Clinical trial NCT02875366
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2016-09-01; Completion date: 2017-10-01
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 4, randomized, double-blind, placebo-controlled, parallel-group study in subjects aged 12 years and older with CF who are homozygous for the F508del-CFTR mutation. This study is designed to evaluate the effect of LUM/IVA on exercise tolerance in subjects with CF, homozygous for the F508del-CFTR mutation.

Detailed description:

Arms: arm 1: Placebo matched to LUM/IVA fixed-dose combination tablet orally every 12 hours (q12h) for 24 weeks. arm 2: LUM 400 milligram (mg)/IVA 250 mg fixed-dose combination tablet orally q12h for 24 weeks.
Interventions: intervention 1: LUM/IVA intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 


Protocol VX15-809-112, Version1.0
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PROTOCOL SYNOPSIS
Title A Phase 4, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design 
Study of the Effect of Lumacaftor/Ivacaftor Combination Therapyon Exercise 
Tolerance in Subjects Aged 12 Years and Older With Cystic Fibrosis, 
Homozygous for the F508del-CFTRMutation
Brief Title A Study of the Effects of Lumacaftor/Ivacaftor on Exercise Tolerance in Subjects 
With Cystic Fibrosis, Homozygous for theF508del-CFTRMutation
Clinical Phase and 
Clinical Study Type 
Phase4, investigation of exercise tolerance
Objectives
Primary Objective
To evaluate the effect of lumacaftor/ivacaftor (LUM/IVA) combination therapy
on exercise tolerance in subjects with cystic fibrosis (CF), homozygous for the 
F508del-CFTRmutation
Secondary Objective
To evaluate the effect of LUM/IVA on manifestations of CF affected by exercise 
tolerance and training
Endpoints Primary Endpoint
Percentage change from baseline in maximal oxygen consumption (VO
2max) 
during cardiopulmonary exercise testing (CPET) at Week24
Secondary Endpoints
Key Secondary Endpoint
Change from baseline in exercise durationduring CPET at Week24
Other Secondary Endpoints
Change from baseline in oxygen consumption (VO2) at anaerobic threshold 
(AT) (the exercise intensity at which lactate starts to accumulate) at Week24
Change from baseline in functional VO
2gain at Week24
Change from baseline in the pulmonary ventilation (VE) versus carbon 
dioxide production (VCO2) slope at Week24
Change from baseline in percent predicted forced expiratory volume in 
1second (ppFEV1) at Week24 
Change from baseline in body mass index (BMI) at Week24 
Change from baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
respiratory domainscoreat Week24
Change from baseline in overall Patient Health Questionnaire (PHQ-8) and 
Generalized Anxiety Disorder (GAD-7) scores at Week24
Change from baseline in physical activity as determined by actigraphy at 
Week 24
Change from baseline in duration of sleep time and change in sleep quality 
during the night at Week24
Safety and tolerability assessments based on adverse events (AEs), clinical 
laboratory values (serum chemistry and hematology), vital signs,and
ophthalmologic examinations (for subjects under 18years of age only).




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Statistical Analyses Statistical analysis details will be provided in the statistical analysis plan(SAP). 
The Vertex Biometrics department or a designated contract research organization
will analyze the data derived from this study. 
Sample Size and Power
Assuming a common standard deviation (SD) of 10% for the primary efficacy
endpoint and a dropout rate of 10%, a sample size of 33subjects in each treatment 
group would provide at least 80% power to detect a difference of 7.5% between 
the means for the 2treatment groups using a 2-sided test at the 0.05 significance 
level. If the true difference is smaller, or if there is greater variability, a larger 
sample size would be required to provide 80% power. Sample sizes needed for 
80% power under various conditions are shown in Section12.1.
Because LUM/IVA has recently been approved in several countries, it is expected 
that additional data, independent of this study, will emerge while this study is 
underway and will allow more precise estimation of the true treatment effect. The 
final sample size will be based on these data, and the protocol maybe amended as 
appropriate.
Analysis Sets
The Full Analysis Set (FAS) is defined as all randomized subjects who have 
received at least 1dose of study drug. The FAS will be used for all efficacy 
analyses, with subjects analyzed according to their randomized treatment group. 
The Safety Set is defined as all subjects who received at least 1dose of study 
drug. The Safety Set will be used for all safety analyses, with subjects analyzed 
according to the treatment they received.
Efficacy Analyses
For the primary analysis, the null hypothesis is that the mean percentage change 
from study baseline in VO
2maxat Week24 is the same for the LUM/IVA and 
placebo groups.
The primary analysis will use a restricted maximum likelihood (REML)-based 
mixed effect model for repeated measures (MMRM). The model will include the 
percentage change from baseline in VO2maxas the dependent variable; treatment, 
visit, and treatment-by-visitinteraction as fixed effects; and subject as a random 
effect with adjustment for sex (male versus female), age group at baseline 
(<18versus ≥18years old), and ppFEV1at Screening (<70% versus≥70%).
The primary result obtained from the model will be the estimated treatment effect 
at Week24 based on a contrast test. The estimated mean treatment effect at 
Week 24, a 95% confidence interval, and a 2-sided Pvalue will be provided.
Secondary endpoints will be analyzed in a similar fashion. 


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SafetyAnalyses
The overall safety profile of study treatments will be assessed in terms of the 
following safety endpoints: 
Incidence of treatment-emergent adverse events (TEAEs)
Clinical laboratory values
Vital signs
Ophthalmologic examinations (for subjects under 18years of age only)
For safety variables, the scheduled Day1, predose measurement will be used as 
the baseline value, whenavailable; otherwise, the baseline value will be defined as 
the value at the Screening Visit.
All safety data will be listed by subject in data listings.
Summaries of TEAEs will be presented by MedDRA system organ class and 
preferred term using frequency counts and percentages. Summaries will be 
presented for all TEAEs, TEAEs by relationship, TEAEs by maximum severity, 
TEAEs leading to treatment discontinuation, serious TEAEs, TEAEs leading to 
death, and f
requently reported TEAEs.


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SCHEDULE OF ASSESSMENTS
Schedules of Assessments are shown in Table3-1and Table3-2.
Table3-1
Study VX15-809-112: Screening
Assessment
Screening Visit
Day-28 to Day-1
Informed consent 
X
Demographics
X
Medical history
X
Ophthalmological history
X
Prior and concomitant medications
X
Height, weight, and BMIa
X
Vital signsb
X
Ophthalmologic examinationc
X
Physical examinationd
X
Standard 12-lead electrocardiogram (ECG)
e
X
CFTRgenotypef
X
Sweat chlorideg
X
Spirometryh
X
Urinalysisi
X
Serum FSH (postmenopausal female subjects only)
X
Serum β-HCG (all female subjects)
X
Serum chemistryj
X
Hematologyj
X
Coagulationj
X
Activity tracking via actigraphy
Continuous for 1week during the Screening Period
Adverse events
Continuous from signing of ICF through 
Safety Follow-up Visit
a
Height and weight will be measured with shoes off.
b
Vital signs (systolic and diastolicblood pressure, oral temperature, pulse rate, and respiration rate) will be 
collected after the subject has been seated for at least5minutes. Blood pressure will be taken using a 
manual sphygmomanometer.
c
For all subjects <18years of age, exceptforthose who have had bilateral lens removal, an ophthalmologic 
examination will be conducted by alicensedophthalmologist or optometrist. If there is documentation that 
an examination meeting protocol criteria was conducted within 3months before the Screening Visit, the 
ophthalmologic examination does not need to be performedduring the Screening Period.
d
The physical examination includes an assessment of all body systems.
e
The ECG will be performed before any other procedures that may affect heart rate (e.g.,blood draws).
f
CFTRgenotyping will be performed to determine thatthe subject is homozygous for the F508del-CFTR
mutation.If homozygous F508del-CFTRgenotype is documented in the subject’s medical records, CFTR
genotyping during screening is not required.
g
A sweat chloride assessment at the Screening Visit is requiredonlyif the subject does not have a sweat 
chloride value documented in their medical history that meets the study eligibility criteria.
h
Spirometry will be assessed before the cardiopulmonary exercise test.
i
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination 
of urine will be performed.
j
Blood samples will be collected for clinical laboratory assessments after a fast of at least 4hours.


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Table3-2
Study VX15-809-112: Treatment Period and Safety Follow-up Visit
Event/Assessment
Treatment Period
Early Termination 
of Treatmenta
Safety Follow-up
4Weeks (± 7Days) After 
Last Dosea
Day1
Week 12
(±7Days)
Week 24
(±7Days)
Clinic Visit
X
X
X
X
X
Randomization
X
CFQ-R, PHQ-8, and GAD-7 
b
X
X
X
X
Height and weightc
X
X
X
X
X
Vital signsd
X
X
X
X
X
Spirometrye
X
X
X
X
Physical examination (PE)f
X
X
Ophthalmologic examination
Xg
Xg
Xg
Cardiopulmonary exercise test (CPET)
h
X
X
X
X
Urine β-HCGi
X
X
X
X
X
Serum chemistryj
X
X
X
X
X
Hematologyj
X
X
X
X
X
a
If the subject prematurely discontinues study drug, an Early Termination of Treatment (ETT) Visit should be scheduled as soonas possible after the subject decides to 
discontinue. If the ETT Visit occurs 3weeks after the last dose of study drug orlater, then the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety 
Follow-up Visit will not be required. When the Safety Follow-up Visit is complete, the subject has completed the study.
b
All questionnaires must be completed before the start of any other assessments scheduled at that visit. The CFQ-R must be completed first, then the PHQ-8 and GAD-7.
c
During the Treatment Period and at the Safety Follow-up Visit, height will be collected only for subjects who were 21 years of age or younger at the Screening Visit.Height 
and weight will be measured with shoes off.
d
Vital signs(systolic and diastolic blood pressure, oral temperature, pulse rate, and respiration rate) will be collectedbefore study drug dosing and after the subject has been 
seated for at least 5minutes. Blood pressure will be taken using a manual sphygmomanometer.
e
Spirometry will be assessed before the CPET. 
f
The physical examination includes anassessment of all body systems. Symptom-directed physical examinations will occur at any time during the study if triggered by AEs or 
if deemed necessary by the investigator.
g
For all subjects <18years of age at the Screening Visit,except for those who have had bilateral lens removal, an ophthalmologic examination will be conducted by a licensed 
ophthalmologist or optometrist at 1 of the following visits: the Week24 Visit, the ETTVisit, or the Safety Follow-up Visit.
h
The CPET includes pulse oximetry.
i
Pregnancy tests will be performed for all female subjects of childbearing potential. A urine β–hCG test will be performed on Day1 (before first dose of study drug) and every 
4weeks thereafter. When there is not a scheduled study visit, the pregnancy test will be conducted with a urine home pregnancytest kit provided by the study site. For tests 
performed at home, the site staff will telephone the subject to confirm the test results.
j
On Day 1, blood samples for chemistry and hematology tests will be collected before the first dose of study drug. At other scheduled visits,these samples may be collected at 
any time during the visit.


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Table3-2
Study VX15-809-112: Treatment Period and Safety Follow-up Visit
Event/Assessment
Treatment Period
Early Termination 
of Treatmenta
Safety Follow-up
4Weeks (± 7Days) After 
Last Dosea
Day1
Week 12
(±7Days)
Week 24
(±7Days)
Study drug dispensed
k
X
X
Study drug dosing
LUM400mg/IVA250mgq12h orplacebo q12h
Study drug count
X
X
X
Reminder of standard exercise 
recommendations
l
X
X
Activity and sleep tracking via actigraphy
Continuous from Day 1 through Week24 Visit
Recording concomitant medications and 
treatments/procedures
Continuous from signing of ICF through Safety Follow-up Visit
Recording AEs
Continuous from signing of ICF through Safety Follow-up Visit
k
Study drug will be administered orally, 2 times a day, within 30 minutes of consumption of fat-containing food. Details are provided in Section10.2.
l
All subjects will be reminded of the standard exercise recommendations for patients with CF.


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4
TABLE OF CONTENTS
1 Title Page......................................................................................................................1
2 Protocol Synopsis..........................................................................................................2
3 Schedule of Assessments...............................................................................................6
4 Table of Contents..........................................................................................................9
List of Tables..................................................................................................................13
List of Figures................................................................................................................13
5 Introduction................................................................................................................14
5.1 Study Rationale.....................................................................................................14
5.2 Background...........................................................................................................14
6 Study Objectives.........................................................................................................16
6.1 Primary Objective..................................................................................................16
6.2 Secondary Objectives............................................................................................16
7 Study Endpoints.........................................................................................................16
7.1 Primary Endpoint..................................................................................................16
72 Secondary Endpoints
16
8 Study Design...............................................................................................................17
8.1 Overview of Study Design.....................................................................................17
8.1.1
Screening.......................................................................................................18
8.1.2
Treatment Period...........................................................................................19
8.1.3
Follow-up......................................................................................................19
8.1.4
Early Termination of Treatment.....................................................................19
8.2 Rationale for Study Design and Study Drug Regimens..........................................19
8.2.1
Study Design.................................................................................................19
8.2.2
Study Drug Dose and Duration......................................................................20
8.2.3
Rationale for Study Assessments...................................................................20
9 Study Population........................................................................................................21
9.1 Inclusion Criteria...................................................................................................21
9.2 Exclusion Criteria..................................................................................................22
9.3 Study Restrictions..................................................................................................24
9.4 Prior and Concomitant Medications.......................................................................24
9.4.1
Prohibited Medications..................................................................................24
9.4.2
Prior and Concomitant Medications...............................................................25
9.5 Removal of Subjects..............................................................................................25
9.6 Replacement of Subjects........................................................................................25
10 Study Drug Administration and Management..........................................................25
10.1Preparation and Dispensing...................................................................................25
10.2Administration.......................................................................................................26
10.3Missed Doses........................................................................................................26
10.4StudyDrug Interruption.........................................................................................26
10.5Method of Assigning Subjects to Treatment Groups..............................................27


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10.6Packaging and Labeling.........................................................................................27
10.7Study Drug Supply, Storage, and Handling............................................................27
10.8Drug Accountability..............................................................................................27
10.9Disposal, Return, or Retention of Unused Drug.....................................................27
10.10Compliance...........................................................................................................28
10.11Blindingand Unblinding.......................................................................................28
10.11.1Blinding.........................................................................................................28
10.11.2Unblinding.....................................................................................................28
11 Assessments................................................................................................................29
11.1Timing of Assessments..........................................................................................29
11.2Subject and Disease Characteristics.......................................................................29
11.3Pharmacokinetics...................................................................................................29
11.4Efficacy.................................................................................................................30
11.4.1 Cardiopulmonary Exercise Testing................................................................30
11.4.2 Spirometry.....................................................................................................30
11.4.3 Actigraphy.....................................................................................................31
11.4.4 Height, Weight, and BMI...............................................................................31
11.4.5 Cystic Fibrosis Questionnaire –Revised........................................................31
11.4.6 Patient Health Questionnaire (PHQ-8)...........................................................31
11.4.7 Generalized Anxiety Disorder (GAD-7).........................................................32
11.5Safety....................................................................................................................32
11.5.1 Adverse Events..............................................................................................32
11.5.2 Clinical Laboratory Assessments...................................................................32
11.5.3 Elevation of Liver Function Test Parameters..................................................34
11.5.4 Physical Examinations and Vital Signs..........................................................35
11.5.5 Electrocardiograms........................................................................................35
11.5.6 Ophthalmologic Examinations and History....................................................35
11.5.7 Contraception and Pregnancy.........................................................................36
11.5.7.1 Contraception..........................................................................................36
11.5.7.2 Pregnancy................................................................................................38
12 Statistical and Analytical Plans..................................................................................38
12.1Sample Size and Power.........................................................................................39
12.2Analysis Sets.........................................................................................................39
12.3Statistical Analysis................................................................................................39
12.3.1 General Considerations..................................................................................39
12.3.2 Background Characteristics............................................................................40
12.3.2.1 Subject Disposition..................................................................................40
12.3.2.2 Demographics and Baseline Characteristics.............................................40
12.3.2.3 Prior and Concomitant Medications.........................................................41
12.3.2.4 Study Drug Exposure and Compliance.....................................................41
12.3.2.5 Important Protocol Deviations.................................................................41
12.3.3 Efficacy Analysis...........................................................................................41
12.3.3.1 Analysis of Primary Variables.................................................................41


