administered in the clinic. In this event, all assessments will be collected 
relative to the evening dose.
7. For visits after the Week -4 Visit, subjects will be instructed to bring all used and unused 
study drug to the site; study drug will be dispensed at each visit, as appropriate.
8. At the Week 8 Visit, the morning dose of study drug will NOT be administered. The last 
dose of study drug will be the evening dose administered the day before the Week 8 
Visit.
10.3
Method of Assigning Subjects to Treatment Groups
Approximately 160 subjects will be stratified by age at the Screening Visit (<18 versus 
 years of age), type of mutation on the second CFTR allele (R117H versus other allowed 
mutations; Section 16), and percent predicted FEV1 severity determined at the end of the 
Ivacaftor Run-LQ3HULRGYHUVXVDQGWKHQUDQGRPL]HGWRUHFHLYHHLWKHUWKH
VX-661/ivacaftor combination therapy or ivacaftor monotherapy during the Active
Comparator Treatment Period. 
An interactive web response system (IWRS) will be used to assign subjects to study 
treatment, as well as to ensure randomization of approximately 15% of subjects with an 
R117H mutation on the second CFTR allele. Detailed instructions for randomization will be 
provided separately.  
10.4
Dose Modification for Toxicity
Neither the dosage of individual study drugs nor the combination therapy can be altered, but 
the investigator can interrupt or stop treatment with all study drugs.
10.5
Study Drug Interruption
If study drug dosing must be interrupted for more than 72 hours, the medical monitor must be 
notified. In these instances, study drug dosing may only resume after approval by the medical 
monitor. Specific instructions for interruption for elevated LFT levels and elevated QTc 
levels are provided in Section 11.7.7 and Section 11.7.4, respectively. 
10.6
Missed Doses
If a subject misses a dose and remembers 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,
x
if the morning dose of study drug should have been taken at approximately 08:00, and the 
subject remembers at 12:00 that he/she forgot to take his/her dose, he/she should take the 
dose with food as soon as possible. 
x
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. 


Protocol VX14-661-109, Version 4.0
Page 38 of 81
Vertex Pharmaceuticals Incorporated
10.7
Packaging and Labeling
Study drug tablets will be supplied in blister cards by Vertex. Study drug cards will be 
provided and replaced via the IWRS. A detailed study drug dispensation plan will be 
provided in the Pharmacy Manual. 
Study drug labeling will be in compliance with applicable local and national regulations.
10.8
Study Drug Supply, Storage, and Handling
VX-661/ivacaftor (100 mg/150 mg) and matching placebo will be supplied as light yellow 
film-coated tablets of similar size and appearance containing 100 mg VX-661/150 mg 
ivacaftor and 0 mg VX-661/0 mg ivacaftor, respectively.  
Ivacaftor (150 mg) and matching placebo will be supplied as light blue film-coated tablets of 
similar size and appearance containing 150 mg ivacaftor and 0 mg ivacaftor, respectively.
Blister cards must be stored at room temperature according to Table 10-3 and to the 
instructions provided in the Pharmacy Manual. While at the clinical site, the investigator, or 
an authorized designee (e.g., a licensed pharmacist), will ensure that all investigational 
product is stored in a secured area, under recommended study conditions, and in accordance 
with applicable regulatory requirement. To ensure adequate records, all study drugs will be 
accounted for as detailed in Section 10.9.
Instructions regarding the storage and handling of study drug after dispensation to subjects 
will be provided to sites in the Pharmacy Manual. 
Table 10-3 
Identity of Study Drugs, Dosage, and Storage 
Drug Name
Strength/Formulation/Route
Dosage
Storage Condition
VX-661/ivacaftor 
fixed-dose tablet
100-mg/150-mg tablet; oral
100 mg/
150 mg, morning dose
&)ZLWK
excursions to 30°C (86°F)
Ivacaftor
150-mg tablet, oral
150 mg, morning and 
evening dose
&)ZLWK
excursions to 30°C (86°F)
VX-661/ivacaftor 
matching placebo
0-mg/0-mg tablet; oral
0 mg/
0 mg, morning dose
&)ZLWK
excursions to 30°C (86°F)
Ivacaftor, matching 
placebo
0-mg tablet, oral
0 mg, morning dose
&)ZLWK
excursions to 30°C (86°F)
10.9
Drug Accountability
The pharmacist or designated site staff will maintain records documenting the dates and 
amounts of  
x
study drug received,  
x
study drug dispensed to the subjects, and  
x
study drug returned by the subjects.  


Protocol VX14-661-109, Version 4.0
Page 39 of 81
Vertex Pharmaceuticals Incorporated
Subjects will be instructed to return all used, partially used, and full study drug blister cards 
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 verify 
study drug records and inventory throughout the study. 
10.10
Disposal, Return, or Retention of Unused Drug
The site staff or pharmacy personnel will retain all materials returned by the subjects until the 
site 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.
Procedures for destruction or return of the study drug will be detailed in the Pharmacy 
Manual.
10.11
Compliance
To ensure treatment compliance, the investigator or designee will supervise all study drug 
dosing that occurs at the site. At each visit, site personnel will review that the subject is 
compliant with study drug dosing and remind the subject of study drug dosing requirements. 
Compliance will also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should contact the medical monitor to discuss discontinuation of the 
subject from the study treatment.
10.12
Blinding and Unblinding
This is a double-blind study. 
10.12.1
Blinding
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: 
x
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
x
Any site personnel for whom this information is important to ensure the safety of the 
subject and their fetus in the event of a pregnancy 
x
Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy SAE 
processing and reporting regulations 
x
Unblinded statistician preparing the final (production) randomization list who is not part 
of the study team 
x
Vertex Clinical Operations IWRS management
x
Vertex Clinical Supply Chain


Protocol VX14-661-109, Version 4.0
Page 40 of 81
Vertex Pharmaceuticals Incorporated
x
IDMC
x
Vendor preparing the unblinded analysis for the IDMC 
x
Vendor analyzing PK samples
x
Vertex personnel or vendor conducting the population PK analysis 
x
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 corresponding active control. 
Therefore, during the conduct of the study, the Vertex study team will not have access to the 
postdose spirometry data during the Active Comparator Treatment Period. The vendor for 
central reading of the spirometry data will only send the blinded spirometry files (blinded 
treatment group with dummy values for all the spirometry assessment after baseline in the 
Active Comparator Treatment Period) to Vertex to be used for developing the statistical 
programs. Furthermore, subjects and their caregivers should not be informed of their 
study-related spirometry results during the Active Comparator Treatment Period regardless 
of whether the subject has prematurely discontinued treatment.
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 treatment or corresponding active 
control. Therefore, during the conduct of the study, the Vertex study team will not have 
access to the postdose sweat chloride data; dummy data will be used to develop statistical 
programs. During the process of locking the clinical database and after all study visits have 
been completed, treatment-blinded access to the sweat chloride data will be provided to a 
small group of individuals who are not involved in the study. 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.
10.12.2
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 should 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 that it is not necessary to 
unblind immediately, they will first attempt to contact the medical monitor to discuss and 


Protocol VX14-661-109, Version 4.0
Page 41 of 81
Vertex Pharmaceuticals Incorporated
agree to the need for unblinding. If investigators have tried but are unable to reach the 
medical monitor, they should 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.
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document.
In addition, the Vertex Medical Information Call Center 
 will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the Vertex 
medical monitor or appropriate backup.  
If a subject's treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the Vertex medical monitor should be notified within 24 hours of the 
unblinding event. The reason and the date of the unblinding should be documented clearly in 
the subject's study file. Information about the treatment assignment obtained from the 
unblinding will be maintained in a secure location with controlled access and will not be 
shared with the sponsor (Vertex), contract research organization (CRO), or any site personnel 
(other than the physician treating the subject). In addition, the investigator will consider 
whether the clinical event that prompted unblinding will be considered an SAE, according to 
the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to Vertex GPS 
or designee, per Section 13.1.2.
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. 
11
ASSESSMENTS
11.1
Timing of Assessments
The timing of assessments is shown in Table 3-1 and Table 3-2.
The CFQ-R questionnaire must be performed before any other assessment at the clinic visits 
when it is required. For the remaining assessments, the following assessments must be 
performed in the following order when more than 1 assessment is required at a particular 
time point:
3. standard 12-lead ECG recordings  
4. vital signs and pulse oximetry
5. spirometry
6. sweat chloride
7. safety laboratory assessments (including blood draws) 
8. PK sampling


Protocol VX14-661-109, Version 4.0
Page 42 of 81
Vertex Pharmaceuticals Incorporated
Note: where repeats of the same assessment are required at a given visit, if study drug is not 
administered on the day of the visit (for any reason, including study drug interruption or 
premature discontinuation of study drug), only 1 set of assessments will be collected 
(Table 3-2).
11.1.1
Informed Consent/Assent
Each subject of age of consent (per local requirements) must sign and date a study-specific 
ICF before any study-specific procedures can be performed. Subjects not of age of consent 
must assent, if applicable per local requirements, to participate in the study, and the subject's 
parent or legal guardian must sign and date a study-specific ICF before any study-specific 
procedures can be performed. The consent forms will comply with all applicable regulations 
governing the protection of human subjects. An ICF and Assent Form, approved by Vertex 
and the site's institutional review board (IRB) or ethics committee, must be used. 
11.1.2
Assigning Subject Number
Once a subject has signed an ICF or assent, if applicable, a subject number will be assigned. 
The subject will retain this number for the entire study. Detailed instructions on assigning 
subject numbers will be provided in the Study Reference Manual. If a subject is rescreened, 
the subject retains the original subject number.
11.2
Subject and Disease Characteristics
Subject and disease characteristics include the following: demographics, medical history, 
height, and weight. 
Medical history will be elicited from each subject during screening. Based on the medical 
history, the subject will be assessed for any disqualifying medical conditions as specified in 
the inclusion and exclusion criteria. The medical history shall include a complete review of 
systems, past medical and surgical histories, and any allergies.
11.3
Total Blood Volume
Total blood volume will be outlined in the laboratory manual.  
11.4
Pharmacokinetics
11.4.1
Blood Sampling
Blood samples will be collected as shown in Table 3-2.
At the visits and time points indicated in Table 3-2, blood samples will be collected for the 
determination of the concentrations of VX-661, M1-661, ivacaftor, and M1-ivacaftor. Blood 
samples collected before dosing must be collected within 60 minutes before dosing. The 
acceptable windows for PK sampling time points are detailed in Table 11-1.
Samples from the PK sampling will be kept frozen by Vertex or its designee until all analyses 
have been completed and then disposed of according to Vertex or designee standard 
operating procedures. 
For each visit with a PK blood draw, a record of study drug administration will be collected 
as described in Section 10.2. The collection date and time that each PK blood sample is 
drawn will also be recorded.


Protocol VX14-661-109, Version 4.0
Page 43 of 81
Vertex Pharmaceuticals Incorporated
Details on sample collection, processing, and shipping will be provided in a separate 
protocol-specific Laboratory Manual.
Table 11-1 
Acceptable PK Sampling Windows
Sampling Time
Time From Sampling Schedule Allowed
Predose
Within 60 minutes before study drug dose on PK sampling days
2, 3, 6, and 8 hours after study drug 
dosing
± 30 minutes
PK: pharmacokinetic.
11.4.2
Processing and Handling of Pharmacokinetic Samples
Detailed procedures for the collection of blood samples, and further procedures for 
processing and handling of samples for PK analysis, will be provided in the Laboratory 
Manual. The shipment address and assay laboratory contact information will be provided to 
the investigational site before initiation of the study.
11.4.3
Bioanalysis
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee standard operating procedures. A description of the assay methods 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 
ivacaftor 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 ivacaftor. These data will be used for exploratory purposes 
and may not be included in the clinical study report. 


Protocol VX14-661-109, Version 4.0
Page 44 of 81
Vertex Pharmaceuticals Incorporated
11.6
Efficacy
11.6.1
Spirometry
Spirometry will be performed according to the ATS/ERS guidelines20 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 
x
withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment;
x
withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before 
the spirometry assessment; and
x
withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide 
[Spiriva®]) for more than 24 hours before the spirometry assessment.
During the treatment periods (both Ivacaftor Run-in Period and the Active Comparator 
Treatment Period), spirometry assessments must be performed before dosing. In adolescent 
subjects (<18 years of age at the Screening Visit) additional postdose spirometry assessments 
on Day 1 and Day 15 will be performed at 2 and 4 hours after the morning dose as a safety 
assessment. A window for ± 15 minutes will be allowed around the nominal times for all 
postdose spirometry assessments.
During the Screening Period, spirometry assessments may be performed pre- or 
postbronchodilators. At all other visits, all spirometry assessments should be performed 
“prebronchodilator.” 
In the event that a subject does not withhold his/her bronchodilator(s), spirometry should be
performed according to the following: 
During the Ivacaftor Run-in Period 
x
If a subject's Week -4 spirometry is prebronchodilator, but, on a subsequent visit during 
the Ivacaftor Run-in Period, the subject does not withhold bronchodilator use, a 
postbronchodilator spirometry will be obtained for that visit only, and the visit will not be 
rescheduled.
x
If, on Week -4, the subject does not withhold his/her dose of bronchodilator, spirometry 
should be performed postbronchodilator, and subsequent spirometric measurements 
during the Ivacaftor Run-in Period (according to the schedule of assessments detailed in 
Table 3-2) should be performed postbronchodilator. 
During the Active Comparator Treatment Period
x
If a subject's Day 1 spirometry is prebronchodilator, but, on a subsequent visit during the 
Active Comparator Treatment Period, the subject does not withhold bronchodilator use, a 
postbronchodilator spirometry will be obtained for that visit only, and the visit will not be 
rescheduled.


Protocol VX14-661-109, Version 4.0
Page 45 of 81
Vertex Pharmaceuticals Incorporated
x
If, on Day 1, the subject does not withhold his/her dose of bronchodilator, spirometry 
should be performed postbronchodilator, and all subsequent spirometric measurements 
during the Active Comparator Treatment Period (according to the schedule of 
assessments detailed in Table 3-2) should be performed postbronchodilator. 
x
Spirometry assessments that occur after dosing (postdose) on Day 1 and Day 15 (for 
subjects <18 years of age at the Screening Visit) should be performed prebronchodilator. 
If Day 1 and/or Day 15 predose spirometry is performed postbronchodilator, the subject 
should withhold any further bronchodilator use until after completion of the 4-hour 
postdose spirometry assessment on that day. 
x
For both Ivacaftor Run-in Period and the Active Comparator Treatment Period, each 
spirometry assessment will be recorded in the source documents as pre- or 
postbronchodilator. 
All sites will be provided with spirometers to be used for all study assessment. Spirometry 
data will be transmitted to a centralized spirometry service for quality review.
Subjects and their parent/caregiver should not be informed of their study-related spirometry 
results during the Active Comparator Treatment Period (Day 1 through Week 8), regardless 
of whether the subject prematurely discontinues treatment.
The parameters listed below will be normalized using the standards of Wang et al30 (for 
female subjects aged 12 to 15 years [inclusive] and male subjects aged 12 to 17 years 
[inclusive]) or Hankinson et al29 (for female subjects aged 16 years and older and male 
subjects aged 18 years and older).  
x
FEV1 (L)
x
Forced vital capacity (FVC) (L)
x
FEV1/FVC (ratio)
x
Forced expiratory flow (L/s) 
11.6.2
Sweat Chloride Testing
The sweat chloride test is a standard diagnostic tool for CF, serving as a biomarker of CFTR 
activity. Collection of sweat samples will be performed at visits specified in Table 3-1 and 
Table 3-2, using an approved collection device. Sweat samples will be sent to a central 
laboratory for testing and interpretation of results. Individual sweat chloride test results will 
not be disclosed to the study sites. Specific instructions for collection, handling, processing, 
and shipping of sweat chloride samples to the central laboratory will be provided separately.
The sweat chloride collection on dosing days should occur before the morning dose of the 
study drugs. At each time point, 2 samples will be collected, 1 from each arm (left and right). 
Additionally, sweat chloride collection will be performed at the Screening Visit and the ETT 
Visit. For subjects using sweat chloride values documented in their medical records to 
establish eligibility, the sweat chloride test at the Screening Visit is optional. Collection of 
sweat chloride will not overlap with any other study assessments.


Protocol VX14-661-109, Version 4.0
Page 46 of 81
Vertex Pharmaceuticals Incorporated
11.6.3
Cystic Fibrosis Questionnaire-Revised
Subjects will be asked to complete the CFQ-R in their native language.26,35 The CFQ-R will
be completed before the start of any other assessments, as noted in Table 3-1 and Table 3-2.
At all visits, subjects who are 12 and 13 years of age at Week -4 will complete the CFQ-R
Child version themselves, and their parents/caregivers will complete the CFQ-R Parent 
version, regardless of whether the subject subsequently turns 14 years of age during the 
study. Subjects 14 years of age and older at Week -4 will complete the Adolescent/Adult 
version of the questionnaire themselves at all visits. The questionnaires provide information 
about demographics; general quality of life, school, work, or daily activities; and symptom 
difficulties (pertaining to CF). Copies of the CFQ-R used in this study will be provided in the 
Study Reference Manual. Validated translations27,28 of the CFQ-R will be provided for 
participating centers in non-English-speaking countries.


Protocol VX14-661-109, Version 4.0
Page 47 of 81
Vertex Pharmaceuticals Incorporated
11.7
Safety
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of 
vital signs, ECGs, pulse oximetry, spirometry, PEs, and ophthalmologic exams. 
11.7.1
Adverse Events
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE electronic 
case report form completion guidelines for investigators as well as training will be provided.
11.7.2
Clinical Laboratory Assessments
Blood and urine samples will be analyzed at a central laboratory, with the exception of urine 
pregnancy tests, which are performed and analyzed at the site. Blood samples requiring a 4-
hour fast will be collected on Day 1, Week 8, the ETT, and the Safety Follow-up Visit. 
Fasting is not required at other time points unless specified in the assessment table. At the 
Week -4 and Day 1 Visits, blood samples will be collected before the first dose of the study 


Protocol VX14-661-109, Version 4.0
Page 48 of 81
Vertex Pharmaceuticals Incorporated
drug. At all other scheduled visits, these samples will be collected at any time during the 
visit, relative to the order of assessments indicated in Section 11.1and according to the 
schedule of assessments 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 (Section 13.1.1). 
The safety laboratory test panels are shown in Table 11-2.
Table 11-2 
Safety Laboratory Test Panels 
Serum Chemistry
Hematology
Urinalysisa
Glucose
Blood urea nitrogen
Creatinine
Sodium
Potassium
Calcium
Chloride
Magnesium
Bicarbonate
Inorganic phosphate 
Total bilirubin, direct bilirubin
Alkaline phosphatase
Aspartate aminotransferase 
Alanine aminotransferase
Lactate dehydrogenase
Gamma-glutamyl transpeptidase
Total protein
Albumin
Creatine kinase
Amylase
Lipase
Hemoglobin
Erythrocytes
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume
Reticulocytes
Platelets
Leukocytes
Differential (absolute and percent):
Eosinophils
Basophils
Neutrophils
Lymphocytes 
Monocytes
Coagulation Studies
Activated partial thromboplastin time 
Prothrombin time
Prothrombin time International 
Normalized Ratio
Leukocyte esterase
Nitrite
Urobilinogen 
Urine protein 
pH
Urine blood
Specific gravity 
Urine ketones 
Urine bilirubin 
Urine glucose 
Vitamin Levels
Vitamin levels A, D, E, K, B12
Lipid Panel
Total cholesterol, triglycerides
Low-density lipoprotein
High-density lipoprotein
a
If urine is positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of urine will 
be performed for leukocytes, erythrocytes, crystals, bacteria, and casts.
3UHJQDQF\ȕ-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 3-2. The urine pregnancy test at the Week -4 Visit must be negative before the first 
dose of study drug.  


Protocol VX14-661-109, Version 4.0
Page 49 of 81
Vertex Pharmaceuticals Incorporated
Follicle-stimulating Hormone (Screening Period only): Blood sample for FSH will be 
measured for any potentially postmenopausal female with at least 12 months of continuous 
spontaneous amenorrhea. 6HUXP)6+OHYHOVPXVWEH40 mIU/mL to be considered 
postmenopausal. 
CFTR Genotype (Screening Period only): CF genotyping will be performed on all subjects to 
confirm the genotype documented in the subject's medical record. The results of the 
confirmatory genotype sample obtained at the Screening Visit must be reviewed before 
enrollment. In patients with confirmed R117H mutation, linkage to poly-T track 
polymorphisms will also be determined. Specific instructions will be provided in the 
Laboratory Manual.
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 PE of all body systems and vital signs assessment will be performed at the Screening and 
Week -4 Visits (see 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; 
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 (oral), pulse rate, and 
respiration rate. These will be assessed following a 5-minute rest in the seated or supine 
position. 


Protocol VX14-661-109, Version 4.0
Page 50 of 81
Vertex Pharmaceuticals Incorporated
11.7.4
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 ± 15 minutes will be 
allowed around the nominal times for all postdose ECG assessments. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of 
all ECGs will adhere to the following guidelines:
x
The subject will be instructed to rest in the supine position for at least 5 minutes before 
having an ECG performed. 
x
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 
EDVHOLQHRUDQDEVROXWH47F)YDOXHLV 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 PVHFIURPEDVHOLQHRU msec), a single ECG will be repeated at least hourly until 
QTcF values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement. 
If the QTcF value remains above the threshold value (>45 msec from the average of the 
3 SUHGRVHYDOXHVRQ'D\RUPVHFRQUHSHDWHGPHDVXUHPHQWRULVQRWHGRQ
>2 occasions with no identified alternative etiology for the increased QTcF study drug, then 
discontinuation from study treatment may be required after discussion with the medical 
monitor. 
Subjects who discontinue treatment 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 ivacaftor on conception, 
pregnancy, and lactation in humans are not known. Neither VX-661 nor ivacaftor showed 
any genotoxic potential in a standard battery of in vitro (Ames test, Chinese hamster ovary 
cell chromosomal aberration) and in vivo (mouse micronucleus) studies. VX-661 and 
ivacaftor were each found to be nonteratogenic in reproductive toxicology studies in rats and 
rabbits.18,19 Subjects should follow the contraception requirements outlined in this study 
protocol. The effects of VX-661 monotherapy or in combination with ivacaftor 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.


Protocol VX14-661-109, Version 4.0
Page 51 of 81
Vertex Pharmaceuticals Incorporated
At this stage in the development of VX-661 in combination with ivacaftor, participation in 
this study requires a commitment from the research subject and his/her partner to use at least 
1 effective method of birth control. Acceptable methods of contraception for participants of 
this study and their partners are listed below. Methods of contraception should be in 
successful use from signing of consent, approximately 28 days, before the first dose of study 
drug (unless otherwise noted), and until 90 days following the last dose of study drug. 
Contraception for the couple is waived for the following:
x
True abstinence for the subject, when this is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
x
If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented 
through examination of a semen specimen or by demonstration of the absence of the vas 
deferens by ultrasound or medical record before the first dose of study drug. 
x
If the female is of non-childbearing potential, per the following: 
o
Postmenopausal: spontaneous amenorrhea for at least 12 consecutive months and 
serum FSH level  mIU/mL at Screening
o
Documented hysterectomy or a bilateral oophorectomy/salpingo-oophorectomy 
o
Has not achieved menarche (has not had her first menstrual period). Females who fall 
into this category are considered not to be of childbearing potential only as long as 
they have not had their first menstrual period. If a female achieves menarche during 
the study, she will need to provide consent for compliance (proper method of 
contraception or abstinence).  
x
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: 
x
Vasectomy 6 months or more previously, with a documented negative postvasectomy 
semen analysis for sperm
x
Condom and spermicide  
o
In countries where spermicide is not available, condom without spermicide will be 
considered acceptable.
o
Local regulations may require use of an additional acceptable method of 
contraception.  


Protocol VX14-661-109, Version 4.0
Page 52 of 81
Vertex Pharmaceuticals Incorporated
Acceptable contraceptive methods for female subjects include the following: 
x
Bilateral tubal ligation performed at least 6 months previously 
x
Continuous use of an intrauterine device (non-hormone-releasing) for at least 90 days 
before the first dose of study drug 
x
Barrier contraception (such as diaphragm, cervical cap, or female condom) and 
spermicide 
o
In countries where spermicide is not available, barrier contraception without 
spermicide will be considered acceptable.
o
Local regulations may require use of an additional acceptable method of 
contraception.  
x
NOTE: Hormonal contraceptives will not be considered as an effective method; however, 
female subjects are not required to discontinue hormonal contraceptives. 
Acceptable contraceptive methods for female partners of male subjects: 
x
Bilateral tubal ligation performed at least 6 months previously 
x
Continuous use of an intrauterine device for at least 90 days before the first dose of study 
drug 
x
Barrier contraception (such as diaphragm, cervical cap, or female condom) and 
spermicide
o
In countries where spermicide is not available, condom without spermicide will be 
considered acceptable.  
o
Local regulations may require use of an additional acceptable method of 
contraception. 
x
Hormonal contraceptives, if successfully used for at least 60 days before the first dose of 
study drug  
Additional notes:
x
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. 
x
A female condom cannot be used with male condom (as a double method of 
contraception) due to risk of tearing. 
x
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. 
x
If applicable, additional contraception requirements may need to be followed according 
to local regulations and/or requirements. 


Protocol VX14-661-109, Version 4.0
Page 53 of 81
Vertex Pharmaceuticals Incorporated
x
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. 
x
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. 
x
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. 
x
Female subjects should not nurse a child from the start of study drug dosing through 
90 days following the last dose of study drug. 
x
Unique situations that may not fall within the above specifications should be discussed 
with the medical monitor.
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. 
If a female subject or the female partner of a male subject becomes pregnant while 
participating in the study, study drug must be permanently discontinued immediately. For 
male subjects, study drug does not need to be permanently discontinued if the female 
partner's pregnancy resulted from donated sperm or sperm banked before study drug 
exposure (Section 11.7.5.1). 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 study drug, the subject or partner will be followed until 
the end of the pregnancy and the infant will be followed for 1 year after the birth, provided 
informed consent is obtained. A separate ICF will be provided to explain these follow-up 
activities. Pregnancy itself does not constitute an AE.
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. 


Protocol VX14-661-109, Version 4.0
Page 54 of 81
Vertex Pharmaceuticals Incorporated
11.7.7
Liver Function Test Parameters
Liver Function Testing 
Liver function testing (ALT, AST, GGT, ALP, direct bilirubin, and total bilirubin) must be 
performed as noted in Table 3-2 for serum chemistry, while subjects are receiving study drug 
treatment and at the Safety Follow-up Visit. These blood samples should be processed and 
shipped immediately per the Laboratory Manual. 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN and clinical 
symptoms must be followed closely, including repeat confirmatory testing performed by the 
central laboratory within 48 to 72 hours of the initial finding and subsequent close 
monitoring of ALT and AST levels, as clinically indicated. In addition, if ALT or AST is 
>5 × ULN, repeat follow-up levels must be obtained within 7 ± 2 days. 
If a subject cannot return to the site for liver function testing, a local laboratory may be used. 
Elevations in LFTs at the local laboratory must be reported immediately to the medical 
monitor, and the subject must have the tests repeated and sent to the central laboratory as 
soon as possible (ideally within 48 to 72 hours). 
Study Drug Interruption
Study drug administration must be interrupted immediately (prior to confirmatory testing), 
and the medical monitor must be notified, if any of the following criteria is met and 
confirmed with repeat testing:
x
ALT or AST >8 × ULN
x
ALT or AST >5 × ULN for more than 2 weeks
x
ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical 
jaundice 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression. 
If no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, or alcohol 
ingestion) for the elevated transaminases is identified, regardless of whether ALT or AST 
levels have improved, study 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 
PD\EHUHVXPHGRQFHWUDQVDPLQDVHVUHWXUQWREDVHOLQHRUDUH × ULN, whichever is higher. 
Approval of the medical monitor is required before resumption of study drug. Upon 
resumption of study drug, transaminases should be assessed weekly for 4 weeks. If a 
protocol-defined transaminase elevation occurs within 4 weeks of rechallenge with the study 
drug (with confirmation of the initial elevation by repeat testing within 48 to 72 hours), then 
the study drug must be permanently discontinued, regardless of the presumed etiology. 