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12.3.3.2 Analysis of Secondary Efficacy Variables................................................42
12.3.3.3 Correlation Analyses...............................................................................42
12.3.4 Safety Analysis..............................................................................................43
12.3.4.1 Adverse Events........................................................................................43
12.3.4.2 Clinical Laboratory Assessments.............................................................44
12.3.4.3 Electrocardiogram...................................................................................44
12.3.4.4 Vital Signs...............................................................................................44
12.3.4.5 Physical Examination..............................................................................45
12.3.4.6 Other Safety Analysis..............................................................................45
12.3.5 Interim and IDMC Analyses..........................................................................45
13 Procedural, Ethical, Regulatory, and Administrative Considerations.....................45
13.1Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting..............................................................................................................45
13.1.1 Adverse Events..............................................................................................45
13.1.1.1 Definition of an Adverse Event................................................................45
13.1.1.2 Clinically Significant Assessments..........................................................46
13.1.1.3 Documentation of Adverse Events...........................................................46
13.1.1.4 Adverse Event Severity...........................................................................47
13.1.1.5 Adverse EventCausality..........................................................................47
13.1.1.6 Study Drug Action Taken........................................................................48
13.1.1.7 Adverse Event Outcome..........................................................................48
13.1.1.8 Treatment Given......................................................................................49
13.1.2 Serious Adverse Events.................................................................................49
13.1.2.1 Definition of a Serious Adverse Event.....................................................49
13.1.2.2 Documentation of Serious Adverse Events..............................................50
13.1.2.3 Reporting Serious Adverse Events...........................................................50
13.1.2.4 Expedited Reporting and Investigator Safety Letters................................50
13.2Administrative Requirements................................................................................51
13.2.1 Ethical Considerations...................................................................................51
13.2.2 Subject Information and Informed Consent....................................................51
13.2.3 Investigator Compliance................................................................................51
13.2.4 Access to Records..........................................................................................51
13.2.5 Subject Privacy..............................................................................................52
13.2.6 Record Retention...........................................................................................52
13.2.7 Study Termination.........................................................................................52
13.3Data Quality Assurance.........................................................................................53
13.4Monitoring............................................................................................................53
13.5Electronic Data Capture.........................................................................................53
14 References...................................................................................................................55
15 Protocol Signature Pages............................................................................................59
15.1Sponsor Signature Page.........................................................................................59


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15.2Investigator Signature Page...................................................................................60


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List of Tables
Table3-1
Study VX15-809-112: Screening....................................................................6
Table3-2
Study VX15-809-112: Treatment Period and Safety Follow-up Visit..............7
Table9-1
Study Restrictions........................................................................................24
Table 10-1
Study Drug...................................................................................................27
Table11-1
Safety Laboratory Test Panels......................................................................33
Table12-1
Sample Sizes for 80% Power........................................................................39
Table13-1
Grading of AE Severity................................................................................47
Table13-2
Classifications for AE Causality...................................................................48
Table13-3
Classifications for Study Drug Action Taken With Regard to an AE............48
Table13-4
Classifications for Outcome of an AE...........................................................49
List of Figures
Figure8-1
Schematic View of the Study Design............................................................18




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salt and water absorption and secretion in various tissues.
18This function is defective in 
patients with CF due to loss of cell surface expression and/or function of CFTR.
More than 1900 mutations in the CFTRgene have been identified.
19The most prevalent 
mutation is an in-frame deletion in the CFTRgene resulting in a loss of phenylalanine at 
position508 in the wild-type CFTR protein (F508del-CFTR).
20In the US, almost 87% of 
patients with CF have at least 1copy of theF508del-CFTRmutation, and about 47% have 
2copies.21In the EU, approximately 85% of patients with CF have at least 1copyof the 
F508del-CFTRmutation, and approximately 38.7% of patients with CF in the United 
Kingdom have 2copies.22The F508del-CFTRmutation interferes with the ability of the 
CFTR protein to reach and remain at the cell surface, as well as to open and close, resulting 
in decreased Cl
−transport.
23,24Because of the near-complete loss of CFTR chloride transport, 
the F508del/F508delgenotype is typically associated with a severe form of CF, characterized 
by a rapid rate of lung function decline, colonization with Pseudomonasaeruginosa, a high 
incidence of pancreatic insufficiency, and reduced life expectancy
.
25,26,27,28
Based on the understanding of the molecular defects caused by CFTRmutations, 
2complementary approaches have been developed to address the decreased quantity and/or 
function of CFTR in order to enhance chloride transport in patients with CF. The first 
approach is to increase the quantity of CFTR delivered to the cell surface using small 
molecules known as CFTR correctors. The second approach is to increase the channel gating 
activity of CFTR at the cell surface using small molecules known as CFTR potentiators. One 
or both of these mechanisms may be necessary depending on the specific mutation. Because 
the channel gating activity of CFTR delivered to the cell surface by CFTR correctors can be 
enhanced by CFTR potentiators, together, CFTR correctors and potentiators provide 
complementary therapeutic approaches to improve chloride transport. 
Lumacaftor (LUM) is aCFTR corrector that improves the processing and trafficking of the 
F508del-CFTR protein, resulting in an increase in the quantity of F508del-CFTR protein at 
the cell surface. IVA increases the channel-open probability of the F508del-CFTR protein 
deliveredto the cell surface by LUM, thereby enhancing total chloride transport. In the 
absence of LUM, there is very little F508del-CFTR protein at the cell surface for IVA to 
potentiate. The combined effect of LUM and IVA is increased quantity and function of 
F508del-CFTR at the cell surface.
LUM and IVA in combination is the first medicine designed to treat the underlying 
molecular defect and enhance the function of CFTR in patients homozygous for F508del. 
The LUM/IVA development program targets patients with CF who have the F508del
mutation, the most common mutation in the CFTRgene. The program is designed to support 
the hypothesis that an oral chronic treatment restoring CFTR function can lead to improved 
pulmonary and extrapulmonary manifestations of CF, prevent progressive lung damage, and 
ultimately prolong survival. 
Details about the LUM/IVA development program can be found in the Investigator’s 
Brochure.29


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6
STUDY OBJECTIVES
6.1
Primary Objective
To evaluate the effect of LUM/IVA on exercise tolerance in subjects with CF, homozygous 
for the F508del-CFTR mutation
6.2
Secondary Objectives
To evaluate the effect of LUM/IVA on manifestations of CF affected by exercise tolerance 
and training
7
STUDY ENDPOINTS
7.1
PrimaryEndpoint
Percentage change from baseline in VO2maxduring cardiopulmonary exercise testing (CPET) 
at Week24
7.2
Secondary Endpoints
Key Secondary Endpoint
Change from baseline in exercise durationduring CPET at Week24
Other Secondary Endpoints
Change from baseline in oxygen consumption (VO2) at anaerobic threshold (AT) (the 
exercise intensity at which lactate starts to accumulate) at Week24
Change from baseline in functional VO2gain at Week24
Change from baseline in the pulmonary ventilation (VE) versus carbon dioxide 
production (VCO2) slope at Week24
Change from baseline in percent predicted forced expiratory volume in 1second 
(ppFEV1) at Week24 
Change from baseline in body mass index (BMI) at Week24 
Change from baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R)respiratory 
domain score at Week24
Changefrom baseline in overall Patient Health Questionnaire (PHQ-8)and 
Generalized Anxiety Disorder (GAD-7)scores at Week24
Change from baseline in physical activity as determined by actigraphy at Week24
Change from baseline in duration of sleep time and change in sleep quality during the 
night at Week24
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory 
values (serum chemistry and hematology), vital signs, and ophthalmologic examinations 
(for subjects under 18years of age only).


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8
STUDY DESIGN
8.1
Overview of Study Design
Thisis a Phase4, randomized, double-blind, placebo-controlled, parallel-group study in 
subjects aged 12 years and older with CF who are homozygous for the F508del-CFTR
mutation. This study is designed to evaluate the effect of LUM/IVA on exercise tolerance.
The studyincludes a Screening Period, a Treatment Period, and a Safety Follow-up Visit. 
Approximately66subjects will be randomized 1:1 (LUM/IVA:placebo) to the treatment 
arms shown in Figure8-1and stratified byppFEV1 at baseline (<70%and ≥70% predicted). 
Subjects will receive study drug (LUM/IVA or placebo) for 24weeks, in addition to their 
current CF medication regimen. They will return to the study center 4weeks after their last 
dose of study drug for the Safety Follow-up Visit. It is recommended that subjects remain on 
a stableCFmedication regimen from 4weeks before Day1 through the Safety Follow-up 
Visit. 
Subjects willbe reminded of the standard exercise recommendations for patients with CF,
and their daily activity will be tracked using an actigraphy device. 




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of a laboratory error (e.g.,hemolysis of sample). In all cases, the medical monitor must 
authorize retesting.
8.1.2
Treatment Period
Treatment Period assessments are listed in Table3-2.
The Treatment Periodwill be conducted as described previously in Section8.1. Dosing 
details are given in Section10.2.
Subjects who prematurely discontinue study drug treatment will remain in the study from the 
time of discontinuation through the Safety Follow-up Visit, as described in Section8.1.4.
8.1.3
Follow-up
Subjects will have a SafetyFollow-up Visit 4weeks(±7days)after the last study drug dose. 
Safety Follow-up Visit assessments are listed in Table3-2.When the Safety Follow-up Visit 
is complete, the subject has completed the study.
8.1.4
Early Termination of Treatment 
If the subject prematurely discontinues study drug, an Early Termination of Treatment (ETT) 
Visit will be scheduled as soon as possible after the subject decides toterminate study drug. 
Subjects who prematurely discontinue study drugwill also complete the Safety Follow-up 
Visit, approximately 4weeks ±7 days after their last dose of study drug. The assessments 
performed at the Safety Follow-up Visit are listed in Table3-2.
If the ETT Visit occurs 3weeks after the last dose of study drug or later, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required.
If the subject withdraws consent for the study, no further evaluations will be performed, and 
no additional data will be collected. Vertex Pharmaceuticals Incorporated(Vertex) may 
retain and continue to use any datacollected before such withdrawal of consent.
8.2
Rationale for Study Design and Study Drug Regimens
8.2.1
Study Design
This study is designed to evaluate the effect of LUM/IVA therapy on exercise tolerance in 
subjects with CF after up to 24weeks of LUM/IVA therapy. CPETs will be used to assess 
improvements in exercise tolerance, as measured by VO
2max.
The use of a placebo control groupis deemed necessary because exercise tolerance can be 
affected by a number of factors, including activity level, and subject activity may increase as 
a result of being involved in an exercise tolerance study.
This study will only enroll subjects who have not previously been exposed to LUM or IVA, 
and all subjects will continue their normal, stable treatment for CF throughout the study.
The study population will be subjects with CF who are 12 years of age and older and are 
homozygous for the F508del-CFTRmutation. Efficacy, safety, and pharmacokineticprofiles 
for LUM/IVA therapy were established in subjects 12years of age and older with CF 
homozygous for the F508del-CFTRmutation in StudiesVX12-809-103 (Study103)and 


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VX12-809-104 (Study104). Furthermore, this is the population for which LUM/IVA 
treatment has beenapproved inEurope and inthe US.
8.2.2
Study Drug Dose and Duration
The dosing regimen for LUM/IVA (LUM 400mg/IVA 250mgevery 12hours [q12h]) was 
selected on the basis of acceptable tolerability and favorable exposure observed in previous 
clinical studies of LUM/IVA,29and because it has been approved in Europe and in the US for 
the treatment of CF in patients age 12years and older who are homozygous for the F508del
mutation.30,31
8.2.3
Rationale for Study Assessments
CPET:Maximal cardiopulmonary exercise testing that incorporates measurements of gas 
exchange provides precise measurements of exercise tolerance. This assessment provides 
several parameters of exercise tolerance and aerobic fitness including VO2, functional VO2
gain,VCO2, AT, and VE. Functional VO2gain relates oxygen uptake to total ventilation 
during exercise and isan index of cardiopulmonary reserve. The VE versus VCO
2slope is a 
measure of ventilatory efficiency. The AT is the exercise intensity at which lactate starts to 
accumulate. 
Spirometry:Because lung disease is the major cause of morbidity and mortality for patients 
with CF, FEV
1, as measured by spirometry, is the most widely implemented standardized 
assessment to evaluate lung functionin CF.
Actigraphy:Exercise tolerance can be affected by a number of factors, including activity 
level. In this study, subjects’ activity levels will be monitored by actigraphy to determine 
whether subjects’ activity increased with LUM/IVA treatment andtoexamine the 
relationship betweenphysicalactivity andchanges in exercise tolerance. Actigraphy will also 
be used to capture sleep/wake data, which reflect both functional and physiological health of 
subjects. The actigraph device can capture continuous sleep/wake data over a long period of 
time, is a cost-effective and minimally invasive in-home alternative to other methods to 
measure these behaviors (e.g.,polysomnography), and offers a level of accuracy and 
reliability that cannot be achieved through subjective reports.
BMI:Malnutrition is common in patients with CF because of increased energy expenditures 
due to lung disease and fat malabsorption. Improved nutritional status, defined as an increase 
in weight and/or BMI, is an endpoint that has beenused in previous clinical studies of 
LUM/IVA therapy (Studies103 and 104). 
Questionnaires pertaining to quality of life, depression, and anxiety—the CFQ-R, 
PHQ-R, and GAD-7:The CFQ-R is a validated CF-specific instrument that measures the 
health-related quality of life of patients with CF.
32,33,34The adolescent/adult version, the 
parent/caregiver version, and the child version measure quality-of-life domains including 
respiratory symptoms, digestive symptoms, emotion, and health perception. Furthermore, the 
CFQ-R has been evaluated in clinical studies involving therapies for CF lung disease.
35,36,37
Linguistically validated versions of the CFQ-R
38,39are available, thereby allowing consistent 
interpretation of the results in this global study.


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Several recent studies have documented the high rates of symptoms of depression and 
anxiety in patients with CF.
40-43The PHQ-8 is used to assess the presence of depressive 
symptoms in non-depression studies via 8 items that correspond to diagnostic criteria for 
major depressive disorder and depression severity. Various levels in the resulting score 
correspond to various levels of depression severity. The GAD-7 assesses the presence of 
anxiety symptoms via 7items that are based on the symptom criteria for generalized anxiety 
disorder
9
STUDY POPULATION
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled.
9.1
Inclusion Criteria
Subjects who meet all of the following inclusion criteria will be eligible:
1. Subject (or their legally appointed and authorized representative) will sign and date an 
informed consent form (ICF), and where appropriate, assent form. 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures.
3. Subjects (male and female) will be at least 12years old on the date of informed consent.
4. Homozygous for the F508del-CFTRmutation (as documented in the subject’s medical 
recordsorfrom genotyping performed during screening).


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5. Confirmed diagnosis of CF44defined as a sweat chloride value 60mmol/L by 
quantitative pilocarpine iontophoresis,as documented:
in the subject’s medical recordsOR
from sweat chloride test result obtained during screening(to be conducted only if the 
subject does not have a sweat chloride test result in the medical records).
6. Stable CF disease as judged by the investigator.
7. FEV1at least 40% and not greater than 90% of predicted.
8. Willing to remain on a stable CF medication regimen through the Safety Follow-up Visit.
9.2
Exclusion Criteria
Subjects who meet any of the following exclusion criteria will notbe eligible:
1. History of any comorbidity that might confound the results of the study, interfere with the
use of CPET as an assessment, or pose an additional risk in administering study drug to 
the subject. For example:
history of cirrhosis with portal hypertension.
inability to exercise.
requiring additional oxygen with exercise.
2. Any of the following abnormal laboratory values at Screening:
hemoglobin <10g/dL.
any 2or more of the following: aspartate aminotransferase (AST)≥3×upper limit of 
normal (ULN), alanine aminotransferase (ALT)≥3×ULN, gamma-glutamyl 
transpeptidase (GGT)≥3×ULN, or alkaline phosphatase (ALP)≥3×ULN.
total bilirubin≥2×ULN.
AST or ALT ≥5×ULN.
glomerular filtration rate ≤50mL/min/1.73m2(calculated by the Modification of Diet 
in Renal Disease Study Equation)45,46for subjects ≥18years of age and 
≤45mL/min/1.73m2(calculated by the Counahan-Barratt equation)47for 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 28days before Day1.
4. A 12-lead electrocardiogram (ECG)demonstrating QTc >450msec at Screening. If QTc 
exceeds 450msecfor the screening ECG, the ECG will be repeated 2more times during 
the Screening Period, and the average of the 3QTc values will be used to determine the 
subject’s eligibility.


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5. History ofcardiac arrhythmia, ischemic heart disease, congestive heart failure,or other 
clinically significant cardiac condition, or medical condition requiring chronic use of a 
beta blocker,non-dihydropyridine calcium channel blocker, or other cardiac medication
known to affect exercise tolerance.
6. History of solid organ or hematological transplantation.
7. For subjects under 18 years of age at Screening, except those who have had bilateral lens 
removal: history or evidenceof cataract, lens opacity, Y-suture, or lamellar rings 
determined to be clinically significant by the ophthalmologist or optometrist during the 
ophthalmologic examination during the Screening Period. (The ophthalmologic 
examination does not need to be performed at Screeningif there is documentation of an 
examination meeting protocol criteria that was conducted within 3months before the 
Screening Visit.)
8. Using or expected to require any concomitant medication that is prohibited in this study, 
as discussedin Section9.4.1.
9. History of alcohol or drug abuse, as deemed by the investigator, in the past year, 
including but not limited tocannabis, cocaine, and opiates.
10.Participation in an investigational drug study within 30days before the Screening Visit.
11.Any previous exposure to LUM or IVA. 
12.Pregnant or nursing females (females of childbearing potential must have a negative 
pregnancy test at Screening and Day1);males with a female partner who is pregnant or 
nursing. 
13.The subject or a close relative of the subject is the investigator or a subinvestigator, 
research assistant, pharmacist, study coordinator, or other staff directly involved with the 
conduct of the study. An adult (aged 18 years or older) who is a relative of a study staff 
member may be randomized in the study provided that
the adult lives independently of and does not reside with the study staff member.
the adult participates in the study at a site other than the site at which the family 
member is employed.
14.Colonization with organisms associated with a more rapid decline in pulmonary status 
(e.g., Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus). For 
subjects who have had a history of a positive culture in the past, the investigator could be 
guided by the following suggested criteria for a subject to be considered free of 
colonization:
The subject should have had 2 respiratory tract cultures negative for these organisms 
within the past 12 months, with no subsequent positive cultures.
These 2 respiratory tract cultures should have been separated by at least 3months.
One of these 2 respiratory tract cultures should have been obtained within the past 
6months.


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9.3
Study Restrictions
Prohibited medications and certain foods are not allowed (Screening Period through 
Week 24) as summarized in Table9-1.
A nonexhaustive list of study prohibitions and cautions for food and medication will be 
provided.
Table9-1
Study Restrictions
Restricted Medication/Fooda
Study Period
Screening Period
Treatment Period
Strong CYP3A inducers
None allowed within 14days before 
the first dose of study drug
None allowed
Strong CYP3A inhibitors
None allowed within 14days before 
the first dose of study drug
Use with caution
Note: The use of restricted medication in subjects with a medical need will be addressed on a case-by-case basis 
with the medical monitor or authorized designee.
a
See Section 9.4for guidance for concomitant medications.
9.4
Prior and Concomitant Medications
9.4.1
Prohibited Medications
Prohibited medications as described in Table9-1are not allowed while subjects are receiving 
study drug.
The use of cytochrome P450 (CYP) 3Asubstrates is not prohibited, but investigators need to 
be aware that LUM appears to be a strong inducer of this CYP isoenzyme. Therefore, the 
efficacy of drugs extensively metabolized by this isoenzyme may be affected. Each 
investigator should evaluate the benefit/risk ratio of using such drugs with LUM during this 
study. Investigators should discuss any concerns regarding the use of CYP3A substrates 
during this study with the Vertex medical monitor or authorized designee.
The use of CYP2C and CYP2B6 substrates are not prohibited, but investigators need to be 
aware that LUM has been shown in vitro to induce CYP2B6, CYP2C8, CYP2C9, and 
CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, 
in vitro studies suggest that IVA may inhibit CYP2C9. Therefore, concomitant use of LUM 
in combination with IVA with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may 
alter the exposure of these substrates. 
Each investigator should evaluate the benefit-risk ratio of using such drugs with LUM and 
IVA during this study and discuss the use of these substrates during this study with the 
medical monitor or authorized designee.
The use of strong inhibitors of CYP3A is not prohibited, but investigators need to be aware 
that a strong inhibitor of CYP3A has been shown to increase the exposure of IVA when 
given in combination with LUM; however, due to the induction effect of LUM, the net 
exposure of IVA is not expected to exceed previousexperiences with IVA monotherapy. 
Subjects who are using strong CYP3A inhibitors do not require study drug interruption. 


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However, if they interrupt study drug for more than 72 hours, study drug resumption requires 
medical monitor discussion and approval. Each investigator should evaluate the benefit-risk 
ratio of using such drugs with LUM and IVA during this study
 and discuss the use of these 
strong inhibitors of CYP3A during this study with the medical monitor or authorized 
designee.
A nonexhaustive studyprohibitions and cautions list for food and medications will be 
provided.
9.4.2
Prior and Concomitant Medications
Information regarding all prior and concomitant medications, including the subject’s CF 
medications, other medications, and herbal and naturopathicremedies, administered from 
30days before the Screening Period through the Safety Follow-up Visit will be recorded in 
each subject’s source documents and electronic case report form (eCRF). 
It is recommended that subjects remain on a stable medication regimen for their CF from 
4weeks before Day1 through theSafety Follow-up Visit. Stable medication regimen is 
defined as the current medication regimen for CF that subjects have been following for at 
least 4weeks before Day1.
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 discontinued study drug treatment, the subject will continue to be followed, 
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 
for a Safety Follow-up Visit, if applicable (see Section8.1.4), and followup with the subject 
regarding any unresolved AEs.
If the subject withdraws consent for the study, no further evaluations will be performed and 
no additional data will be collected. Vertex may retain and continue to use any data collected 
before such withdrawal of consent.
Specific instructions for interruption for elevated liver function test (LFT)levels are provided 
in Section11.5.3.
9.6
Replacement of Subjects
Subjects who withdraw or are withdrawn during the Treatment Periodwill not be replaced.
10
STUDY DRUG ADMINISTRATION AND MANAGEMENT
10.1
Preparation and Dispensing
Study drug (LUM/IVA or placebo) may be dispensed only under the supervision of the 
investigator or an authorized designee and only for administration to the study subjects.


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10.2
Administration
Study drug will be administered orally
, 2times a day, with food. Study drug should be 
administered within 30minutes of consuming fat-containing food such as a standard CF 
high-fat, high-calorie meal or snack according to the following guidelines:
1. Study drug will be administered q12h (±2hours).
2. On days of scheduled visits, the morning dose of study drug will be administered at the 
site after predose assessments have been completed. The meal or snack will be provided 
by the site for the morning dose of study drug. 
3. If a subject’s scheduled visit is to occur in the afternoon, the following guidelines must be 
used:
If the dose in the clinic will be within 6hours of the subject’s scheduled morning 
dose, the subject should withhold their morning dose of study drug and the morning 
dose will be administered in the clinic.
If the dose in the clinic will be more than 6hours after the subject’s scheduled 
morning dose, the subject should take the morning dose at home and the evening dose 
will be administered in the clinic. In this event, all assessments will be collected 
relative to the evening dose.
4. For visits after the Day1 Visit, subjects will be instructed to bring all used and unused 
study drugto the site; study drug will be dispensed at each visit, as appropriate.
5. At the Week24 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 Week24 
Visit.
10.3
Missed Doses
If subjects miss a dose and recall the missed dose within 6hours, they should take their dose 
with food. If more than 6hours have elapsed after their usual dosing time, they should skip 
that dose and resume their normal schedule for the following dose. For example:
If the morning dose of study drug should have been taken at approximately 08:00,and the 
subject remembers at 12:00 that he/she forgot to take the morningdose, the subject
should take the dose with food as soon as possible.The subject should then take the 
evening dose at the usual time, approximately20:00.
If the morning dose of study drug should have been taken at approximately 08:00, and the 
subject does not remember until after 14:00, the subject should resume dosing with the 
evening dose at approximately 20:00.
10.4
Study Drug Interruption
If study drug dosing must be interrupted formore than 72hours, 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 are provided in 
Section11.5.3.


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10.5
Method of Assigning Subjects to Treatment Groups
An interactive web or voice response system (IXRS) will be used to assign subjects to 
treatment. The randomization code will be produced by Vertex Biostatistics or a qualified 
randomization vendor. The Vertex study biostatistician will review and approve the 
production of the final randomization list, which will be reviewed and approved by a 
designated unblinded biostatistician who is not a member of the study team. 
10.6
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.
10.7
Study Drug Supply, Storage, and Handling
Table 10-1provides the study drug information. The investigator, or an authorized designee 
(e.g., a licensed pharmacist), will ensure that all investigational product is stored in a secured 
area, underrecommended storage conditions, and in accordance with applicable regulatory 
requirements. To ensure adequate records, all study drugs will be accounted for via the drug 
accountability forms as instructed by Vertex.
Detailed instructions regarding the storage, handling, and dispensation of the study drug will 
be provided in the Pharmacy Manual.
Table 10-1
Study Drug 
Drug Name
Formulation/
Route
Packaging (Formulation 
Strength)
Storage
Condition
Lumacaftor/ivacaftor 
(fixed-dose)
Fixed-dose tablet/
Oral
Supplied as 200-mg 
lumacaftor/125-mg ivacaftor 
tablets 
Store at ≤30°C (86°F)
Placebo(appearance matched 
to lumacaftor/ivacaftor tablets)
Tablet/Oral
No active drug
Store at ≤30°C (86°F)
10.8
Drug Accountability
The pharmacist or designated study site staff will maintain information regarding the dates 
and amounts of study drug received,study drug dispensed to the subjects,andstudy drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site 
according to instructions provided by Vertex or its designee until inventoried by the study 
monitor. The study monitor will review study drug records and inventory throughout the 
study.
10.9
Disposal, Return, or Retention of Unused Drug
The study site staff or pharmacy personnel will retain all materials returned by the subjects 
until the study monitor has performed drug accountability. At the end of the study, the study 


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monitor will provide instructions as to the disposition of any unused investigational product. 
If the study monitor authorizes destruction at the study site, the investigator will ensure that 
the materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Vertex. Destruction will be 
adequately documented.
10.10
Compliance
For study drug doses administered during study visits, doses will be administered under the 
direct supervision of the investigator or designee.
For study drug doses administered outside of study visits, drug accountability will be 
assessed at each visit by counting returned dosage units. Discrepancies will be discussed with 
the subject and recorded in the source documents. If a subjectdemonstratescontinued 
noncompliance of studydrug dosing despite educational efforts, the investigator will contact 
the medical monitor to discuss withdrawingthe subject from the study. 
10.11
Blinding and Unblinding
This isa double-blind study.
10.11.1
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:
Any site personnel for whom this information is important to ensure the safety of the 
subject in the event of a life-threatening medical emergency
Any site personnel for whom this information is important to ensure the safety of the 
subject and their fetus in the event of a pregnancy
Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel for whom this 
information is important to satisfy serious adverse event (SAE) processing and reporting 
regulations
Unblinded statistician preparing the final (production) randomization list, who is not part 
of the study team
Unblinded personnel from Vertex Data ManagementIWRSmanagement
Unblinded personnelfrom Vertex Clinical Supply Chain
The Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time.
Subjects and their parents/caregivers will not be informed of their study-related efficacy 
results during the study,regardless of whether or not the subject prematurely discontinues
treatment. 
10.11.2
Unblinding
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process.


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Unblinding of the individual subject’s treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject’s study treatment 
is necessary for clinical management. In such cases, investigators will use their best 
judgment as to whether to unblind without first attempting to contact the medical monitor to 
discuss and agree to the need for unblinding. If investigators deem it not necessary to unblind 
immediately, they will first attempt to contact the medical monitor to discuss and agree to the 
need for unblinding. If investigators have tried but are unable to reach the medical monitor, 
they will use their best judgment, based on the nature and urgency of the clinical situation, 
and may proceed with unblinding without having successfully
 reached and discussed the 
situation with the medical monitor.
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 
24hours a day, 7days a week, 365days of the year, and will triage these calls to the study 
medical monitor or appropriate backup.
If a subject’s treatment assignment has been unblinded for amedical emergency or urgent 
clinical situation, the medical monitor will be notified within 24hours of the unblinding 
event. The reason and the date of the unblinding will be documented clearly in the subject’s 
study file. Information about the treatmentassignment 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(Section13.1.2.1), and if so, submit an SAE report to Vertex 
GPS or designee, per Section13.1.2.3.
Vertex GPS or designee will alsounblind 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 Table3-1and Table3-2.
11.2
Subject and Disease Characteristics
Subject and disease characteristics include the following: demographics, medical history, 
height, and weight.
11.3
Pharmacokinetics
Not applicable.


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11.4
Efficacy
Subjects and their parents/caregivers will not be informed of their study-related efficacy 
results during the study,regardless of whether or not the subject prematurely discontinues
treatment. 
11.4.1
Cardiopulmonary Exercise Testing
The CPET will be assessed at the time points noted in Table3-2.The CPET will be 
conducted using the Godfrey protocol
48, which has been used in a number of studies of 
exercise tolerance in patients with CF. According to the Godfrey protocol, the CPET will be 
conducted using a cycle that ramps resistance over time.The CPET includes pulse oximetry.
11.4.2
Spirometry
Spirometry will be performed according to the American Thoracic Society Guidelines49at 
the time points noted in Table3-1and Table3-2according to the additional guidelines that 
follow.
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who 
have
withheld their short-acting bronchodilators (e.g.,albuterol) or anticholinergic 
(e.g.,Atrovent®) for more than 4hours before the spirometry assessment;
withheld their long-acting bronchodilator (e.g.,salmeterol) for more than 12hours before 
the spirometry assessment; and
withheld their once-daily, long-acting bronchodilator (e.g.,tiotropium bromide 
[Spiriva®]) for more than 24hours before the spirometry assessment.
All spirometry assessments should be performed post-bronchodilator(unless the subject is 
not using a bronchodilator on a regular basis). During the Treatment Period, spirometry
 
assessments must be performed before administration of study drug.At visits that include 
both spirometryand the CPET, spirometry will be assessed before the CPET.
Each spirometry assessment will be recorded in the source documents as pre-bronchodilator 
or post-bronchodilator.
All sites will be provided with spirometers to be used for all study assessment. 
The parameters listed below will be normalized using the standards of Wang et al.
50(for 
female subjects aged 12to 15years [inclusive] and male subjects aged 12 to 17years 
[inclusive]) or Hankinson et al.
51(for female subjects aged 16years and older andmale 
subjects aged 18years and older). 
FEV1(L)
Forced vital capacity (FVC) (L)
FEV1/FVC (ratio)
Forced expiratory flow (FEF25%-75%) (L/s)


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11.4.3
Actigraphy
Subjects will be provided with a wrist-worn actigraphy device at the Screening Visit and will 
wear the device through the Week 24Visit, as specified in Table3-1and Table3-2. The 
device is non-invasive, similar to a wrist watch. The subjects will wear the device on the 
wrist of their nondominant handandcan wear it 24hours per day. The device will 
continuously collect data about daily activities and sleep duration and quality. Subjects will 
bring in the device during studyvisits for the sitestaff to upload the data from the device. 
Actigraphy data will be centrally read. The device will be returned to the study siteat the 
subject’s final studyvisit.
11.4.4
Height,Weight, and BMI
Height and weight will be measured with shoes off at time points noted in Table3-1and 
Table3-2. During the Treatment Period and at the Safety Follow-up Visit, height will be 
collected only for subjects who were 21 years of age or younger at the screening visit.
As children gain weight and height as part of normal growth, adjustment for age and sex is 
necessary to assess changes in nutritional status in a population of boys and girls atvarying 
stages of growth. To evaluate the effect of LUM/IVA on growth and nutrition adjusted for 
age and sex, weight-for-age, BMI-for-age, BMI-for-age z-scores, and height-for-age z-scores 
will be determined. Height and weight will be collected at the study visits indicated in the 
schedule of assessments. 
11.4.5
Cystic Fibrosis Questionnaire –Revised
CFQ-R will be completed at the time points noted in Table3-2. All questionnaires must be 
completed before the start of any other assessments scheduled at that visit. The CFQ-R must 
be completed first, then the PHQ-8 and GAD-7.
The CFQ-R will be completed before the start of any other assessments. Subjects who are 
12or13 years of age at the Screening Visit will complete the CFQ-R Child version 
themselves for the entire study duration, regardless of whether the subject turns 14years of 
age during the study. Subjects 14 years of age and older at the Screening Visit willcomplete 
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). Copiesof the CFQ-R used in this 
study will be provided. Validated translations38,39of the CFQ-R will be provided for 
participating centers in non-English-speaking countries.
11.4.6
Patient Health Questionnaire (PHQ-8)
The PHQ-8 will be completed at the time points noted in Table3-2. All questionnaires must 
be completed before the start of any other assessments scheduled at that visit. The CFQ-R 
must be completed first, then the PHQ-8 and GAD-7.
The PHQ-8 provides information about 8 items that correspond to diagnostic criteria for 
major depressive disorder and depression severity. 


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11.4.7
Generalized Anxiety Disorder (GAD-7)
The GAD-7 will be completed at the time points noted in Table3-2. All questionnaires must 
be completed before the start of any other assessments scheduled at that visit. The CFQ-R 
must be completed first, then the PHQ-8 and GAD-7.
TheGAD-7 provides information about 7items that are based on the symptom criteria for 
generalized anxiety disorder.
11.5
Safety
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of 
vital signs, ophthalmologic examinations(for subjects under 18years of age only), and 
physical examinations (PEs).Spirometry data will also be used as safety-supporting data.
11.5.1
Adverse Events
All AEs will be assessed, documented, and reported in accordance with ICHGCP guidelines. 
Section13.1outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF 
completion guidelines for investigators as well as training will be provided.
11.5.2
Clinical Laboratory Assessments
Blood and urine samples will be analyzed at a centrallaboratory. At the Screening Visit, 
blood specimens will be collected for safety laboratory tests after a fast of at least4hours. 
Fasting is not required at other time points. On Day1, blood samples will be collected before 
the first dose of the study drug. At all other scheduled visits, these samples will be collected 
at any time during the visit.
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table3-1and Table3-2. Laboratory test results that are abnormal and considered clinically 
significant will be reported as AEs (see Section13.1).
The safety laboratory test panels are shown in Table11-1. 