Protocol VX14-661-109, Version 4.0
Page 55 of 81
Vertex Pharmaceuticals Incorporated
11.7.8
Ophthalmologic Examination
Subjects will undergo an ophthalmologic examination performed by a licensed 
ophthalmologist at screening, which includes 
x
measurement of best corrected distance visual acuity of each eye; 
x
measurement of lens refracting power following cycloplegia (e.g., autorefractor or 
ophthalmoscopy streak); and 
x
pharmacologically dilated examination of the lens with a slit lamp.
The screening ophthalmologic examination must be completed and the results reviewed 
before enrollment. 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 or if there is documentation of bilateral lens removal.
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 (Section 9.2). If a cataract or lens opacity is identified and 
determined to be clinically significant by the ophthalmologist after dosing, the subject and 
Vertex medical monitor will be notified. After discussion with the principal investigator, who 
collaborates with the Vertex medical monitor, the subject may elect to continue or 
discontinue study drug treatment. If the subject discontinues study drug treatment, the subject 
should complete the ETT Visit, all subsequent scheduled visits per Table 3-2, and the Safety 
Follow-up Visit (see Sections 8.1.4 and 8.1.5). If the subject continues study drug treatment, 
more frequent ophthalmologic monitoring should be considered. 
In addition to the Screening Visit, an ophthalmologic examination will be performed by a 
licensed ophthalmologist at the Safety Follow-up Visit or ETT Visit for the following 
subjects:
x
subjects <18 years of age at the Screening Visit who discontinue study drug treatment 
after receiving at least 1 dose of study drug, 
x
subjects <18 years of age at the Screening Visit who complete study drug treatment but 
do not enroll in a separate extension study of VX-661/ivacaftor within 28 days after the 
last dose of study drug. 
This examination may be completed at either the ETT Visit or Safety Follow-up Visit, but 
must be completed by the date of the Safety Follow-up Visit.  
Subjects \HDUVRIDJHDWWKH6FUHHQLQJ9LVLWDUHQRWUHTXLUHGWRFRPSOHWHRSKWKDOPRORJLF
examinations at the ETT Visit or Safety Follow-Up Visit.
Additional ophthalmologic examinations may be conducted at the discretion of the 
investigator. The medical monitor should be notified of any additional ophthalmologic 
examinations.
Subjects who have documentation of bilateral lens removal are not required to complete the 
ophthalmologic examination at the Safety Follow-up Visit or ETT Visit.




Protocol VX14-661-109, Version 4.0
Page 57 of 81
Vertex Pharmaceuticals Incorporated
12.2
Analysis Sets
Assignment of subjects to analysis sets will be done before the clinical data lock for the 
study.  
The All Subjects Set is defined as all subjects who were enrolled, randomized, or received at 
least 1 dose of study drug in either the Ivacaftor Run-in Period or the Active Comparator 
Treatment Period (i.e., all subjects in the study). This analysis set will be used in subject 
listings and disposition summary table unless otherwise specified. 
The Active Comparator Subjects Set includes all subjects randomized in the Active 
Comparator Treatment Period or dosed with at least 1 dose of blinded study drug. This 
analysis set will be used for specific disposition for the Active Comparator Treatment Period 
and subject listings related to the Active Comparator Treatment Period only. 
The Full Analysis Set (FAS) is defined as all randomized subjects who have received at least 
1 dose of blinded study drug during the Active Comparator Treatment Period. The FAS is to 
be used in efficacy analyses in which subjects will be analyzed according to their randomized 
treatment group.
The Safety Set, defined separately for the Ivacaftor Run-in Period and the Active Comparator 
Treatment Period, includes all subjects who received at least 1 dose of study drug in the 
corresponding treatment period. The Safety Set is to be used for all safety analyses in which 
subjects will be analyzed according to the treatment they received.
12.3
Statistical Analysis
The primary objective of this study is to evaluate the efficacy of VX-661 in combination with 
ivacaftor in subjects with CF who are heterozygous for the F508del mutation on the CFTR
gene and a second CFTR allele with a gating defect that is clinically demonstrated to be 
ivacaftor responsive. 
This section presents a summary of the planned statistical analyses of efficacy and safety for 
this study. The Vertex Biometrics department or a designated CRO will analyze the data 
derived from this study. Statistical Analysis System Version 9.2 or higher will be used to 
generate all statistical outputs (tables, figures, listings, and data sets).
Statistical analysis and presentation details will be provided in the SAP for the study. 
12.3.1
General Considerations
All individual subject data for subjects exposed to study drug will be presented in data 
listings.
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, SD, median, minimum value (min), and 
maximum value (max). 
Categorical variables will be summarized using counts and percentages.  
Baseline value, absolute change from baseline, and relative change from baseline will be 
defined separately for the Ivacaftor Run-in Period and the Active Comparator Treatment 
Period: 


Protocol VX14-661-109, Version 4.0
Page 58 of 81
Vertex Pharmaceuticals Incorporated
x
Baseline value:
o
Unless otherwise specified, baseline for the Ivacaftor Run-in Period will be defined as 
the most recent non-missing measurement (scheduled or unscheduled) collected prior 
to initial administration of Ivacaftor monotherapy. 
o
Unless otherwise specified, the baseline for the Active Comparator Treatment Period 
will be defined as the most recent non-missing measurement (scheduled or 
unscheduled) collected prior to initial administration of the VX-661/ivacaftor 
combination therapy, but no earlier than the measurement at Week -2. 
o
For spirometry, the baseline value used for the Active Comparator Treatment Period 
will be the average of the measurement at Week -2 and the measurement on Day 1 
predose. If a subject has an AE leading to an approved extension of the Ivacaftor 
Run-in Period, and the Week -2 spirometry assessment is between the start and end 
date (inclusive) of the AE, then the measurement on Day 1 predose will serve as 
baseline for the Active Comparator Treatment Period.
o
For ECG, the baseline will be defined as the average of the 3 pretreatment 
measurements at the first day of the corresponding treatment period. 
x
Change (absolute change) from baseline will be calculated as postbaseline 
value - baseline value.
x
Relative change from baseline will be calculated as (postbaseline value - baseline 
value)/baseline value.
The Treatment-emergent (TE) Period will be defined separately for the Ivacaftor Run-in 
Period and the Active Comparator Treatment Period: 
x
The TE Period for the Ivacaftor Run-in Period is defined as the first dose in the Ivacaftor 
Run-in Period to the earlier of the last day prior to the first dose of the Active Comparator 
Treatment Period or either the Safety Follow-up Visit or 28 days (inclusive) after the last 
dose for subjects who do not have Safety Follow-up Visit in the Ivacaftor Run-in Period.  
x
The TE Period for the Active Comparator Treatment Period is defined as the first dose of 
the Active Comparator Treatment Period to the Safety Follow-up Visit or 28 days 
(inclusive) after the last dose for subjects who do not have Safety Follow-up Visit in the 
Active Comparator Treatment Period. 
The TE Period will be used for all safety analyses in the corresponding treatment period.  
12.3.2
Background Characteristics
Subject disposition, demographic and baseline characteristics, prior and concomitant 
medications, study drug exposure and compliance, and other background characteristics will 
be summarized. Additionally, all subject data will be presented in subject data listings. No 
statistical hypothesis testing will be performed on background characteristics.


Protocol VX14-661-109, Version 4.0
Page 59 of 81
Vertex Pharmaceuticals Incorporated
12.3.2.1
Subject Disposition
Number and percentage of subjects in the following categories will be summarized separately 
for the Ivacaftor Run-in Period and the Active Comparator Treatment Period, as appropriate: 
x
All Subjects Sets
x
Dosed (Safety Set) in the Ivacaftor Run-in Period 
x
Completed treatment in the Ivacaftor Run-in Period
x
Prematurely discontinued the treatment during the Ivacaftor Run-in Period and the 
reasons for treatment discontinuation 
x
Prematurely discontinued the study during the Ivacaftor Run-in Period and the reasons 
for study discontinuation 
x
Active Comparator Subjects Set (Randomized or dosed) in the Active Comparator 
Treatment Period
x
Randomized in the Active Comparator Treatment Period 
x
Dosed (Safety Set) in the Active Comparator Treatment Period
x
Randomized and dosed (FAS) in the Active Comparator Treatment Period 
x
Completed treatment in the Active Comparator Treatment Period
x
Prematurely discontinued the treatment during the Active Comparator Treatment Period 
and the reasons for treatment discontinuation 
x
Prematurely discontinued the study during the Active Comparator Treatment Period and 
the reasons for study discontinuation 
x
Completed study/Safety Follow-up Visit 
x
Prematurely discontinued the study after the Active Comparator Treatment Period and 
the reasons for study discontinuation 
x
Rollover to extension study 
12.3.2.2
Demographics and Baseline Characteristics
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized separately for the Ivacaftor Run-in Period and the Active Comparator Treatment 
Period. Protocol deviations/violations will be provided as a subject data listing only.  
The following demographics and baseline characteristics will be summarized: sex, race, 
ethnicity, age, weight, height, BMI, region, baseline percent predicted FEV1, baseline sweat 
chloride, and baseline score of CFQ-R respiratory domain. The summary will be based on the  
Safety Set for the Ivacaftor Run-in Period. For the Active Comparator Treatment Period, the 
summary will be based on the FAS.  


Protocol VX14-661-109, Version 4.0
Page 60 of 81
Vertex Pharmaceuticals Incorporated
12.3.2.3
Prior and Concomitant Medications
Medications used in this study will be coded by using the World Health Organization-Drug 
Dictionary Enhanced and categorized as the following:  
x
Prior medication: any medication that started before initial dosing of study drug in the 
Ivacaftor Run-in Period, regardless of when it ended. 
x
Concomitant medication during the Ivacaftor Run-in Period: medication continued 
or newly received at or after initial dosing of the study drug through the end of the TE 
Period for the Ivacaftor Run-in Period.  
x
Concomitant medication during the Active Comparator Treatment Period:
medication continued or newly received at or after initial dosing of study drug through 
the end of the TE Period of the Active Comparator Treatment Period. 
x
Post-treatment medication: medication continued or newly received beyond the TE 
Period of the Active Comparator Treatment Period.
A given medication can be classified as a prior medication, a concomitant medication 
(concomitant medication during the Ivacaftor Run-in Period and/or a concomitant medication 
during the Active Comparator Treatment Period), or a post-treatment medication; both prior 
and concomitant; both concomitant and post-treatment; or prior, concomitant, and post-
treatment. If a medication has a missing or partial missing start/end date or time and cannot 
be determined whether it was taken before initial dosing, concomitantly, or beyond the TE 
Period, it will be considered as prior, concomitant, and post-treatment.
Prior medications and concomitant medications in the Ivacaftor Run-in Period will be 
summarized descriptively based on the Safety Set in that period.  
Prior medications, concomitant medication in the Ivacaftor Run-in Period will be 
summarized descriptively again based on the FAS for the Active Comparator Treatment 
Period. Concomitant medications in the Active Comparator Treatment Period will also be 
summarized descriptively based on the FAS.  
Post-treatment medications will be listed for each subject.
12.3.2.4
Study Drug Exposure and Compliance
Study drug exposure and compliance will be summarized separately for the Ivacaftor Run-in 
Period and Active Comparator Treatment Period. Exposure to study drug (i.e., duration of 
treatment) will be summarized for the Safety Set for the Ivacaftor Run-in Period and the FAS 
for the Active Comparator Treatment Period in terms of duration of treatment a subject 
received (in days), defined as the last day minus the first day of study drug in the 
corresponding treatment period plus 1, regardless of any interruptions in dosing. Dosing 
compliance is calculated as the actual number of dosing occasions at which study drug was 
administered, as a percentage of the planned number of dosing occasions, for the 
corresponding treatment period. Dosing compliance will be summarized for the Safety Set 
for the Ivacaftor Run-in Period and for the FAS for the Active Comparator Treatment Period. 
Duration of treatment and dosing compliance will be summarized by means of descriptive 
summary statistics.




Protocol VX14-661-109, Version 4.0
Page 62 of 81
Vertex Pharmaceuticals Incorporated
x
Absolute change in the CFQ-R respiratory domain score from baseline through 
Week 8 in the Active Comparator Treatment Period: Analysis of this domain will be 
similar to that of the primary analysis of the primary efficacy endpoint, with the addition 
of the CFQ-R respiratory domain score at baseline as a covariate.
Adjustment for Multiple Comparisons
A hierarchical testing procedure will be used to control the Type I error for the multiple 
HQGSRLQWVWHVWHGDWĮ = 0.05. For a test at any step to be considered statistically significant 
within the testing hierarchy, it must be statistically significant, and all previous tests (if any) 
within the hierarchy must be statistically significant, at the 0.05 level. The testing hierarchy 
is as follows: 
1. Absolute change in percent predicted FEV1 from baseline through Week 8 
2. Relative change in percent predicted FEV1 from baseline through Week 8 
3. Absolute change in CFQ-R respiratory domain score from baseline through Week 8 
12.3.3.3
Analysis of Secondary Efficacy Variables
Absolute change in sweat chloride from baseline through Week 8 in the Active 
Comparator Treatment Period: Analysis of this variable will be performed using the same 
model as described for the absolute change in percent predicted FEV1 from baseline, with the 
addition of baseline sweat chloride value as a covariate.
12.3.4
Safety Analysis
Safety analyses will be based on the Safety Set with the associated TE Period and separately 
for the Ivacaftor Run-in Period and the Active Comparator Treatment Period, as appropriate. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints: 
x
Incidence of treatment-emergent adverse event (TEAEs)
x
Clinical laboratory values (i.e., urinalysis, hematology, serum chemistry, coagulation 
studies, vitamin levels, lipid panel)
x
ECGs
x
Vital signs
x
Pulse oximetry
x
Spirometry
All safety data will be presented in individual subject data listings. 
12.3.4.1
Adverse Events
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs during the 
Ivacaftor Run-in Period, TEAEs during the Active Comparator Treatment Period, or 
post-treatment AEs, defined as follows: 


Protocol VX14-661-109, Version 4.0
Page 63 of 81
Vertex Pharmaceuticals Incorporated
x
Pretreatment AE: any AE that started before initial dosing of study drug in the Ivacaftor 
Run-in Period. 
x
TEAEs during the Ivacaftor Run-in Period: any AE that increased in severity or that 
was newly developed at or after initial dosing of study drug through the end of the TE 
Period for the Ivacaftor Run-in Period. 
x
TEAEs during the Active Comparator Treatment Period: any AE that increased in 
severity or that was newly developed at or after initial dosing of study drug through the 
end of the TE Period for the Active Comparator Treatment Period. 
x
Post-treatment AE: any AE that increased in severity or that was newly developed 
beyond the TE Period. 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study treatment, then the AEs will be classified as TEAEs. If there is no clear 
evidence that the AEs started before or after the start of the Active Comparator Treatment, 
then the AEs will be classified as TEAEs during the Active Comparator Treatment Period.
AE summary tables will be presented for TEAEs, separately for the Ivacaftor Run-in Period 
and the Active Comparator Treatment Period, and will include the following: 
x
All TEAEs 
x
TEAEs by relationship  
x
TEAEs by maximal severity
x
TEAEs leading to treatment discontinuation
x
Serious TEAEs
x
TEAEs leading to death
x
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 as 
well as total number of events). When summarizing the number and percentage of subjects 
with an event, subjects with multiple occurrences of the same AE or a continuing AE will be 
counted once, only the maximum severity level will be presented in the severity summaries, 
and the worst/highest relationship level will be presented in the relationship summaries. An 
AE overview table will be provided. A separate table will summarize all TEAEs when each 
of them is considered unique, hereafter referred to as an AE count table. In addition, a listing 
containing individual subject AE data for all deaths and other serious and significant AEs 
will be provided separately. All AEs, including pre- and post-treatment AEs, will be 
presented in individual subject data listings. 
12.3.4.2
Clinical Laboratory Assessments
The raw values and change from the corresponding treatment period baseline values of the 
continuous laboratory parameters will be summarized in SI units at each scheduled time 
point during the TE Period based on the corresponding Safety Set for the Ivacaftor Run-in 


Protocol VX14-661-109, Version 4.0
Page 64 of 81
Vertex Pharmaceuticals Incorporated
Period, and by treatment group for the Active Comparator Treatment Period, separately. In 
addition, mean value at each visit will be plotted for each of the liver function parameters. 
The plots will be separate for the Ivacaftor Run-in Period and by treatment groups in the 
Active Comparator Treatment Period.
The number and percentage of subjects with at least 1 potentially clinically significant (PCS) 
event during the treatment-emergent period will be summarized for the Ivacaftor Run-in 
Period and by treatment group during the Active Comparator Treatment Period, separately. 
The PCS (postbaseline) shift from the corresponding treatment period baseline will also be 
summarized for selected laboratory parameters for the Ivacaftor Run-in Period and by 
treatment groups in the Active Comparator Treatment Period, separately, separately. 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 laboratory assessment values 
outside the reference ranges will be provided. This listing will include data from scheduled 
and unscheduled time points. 
12.3.4.3
Electrocardiogram
The raw values and change from the corresponding treatment period baseline values will be 
summarized at each scheduled time point during the TE Period based on the corresponding 
Safety Set for the Ivacaftor Run-in Period and by treatment group for the Active Comparator 
Treatment Period. The analyzed standard digital ECG measurements include PR, QT, and 
QTc for heart rate (HR) interval (QTcF), QRS duration, and HR. In addition, the mean value 
of QTc at each visit will be plotted for the Safety Set in the Ivacaftor Run-in Period and by 
treatment groups for the Active Comparator Treatment Period, separately. 
The number and percentage of subjects with at least 1 PCS event in the corresponding TE 
Period will be tabulated for the Ivacaftor Run-in Period and by treatment group for the 
Active Comparator Treatment Period, separately. The PCS criteria for ECG data will be 
provided in the SAP. 
Additional ECG analyses will be described in the SAP. 
12.3.4.4
Vital Signs
The raw values and change from the corresponding treatment period baseline values will be 
summarized at each scheduled time point during the TE Period based on the corresponding 
Safety Set in the Ivacaftor Run-in Period and by treatment group in the Active Comparator 
Treatment Period: systolic and diastolic blood pressure (mm Hg), body temperature (qC), 
pulse rate (beats per minute [bpm]), and respiratory rate (breaths per minute).  
The number and percentage of subjects with at least 1 PCS event during the TE Period based 
on the corresponding Safety Set will be tabulated for the Ivacaftor Run-in Period and by 
treatment group for the Active Comparator Treatment Period. The PCS criteria for vital signs 
data will be provided in the SAP. 
Additional vital sign analyses will be described in the SAP.


Protocol VX14-661-109, Version 4.0
Page 65 of 81
Vertex Pharmaceuticals Incorporated
12.3.4.5
Physical Examination
PE findings will be presented as a data listing only. Clinically relevant results identified after 
screening will be reported as AEs. 
12.3.4.6
Other Safety Analysis
12.3.4.6.1
Pulse Oximetry
The raw values and change from the corresponding treatment period baseline values will be 
summarized at each scheduled time point during the TE Period based on the corresponding 
Safety Set for the Ivacaftor Run-in Period and by treatment groups for the Active Comparator 
Treatment Period, separately. In addition, the mean value at each visit during the TE Period 
will be plotted for the Ivacaftor Run-in Period and by treatment group for the Active 
Comparator for the percent of oxygen saturation.  
12.3.4.6.2
Postdose Spirometry
For the 2-hour and 4-hour postdose spirometry measurements on Day 1 and Day 15, a 
summary of raw values for percent predicted FEV1 will be provided by treatment group at 
each time point. The absolute change from the predose value of percent predicted FEV1 on 
the same day will be provided by treatment group at each time point. In addition, a boxplot 
by time point will be provided. Within each treatment group, Day 1 and Day 15 values will 
be presented on the same plot. 
The above analyses will be repeated for FEV1.
In addition, the number and percentage of subjects with percent predicted FEV1 GHFOLQH
DQG  percentage points in the absolute change from the predose value will be 
summarized by treatment group and by assessment day and time. 
12.3.5
Interim and IDMC Analyses
12.3.5.1
Interim Analysis
No interim analyses of efficacy are planned.
12.3.5.2
IDMC Analysis
An IDMC will be formed before study initiation. The IDMC’s objectives and operational 
details will be defined in a separate document (IDMC charter), which will be finalized before 
the first subject is screened. The IDMC will conduct regular planned safety reviews of study 
data as outlined in the IDMC charter.
12.4
Clinical Pharmacology Analysis
A detailed description of the clinical pharmacology analyses will be provided in a CPAP. 
Listings of plasma concentration data of VX-661, ivacaftor, and their metabolites will be 
provided in the clinical study report. A population approach will be used to analyze the time-
versus-plasma concentration data of VX-661, ivacaftor, and their metabolites. The PK/PD 
relationship between concentrations of VX-661 and ivacaftor (and their metabolites as 
appropriate) and efficacy and safety measurements may be investigated. The results of the 
PK and PK/PD analyses using a population approach will be presented in a separate report. 


Protocol VX14-661-109, Version 4.0
Page 66 of 81
Vertex Pharmaceuticals Incorporated
13
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS
13.1
Adverse Event and Serious Adverse Event Documentation, 
Severity Grading, and Reporting
13.1.1
Adverse Events
13.1.1.1
Definition of an Adverse Event
An AE is defined as any untoward medical occurrence in a subject during the study; the 
event does not necessarily have a causal relationship with the treatment. This includes any 
newly occurring event or worsening of a preexisting condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.
13.1.1.2
Clinically Significant Assessments
Study assessments including laboratory tests, ECGs, PEs, pulse oximetry, 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: 
x
Concomitant signs or symptoms related to the abnormal study assessment
x
Further diagnostic testing or medical/surgical intervention
x
A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of 
whether the study assessment results are clinically significant will be made by the 
investigator.
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory 
value will be an SAE if the clinical status of the subject indicates a life-threatening AE.
13.1.1.3
Documentation of Adverse Events
All AEs will be collected from the time ICF is signed until the following time points:
x
For subjects who do not enroll: until time of screen failure (e.g., screen failure, 
withdrawal of consent) 
x
For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up 
Visit


Protocol VX14-661-109, Version 4.0
Page 67 of 81
Vertex Pharmaceuticals Incorporated
x
For enrolled subjects who do not have a Safety Follow-up Visit: the earliest of
o
28 days after the last dose of study drug
o
The ETT Visit, if that visit is 3 weeks or later following the last dose of study drug 
(Section 8.1.5)
o
prior to the first dose of study drug in the extension study  
All subjects will be queried, using non-leading questions, about the occurrence of AEs at 
each study visit. When possible, a constellation of signs and/or symptoms will be identified 
as 1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the eCRF 
and source document. 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: 
x
Description of the event 
x
Classification of “serious” or “nonserious” 
x
Date of first occurrence and date of resolution (if applicable) 
x
Severity
x
Causal relationship to study drug(s)  
x
Action taken  
x
Outcome 
x
Concomitant medication or other treatment given
x
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 
August 2012). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” In 
considering the severity of an AE in a pediatric subject, the investigator will consider that 
reference ranges for pediatric clinical laboratory parameters may differ from those given in 
the CTCAE. The severity of an AE that does not appear in the CTCAE will be determined 
according to the definitions in Table 13-1.  


Protocol VX14-661-109, Version 4.0
Page 68 of 81
Vertex Pharmaceuticals Incorporated
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
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. 


Protocol VX14-661-109, Version 4.0
Page 69 of 81
Vertex Pharmaceuticals Incorporated
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
Not applicable for this study
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.


Protocol VX14-661-109, Version 4.0
Page 70 of 81
Vertex Pharmaceuticals Incorporated
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:
x
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) 
x
Life-threatening, such that the subject was at immediate risk of death from the reaction as 
it occurred 
x
Inpatient hospitalization or prolongation of hospitalization 
x
Persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person's ability to conduct normal life functions) 
x
Congenital anomaly or birth defect 
x
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 




Protocol VX14-661-109, Version 4.0
Page 72 of 81
Vertex Pharmaceuticals Incorporated
the subject (if applicable), before study participation. The method of obtaining and 
documenting the informed consent and assent (if applicable) and the contents of the consent 
will comply with ICH GCP and all applicable laws and regulations and will be subject to 
approval by Vertex or its designee. 
13.2.3
Investigator Compliance
No modifications to the protocol will be made without the approval of both the investigator 
and Vertex. Changes that significantly affect the safety of the subjects, the scope of the 
investigation, or the scientific quality of the study (i.e., efficacy assessments) will require 
IRB/IEC notification before implementation, except where the modification is necessary to 
eliminate an apparent immediate hazard to human subjects. Vertex will submit all protocol 
modifications to the required regulatory authorities.
When circumstances require an immediate departure from procedures set forth in the 
protocol, the investigator will contact Vertex to discuss the planned course of action. If 
possible, contact will be made before the implementation of any changes. Any departures 
from protocol will be fully documented in the source documentation and in a protocol 
deviation log. 
13.2.4
Access to Records
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit 
and for audits. The records will also be available for direct inspection, verification, and 
copying, as required by applicable laws and regulations, by officials of the regulatory health 
authorities (FDA and others). The investigator will comply with applicable privacy and 
security laws for use and disclosure of information related to the research set forth in this 
protocol. 
13.2.5
Subject Privacy
To maintain subject confidentiality, all electronic case report forms (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 
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 


Protocol VX14-661-109, Version 4.0
Page 73 of 81
Vertex Pharmaceuticals Incorporated
records, custody will be transferred to a person willing to accept the responsibility and 
Vertex will be notified.
13.2.7
Study Termination
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs 
may terminate the study at their center.
Conditions that may lead to reasonable cause and warrant termination include, but are not 
limited to:
x
Subject or investigator noncompliance 
x
Unsatisfactory subject enrollment
x
Lack of adherence to protocol procedures 
x
Lack of evaluable and/or complete data
x
Potentially unacceptable risk to study subjects
x
Decision to modify drug development plan 
x
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 


Protocol VX14-661-109, Version 4.0
Page 74 of 81
Vertex Pharmaceuticals Incorporated
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.  
eCRFs 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 eCRFs. 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 eCRFs 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 must 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 
eCRFs in the form of a compact disc or other electronic media will be placed in the 
investigator's study file.


Protocol VX14-661-109, Version 4.0
Page 75 of 81
Vertex Pharmaceuticals Incorporated


Protocol VX14-661-109, Version 4.0
Page 76 of 81
Vertex Pharmaceuticals Incorporated
14
REFERENCES
1 
Cystic Fibrosis Foundation Website [Internet]. Available at: 
http://www.cff.org/AboutCF/. Accessed 11 November 2014. 
2 
Kriendler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new 
therapies. Pharmacol Ther. 2010;125:219-29. 
3
FDA Office of Orphan Products Development (OOPD) [Internet]. Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/defa
ult.htm. Accessed 11 November 2014. 
4  
The Committee for Orphan Medicinal Products (COMP) [Internet]. Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_conte
nt_000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30.
Accessed 11 November 2014. 
5 
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2009 annual 
data report. Bethesda, Maryland; 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 Mutation Database (CFTR1). Cystic Fibrosis Centre at the Hospital 
for Sick Children in Toronto Website [Internet]. Available at: 
http://www.genet.sickkids.on.ca/cftr/StatisticsPage.html. Accessed 
11 November 2014.
8 
Castellani C, Bonizzato A, Cabrini G, Mastella G. Newborn screening strategy for 
cystic fibrosis: a field study in an area with high allelic heterogeneity. Acta Paediatr. 
1997;86(5):497-502. 
9 
Van Goor F, Hadida S, Grootenhuis P. Pharmacological rescue of mutant CFTR
function for the treatment of cystic fibrosis. Top Med Chem. 2008;3:91-120. 
10 
McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of genotype on phenotype 
and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 
2003;361(9370):1671-6. 
11  
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2011 annual 
data report. Bethesda, Maryland; 2012. 
12  
European Cystic Fibrosis Society. European Cystic Fibrosis Society Patient Registry 
2008-2009. Karup, Denmark; 2012. Available at: 
http://www.ecfs.eu/files/webfm/webfiles/File/ecfs_registry/ECFSPR_Report0809_v3
2012.pdf. Accessed 11 November 2014. 


Protocol VX14-661-109, Version 4.0
Page 77 of 81
Vertex Pharmaceuticals Incorporated
13 
Cheng SH, Gregory RJ, Marshall J, Sucharita P, Souza DW, White GA, et al. 
Defective intracellular transport and processing of CFTR is the molecular basis of 
most cystic fibrosis. Cell. 1990;63:827-34. 
14 
Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, et al. Altered 
chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. 
Nature. 1991;354:526-8. 
15 
Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 
2005;352:1992-2001. 
16 
Vertex Pharmaceuticals Incorporated. Report G016. Effects of VRT-893661 on 
CFTR-mediated chloride secretion in human bronchial epithelia isolated from cystic 
fibrosis subjects. Report date: 17 February 2010. 
17 
Lukacs GL, Chang XB, Bear C, Kartner N, Mohamed A, Riordan JR, et al. The delta 
F508 mutation decreases the stability of cystic fibrosis transmembrane conductance 
regulator in the plasma membrane. Determination of functional half-lives on 
transfected cells. J Biol Chem. 1993;268:21592-8. 
18
Vertex Pharmaceuticals Incorporated. VX-661 Investigator's Brochure, Version 7.0. 
Report date: 08 May 2015.  
19
Vertex Pharmaceuticals Incorporated. Ivacaftor (VX-770) Investigator's Brochure, 
Version 12.0. Report date: 08 May 2015. 
20
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
21  
Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic approach for the 
scaling of clearance in children. Clin Pharmacokinet. 2006;45(7):683-704. 
22 
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. 
23 
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. 
24 
Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life 
measure for children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32. 
25 
Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4:1-9. 
26 
Modi AC, Quittner AL. Validation of a disease-specific measure of health-related 
quality of life for children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45. 
27 
Wenninger K, Aussage P, Wahn U, Staab D. German Cystic Fibrosis Questionnaire 
study group. The revised German Cystic Fibrosis Questionnaire: validation of a 


Protocol VX14-661-109, Version 4.0
Page 78 of 81
Vertex Pharmaceuticals Incorporated
disease-specific health-relate quality of life instrument. Qual Life Res. 
2003;12(1):77-85. 
28 
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual 
Life Res. 2003;12(1):63-76. 
29 
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. 
30  
Wang X, Dockery DQ, Wypij D, Fay ME, Ferris BG. Pulmonary function between 6 
and 18 years of age. Pediatr Pulmonol. 1993;15:75-88. 
31 
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. 
Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998;132(4):589-95. 
32 
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. 
33 
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. 
34  
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51(11):875-8. 
35 
Quitttner Al, Buu A, Messer MA, Modi AC, Watrous M. Development and validation 
of the cystic fibrosis questionnaire in the United States: a health-related quality of life 
measure for cystic fibrosis. Chest. 2005;128:2347-54. 
36 
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 
1994;331:637-42. 
37
5DPVH\%:'DYLHV-0F(OYDQH\1*7XOOLV(%HOO6&'ĜHYtQHN3HWDO$&)75
potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 
2011;365:1663-72. 