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Table11-1
Safety Laboratory Test Panels
Serum Chemistry
Hematology
Urinalysis(at Screening 
only)a
Glucose 
Blood urea nitrogen
Creatinine 
Sodium 
Potassium 
Calcium
Chloride
Magnesium
Bicarbonate 
Phosphate 
Bilirubin, direct bilirubin
ALP
AST
ALT
Amylase
Lactate dehydrogenase 
Lipase
GGT
Protein
Albumin
Creatine kinase
Hemoglobin
Erythrocytes
Mean corpuscular volume
Platelets 
Reticulocytes (absolute)
Leukocytes
Differential (absolute and percent):
Eosinophils 
Basophils
Neutrophils
Lymphocytes
Monocytes 
Coagulation(at Screening only)
Activated partial thromboplastin time 
Prothrombin time
Prothrombin time International 
Normalized Ratio
Leukocyte esterase
Nitrite
Urobilinogen 
Urine protein 
pH
Urine blood
Specific gravity
Urine ketones 
Urine bilirubin
Urine glucose
Note: Screening Visit blood draws will be done after a fast of at least4hours.All subsequent blood draws do 
not require fasting. 
a
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination 
of urine will be performed and results provided for leukocytes, erythrocytes, crystals, bacteria, and casts.
Additional tests at screening:The following additional tests will be performed during 
screening to assess eligibility:
Serum beta-human chorionic gonadotropin(β-HCG) for all female subjects 
Serum follicle-stimulating hormone for suspected postmenopausal female subjects only. 
Levels will be within the laboratories range for postmenopausal for subjects to be 
considered of non-childbearing potential.
CF genotyping will be performed if homozygous F508del-CFTRis not documented in 
the subject’s medical records.
Pregnancy Testing for Female Subjectsof Childbearing Potential: Childbearing potential 
isdefined in Section11.5.7.1. Pregnancy testing will be conducted every 4weeks starting on
Day1 (before the first dose of study drug) and continuing through the Safety Follow-up Visit 
with a urine β-HCGtest. When there is not a scheduled study visit, thepregnancy test will be 
conducted with a urine home pregnancy test kit provided by the study site. For tests 
performed at home, the site staff will telephone the subject to confirm the test results.
If a urine pregnancy test is positive, all study drug dosing will stop and the pregnancy will be 
confirmed with a serum β-HCGtest. If confirmed, thepregnancy will be reported and study 


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drug dosing will be permanently discontinued, as discussed in Section8.1.4.If a pregnancy 
test is positive, the procedures outlined in Section11.5.7.2will be followed.
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. Local laboratories may be used at the discretion of the local investigator for 
management of urgent medical issues. If a local laboratory test value is found to be abnormal 
and clinically significant, it will be verified by the central laboratory as soon as possible after 
the investigator becomes aware of the abnormal result. If it is not possible to send a timely 
specimen to the central laboratory (e.g., the subject was hospitalized elsewhere), the 
investigator may base the assessment of an AE on the local laboratory value.
11.5.3
Elevation of Liver Function Test Parameters
Mandatory Liver Function Testing
Liver function testing (ALT, AST, GGT, ALP, and total bilirubin) must be performed while 
subjects are receiving study drug treatment (Table3-2). These blood samples will be 
processed and shippedimmediately per the Laboratory Manual.
It is strongly recommended that subjects with new treatment-emergent ALT or AST 
elevations of >3×ULN and clinical symptoms be followed closely, including repeat 
confirmatory testing performed by the central laboratory within 48to 72hours of the initial 
finding and subsequent close monitoring of ALT and AST levels, as clinically indicated.
If a subject cannot return to the site for liver function testing, a local laboratory may be used. 
Elevations in LFTs (as indicated above) at the local laboratory must be reported immediately 
to the medical monitor andthe 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 interruptedimmediately, and the medical monitor must 
be notified if any of the following criteria is met:
ALT or AST >8×ULN
ALT or AST >5×ULN for more than 2weeks
ALT or AST >3×ULN, in association with total bilirubin >2×ULN and/or clinical 
jaundice
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression.
If no convincing alternative etiology (e.g.,acetaminophen use, viral hepatitis, or alcohol 
ingestion) for the elevated transaminases is identified, regardless of whether ALT or AST 
levels have improved, study drug treatment must be discontinued, in consultation with the 
Vertex medical monitor or authorized designee. Subjects in whom treatment is discontinued 
for elevated transaminases should have their transaminases monitored closely until levels 
normalize or return to baseline.


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Resumption of Study Drug
If a convincing alternative etiology is identified for the elevated transaminases (ALT, AST, 
and total bilirubin), study drug may be resumed when transaminases return to baseline or are 
≤2×ULN, whichever is higher. Approval of the Vertex medical monitor or designee is 
required before resumption of study drug. Upon resumption of study drug, transaminases will 
be assessed weekly for 4weeks. If a protocol-defined transaminase elevation occurs within 
4weeks of rechallenge with the study drug, then the study drug must be discontinued, 
regardless of the presumed etiology.
11.5.4
Physical Examinations andVital Signs
A PE of all body systems and vital signs assessment will be performed at the Screening Visit
and select study visits (see Table3-1and Table3-2). At other visits, symptom-directed PEs 
and symptom-directed vital sign assessments can be performed at the discretion of the 
investigator orhealthcare provider.
A PE includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/throat 
(EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be 
reported as AEs.
Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse rate, and 
respiration rate. These will be assessed after the subjecthas been seated for at least 5minutes
and before administration of study drug (if applicable). Blood pressure will be taken using a 
manual sphygmomanometer.
11.5.5
Electrocardiograms
Standard 12-lead ECGs will be performed using a machine with printout at Screening as 
shown inTable3-1. Additional standard 12-lead ECGs will be performed at any other time if 
clinically indicated. 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 Visit. A printout of 
the ECG traces will be made for safety review by theinvestigator and maintained with source 
documentation. Clinically significant ECG abnormalities occurring during the study through 
the Safety Follow-upVisit will be recorded as AEs.
11.5.6
Ophthalmologic Examinationsand History
All subjects who are <18 years of age at the Screening Visit, except those who have had 
bilateral lens removal,will undergo an ophthalmologic examination at the Screening Visit 
and at 1of the following visits: the Week24 Visit, the ETT Visit, or the Safety Follow-up 
Visit. These examinations will include:
measurement of best corrected distance visual acuity of each eye
measurement of lens refracting power (e.g., autorefractor or ophthalmoscopy streak 
following cycloplegia)


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pharmacologically dilated examination of the lens with a slit lamp
presence of Y-suture or lamellar rings
These examinations will be conducted by a licensed ophthalmologistor optometrist. The 
screening ophthalmologic examination will be completed and the results reviewed before 
enrollment. Ifa cataract, lens opacity, Y-suture, or lamellar ringsareidentified and 
determined to be clinically significant by the ophthalmologist or optometrist at the Screening 
Examination, the subject will not be enrolled. If there is documentation that an examination 
meeting protocol criteria was conducted within the 3months before the Screening Visit, the 
ophthalmologic examination does not need to be repeated during the Screening Period.
In addition, at the Screening Visit, the following history will be obtained for all subjects:
history of steroid use
history or presence of diabetes
any prior ophthalmologic or optometric examinations
history of trauma to the eye
any family history of glaucoma, congenital cataracts, or cataracts arising later in life
use of corrective lenses (contactlenses or eyeglasses)
history of prolonged exposure to sunlight or ultraviolet light and use of sunglasses
history of exposure to secondhand smoke
Additional ophthalmologic examinations may be conducted at the discretion of the 
investigator. The Vertex medical monitor or designee should be notified of any additional 
ophthalmologic examinations.
11.5.7
Contraception and Pregnancy
11.5.7.1
Contraception
The effects of LUM and IVA combination therapy on conception, pregnancy, and lactation in 
humans are not known. Neither LUM nor IVA showed any genotoxic potential in a standard 
battery of in vitro (Ames, Chinese hamster ovary cell chromosomal aberration) and in vivo 
(mouse micronucleus) studies. LUM and IVA were each found to be non-teratogenic in 
reproductive toxicology studies in rats and rabbits (see the LUM/IVA Investigator’s 
Brochure29). However, a metabolite of LUM, M28-lumacaftor, when given to pregnant rats at 
very high levels far beyond levels observed in humans (>100-fold), produced fetal 
malformations. The significance of this finding in humans is unclear, but is highly unlikely to 
be of any clinical significance. Subjects should follow the contraception requirements 
outlined in this protocol. The effects of LUM in combination with IVA on the 
pharmacokineticsof hormonal contraceptives are not known; however, since LUM is an 
inducer of CYP3A, it may reduce the effectiveness of hormonal contraceptives. Hormonal
contraceptives should not be relied upon as an effective method of contraception. 
Participation in this LUM/IVAstudy requires a commitment from the subject and his/her 
partner to use at least 1effective method of birth control (as a couple). Acceptablemethods 


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of contraception for subjectsand their partners are listed below. Methods of contraception 
should be in successful use from at least 14days before the first dose of study drug (unless 
otherwise noted) until 90days afterthe last dose of study drug.
Contraception for the couple is waived for the following:
True abstinence for the subject, when this is consistentwith the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g.,calendar, ovulation, symptothermal, 
postovulationmethods) and withdrawal are not acceptable methods of contraception.
If the male is infertile (e.g.,bilateral orchiectomy). Infertility may be documented 
through examination of a semen specimen or by demonstration of the absence of the vas 
deferens by ultrasound before the first dose of the study drug.
If the female is of non-childbearing potential, per the following:
o Postmenopausal: spontaneous amenorrhea for at least 12consecutive months and a 
serum FSH level ≥40mIU/mL at the Screening Visit
o Documented hysterectomy or a bilateral oophorectomy/salpingo-oophorectomy
o Note: All other female subjects who have had their first menstrual periodfrom the 
time of screening, or at any point through the Safety Follow-up Visit(including 
subjects with tubal ligations),will be considered to be of childbearing potential.
Acceptable Contraceptive Methods:
Acceptable contraceptive methods for male subjects ormale partnersof female subjects 
include the following: 
Vasectomyat least6months previously, with a negative post-vasectomy semen analysis 
for sperm
Condom with spermicide (either as a single product if commercially available and/or 
allowed according to local regulations; otherwise, condom and spermicide as separate 
products). Local regulations may require use of an additional acceptable method of 
contraception.
Acceptable contraceptive methods for female subjectsinclude the following:
Bilateral tubal ligation performed at least 6months previously
Continuous use of an intrauterine device (non-hormone-releasing) for at least 90days
Barrier contraception (such as diaphragm, cervical cap, or female condom) with 
spermicide. Local regulations may require use of an additional acceptable method of 
contraception.
Note: Hormonal contraceptives, including oral, injectable, transdermal, and implantable, 
will not be considered as an effective method; however, female subjects are not required 
to discontinue hormonal contraceptives.
Acceptable contraceptive methods for female partners of male subjects: 
Bilateral tubal ligation performed at least 6months previously


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Continuous use of an intrauterine device for at least 90days
Barrier contraception (such as diaphragm, cervical cap, or female condom) with 
spermicide. Local regulations may require use of an additional acceptable method of 
contraception.
Hormonal contraceptives, if successfully used for at least 60 days
Additional notes:
Female condom cannot be used with male condom (as a double method of contraception) 
due to risk of tearing.
Male and female subjects who are not sexually active at the time of screening must agree 
to follow the contraceptive requirements of this study if they become sexually active with 
a partner of the opposite sex.
If applicable, additional contraception requirements may need to be followed according 
to local regulations and/or requirements.
Male subjects must not donate sperm after the first dose of study drug, throughout the 
study, and for 90days afterthe last dose of study drug.
Female subjects and female partners of male subjects should not plan to become pregnant 
during the study through 90days afterthe last dose of study drug.
Female subjects should not nurse a child from the start of study drug dosing through 
90days afterthe last dose of study drug.
Unique situations that may not fall within the above specifications may be discussed with the 
Vertex medical monitor or authorized designeeon an individual basis.
11.5.7.2
Pregnancy
Subjects will be counseled to inform the investigator of any pregnancy that occurs during 
study treatment and for 90days after the last dose of study drug.
If a subject or the female partner of a male subject becomes pregnant while participating in 
the study, study drug will be permanently discontinued immediately. The investigator will 
notify the medical monitorand Vertex Global Patient Safety within 24hours of the site’s 
knowledge of the subject’s (or partner’s) pregnancy using the Pregnancy Information 
Collection Form.
If the subject is confirmed to be on active drug, the subject or partner will be followed until 
the end of the pregnancy and the infant will be followed for 1year after the birth, provided 
informed consent is obtained. A separate ICF will be provided to explain these follow-up 
activities. Pregnancy itself does not constitute an AE.
12
STATISTICAL AND ANALYTICAL PLANS
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in thestatistical analysis plan (SAP), which will be finalized before 
the clinical data lock for the study.


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12.1
Sample Size and Power
Assuming a common standard deviation (SD) of 10% for the primary efficacy endpoint and a 
dropout rate of 10%, a sample size of 33subjects in each treatment group would provide at 
least 80% power to detect a difference of 7.5% between the means for the 2treatment groups 
using a 2-sided test at the 0.05 significance level. If the true difference is smaller, or if there 
is greater variability, a larger sample size would be required to provide 80% power. 
Table12-1showsthe required sample sizesfor various assumptions about the true treatment 
effect using a 2-sided test at the 0.05 significance level.
Because LUM/IVA has recently been approved in several countries, it is expected that 
additional data,independent of this study, will emerge while this study is underwayand will
allow more precise estimation of the true treatment effect. The final sample size will be based 
on thesedata, andtheprotocolmaybeamended as appropriate.
Table12-1
Sample Sizes for 80% Power
True Difference Between Placebo and 
LUM/IVA Effects on Primary Endpoint
Sample Size Needed for 80% Power
(subjects per treatment group)
5.0%
72
5.5%
59
6.0%
50
6.5%
44
7.0%
38
7.5%
33
12.2
Analysis Sets
The Full Analysis Set (FAS) is defined as all randomized subjects who have received at least 
1dose of study drug. The FAS will be used for all efficacy analyses, with subjects analyzed 
according to their randomized treatment group. 
The Safety Set is defined as all subjects who received at least 1dose of study drug. The 
Safety Set will be used forall safety analyses, with subjects analyzed according to the 
treatment they received.
12.3
Statistical Analysis
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.
12.3.1
General Considerations
All individual subject data for the FAS will be presented in data listings. 
Continuous variableswill be summarized using the following descriptive summary 
statistics: the number of observations(n), mean, SD, median, minimum value (min), and 
maximum value (max). 
Categorical datawill be summarized using counts and percentages. 


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Baselinefor a variable will, unless specifically stated otherwise, be defined as the most 
recentnon-missing measurement (scheduled or unscheduled) collected before the initial 
administration of study drug. For actigraphy variables, baseline will be the data collected for 
1week during the Screening Period.
Change from baselinewill be calculated as post-baseline value minus baseline value.
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 data listings. All 
summaries will be based on the FAS unless otherwise specified in the SAP for the study. No 
statistical hypothesis testing will be performed on background characteristics.
12.3.2.1
Subject Disposition
Number and percentage of subjects in the following disposition categories will be 
summarized by treatment group:
Randomized
Dosed (Safety Set)
Randomized and dosed (FAS)
Completed Treatment Period
Prematurely discontinuedstudy drugbefore completing the assigned duration of dosing 
and the reasons for discontinuation
Completed Safety Follow-up Visit
Prematurely withdrawn fromthe study (did not complete Safety Follow-up Visit) and the 
reasons for withdrawal
12.3.2.2
Demographics and Baseline Characteristics
Demographic, background (e.g.,medical history), and baseline characteristics will be 
summarized by treatment group. The following demographics and baseline characteristics 
will be summarized by treatment group for the FAS: sex, race, age, weight, height, BMI, 
baseline ppFEV1, and site.
No statistical tests will be carried out to evaluate any baseline imbalance between treatment 
groups.


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12.3.2.3
Prior and Concomitant Medications
Medications used in this study will be coded using the World Health Organization Drug 
Dictionary Enhanced and categorized as follows:
Prior medication:any medication that started before initial dosing of study drug, 
regardless of when it ended.
Concomitant medication: medication continued or newly received at or after initial 
dosing of study drug to 28 days after the last dose of study drug. 
Post-treatment medication:medication continued or newly received after 28 days after 
the last dose of study drug.
A given medication can be included in 1, 2, or all3 of these categories. If a medication has a 
missing or partial missing start/end date or time and it cannot be determined whether the 
medication was taken before initial dosing, concomitantly, or after 28days after the last dose 
of study drug, it will be considered as prior, concomitant, and post-treatment.
Prior medications and concomitant medications will be summarized by treatment group 
based on the FAS. Post-treatment medications will be listed for each subject.
12.3.2.4
Study Drug Exposure and Compliance
Exposure to study drug (i.e.,duration of treatment in days) will be defined as the last day 
minus the first day of study drug plus1. Exposure will be summarized by treatment group for 
the Safety Set.
Dosing compliance will be calculated as the actual number of dosing occasions at which 
study drug was administered, as a percentage of the planned number of dosing occasions 
while the subject was on study drug (i.e.,beforestudy drug discontinuationor completion). 
Dosing compliance will be summarized for the FAS.
Duration of treatment and dosing compliance will be summarized by means of descriptive 
summary statistics.
12.3.2.5
Important Protocol Deviations
Important protocol deviations (IPDs) are defined as protocol deviations that may 
significantly impact the completeness, accuracy, and/or reliability of the study data or that 
may significantly affect a subject’s rights, safety, or well-being. Protocol deviations will be 
reviewed beforedatabase lock in a blinded manner to establish rules for identifying the IPDs. 
The IPDs identified through this process will be presented in a data listing. 
12.3.3
Efficacy Analysis
12.3.3.1
Analysis of Primary Variables
The primary efficacy endpoint is the percentage change from baseline in VO2maxduring 
CPET at Week24. The null hypothesis to be tested is that the mean percentage changefrom 
study baseline in VO
2maxat Week24 is the same for the LUM/IVAand placebo groups.
The primary analysis will use a restricted maximum likelihood (REML)-based mixed effect 
model for repeated measures (MMRM). The model will include the percentage change from 


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baseline in VO2maxas the dependent variable; treatment, visit, and treatment-by-visit
interaction as fixed effects; and subject as a random effect with adjustment for sex (male 
versus female), age group at baseline (<18versus ≥18years old), and ppFEV1at Screening 
(<70% versus≥70%). In the model, visit will be treated as a class variable, and an 
unstructured covariance matrix will be assumed to model the within-subject variability, 
which imposes no assumptions on the correlational structure. Denominator degrees of 
freedom for the F-test for fixed effects will be estimated using the Kenward-Roger 
approximation. No imputation of missing data will be performed.
The primary result obtained from the model will be the estimated treatment effect at Week24 
based on a contrast test. The estimated mean treatment effect at Week24, a 95% confidence 
interval, and a 2-sided Pvalue will be provided. Furthermore, the treatment effect at each 
post-baseline visit, obtained from the model, also will be provided.
If there is a convergence problem due to the use of an unstructured covariance matrix, the 
unstructured covariance matrix will be replaced by compound symmetry in the primary 
analysis.
12.3.3.2
Analysis of Secondary Efficacy Variables
Key Secondary Efficacy Endpoint:
The key secondary efficacy endpoint is the change from baseline in exercise durationduring
CPET at Week24. The same analysis method as for the primary efficacy endpoint will be 
used, with change from baseline in exercise durationas the dependent variable. To control 
for multiplicity, the test for change in exercise durationwill only be considered statistically 
significant if the 2-sided Pvalue is 0.05 or less and the test for the primary endpoint also is 
statistically significant.
Other Secondary Efficacy Endpoints:
All other secondary efficacy endpoints will be analyzed in a similar fashion. No adjustment 
for multiplicity will be made for these endpoints. The other secondary endpoints are listed in 
Section7.2.
12.3.3.3
Correlation Analyses
The correlations between changes in exercise tolerance assessments and changes in selected 
efficacy outcome measures, including ppFEV1and BMI, will be calculated for each 
treatment group.