Protocol VX14-661-109, Version 4.0
Page 80 of 81
Vertex Pharmaceuticals Incorporated
15.2
Investigator Signature Page
Protocol #:
VX14-661-109
Version #:
4.0
Version Date
18 April 2017
Study Title: A Phase 3, Randomized, Double-Blind, Ivacaftor-Controlled, Parallel-Group 
Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in 
Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-
CFTR Mutation and a Second CFTR Allele With a Gating Defect That Is Clinically 
Demonstrated to be Ivacaftor Responsive
I have read Protocol VX14-661-109, Version 4.0 and agree to conduct the study according to 
its terms. I understand that all information concerning VX-661 and ivacaftor and this 
protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential.  
Printed Name
Signature
Date


Protocol VX14-661-109, Version 4.0
Page 81 of 81
Vertex Pharmaceuticals Incorporated
16
APPENDIX A: SECOND CFTR ALLELE MUTATIONS INCLUDED 
FOR SUBJECTS WHO ARE HETEROZYGOUS FOR THE
F508del-CFTR MUTATION
Per the study eligibility criteria, heterozygous F508del-CFTR subjects must have a second 
CFTR allele that encodes a mutation with a gating defect clinically demonstrated to be 
ivacaftor-responsive. The list below represents acceptable mutations. 
CFTR Mutations With a Gating Defect Clinically Demonstrated to be Ivacaftor-
Responsive
R117H
G178R
S549N
S549R
G551D
G551S
G1244E
S1251N
S1255P
G1349D
Source: CFTR2.org [Internet]. Baltimore (MD): Clinical and functional translation of CFTR. The Clinical and 
Functional Translation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins University, the 
Hospital for Sick Children. Available at: http://www.cftr2.org/. Accessed 15 September 2014

SAP_001.pdf: 


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

1 
TABLE OF CONTENTS
 
7DEOHRI&RQWHQWV 
 
/,672)$%%5(9,$7,216 
 
,QWURGXFWLRQ 
 
6WXG\2EMHFWLYHV 
 
3ULPDU\2EMHFWLYH 
 
6HFRQGDU\2EMHFWLYHV 
 
6WXG\(QGSRLQWV 
 
(IILFDF\(QGSRLQW 
 
3ULPDU\(IILFDF\(QGSRLQW 
 
.H\6HFRQGDU\(IILFDF\(QGSRLQWV 
 
6HFRQGDU\(IILFDF\(QGSRLQWV 
 
6DIHW\(QGSRLQWV 
 
6WXG\'HVLJQ 
 
2YHUDOO'HVLJQ 
 
6DPSOH6L]HDQG3RZHU 
 
5DQGRPL]DWLRQ 
 
%OLQGLQJDQG8QEOLQGLQJ 
 
%OLQGLQJ 
 
8QEOLQGLQJ 
 
$QDO\VLV6HWV 
 
$OO6XEMHFWV6HW 
 
)XOO$QDO\VLV6HW 
 
6DIHW\6HW 
 
6WDWLVWLFDO$QDO\VLV 
 
*HQHUDO&RQVLGHUDWLRQV 
 
%DFNJURXQG&KDUDFWHULVWLFV 
 
6XEMHFW'LVSRVLWLRQ 
 
'HPRJUDSKLFVDQG%DVHOLQH&KDUDFWHULVWLFV 
 
0HGLFDO+LVWRU\ 
 
3ULRUDQG&RQFRPLWDQW0HGLFDWLRQV 
 
6WXG\'UXJ([SRVXUH 
 
6WXG\'UXJ&RPSOLDQFH 
 
,PSRUWDQW3URWRFRO'HYLDWLRQV 
 
(IILFDF\$QDO\VLV 
 
$QDO\VLVRI3ULPDU\(IILFDF\(QGSRLQWV 
 
'HILQLWLRQ 
 
6XPPDU\LQ,YDFDIWRU5XQLQ3HULRG 
Page 2 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

 
3ULPDU\$QDO\VLV 
 
$QDO\VLVRI.H\6HFRQGDU\(IILFDF\(QGSRLQWV 
 
'HILQLWLRQRI.H\6HFRQGDU\(IILFDF\(QGSRLQWV 
 
$QDO\VLVRI.H\6HFRQGDU\(IILFDF\(QGSRLQWV 
 
$QDO\VLVRI6HFRQGDU\(IILFDF\(QGSRLQWV 
 
'HILQLWLRQRI6HFRQGDU\(IILFDF\(QGSRLQWV 
 
0XOWLSOLFLW\$GMXVWPHQW 
 
6DIHW\$QDO\VLV 
 
$GYHUVH(YHQWV 
 
2YHULHZRI7($(V 
 
7($(VE\6\VWHP2UJDQ&ODVV62&DQG3UHIHUUHG7HUP37 
 
5HVSLUDWRU\(YHQWVDQG6\PSWRPV 
 
6XEJURXS$QDO\VLV 
 
&OLQLFDO/DERUDWRU\ 
 
(OHFWURFDUGLRJUDP 
 
9LWDO6LJQV 
 
3K\VLFDO([DPLQDWLRQ 
 
3XOVH2[LPHWU\ 
 
3RVWGRVH6SLURPHWU\ 
 
2SKWKDOPRORJ\([DPLQDWLRQ 
 6XPPDU\RI,QWHULPDQG,'0&$QDO\VHV 
 ,QWHULP$QDO\VLV 
 ,'0&$QDO\VLV 
 5HIHUHQFHV 
 /LVWRI$SSHQGLFHV 
$SSHQGL[$6(&21'&)75$//(/(087$7,216,1&/8'(')2568%-(&76
:+2$5(+(7(52=<*286)257+()GHO&)75087$7,21 
$SSHQGL[% 
5DQGRPL]DWLRQ3URFHGXUHV 
$SSHQGL[&6FKHGXOHRI$VVHVVPHQWV 
$SSHQGL['$QDO\VLV9LVLW:LQGRZ0DSSLQJ5XOHVIRU(IILFDF\DQG6DIHW\
0HDVXUHPHQWV 
$SSHQGL[(,PSXWDWLRQ5XOHVIRU0LVVLQJ3ULRU&RQFRPLWDQW0HGLFDWLRQ'DWHV 
$SSHQGL[)&RHIILFLHQWVIRU+DQNLQVRQDQG:DQJ0HWKRGVIRU&DOFXODWLQJ3UHGLFWHG
6SLURPHWU\3DUDPHWHUV 
Page 3 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

$SSHQGL[,7KUHVKROG&ULWHULDIRU&OLQLFDO&KHPLVWU\DQG+HPDWRORJ\ 
Page 4 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

2 
 LIST OF ABBREVIATIONS 
$EEUHYLDWLRQ
7HUP
$(
DGYHUVHHYHQW
$/3
DONDOLQHSKRVSKDWDVH
$/7
DODQLQHDPLQRWUDQVIHUDVH
$1&29$
DQDO\VLVRIFRYDULDQFH
$67
DVSDUWDWHDPLQRWUDQVIHUDVH
%0,
ERG\PDVVLQGH[
ESP
EHDWVSHUPLQXWH
&)
F\VWLFILEURVLV
&)45
&\VWLF)LEURVLV4XHVWLRQQDLUH±5HYLVHG
&)75
F\VWLFILEURVLVWUDQVPHPEUDQHFRQGXFWDQFHUHJXODWRU
&,
FRQILGHQFHLQWHUYDO
&5)
FDVHUHSRUWIRUP
&52
FRQWUDFWUHVHDUFKRUJDQL]DWLRQ
'0&
GDWDPRQLWRULQJFRPPLWWHH
(&*
HOHFWURFDUGLRJUDP
H&5)
HOHFWURQLFFDVHUHSRUWIRUP
)$6
IXOODQDO\VLVVHW
)'&
9;PJ,9$PJIL[HGGRVHWDEOHW
)()
IRUFHGH[SLUDWRU\IORZPLGH[SLUDWRU\SKDVH
)(9
IRUFHGH[SLUDWRU\YROXPHLQVHFRQG
)9&
IRUFHGYLWDOFDSDFLW\
F508del
CFTRJHQHPXWDWLRQZLWKDQLQIUDPHGHOHWLRQRIDSKHQ\ODODQLQHFRGRQ
FRUUHVSRQGLQJWRSRVLWLRQRIWKHZLOGW\SHSURWHLQ
+19)(9
+DQNLQVRQSUHGLFWHGYDOXHRI)(9/
+19)()
+DQNLQVRQSUHGLFWHGYDOXHRI)()/VHF
+19)9&
+DQNLQVRQSUHGLFWHGYDOXHRI)9&/
,9$
LYDFDIWRU
/6PHDQV
/HDVWVTXDUHVPHDQV
/)7
OLYHUIXQFWLRQWHVW
PD[
PD[LPXPYDOXH
0HG'5$
0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV
0,
PXOWLSOHLPSXWDWLRQ
PLQ
PLQLPXPYDOXH
0050
PL[HGPRGHOUHSHDWHGPHDVXUH
1
QXPEHURIVXEMHFWV
3'
SKDUPDFRG\QDPLFSKDUPDFRG\QDPLFV
3.
SKDUPDFRNLQHWLFSKDUPDFRNLQHWLFV
SS)(9
SHUFHQWSUHGLFWHG)(9
37
SUHIHUUHGWHUP
TK
HYHU\KRXUV
Page 5 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

$EEUHYLDWLRQ
7HUP
456
45DQG6ZDYHGHILQHWKH456FRPSOH[LQDQ(&*
47
47LQWHUYDO7KHGXUDWLRQRIYHQWULFXODUGHSRODUL]DWLRQDQGVXEVHTXHQW
UHSRODUL]DWLRQLWLVPHDVXUHGIURPWKHEHJLQQLQJRIWKH456FRPSOH[WRWKHHQG
RIWKH7ZDYH
47F
47LQWHUYDOFRUUHFWHGIRUKHDUWUDWH
47F)
47LQWHUYDOFRUUHFWHGIRUKHDUWUDWHZLWK)ULGHULFLD¶VFRUUHFWLRQ
6$(
VHULRXVDGYHUVHHYHQW
6$3
6WDWLVWLFDO$QDO\VLV3ODQ
6'
VWDQGDUGGHYLDWLRQ
6(
VWDQGDUGHUURU
62&
V\VWHPRUJDQFODVV
7($(
WUHDWPHQWHPHUJHQWDGYHUVHHYHQW
8/1
XSSHUOLPLWRIQRUPDO
:19)(9
:DQJSUHGLFWHGYDOXHRI)(9/
:19)()
:DQJSUHGLFWHGYDOXHRI)()/VHF
:19)9&
:DQJSUHGLFWHGYDOXHRI)9&/
:+2''(
:RUOG+HDOWK2UJDQL]DWLRQ'UXJ'LFWLRQDU\(QKDQFHG

Page 6 of 108




6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

4 
INTRODUCTION
7KLVVWDWLVWLFDODQDO\VLVSODQ6$30HWKRGVIRUWKHILQDODQDO\VLVLVEDVHGRQWKHDSSURYHG
FOLQLFDOVWXG\SURWRFRO&63GDWHG$359HUVLRQILQDOHOHFWURQLFFDVHUHSRUW
IRUPH&5)FRPSOHWLRQJXLGHOLQHV9HUVLRQGDWHG-8/DQGDSSURYHGH&5)
9HUVLRQGDWHG2&7
6WXG\9;LVD3KDVHUDQGRPL]HGGRXEOHEOLQGLYDFDIWRUFRQWUROOHGSDUDOOHO
JURXSPXOWLFHQWHUVWXG\LQVXEMHFWVDJHG\HDUVDQGROGHUZLWK&)ZKRDUHKHWHUR]\JRXV
IRUWKHF508del CFTRPXWDWLRQDQGDVHFRQGCFTRDOOHOHZLWKDJDWLQJGHIHFWWKDWLV
FOLQLFDOO\GHPRQVWUDWHGWREHLYDFDIWRUUHVSRQVLYHVHH$SSHQGL[$
7KLVVWXG\LVGHVLJQHGWRFRPSDUHDFWLYHWUHDWPHQWRI9;PJGDLO\>TG@DQG
LYDFDIWRUPJHYHU\KRXUV>TK@FRPELQDWLRQWKHUDS\ZLWKLYDFDIWRUPRQRWKHUDS\
PJTK
7KHWUHDWPHQWUHJLPHQVZLOOEHDVIROORZV
x
9;LYDFDIWRUFRPELQDWLRQWKHUDS\
o
0RUQLQJGRVHWDEOHWRIIL[HGGRVHFRPELQDWLRQRI9;PJLYDFDIWRU
PJDQGWDEOHWRISODFHERYLVXDOO\PDWFKHGWRLYDFDIWRU
o
(YHQLQJGRVHWDEOHWRILYDFDIWRUPJ
x
,YDFDIWRUPRQRWKHUDS\
o
0RUQLQJGRVHWDEOHWRISODFHERYLVXDOO\PDWFKHGWRWKHIL[HGGRVHFRPELQDWLRQ
WDEOHWDQGWDEOHWRILYDFDIWRUPJ
o
(YHQLQJGRVHWDEOHWRILYDFDIWRUPJ

7KLV6$30HWKRGVGRFXPHQWVWKHSODQQHGILQDOVWDWLVWLFDODQDO\VLVRIHIILFDF\DQGVDIHW\
HQGSRLQWVGHILQHGLQWKHVWXG\SURWRFRORI9;DQGGHVFULEHVWKHFRUUHVSRQGLQJ
GDWDSUHVHQWDWLRQV,WDOVRGRFXPHQWVDGGLWLRQDOHIILFDF\DQGVDIHW\DQDO\VHVQRWVSHFLILHGLQ
WKHSURWRFROZKLFKZLOOSURYLGHVXSSRUWLYHLQIRUPDWLRQWRWKHVFLHQWLILFXQGHUVWDQGLQJRIWKH
GUXJHQWLW\7KHVWXG\ZLOODOVRHYDOXDWHVRPHH[SORUDWRU\HQGSRLQWVGHVFULEHGLQWKHVWXG\
SURWRFRO6XPPDU\VWDWLVWLFVZLOOEHSURYLGHGE\YLVLWIRUVHOHFWHGH[SORUDWRU\HQGSRLQWV
$GGLWLRQDODQDO\VHVRIWKHVHHQGSRLQWVZLOOEHGRFXPHQWHGVHSDUDWHO\LQWKHH[SORUDWRU\
DQDO\VLVSODQ($3
7KHVWXG\ZLOODOVRHYDOXDWHWKHSKDUPDFRNLQHWLF3.DQGSKDUPDFRG\QDPLF
3'FKDUDFWHULVWLFVRI9;LYDFDIWRULQWKLVVXEMHFWSRSXODWLRQ3.DQG3'DQDO\VHVZLOO
EHGRFXPHQWHGVHSDUDWHO\LQWKHFOLQLFDOSKDUPDFRORJ\DQDO\VLVSODQ&3$3IRUWKHVWXG\
7KH9HUWH[%LRPHWULFV'HSDUWPHQWZLOOSHUIRUPWKHILQDOVWDWLVWLFDODQDO\VLVRIWKHHIILFDF\
DQGVDIHW\GDWD6$69HUVLRQ6RIWZDUH6$6,QVWLWXWH&DU\1RUWK&DUROLQD86$RU
KLJKHUZLOOEHXVHGWRJHQHUDWHDOOVWDWLVWLFDORXWSXWVWDEOHVILJXUHVOLVWLQJVDQGGDWDVHWV
Page 8 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

7KH6$30HWKRGVIRUWKHILQDODQDO\VLVZLOOEHILQDOL]HGDQGDSSURYHGEHIRUHGDWDEDVHORFN
IRUWKHILQDODQDO\VLV$Q\FKDQJHVPDGHWRWKH6$30HWKRGVDIWHUWKHFOLQLFDOGDWDEDVHORFN
KDVRFFXUUHGZLOOEHGRFXPHQWHGLQWKHFOLQLFDOVWXG\UHSRUWIRUWKLVVWXG\
5 
STUDY OBJECTIVES 
5.1
Primary Objective
7KHSULPDU\REMHFWLYHRIWKHVWXG\LVWRHYDOXDWHWKHHIILFDF\RI9;LQFRPELQDWLRQZLWK
LYDFDIWRULQVXEMHFWVZLWK&)ZKRDUHKHWHUR]\JRXVIRUWKHF508delPXWDWLRQRQWKHCFTR 
JHQHDQGDVHFRQGCFTRDOOHOHZLWKDJDWLQJGHIHFWWKDWLVFOLQLFDOO\GHPRQVWUDWHGWREH
LYDFDIWRUUHVSRQVLYH
5.2
Secondary Objectives 
7KHVHFRQGDU\REMHFWLYHVRIWKHVWXG\DUH
x
7RHYDOXDWHWKHVDIHW\RI9;LQFRPELQDWLRQZLWKLYDFDIWRU
x
7RLQYHVWLJDWHWKHSKDUPDFRNLQHWLFV3.RI9;DQGLWVPHWDEROLWH00
DQGLYDFDIWRUDQGLWVPHWDEROLWH00LYDFDIWRU
6 
STUDY ENDPOINTS
6.1
Efficacy Endpoint
7KH,YDFDIWRU5XQLQ3HULRGZLOOKDYHDWRWDOGXUDWLRQRIZHHNVDQGLVGHVLJQHGWRHVWDEOLVK
DUHOLDEOHRQWUHDWPHQWLYDFDIWRUPRQRWKHUDS\EDVHOLQHIRUDOOVXEMHFWVIRUWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRG7KHDQDO\VLVSHULRGIRUWKHHIILFDF\HYDOXDWLRQLVWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRG7KHEDVHOLQHIRUHYDOXDWLQJWKHHIILFDF\RI9;LYDFDIWRU
FRPELQDWLRQWKHUDS\RYHULYDFDIWRUPRQRWKHUDS\LVGHILQHGLQ6HFWLRQ
6.1.1
Primary Efficacy Endpoint
$EVROXWHFKDQJHLQSHUFHQWSUHGLFWHGIRUFHGH[SLUDWRU\YROXPHLQVHFRQG)(9IURP
EDVHOLQHWKURXJK:HHNLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
6.1.2
Key Secondary Efficacy Endpoints
x
5HODWLYHFKDQJHLQSHUFHQWSUHGLFWHG)(9IURPEDVHOLQHWKURXJK:HHNLQWKH
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
x
$EVROXWHFKDQJHLQ&\VWLF)LEURVLV4XHVWLRQQDLUH±5HYLVHG&)45UHVSLUDWRU\
GRPDLQVFRUHIURPEDVHOLQHWKURXJK:HHNLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW
3HULRG
6.1.3
Secondary Efficacy Endpoints
x
$EVROXWHFKDQJHLQVZHDWFKORULGHIURPEDVHOLQHWKURXJK:HHNLQWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRG
x
6DIHW\DQGWROHUDELOLW\DVVHVVPHQWVEDVHGRQDGYHUVHHYHQWV$(VFOLQLFDOODERUDWRU\
YDOXHVKHPDWRORJ\VHUXPFKHPLVWU\OLSLGSDQHOYLWDPLQOHYHOVFRDJXODWLRQVWXGLHV
Page 9 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

DQGXULQDO\VLVVWDQGDUGGLJLWDOHOHFWURFDUGLRJUDPV(&*VYLWDOVLJQVSXOVH
R[LPHWU\DQGVSLURPHWU\
x
3.SDUDPHWHUVRI9;0LYDFDIWRUDQG0LYDFDIWRU
6.2
Safety Endpoints
6DIHW\DQDO\VHVZLOOEHEDVHGRQWKH6DIHW\6HWZLWKWKHDVVRFLDWHG7(3HULRGDQGSHUIRUPHG
VHSDUDWHO\IRUWKH,YDFDIWRU5XQLQ3HULRGDQGWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGDV
DSSURSULDWH
7KHRYHUDOOVDIHW\SURILOHRIVWXG\GUXJZLOOEHDVVHVVHGLQWHUPVRIWKHIROORZLQJVDIHW\DQG
WROHUDELOLW\HQGSRLQWV
x
,QFLGHQFHRIWUHDWPHQWHPHUJHQWDGYHUVHHYHQW7($(V
x
&OLQLFDOODERUDWRU\YDOXHVLHKHPDWRORJ\VHUXPFKHPLVWU\OLSLGSDQHOYLWDPLQ
OHYHOVFRDJXODWLRQVWXGLHVDQGXULQDO\VLV
x
(&*V
x
9LWDOVLJQV
x
3XOVHR[LPHWU\
x
6SLURPHWU\
7 
STUDY DESIGN 
7.1
Overall Design 
7KLVLVD3KDVHUDQGRPL]HGGRXEOHEOLQGLYDFDIWRUFRQWUROOHGSDUDOOHOJURXSPXOWLFHQWHU
VWXG\LQVXEMHFWVDJHG\HDUVDQGROGHUZLWK&)ZKRDUHKHWHUR]\JRXVIRUWKH
F508del-CFTRPXWDWLRQDQGDVHFRQGCFTRDOOHOHZLWKDJDWLQJGHIHFWWKDWLVFOLQLFDOO\
GHPRQVWUDWHGWREHLYDFDIWRUUHVSRQVLYH6HFWLRQRISURWRFRO$SSHQGL[$
7KLVVWXG\LVGHVLJQHGWRFRPSDUHDFWLYHWUHDWPHQWRI9;PJGDLO\>TG@DQG
LYDFDIWRUPJHYHU\KRXUV>TK@FRPELQDWLRQWKHUDS\ZLWKLYDFDIWRUPRQRWKHUDS\
PJTK
7KHWUHDWPHQWUHJLPHQVZLOOEHDVIROORZV
x
9;LYDFDIWRUFRPELQDWLRQWKHUDS\
Page 10 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

o
0RUQLQJGRVHWDEOHWRIIL[HGGRVHFRPELQDWLRQRI9;PJLYDFDIWRU
PJDQGWDEOHWRISODFHERYLVXDOO\PDWFKHGWRLYDFDIWRU
o
(YHQLQJGRVHWDEOHWRILYDFDIWRUPJ
x
,YDFDIWRUPRQRWKHUDS\
o
0RUQLQJGRVHWDEOHWRISODFHERYLVXDOO\PDWFKHGWRWKHIL[HGGRVHFRPELQDWLRQ
WDEOHWDQGWDEOHWRILYDFDIWRUPJ
o
(YHQLQJGRVHWDEOHWRILYDFDIWRUPJ
7KLVVWXG\LQFOXGHVD6FUHHQLQJ3HULRGDSSUR[LPDWHO\GD\VDQ,YDFDIWRU5XQLQ3HULRG
DSSUR[LPDWHO\ZHHNVDQ$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGXSWRZHHNVDQGD
6DIHW\)ROORZXS9LVLWDSSUR[LPDWHO\GD\VDIWHUODVWGRVH)ROORZLQJWKH,YDFDIWRU
5XQLQ3HULRGDSSUR[LPDWHO\VXEMHFWVZLOOEHUDQGRPL]HGLQDUDWLRRIWRUHFHLYH
HLWKHU9;LYDFDIWRUFRPELQDWLRQWKHUDS\RULYDFDIWRUPRQRWKHUDS\IRUZHHNVGXULQJ
WKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG7KHUDQGRPL]DWLRQZLOOEHVWUDWLILHGE\DJHDWWKH
6FUHHQLQJ9LVLWYHUVXV\HDUVRIDJHW\SHRIPXWDWLRQRQWKHVHFRQGCFTRDOOHOH
R117H YHUVXVRWKHUDOORZHGPXWDWLRQV$SSHQGL[$DQGSHUFHQWSUHGLFWHG)(9VHYHULW\
GHWHUPLQHGDWWKHHQGRIWKH,YDFDIWRU5XQLQ3HULRGYHUVXVtVHH)LJXUH2IWKH
UDQGRPL]HGVXEMHFWVDSSUR[LPDWHO\ZLOOFDUU\DQR117HPXWDWLRQRQWKHVHFRQGCFTR
DOOHOH:HHNLVWKHFRQFOXVLRQRIWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGRIWKHVWXG\
6XEMHFWVZKRFRPSOHWHWKH:HHN9LVLWUHJDUGOHVVRIZKHWKHUWKH\KDYHSUHPDWXUHO\
GLVFRQWLQXHGVWXG\GUXJWUHDWPHQWZLOOEHRIIHUHGWKHRSSRUWXQLW\WRHQUROOLQDQH[WHQVLRQ
VWXG\LIWKH\PHHWWKHHOLJLELOLW\FULWHULD
$OOVXEMHFWVUDQGRPL]HGLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGZLOOEHUHTXLUHGWR
FRPSOHWHVWXG\DVVHVVPHQWVIRUDOOVFKHGXOHGYLVLWVWKURXJK:HHNUHJDUGOHVVRIZKHWKHU
WKH\KDYHSUHPDWXUHO\GLVFRQWLQXHGVWXG\WUHDWPHQW6HFWLRQRISURWRFRO
Page 11 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

)LJXUH
6FKHPDWLF9LHZRIWKH6WXG\'HVLJQ

7.2
Sample Size and Power
7KHSULPDU\HIILFDF\HQGSRLQWLVWKHDEVROXWHFKDQJHLQSHUFHQWSUHGLFWHG)(9IURP
EDVHOLQHWKURXJK:HHNLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
7KHQXOOK\SRWKHVLVWREHWHVWHGLVWKDWWKHPHDQDEVROXWHFKDQJHLQSHUFHQWSUHGLFWHG)(9
IURPEDVHOLQHWKURXJK:HHNLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGLVWKHVDPHIRUWKH
9;LYDFDIWRUFRPELQDWLRQWKHUDS\DQGWKHLYDFDIWRUPRQRWKHUDS\$VVXPLQJDFRPPRQ
VWDQGDUGGHYLDWLRQ6'RISHUFHQWDJHSRLQWVDQGDGURSRXWUDWHDVDPSOHVL]HRI
VXEMHFWVZLOOKDYHDWOHDVWSRZHUWRGHWHFWDWUHDWPHQWGLIIHUHQFHRISHUFHQWDJH
SRLQWVEHWZHHQWUHDWPHQWDUPVLQDEVROXWHFKDQJHLQSHUFHQWSUHGLFWHG)(9DWDVLGHG
VLJQLILFDQFHOHYHO$PYDOXHRIRUOHVVZLOOEHLQWHUSUHWHGDVVXIILFLHQWHYLGHQFHWR
6FUHHQLQJ
3HULRGD
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGF
6DIHW\)ROORZXS3HULRGG
:HHNWR'D\
:HHNV
WR
:HHN
)(9IRUFHGH[SLUDWRU\YROXPHLQVHFRQG,9$LYDFDIWRUTKHYHU\KRXUVTGRQFHGDLO\
D
$SSUR[LPDWHO\VXEMHFWVZLOOEHVWUDWLILHGE\DJHDWWKH6FUHHQLQJ9LVLWYHUVXV\HDUVRIDJHW\SHRI
PXWDWLRQRQWKHVHFRQGCFTRDOOHOHR117HYHUVXVDOORWKHUDOORZHGPXWDWLRQVDQGSHUFHQWSUHGLFWHG)(9
VHYHULW\GHWHUPLQHGDWWKHHQGRIWKH,YDFDIWRU5XQLQ3HULRGYHUVXVtDQGZLOOEHUDQGRPL]HGEHIRUH
WKHILUVWGRVHRIVWXG\GUXJDW'D\
E
7KH,YDFDIWRU5XQLQ3HULRGKDVDWRWDOGXUDWLRQRIDSSUR[LPDWHO\ZHHNVDQGLVGHVLJQHGWRHVWDEOLVKDUHOLDEOH
RQWUHDWPHQWLYDFDIWRUPRQRWKHUDS\EDVHOLQH
F
6XEMHFWVZLOOUHFHLYHWKHVDPHQXPEHURIWDEOHWVHDFKGD\WRPDLQWDLQWKHEOLQGGXULQJWKH$FWLYH&RPSDUDWRU
7UHDWPHQW3HULRG6XEMHFWVLQWKH9;,YDFDIWRU$UPZLOOUHFHLYHPJ9;PJLYDFDIWRUIL[HG
GRVHFRPELQDWLRQWDEOHWDQGDSODFHERWDEOHWYLVXDOO\PDWFKHGWRWKH,9$PJWDEOHWIRUWKHPRUQLQJGRVH
DQGDQ,9$PJWDEOHWIRUWKHHYHQLQJGRVH6XEMHFWVLQWKH,YDFDIWRU0RQRWKHUDS\$UPZLOOUHFHLYHSODFHER
WDEOHWYLVXDOO\PDWFKHGWRWKH9;PJLYDFDIWRUPJIL[HGGRVHFRPELQDWLRQWDEOHWDQGPJ
LYDFDIWRUIRUWKHPRUQLQJGRVHDQGPJLYDFDIWRUIRUWKHHYHQLQJGRVH
G
7KH6DIHW\)ROORZXS9LVLWLVVFKHGXOHGWRRFFXUGD\VDIWHUWKHODVWGRVHRIVWXG\GUXJ7KH6DIHW\
)ROORZXS9LVLWLVQRWUHTXLUHGIRUVXEMHFWVZKRFRPSOHWHWKH:HHN9LVLWDQGKDYHHQUROOHGLQWKHH[WHQVLRQ
VWXG\RI9;LQFRPELQDWLRQZLWKLYDFDIWRUZLWKLQGD\VDIWHUWKHODVWGRVHRIVWXG\GUXJ
([WHQVLRQ6WXG\
6DIHW\
)ROORZXS9LVLW
9;PJTG
,9$PJTKF

,9$PJTKF
,YDFDIWRU5XQLQ
3HULRGE
:HHN
6FUHHQLQJ
,YDFDIWRU
5XQLQ
Page 12 of 108




6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

x
8QEOLQGHGVWDWLVWLFLDQSUHSDULQJWKHILQDOSURGXFWLRQUDQGRPL]DWLRQOLVWZKRLVQRW
SDUWRIWKHVWXG\WHDP
x
9HUWH[&OLQLFDO2SHUDWLRQV,:56PDQDJHPHQW
x
9HUWH[&OLQLFDO6XSSO\&KDLQ
x
,'0&
x
9HQGRUSUHSDULQJWKHXQEOLQGHGDQDO\VLVIRUWKH,'0&
x
9HQGRUDQDO\]LQJ3.VDPSOHV
x
9HUWH[SHUVRQQHORUYHQGRUFRQGXFWLQJWKHSRSXODWLRQ3.DQDO\VLV
x
9HUWH[PHGLFDOPRQLWRUPD\IRUPDWWHUVUHODWLQJWRVDIHW\FRQFHUQVXQEOLQG
LQGLYLGXDOVXEMHFWVDWDQ\WLPH
9HUWH['UXJ0HWDEROLVPDQG3KDUPDFRNLQHWLFVODERUDWRU\SHUVRQQHOZLOOQRWEHLQYROYHGLQ
WKHFRQGXFWRIWKHVWXG\DQGZLOOEHXQEOLQGHGWRWKHELRDQDO\VLVUHVXOWVEXWZLOOUHPDLQ
EOLQGHGWRVXEMHFWQXPEHUDQGWUHDWPHQWDVVLJQPHQW
6SLURPHWU\'DWD%OLQGLQJ
'HVSLWHWUHDWPHQWEOLQGLQJNQRZOHGJHRIWKHVSLURPHWU\UHVXOWVKDVWKHSRWHQWLDOWRVXJJHVW
ZKHWKHUDVXEMHFWKDVEHHQDGPLQLVWHUHGDFWLYHVWXG\GUXJRUFRUUHVSRQGLQJDFWLYHFRQWURO
7KHUHIRUHGXULQJWKHFRQGXFWRIWKHVWXG\WKH9HUWH[VWXG\WHDPZLOOQRWKDYHDFFHVVWRWKH
SRVWGRVHVSLURPHWU\GDWDGXULQJWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG7KHYHQGRUIRU
FHQWUDOUHDGLQJRIWKHVSLURPHWU\GDWDZLOORQO\VHQGWKHEOLQGHGVSLURPHWU\ILOHVEOLQGHG
WUHDWPHQWJURXSZLWKGXPP\YDOXHVIRUDOOWKHVSLURPHWU\DVVHVVPHQWDIWHUEDVHOLQHLQWKH
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGWR9HUWH[WREHXVHGIRUGHYHORSLQJWKHVWDWLVWLFDO
SURJUDPV)XUWKHUPRUHVXEMHFWVDQGWKHLUFDUHJLYHUVVKRXOGQRWEHLQIRUPHGRIWKHLU
VWXG\UHODWHGVSLURPHWU\UHVXOWVGXULQJWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGUHJDUGOHVV
RIZKHWKHUWKHVXEMHFWKDVSUHPDWXUHO\GLVFRQWLQXHGWUHDWPHQW
6ZHDW&KORULGH'DWD%OLQGLQJ
'HVSLWHWUHDWPHQWEOLQGLQJNQRZOHGJHRIWKHVZHDWFKORULGHGDWDKDVWKHSRWHQWLDOWRVXJJHVW
ZKHWKHUDVXEMHFWKDVEHHQDGPLQLVWHUHGDFWLYHVWXG\WUHDWPHQWRUFRUUHVSRQGLQJDFWLYH
FRQWURO7KHUHIRUHGXULQJWKHFRQGXFWRIWKHVWXG\WKH9HUWH[VWXG\WHDPZLOOQRWKDYH
DFFHVVWRWKHSRVWGRVHVZHDWFKORULGHGDWDGXPP\GDWDZLOOEHXVHGWRGHYHORSVWDWLVWLFDO
SURJUDPV'XULQJWKHSURFHVVRIORFNLQJWKHFOLQLFDOGDWDEDVHDQGDIWHUDOOVWXG\YLVLWVKDYH
EHHQFRPSOHWHGWUHDWPHQWEOLQGHGDFFHVVWRWKHVZHDWFKORULGHGDWDZLOOEHSURYLGHGWRD
VPDOOJURXSRILQGLYLGXDOVZKRDUHQRWLQYROYHGLQWKHVWXG\7KLVJURXSZKLFKZLOOFRQVLVW
RIDELRVWDWLVWLFLDQDVWDWLVWLFDOSURJUDPPHUDYDOLGDWLRQVWDWLVWLFDOSURJUDPPHUDQGD
FOLQLFDOUHYLHZHUZLOOUHYLHZWKHVZHDWFKORULGHGDWDWRHQVXUHWKHUHDUHQRVLJQLILFDQWGDWD
LVVXHVDQGZLOOXVHWKHEOLQGHGGDWDVHWWRUHILQHWKHVWDWLVWLFDOSURJUDPV
7.4.2
Unblinding
$WWKHLQLWLDWLRQRIWKHVWXG\WKHVWXG\VLWHVZLOOEHLQVWUXFWHGRQWKHPHWKRGIRUEUHDNLQJWKH
EOLQG7KHXQEOLQGLQJPHWKRGZLOOEHHLWKHUDPDQXDORUHOHFWURQLFSURFHVV
Page 14 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

8QEOLQGLQJRIWKHLQGLYLGXDOVXEMHFW
VWUHDWPHQWE\WKHLQYHVWLJDWRUZLOOEHOLPLWHGWRPHGLFDO
HPHUJHQFLHVRUXUJHQWFOLQLFDOVLWXDWLRQVLQZKLFKNQRZOHGJHRIWKHVXEMHFW
VVWXG\WUHDWPHQW
LVQHFHVVDU\IRUFOLQLFDOPDQDJHPHQW,QVXFKFDVHVLQYHVWLJDWRUVVKRXOGXVHWKHLUEHVW
MXGJPHQWDVWRZKHWKHUWRXQEOLQGZLWKRXWILUVWDWWHPSWLQJWRFRQWDFWWKHPHGLFDOPRQLWRUWR
GLVFXVVDQGDJUHHWRWKHQHHGIRUXQEOLQGLQJ,ILQYHVWLJDWRUVGHHPWKDWLWLVQRWQHFHVVDU\WR
XQEOLQGLPPHGLDWHO\WKH\ZLOOILUVWDWWHPSWWRFRQWDFWWKHPHGLFDOPRQLWRUWRGLVFXVVDQG
DJUHHWRWKHQHHGIRUXQEOLQGLQJ,ILQYHVWLJDWRUVKDYHWULHGEXWDUHXQDEOHWRUHDFKWKH
PHGLFDOPRQLWRUWKH\VKRXOGXVHWKHLUEHVWMXGJPHQWEDVHGRQWKHQDWXUHDQGXUJHQF\RIWKH
FOLQLFDOVLWXDWLRQDQGPD\SURFHHGZLWKXQEOLQGLQJZLWKRXWKDYLQJVXFFHVVIXOO\UHDFKHGDQG
GLVFXVVHGWKHVLWXDWLRQZLWKWKHPHGLFDOPRQLWRU
&RQWDFWLQIRUPDWLRQIRUWKHPHGLFDOPRQLWRURUDSSURSULDWHEDFNXSZLOOEHSURYLGHGLQD
VHSDUDWHGRFXPHQW
,QDGGLWLRQWKH9HUWH[0HGLFDO,QIRUPDWLRQ&DOO&HQWHU
ZLOODQVZHUFDOOV
KRXUVDGD\GD\VDZHHNGD\VRIWKH\HDUDQGZLOOWULDJHWKHVHFDOOVWRWKH9HUWH[
PHGLFDOPRQLWRURUDSSURSULDWHEDFNXS
,IDVXEMHFW
VWUHDWPHQWDVVLJQPHQWKDVEHHQXQEOLQGHGIRUDPHGLFDOHPHUJHQF\RUXUJHQW
FOLQLFDOVLWXDWLRQWKH9HUWH[PHGLFDOPRQLWRUVKRXOGEHQRWLILHGZLWKLQKRXUVRIWKH
XQEOLQGLQJHYHQW7KHUHDVRQDQGWKHGDWHRIWKHXQEOLQGLQJVKRXOGEHGRFXPHQWHGFOHDUO\LQ
WKHVXEMHFW
VVWXG\ILOH,QIRUPDWLRQDERXWWKHWUHDWPHQWDVVLJQPHQWREWDLQHGIURPWKH
XQEOLQGLQJZLOOEHPDLQWDLQHGLQDVHFXUHORFDWLRQZLWKFRQWUROOHGDFFHVVDQGZLOOQRWEH
VKDUHGZLWKWKHVSRQVRU9HUWH[FRQWUDFWUHVHDUFKRUJDQL]DWLRQ&52RUDQ\VLWHSHUVRQQHO
RWKHUWKDQWKHSK\VLFLDQWUHDWLQJWKHVXEMHFW ,QDGGLWLRQWKHLQYHVWLJDWRUZLOOFRQVLGHU
ZKHWKHUWKHFOLQLFDOHYHQWWKDWSURPSWHGXQEOLQGLQJZLOOEHFRQVLGHUHGDQ6$(DFFRUGLQJWR
WKHUHJXODWRU\GHILQLWLRQVRUFULWHULDIRU6$(VDQGLIVRVXEPLWDQ6$(UHSRUWWR9HUWH[*36
RUGHVLJQHHSHU6HFWLRQRISURWRFRO
9HUWH[*36RUGHVLJQHHZLOODOVRXQEOLQGDQ\6$(UHSRUWVLQFRPSOLDQFHZLWKUHJXODWRU\
UHSRUWLQJUHTXLUHPHQWV,QDGGLWLRQ9HUWH[PD\IRUPDWWHUVUHODWLQJWRVDIHW\FRQFHUQV
XQEOLQGLQGLYLGXDOVXEMHFWVDWDQ\WLPH
8 
ANALYSIS SETS
7KHIROORZLQJDQDO\VLVVHWVZLOOEHGHILQHGLQWKLVVWXG\$OO6XEMHFWV6HW6DIHW\6HWLQWKH
,YDFDIWRU5XQLQ3HULRG$FWLYH&RPSDUDWRU6XEMHFWV6HW)XOO$QDO\VLV6HW)$6LQWKH
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGDQG6DIHW\6HWLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW
3HULRG
7KHVWXG\KDVWZRVFKHGXOHGGRVLQJSHULRG
,YDFDIWRU5XQLQ3HULRGVWDUWVIURPWKHILUVWGRVHGDWHRIRSHQODEHOLYDFDIWRUPRQRWKHUDS\
DQGHQGVSULRUWRUDQGRPL]DWLRQ
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGVWDUWVDIWHUWKHUDQGRPL]DWLRQWRHLWKHU9;
,YDFDIWRUFRPELQDWLRQWKHUDS\RULYDFDIWRUPRQRWKHUDS\DQGUXQVIURPWKHILUVWGRVHGDWH
RIWKHUDQGRPL]HGVWXG\GUXJGXULQJWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGWRWKH
VFKHGXOHGODVWGRVHDWWKH:HHNYLVLW
Page 15 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

8.1
All Subjects Set
7KH$OO6XEMHFWV6HWLVGHILQHGDVDOOVXEMHFWVZKRZHUHHQUROOHGLQHLWKHUWKH,YDFDIWRU5XQ
LQ3HULRGRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGLHDOOVXEMHFWVLQWKHVWXG\7KLV
DQDO\VLVVHWZLOOEHXVHGIRUDOOLQGLYLGXDOVXEMHFWGDWDOLVWLQJVDQGIRUWKHGLVSRVLWLRQ
VXPPDU\WDEOHXQOHVVVSHFLILHGRWKHUZLVH
7KH$FWLYH&RPSDUDWRU6XEMHFWV6HWLQFOXGHVDOOVXEMHFWVUDQGRPL]HGRUZKRUHFHLYHGDW
OHDVWGRVHRIVWXG\GUXJLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG7KLVDQDO\VLVVHWZLOO
EHXVHGIRUVSHFLILFGLVSRVLWLRQIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGDQGVXEMHFW
OLVWLQJVUHODWHGWRWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGRQO\
8.2
Full Analysis Set
7KH)XOO$QDO\VLV6HW)$6LVGHILQHGDVDOOUDQGRPL]HGVXEMHFWVZKRFDUU\WKHLQWHQGHG
&)75DOOHOHPXWDWLRQDQGKDYHUHFHLYHGDWOHDVWGRVHRIVWXG\GUXJGXULQJWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRGDIWHUUDQGRPL]DWLRQ(IILFDF\DQDO\VHVZLOOEHSHUIRUPHGLQ
WKH)$6LQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGLQZKLFKVXEMHFWVZLOOEHDQDO\]HG
DFFRUGLQJWRWKHLUUDQGRPL]HGWUHDWPHQWJURXS
8.3
Safety Set
7KH6DIHW\6HWGHILQHGVHSDUDWHO\IRUWKH,YDFDIWRU5XQLQ3HULRGDQGWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRGLQFOXGHVDOOVXEMHFWVZKRUHFHLYHGDWOHDVWGRVHRIVWXG\
GUXJLQWKHFRUUHVSRQGLQJWUHDWPHQWSHULRG7KHVDIHW\DQDO\VHVZLOOEHSHUIRUPHGVHSDUDWHO\
IRUWKH,YDFDIWRU5XQLQ3HULRGDQGWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGVXEMHFWVZLOOEH
DQDO\]HGDFFRUGLQJWRWKHWUHDWPHQWWKH\UHFHLYHG

)RUWKHVDIHW\DQDO\VLVWKHIROORZLQJDQDO\VHVSHULRGZLOOEHGHILQHGDVEHORZ
x
7KHSUHWUHDWPHQWSHULRG,YDFDIWRU5XQLQ3HULRGRQO\LVGHILQHGDVWKHSHULRGDIWHU
WKHLQIRUPHGFRQVHQWDVVHQWGDWHDQGEHIRUHWKHLQLWLDOGRVLQJRIVWXG\GUXJLQWKH
,YDFDIWRU5XQLQ3HULRG
x
7KH7UHDWPHQWHPHUJHQW7(3HULRGZLOOEHGHILQHGVHSDUDWHO\IRUWKH,YDFDIWRU5XQ
LQ3HULRGDQGWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG

7KH7(3HULRGIRUWKH,YDFDIWRU5XQLQ3HULRGLVGHILQHGDVWKHGDWHRIWKHILUVW
GRVHLQWKH,YDFDIWRU5XQLQ3HULRGWRWKHODVWGD\SULRUWRWKHILUVWGRVHRIWKH
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGRUHLWKHUWKH6DIHW\)ROORZXS9LVLWRU
GD\VLQFOXVLYHDIWHUWKHODVWGRVHZKLFKHYHULVHDUOLHUIRUVXEMHFWVZKR
GLVFRQWLQXHWUHDWPHQWGXULQJWKH,YDFDIWRU5XQLQ3HULRGDQGDUHQRWUDQGRPL]HG
LQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG

7KH7(3HULRGIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGLVGHILQHGDVWKHILUVW
GRVHRIWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGWRWKH6DIHW\)ROORZXS9LVLWRU
GD\VLQFOXVLYHDIWHUWKHODVWGRVHZKLFKHYHULVHDUOLHULQWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRG
Page 16 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

9 
STATISTICAL ANALYSIS
9.1
General Considerations
7KH6FKHGXOHRI$VVHVVPHQWVLVSURYLGHGLQ$SSHQGL[&7KHSUHFLVLRQVWDQGDUGVIRU
UHSRUWLQJVDIHW\DQGHIILFDF\YDULDEOHVDUHSURYLGHGLQDQLQWHUQDO%LRPHWULFVGRFXPHQWWKDW
VSHFLILHVWKHSURJUDPPLQJUXOHVLQFOXGLQJWKHSUHFLVLRQIRUGHULYHGYDULDEOHV
$OOLQGLYLGXDOVXEMHFWGDWDIRUVXEMHFWVZKRZHUHUDQGRPL]HGRUUHFLYHGDWOHDVWGRVHRI
VWXG\GUXJLH$OO6XEMHFWV6HWZLOOEHSUHVHQWHGLQGDWDOLVWLQJVZLWKLQGLFDWRURIGRVLQJ
SHULRGLH,YDFDIWRU5XQLQ3HULRGYV$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGDVDSSOLFDEOH
/LVWLQJVUHODWHGWR$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGRQO\ZLOOEHEDVHGRQWKH$FWLYH
&RPSDUDWRU6XEMHFWV6HW

&RQWLQXRXVYDULDEOHVZLOOEHVXPPDUL]HGXVLQJWKHIROORZLQJGHVFULSWLYHVXPPDU\
VWDWLVWLFVWKHQXPEHURIVXEMHFWVQPHDQVWDQGDUGGHYLDWLRQ6'VWDQGDUGHUURU6(
PHGLDQPLQLPXPYDOXHPLQDQGPD[LPXPYDOXHPD[

&DWHJRULFDOYDULDEOHVZLOOEHVXPPDUL]HGXVLQJFRXQWVDQGSHUFHQWDJHV

%DVHOLQHYDOXH$EVROXWHFKDQJHIURPEDVHOLQHDQG5HODWLYHFKDQJHIURPEDVHOLQHZLOO
EHGHILQHGVHSDUDWHO\IRUWKH,YDFDIWRU5XQLQ3HULRGDQGWKH$FWLYH&RPSDUDWRU7UHDWPHQW
3HULRG
%DVHOLQHYDOXH
x
8QOHVVVSHFLILHGRWKHUZLVHEDVHOLQHIRUWKH,YDFDIWRU5XQLQ3HULRGZLOOEHGHILQHGDV
WKHPRVWUHFHQWQRQPLVVLQJPHDVXUHPHQWVFKHGXOHGRUXQVFKHGXOHGFROOHFWHGSULRU
WRLQLWLDODGPLQLVWUDWLRQRI,YDFDIWRUPRQRWKHUDS\
x
8QOHVVVSHFLILHGRWKHUZLVHWKHEDVHOLQHIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
ZLOOEHGHILQHGDVWKHPRVWUHFHQWQRQPLVVLQJPHDVXUHPHQWVFKHGXOHGRU
XQVFKHGXOHGFROOHFWHGSULRUWRLQLWLDODGPLQLVWUDWLRQRIWKH9;LYDFDIWRU
FRPELQDWLRQWKHUDS\RULYDFDIWRUPRQRWKHUDS\SODFHERLYDFDIWRUGXULQJWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRGEXWQRHDUOLHUWKDQWKHPHDVXUHPHQWDW:HHN
x
)RUVSLURPHWU\WKHEDVHOLQHYDOXHXVHGIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
ZLOOEHWKHDYHUDJHRIWKHPHDVXUHPHQWDW:HHNDQGWKHPHDVXUHPHQWRQ'D\
SUHGRVH,IDVXEMHFWKDVDQ$(OHDGLQJWRDQDSSURYHGH[WHQVLRQRIWKH,YDFDIWRU5XQ
LQ3HULRGDQGWKH:HHNVSLURPHWU\DVVHVVPHQWLVEHWZHHQWKHVWDUWDQGHQGGDWH
LQFOXVLYHRIWKH$(WKHQWKHPHDVXUHPHQWRQ'D\SUHGRVHZLOOVHUYHDVEDVHOLQH
IRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
x
)RU(&*WKHEDVHOLQHZLOOEHGHILQHGDVWKHDYHUDJHRIWKHQRQPLVVLQJSUHWUHDWPHQW
PHDVXUHPHQWVWULSOLFDWHRQ'D\WKHILUVWGD\RIWKHFRUUHVSRQGLQJWUHDWPHQW
SHULRG
Page 17 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

x
)RUVZHDWFKORULGHWKHEDVHOLQHYDOXHZLOOEHWKHPHDQRIWKHODVWYDOXHVRQWKHOHIW
DQGWKHULJKWDUPSULRUWRWKHILUVWGRVHRIWKHVWXG\GUXJRIWKHFRUUHVSRQGLQJ
WUHDWPHQWSHULRG
1RWHWKDWUHIHUHQFHVWREDVHOLQHKHUHDIWHUVKRXOGDOZD\VEHLQWHUSUHWHGLQWKHFRQWH[WRIWKH
FRUUHVSRQGLQJWUHDWPHQWSHULRG
&KDQJHDEVROXWHFKDQJHIURPEDVHOLQHZLOOEHFDOFXODWHGDV3RVW
EDVHOLQHYDOXHí%DVHOLQHYDOXH
5HODWLYHFKDQJHIURPEDVHOLQHZLOOEHFDOFXODWHGDQGH[SUHVVHGLQSHUFHQWDJHDV
î3RVWEDVHOLQHYDOXHí%DVHOLQHYDOXH%DVHOLQHYDOXH

7UHDWPHQWHPHUJHQW7(3HULRG
7KHUHDUHWZRWUHDWPHQWSHULRGVLQWKLVVWXG\DVGHILQHGLQ6HFWLRQ7KH7(SHULRGVZLOO
EHXVHGIRUVDIHW\DQDO\VHVXQOHVVVSHFLILHGRWKHUZLVH

8QVFKHGXOHGYLVLWV8QVFKHGXOHGYLVLWPHDVXUHPHQWVZLOOEHLQFOXGHGLQDQDO\VLVDVIROORZV
x
,QVFKHGXOHGYLVLWZLQGRZVSHUVSHFLILHGYLVLWZLQGRZLQJUXOHV
x
,QWKHGHULYDWLRQRIEDVHOLQHODVWRQWUHDWPHQWPHDVXUHPHQWV
x
,QWKHGHULYDWLRQRIPD[LPXPPLQLPXPRQWUHDWPHQWYDOXHVDQGPD[LPXPPLQLPXP
FKDQJHIURPEDVHOLQHYDOXHVIRUVDIHW\DQDO\VHV
x
,QLQGLYLGXDOVXEMHFWGDWDOLVWLQJVDVDSSURSULDWH

9LVLWZLQGRZLQJUXOHV7KHDQDO\VLVYLVLWZLQGRZVIRUSURWRFROGHILQHGYLVLWVDUHSURYLGHG
LQ$SSHQGL[&7KHZLQGRZVZLOOEHDSSOLHGXVLQJWKHIROORZLQJUXOHVIRUERWKVFKHGXOHG
DQGXQVFKHGXOHGYLVLWV
 ,IQRPHDVXUHPHQWLVDYDLODEOHZLWKLQDYLVLWZLQGRZWKHDVVHVVPHQWZLOOEH
FRQVLGHUHGPLVVLQJIRUWKHYLVLW
 ,IWKHUHLVPRUHWKDQRQHPHDVXUHPHQWDYDLODEOHZLWKLQWKHVDPHYLVLWZLQGRZXVH
WKHIROORZLQJUXOHV
x
)RUDOOHIILFDF\SDUDPHWHUVLIWKHUHDUHPXOWLSOHPHDVXUHPHQWVZLWKLQDYLVLWZLQGRZ
WKHUHFRUGDWWKHVFKHGXOHGYLVLWZLOOEHXVHG2WKHUZLVH
o
7KHUHFRUGFORVHVWWRWKHWDUJHWGD\ZLOOEHXVHG
o
,IWKHUHDUHPXOWLSOHUHFRUGVZLWKWKHVDPHGLVWDQFHWRWKHWDUJHWGD\WKHODWHVW
UHFRUGZLOOEHXVHG
o
$VVHVVPHQWVDWHDUO\WUHDWPHQWWHUPLQDWLRQ(77YLVLWZLOOIROORZWKH
ZLQGRZLQJUXOHVIRUUHJXODUYLVLWVXSWR:HHN
o
$VVHVVPHQWVDWVDIHW\IROORZXS6)8YLVLWZLOOIROORZWKHZLQGRZLQJUXOHV
IRUUHJXODUYLVLWVLIWKH\IDOOZLWKLQWKHXSSHUERXQGDU\RIWKHZLQGRZIRU
Page 18 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

:HHNRUUHPDLQDV6)8LIWKH\JREH\RQGWKHXSSHUERXQGDU\RIWKH
ZLQGRZIRU:HHN
x
)RUDOOVDIHW\SDUDPHWHUVLIWKHUHDUHPXOWLSOHPHDVXUHPHQWVZLWKLQDYLVLWZLQGRZ
WKHQWKHUHFRUGFORVHVWWRWKHWDUJHWGD\ZLOOEHXVHGLIWKHUHDUHPXOWLSOH
UHFRUGVZLWKLQWKHVDPHGLVWDQFHIURPWKHWDUJHWGD\WKHODWHVWUHFRUGZLOOEHXVHGRU
6)8YLVLWZLOOQRWEHZLQGRZHGLQVWHDGLWZLOOEHXVHGDFFRUGLQJWRWKHQRPLQDO
YLVLWLQUHOHYDQWDQDO\VHV
1RWHVSLURPHWU\DVVHVVPHQWV%0,ZHLJKWDQGKHLJKWZLOOEHXVHGIRUERWKHIILFDF\DQG
VDIHW\SXUSRVHV7KHLUPHDVXUHPHQWVZLOOIROORZWKHYLVLWZLQGRZLQJUXOHVIRUHIILFDF\
SDUDPHWHUV

,QFRPSOHWHPLVVLQJGDWDZLOOQRWEHLPSXWHGXQOHVVVSHFLILHGRWKHUZLVH

2XWOLHUV1RIRUPDOVWDWLVWLFDODQDO\VHVZLOOEHSHUIRUPHGWRGHWHFWRUUHPHG\WKHSUHVHQFH
RIVWDWLVWLFDORXWOLHUVXQOHVVVSHFLILHGRWKHUZLVH

0XOWLSOLFLW\$KLHUDUFKLFDOWHVWLQJSURFHGXUHZLOOEHXVHGWRFRQWUROWKH7\SH,HUURUDWWZR
VLGHGĮ DPRQJWKHSULPDU\DQGWKHNH\VHFRQGDU\HQGSRLQWV7KHWHVWLQJKLHUDUFK\LV
DVIROORZV
$EVROXWHFKDQJHLQSHUFHQWSUHGLFWHG)(9IURPEDVHOLQHWKURXJK:HHN
5HODWLYHFKDQJHLQSHUFHQWSUHGLFWHG)(9IURPEDVHOLQHWKURXJK:HHN
$EVROXWHFKDQJHLQ&)45UHVSLUDWRU\GRPDLQVFRUHIURPEDVHOLQHWKURXJK:HHN

9.2
Background Characteristics 
9.2.1
Subject Disposition
7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVLQWKHIROORZLQJFDWHJRULHVZLOOEHVXPPDUL]HG
x
$OO6XEMHFWV6HW1XPEHURQO\

,YDFDIWRU5XQLQ3HULRG
x
'RVHG6DIHW\6HWLQWKH,YDFDIWRU5XQLQ3HULRG
x
&RPSOHWHGWUHDWPHQWLQWKH,YDFDIWRU5XQLQ3HULRG
x
3UHPDWXUHO\GLVFRQWLQXHGWUHDWPHQWGXULQJWKH,YDFDIWRU5XQLQSHULRGDQGWKH
UHDVRQVIRUWUHDWPHQWGLVFRQWLQXDWLRQ