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12.3.4
Safety Analysis
The overall safety profile of study treatments will be assessed in terms of the following 
safety endpoints: 
Incidence of treatment-emergent adverse events (TEAEs)
Clinical laboratory values
Vital signs
Ophthalmologic examinations (for subjects under 18years of ageonly)
Safety analysis will bebased on the set of data associated with the period from the signing of 
informed consent through the Safety Follow-up Visit. Safety analyses will be based on the 
Safety Set. The summaries will be by treatment group, which will be defined according to the 
treatment actually received.
For safety variables, the scheduled Day1, predose measurement will be used as the baseline 
value, when available; otherwise, the baseline value will be defined as the value at the 
Screening Visit.
All safety data will be listed by subjectin data listings.
12.3.4.1
Adverse Events
AEs will be coded according to MedDRA. The number and percentage of subjects 
experiencing an AE will be summarized by the MedDRA system organ class and preferred 
term, as well as by treatment group. AEs will beclassified as pretreatment or 
treatment-emergent. 
Pretreatment AEs are defined as AEs that were reported or worsened after signing the ICF 
up to the start of study drug dosing.
Treatment-emergent AEsare defined as AEs that were reported or worsened on or after the 
start of study drug dosing through the 28-day Safety Follow-up Visit.
For an AE with a missing or partial start date, if there is no clear evidence that the AE started 
before or after study treatment, then the AE will be classified as a TEAE.
AE summary tables will be presented for TEAE only by treatment group and will include the 
following:
All TEAEs 
TEAEs by relationship 
TEAEs by maximumseverity
TEAEs leading to treatment discontinuation


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Serious TEAEs
TEAEs leading to death
Frequently reported TEAEs
Summaries will be presented by MedDRA system organ class and preferred term using 
frequency counts and percentages (i.e.,number and percentage of subjects with an event). 
The following rules will apply to the summarization of AEs: (1)a subjectwith multiple 
occurrences of the same AE or a continuing AEwill only be counted once; (2)only the 
maximum severity level will be presented in the severity summary; and (3)only the worst 
relationship level will be presented in the relationship summary.
All AEs through the Safety Follow-up Visit will be listedby subject in adata listing, 
including pretreatment AEs. AEs leading to death, dose interruption, and permanent 
discontinuation, as well as SAEs, will be listed separately.
12.3.4.2
Clinical Laboratory Assessments
All statistical analyses of laboratory values will be performed using SI units. Hematology and 
clinical chemistry results will be summarized by treatment group at each scheduled time 
point. In addition, mean values at each visit will be plotted by treatment group for each of the 
liver function parameters.
A listing of abnormal individual subject hematology and clinical chemistry values from 
scheduled and unscheduled time points will be provided. Grade3 toxicity laboratory values 
will be listed by subjectin a data listing. Coagulation and urinalysis results will be listed
only; these results will not be summarized. Clinically significant abnormal laboratory 
findings will be reported as AEs.
12.3.4.3
Electrocardiogram
ECGfindings will be listed. Clinically significant abnormal findings will be reported as AEs.
12.3.4.4
Vital Signs
The following vital signs will be summarized by treatment group at each scheduled time 
point: systolic and diastolic blood pressure (mmHg), body temperature, pulse rate (beats per 
minute), and respiratory rate (breaths per minute). Clinically significant abnormal findings in 
vital signs will be reported as AEs.
The number and percentage of subjects who meet the abnormal criteria for the vital signs 
evaluation during the Treatment Period willbe tabulated by treatment group: HR≤50bpm 
and a decrease from baseline≥20bpm, HR≥120bpm and an increase from 
baseline≥20bpm, systolic blood pressure≤95mmHg and a decrease from 
baseline≥20mmHg, systolic blood pressure ≥160mmHg and an increase from baseline 
≥20mmHg, diastolic blood pressure ≤45mmHg and a decrease from baseline ≥10mmHg, 
diastolic blood pressure ≥110mmHg and an increase from baseline ≥10mmHg, weight 
≥5% increase from baseline, and weight ≥5% decrease from baseline. 


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12.3.4.5
Physical Examination
PEresults will be listed by subjectin data listings only. Clinically relevant results identified 
after screening will be reported as AEs.
12.3.4.6
Other Safety Analysis
Ophthalmologic examination findings will be listed.
Spirometry data will be summarized descriptively as safety-supporting data. The following
summaries will be provided at each visit based on the Safety Set:
Numbers and percentages of subjects withdecrease of≥5percentage points and with 
decrease of ≥10percentage points in absolute change from baseline in ppFEV1at each 
visit.
Numbers and percentages of subjects with ≥5%decrease and with ≥10%decrease in 
relative change from baseline in ppFEV1at each visit.
Numbers and percentagesofsubjects withdecrease of≥0.05L and withdecrease of
≥0.10L in absolute change from baseline in FEV1at each visit.
Numbers and percentages of subjects with ≥5% decreaseand with≥10% decrease in 
relative change from baseline in FEV1at each visit.
Subjects withdecrease of≥5 percentage points in absolute change from baseline in ppFEV1
or absolute change from baseline in FEV
1at any visit will be listed. The listing will include 
raw values and absolute/relative changes from baseline in FEV1and ppFEV1at all visits.
12.3.5
Interim andIDMC Analyses
No interim analysis is planned.
No independent data monitoring committee (IDMC) will be used for this study.
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 pre-existing condition (e.g.,increase in its severity 
or frequency) after the ICF is signed. 
An AE is considered serious if it meets the definition in Section13.1.2.1. 


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13.1.1.2
Clinically Significant Assessments
Study assessments including laboratory tests, PEs, and vital signs will be assessed and those 
deemed to have clinically significant worsening from baseline will be documented as an AE. 
When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g.,urinary tract infection, anemia). In the absence of a 
diagnosis, the abnormal study assessment itself willbe listed as the AE (e.g.,bacteria in urine 
or decreased hemoglobin).
An abnormal study assessment is considered clinically significant if the subject has 1or more 
of the following:
Concomitant signs or symptoms related to the abnormal study assessment
Further diagnostic testing or medical/surgical intervention
A change in the dose of study drug or discontinuation from the study
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of 
whether the study assessment results are clinically significant will be made by the 
investigator.
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4laboratory 
value willbe an SAE if the subject’s clinical status indicates a life-threatening AE.
13.1.1.3
Documentation of Adverse Events
All AEs will be collected from the time ICF is signed until the following time points:
For subjects who do not enroll: until time of screen failure(e.g.,screen failure, 
withdrawal of consent)
For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up 
Visit
For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of
o 4weeks after the last dose of study drug, or
o the ETT Visit, if that visit is 3weeks after the last dose of study drug or later (see 
Section8.1.4).
All subjects will be queried, usingnonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened,but not subsequently enrolled in the 
study,will be recorded only in the subject’s source documents. The following data will be 
documented for each AE:
Description of the event
Classification of “serious” or “nonserious”
Date of first occurrence and date of resolution (if applicable)


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Severity
Causal relationship to study drug(s) 
Action taken 
Outcome 
Concomitant medication or other treatment given
13.1.1.4
Adverse Event Severity
The investigator will determine and record the severity of all serious and nonserious AEs. 
The guidance available at the following website will be consulted: Common Terminology 
Criteria for Adverse Events (CTCAE), Version4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm(accessed 
January2016). AEs of CTCAE Grades4 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 Table13-1. 
Table13-1
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 (Grade3)
Significant level of discomfort and prevents regular activities
Life-threatening 
(Grade4)
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death 
13.1.1.5
Adverse EventCausality
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 Table13-2.


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Table13-2
Classifications for AE Causality
Classification
Definition
Related
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled 
out, and/or the event reappeared on re-exposure to the investigational study drug.
Possibly related
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease.
Unlikely related
The event is unlikely to be related to the investigational study drug and likely to 
be related to factors other than investigational study drug. 
Not related
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject’s medical records).
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 Table13-3.
Table13-3
Classifications for Study Drug Action Taken With Regard to an AE
Classification
Definition
Dose not changed
Study drug dose not changed in response to an AE
Dose reduced
Study drug dose reduced in response to an AE
Drug interrupted
Study drug administration interrupted in response to an AE 
Drug withdrawn
Study drug administration permanently discontinued in response to an AE
Not applicable
Action taken regarding study drug administration does not apply. 
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible.
13.1.1.7
Adverse Event Outcome
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table13-4.


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Table13-4
Classifications for Outcome of an AE
Classification
Definition
Recovered/Resolved
Resolution of an AE with no residual signs or symptoms
Recovered/Resolved 
With Sequelae
Resolution of an AE with residual signs or symptoms
Not Recovered/Not 
Resolved (Continuing)
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing
Fatal
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE.
Unknown
Outcome of an AE is not known (e.g.,a subject lost to follow-up)
13.1.1.8
Treatment Given
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was 
given in response to an AE, and may include treatments such as other medications, 
hospitalization, surgery, or physical therapy. “No” indicates the absence of any kind of 
treatment for an AE.
13.1.2
Serious Adverse Events
13.1.2.1
Definition of a Serious Adverse Event
An SAE is any AE that meets any of the following outcomes:
Fatal (death, regardless of cause, that occurs during participation in the study or occurs 
after participation in the study and is suspected of being a delayed toxicity due to 
administration of the study drug)
Life-threatening, such that the subject was at immediate risk of death from the reaction as 
it occurred 
Inpatient hospitalization or prolongation of hospitalization
Persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions)
Congenital anomaly or birth defect
Important medical event that, based upon appropriate medical judgment, may jeopardize 
the subject or may require medical or surgical intervention to prevent1 of the outcomes 
listed above (e.g.,an allergic bronchospasm requiring intensive treatmentin an 
emergency room or at home) 
If a subject has a hospitalization or procedure (e.g.,surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled 
sooner or to be prolonged relative to what was planned. In addition, hospitalizations clearly 


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not associated with an AE (e.g.,social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE.
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may 
be of relatively minor medical significance, such as a severe headache. This is not the same 
as “serious,” which is based on subject/event outcome or action described above, and is 
usually associated with events that pose a threat to a subject’s life or functioning. 
Seriousness, not severity, serves as a guide for defining expedited regulatory reporting 
obligations.
13.1.2.2
Documentation of Serious Adverse Events
All SAEs that occur after obtaining informed consent and assent (where applicable) through 
the Safety Follow-up Visit, regardless of causality, will be reported by the investigator to 
Vertex GPS. In addition, all SAEs that occur after the Safety Follow-up Visit and are 
considered related to study drug(s) will be reported to Vertex GPS within 24hours.
SAEs will be recorded on the Vertex Organized Safety Information Collection Form 
(hereafter referred to as the “SAE Form”) using a recognized medical term or diagnosis that 
accurately reflects the event. SAEs will be assessed by the investigator for relationship to the 
investigational study drug(s) and possible etiologies. On the SAE Form, relationship to study 
drug(s) will be assessed only as related (includespossibly related) or not related (includes 
unlikely related), and severity assessment will not be required. For the purposes of study 
analysis, if the event has not resolved at the end of the study reporting period, it will be 
documented as ongoing. For purposes of regulatory safety monitoring, the investigator is 
required to follow the event to resolution and report to Vertex the outcome of the event using 
the SAE Form.
13.1.2.3
Reporting Serious Adverse Events
The investigator is responsible for notifying the sponsor within 24hours of identifying an 
SAE, regardless of the presumed relationship to the investigational study drug. The SAE 
Form will be completed for new/initial events as well as to report follow-up information on 
previously reported events. Investigators are asked to report follow-up information as soon as 
it becomes available to ensure timely reporting to health authorities. 
Please send completed SAE Forms to Vertex GPS via:
Email: 
(Preferred Choice)
Fax: 
Contact Telephone: 
13.1.2.4
Expedited Reporting and Investigator Safety Letters
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities and participating 
investigators in accordance with ICH Guidelines and/or local regulatory requirements, as 


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applicable. In addition, Vertex, or authorized designee, will be responsible for the submission 
of safety letters to central IECs. 
It is the responsibility of the investigator or designee to promptly notify the local IRB/local 
IEC ofall unexpected serious adverse drug reactions involving risk to human subjects.
13.2
Administrative Requirements
13.2.1
Ethical Considerations
The study will be conducted in accordance with the current ICHGCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in 
accordance with local applicable laws and regulations. The IRB/IEC will review all 
appropriate study documentation to safeguard the rights, safety, and well-being of the 
subjects. The study will only be conducted at sites where IRB/IEC approval has been 
obtained. The protocol, Investigator’s Brochure, sample ICF, advertisements (if applicable), 
written information given to the subjects (including diary cards), safety updates, annual 
progress reports, and any revisions to these documents will be provided to the IRB/IEC by 
the investigator or Vertex, as allowable by local applicable laws and regulations.
13.2.2
Subject Information and Informed Consent
After the study has been fully explained, written informed consentwill be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from 
the subject (if applicable), before study participation. The method of obtaining and 
documenting the informed consent and assent (if applicable) and the contents of the consent 
will comply with ICHGCP 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 approvalof 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 proceduresset forth in the 
protocol, the investigator will contact Vertex to discuss the planned course of action. If 
possible, contact will be made before the implementation of any changes. Any departures 
from the protocol will be fully documented in the source documentation and in a protocol 
deviation log. 
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 


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security laws for use and disclosure of information related to the research set forth in this 
protocol. 
13.2.5
Subject Privacy
To maintain subject confidentiality and to comply with applicable data protection and 
privacy laws and regulations, all CRFs, study reports, and communications relating to the 
study will identify subjects by assigned subject numbers and access to subject names linked 
to such numbers shall be limited to the site and the study physician and shall not be disclosed 
to Vertex.As required by applicable laws and regulations in the countries in which the study 
is being conducted, the investigator will allow Vertex and/or its representatives access to all 
pertinent medical records to allow for the verification of data gathered in the CRFs/SAE 
forms and the review of the data collection process. The FDA and regulatory authorities in 
other jurisdictions, including the IRB/IEC, may also request access to all study records, 
including source documentation, for inspection.
For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act and associated regulations (“HIPAA”) an executed 
HIPAA authorization shall be obtained by the site from each subject (or the legal 
representative of the subject) before research activities may begin. Each HIPAA 
authorization shall comply with all HIPAA requirements including authorization allowing the 
site access to and use of the subject’s personally identifiable health information, 
authorization for the site to disclose such information to Vertex, the FDA, and other parties 
requiring access under the protocol, and statements as to the purpose for which such 
information may be used and for how long.
13.2.6
Record Retention
The investigator will maintainall study records according to ICHGCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and 
Vertex will be notified.
13.2.7
Study Termination
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs 
may terminate the study at their center.
Conditions that may lead to reasonable cause and warrant termination include, but are not 
limited to:
Subject or investigator noncompliance
Unsatisfactory subject enrollment
Lack of adherence to protocol procedures
Lack of evaluable and/or complete data
Potentially unacceptable risk to study subjects


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Decision to modify drug development plan
Decision by the FDA or other regulatory authority
Written notification that includes the reason for the clinical study termination is required.
13.3
Data Quality Assurance
Vertex or its designated representative will conduct a study site visit to verify the 
qualifications of each investigator, inspect clinical study site facilities, and inform the 
investigator of responsibilities and procedures for ensuring adequate and correct study 
documentation.
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by
 study site 
personnelusing a secure, validated, web-based electronic data capture (EDC) application. 
Vertex will have read-onlyaccess to site-entered clinical data in the EDC application. 
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator 
for resolution. Any changes to study data will be made to the CRF and documented in an 
audit trail, which will be maintained within the clinical database.
13.4
Monitoring
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness 
and clarity, cross-checking with source documents, and clarification of administrative matters 
will be performed.
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements.
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 correctinformation in the CRFs on the 
subjects for which they are responsible. 
A CRF will be completed for each enrolled study subject. It is the investigator’s 
responsibility to ensure the accuracy, completeness, clarity, and timeliness of the data 
reported in the subject’s CRF. Source documentation supporting the CRF data will indicate 
the subject’s participation in the study and will document the dates and details of study 
procedures, AEs, other observations, and subject status.
The investigator, or designated representative, will complete the CRF as soon as possible 
after information is collected. 
The audit trail entry will show the user’sidentification information and the date and time of 
any correction. The investigator will provide formal approval of all the information in the 


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CRFs, including any changes made to the CRFs, to endorse the final submitted data for the 
subjects for whom theinvestigator is responsible. 
Vertex will retain the CRF dataand corresponding audit trails. A copy of the final archival 
CRF in the form of a CD or other electronic media will be placed in the investigator’s 
studyfile.