$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
x
5DQGRPL]HGLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG1XPEHURQO\
Page 19 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

x
'RVHGLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG1XPEHURQO\
x
)$6UDQGRPL]HGGRVHGDQGZLWKWKHLQWHQGHG&)75DOOHOHPXWDWLRQLQWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRG1XPEHURQO\
x
&RPSOHWHGWUHDWPHQWLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
x
3UHPDWXUHO\GLVFRQWLQXHGWUHDWPHQWGXULQJWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
DQGWKHUHDVRQVIRUWUHDWPHQWGLVFRQWLQXDWLRQ
x
&RPSOHWHGWKHVWXG\RUWKH6DIHW\)ROORZXS9LVLW
x
3UHPDWXUHO\GLVFRQWLQXHGWKHVWXG\DQGWKHUHDVRQVIRUGLVFRQWLQXDWLRQE\WKH
IROORZLQJVXEFDWHJRULHV
o
'LVFRQWLQXHGWKHVWXG\GXULQJWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
o
'LVFRQWLQXHGWKHVWXG\DIWHUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
x
/DVWVFKHGXOHGYLVLWFRPSOHWHGIRUHYHU\RQHLQ)$6
)RUFDWHJRULHVUHODWHGWRWKH,YDFDIWRU5XQLQ3HULRGWKHQXPEHUDQGSHUFHQWDJHRIVXEMHFWV
LQHDFKGLVSRVLWLRQFDWHJRU\ZLOOEHVXPPDUL]HGZLWKWKHQXPEHULQWKHVDIHW\VHWLQWKH
,YDFDIWRU5XQLQ3HULRGDVWKHGHQRPLQDWRUWRJHWKHUZLWKWKHQXPEHURIVXEMHFWVHQUROOHG
EXWQHYHUGRVHG$OLVWLQJZLOOEHSURYLGHGIRUVXEMHFWVZKRGLVFRQWLQXHGWUHDWPHQWGXULQJ
WKH,YDFDIWRU5XQLQ3HULRGRUZKRGLVFRQWLQXHGWKHVWXG\GXULQJWKH,YDFDIWRU5XQLQ3HULRG
ZLWKWKHUHDVRQVIRUGLVFRQWLQXDWLRQ
7KHQXPEHUDQGSHUFHQWDJHRIHQUROOHGVXEMHFWVLQWKH,YDFDIWRU5XQLQ3HULRGZLOOEH
VXPPDUL]HGRYHUDOOXVLQJWKHQXPEHURIVXEMHFWVLQWKH$OO6XEMHFWV6HWDVWKHGHQRPLQDWRU
$QHQUROOPHQWOLVWLQJZLOOEHSURYLGHGZLWKVXEMHFWVHQUROOHGRUGHUHGE\WKHHQUROOPHQWGDWH
)RUWKHFDWHJRULHVUHODWHGWRWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGWKHQXPEHUDQG
SHUFHQWDJHRIVXEMHFWVLQHDFKGLVSRVLWLRQFDWHJRU\ZLOOEHVXPPDUL]HGZLWKWKHQXPEHURI
VXEMHFWVLQWKH)$6DVWKHGHQRPLQDWRUH[FHSWDVQRWHGDERYH
7KHQXPEHUDQGSHUFHQWDJHRIUDQGRPL]HGVXEMHFWVLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW
3HULRGZLOOEHVXPPDUL]HGE\VWUDWLILFDWLRQIDFWRUVDQGE\FRXQWU\DQGE\VLWHXVLQJWKH
$FWLYH&RPSDUDWRU6XEMHFWV6HW$UDQGRPL]DWLRQOLVWLQJZLOOEHSURYLGHGZLWKVXEMHFWV
RUGHUHGE\UDQGRPL]DWLRQGDWH
$OLVWLQJZLOOEHSURYLGHGIRUVXEMHFWVZKRGLVFRQWLQXHGWUHDWPHQWGXULQJWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRGRUZKRGLVFRQWLQXHGVWXG\GXULQJWKH$FWLYH&RPSDUDWRU
7UHDWPHQWSHULRGZLWKWKHUHDVRQVIRUGLVFRQWLQXDWLRQ
9.2.2
Demographics and Baseline Characteristics
'HPRJUDSKLFVPHGLFDOKLVWRU\DQGEDVHOLQHFKDUDFWHULVWLFVZLOOEHVXPPDUL]HGRYHUDOOEDVHG
RQWKH6DIHW\6HWLQWKH,YDFDIWRU5XQLQ3HULRGDQGRQWKH)$6E\UDQGRPL]HGWUHDWPHQW
JURXSLQWKH$FWLYH&RPSDUDFWRU7UHDWPHQW3HULRG
'HPRJUDSKLFGDWDZLOOLQFOXGHWKHIROORZLQJ
x
$JHLQ\HDUV
Page 20 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

x
$JHJURXSVDWWKH6FUHHQLQJYLVLWYHUVXV\HDUVRIDJH
x
6H[
x
(WKQLFLW\+LVSDQLFRU/DWLQRQRW+LVSDQLFRU/DWLQRDQGQRWFROOHFWHGSHUORFDO
UHJXODWLRQV
x
5DFH:KLWH%ODFNRU$IULFDQ$PHULFDQ$VLDQ$PHULFDQ,QGLDQRU$ODVND1DWLYH
1DWLYH+DZDLLDQRU2WKHU3DFLILF,VODQGHUDQG2WKHU
x
*HRJUDSKLFUHJLRQ1RUWK$PHULFD(XURSH$XVWUDOLD
%DVHOLQHFKDUDFWHULVWLFVZLOOLQFOXGHWKHIROORZLQJ
x
7\SHRIPXWDWLRQLQWKHVHFRQGCFTRDOOHOH5+2WKHUV
x
:HLJKWNJ
x
+HLJKWFP
x
%0,NJP
x
:HLJKW]VFRUHVXEMHFWV\HDUVROG
x
+HLJKW]VFRUHVXEMHFWV\HDUVROG
x
%0,]VFRUHVXEMHFWV\HDUVROG
x
W\SHRIPXWDWLRQRQWKHVHFRQGCFTRDOOHOHR117H YHUVXVRWKHUDOORZHGPXWDWLRQV
'LVHDVHFKDUDFWHULVWLFVZLOOLQFOXGHWKHIROORZLQJ
x
3HUFHQWSUHGLFWHG)(9DWVFUHHQLQJIRU,YDFDIWRU5XQLQ3HULRG
x
3HUFHQWSUHGLFWHG)(9DWEDVHOLQHWRWR!IRU$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRG
x
3HUFHQWSUHGLFWHG)(9DWEDVHOLQH
x
)(9/
x
)9&/
x
3HUFHQWSUHGLFWHG)9&
x
)()25-75% /VHF
x
3HUFHQWSUHGLFWHG)()25-75% 
x
)(9)9&
x
6ZHDW&KORULGH
x
&)45UHVSLUDWRU\GRPDLQ
x
5HFHLYHGGRUQDVHDOIDEHIRUHILUVWGRVHRIVWXG\GUXJ<HV1R
x
5HFHLYHGDQ\LQKDOHGDQWLELRWLFEHIRUHILUVWGRVHRIVWXG\GUXJ<HV1R
x
5HFHLYHGDQ\EURQFKRGLODWRUEHIRUHILUVWGRVHRIVWXG\GUXJ<HV1R
Page 21 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

1RWH2QWKHEURQFKRGLODWRUSDJHRQO\WKRVHFRGHGDVEURQFKRGLODWRUZLOOEHLQFOXGHG
x
5HFHLYHGDQ\LQKDOHGEURQFKRGLODWRUEHIRUHILUVWGRVHRIVWXG\GUXJ<HV1R
1RWH2QWKHEURQFKRGLODWRUSDJHRQO\WKRVHFRGHGDVEURQFKRGLODWRUZLOOEHLQFOXGHG
x
5HFHLYHGDQ\LQKDOHGK\SHUWRQLFVDOLQHEHIRUHILUVWGRVHRIVWXG\GUXJ<HV1R
x
5HFHLYHGDQ\LQKDOHGFRUWLFRVWHURLGVEHIRUHILUVWGRVHRIVWXG\GUXJ<HV1R
x
&RORQL]DWLRQRI Pseudomonas aeruginosaVWDWXVEHIRUHWKH,YDFDIWRU5XQLQ3HULRG
3RVLWLYH1HJDWLYH
6XEMHFWVZLWKH[FOXVLRQDU\OLYHUIXQFWLRQWHVWUHVXOWVDWVFUHHQLQJFRXOGEHUHWHVWHGRQFH
ZLWKLQGD\VDQGZHUHFRQVLGHUHGHOLJLEOHLIWKHVHUHSHDWHGUHVXOWVPHWHOLJLELOLW\
FULWHULD7ZRVXPPDULHVZLOOEHSURYLGHGRQHIRUWKHLQLWLDOOLYHUIXQFWLRQWHVWLQJWHVW
RQO\DQGRQHEDVHGRQWKHUHWHVWLQJUHVXOWVLIDYDLODEOH
9.2.3
Medical History
0HGLFDOKLVWRU\ZLOOEHFRGHGE\XVLQJWKH0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV
0HG'5$DQGZLOOEHVXPPDUL]HGGHVFULSWLYHO\XVLQJWKH)$6SRSXODWLRQ0HGLFDOKLVWRU\
ZLOOEHVXPPDUL]HGGHVFULSWLYHO\E\V\VWHPRUJDQFODVV62&DQGSUHIHUUHGWHUP37,Q
DGGLWLRQWKHQXPEHURIVXEMHFWVUHSRUWHGWRKDYHKDGSRVLWLYHFXOWXUHVIRUUHVSLUDWRU\
SDWKRJHQVLQWKH\HDUVSULRUWRVFUHHQLQJLHDQVZHUHG\HVRQWKHUHVSLUDWRU\
PLFURELRORJ\IRUPZLOOEHVXPPDUL]HGE\WHVWDQGVXEFDWHJRULHVZLWKLQWKHWHVW
+RVSLWDOL]DWLRQDQGFOLQLFYLVLWKLVWRU\LQWKHSDVW\HDUZLOOEHOLVWHG
9.2.4
Prior and Concomitant Medications
0HGLFDWLRQXVHZLOOEHFRGHGXVLQJWKH:RUOG+HDOWK2UJDQL]DWLRQ'UXJ'LFWLRQDU\
(QKDQFHGDQGFDWHJRUL]HGDV
x
3ULRUPHGLFDWLRQDQ\PHGLFDWLRQWKDWVWDUWHGEHIRUHLQLWLDOGRVLQJRIVWXG\GUXJLQ
WKH,YDFDIWRU5XQLQ3HULRGUHJDUGOHVVRIZKHQLWHQGHG
x
&RQFRPLWDQWPHGLFDWLRQGXULQJWKH,YDFDIWRU5XQLQ3HULRGPHGLFDWLRQWKDW
FRQWLQXHGRUWKDWVWDUWHGDWRUDIWHUWKHILUVWGRVHRIVWXG\GUXJWKURXJKWKHHQGRIWKH
7(3HULRGIRUWKH,YDFDIWRU5XQLQ3HULRG
x
&RQFRPLWDQWPHGLFDWLRQGXULQJWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
PHGLFDWLRQWKDWFRQWLQXHGRUWKDWVWDUWHGDWRUDIWHUWKHILUVWGRVHRIVWXG\GUXJ
WKURXJKWKHHQGRIWKH7(3HULRGRIWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
x
3RVWWUHDWPHQWPHGLFDWLRQPHGLFDWLRQWKDWFRQWLQXHGRUWKDWVWDUWHGDIWHUWKHHQGRI
WKH7(3HULRGRIWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG

$JLYHQPHGLFDWLRQFDQEHFODVVLILHGDVDSULRUPHGLFDWLRQDFRQFRPLWDQWPHGLFDWLRQ
FRQFRPLWDQWPHGLFDWLRQGXULQJWKH,YDFDIWRU5XQLQ3HULRGDQGRUDFRQFRPLWDQWPHGLFDWLRQ
GXULQJWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGRUDSRVWWUHDWPHQWPHGLFDWLRQERWKSULRU
DQGFRQFRPLWDQWERWKFRQFRPLWDQWDQGSRVWWUHDWPHQWRUSULRUFRQFRPLWDQWDQG
SRVWWUHDWPHQW,IDPHGLFDWLRQKDVDPLVVLQJRUSDUWLDOO\PLVVLQJVWDUWHQGGDWHRUWLPHDQGLW
Page 22 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

FDQQRWEHGHWHUPLQHGZKHWKHULWZDVWDNHQEHIRUHLQLWLDOGRVLQJFRQFRPLWDQWO\RUEH\RQG
WKH7(3HULRGLWZLOOEHFRQVLGHUHGDVSULRUFRQFRPLWDQWDQGSRVWWUHDWPHQW
3ULRUPHGLFDWLRQVDQGFRQFRPLWDQWPHGLFDWLRQVLQWKH,YDFDIWRU5XQLQ3HULRGZLOOEH
VXPPDUL]HGGHVFULSWLYHO\EDVHGRQWKH6DIHW\6HWLQWKDWSHULRG

3ULRUPHGLFDWLRQVDQGFRQFRPLWDQWPHGLFDWLRQLQWKH,YDFDIWRU5XQLQ3HULRGDOVRZLOOEH
VXPPDUL]HGGHVFULSWLYHO\EDVHGRQWKH)$6IRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
&RQFRPLWDQWPHGLFDWLRQVLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGDOVRZLOOEH
VXPPDUL]HGGHVFULSWLYHO\EDVHGRQWKH)$6

3RVWWUHDWPHQWPHGLFDWLRQVZLOOEHOLVWHGIRUHDFKVXEMHFW
'HWDLOVIRULPSXWLQJPLVVLQJRUSDUWLDOVWDUWDQGRUVWRSGDWHVRIPHGLFDWLRQDUHGHVFULEHGLQ
$SSHQGL[(
9.2.5
Study Drug Exposure 
'XUDWLRQRIVWXG\GUXJH[SRVXUHLQGD\VZLOOEHFDOFXODWHGDVODVWGRVHGDWH±ILUVWGRVH
GDWHGD\UHJDUGOHVVRIVWXG\GUXJLQWHUUXSWLRQ
([SRVXUHZLOOEHVXPPDULHGVHSDUDWHGIRUWKH,YDFDIWRU5XQLQ3HULRGDQGWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRGEDVHGRQWKHFRUUHVSRQGLQJVDIHW\VHW
9.2.6
Study Drug Compliance 
6WXG\GUXJFRPSOLDQFHEDVHGRQVWXG\GUXJH[SRVXUHZLOOEHFDOFXODWHGDVu>íWRWDO
QXPEHURIGD\VRIDQ\VWXG\GUXJLQWHUUXSWLRQGXUDWLRQRIVWXG\GUXJH[SRVXUHLQGD\V@
6WXG\GUXJFRPSOLDQFHZLOOEHVXPPDUL]HGGHVFULSWLYHO\E\WKHQXPEHURIVXEMHFWVQ
PHDQ6'6(PHGLDQPLQDQGPD[&RPSOLDQFHDOVRZLOOEHVXPPDUL]HGLQFDWHJRULHV
DQGXVLQJIUHTXHQF\WDEOHV
6WXG\GUXJFRPSOLDQFHZLOOEHVXPPDUL]HGIRUWKH,YDFDIWRU5XQLQ3HULRGEDVHGRQWKH
,YDFDIWRU5XQLQ3HULRG6DIHW\6HWDQGIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQWSHULRGEDVHG
RQWKH)$6
9.2.7
Important Protocol Deviations 
,PSRUWDQWSURWRFROGHYLDWLRQV,3'DUHDVXEVHWRISURWRFROGHYLDWLRQVWKDWPD\VLJQLILFDQWO\
LPSDFWWKHFRPSOHWHQHVVDFFXUDF\DQGRUUHOLDELOLW\RIWKHVWXG\GDWDRUWKDWPD\
VLJQLILFDQWO\DIIHFWDVXEMHFW
VULJKWVVDIHW\RUZHOOEHLQJ,3'UXOHVZLOOEHGHYHORSHGDQG
ILQDOL]HGEHIRUHGDWDEDVHORFN
7KHSURWRFROGHYLDWLRQVWKDWVKRXOGEHFRQVLGHUHGDVSRWHQWLDO,3'VLQFOXGHEXWDUHQRW
OLPLWHGWR
x
9LRODWLRQRIVXEMHFWVULJKWVVDIHW\RUZHOOEHLQJ
x
6XEMHFWHQWHUHGWKHVWXG\GHVSLWHYLRODWLRQRIDQ\LQFOXVLRQRUH[FOXVLRQFULWHULD
x
6XEMHFWZDVOHVVWKDQFRPSOLDQWZLWKVWXG\PHGLFDWLRQV
x
6XEMHFWUHFHLYHGH[FOXGHGFRQFRPLWDQWPHGLFDWLRQV
Page 23 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

x
6XEMHFWUHFHLYHGWKHZURQJWUHDWPHQWRULQFRUUHFWGRVHV
x
6XEMHFWUHPDLQHGLQVWXG\GHVSLWHPHHWLQJZLWKGUDZDOFULWHULD
2FFXUUHQFHRIDQ\RIWKHVHHYHQWVVKRXOGEHFRQVLGHUHGDVSRWHQWLDO,3'VEXWWKHEOLQGHG
WHDPVKRXOGFDWHJRUL]HWKHPDV,3'VRQO\LIWKH\KDYHWKHSRWHQWLDOWRDIIHFWLQWHUSUHWDWLRQRI
VWXG\UHVXOWV
,3'VIURPWKHFOLQLFDOGDWDEDVHRUIURPWKHVLWHGHYLDWLRQORJZLOOEHVXPPDUL]HG
GHVFULSWLYHO\DQGSUHVHQWHGLQDQLQGLYLGXDOVXEMHFWGDWDOLVWLQJ

9.3
Efficacy Analysis 
$OOHIILFDF\DQDO\VHVGHVFULEHGLQWKLVVHFWLRQZLOOEHEDVHGRQWKH)$6GXULQJWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRGXQOHVVVSHFLILHGRWKHUZLVH7KHDQDO\VLVZLOOLQFOXGHDOO
DYDLODEOHPHDVXUHPHQWVWKURXJKWKHODVWDVVHVVPHQWLQFOXGLQJPHDVXUHPHQWVDIWHUWUHDWPHQW
GLVFRQWLQXDWLRQSHUWKHYLVLWZLQGRZLQJUXOHVGHVFULEHGLQ$SSHQGL['
6XPPDU\VWDWLVWLFVPD\EHSURYLGHGIRUHIILFDF\HQGSRLQWVGXULQJWKH,YDFDIWRU5XQLQ
3HULRG
9.3.1
Analysis of Primary Efficacy Endpoint(s)
9.3.1.1
Definition  
7KHSULPDU\HIILFDF\HQGSRLQWLVWKHDYHUDJHDEVROXWHFKDQJHIURPEDVHOLQHLQSHUFHQW
SUHGLFWHG)(9ZLWKDXQLWRISHUFHQWDJHSRLQWVWKURXJK:HHNLQWKH$FWLYH&RPSDUDWRU
7UHDWPHQW3HULRG
3HUFHQWSUHGLFWHG)(9LVWKHUDWLRRI)(9/WRWKHSUHGLFWHG)(9/H[SUHVVHGDVD
SHUFHQWDJH7KHSUHGLFWHG)(9ZLOOEHFDOFXODWHGXVLQJWKH+DQNLQVRQDQG:DQJ
VWDQGDUGVZLWKGHWDLOVLQ$SSHQGL[)
9.3.1.2 Summary in Ivacaftor Run-in Period
3HUFHQWSUHGLFWHG)(9ERWKWKHUDZYDOXHVDQGWKHLUDEVROXWHFKDQJHIURPEDVHOLQHZLOOEH
VXPPDUL]HGE\YLVLWIRUWKH,YDFDIWRU5XQLQ3HULRG:HHN:HHNDQG'D\SUHGRVH
9.3.1.3
Primary Analysis 
7KHSULPDU\DQDO\VLVIRUWKHSULPDU\HIILFDF\HQGSRLQWZLOOEHEDVHGRQDPL[HGPRGHOIRU
UHSHDWHGPHDVXUHV0050XVLQJ6$6352&0,;('LQWKH)$6IRUWKH$FWLYH
FRPSDUDWRU7UHDWPHQW3HULRG7KHQXOOK\SRWKHVLVWREHWHVWHGLVWKDWWKHDYHUDJHDEVROXWH
FKDQJHIURPEDVHOLQHLQSHUFHQWSUHGLFWHG)(9WKURXJK:HHNLVWKHVDPHIRUWKHWZR
WUHDWPHQWDUPV7KH0050ZLOOEHXVHGWRWHVWWKHGLIIHUHQFHEHWZHHQWUHDWPHQWJURXSV$
PYDOXHRIRUOHVVZLOOEHLQWHUSUHWHGDVVXIILFLHQWHYLGHQFHWRUHMHFWWKHQXOOK\SRWKHVLV
7KHPRGHOZLOOLQFOXGHDEVROXWHFKDQJHIURPEDVHOLQHLQSHUFHQWSUHGLFWHG)(9LQFOXGLQJ
DOOPHDVXUHPHQWVXSWR:HHN>LQFOXVLYH@ERWKRQWUHDWPHQWPHDVXUHPHQWVDQG
PHDVXUHPHQWVDIWHUWUHDWPHQWGLVFRQWLQXDWLRQDVWKHGHSHQGHQWYDULDEOHWUHDWPHQWYLVLWDV
DFODVVYDULDEOHDQGWUHDWPHQWE\YLVLWLQWHUDFWLRQDVIL[HGHIIHFWVZLWKDGMXVWPHQWIRUDJH
Page 24 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

JURXSDWVFUHHQLQJYHUVXV\HDUVRIDJHW\SHRIPXWDWLRQRQWKHVHFRQGCFTR
DOOHOHR117H YHUVXV2WKHUVDQGEDVHOLQHSHUFHQWSUHGLFWHG)(9YDOXHIRUWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRGDVIL[HGHIIHFWVDQGVXEMHFWDVDUDQGRPHIIHFW$Q
XQFRQVWUXFWHGFRYDUDLDQFHVWUXFWXUHZLOOEHXVHGWRPRGHOWKHZLWKLQVXEMHFWHUURUV
$.HQZDUG5RJHUDSSUR[LPDWLRQZLOOEHXVHGIRUWKHGHQRPLQDWRUGHJUHHVRIIUHHGRP,I
WKHUHLVDFRQYHUJHQFHSUREOHPGXHWRWKHXQVWUXFWXUHGFRYDULDQFHPDWUL[DFRPSRXQG
V\PPHWU\FRYDULDQFHVWUXFWXUHZLOOEHXVHGWRPRGHOWKHZLWKLQVXEMHFWHUURUV1R
LPSXWDWLRQRIPLVVLQJGDWDZLOOEHGRQH
7KHSULPDU\UHVXOWREWDLQHGIURPWKHPRGHOZLOOEHWKHDYHUDJHWUHDWPHQWHIIHFWWKURXJK
:HHNLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG$FRQWUDVWEDVHGRQWKHIL[HGHIIHFWVLQ
WKHPRGHOZLOOEHXVHGWRHVWLPDWHWKHDYHUDJHWUHDWPHQWHIIHFWDFURVVSRVWEDVHOLQHYLVLWV
WKURXJK:HHN7KHFRQWUDVWZLOOEHFRQVWUXFWHGDWWKHEDVHOLQHFRYDULDWHPHDQIRUWKH
FRPELQHGWUHDWPHQWJURXSVXVLQJXQLTXHVXEMHFWVLQWKH)$6ZKRKDYHDWOHDVWRQHSRVW
EDVHOLQHPHDVXUHPHQWWKURXJK:HHN
'HVFULSWLYHVXPPDU\VWDWLVWLFVLQFOXGLQJQXPEHURIVXEMHFWVPHDQVWDQGDUGGHYLDWLRQ6'
DQG/6PHDQVVWDQGDUGHUURU6(DQGVLGHGFRQILGHQFHLQWHUYDODORQJZLWKWKHP
YDOXHZLOOEHSURYLGHG,QSDUWLFXODUWKHGLIIHUHQFHLQ/6PHDQV6(DQGWKHFRUUHVSRQGLQJ
VLGHG&,ZLOOEHSURYLGHGDORQJZLWKWKHPYDOXHWRDVVHVVWKHDYHUDJHWUHDWPHQW
GLIIHUHQFHEHWZHHQ9;LYDFDIWRUFRPELQDWLRQWKHUDS\DQG,YDFDIWRUPRQRWKHUDS\
WKURXJK:HHNLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG$GGLWLRQDOO\WKHPYDOXH
WHVWLQJWKHWUHDWPHQWE\YLVLWLQWHUDFWLRQZLOOEHSURYLGHGWRDVVHVVWKHFRQVLVWHQF\RI
WUHDWPHQWHIIHFWVDFURVVGLIIHUHQWYLVLWV
,QDGGLWLRQWKHDYHUDJHUDZYDOXHVDQGDYHUDJHDEVROXWHFKDQJHIURPEDVHOLQHLQSHUFHQW
SUHGLFWHG)(9WKURXJK:HHN:HHNVDQGZLOOEHVXPPDUL]HGGHVFULSWLYHO\
QXPEHUPHDQ6'6(PHGLDQPLQDQGPD[,QWKHUDZYDOXHVXPPDULHVWKHDYHUDJH
UDZYDOXHVWKURXJK:HHNZLOOEHGHULYHGDVWKHDULWKPHWLFPHDQRIWKHDYDLODEOH
SRVWEDVHOLQHPHDVXUHPHQWVDWHDFKYLVLW7KHDYHUDJHDEVROXWHFKDQJHIURPEDVHOLQHLQ
SHUFHQWSUHGLFWHG)(9WKURXJK:HHNZLOOEHGHULYHGDVWKHDULWKPHWLFPHDQRIWKH
DEVROXWHFKDQJHIURPEDVHOLQHLQSHUFHQWSUHGLFWHG)(9DWHDFKDYDLODEOHSRVWEDVHOLQHYLVLW
7KHFXPXODWLYHGLVWULEXWLRQSORWRIWKHDYHUDJHDEVROXWHFKDQJHIURPEDVHOLQHLQSHUFHQW
SUHGLFWHG)(9WKURXJK:HHNZLOOEHSORWWHGE\WUHDWPHQWJURXS6XEMHFWVPLVVLQJ
DEVROXWHFKDQJHIURPEDVHOLQHLQSHUFHQWSUHGLFWHG)(9DWDOOSRVWEDVHOLQHYLVLWWKURXJK
:HHNZLOOKDYHPLVVLQJDYHUDJHDEVROXWHFKDQJHWKURXJK:HHNDQGZLOOQRWEHLQFOXGHG
LQWKHUHODWHGVXPPDULHVRULQWKHSORW
$EVROXWHFKDQJHIURPEDVHOLQHLQSHUFHQWSUHGLFWHG)(9DWHDFKYLVLW
$EVROXWHFKDQJHIURPEDVHOLQHLQSHUFHQWSUHGLFWHG)(9DWHDFKSRVWEDVHOLQHYLVLW:HHNV
DQGGXULQJWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGZLOOEHGHULYHGIURPWKHPDLQ
PRGHOEDVHGRQWKH)$6'HVFULSWLYHVXPPDU\VWDWLVWLFVLQFOXGLQJQXPEHURIVXEMHFWVPHDQ
6'DQG/6PHDQV6(DORQJZLWKWKHFRUUHVSRQGLQJVLGHG&,VDQGWKHPYDOXHV
ZLOOEHSURYLGHG,QDGGLWLRQWKHGLIIHUHQFHLQ/6PHDQV6(EHWZHHQ9;LYDFDIWRU
FRPELQDWLRQWKHUDS\DQG,YDFDIWRUPRQRWKHUDS\DQGWKHFRUUHVSRQGLQJ&,ZLOOEH
SURYLGHG7KH/6PHDQV&,DWHDFKYLVLWZLOOEHSORWWHGE\WUHDWPHQWJURXSV
Page 25 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

,QDGGLWLRQWKHUDZYDOXHVDQGWKHDEVROXWHFKDQJHIURPEDVHOLQHLQSHUFHQWSUHGLFWHG)(9
DWHDFKSRVWEDVHOLQHYLVLW:HHNVDQGUHJDUGOHVVRIWKHWUHDWPHQWVWDWXVDWWKHYLVLW
ZLOOEHVXPPDUL]HGGHVFULSWLYHO\QXPEHUPHDQ6'6(PHGLDQPLQDQGPD[
Page 26 of 108






6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

9.3.2
Analysis of Key Secondary Efficacy Endpoints
9.3.2.1
Definition of Key Secondary Efficacy Endpoints
7KHNH\VHFRQGDU\HIILFDF\HQGSRLQWVDUHDVIROORZV
x
5HODWLYHFKDQJHLQSHUFHQWSUHGLFWHG)(9IURPEDVHOLQHWKURXJK:HHNLQWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRG
x
$EVROXWHFKDQJHLQ&\VWLF)LEURVLV4XHVWLRQQDLUH±5HYLVHG&)45UHVSLUDWRU\GRPDLQ
VFRUHIURPEDVHOLQHWKURXJK:HHNLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
Page 29 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG