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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 


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Vertex Pharmaceuticals Incorporated
Life Res. 2003;12(1):63-76.
40
Fidika A, Herle M, Goldbeck L. Symptoms of depression impact the course of lung 
function in adolescents and adults with cystic fibrosis. BMC Pulm Med. 2014;14:205.
41
Ploessl C, Pettit RS, Donaldson J. Prevalence of depression and antidepressant 
therapy use in a pediatric cystic fibrosis population. Anals of Pharmacology. 
2014;48:488-93.
42
Quittner AL, Goldbeck L, Abbott J, Duff A, Lambrecht P, Solé A, et al. Prevalence of 
depression and anxiety in patients with cystic fibrosis and parent caregivers: results of 
the International Depression Epidemiological Study across nine countries. Thorax. 
2014 Dec;69:1090 7.
43
Yohannes AM, Willgoss TG, Fatoye FA, Dip MD, Webb K. Relationship between 
anxiety, depression, and quality of life in adult patients with cystic fibrosis. Respir 
Care. 2012 Apr;57(4):550 6.
44
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. 
Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998;132:589-95.
45
LeveyAS, 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.
46
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.
47
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51:875-8.
48
Godfrey S, Mearns M. Pulmonary Function and response to exercise in cystic 
fibrosis. Arch Dis Child. 1971;46:144-151.
49
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J.2005;26:319-38.
50
Wang X, Dockery DQ, Wypij D, Fay ME, Ferris BG. Pulmonary function between 6 
and 18years of age. Pediatr Pulmonol. 1993;15:75-88.
51
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.


Protocol VX15-809-112, Version1.0
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15
PROTOCOL SIGNATURE PAGES
15.1
Sponsor Signature Page
Protocol #: VX15-809-112 Version #:
1.0
Version Date: 15 January 2016
Study Title:A Phase 4, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design 
Study of the Effect of Lumacaftor/Ivacaftor Combination Therapyon Exercise Tolerance in 
Subjects Aged 12Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR
Mutation
This Clinical Study Protocol has been reviewed and approved by the sponsor.
Printed Name
Title
Signature
Date


Protocol VX15-809-112, Version1.0
Page 60of 60
Vertex Pharmaceuticals Incorporated
15.2
Investigator Signature Page
Protocol #: VX15-809-112 Version #:
1.0
Version Date: 15 January 2016
Study Title: A Phase 4, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design 
Study of the Effect of Lumacaftor/Ivacaftor Combination Therapyon Exercise Tolerance in 
Subjects Aged 12Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR
Mutation
I have read Protocol VX15-809-112, Version 1.0, and agree to conduct the study according 
to its terms. I understand that all information concerning lumacaftor/ivacaftorand this 
protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) areconfidential.
Printed Name
Signature
Date

SAP_001.pdf: 
Statistical Analysis Plan Methods 
Page 1 of 55
Protocol Number: VX15-809-112 
Vertex Pharmaceuticals Incorporated 
VERTEX PHARMACEUTICALS INCORPORATED 
Statistical Analysis Plan  
Protocol Number VX15-809-112
A Phase 4, Randomized, Double-Blind, Placebo- 
Controlled, Parallel-Design Study of the Effect of 
Lumacaftor/Ivacaftor Combination Therapy on 
Exercise Tolerance in Subjects Aged 12 Years and 
Older With Cystic Fibrosis, Homozygous for the 
F508del-CFTR Mutation 
Author of SAP:  
 
Version: 1.0 
Version Date of SAP: 17 May 2017
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, MA 02210-1862 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
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1
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ................................................................................................ 2 
List of Tables ....................................................................................................................... 3 
2 
LIST OF ABBREVIATIONS ......................................................................................... 5 
3 
SUMMARY OF MODIFICATIONS ............................................................................. 7 
4 
INTRODUCTION ........................................................................................................... 7 
5 
STUDY OBJECTIVES ................................................................................................... 7 
5.1 
Primary Objective....................................................................................................... 7 
5.2 
Secondary Objectives ................................................................................................. 7 
6 
STUDY ENDPOINTS ..................................................................................................... 8 
6.1 
Efficacy Endpoints ..................................................................................................... 8 
6.1.1 
Primary Endpoint................................................................................................ 8 
6.1.2 
Secondary Endpoints.......................................................................................... 8 
6.2 
Safety Endpoints......................................................................................................... 9 
6.3 
Pharmacokinetic Endpoints........................................................................................ 9 
7 
STUDY DESIGN ............................................................................................................. 9 
7.1 
Overall Design............................................................................................................ 9 
7.2 
Sample Size and Power ............................................................................................ 10 
7.3 
Randomization.......................................................................................................... 11 
7.4 
Blinding and Unblinding .......................................................................................... 12 
7.4.1 
Blinding ............................................................................................................ 12 
7.4.2 
Unblinding........................................................................................................ 12 
8 
ANALYSIS SETS .......................................................................................................... 13 
8.1 
Efficacy Sets............................................................................................................. 13 
8.1.1 
Full Analysis Set (FAS).................................................................................... 13 
8.2 
Safety Set.................................................................................................................. 13 
8.3 
Other Analysis Set.................................................................................................... 13 
9 
STATISTICAL ANALYSIS ......................................................................................... 13 
9.1 
General Considerations ............................................................................................ 13 
9.2 
Background Characteristics...................................................................................... 15 
9.2.1 
Subject Disposition........................................................................................... 15 
9.2.2 
Demographics and Baseline Characteristics..................................................... 15 
9.2.3 
Prior and Concomitant Medications................................................................. 17 
9.2.4 
Study Drug Exposure........................................................................................ 19 
9.2.5 
Study Drug Compliance ................................................................................... 19 
9.3 
Efficacy Analysis...................................................................................................... 20 
9.3.1 
Analysis of Primary Efficacy Endpoint............................................................ 20 
9.3.1.1 
Definition of Primary Efficacy Endpoint................................................... 20 
9.3.1.2 
Primary Analysis of Primary Efficacy Endpoint ....................................... 20 
9.3.2 
Analysis of Secondary Efficacy Endpoints ...................................................... 23 
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9.3.2.1 
Definition of Secondary Efficacy Endpoints ............................................. 24 
9.3.2.1.1 Definition of Key Secondary Efficacy Endpoints................................. 24 
9.3.2.1.2 Definition of Additional Secondary Efficacy Endpoints ...................... 24 
9.3.2.2 
Analysis of Secondary Endpoints .............................................................. 33 
9.3.2.2.1 Analysis of Key Secondary Efficacy Endpoints ................................... 33 
9.3.2.2.2 Analysis of Additional Secondary Efficacy Endpoints......................... 33 
9.3.2.3 
Correlation analysis.................................................................................... 36 
9.3.2.4 
Multiplicity adjustment.............................................................................. 36 
9.4 
Safety Analysis......................................................................................................... 36 
9.4.1 
Adverse Events................................................................................................. 37 
9.4.2 
Clinical Laboratory........................................................................................... 39 
9.4.3 
Vital Signs ........................................................................................................ 40 
9.4.4 
Pulse Oximetry ................................................................................................. 40 
9.4.5 
Physical Examination ....................................................................................... 40 
9.4.6 
Ophthalmologic Examination........................................................................... 40 
9.5 
Narratives Listings.................................................................................................... 40 
10 INTERIM AND DMC ANALYSES ............................................................................. 41 
10.1 Interim Analysis ....................................................................................................... 41 
10.2 DMC Analysis.......................................................................................................... 41 
11 REFERENCES .............................................................................................................. 42 
12 APPENDICES ................................................................................................................ 43 
Appendix A 
Schedule of Assessments ........................................................................... 43 
Appendix B 
Precisions of Summary for Continuous Variables..................................... 45 
Appendix C 
Analysis Visit Window Mapping Rules for Safety and Pharmacodynamic 
and Actigraphy Measurements................................................................................. 46 
Appendix D 
Coefficients for Hankinson and Wang Methods for Calculating Predicted 
Spirometry Parameters ............................................................................................. 47 
Appendix F 
Criteria for Potentially Clinically Significant Events ................................ 52 
Appendix G     Important Protocol Deviation Programming Rules..………..…...……….53
List of Tables 
 
Table 7-1  
Sample size for 80% of Power ......................................................................... 11
Table 9-1 
Logic for Determining the Category of a Medication ...................................... 18 
Table 9-2 
CFQ-R for Children Ages 12 and 13 ................................................................ 28 
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Table 9-3 
CFQ-R for Adolescents and Adults (subjects 14 years and older) ................... 28 
Table 9-4 
CFQ-R for Parents/Caregivers (subjects 13 years and younger) ...................... 29 
Table 12-1 
Screening Period Assessments ......................................................................... 42 
Table 12-2  Precisions of Summary for Continous Variables ............................................. 44 
Table 12-3 
Visit Window Mapping Rules for Safety and Safety-Supporting 
Measurements.. .............................................................................................................. .45 
Table 12-4 
HNVs Equation Coefficients by Sex, Race, and Age ....................................... 47 
Table 12-5 
WNVs Equation Coefficients by Sex and Age in White Boys and Girls ......... 48 
Table 12-6 
WNVs Equation Coefficients by Sex and Age in Black Boys and Girls ......... 49 
Table 12-7 
Criteria for Potentially Clinically Significant Laboratory Tests ...................... 51 
Table 12-8  Criteria for Potentially Clinically Significant Vital Signs ................................ 52 
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2
LIST OF ABBREVIATIONS 
Abbreviation
Term
AE
adverse event
ALP
alkaline aminotransferase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AR(1)
autoregressive model of order 1
AST
aspartate aminotransferase
AT
BMI
Anaerobic threshold
body mass index (kg/m2)
bpm
beats per minute
CF
cystic fibrosis
CFQ-R
Cystic Fibrosis Questionnaire – Revised
CFTR
cystic fibrosis transmembrane conductance regulator
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CPET
CRF
Cardiopulmonary exercise testing
case report form
CRO
contract research organization
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
FEF25-75%
forced expiratory flow, midexpiratory phase
FEV1
forced expiratory volume in 1 second
FVC
forced vital capacity 
F508del
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein
GAD-7
HNVFEV
Generalized Anxiety Disorder
Hankinson predicted value of FEV1 (L)
HNVFEF25-75%
Hankinson predicted value of FEF25-75% (L/sec)
HNVFVC
Hankinson predicted value of FVC (L)
ISE
integrated summary of efficacy
LFT
liver function test
LOCF
last observation carried forward
M1
VRT-837018, hydroxymethyl-ivacaftor, metabolite of ivacaftor
M6
VRT-842917, carboxy-ivacaftor, ivacaftor acid, metabolite of ivacaftor
MH
Mantel-Haenszel
max
maximum value
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
min
minimum value
MMRM
mixed model repeated measure
N
number of subjects
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Abbreviation
Term
PD
pharmacodynamic/pharmacodynamics 
PHQ-8
PK
Patient Health Questionnaire
pharmacokinetic/pharmacokinetics
PPS
per protocol set
PT
preferred term
q12h
every 12 hours
QRS
Q, R, and S-wave define the QRS-complex in an ECG
QT
QT interval: The duration of ventricular depolarization and subsequent 
repolarization; it is measured from the beginning of the QRS complex to the end 
of the T wave
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate with Fridericia’s correction 
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SE
standard error
SI
System International
SOC
system organ class
TEAE
treatment-emergent adverse event
TSQM
Treatment Satisfaction Questionnaire for Medication
ULN
upper limit of normal
VCO2
VO2
VO2max
WNVFEV
Carbon dioxide production
Oxygen consumption
Maximal Oxygen consumption
Wang predicted value of FEV1 (L)
WNVFEF25-75%
Wang predicted value of FEF25-75% (L/sec)
WNVFVC
Wang predicted value of FVC (L)
WHODDE
World Health Organization Drug Dictionary Enhanced
 