5HODWLYHFKDQJHLQSHUFHQWSUHGLFWHG)(9IURPEDVHOLQHWKURXJK:HHNLQWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRG
5HODWLYHFKDQJHLQSHUFHQWSUHGLFWHG)(9DWHDFKYLVLWZLOOEHGHILQHGDVWKHDEVROXWH
FKDQJHLQSHUFHQWSUHGLFWHG)(9DWHDFKYLVLWGLYLGHGE\WKHEDVHOLQHSHUFHQWSUHGLFWHG
)(9LQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
$EVROXWHFKDQJHLQ&)45UHVSLUDWRU\GRPDLQIURPEDVHOLQHWKURXJK:HHNLQWKH
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
7KH&)45LVDYDOLGDWHG&)VSHFLILFLQVWUXPHQWWKDWPHDVXUHVTXDOLW\RIOLIHGRPDLQV7KH
GHWDLOVRQWKH&)45IRUPVDQGWKH&)45VFRULQJPDQXDODUHSURYLGHGLQ$SSHQGL[*
9.3.2.2
Analysis of Key Secondary Efficacy Endpoints
5HODWLYHFKDQJHLQSHUFHQWSUHGLFWHG)(9IURPEDVHOLQHWKRURXJK:HHNLQWKH
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
$PRGHOVLPLODUWRWKH0050IRUWKHSULPDU\DQDO\VLVRIWKHSULPDU\HIILFDF\HQGSRLQWZLOO
EHXVHG$YHUDJHUHODWLYHFKDQJHIURPEDVHOLQHLQSHUFHQWSUHGLFWHG)(9WKURXJK:HHN
DQGWKHUHODWLYHFKDQJHIURPEDVHOLQHLQSHUFHQWSUHGLFWHG)(9DWHDFKSRVWEDVHOLQHYLVLW
:HHNVDQGLQFOXGLQJ/6PHDQVVWDQGDUGHUURU6(DQGWKHVLGHG
FRQILGHQFHLQWHUYDODORQJZLWKWKHPYDOXHZLOODOVREHGHULYHGIURPWKH0050PRGHOIRU
WKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGEDVHGRQWKH)$67KH/6PHDQV&,DWHDFK
YLVLWZLOOEHSORWWHGE\WUHDWPHQWJURXSV
,QDGGLWLRQDYHUDJHUDZYDOXHVDQGDYHUDJHUHODWLYHFKDQJHIURPEDVHOLQHLQSHUFHQW
SUHGLFWHG)(9WKURXJK:HHNDQGUDZYDOXHVDQGUHODWLYHFKDQJHIURPEDVHOLQHLQSHUFHQW
SUHGLFWHG)(9DWHDFKYLVLW:HHNVDQGZLOOEHVXPPDUL]HGXVLQJGHVFULSWLYH
VXPPDU\VWDWLVWLFV
7KHFXPXODWLYHGLVWULEXWLRQSORWRIDYHUDJHUHODWLYHFKDQJHIURPEDVHOLQHLQSHUFHQW
SUHGLFWHG)(9WKURXJK:HHNZLOOEHSORWWHGE\WUHDWPHQWJURXSV,QDGGLWLRQDEDUFKDUW
VKRZLQJWKHSHUFHQWDJHRIVXEMHFWVE\UHVSRQVHFDWHJRULHVWR
WRWRWRWRWRWR
WRRIDYHUDJHUHODWLYHFKDQJHIURPEDVHOLQHLQSHUFHQWSUHGLFWHG
)(9WKURXJK:HHNZLOOEHSORWWHGE\WUHDWPHQWJURXSV
$EVROXWHFKDQJHLQ&)45UHVSLUDWRU\GRPDLQIURPEDVHOLQHWKURXJK:HHNLQWKH
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
$QDO\VLVIRUWKHDEVROXWHFKDQJHIURPEDVHOLQHLQ&)45UHVSLUDWRU\GRPDLQ3RROHG

&KLOGUHQ$JHVDQG
9HUVLRQDQG
$GROHVFHQWVDQG$GXOWV
9HUVLRQWKURXJK:HHN
ZLOOEHVLPLODUWRWKDWXVHGIRUWKHSULPDU\DQDO\VLVZLWKWKHDGGLWLRQRIWKHEDVHOLQH&)45
UHVSLUDWRU\GRPDLQVFRUHDVDFRYDULDWH7KHSULPDU\UHVXOWREWDLQHGIURPWKLVPRGHOZLOOEH
WKHDYHUDJHWUHDWPHQWHIIHFWWKURXJK:HHN
$EVROXWHFKDQJHIURPEDVHOLQHLQ&)45UHVSLUDWRU\GRPDLQDWHDFKSRVWEDVHOLQHYLVLW
:HHNDQG:HHNZLOOEHGHULYHGIURPWKHVDPHPRGHO7KH/6PHDQV6(&,DQG
3YDOXHVDWHDFKYLVLWZLOOEHSURYLGHG/6PHDQV&,ZLOOEHSORWWHGE\WUHDWPHQW
Page 30 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

JURXSV,QDGGLWLRQDYHUDJHUDZYDOXHVDQGDYHUDJHDEVROXWHFKDQJHIURPEDVHOLQHLQ&)45
UHVSLUDWRU\GRPDLQWKURXJK:HHNDQGUDZYDOXHVDQGDEVROXWHFKDQJHIURPEDVHOLQHLQ
&)45UHVSLUDWRU\GRPDLQDWHDFKSRVWEDVHOLQHYLVLW:HHNDQG:HHNZLOOEH
VXPPDUL]HGXVLQJGHVFULSWLYHVXPPDU\VWDWLVWLFV
9.3.3
Analysis of Secondary Efficacy Endpoints
9.3.3.1 Definition of Secondary Efficacy Endpoints
$EVROXWHFKDQJHIURPEDVHOLQHLQVZHDWFKORULGHIURPEDVHOLQHWKURXJK:HHNLQWKH
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
)RUHDFKVXEMHFWDQGDWHDFKWLPHSRLQWVZHDWFKORULGHPHDVXUHPHQWVZLOOEHFROOHFWHG
IURPWKHULJKWDUPDQGIURPOHIWDUP2QO\WKHVZHDWFKORULGHYDOXHVREWDLQHGIURPD
VDPSOHYROXPHtP/ZLOOEHXVHGLQDQ\DQDO\VLV
1RWH$YROXPHRIȝ/LVUHTXLUHGIRUDQDFFXUDWHGHWHUPLQDWLRQRIVZHDWFKORULGH$Q\
UHVXOWVUHSRUWHGKDYLQJYROXPHȝ/RU³4XDQWLW\1RW6XIILFLHQW´416ZLOOEH
FRQVLGHUHGPLVVLQJ
7KHVZHDWFKORULGHUHVXOWVIRUWKHOHIWDQGULJKWDUPVZLOOEHDYHUDJHGDQGXVHGLQWKH
DQDO\VLVSURYLGHGWKDWWKHVZHDWFKORULGHYROXPHVIRUWKHOHIWDQGULJKWDUPVDUHERWKtP/
LIRQO\DUPKDVDYROXPHtP/WKHQRQO\WKDWYDOXHZLOOEHXVHG,IDVXEMHFWKDV
UHSOLFDWHGPHDVXUHPHQWVDWDSRVWEDVHOLQHWLPHSRLQWWKHQWKHPHGLDQRIWKHYDOXHVZLOOEH
XVHGLQGDWDDQDO\VHV
1RWHDQ\VZHDWFKORULGHYDOXHVUHSRUWHGDVPPRO/RU!PPRO/9DOXHV!
PPRO/RUPPRO/ZLOOEHVHWWRPLVVLQJDQGH[FOXGHGIURPWKHDQDO\VLVEHFDXVHWKHVH
YDOXHVDUHFRQVLGHUHGFOLQLFDOO\LPSRVVLEOH
9.3.3.2 Analysis of Secondary Efficacy Endpoints
$EVROXWHFKDQJHIURPEDVHOLQHLQVZHDWFKORULGHIURPEDVHOLQHWKURXJK:HHNLQWKH
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
$PRGHOVLPLODUWRWKH0050IRUWKHSULPDU\DQDO\VLVRIWKHSULPDU\HIILFDF\HQGSRLQWZLOO
EHXVHGZLWKWKHDGGLWLRQRIEDVHOLQHVZHDWFKORULGHDVDFRYDULDWH$YHUDJHDEVROXWHFKDQJH
IURPEDVHOLQHLQVZHDWFKORULGHWKURXJK:HHNDQGDEVROXWHFKDQJHIURPEDVHOLQHLQVZHDW
FKORULGHDWHDFKSRVWEDVHOLQHYLVLW:HHNVDQGLQFOXGLQJ/6PHDQVVWDQGDUGHUURU6(
DQGWKHVLGHGFRQILGHQFHLQWHUYDODORQJZLWKWKHPYDOXHZLOOEHGHULYHGIURPWKH
PDLQPRGHOEDVHGRQWKH)$67KH/6PHDQV&,DWHDFKYLVLWZLOOEHSORWWHGE\
WUHDWPHQWJURXSV
,QDGGLWLRQDYHUDJHUDZYDOXHVDQGDYHUDJHDEVROXWHFKDQJHIURPEDVHOLQHLQVZHDWFKORULGH
WKURXJK:HHNDQGUDZYDOXHVDQGDEVROXWHFKDQJHIURPEDVHOLQHLQVZHDWFKORULGHDWHDFK
YLVLW:HHNDQG:HHNZLOOEHVXPPDUL]HGXVLQJGHVFULSWLYHVXPPDU\VWDWLVWLFV
Page 31 of 108








6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG
&RQILGHQWLDO,QIRUPDWLRQ
9.3.6
Multiplicity Adjustment
$KLHUDUFKLFDOWHVWLQJSURFHGXUHZLOOEHXVHGWRFRQWUROWKH7\SH,HUURUDWWZRVLGHGĮ 
DPRQJWKHSULPDU\DQGNH\VHFRQGDU\HQGSRLQWV)RUDWHVWDWDQ\VWHSWREHFRQVLGHUHG
VWDWLVWLFDOO\VLJQLILFDQWZLWKLQWKHWHVWLQJKLHUDUFK\LWPXVWEHVWDWLVWLFDOO\VLJQLILFDQWDQGDOO
SUHYLRXVWHVWVLIDQ\ZLWKLQWKHKLHUDUFK\PXVWEHVWDWLVWLFDOO\VLJQLILFDQWDWWKHOHYHO
7KHWHVWLQJKLHUDUFK\LVDVIROORZV
 $EVROXWHFKDQJHLQSHUFHQWSUHGLFWHG)(9IURPEDVHOLQHWKURXJK:HHN
 5HODWLYHFKDQJHLQSHUFHQWSUHGLFWHG)(9IURPEDVHOLQHWKURXJK:HHN
 $EVROXWHFKDQJHLQ&)45UHVSLUDWRU\GRPDLQVFRUHIURPEDVHOLQHWKURXJK:HHN
Page 35 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG


9.4
Safety Analysis
6DIHW\HQGSRLQWVZLOOEHDQDO\]HGVHSDUDWHO\IRUWKH,YDFDIWRU5XQLQ3HULRGDQGWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRGEDVHGRQWKHFRUUHVSRQGLQJ6DIHW\6HW2QO\GHVFULSWLYH
VXPPDULHVRIVDIHW\ZLOOEHSURYLGHGLHQRVWDWLVWLFDOWHVWLQJZLOOEHSHUIRUPHG
7KHRYHUDOOVDIHW\SURILOHRIVWXG\GUXJZLOOEHDVVHVVHGLQWHUPVRIWKHIROORZLQJVDIHW\DQG
WROHUDELOLW\HQGSRLQWV
x
$GYHUVHHYHQWV
x
&OLQLFDOODERUDWRU\YDOXHVKHPDWRORJ\VHUXPFKHPLVWU\FRDJXODWLRQVWXGLHVDQG
XULQDO\VLV
x
6WDQGDUGOHDGHOHFWURFDUGLRJUDPV
x
9LWDOVLJQV
x
3XOVHR[LPHWU\
7KHVDIHW\SURILOHZLOODOVRLQFOXGHWKHIROORZLQJVDIHW\VXSSRUWLQJGDWD
x
:HLJKW
x
%0,
x
2SKWKDOPRORJLFDO([DPLQDWLRQ
9.4.1
Adverse Events 
)RUDQDO\VLVSXUSRVHV$(VZLOOEHFODVVLILHGDVSUHWUHDWPHQW$(V7($(VGXULQJWKH
,YDFDIWRU5XQLQ3HULRG7($(VGXULQJWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGRU
SRVWWUHDWPHQW$(VGHILQHGDVIROORZV
x
3UHWUHDWPHQW$(DQ\$(WKDWVWDUWHGEHIRUHLQLWLDOGRVLQJRIVWXG\GUXJLQWKH,YDFDIWRU
5XQLQ3HULRG
x
7($(VGXULQJWKH,YDFDIWRU5XQLQ3HULRGDQ\$(WKDWLQFUHDVHGLQVHYHULW\RUWKDW
ZDVQHZO\GHYHORSHGDWRUDIWHULQLWLDOGRVLQJRIVWXG\GUXJWKURXJKWKHHQGRIWKH7(
3HULRGIRUWKH,YDFDIWRU5XQLQ3HULRG
x
7($(VGXULQJWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGDQ\$(WKDWLQFUHDVHGLQ
VHYHULW\RUWKDWZDVQHZO\GHYHORSHGDWRUDIWHULQLWLDOGRVLQJRIVWXG\GUXJWKURXJKWKH
HQGRIWKH7(3HULRGIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
x
3RVWWUHDWPHQW$(VDQ\$(WKDWLQFUHDVHGLQVHYHULW\RUWKDWZDVQHZO\GHYHORSHG
EH\RQGWKH7(3HULRG
)RU$(VZLWKDPLVVLQJRUSDUWLDOVWDUWGDWHLIWKHUHLVQRFOHDUHYLGHQFHWKDWWKH$(VVWDUWHG
RULQFUHDVHGLQVHYHULW\EHIRUHRUDIWHUWKHILUVWGRVHGDWHIRUWKH$FWLYH&RPSDUDWRU
7UHDWPHQW3HULRGWKH$(ZLOOEHFRQVLGHUHGWREHD7($(IRUWKH$FWLYH&RPSDUDWRU
7UHDWPHQW3HULRGVHH6HFWLRQ,IWKHUHLVFOHDUHYLGHQFHWKDWWKH$(VWDUWHGEHIRUHWKH
ILUVWGRVHGDWHIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGEXWWKHUHLVQRFOHDUHYLGHQFH
Page 36 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

WKDWWKH$(VWDUWHGEHIRUHRUDIWHUWKHILUVWGRVHGDWHIRUWKH,YDFDIWRU5XQLQ3HULRGWKH$(
ZLOOEHFRQVLGHUHGWREHD7($(IRUWKH,YDFDIWRU5XQLQ3HULRG6LPLODUO\LIWKHUHLVQR
FOHDUHYLGHQFHWKDWWKH$(VVWDUWHGRULQFUHDVHGLQVHYHULW\EHIRUHRUDIWHUWKHVWDUWRIWKH
SRVWWUHDWPHQWSHULRGWKHVWDUWGDWHZLOOEHLPSXWHGWREHWKHHDUOLHVWSRVVLEOHWLPHLQWKH
7($(SHULRGDQGWKH$(ZLOOEHFRQVLGHUHGWREHD7($(

8QOHVVRWKHUZLVHVWDWHGDOO7($(VXPPDULHVZLOOEHSURYLGHGVHSDUDWHO\IRUWKH,YDFDIWRU
5XQLQ3HULRGDQGWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG3UHVHQWHGSHUFHQWDJHVZLOOEH
FDOFXODWHGEDVHGRQWKHQXPEHURIVXEMHFWVLQWKH6DIHW\6HWRIWKHFRUUHVSRQGLQJSHULRG
%DVHGRQWKHUHSRUWHGVHYHULW\DQGUHODWLRQVKLSWRVWXG\GUXJV7($(VFDQEHFDWHJRUL]HGDV
IROORZV
%\UHODWLRQVKLSWRWKHVWXG\GUXJVWUHDWPHQWHPHUJHQWDGYHUVHHYHQWV7($(VZLOOEH
FODVVLILHGLQWRFDWHJRULHV
x
1RWUHODWHG
x
8QOLNHO\UHODWHG
x
3RVVLEO\UHODWHG
x
5HODWHG
%\VHYHULW\7($(VZLOOEHFODVVLILHGLQWRFDWHJRULHV
x
0LOG*UDGH0LOGOHYHORIGLVFRPIRUWDQGGRHVQRWLQWHUIHUHZLWKUHJXODUDFWLYLWLHV
x
0RGHUDWH*UDGH0RGHUDWHOHYHORIGLVFRPIRUWDQGVLJQLILFDQWO\LQWHUIHUHVZLWK
UHJXODUDFWLYLWLHV
x
6HYHUH*UDGH6LJQLILFDQWOHYHORIGLVFRPIRUWDQGSUHYHQWVUHJXODUDFWLYLWLHV
x
/LIHWKUHDWHQLQJ*UDGHDQG$Q\DGYHUVHGUXJH[SHULHQFHWKDWSODFHVWKH
VXEMHFWLQWKHYLHZRIWKHLQYHVWLJDWRUDWLPPHGLDWHULVNRIGHDWK
9.4.1.1
Overiew of TEAEs  
$QRYHUYLHZRIWKH7($(SURILOHZLOOEHSURYLGHGIRUWKHWRWDOQXPEHURI7($(VDQGZLWK
QXPEHUDQGSHUFHQWRIVXEMHFWVLQFOXGLQJWKHIROORZLQJFDWHJRULHV
x
$OO7($(V
x
6HULRXV7($(V
x
*UDGH7($(V
x
7($(VE\UHODWLRQVKLS
x
7($(VE\VHYHULW\
x
7($(VOHDGLQJWRGHDWK
x
7($(VOHDGLQJWRWUHDWPHQWGLVFRQWLQXDWLRQ
x
7($(VOHDGLQJWRWUHDWPHQWLQWHUUXSWLRQ
1RWHWKDWSHUSURWRFROµ1HLWKHUWKHGRVDJHRILQGLYLGXDOVWXG\GUXJVQRUWKH
FRPELQDWLRQWKHUDS\FDQEHDOWHUHGEXWWKHLQYHVWLJDWRUFDQLQWHUUXSWRUVWRS
Page 37 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

WUHDWPHQWZLWKDOOVWXG\GUXJV¶VHFWLRQRISURWRFRO,QWKHUDUHHYHQWZKHQWKHUH
DUHGLIIHUHQWDFWLRQVDSSOLHGWR9;PJ,9$PJIL[HGGRVHWDEOHW)'&
DQGWR,9$PJWDEOHW7($(VOHDGLQJWRWUHDWPHQWGLVFRQWLQXDWLRQZLOOLQFOXGH
7($(VOHDGLQJWRZLWKGUDZQRIERWK)'&DQG,9$WDEOHWVRUHLWKHU)'&RU,9$
WDEOHWV7($(VOHDGLQJWRWUHDWPHQWLQWHUUXSWLRQZLOOLQFOXGH7($(VOHDGLQJWRGUXJ
LQWHUUXSWLRQIRUERWK)'&DQG,9$WDEOHWVRUHLWKHU)'&RU,9$WDEOHWV
9.4.1.2
TEAEs by System Organ Class (SOC) and Preferred Term (PT)
6XPPDULHVZLOOEHSUHVHQWHGE\0HG'5$V\VWHPRUJDQFODVV62&DQGSUHIHUUHGWHUP
XVLQJIUHTXHQF\FRXQWVDQGSHUFHQWDJHVLHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVZLWKDQ
HYHQW:KHQVXPPDUL]LQJWKHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVZLWKDQHYHQWVXEMHFWV
ZLWKPXOWLSOHRFFXUUHQFHVRIWKHVDPH$(RUDFRQWLQXLQJ$(ZLOOEHFRXQWHGRQFH2QO\WKH
PD[LPXPVHYHULW\OHYHOZLOOEHSUHVHQWHGLQWKHVHYHULW\VXPPDULHVDQGWKHVWURQJHVW
UHODWLRQVKLSOHYHOZLOOEHSUHVHQWHGLQWKHUHODWLRQVKLSVXPPDULHV
$GGLWRQDOVXPPDU\WDEOHVPD\EHSUHVHQWHGIRU7($(VLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW
3HULRGRQO\VKRZLQJQXPEHUDQGSHUFHQWDJHRIVXEMHFWV
x
$Q\7($(E\37
x
7($(ZLWKDIUHTXHQF\RILQDQ\WUHDWPHQWJURXSE\37$FWLYH&RPSDUDWRU
7UHDWPHQW3HULRG
x
7($(ZLWKDIUHTXHQF\RILQDQ\WUHDWPHQWJURXSE\62&DQG37$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRG
x
7($(VRIPRUHIUHTXHQWDWWKH37OHYHOLQWKH9;LYDFDIWRUFRPELQDWLRQ
WKHUDS\WKDQLYDFDIWRUPRQRWKHUDS\E\37
x
7($(VRIPRUHIUHTXHQWDWWKH37OHYHOLQWKH9;LYDFDIWRUFRPELQDWLRQ
WKHUDS\WKDQLYDFDIWRUPRQRWKHUDS\E\62&DQG37
9.4.1.3
Respiratory Events and Symptoms
5HVSLUDWRU\V\PSWRPVDUHGHILQHGDVDQ\7($(VIRUWKHIROORZLQJ37V
x
&KHVWGLVFRPIRUW
x
'\VSQRHD
x
5HVSLUDWLRQDEQRUPDO
5HVSLUDWRU\HYHQWVDUHGHILQHGDVDQ\RIWKHDIRUHPHQWLRQHGUHVSLUDWRU\V\PSWRPVRUDQ\
7($(VIRUWKHIROORZLQJDGGLWLRQDO37V
x
$VWKPD
x
%URQFKLDOK\SHUUHDFWLYLW\
x
%URQFKRVSDVP
x
:KHH]LQJ
$VXPPDU\RIUHVSLUDWRU\V\PSWRPVDQGHYHQWVZLOOEHSUHVHQWHGE\SUHIHUUHGWHUP
Page 38 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

9.4.1.4
Subgroup Analysis  
7($(VXPPDULHVLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGZLOODOVREHSUHVHQWHGE\62&
DQG37IRUWKHIROORZLQJVXEJURXSV
x
$JHJURXSDWVFUHHQLQJDQGt\HDUV
x
3HUFHQWSUHGLFWHG)(9VHYHULW\DWWKHHQGRI,YDFDIWRU5XQLQ3HULRGDVDVWUDWLILFDWLRQ
IDFWRUSHU,:56DQG
x
5HJLRQ1RUWK$PHULFDDQG2WKHUV
x
7\SHRIPXWDWLRQRQWKHVHFRQGCFTRDOOHOHR117H YHUVXVRWKHUV
,QDGGLWLRQDOLVWLQJFRQWDLQLQJLQGLYLGXDOVXEMHFWDGYHUVHHYHQWGDWDIRU7($(VOHDGLQJWR
WUHDWPHQWGLVFRQWLQXDWLRQ7($(VOHDGLQJWRWUHDWPHQWLQWHUUXSWLRQ6$(VDQGDOOGHDWKVZLOO
EHSURYLGHGVHSDUDWHO\ZLWKDIODJLQGLFDWLQJWKH7($(VWDWXVIRU6$(VDQGGHDWKV
9.4.1.5
Clinical Laboratory
7KHDQDO\VLVRIFOLQLFDOODERUDWRU\PHDVXUHPHQWVZLOOEHSUHVHQWHGVHSDUDWHO\IRUWKH
,YDFDIWRU5XQLQ3HULRGDQGE\WUHDWPHQWJURXSDWHDFKVFKHGXOHGWLPHSRLQWIRUWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRGEDVHGRQWKHFRUUHVSRQGLQJ6DIHW\6HW
)RUWUHDWPHQWHPHUJHQWODERUDWRU\PHDVXUHPHQWVWKHUDZYDOXHVDQGFKDQJHIURPEDVHOLQH
YDOXHVRIWKHFRQWLQXRXVKHPDWRORJ\DQGFKHPLVWU\UHVXOWVLQFOXGLQJFRDJXODWLRQVWXGLHVZLOO
EHVXPPDUL]HGLQ6,XQLWVE\WUHDWPHQWJURXSDQGYLVLW
7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVZLWKDWOHDVWSRWHQWLDOO\FOLQLFDOO\VLJQLILFDQW3&6
ODERUDWRU\HYHQWGXULQJWKH7(SHULRGZLOOEHVXPPDUL]HGRYHUDOODQGE\WUHDWPHQWJURXS
LQFOXGLQJWKHVKLIWRIWKH3&6HYHQWIURPEDVHOLQHWRSRVWEDVHOLQH7KH3&6FULWHULDDUH
SURYLGHGLQ$SSHQGL[,
)RUHDFKOLYHUIXQFWLRQWHVW/)7ODERUDWRU\WHVWDODQLQHDPLQRWUDQVIHUDVH>$/7@DVSDUWDWH
DPLQRWUDQVIHUDVH>$67@DONDOLQHSKRVSKDWDVH>$/3@JDPPDJOXWDP\OWUDQVIHUDVH>**7@
DQGWRWDOELOLUXELQWKHIROORZLQJDGGLWLRQDODQDO\VHVZLOOEHFRQGXFWHGIRUWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRG
x
$OLVWLQJRIVXEMHFWVZLWKHOHYDWHG/)7UHVXOWVGXULQJWKH7(SHULRGZLOOEHSUHVHQWHG
)RUHDFKVXEMHFWLQWKHOLVWLQJ/)7DVVHVVPHQWVDWDOOWLPHSRLQWVZLOOEHLQFOXGHG
VFKHGXOHGDQGXQVFKHGXOHG
x
)RUHDFKRIWKH/)7VPHDQYDOXHVr6'ZLOOEHSORWWHGE\YLVLWDQGDER[SORWRI
WKH/)7YDOXH8/1ZLOOEHSORWWHGE\YLVLW
x
7KHLQFLGHQFHRI/)7VPHHWLQJWKUHVKROGFULWHULD
x
)RUHDFKRIWKH/)7VPHDQYDOXHVr6'ZLOOEHSORWWHGE\YLVLWDQGDER[SORWRI
WKH/)7YDOXH8/1ZLOOEHSORWWHGE\YLVLW
x
7KHLQFLGHQFHRI/)7VPHHWLQJWKUHVKROGFULWHULDDJDLQVWWKHEDVHOLQHWKUHVKROG
FULWHULDDOVRZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXS/)7SDUDPHWHUVDQGYLVLWRQO\
VKLIWVWRYDOXHVZRUVHWKDQEDVHOLQHZLOOEHSUHVHQWHG
Page 39 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

x
$VFDWWHUSORWRIWKHPD[LPXP$/7YDOXHDFURVVYLVLWVYHUVXVWKHPD[LPXPWRWDO
ELOLUXELQYDOXHDOVRZLOOEHSUHVHQWHG7KH$/7DQGWRWDOELOLUXELQYDOXHVZLOOEH
SUHVHQWHGRQDORJDULWKPLFVFDOH7KHJUDSKZLOOEHGLYLGHGLQWRTXDGUDQWVZLWKD
YHUWLFDOOLQHFRUUHVSRQGLQJWR[8/1IRU$/7DQGDKRUL]RQWDOOLQHFRUUHVSRQGLQJWR
[8/1IRUWRWDOELOLUXELQ$VLPLODUJUDSKRIPD[LPXP$67YDOXHYHUVXVPD[LPXP
WRWDOELOLUXELQYDOXHZLOOEHSUHVHQWHGDVZHOO

)RUWKH$FWLYH7UHDWPHQW3HULRGDVXPPDU\WDEOHIRUWKHVKLIWIURPEDVHOLQHWRWKHYDOXHDW
:HHNZLOOEHSUHVHQWHGE\WUHDWPHQWJURXSIRUYLWDPLQOHYHOVDQGOLSLGSDQHO$ER[SORWRI
YLWDPLQOHYHOVDQGOLSLGSDQHODOVRZLOOEHSORWWHGDJDLQVWYLVLW
,QDGGLWLRQDOLVWLQJFRQWDLQLQJLQGLYLGXDOVXEMHFWKHPDWRORJ\FKHPLVWU\DQGFRDJXODWLRQ
YDOXHVRXWVLGHWKHQRUPDOUHIHUHQFHUDQJHVZLOOEHSURYLGHG7KLVOLVWLQJZLOOLQFOXGHGDWD
IURPERWKVFKHGXOHGDQGXQVFKHGXOHGYLVLWV6XEMHFWZLWKSRVLWLYHSUHJDQDQF\WHVWUHVXOWV
ZLOOEHOLVWHG$EQRUPDOXULQDO\VLVUHVXOWVZLOODOVREHOLVWHGLQLQGLYLGXDOVXEMHFWGDWD
OLVWLQJV
9.4.2
Electrocardiogram
)RUWUHDWPHQWHPHUJHQW(&*PHDVXUHPHQWVDVXPPDU\RIUDZYDOXHVDQGFKDQJHIURP
EDVHOLQHYDOXHVIRUWKH$FWLYH7UHDWPHQW3HULRGZLOOEHSURYLGHGE\WUHDWPHQWJURXSDQGYLVLW
IRUWKHIROORZLQJVWDQGDUGOHDG(&*PHDVXUHPHQWV55PV+5ESP35PV456
GXUDWLRQPV456D[LVGHJUHHV47PVDQG47FRUUHFWHGIRU+5LQWHUYDOV>47F)PV@
7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVZLWKDWOHDVW3&6(&*HYHQWGXULQJWKH7(SHULRG
ZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXSDQG(&*SDUDPHWHUV7KH3&6FULWHULDDUHSURYLGHG
LQ$SSHQGL[,
9.4.3
Vital Signs
7KHUDZYDOXHVDQGFKDQJHIURPWKHFRUUHVSRQGLQJWUHDWPHQWSHULRGEDVHOLQHYDOXHVZLOOEH
VXPPDUL]HGDWHDFKVFKHGXOHGWLPHSRLQWGXULQJWKH7(3HULRGEDVHGRQWKHFRUUHVSRQGLQJ
6DIHW\6HWLQWKH,YDFDIWRU5XQLQ3HULRGDQGE\WUHDWPHQWJURXSLQWKH$FWLYH&RPSDUDWRU
7UHDWPHQW3HULRGV\VWROLFDQGGLDVWROLFEORRGSUHVVXUHPP+JERG\WHPSHUDWXUHr&
SXOVHUDWHEHDWVSHUPLQXWH>ESP@DQGUHVSLUDWRU\UDWHEUHDWKVSHUPLQXWH
9.4.4
Physical Examination 
3K\VLFDOH[DPLQDWLRQILQGLQJVZLOOEHSUHVHQWHGDVDQLQGLYLGXDOVXEMHFWGDWDOLVWLQJRQO\
9.4.5
Pulse Oximetry
7KHUDZYDOXHVDQGFKDQJHIURPWKHFRUUHVSRQGLQJWUHDWPHQWSHULRGEDVHOLQHYDOXHVZLOOEH
VXPPDUL]HGDWHDFKVFKHGXOHGWLPHSRLQWGXULQJWKH7(3HULRGEDVHGRQWKHFRUUHVSRQGLQJ
6DIHW\6HWIRUWKH,YDFDIWRU5XQLQ3HULRGDQGE\WUHDWPHQWJURXSVIRUWKH$FWLYH&RPSDUDWRU
7UHDWPHQW3HULRGVHSDUDWHO\,QDGGLWLRQWKHPHDQYDOXHDWHDFKYLVLWGXULQJWKH7(3HULRG
ZLOOEHSORWWHGE\WUHDWPHQWJURXSIRUWKH$FWLYH&RPSDUDWRUIRUWKHSHUFHQWRIR[\JHQ
VDWXUDWLRQ
Page 40 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

9.4.6
Postdose Spirometry  
)RUWKHKRXUDQGKRXUSRVWGRVHVSLURPHWU\PHDVXUHPHQWVRQ'D\DQG'D\D
VXPPDU\RIUDZYDOXHVIRUSHUFHQWSUHGLFWHG)(9ZLOOEHSURYLGHGE\WUHDWPHQWJURXSDW
HDFKWLPHSRLQW7KHDEVROXWHFKDQJHIURPWKHSUHGRVHYDOXHRISHUFHQWSUHGLFWHG)(9RQ
WKHVDPHGD\ZLOOEHSURYLGHGE\WUHDWPHQWJURXSDWHDFKWLPHSRLQW,QDGGLWLRQDER[SORW
E\WLPHSRLQWZLOOEHSURYLGHG:LWKLQHDFKWUHDWPHQWJURXS'D\DQG'D\YDOXHVZLOO
EHSUHVHQWHGRQWKHVDPHSORW
7KHDERYHDQDO\VHVZLOOEHUHSHDWHGIRU)(9
,QDGGLWLRQWKHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVZLWKSHUFHQWSUHGLFWHG)(9GHFOLQH
DQGSHUFHQWDJHSRLQWVLQWKHDEVROXWHFKDQJHIURPWKHSUHGRVHYDOXHZLOOEH
VXPPDUL]HGE\WUHDWPHQWJURXSDQGE\DVVHVVPHQWGD\DQGWLPH
9.4.7
Ophthalmology Examination
2SKWKDOPRORJLFILQGLQJVFDWDUDFWVGXULQJWKHWUHDWPHQWHPHUJHQWSHULRGZLOOEH
VXPPDUL]HGE\WUHDWPHQWJURXS7KHQXPEHUVDQGSHUFHQWDJHVRIVXEMHFWVZLWKDFDWDUDFWDW
VFUHHQLQJZLOOEHSUHVHQWHG7KHQXPEHUVDQGSHUFHQWDJHVRIVXEMHFWVZLWKDFDWDUDFWDIWHU
WKHILUVWGRVHRIVWXG\GUXJZLOOEHSUHVHQWHG
,QDGGLWLRQRSKWKDOPRORJ\H[DPLQDWLRQUHVXOWVZLOOEHSURYLGHGLQDGDWDOLVWLQJIRUVXEMHFWV
ZKRKDYHGHYHORSHGDQ\FDWDUDFWVGXULQJWKHWUHDWPHQWHPHUJHQWSHULRG6XEMHFWVZLWK
FDWDUDFWDWVFUHHQLQJZLOODOVREHOLVWHG
10
SUMMARY OF INTERIM AND IDMC ANALYSES
10.1
Interim Analysis
1RLQWHULPDQDO\VLVZDVSODQQHGIRUWKLVVWXG\
10.2
IDMC Analysis
$QLQGHSHQGHQWGDWDPRQLWRULQJFRPPLWWHH,'0&ZDVIRUPHGEHIRUHVWXG\LQLWLDWLRQ7KH
,'0&¶VREMHFWLYHVDQGRSHUDWLRQDOGHWDLOVZHUHGHILQHGLQDVHSDUDWHGRFXPHQW,'0&
&KDUWHUZKLFKZDVILQDOL]HGEHIRUHWKHILUVWVXEMHFWZDVVFUHHQHGLQWKHVWXG\7KH,'0&
FRQGXFWHGUHJXODUSODQQHGVDIHW\UHYLHZVRIVWXG\GDWDDVRXWOLQHGLQWKH,'0&&KDUWHUDQG
,'0&$QDO\VLV3ODQ
Page 41 of 108


6WDWLVWLFDO$QDO\VLV3ODQ0HWKRGV
3DJHRI
3URWRFRO1XPEHU9;
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

11
REFERENCES
+DQNLQVRQ-/2GHQFUDQW]-5)HGDQ.%6SLURPHWULFUHIHUHQFHYDOXHVIURPDVDPSOHRI
WKHJHQHUDO86SRSXODWLRQ$P-5HVSLU&ULW&DUH0HG
:DQJ;'RFNHU\'::\SLM')D\0()HUULV%*3XOPRQDU\IXQFWLRQEHWZHHQDQG
\HDUVRIDJH3HGLDWU3XOPRQRO
.HQZDUG0*5RJHU-+6PDOOVDPSOHLQIHUHQFHIRUIL[HGHIIHFWVIURPUHVWULFWHGPD[LPXP
OLNHOLKRRG%LRPHWULFV
5XELQ'%DQG6FKHQNHU1,QWHUYDOHVWLPDWLRQIURPPXOWLSO\LPSXWHGGDWDDFDVHVWXG\
XVLQJDJULFXOWXUHLQGXVWU\FRGHV-RXUQDORIWKH$PHULFDQ6WDWLVWLFDO$VVRFLDWLRQ
±
4XLWWQHU$/0RGL$&UX],6\VWHPDWLFUHYLHZRIKHDOWKUHODWHGTXDOLW\RIOLIHPHDVXUH
IRUFKLOGUHQZLWKUHVSLUDWRU\FRQGLWLRQV3HGLDWU5HVSLU5HY
*RVV&4XLWWQHU$/3DWLHQWUHSRUWHGRXWFRPHVLQF\VWLFILEURVLV3URF$P7KRUDF6RF

0RGL$&4XLWWQHU$/9DOLGDWLRQRIDGLVHDVHVSHFLILFPHDVXUHRIKHDOWKUHODWHGTXDOLW\RI
OLIHIRUFKLOGUHQZLWKF\VWLFILEURVLV-3HGLDWU3V\FKRO
&HQWHUVIRU'LVHDVH&RQWURODQG3UHYHQWLRQ&'&*URZWK&KDUWV$YDLODEOHDW
KWWSZZZFGFJRYJURZWKFKDUWVSHUFHQWLOHBGDWDBILOHVKWP,QFOXGHDOLVWRIUHIHUHQFHVDV
DSSURSULDWH
)'$&HQWHUIRU'UXJ(YDOXDWLRQDQG5HVHDUFK&'(5DQG&HQWHUIRU%LRORJLFV
(YDOXDWLRQDQG5HVHDUFK&%(5*XLGDQFHIRU,QGXVWU\'UXJ,QGXFHG/LYHU,QMXU\
3UHPDUNHWLQJ&OLQLFDO(YDOXDWLRQ-XO\
Page 42 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

12
LIST OF APPENDICES
Appendix A: SECOND CFTR ALLELE MUTATIONS INCLUDED FOR SUBJECTS 
WHO ARE HETEROZYGOUS FOR THE F508del-CFTR MUTATION
3HUWKHVWXG\HOLJLELOLW\FULWHULDKHWHUR]\JRXVF508del-CFTRVXEMHFWVPXVWKDYHDVHFRQG
CFTRDOOHOHWKDWHQFRGHVDPXWDWLRQSUHGLFWHGWRKDYHUHVLGXDOIXQFWLRQ7KHOLVWEHORZ
UHSUHVHQWVDFFHSWDEOHPXWDWLRQV
&)750XWDWLRQVZLWKD*DWLQJ'HIHFW&OLQLFDOO\3URYHQDV,YDFDIWRU5HVSRQVLYH
5+
*5
61
65
*'
*6
*(
61
63
*'
6RXUFH&)75RUJ>,QWHUQHW@%DOWLPRUH0'&OLQLFDODQGIXQFWLRQDOWUDQVODWLRQRI&)757KH&OLQLFDODQG
)XQFWLRQDO7UDQVODWLRQRI&)75&)7586&\VWLF)LEURVLV)RXQGDWLRQ-RKQV+RSNLQV8QLYHUVLW\WKH
+RVSLWDOIRU6LFN&KLOGUHQ$YDLODEOHDWKWWSZZZFIWURUJ$FFHVVHG6HSWHPEHU

Page 43 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

Appendix B : Randomization Procedures
7KHUDQGRPL]DWLRQFRGHVZHUHSURGXFHGE\WKHGHVLJQDWHGYHQGRU
,QRUGHUWR
SURWHFWWKHVWXG\EOLQGDQGPDLQWDLQWKHVFLHQWLILFLQWHJULW\RIWKHGDWDQR9HUWH[
ELRVWDWLVWLFLDQLVXQEOLQGHGWRWKHDFWXDOUDQGRPL]DWLRQOLVWEHIRUHGDWDEDVHORFN%HORZLVD
EULHIGHVFULSWLRQRIWKHUDQGRPL]DWLRQSURFHVV
x
7KHVWXG\ELRVWDWLVWLFLDQFUHDWHGWKHUDQGRPL]DWLRQVSHFLILFDWLRQ
x
7KHH[WHUQDOGHVLJQDWHGYHQGRU
FUHDWHGWKHGXPP\UDQGRPL]DWLRQFRGH
XVLQJWKHUDQGRPL]DWLRQVSHFLILFDWLRQ
x
7KHVWXG\ELRVWDWLVWLFLDQUHYLHZHGWKHGXPP\UDQGRPL]DWLRQFRGHDQGSURYLGHG
FRPPHQWVWRWKHYHQGRU$IWHUDOORXWVWDQGLQJLVVXHVZHUHUHVROYHGWKHVWXG\
ELRVWDWLVWLFLDQDSSURYHGWKHGXPP\UDQGRPL]DWLRQFRGH
x
8SRQDSSURYDORIWKHGXPP\UDQGRPL]DWLRQWKHH[WHUQDOGHVLJQDWHGYHQGRU

JHQHUDWHGWKHILQDOUDQGRPL]DWLRQOLVWDQGSURYLGHGLWGLUHFWO\WRWKH,QWHUDFWLYH:HE
5HVSRQVH6\VWHP,:56YHQGRU

Page 44 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

Appendix C: Schedule of Assessments
7DEOHDQG7DEOHSURYLGHWKHVFKHGXOHRIDVVHVVPHQWVGXULQJWKHVWXG\IURPWKH
6FUHHQLQJ3HULRGWKURXJKWKH6DIHW\)ROORZXS9LVLW
$OOYLVLWVDUHWREHVFKHGXOHGUHODWLYHWRWKH'D\9LVLWILUVWGRVHRIUDQGRPL]HGVWXG\
GUXJ)RUH[DPSOHWKH:HHNGD\V9LVLWZRXOGRFFXUDIWHUZHHNVRIVWXG\GUXJ
DGPLQLVWUDWLRQLQWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGKDVEHHQFRPSOHWHGLH'D\
ILUVWGD\RI:HHN
7DEOH
6FUHHQLQJ3HULRG$VVHVVPHQWV±6WXG\9;
(YHQW$VVHVVPHQW
6FUHHQLQJ3HULRG
:HHN7KURXJK:HHN
,&)DQGDVVHQWZKHQDSSOLFDEOH
;
'HPRJUDSKLFV
;
0HGLFDOKLVWRU\
;
2SKWKDOPRORJLFDOKLVWRU\
;
&)45D
;
CFTRJHQRW\SHE
;
+HLJKWDQGZHLJKWF
;
2SKWKDOPRORJLFH[DPLQDWLRQG
;
&RPSOHWH3(
;
)6+H
;
6HUXPSUHJQDQF\WHVWDOOIHPDOHVRIFKLOGEHDULQJSRWHQWLDOI
;
6WDQGDUGGLJLWDO(&*J
;
9LWDOVLJQVK
;
3XOVHR[LPHWU\K
;
6SLURPHWU\L
;

D
7KH&)45
PXVWEHFRPSOHWHGSULRUWRWKHVWDUWRIDQ\RWKHUDVVHVVPHQWVVFKHGXOHGDWWKDWYLVLW
E
$OOVXEMHFWVZLOOEHWHVWHGIRUCFTRJHQRW\SH7KHUHVXOWVRIWKHFRQILUPDWRU\JHQRW\SHVDPSOHREWDLQHGDWWKH
6FUHHQLQJ9LVLWPXVWEHUHYLHZHGEHIRUHHQUROOPHQW,QVXEMHFWVZLWKFRQILUPHGR117HPXWDWLRQOLQNDJHWRSRO\7
WUDFNSRO\PRUSKLVPVZLOODOVREHGHWHUPLQHG6SHFLILFLQVWUXFWLRQVZLOOEHSURYLGHGLQWKH/DERUDWRU\0DQXDO
F
:HLJKWDQGKHLJKWZLOOEHPHDVXUHGZLWKVKRHVRII
G
$QRSKWKDOPRORJLFH[DPLQDWLRQZLOOEHFRQGXFWHGRQVXEMHFWVRIDOODJHVE\DQRSKWKDOPRORJLVW7KHRSKWKDOPRORJLF
H[DPLQDWLRQGRHVQRWQHHGWREHUHSHDWHGLIWKHUHLVGRFXPHQWDWLRQRIDQH[DPLQDWLRQWKDWPHWWKHSURWRFROFULWHULDDQG
WKDWZDVFRQGXFWHGZLWKLQPRQWKVEHIRUHWKH6FUHHQLQJ3HULRGRULIWKHUHLVGRFXPHQWDWLRQRIELODWHUDOOHQVUHPRYDO
6HFWLRQ6XEMHFWVZLWKFOLQLFDOO\VLJQLILFDQWFDWDUDFWVOHQVRSDFLW\<VXWXUHRUODPHOODUULQJVZLOOEHH[FOXGHG
IURPWKHVWXG\
H
)6+ZLOOEHPHDVXUHGIRUDQ\SRWHQWLDOO\SRVWPHQRSDXVDOIHPDOHZLWKDWOHDVWPRQWKVRIFRQWLQXRXVVSRQWDQHRXV
DPHQRUUKHD6HUXP)6+OHYHOVPXVWEHP,8P/WREHFRQVLGHUHGSRVWPHQRSDXVDO
I
$Q\IHPDOHVXEMHFWZKRGRHVQRWPHHWWKHFULWHULDIRUQRQFKLOGEHDULQJSRWHQWLDOLVFRQVLGHUHGWREHRIFKLOGEHDULQJ
SRWHQWLDODQGPXVWKDYHDVHUXPSUHJQDQF\WHVW
J
$VWDQGDUGGLJLWDO(&*ZLOOEHSHUIRUPHGDIWHUWKHVXEMHFWKDVEHHQVXSLQHIRUDWOHDVWPLQXWHV
K
9LWDOVLJQVDQGSXOVHR[LPHWU\ZLOOEHFROOHFWHGDIWHUWKHVXEMHFWKDVEHHQDWUHVWVHDWHGRUVXSLQHIRUPLQXWHV
L
6SLURPHWU\PD\EHSHUIRUPHGSUHRUSRVWEURQFKRGLODWRU6HFWLRQ6FUHHQLQJVSLURPHWU\HYDOXDWLRQPD\EH
UHSHDWHGDVVSHFLILHGLQ6HFWLRQ
Page 45 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

7DEOH
6FUHHQLQJ3HULRG$VVHVVPHQWV±6WXG\9;
6ZHDWFKORULGHM
;
8ULQDO\VLV
;
+HPDWRORJ\
;
&RDJXODWLRQ
;
6HUXPFKHPLVWU\
;
,QFOXVLRQH[FOXVLRQFULWHULDUHYLHZ
;
3ULRUDQGFRQFRPLWDQWPHGLFDWLRQV
;
$(VDQG6$(V
&RQWLQXRXVIURPVLJQLQJRI,&)DQGDVVHQWZKHUH
DSSOLFDEOHWKURXJK6DIHW\)ROORZXS9LVLWN
$(DGYHUVHHYHQW&)75F\VWLFILEURVLVWUDQVPHPEUDQHFRQGXFWDQFHUHJXODWRU&)45&\VWLF)LEURVLV4XHVWLRQQDLUH
5HYLVHG(&*HOHFWURFDUGLRJUDP)6+IROOLFOHVWLPXODWLQJKRUPRQH,&)LQIRUPHGFRQVHQWIRUP3(SK\VLFDO
H[DPLQDWLRQ
6$(VHULRXVDGYHUVHHYHQW


M
$VZHDWFKORULGHWHVWPXVWEHSHUIRUPHGDWWKH6FUHHQLQJ9LVLWLIDQHOLJLEOHVZHDWFKORULGHYDOXHLVQRWDYDLODEOHLQWKH
VXEMHFW¶VPHGLFDOUHFRUGVDQGWKH6FUHHQLQJ9LVLWYDOXHLVQHHGHGWRHVWDEOLVKHOLJLELOLW\)RUVXEMHFWVXVLQJVZHDW
FKORULGHYDOXHVGRFXPHQWHGLQWKHLUPHGLFDOUHFRUGVWRHVWDEOLVKHOLJLELOLW\WKHVZHDWFKORULGHWHVWDWWKH6FUHHQLQJ
9LVLWLVRSWLRQDO
N
)RUHQUROOHGVXEMHFWVZKRGRQRWKDYHD6DIHW\)ROORZXS9LVLW$(VDQG6$(VZLOOEHFROOHFWHGWKURXJKWKHHDUOLHVWRI
WKHIROORZLQJGD\VDIWHUWKHODVWGRVHRIVWXG\GUXJWKH(779LVLWLIWKDWYLVLWLVZHHNVRUODWHUIROORZLQJWKHODVW
GRVHRIVWXG\GUXJ6HFWLRQRUSULRUWRWKHILUVWGRVHRIVWXG\GUXJLQWKHH[WHQVLRQVWXG\
Page 46 of 108




3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

7DEOH
,YDFDIWRU5XQLQ3HULRG$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG(77DQG6DIHW\)ROORZXS9LVLW$VVHVVPHQWV±
6WXG\9;
(YHQW$VVHVVPHQWD
,YDFDIWRU5XQLQ3HULRGE
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
(77
9LVLWF
6DIHW\
)ROORZXS9LVLW
GD\V
'D\V
$IWHU/DVW'RVHG
:HHN
'D\
'D\V
:HHN
'D\
'D\V
'D\
:HHN
'D\
'D\V
:HHN
'D\
'D\V
:HHN
'D\
'D\V
3UHJQDQF\WHVWL
;

;

;
;
;
;
6WDQGDUGGLJLWDO(&*M
;
;
;
;
;
;
;
;
9LWDOVLJQVN
;
;
;
;
;
;
;
;
3XOVHR[LPHWU\N
;
;
;
;
;
;
;
;
6SLURPHWU\O
;
;
;
;
;
;
;
;
6ZHDWFKORULGHP
;

;

;
;
;
;
8ULQDO\VLV
;

;


;
;
;
+HPDWRORJ\
;

;

;
;
;
;
&RDJXODWLRQ
;

;


;
;
;
6HUXPFKHPLVWU\
;Q
;
;Q
;
;
;
;
;
/LSLGSDQHOR


;


;
;
;
9LWDPLQOHYHOV


;


;
;
;

K
6\PSWRPWDUJHWHG3(VZLOORFFXUDWDQ\WLPHGXULQJWKHVWXG\LIWULJJHUHGE\$(VRULIGHHPHGQHFHVVDU\E\WKHLQYHVWLJDWRU
L
3UHJQDQF\WHVWVZLOOEHSHUIRUPHGIRUDOOIHPDOHVXEMHFWVRIFKLOGEHDULQJSRWHQWLDO$XULQHȕK&*WHVWZLOOEHSHUIRUPHGDWWKH:HHNEHIRUHILUVWGRVHRIVWXG\GUXJ
'D\DQG:HHN9LVLWV$VHUXPSUHJQDQF\WHVWZLOOEHSHUIRUPHGDWWKH:HHN9LVLWDWWKH(77DQGWKH6DIHW\)ROORZXS9LVLW
M
$OOVWDQGDUGGLJLWDO(&*VZLOOEHSHUIRUPHGEHIRUHGRVLQJDQGDIWHUWKHVXEMHFWKDVEHHQVXSLQHIRUDWOHDVWPLQXWHV$WWKH'D\DQG:HHN9LVLWV(&*VZLOOEH
FROOHFWHGEHIRUHGRVLQJDQGDWDQGKRXUVDIWHUWKHPRUQLQJGRVH7KH(&*ZLOOEHSHUIRUPHGEHIRUHWKHPRUQLQJGRVHRIVWXG\GUXJDW:HHN:HHNDQG
:HHN6LQJOH(&*VZLOOEHSHUIRUPHGDW:HHN(77DQG6DIHW\)ROORZXS9LVLWV(&*VFROOHFWHGRQ:HHNDQG'D\EHIRUHGRVLQJZLOOEHSHUIRUPHGLQWULSOLFDWH
:KHUHUHSHDWVRIWKHVDPHDVVHVVPHQWDUHUHTXLUHGDWDJLYHQYLVLWLIVWXG\GUXJLVQRWDGPLQLVWHUHGRQWKHGD\RIWKHYLVLWLHVWXG\GUXJLQWHUUXSWLRQRUSHUPDQHQW
GLVFRQWLQXDWLRQRIVWXG\GUXJRQO\(&*ZLOOEHFROOHFWHG
N
9LWDOVLJQVDQGSXOVHR[LPHWU\ZLOOEHFROOHFWHGEHIRUHGRVLQJDIWHUWKHVXEMHFWKDVEHHQDWUHVWVHDWHGRUVXSLQHIRUDWOHDVWPLQXWHV
O
$WDOOYLVLWVVSLURPHWU\ZLOOEHSHUIRUPHGIRUDOOVXEMHFWVSUHEURQFKRGLODWRUDQGEHIRUHGRVLQJ6HFWLRQ2Q'D\VDQGVXEMHFWV\HDUVRIDJHDWWKH6FUHHQLQJ
9LVLWZLOOKDYHDGGLWLRQDOVSLURPHWU\DVVHVVPHQWVSHUIRUPHGDWDQGKRXUVSRVWGRVH,IPRUHWKDQVSLURPHWU\DVVHVVPHQWLVUHTXLUHGDWDYLVLWEURQFKRGLODWRUVZLOOEH
ZLWKKHOGXQWLOWKHODVWVFKHGXOHGVSLURPHWU\DVVHVVPHQWLVFRPSOHWHG
P
7KHVZHDWFKORULGHFROOHFWLRQRQGRVLQJGD\VVKRXOGRFFXUEHIRUHWKHPRUQLQJGRVHRIWKHVWXG\GUXJV$WHDFKWLPHSRLQWVDPSOHVZLOOEHFROOHFWHGIURPHDFKDUPOHIW
DQGULJKW&ROOHFWLRQRIVZHDWFKORULGHZLOOQRWRYHUODSZLWKDQ\RWKHUVWXG\DVVHVVPHQWV
Q
%ORRGVDPSOHVZLOOEHFROOHFWHGEHIRUHWKHILUVWGRVHRIVWXG\GUXJ
R
6XEMHFWVZLOOUHTXLUHKRXUVRIIDVWLQJEHIRUHWKHEORRGVDPSOHIRUWKHOLSLGSDQHOLVREWDLQHG
Page 48 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

7DEOH
,YDFDIWRU5XQLQ3HULRG$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG(77DQG6DIHW\)ROORZXS9LVLW$VVHVVPHQWV±
6WXG\9;
(YHQW$VVHVVPHQWD
,YDFDIWRU5XQLQ3HULRGE
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
(77
9LVLWF
6DIHW\
)ROORZXS9LVLW
GD\V
'D\V
$IWHU/DVW'RVHG
:HHN
'D\
'D\V
:HHN
'D\
'D\V
'D\
:HHN
'D\
'D\V
:HHN
'D\
'D\V
:HHN
'D\
'D\V
3.VDPSOLQJS

;

;


;
;
5DQGRPL]DWLRQU


;





0HDOVRUVQDFNVDWVLWHV
;
;
;
;
;



,YDFDIWRUGRVLQJW
;






5DQGRPL]HGWUHDWPHQWGRVLQJX


;
;
;



6WXG\GUXJFRXQW

;
;
;
;
;
;

&RQFRPLWDQWPHGLFDWLRQVY
;
;
;
;
;
;
;
;
&RQFRPLWDQWWUHDWPHQWVDQG
SURFHGXUHV
;
;
;
;
;
;
;
;

S
3.EORRGVDPSOHVZLOOEHFROOHFWHGDW:HHNEHIRUHWKHPRUQLQJGRVHDQGDWDQGKRXUVDIWHUWKHPRUQLQJGRVHDQG:HHNEHIRUHWKHPRUQLQJGRVHDQGDWDQG
KRXUVDIWHUWKHPRUQLQJGRVH,IVWXG\GUXJLVQRWDGPLQLVWHUHGDWWKH:HHN9LVLWRU:HHN9LVLWLHVWXG\GUXJLQWHUUXSWLRQRUSHUPDQHQWGLVFRQWLQXDWLRQRIVWXG\
GUXJDVLQJOH3.EORRGVDPSOHZLOOVWLOOEHFROOHFWHG$WWKH(77DQGWKH6DIHW\)ROORZXS9LVLWVDVDSSOLFDEOHD3.EORRGVDPSOHZLOODOVREHFROOHFWHG
U
5DQGRPL]DWLRQPXVWRFFXUDIWHUDOOLQFOXVLRQDQGH[FOXVLRQFULWHULDDUHPHWDIWHUWKHZHHNV,YDFDIWRU5XQLQ3HULRGDQGEHIRUHWKHILUVWGRVHRIVWXG\GUXJRQ'D\RIWKH
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG5DQGRPL]DWLRQZLOOEHGRQHWKURXJK,:56
V
)DWFRQWDLQLQJIRRGVXFKDVD³VWDQGDUG&)´KLJKIDWKLJKFDORULHPHDORUVQDFNZLOOEHSURYLGHGDWWKHVLWHWRVXEMHFWVDIWHUDOOSUHGRVHDVVHVVPHQWVKDYHEHHQFRPSOHWHG
W
6XEMHFWVZLOOUHFHLYHLYDFDIWRUPJTKIURPWKH:HHN9LVLWWKURXJKWKHHYHQLQJRI'D\GD\SULRUWRWKH'D\9LVLW7KHVWXG\GUXJVKRXOGEHDGPLQLVWHUHG
HYHU\KRXUVKRXUVZLWKLQPLQXWHVDIWHUVWDUWLQJDPHDOZLWKIDWFRQWDLQLQJIRRGVXFKDVD³VWDQGDUG&)´KLJKIDWKLJKFDORULHPHDORUVQDFN2QGD\VRIVFKHGXOHG
YLVLWVWKHPRUQLQJGRVHRIVWXG\GUXJZLOOEHDGPLQLVWHUHGDWWKHVLWHDIWHUSUHGRVHDVVHVVPHQWVKDYHEHHQFRPSOHWHG
X
6XEMHFWVZLOOUHFHLYHUDQGRPL]HGVWXG\WUHDWPHQWIURPUDQGRPL]DWLRQWKURXJKWKHHYHQLQJRIWKHGD\EHIRUHWKH:HHN9LVLW7KHVWXG\GUXJVKRXOGEHDGPLQLVWHUHGHYHU\
KRXUVKRXUVZLWKLQPLQXWHVDIWHUVWDUWLQJDPHDOZLWKIDWFRQWDLQLQJIRRGVXFKDVD³VWDQGDUG&)´KLJKIDWKLJKFDORULHPHDORUVQDFN2QGD\VRIVFKHGXOHGYLVLWV
WKHPRUQLQJGRVHRIVWXG\GUXJZLOOEHDGPLQLVWHUHGDWWKHVLWHDIWHUSUHGRVHDVVHVVPHQWVKDYHEHHQFRPSOHWHG
Y
,QIRUPDWLRQRQFRQFRPLWDQWPHGLFDWLRQVLVFROOHFWHGWKURXJKWKH6DIHW\)ROORZXS9LVLWIRUDOOVXEMHFWV)RUVXEMHFWVZKRGLVFRQWLQXHWUHDWPHQWDQGDUHIROORZHGIRUFHUWDLQ
HIILFDF\DVVHVVPHQWVDIWHUWKH(779LVLWVHH6HFWLRQLQIRUPDWLRQRQFRQFRPLWDQWDQWLELRWLFWKHUDS\IRU³VLQRSXOPRQDU\
VLJQVV\PSWRPV´DUHFROOHFWHGWKURXJKWKH:HHN9LVLWDVGHVFULEHGLQ6HFWLRQ
Page 49 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