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3
SUMMARY OF MODIFICATIONS 
No applicable as of 01 August 2016 
4
INTRODUCTION 
This SAP describes the planned final analyses for the Study VX15-809-112 data and is based 
on the  
x
approved clinical study protocol (Version 1.0, dated 15 January 2016),
x
approved electronic case report form (eCRF) (dated 13 January 2017).  
Study VX15-809-112 is a Phase 4, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Design Study of the Effect of Lumacaftor/Ivacaftor Combination Therapy on Exercise 
Tolerance in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the 
F508del-CFTR Mutation.
This SAP (Methods) documents the planned final statistical analyses of efficacy and safety 
introduced in the study protocol of VX15-809-112, and describes the corresponding data 
presentations. It also documents additional efficacy and safety analyses not specified in the 
protocol, which will provide supportive information to the scientific understanding of the 
drug entity. 
The 
 Biostatistics Department will perform the statistical analysis of the efficacy 
and safety data under the supervision of Vertex Biometrics Department; SAS (Version 9.2, or 
higher) will be used to generate all statistical outputs (tables, figures, listings, and datasets). 
The SAP will be finalized and approved prior to the final clinical data lock and treatment 
unblinding for the study.  
5
STUDY OBJECTIVES 
5.1
Primary Objective 
To evaluate the effect of LUM/IVA on exercise tolerance in subjects with CF, homozygous 
for the F508del-CFTR mutation 
5.2
Secondary Objectives 
To evaluate the effect of LUM/IVA on manifestations of CF affected by exercise tolerance 
and training
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6
STUDY ENDPOINTS 
6.1
Efficacy Endpoints 
6.1.1
Primary Endpoint 
Relative change from baseline in VO2max during cardiopulmonary exercise testing (CPET) 
at Week 24 
6.1.2
Secondary Endpoints 
Key Secondary Endpoint 
x
Relative change from baseline in exercise duration during CPET at Week 24 
Other Secondary Endpoints 
x
Absolute change from baseline in exercise duration during CPET at Week 24
x
Absolute change from baseline in VO2max during cardiopulmonary exercise testing 
(CPET) at Week 24
x
Absolute and relative change from baseline in oxygen consumption (VO2) at anaerobic 
threshold (AT) (the point during exercise at which lactate starts to accumulate) at 
Week 24
x
Absolute and relative change from baseline in functional VO2 gain at Week 24
x
Absolute and relative change from baseline in the slope of pulmonary ventilation (VE) 
versus carbon dioxide production (VCO2) at Week 24
x
Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) at Week 24
x
Relative change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) at Week 24
x
Absolute change from baseline in body mass index (BMI) at Week 24 
x
Relative change from baseline in body mass index (BMI) at week 24 
x
Absolute change from baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
respiratory domain score at Week 24 
x
Absolute change from baseline in overall Patient Health Questionnaire (PHQ-8) and 
Generalized Anxiety Disorder (GAD-7) scores at Week 24
x
Absolute change from baseline in total daily physical activity as determined by 
actigraphy at Week 24 
x
Relative change from baseline in total daily physical activity as determined by actigraphy 
at Week 24 
x
Absolute change from baseline in duration of sleep time during the night at Week 24 
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x
Relative change from baseline in duration of sleep time during the night at Week 24 
x
Absolute change from baseline in time above sedentary duration at Week 24 
x
Relative change from baseline in time above sedentary duration at Week 24 
6.2
Safety Endpoints 
The safety endpoints are as follows: 
x
Adverse events 
x
Clinical laboratory  
x
Vital signs
x
Pulse oximetry
x
Physical examination
x
Ophthalmologic findings (for subjects under 18 years of age only) 
6.3
Pharmacokinetic Endpoints 
Not applicable 
7
STUDY DESIGN  
7.1
Overall Design  
This is a Phase 4, randomized, double-blind, placebo-controlled, parallel-group study in 
subjects aged 12 years and older with CF who are homozygous for the F508del-CFTR
mutation. This study is designed to evaluate the effect of LUM/IVA on exercise tolerance. 
The study includes a Screening Period, a Treatment Period, and a Safety Follow-up Visit. 
Approximately 66 subjects will be randomized 1:1 (LUM/IVA: placebo) to the treatment 
arms shown in Figure 7-1 and stratified by ppFEV1 at baseline (<70% and ≥70% predicted). 
Subjects will receive study drug (LUM/IVA or placebo) for 24 weeks, in addition to their 
current CF medication regimen. They will return to the study center 4 weeks after their last 
dose of study drug for the Safety Follow-up Visit. It is recommended that subjects remain on 
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is greater variability, a larger sample size would be required to provide 80% power. 
Table 7-1 shows the required sample sizes for various assumptions about the true treatment 
effect using a 2-sided test at the 0.05 significance level. 
Because LUM/IVA has recently been approved in several countries, additional data 
independent of this study may emerge while this study is underway, which would allow a
more precise estimation of the true treatment effect. The final sample size may be 
recalculated based on these data, and the protocol may be amended as appropriate. 
Table 7-1 
Sample Sizes for 80% Power 
True Difference Between Placebo and 
LUM/IVA Effects on Primary Endpoint
Sample Size Needed for 80% Power
(subjects per treatment group)
5.0%
72
5.5%
59
6.0%
50
6.5%
44
7.0%
38
7.5%
33
7.3
Randomization 
A total of approximately 66 subjects (33 per arm) who meet eligibility criteria will be 
stratified by age (<18 versus ≥18 years of age), sex (male versus female), and percent 
predicted FEV1 severity determined at the baseline Visit (<70 versus ≥70), and then 
randomized (1:1) to 1 of the 2 treatment arms.  
The randomization codes were produced by a designated vendor 
. In order to protect 
the study blind and maintain the scientific integrity of the data, 1 Vertex biostatistician and 1 
 biostatistician were involved in the randomization process for each study: a Vertex 
biostatistician who is blinded to the actual treatment code and a 
 unblinded 
biostatistician who is not associated with the study. Below is a brief description of the 
randomization process. 
x
The Vertex biostatistician created the randomization specification.  
x
The external designated vendor 
 created the dummy randomization code, which 
was reviewed and approved by the Vertex biostatistician.  
x
After approval, the external designated vendor generated the production randomization 
list and provided it to the unblinded 
 biostatistician for review.  
x
After all outstanding issues were resolved; the external designated vendor generated the 
final randomization list and provided it to the unblinded 
 biostatistician to upload in 
the designated final randomization study area.  
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The unblinded 
 biostatistician provided the final randomization list to the interactive 
web response system (IWRS) vendor. A copy of the final randomization list, provided in 
sealed tamper-evident envelopes, was archived at Vertex. 
7.4
Blinding and Unblinding 
7.4.1
Blinding 
All subjects, site personnel including the investigator, the site monitor, and the Vertex study 
team will be blinded for the duration of the study, 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 serious 
adverse event (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  
x
DMC  
x
Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time 
Subjects and their caregiver should not be informed of their study-related spirometry results 
during the Treatment Period regardless of whether the subject has prematurely discontinued 
treatment. 
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. 
7.4.2
Unblinding 
Unblinding of the individual subject's treatment by the investigator should be limited to 
medical emergencies or urgent clinical situations in which knowledge of the subject's study 
treatment is necessary for clinical management. Details are provided in the clinical study 
protocol Section 11.12.2. 
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 source documents. Information regarding the treatment assignment obtained 
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Protocol Number: VX15-809-112 
Vertex Pharmaceuticals Incorporated 
from the unblinding should be maintained in a secure location with controlled access and 
must not be shared with Vertex, contract research organizations (CROs), or any site 
personnel (other than the physician treating the subject). In addition, the investigator should 
consider whether the clinical event that prompted unblinding should be considered an SAE, 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report 
to Vertex GPS, per corresponding section of the clinical study protocol. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, the Vertex medical monitor may, for matters relating to 
safety concerns, unblind individual subjects at any time. 
8
ANALYSIS SETS 
Assignment of subjects to analysis sets will be done prior to clinical data lock for the study. 
The following analysis sets will be defined: All Subjects Set, Full Analysis Set (FAS) and 
Safety Set.  
The All Subjects Set will be defined as all subjects in the study who were randomized or 
dosed (received any amount of study drug). All subject data listings will be use the All 
Subjects Set, unless otherwise specified. 
8.1
Efficacy Sets 
8.1.1
Full Analysis Set (FAS) 
The FAS will include all randomized subjects who received any amount of study drug. The 
treatment assignment for the FAS will be as randomized. The FAS will be used for all 
efficacy analyses. 
8.2
Safety Set 
The Safety Set will include all subjects who received any amount of study drug. The 
treatment assignment for the Safety Set will be as treated. All safety analyses will be 
conducted using the Safety Set. 
8.3
Other Analysis Set 
Not applicable. 
9
STATISTICAL ANALYSIS 
9.1
General Considerations 
The Schedule of Assessments is provided in Appendix A.
All individual subject data for those randomized or exposed to study drug will be presented 
in data listings. 
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Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard error (SE), standard deviation (SD), 
median, minimum value (min), and maximum value (max). The precision of the 
measurement for each continuous variable will be used to determine the number of decimal 
places to present in tables, figures, and derived listings. Minimum and maximum values will 
be reported with the same precision as the units of measure. The mean and median will be 
reported to 1 greater decimal place, and the SE and SD will be reported to 2 additional 
decimal places. Any values that require transformation to standard units (metric or SI) will be 
converted with the appropriate corresponding precision. 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place.  
Baseline Value: Unless otherwise specified, the baseline value will be defined as the most 
recent non-missing measurement (scheduled or unscheduled) collected prior to the initial 
administration of study drug. Baseline CPET data will be collected on Day 1 prior to the 
initial administration of study drug. Unscheduled visit measurements will be included for 
derivation of baseline.  For actigraphy variables, baseline data will be defined as the mean of 
the data collected for the 7 days immediately preceding Day 1 (Day -7 to Day -1) during the 
Screening Period. 
Absolute Change from baseline will be calculated as Post baseline value - Baseline value.  
Relative change from baseline will be calculated and expressed in percentages as 100× 
(Post baseline value - Baseline value)/Baseline value. 
Unscheduled Visits: Unscheduled visit measurements will be included in listings, for 
derivation of visit windows and computation of baseline/last on-treatment visit, and for the 
analysis of maximum/minimum on-treatment values and maximum/minimum changes from 
baseline values. 
Visit Windows: Appendix C defines the visit window mapping rules to derive the analysis 
visits.  
Repeated observations within the same visits window 
x
For all efficacy parameters, if there are multiple measurements within a visit window, the 
record at the scheduled visit will be used. If there are no measurements at the scheduled 
visit, then 1) the record closest to the target day will be used; or 2) if there are multiple 
records with the same distance to the target day, the latest record will be used.   
x
For all safety parameters, if there are multiple measurements within a visit window, then 
1) the record closest to the target day will be used; or 2) if there are multiple records with 
the same distance to the target day, the latest record will be used. 
BMI will follow visit window rules for efficacy parameters when being considered as an 
efficacy endpoint. 
Incomplete/Missing data will not be imputed, unless otherwise specified; i.e., all missing 
values will remain as missing in all statistical analyses and listings, unless otherwise 
specified. Missing post-baseline values will not be imputed for efficacy analysis conducted 
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using a mixed model for repeated measures (MMRM) approach, which makes use of all 
available data even if a subject has missing data at some post-baseline visits. 
Outliers: No formal statistical analyses will be performed to detect and/or remedy the 
presence of statistical outliers. 
Repeated Observations: Measurements recorded at different time points are defined as 
repeated observations. If an assessment has planned repeated measurements, then statistical 
summaries will present all planned time points, as appropriate.   
9.2
Background Characteristics  
9.2.1
Subject Disposition 
The number of subjects in the following analyses sets will be summarized:  
x
All Subjects Set 
x
Randomized 
x
FAS (randomized and dosed) 
x
Safety Set 
The number and percentage of subjects in each disposition category will be summarized with 
the number in the FAS as the denominator, together with the number of subjects randomized 
but never dosed: 
x
Randomized but never dosed (only showing number of subjects) 
x
Completed treatment 
x
Prematurely discontinued treatment and the reasons for discontinuations 
x
Last completed on-treatment scheduled visit for subjects who discontinued treatment  
x
Completed study 
x
Prematurely discontinued the study and the reasons for discontinuations 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. A randomization listing will be provided with subjects 
ordered by randomization date. 
9.2.2
Demographics and Baseline Characteristics 
Demographic data will be summarized based on the FAS: 
x
Age 
x
Age groups (< 18 and t18 years) 
x
Sex (female and male) 
x
Ethnicity  
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x
Race  
Baseline characteristics will be summarized based on the FAS: 
x
Weight (kg) 
x
Weight z-score (subjects ≤20 years old) Weight, adjusted for age and sex, will be 
analyzed as weight-for-age z-score (weight z-score). The calculation of weight z-score is 
similar to that of BMI z-score (using the CDC growth charts and the derivation 
described). Using the same equation as in the CDC growth charts and the derivation 
described in the website below, X in the equation is the collected weight and L, M, and S
parameters are selected from the CDC weight-for-age chart. The WTAGE file contains 
these parameters by sex and age; it is available at the website 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. NOTE: The CDC growth 
charts are designed for use in pediatric populations (2 to 20 years of age); therefore, 
weight z-score will be calculated only for subjects in this age range.   
x
Height (cm) 
x
Height z-score (subjects ≤20 years old) Height, adjusted for age and sex, will be referred 
to as height-for-age z-score (or height z-score). The calculation of height z-score is 
similar to that of BMI z-score (using the CDC growth charts and the derivation 
described). Using the same equation as in the CDC growth charts and the derivation 
described in the website below, X in the equation is the collected height and L, M, and S
parameters are selected from the CDC height-for-age chart. The STATAGE file contains 
these parameters by sex and age; it is available at the website 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. NOTE: The CDC growth 
charts are designed for use in pediatric populations (2 to 20 years of age); therefore, 
height z-score will be calculated only for subjects in this age range. 
x
BMI (kg/m2) 
x
BMI z-score (subjects ≤20 years old) 
x
Percent predicted FEV1 at screening (<70, ≥70)
x
Percent predicted FEV1 at baseline (<40, ≥40 to <70, ≥70 to ≤90, >90) 
x
Percent predicted FEV1 at baseline 
x
FEV1 (L) 
x
FVC (L) 
x
Percent predicted FVC
x
FEF25-75% (L/sec) 
x
Percent predicted FEF25-75%
x
FEV1/FVC 
x
VO2max 
x
Exercise duration during CPET  
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x
Oxygen consumption (VO2) at anaerobic threshold (AT) (the point during exercise at 
which lactate starts to accumulate)  
x
Functional VO2 gain  
x
Slope of pulmonary ventilation (VE) vs. carbon dioxide production (VCO2) 
x
Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score  
x
Overall Patient Health Questionnaire (PHQ-8) score 
x
Generalized Anxiety Disorder (GAD-7) score  
x
Physical activity as determined by actigraphy 
x
Duration of sleep time during the night  
x
Received dornase alfa before first dose of study drug (Yes, No) 
x
Received any inhaled antibiotic before first dose of study drug (Yes, No) 
x
Received any bronchodilator before first dose of study drug (Yes, No) Note: On the Prior 
and Concomitant Medications page, only those coded as bronchodilator will be included. 
x
Received any inhaled bronchodilator before first dose of study drug (Yes, No) Note: On 
the Prior and Concomitant Medications page, only those coded as bronchodilator will be 
included. 
x
Received any inhaled bronchodilator before first dose of study drug (Short-Acting Only, 
vs (Short-Acting and Long-Acting) or Long-Acting only, vs No) 
x
Received any inhaled hypertonic saline before first dose of study drug (Yes, No) 
x
Received any inhaled corticosteroids before first dose of study drug (Yes, No) 
Medical history summary will be presented for the FAS.  
The important protocol deviation programming rules (based on the clinical database) are 
provided in Appendix G. Important protocol violations/deviations (based on the clinical 
database or from the site deviation log) will be summarized descriptively based on the FAS. 
Important protocol deviations/violations will be provided as a subject data listing. 
9.2.3
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced (WHODDE) and categorized as the following: 
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x
Prior medication: medication started before initial dosing of study drug, regardless of 
when it ended. 
x
Concomitant medication: medication continued or newly received at or after initial 
dosing of study drug to 28 days after the last dose of study drug. 
x
Post-treatment medication: medication continued or newly received after 28 days after 
the last dose of study drug. 
A given medication can be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; 
or prior, concomitant, and post-treatment. If a medication has a missing or partially missing 
start/end date or time and it cannot be determined whether it was taken before initial dosing, 
concomitantly, or more than 28 days after the last dose of study drug, it will be considered as 
prior, concomitant, and post-treatment. 
Prior medications and concomitant medications will be summarized descriptively by 
preferred term (PT) based on the FAS. Prior medications and concomitant medications with a 
frequency of ≥5% at the PT level in any treatment group will be summarized descriptively by 
PT. Post-treatment medications will be listed for each subject.  
In addition, to evaluate whether the medications have stable use after receiving study drug, 
shifts from use prior to the first dose (Yes, No) to use during the treatment-emergent period 
(chronic versus intermittent) will be summarized using number of subjects and percentages 
for the following medication categories:  
x
Inhaled antibiotics 
x
Inhaled bronchodilator 
x
Inhaled hypertonic saline 
x
Inhaled corticosteroids 
A medication is considered to be used chronically during the treatment-emergent period if it 
is used on ≥ 25% of days during the treatment-emergent period; and is considered to be used 
intermittently during the treatment-emergent period if it is used on <25% of days during the 
treatment-emergent period. The treatment-emergent period is the period at or after the initial 
dosing of study drug to 28 days after the last dose of study drug. 
As an intermediate step for programming purposes, medications with missing or partially 
missing start dates will have 2000 imputed for the missing year, January for the missing 
month, and 1 for the missing day; medications with missing or partially missing stop dates 
will have 2050 imputed for the missing year, December for the missing month, and the last 
day of the month for the missing day. The logic to decide the category of a medication is 
presented in Table 9-1:
Table 9-1 
Logic for Determining the Category of a Medication 
Medication start date
Medication end date
< first dose date of ≥ first dose date and > last dose date + 28 
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study drug
≤ last dose date +28 
days
days
< first dose date of study drug
P
PC
PCA
≥ first dose date and 
≤ last dose date + 28 days
-
C
CA
> last dose date + 28 days
-
-
A
P: Prior; C: Concomitant; A: Post
9.2.4
Study Drug Exposure 
Duration of study drug exposure is defined as: last dose date – first dose date + 1 day, 
regardless of any interruptions in dosing. If the last dose date of study drug is missing, the 
subject’s discontinuation or completion date will be used for analysis purpose. 
Duration of study drug exposure will be summarized descriptively as quantitative variables 
(number, mean, SE, SD, median, minimum [min], and maximum [max]). Additionally, the 
total duration of study drug exposure, defined as the sum of the subject’s duration of 
treatment exposure and expressed in patient years, will be provided.  
Exposure summaries will be based on the FAS. 
9.2.5
Study Drug Compliance 
Study drug compliance will be calculated as follows:  
100 × [1 - (Total number of days study drug interrupted) /  
(Duration of study drug exposure)]. 
The total number of days of study drug interrupted is defined as the sum of (number of days 
of study drug interrupted in each interval), where number of days of study drug interrupted in 
each interval is defined as the interruption end date - the corresponding interruption start date 
+ 1. 
In calculating the total number of days study drug interrupted, only interruptions with 
duration of ≥3 days will be considered. An interruption with duration of < 3 days will not be 
considered in the calculation. 
Treatment compliance percentages will be summarized descriptively as quantitative variables 
(number, mean, SE, SD, median, min, and max). The n and percentage of subjects whose 
compliance is <80% or ≥80% will be summarized.
A list of subjects with <80% compliance will be provided. 
Study drug compliance will be summarized based on the FAS. 
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9.3
Efficacy Analysis 
Unless otherwise defined, all efficacy analyses described in this section will include all 
measurements up to Week 24 [inclusive], both on-treatment measurements and 
measurements after treatment discontinuation. 
9.3.1
Analysis of Primary Efficacy Endpoint 
9.3.1.1
Definition of Primary Efficacy Endpoint 
The primary efficacy endpoint is the percentage change from baseline in VO2max 
(mL/kg/min [milliliter per kilogram per minute]) during cardiopulmonary exercise testing 
(CPET) at Week 24, defined as VO2max (mL/kg/min) during cardiopulmonary exercise 
testing (CPET) at Week 24 minus VO2max (mL/kg/min) during cardiopulmonary exercise 
testing (CPET) at baseline, divided by VO2max (mL/kg/min) during cardiopulmonary 
exercise testing (CPET) at baseline. 
VO2max is the largest VO2 value during exercise.  
VO2max is found in the column(s) with a heading of VO2 in the 20-second averaged CPET 
spreadsheets.  
Some spreadsheets have a column reporting VO2 in units of mL/min or L/min only, while 
others have an additional column reporting VO2 as weight-based units with a designation of 
kg in the column header. The header title may vary, but when the term kg appears in the 
header, the actual units are mL/kg/min.  
If the VO2 is reported in L/min, it will need to be converted to achieve final reported units of 
mL/kg/min (1L=1000mL).  
If there is no weight-based column showing kg (i.e., VO2 is reported only in mL/min or 
L/min), the weight in kg will need to be pulled from the eCRF in order to convert these 
values to mL/kg/min.  
9.3.1.2
Primary Analysis of Primary Efficacy Endpoint 
The primary analysis for the primary efficacy endpoint will be based on a mixed model 
repeated measures (MMRM) using SAS PROC MIXED based on the FAS.  
The model, including percentage change from baseline in VO2max (including all 
measurements up to Week 24 [inclusive], both on-treatment measurements and 
measurements after treatment discontinuation) as the dependent variable, treatment, visit, and 
treatment-by-visit interaction as fixed effects, with adjustment for sex (male versus female), 
age group at baseline (<18 versus ≥18 years old), percent predicted FEV1 at baseline (<70 
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versus ≥70), baseline VO2max value and subject as a random effect will be used to test the 
difference between active treatment group versus placebo. The primary result obtained from 
the model will be the treatment effect at Week 24. 
Descriptive summary statistics including number of subjects, mean, standard error, and least-
square means (LS means) along with the P values will be provided. In particular, the 
difference in LS means as well as LS means within each group and the corresponding 95% 
CI will be provided along with the P values to assess the treatment difference between 
placebo and lumacaftor in combination with ivacaftor. Additionally, the P value testing the 
treatment-by-visit interaction will be provided to assess the consistency of treatment effect 
over different visits. 
The repeated-measures analysis will be based on the restricted maximum likelihood method 
assuming an unstructured covariance structure to model the within-subject errors. A 
Kenward-Roger approximation will be used for the denominator degrees of freedom. If there 
is a convergence problem due to the unstructured covariance matrix, a compound symmetry 
covariance structure will be used to model the within-subject errors. With a mixed effects 
model as the primary analysis model based on restricted maximum likelihood estimation and 
assuming that conditional on fixed and random effects, data are missing at random, no 
imputation of missing data will be done. 
In addition, raw values of percentage change from baseline in VO2max at Week 24, and raw 
values of percentage change from baseline in VO2max at Week 12 will be summarized 
descriptively (number, mean, SE, SD, median, min, and max). 
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9.3.2
Analysis of Secondary Efficacy Endpoints 
Key Secondary Endpoint 
x
Relative change from baseline in exercise duration during CPET at Week 24
Other Secondary Endpoints 
x
Absolute change from baseline in exercise duration during CPET at Week 24
x
Absolute change from baseline in VO2max during cardiopulmonary exercise testing 
(CPET) at Week 24
x
Absolute and relative change from baseline in oxygen consumption (VO2) at anaerobic 
threshold (AT) (the point during exercise at which lactate starts to accumulate) at 
Week 24
x
Absolute and relative change from baseline in functional VO2 gain at Week 24
x
Absolute and relative change from baseline in the slope of pulmonary ventilation (VE) 
versus carbon dioxide production (VCO2) at Week 24
x
Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) at Week 24
x
Relative change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) at Week 24
x
Absolute change from baseline in body mass index (BMI) at Week 24 
x
Relative change from baseline in body mass index (BMI) at week 24 
x
Absolute change from baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
respiratory domain score at Week 24 
x
Absolute change from baseline in overall Patient Health Questionnaire (PHQ-8) and 
Generalized Anxiety Disorder (GAD-7) scores at Week 24
x
Absolute change from baseline in total daily physical activity as determined by 
actigraphy at Week 24 
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x
Relative change from baseline in total daily physical activity as determined by actigraphy 
at Week 24 
x
Absolute change from baseline in duration of sleep time during the night at Week 24 
x
Relative change from baseline in duration of sleep time during the night at Week 24 
x
Absolute change from baseline in time above sedentary duration at Week 24 
x
Relative change from baseline in time above sedentary duration at Week 24 
9.3.2.1
Definition of Secondary Efficacy Endpoints 
9.3.2.1.1 Definition of Key Secondary Efficacy Endpoints 
Relative change from baseline in exercise duration during CPET at Week 24 
Relative change from baseline in exercise duration measured in the unit of seconds during 
CPET at Week 24 is the key secondary efficacy endpoint, defined as exercise duration 
measured in the unit of seconds during CPET at Week 24 minus exercise duration measured 
in the unit of seconds during CPET at baseline, divided by exercise duration measured in the 
unit of seconds during CPET at baseline. 
Exercise duration is defined as the time at the termination of CPET exercise minus the 
corresponding time when CPET starts for each CPET exercise. 
9.3.2.1.2 Definition of Additional Secondary Efficacy Endpoints 
Absolute change from baseline in exercise duration during CPET at Week 24 
Defined as exercise duration measured in the unit of seconds during CPET at Week 24 minus 
exercise duration measured in the unit of seconds during CPET at baseline 
Absolute change from baseline in VO2max (mL/kg/min) during cardiopulmonary 
exercise testing (CPET) at Week 24
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Defined as VO2max (mL/kg/min) during cardiopulmonary exercise testing (CPET) at 
Week 24 minus VO2max (mL/kg/min) during cardiopulmonary exercise testing (CPET) at 
baseline 
Absolute change from baseline in oxygen consumption (VO2) (mL/min) at anaerobic 
threshold (AT) (the point during exercise at which lactate starts to accumulate) at 
Week 24 
Defined as oxygen consumption (VO2) (mL/min) at AT at Week 24 minus oxygen 
consumption (VO2) (mL/min) at AT at baseline. 
Relative change from baseline in oxygen consumption (VO2) (mL/min) at anaerobic 
threshold (AT) (the point during exercise at which lactate starts to accumulate) at 
Week 24 
Defined as oxygen consumption (VO2) (mL/min) at AT at Week 24 minus oxygen 
consumption (VO2) (mL/min) at AT at baseline, divided by oxygen consumption (VO2)
(mL/min) at AT at baseline 
Before reviewing the results for VO2 at the time that AT occurred, it must first be determined 
if the appropriate number of overreaders input this value into the eCRF. There are separate 
eCRF entries for the time at AT and the actual VO2 value at the time of AT. However, each 
of these fields should have the identical number of entries, either 2 or 3. If they do not, no 
further evaluation of these parameters should be carried out, and Vertex must be notified. If 
they do, please proceed. 
The time of AT is reported in the eCRF by either 2 or 3 independent overreaders. The final, 
averaged time at AT will be determined following the guidelines: 
x If the time at AT results is available from two overreaders, the absolute difference
between these results (in seconds) will be divided by the lower of the two results (in 
seconds) to determine if the readings are within 5% (İ5%) of each other. If they are, 
the average value of the two readings will be used as the final time at AT. If the results 
are not within 5% of each other, no further evaluation of this parameter should be 
carried out, and Vertex must be notified. 
x If time at AT results is available from 3 overreaders, the absolute difference between 
the highest and lowest of the 3 results (in seconds) will be divided by the lowest of the 
results (in seconds) to determine if these readings are within 7% (≤7%) of each other. If 
they are, the average value of all three readings will be used as the final time at AT. If 
their results are not within 7% of each other, no further evaluation of this parameter 
should be carried out, and Vertex must be notified.  
Once it has been confirmed that the appropriate number of overreaders have input their 
values, the average of these 2 or 3 VO2 values in the eCRF will be reported as the final VO2
at the time of AT. 
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Absolute change from baseline in functional VO2 gain at Week 24 
Defined as functional VO2 gain at Week 24 minus functional VO2 gain at baseline.  
Relative change from baseline in functional VO2 gain at Week 24 
Defined as functional VO2 gain at Week 24 minus functional VO2 gain at baseline, divided by 
functional VO2 gain at baseline.  
Functional VO2 gain is calculated as ᇞVO2/Max Watts.  
This data is derived from the 20-second averaged CPET spreadsheets.  
x
ᇞVO2 = Final VO2 – Rest VO2  