7DEOH
,YDFDIWRU5XQLQ3HULRG$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG(77DQG6DIHW\)ROORZXS9LVLW$VVHVVPHQWV±
6WXG\9;
(YHQW$VVHVVPHQWD
,YDFDIWRU5XQLQ3HULRGE
$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
(77
9LVLWF
6DIHW\
)ROORZXS9LVLW
GD\V
'D\V
$IWHU/DVW'RVHG
:HHN
'D\
'D\V
:HHN
'D\
'D\V
'D\
:HHN
'D\
'D\V
:HHN
'D\
'D\V
:HHN
'D\
'D\V
$(VDQG6$(V
&RQWLQXRXVIURPVLJQLQJRI,&)DQGDVVHQWZKHUHDSSOLFDEOHWKURXJK6DIHW\)ROORZXS9LVLWZ
$(DGYHUVHHYHQWȕK&*EHWDKXPDQFKRULRQLFJRQDGRWURSLQ&)F\VWLFILEURVLV&)45&\VWLF)LEURVLV4XHVWLRQQDLUH±5HYLVHG(&*HOHFWURFDUGLRJUDP(77(DUO\7UHDWPHQW
7HUPLQDWLRQ,:56LQWHUDFWLYHZHEUHVSRQVHV\VWHP3(SK\VLFDOH[DPLQDWLRQ3.SKDUPDFRNLQHWLF
6$(VHULRXVDGYHUVHHYHQW


Z
)RUHQUROOHGVXEMHFWVZKRGRQRWKDYHD6DIHW\)ROORZXS9LVLW$(VDQG6$(VZLOOEHFROOHFWHGWKURXJKWKHHDUOLHVWRIWKHIROORZLQJGD\VDIWHUWKHODVWGRVHRIVWXG\
GUXJWKH(779LVLWLIWKDWYLVLWLVZHHNVRUODWHUIROORZLQJWKHODVWGRVHRIVWXG\GUXJ6HFWLRQRUSULRUWRWKHILUVWGRVHRIVWXG\GUXJLQWKHH[WHQVLRQVWXG\
Page 50 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG


Appendix D: Analysis Visit Window Mapping Rules for Efficacy and Safety Measurements
7DEOH'
9LVLW:LQGRZ0DSSLQJ5XOHV
$VVHVVPHQWV
9LVLW
7DUJHW6WXG\'D\
9LVLW:LQGRZ
LQVWXG\GD\V
x:HLJKWDQGKHLJKW
x9LWDOVLJQV
x3XOVHR[LPHWU\
x/DEV
o6HUXP&KHPLVWU\

%DVHOLQHIRUWKH,YDFDIWRU5XQLQ3HULRG:HHN

>VFUHHQLQJYLVLWVWGRVHGD\IRU
WKH,YDFDIWRU5XQLQ3HULRG@
:HHN

>GD\DIWHUVWGRVHGD\IRUWKH
,YDFDIWRU5XQLQ3HULRG
GD\SULRUWRVWGRVHGD\IRU
WKH$FWLYH&RPSDUDWRU
7UHDWPHQW3HULRG@
%DVHOLQHIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW
3HULRG

>@
:HHN

>@
:HHN

>@
:HHN

>@
(77
1$
)ROORZWKHLQGLYLGXDOYLVLW
ZLQGRZWREHPDSSHGWR
LQGLYLGXDOYLVLWV
6DIHW\)ROORZXS9LVLW
1$
(IILFDF\DVVHVVPHQWVIROORZWKH
LQGLYLGXDOYLVLWZLQGRZWREH
PDSSHGWRLQGLYLGXDOYLVLWVLI
PHDVXUHGEHIRUHRQ'D\RU
UHPDLQDV6)8LIRWKHUZLVH
6DIHW\DVVHVVPHQWVUHPDLQDV
6)8
x6WDQGDUGOHDG(&*
x6SLURPHWU\
%DVHOLQHIRUWKH,YDFDIWRU5XQLQ3HULRG:HHN

1RPLQDOLIQRQRPLQDO
>VFUHHQLQJYLVLWVWGRVHGD\IRU
WKH,YDFDIWRU5XQLQ3HULRG@
Page 51 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

:HHN

1RPLQDOLIQRQRPLQDO>GD\
DIWHUVWGRVHGD\IRUWKH
,YDFDIWRU5XQLQ3HULRG
GD\SULRUWRVWGRVHGD\IRU
WKH$FWLYH&RPSDUDWRU
7UHDWPHQW3HULRG@
%DVHOLQHIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW
3HULRG

1RPLQDO>@
:HHN

1RPLQDOLIQRQRPLQDO>@
:HHN

>@
:HHN

>@
(77
1$
)ROORZWKHLQGLYLGXDOYLVLW
ZLQGRZWREHPDSSHGWR
LQGLYLGXDOYLVLWV
6DIHW\)ROORZXS9LVLW
1$
(IILFDF\DVVHVVPHQWVIROORZWKH
LQGLYLGXDOYLVLWZLQGRZWREH
PDSSHGWRLQGLYLGXDOYLVLWVLI
PHDVXUHGEHIRUHRQ'D\RU
UHPDLQDV6)8LIRWKHUZLVH
6DIHW\DVVHVVPHQWVUHPDLQDV
6)8
x&)45

%DVHOLQHIRUWKH,YDFDIWRU5XQLQ3HULRG:HHN

>VFUHHQLQJYLVLWVWGRVHGD\IRU
WKH,YDFDIWRU5XQLQ3HULRG@
:HHN

>GD\DIWHUVWGRVHGD\IRUWKH
,YDFDIWRU5XQLQ3HULRG
GD\SULRUWRVWGRVHGD\IRU
WKH$FWLYH&RPSDUDWRU
7UHDWPHQW3HULRG@
%DVHOLQHIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW
3HULRG

>@
:HHN

>@
:HHN

>@
(77
1$
)ROORZWKHLQGLYLGXDOYLVLW
ZLQGRZWREHPDSSHGWR
LQGLYLGXDOYLVLWV
Page 52 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

6DIHW\)ROORZXS9LVLW

1$
(IILFDF\DVVHVVPHQWVIROORZWKH
LQGLYLGXDOYLVLWZLQGRZWREH
PDSSHGWRLQGLYLGXDOYLVLWVLI
PHDVXUHGEHIRUHRQ'D\RU
UHPDLQDV6)8LIRWKHUZLVH
6DIHW\DVVHVVPHQWVUHPDLQDV
6)8
x&)45

%DVHOLQHIRUWKH,YDFDIWRU5XQLQ3HULRG:HHN

>VFUHHQLQJYLVLWVWGRVHGD\IRU
WKH,YDFDIWRU5XQLQ3HULRG@
:HHN

>GD\DIWHUVWGRVHGD\IRUWKH
,YDFDIWRU5XQLQ3HULRG
GD\SULRUWRVWGRVHGD\IRU
WKH$FWLYH&RPSDUDWRU
7UHDWPHQW3HULRG@
%DVHOLQHIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW
3HULRG

>@
:HHN

>@
:HHN

>@
(77
1$
)ROORZWKHLQGLYLGXDOYLVLW
ZLQGRZWREHPDSSHGWR
LQGLYLGXDOYLVLWV
6DIHW\)ROORZXS9LVLW

1$
(IILFDF\DVVHVVPHQWVIROORZWKH
LQGLYLGXDOYLVLWZLQGRZWREH
PDSSHGWRLQGLYLGXDOYLVLWVLI
PHDVXUHGEHIRUHRQ'D\RU
UHPDLQDV6)8LIRWKHUZLVH
6DIHW\DVVHVVPHQWVUHPDLQDV
6)8
x6ZHDWFKORULGH
x+HPDWRORJ\

%DVHOLQHIRUWKH,YDFDIWRU5XQLQ3HULRG:HHN

>VFUHHQLQJYLVLWVWGRVHGD\IRU
WKH,YDFDIWRU5XQLQ3HULRG@
%DVHOLQHIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW
3HULRG

>GD\DIWHUVWGRVHGD\IRUWKH
,YDFDIWRU5XQLQ3HULRG@
:HHN

>@
:HHN

>@
Page 53 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

(77
1$
)ROORZWKHLQGLYLGXDOYLVLW
ZLQGRZWREHPDSSHGWR
LQGLYLGXDOYLVLWV
6DIHW\)ROORZXS9LVLW

1$
(IILFDF\DVVHVVPHQWVIROORZWKH
LQGLYLGXDOYLVLWZLQGRZWREH
PDSSHGWRLQGLYLGXDOYLVLWVLI
PHDVXUHGEHIRUHRQ'D\RU
UHPDLQDV6)8LIRWKHUZLVH
6DIHW\DVVHVVPHQWVUHPDLQDV
6)8
x8ULQDO\VLV
x&RDJXODWLRQ
%DVHOLQHIRUWKH,YDFDIWRU5XQLQ3HULRG:HHN

>VFUHHQLQJYLVLWVWGRVHGD\IRU
WKH,YDFDIWRU5XQLQ3HULRG@
%DVHOLQHIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW
3HULRG

>GD\DIWHUVWGRVHGD\IRUWKH
,YDFDIWRU5XQLQ3HULRG@
:HHN

>@
(77
1$
)ROORZWKHLQGLYLGXDOYLVLW
ZLQGRZWREHPDSSHGWR
LQGLYLGXDOYLVLWV
6DIHW\)ROORZXS9LVLW
1$
(IILFDF\DVVHVVPHQWVIROORZWKH
LQGLYLGXDOYLVLWZLQGRZWREH
PDSSHGWRLQGLYLGXDOYLVLWVLI
PHDVXUHGEHIRUHRQ'D\RU
UHPDLQDV6)8LIRWKHUZLVH
6DIHW\DVVHVVPHQWVUHPDLQDV
6)8
x/LSLGSDQHO
%DVHOLQHIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW
3HULRG

>@
:HHN

>@
(77
1$
)ROORZWKHLQGLYLGXDOYLVLW
ZLQGRZWREHPDSSHGWR
LQGLYLGXDOYLVLWV
6DIHW\)ROORZXS9LVLW
1$
6DIHW\DVVHVVPHQWVUHPDLQDV
6)8
1RWH
Page 54 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG


7RDSSO\WKHDERYHYLVLWZLQGRZVSOHDVHILUVWGHWHUPLQHWKHEDVHOLQHPHDVXUHPHQWVEDVHGRQWKHILUVWGRVHIRUWKH$FWLYH
&RPSDUDWRU7UHDWPHQW3HULRGDQGWKHQODEHO'D\IRUWKHGDWHRIWKHILUVWGRVHIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG
'D\ZLOOEHXVHGWRLQGLFDWHWKHVWGRVHGDWHIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG

$IWHUEDVHOLQHIRUWKH$FWLYH&RPSDUDWRU7UHDWPHQW3HULRGSOHDVHILQGWKHILUVWGRVHIRUWKH,YDFDIWRU5XQLQ3HULRGDQG
GHWHUPLQHWKHEDVHOLQHPHDVXUHPHQWVIRUWKH,YDFDIWRU5XQLQ3HULRGODVWQRQPLVVLQJYDOXHEHIRUHWKHVWGRVHRI,YDFDIWRU
5XQLQ3HULRG

8VHWKHQRPLQDOYLVLWQDPHVWRODEHO6)8IRUVDIHW\

$IWHUEDVHOLQHDQG6)8IRUVDIHW\PHDVXUHPHQWVDUHGHWHUPLQHGWKHDERYHYLVLWZLQGRZVZLOOEHDSSOLHGWRGHWHUPLQHWKH
DQDO\VLVYLVLWQDPHVIRUDOOUHPDLQLQJPHDVXUHVDWVFKHGXOHGRUXQVFKHGXOHGYLVLWV

,IWKHUHLVQRVFKHGXOHG'D\SRVWGRVHYLVLWDQ\DVVHVVPHQWVRQ'D\DIWHUWKHILUVWGRVHZLOOEHFRQVLGHUHGIRUWKHZLQGRZ
RIQH[WYLVLW

)RUVSLURPHWU\DQG(&*QRPLQDOYLVLWZLOOEHXVHGRQO\ZKHQQRPLDOYLVLWLVQRWDYDLODEOHYLVLWZLQGRZLQJUXOHVKDOOEH
DSSOLHG,QVWHDGQRPLQDOYLVLWZLOOEHXVHG

)RUDOOHIILFDF\SDUDPHWHUVLIWKHUHDUHPXOWLSOHPHDVXUHPHQWVZLWKLQDYLVLWZLQGRZWKHUHFRUGDWWKHVFKHGXOHGYLVLWZLOOEH
XVHG
x
,IWKHUHDUHQRPHDVXUHPHQWVDWWKHVFKHGXOHGYLVLWWKHQWKHUHFRUGFORVHVWWRWKHWDUJHWGD\ZLOOEHXVHG
x
,IWKHUHDUHPXOWLSOHUHFRUGVZLWKWKHVDPHGLVWDQFHWRWKHWDUJHWGD\WKHODWHVWUHFRUGZLOOEHXVHG

)RUDOOVDIHW\SDUDPHWHUVLIWKHUHDUHPXOWLSOHPHDVXUHPHQWVZLWKLQDYLVLWZLQGRZWKHQWKHUHFRUGFORVHVWWRWKHWDUJHWGD\
ZLOOEHXVHGRULIWKHUHDUHPXOWLSOHUHFRUGVZLWKLQWKHVDPHGLVWDQFHIURPWKHWDUJHWGD\WKHODWHVWUHFRUGZLOOEHXVHG

)(9%0,:HLJKWDQG+HLJKWDUHIROORZLQJWKHHIILFDF\ZLQGRZLQJUXOHV
6SHFLDOKDQGOLQJIRU(&*
Page 55 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

x
2Q'D\DQG:HHN(&*VZLOOEHFROOHFWHGEHIRUHGRVLQJDQGDWDQGKRXUVDIWHUWKHPRUQLQJGRVH1RQHRIWKH
PHDVXUHVRQ'D\RU:HHNZLOOEHPDSSHGLQWRRWKHUYLVLWV
o'D\SRVWGRVHDQG:HHNSUHSRVWGRVHPHDVXUHPHQWVZLOOEHDQDO\]HGEDVHGRQQRPLQDOYLVLWQDPHV
o2Q:HHNDQG'D\WKHSUHGRVHPHDVXUHPHQWVZLOOEHFROOHFWHGDVWULSOHWVWKHDYHUDJHRIWKHWULSOLFDWHZLOOEHXVHGDV
SUHGRVHPHDVXUHPHQWRQ:HHNDQG'D\UHVSHFWLYHO\2QO\SUHGRVHPHDVXUHPHQWZLWKQRPLQDOYLVLWQDPHVUHODWHGWR
WKHWULSOHWVVKDOOEHXVHGLQWKLVDYHUDJH
x
)RURWKHUSRVWGRVHYLVLWVWKHYLVLWZLQGRZLQWKHDERYHWDEOHZLOODSSO\
Appendix E: Imputation Rules for Missing Prior/Concomitant Medication Dates
,PSXWDWLRQUXOHVIRUPLVVLQJRUSDUWLDOPHGLFDWLRQVWDUWVWRSGDWHVDUHGHILQHGEHORZ
 0LVVLQJRUSDUWLDOPHGLFDWLRQVWDUWGDWH
D
,IRQO\'$<LVPLVVLQJXVHWKHILUVWGD\RIWKHPRQWK
E ,I'$<DQG0RQWKDUHERWKPLVVLQJXVHWKHILUVWGD\RIWKH\HDU
F
,I'$<0RQWKDQG<HDUDUHDOOPLVVLQJXVHDGDWHEHIRUHWKHILUVWGRVHGDWH
 0LVVLQJRUSDUWLDOPHGLFDWLRQVWRSGDWH
D
,IRQO\'$<LVPLVVLQJXVHWKHODVWGD\RIWKHPRQWK
E ,I'$<DQG0RQWKDUHERWKPLVVLQJXVHWKHODVWGD\RIWKH\HDU
F
,I'$<0RQWKDQG\HDUDUHDOOPLVVLQJDVVLJQµFRQWLQXLQJ¶VWDWXVWRVWRSGDWH
,QVXPPDU\WKHSULRUFRQFRPLWDQWRUSRVWFDWHJRUL]DWLRQRIDPHGLFDWLRQLVGHVFULEHGEHORZ

7DEOH(
3ULRU&RQFRPLWDQWDQG3RVW&DWHJRUL]DWLRQRID0HGLFDWLRQ
0HGLFDWLRQ6WDUW'DWH

0HGLFDWLRQ6WRS'DWH
)LUVW'RVH'DWHRI
6WXG\'UXJLQ
,YDFDIWRU5XQLQ
)LUVW'RVH'DWH
DQG(QG'DWHRI
,YDFDIWRU5XQLQ7(
)LUVW'RVH'DWH
DQG(QG'DWHRI
$FWLYH&RPSDUDWRU
!(QG'DWHRI$FWLYH
&RPSDUDWRU7(
3HULRG
Page 56 of 108


3URWRFRO9;9HUVLRQ
3DJHRI
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG

3HULRG
3HULRG
7(3HULRG
)LUVWGRVHGDWHRIVWXG\GUXJLQ
,YDFDIWRU5XQLQ3HULRG
3
3&,9$5XQLQ
3&,9$5XQLQ&$&
3&,9$5XQLQ&$&$
)LUVWGRVHGDWHDQG
(QGGDWHRI,YDFDIWRU5XQLQ7(
SHULRG

&,9$5XQLQ
&,9$5XQLQ&$&
&,9$5XQLQ&$&$
)LUVWGRVHGDWHDQG
(QGGDWHRI$FWLYH&RPSDUDWRU
7(SHULRG


&$&
&$&$
!(QGGDWHRI$FWLYH&RPSDUDWRU
7(SHULRG



$
$3RVW&,9$5XQLQ&RQFRPLWDQWIRU,YDFDIWRU5XQLQ3HULRG&$&&RQFRPLWDQWIRU$FWLYH&RPSDUDWRU7UHDWPHQW3HULRG33ULRU

Page 57 of 108


3URWRFRO9;9HUVLRQ
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG
Appendix F: Coefficients for Hankinson and Wang Methods for Calculating 
Predicted Spirometry Parameters
3HUFHQWSUHGLFWHG)(9LVWKHUDWLRRI)(9/WRWKHSUHGLFWHG)(9/H[SUHVVHGDVD
SHUFHQWDJH7KHSUHGLFWHG)(9/ZLOOEHFDOFXODWHGXVLQJWKH+DQNLQVRQDQG:DQJ
VWDQGDUGV
7KH+DQNLQVRQVWDQGDUGZLOOEHDSSOLHGWRPDOHVXEMHFWV\HDUVDQGROGHUDQGIHPDOH
VXEMHFWV\HDUVDQGROGHUWKH:DQJVWDQGDUGZLOOEHDSSOLHGWRPDOHVXEMHFWVWR
\HDUVDQGIHPDOHVXEMHFWVWR\HDUVRIDJH'XULQJWKHVWXG\WKHVXEMHFWVZKRKDYHD
ELUWKGD\WKDWZRXOGPRYHWKHPIURP:DQJWR+DQNLQVRQZLOOXVHWKH:DQJVWDQGDUG
EHIRUHWKDWELUWKGD\DQGWKH+DQNLQVRQVWDQGDUGDWRUDIWHUWKDWELUWKGD\
+DQNLQVRQ1RUPDO9DOXHV+19VZLOOEHFDOFXODWHGIRU)(9IRUFHGYLWDOFDSDFLW\
)9&IRUFHGH[SLUDWRU\IORZPLGH[SLUDWRU\SKDVH)()DQG)(9)9&XVLQJ
WKH+DQNLQVRQHTXDWLRQ
3UHGLFWHGOXQJIXQFWLRQSDUDPHWHU EEîDJHEîDJHEîKHLJKW
,QWKHHTXDWLRQKHLJKWLVJLYHQLQFHQWLPHWHUVDJHLVJLYHQLQ\HDUVDQGWKHFRHIILFLHQWV
EEEDQGEDUHGHWHUPLQHGEDVHGRQVXEMHFW¶VVH[UDFHDQGDJHJURXSDVVKRZQLQ
7DEOH
:DQJ1RUPDO9DOXHV:19VZLOOEHFDOFXODWHGIRU)(9)9&)()DQG
)(9)9&XVLQJWKH:DQJHTXDWLRQ
OQ3UHGLFWHGOXQJIXQFWLRQSDUDPHWHU DȕOQKHLJKW
:DQJ1RUPDO9DOXHV:19VZLOOEHFDOFXODWHGIRU)(9)9&)()DQG
)(9)9&XVLQJWKH:DQJHTXDWLRQ,QWKHHTXDWLRQKHLJKWLVJLYHQLQPHWHUVDQGWKH
FRHIILFLHQWVĮDQGȕDUHGHWHUPLQHGEDVHGRQVXEMHFW¶VVH[UDFHDQGDJHDVVKRZQLQ
7DEOHDQG7DEOH
,IHLWKHUKHLJKWRUDJHLVPLVVLQJDQGWKHVSLURPHWU\PHDVXUHPHQWLVQRQPLVVLQJWKHODVW
QRQPLVVLQJYDOXHRIKHLJKWDQGDJHZLOOEHXVHGLQWKHFDOFXODWLRQRISUHGLFWHGYDOXHV

Page 58 of 108


3URWRFRO9;9HUVLRQ
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG
7DEOH)+19V(TXDWLRQ&RHIILFLHQWVE\6H[5DFHDQG$JH

3DUDPHWHU
6H[
5DFH
$JH
\HDUV
ER
E
E
E
+19)(9
0DOH
&DXFDVLDQ










$IULFDQ
$PHULFDQ










0H[LFDQ
$PHULFDQ










)HPDOH
&DXFDVLDQ










$IULFDQ
$PHULFDQ










0H[LFDQ
$PHULFDQ










+19)9&
0DOH
&DXFDVLDQ










$IULFDQ
$PHULFDQ










0H[LFDQ
$PHULFDQ










)HPDOH
&DXFDVLDQ










$IULFDQ
$PHULFDQ










0H[LFDQ
$PHULFDQ










+19)()
0DOH
&DXFDVLDQ










$IULFDQ
$PHULFDQ










0H[LFDQ
$PHULFDQ










)HPDOH
&DXFDVLDQ










$IULFDQ
$PHULFDQ










0H[LFDQ
$PHULFDQ










+19)(9)9&
0DOH
&DXFDVLDQ





$IULFDQ
$PHULFDQ





0H[LFDQ
$PHULFDQ





)HPDOH
&DXFDVLDQ





$IULFDQ
$PHULFDQ







0H[LFDQ
$PHULFDQ





6RXUFH5HIHUHQFH7DEOHVDQG

Page 59 of 108


3URWRFRO9;9HUVLRQ
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG
7DEOH) :19V(TXDWLRQ&RHIILFLHQWVE\6H[DQG$JHLQ:KLWH%R\VDQG*LUOV


)(9
)9&
)()
)(9)9&
6H[
$JH
Į
ȕ
Į
ȕ
Į
ȕ
Į
ȕ
0DOH












































































































)HPDOH


























































































6RXUFH5HIHUHQFH7DEOHVDQG

Page 60 of 108


3URWRFRO9;9HUVLRQ
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG
7DEOH) :19V(TXDWLRQ&RHIILFLHQWVE\6H[DQG$JHLQ%ODFN%R\VDQG
*LUOV


)(9
)9&
)()
)(9)9&
6H[
$JH
Į
ȕ
Į
ȕ
Į
ȕ
Į
ȕ
0DOH












































































































)HPDOH


























































































6RXUFH5HIHUHQFH7DEOHVDQG

Page 61 of 108










3URWRFRO9;9HUVLRQ
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG
Appendix I: Threshold Criteria for Clinical Chemistry and Hematology
7KUHVKROG&ULWHULDIRU&OLQLFDO&KHPLVWU\DQG+HPDWRORJ\
3DUDPHWHU
7KUHVKROG&ULWHULD
&RPPHQWV
&OLQLFDO&KHPLVWU\
&3.
!8/1[8/1
![8/1
![8/1
![8/1
&7&$(JUDGHV
&UHDWLQLQH
!8/1[8/1
![8/1
![8/1
![8/1
&7&$(JUDGHV
%ORRG8UHD
1LWURJHQ
!8/1[8/1
![8/1
![8/1
![8/1
6DPHFULWHULDDVFUHDWLQLQH

1R&7&$(
6RGLXP
+\SRQDWUHPLD
//1PPRO/
±PPRO/
PPRO/
&7&$(JUDGH

1R&7&$(JUDGH
+\SHUQDWUHPLD
!8/1PPRO/
!PPRO/PPRO/
!PPRO/PPRO/
!PPRO/
&7&$(JUDGH
3RWDVVLXP
+\SRNDOHPLD
//1±PPRO/
±PPRO/
PPRO/
&7&$(JUDGH	

*UDGHDQGDUHWKHVDPH
+\SHUNDOHPLD
!8/1±PPRO/
!±PPRO/
!±PPRO/
!PPRO/
&7&$(JUDGH
7RWDO&KROHVWHURO
!8/1±PPRO/
!±PPRO/
!±PPRO/
!PPRO/
&7&$(JUDGH
7ULJO\FHULGHV
!±PPRO/
!±PPRO/
!±PPRO/
!PPRO/
&7&$(JUDGH
*OXFRVH






+\SRJO\FHPLD
±PPRO/
PPRO/
PPRO/
&7&$(JUDGH
+\SHUJO\FHPLD
!8/1PPRO/
!±PPRO/
!±PPRO/
!PPRO/
&7&$(JUDGH
$OEXPLQ
J/
&7&$(JUDGH
Page 66 of 108


3URWRFRO9;9HUVLRQ
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG
±J/
J/

$P\ODVH
!8/1[8/1
!±[8/1
!±[8/1
![8/1
&7&$(JUDGH
/LSDVH
!8/1[8/1
!±[8/1
!±[8/1
![8/1
&7&$(JUDGH
'LUHFWELOLUXELQ
!8/1[8/1
!±[8/1
!±[8/1
!±[8/1
![8/1
6DPH&ULWHULDDV7RWDO%LOLUXELQ

1R&7&$(
1RWLQ',/,*XLGDQFH

**7
!8/1[8/1
!±[8/1
!±[8/1
![8/1
&7&$(JUDGH
&DOFLXP
+\SHUFDOFHPLD
!8/1PPRO/
!±PPRO/
!±PPRO/
!PPRO/
&7&$(JUDGH
+\SRFDOFHPLD
//1PPRO/
±PPRO/
±PPRO/
PPRO/
&7&$(JUDGH
0DJQHVLXP

+\SHUPDJQHVHPLD
!8/1PPRO/
!±PPRO/
!PPRO/
&7&$(JUDGH

1R&7&$(JUDGH
+\SRPDJQHVHPLD
//1PPRO/
±PPRO/
±PPRO/
PPRO/
&7&$(JUDGH



,QRUJDQLF
SKRVSKDWH
+\SRSKRVSKDWHPLD

±PPRO/
±PPRO/
PPRO/
&7&$(JUDGH
$/7
!8/1[8/1
!±[8/1
!±[8/1
!±[8/1
![8/1
3HU)'$',/,*XLGDQFH-XODQG
&7&$(

$67
!8/1[8/1
!±[8/1
!±[8/1
!±[8/1
)'$',/,*XLGDQFHDQG&7&$(

Page 67 of 108


3URWRFRO9;9HUVLRQ
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG
![8/1
$/7RU$67
$/7!8/1DQG$/7[8/1RU
$67!8/1DQG$67[8/1
$/7![8/1DQG$/7[8/1RU
$67![8/1DQG$67[8/1
$/7![8/1DQG$/7[8/1RU
$67![8/1DQG$67[8/1
$/7![8/1DQG$/7[8/1RU
$67![8/1DQG$67[8/1
$/7![8/1RU$67![8/1
)'$',/,*XLGDQFH
$ONDOLQH
3KRVSKDWDVH
!8/1[8/1
!±[8/1
!±[8/1
!±[8/1
![8/1
)'$',/,*XLGDQFHDQG&7&$(

7RWDO%LOLUXELQ
!8/1[8/1
!±[8/1
!±[8/1
!±[8/1
![8/1
)'$',/,*XLGDQFHDQG&7&$(


$/7DQG7RWDO
%LOLUXELQ
$/7![8/1DQG7%,/,![8/1
)'$',/,*XLGDQFH-XO

$67DQG7RWDO
%LOLUXELQ
$67![8/1DQG7%,/,![8/1
)'$',/,*XLGDQFH-XO

$/7RU$67DQG
7RWDO%LOLUXELQ
$/7![8/1RU$67![8/1DQG
7%,/,!î8/1
)'$',/,*XLGDQFH-XO

+HPDWRORJ\
:%&
:%&GHFUHDVHG
//1[H/
±[H/
±[H/
[H/
&7&$(JUDGH
/HXNRF\WRVLV
![H/
&7&$(JUDGHRQO\*UDGHDYDLODEOH
/\PSKRF\WHV
/\PSKRF\WHGHFUHDVHG
//1[H/
±[H/
±[H/
[H/
&7&$(JUDGH
/\PSKRF\WHLQFUHDVHG
!±[H/
![H/
&7&$(JUDGHRQO\*UDGHVDYDLODEOH
1HXWURSKLOV
1HXWURSKLOGHFUHDVHG
//1[H/
±[H/
±[H/
[H/
&7&$(JUDGH
+HPRJORELQ
+JEGHFUHDVHGDQHPLD
//1J/
±J/
J/
&7&$(JUDGH
+JELQFUHDVHG
!8/1J/DERYH8/1
!J/DERYH8/1J/DERYH8/1
!J/DERYH8/1
&7&$(JUDGH
Page 68 of 108


3URWRFRO9;9HUVLRQ
9HUWH[3KDUPDFHXWLFDOV,QFRUSRUDWHG
3ODWHOHWV
3ODWHOHWGHFUHDVHG
//1[H/
±[H/
±[H/
[H/
&7&$(JUDGH

Page 69 of 108