Final VO2 (ml/min) is the mean of the last 3 available values of VO2 at the end of 
exercise  

Rest VO2 (ml/min) is the mean of the last 3 available values of VO2 immediately before 
the start of exercise  
x
Maximum Watts achieved during exercise can be found in the WR, Work, or Watts column 
on the 20-sec averaged CPET spreadsheets.  
If VO2 reported in L/min, this will need to be converted to mL/min before applying the formulas 
above (1L=1000mL).  
Absolute change from baseline in the slope of pulmonary ventilation (VE, L/min) versus 
carbon dioxide production (VCO2, L/min) at Week 24 
Defined as the slope of pulmonary ventilation (VE, L/min) versus carbon dioxide production 
(VCO2, L/min) at Week 24 minus the slope of pulmonary ventilation (VE, L/min) versus 
carbon dioxide production (VCO2, L/min) at baseline 
Relative change from baseline in the slope of pulmonary ventilation (VE, L/min) versus 
carbon dioxide production (VCO2, L/min) at Week 24 
Defined as the slope of pulmonary ventilation (VE, L/min) versus carbon dioxide production 
(VCO2, L/min) at Week 24 minus the slope of pulmonary ventilation (VE, L/min) versus 
carbon dioxide production (VCO2, L/min) at baseline, divided by the slope of pulmonary 
ventilation (VE, L/min) versus carbon dioxide production (VCO2, L/min) at baseline 
This data is derived from the breath-by-breath CPET spreadsheets. 
VE and VCO2 data will be measured from the beginning to the end of exercise during each 
corresponding CPET session.  
A linear regression model using pulmonary ventilation (VE, L/min) as the dependent variable 
and carbon dioxide production (VCO2, L/min) as the covariate without an intercept will be 
used to derive the slope estimate from the breath by breath data. 
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Absolute change from baseline in percent predicted forced expiratory volume in 
1 second (ppFEV1) at Week 24
Defined as percent predicted forced expiratory volume in 1 second (ppFEV1) at Week 24
minus percent predicted forced expiratory volume in 1 second (ppFEV1) at baseline (Please 
see appendix D for the definition of ppFEV1) 
Relative change from baseline in percent predicted forced expiratory volume in 
1 second (ppFEV1) at Week 24
Defined as percent predicted forced expiratory volume in 1 second (ppFEV1) at Week 24
minus percent predicted forced expiratory volume in 1 second (ppFEV1) at baseline, divided 
by percent predicted forced expiratory volume in 1 second (ppFEV1) at baseline  (Please see 
appendix D for the definition of ppFEV1) 
Absolute change from baseline in body mass index (BMI) raw score at Week 24  
Defined as body mass index (BMI) raw score at Week 24 minus body mass index (BMI) raw 
score at baseline 
Relative change from baseline in body mass index (BMI) raw score at Week 24  
Defined as body mass index (BMI) raw score at Week 24 minus body mass index (BMI) raw 
score at baseline, divided by body mass index (BMI) raw score at baseline 
BMI will be calculated as the following: 
BMI = Weight (kg)/(height (m)2) 
Absolute change from baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
respiratory domain score at Week 24 
Defined as Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score at 
Week 24 minus Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score at 
baseline 
The CFQ-R2,3,4 is a validated CF-specific instrument that measures quality-of-life domains. 
There are three different versions of CFQ-R forms in this study:  
x
CFQ-R for Children Ages 12 and 13 has a total of 35 questions to form 8 domains. All 
questions are scored 1, 2, 3, or 4.
x
CFQ-R for Adolescents and Adults (subjects 14 years and older) has a total of 50 
questions to form 12 domains. Question 43 is scored 1, 2, 3, 4, or 5 and is not used in 
calculating any domains; all the other 49 questions are scored 1, 2, 3, or 4.
x
CFQ-R for Parents/Caregivers (subjects 13 years and younger) has a total of 44 questions 
to form 11 domains. Question 37 is scored 1, 2, 3, 4, or 5 and is not used in calculating 
any domains; all the other 43 questions are scored 1, 2, 3, or 4.
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For all three CFQ-R versions, to calculate the score for each domain, the response scores on 
the negatively phrased questions are reversed (reversed scores = 5 – response scores) so that 
1 always represents the worst condition and 4 always represents the best condition. In each 
domain, in cases where individual questions were skipped, the missing scores are imputed 
with the mean score of the non-missing questions for that domain rounded to the nearest 
integer.  
The scaled score for each domain ranges from 0 (worst condition) to 100 (best condition) and 
is calculated as follows: 
Scaled score for a domain = 100 × (mean(scores of all questions in that domain) - 1)/3 
The scaled score for a specific domain will not be calculated if more than half of the 
questions in the domain have missing scores. 
Table 9-2, Table 9-3, and Table 9-4 provide the questions included in each domain, the 
questions with the reversed scores, as well as the maximum number of missing questions for 
the CFQ-R for Children Ages 12 and 13, the CFQ-R for Adolescents and Adults, and the 
CFQ-R for Parents/Caregivers respectively. 
Table 9-2 
CFQ-R for Children Ages 12 and 13  
Domain
Questions
Reversed questions
Maximum number of 
missing questions
Total
Individual
Physical
6
1, 2, 3, 4, 5, 6
1, 2, 3, 4, 5
3
Emotion
8
7, 8, 9, 10, 11, 12, 13, 14
14
4
Social
7
20, 21, 22, 23, 24, 25, 26
20, 22, 24, 26
3
Body
3
27, 28, 29
-
1
Eat
3
15, 17, 19
19
1
Treatment burden
3
16, 18, 30
18
1
Respiration
4
31, 32, 33, 34
-
2
Digestion
1
35
-
0
Table 9-3 
CFQ-R for Adolescents and Adults (subjects 14 years and older)  
Domain
Questions
Reversed questions
Maximum number of 
missing questions
Total
Individual
Physical
8
1, 2, 3, 4, 5, 13, 19, 20
13
4
Role
4
35, 36, 37, 38
35
2
Vitality
4
6, 9, 10, 11
6, 10
2
Emotion
5
7, 8, 12, 31, 33
-
2
Social
6
22, 23, 27, 28, 29, 30
23, 28, 30
3
Body
3
24, 25, 26
-
1
Eat
3
14, 21, 50
-
1
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Table 9-3 
CFQ-R for Adolescents and Adults (subjects 14 years and older)  
Domain
Questions
Reversed questions
Maximum number of 
missing questions
Total
Individual
Treatment burden
3
15, 16, 17
15, 17
1
Health perceptions
3
18, 32, 34
18, 32, 34
1
Weight
1
39
-
0
Respiration*
6
40, 41, 42, 44, 45, 46
43
3
Digestion
3
47, 48, 49
-
1
*: Question 43 not used to calculate a domain.  
Table 9-4 
CFQ-R for Parents/Caregivers (subjects 13 years and younger)  
Domain
Questions
Reversed questions
Maximum number of 
missing questions
Total
Individual
Physical
9
1, 2, 3, 4, 5, 13, 14, 15, 16
15
4
Vitality
5
8, 9, 10, 11, 12
10, 12
2
Emotion
5
6, 7, 23, 25, 26
6
2
School
3
27, 28, 29
28
1
Body
3
19, 20, 21
-
1
Eat
2
17, 44
-
0
Treatment burden
3
18, 30, 31
31
1
Health perceptions
3
22, 24, 32
22, 24, 32
1
Weight
1
33
-
0
Respiration*
6
34, 35, 36, 38, 39, 40
37
3
Digestion
3
41, 42, 43
-
1
*: Question 37 not used to calculate a domain.  
The absolute change from baseline in the respiratory domain of the CFQ-R (Pooled 'Children 
Ages 12 and 13' Version and 'Adolescents and Adults' Version) at Week 24 is one of the 
secondary endpoints. 
Absolute change from baseline in overall Patient Health Questionnaire (PHQ-8) and 
Generalized Anxiety Disorder (GAD-7) scores at Week 24
Defined as overall Patient Health Questionnaire (PHQ-8) and Generalized Anxiety Disorder 
(GAD-7) scores at Week 24 minus overall Patient Health Questionnaire (PHQ-8) and 
Generalized Anxiety Disorder (GAD-7) scores at baseline, correspondingly 
Both GAD-7 and PHQ-8 will be summarized by proportion of patients in each severity 
category at both baseline and Week 24. The detailed information with regard to these two 
scores and the severity category is indicated below. 
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PHQ-8 Depression Severity. This is calculated by assigning scores of 0, 1, 2, and 3, to the 
response categories of ―not at all, ―several days, ―more than half the days, and ―nearly 
every day, respectively. PHQ-8 total score for the eight items ranges from 0 to 24. Scores of 
5, 10, 15, and 20 represent cutpoint for mild, moderate, moderately severe and severe 
depression, respectively. Sensitivity to change has also been confirmed.  
GAD-7 Anxiety Severity. This is calculated by assigning scores of 0, 1, 2, and 3, to the 
response categories of ―not at all, ―several days, ―more than half the days, and ―nearly 
every day, respectively. GAD-7 total score for the seven items ranges from 0 to 21. Scores of 
5, 10, and 15 represent cutpoint for mild, moderate, and severe anxiety, respectively. Though 
designed primarily as a screening and severity measure for generalized anxiety disorder, the 
GAD-7 also has moderately good operating characteristics for three other common anxiety 
disorders – panic disorder, social anxiety disorder, and post-traumatic stress disorder. When 
screening for anxiety disorders, a recommended cutpoint for further evaluation is a score of 
10 or greater. 
Absolute change from baseline in physical activity as determined by actigraphy at 
Week 24 
Defined as total activity count at Week 24 minus total activity count at baseline. Baseline is 
defined as the daily mean of data obtained in the 7 days prior to Day 1 (Day -7 through Day  
-1). Week 24 is defined as the mean of data obtained in the calendar week prior to Week 24. 
Relative change from baseline in physical activity as determined by actigraphy at 
Week 24 
Defined as total activity count at Week 24 minus total activity count at baseline, divided by 
total activity count at baseline. Baseline is defined as the daily mean of data obtained in the 7 
days prior to Day 1 (Day -7 through Day  -1). Week 24 is defined as the mean of data 
obtained in the calendar week prior to Week 24 visit.
Absolute change from baseline in duration of sleep time during the night at Week 24 
Defined as average duration of sleep time at Week 24 minus average duration of sleep time at 
baseline. Baseline is defined as the daily mean of data obtained in the 7 days prior to Day 1 
(Day -7 through Day -1).; week 24 is defined as the mean of data obtained in the calendar 
week prior to Week 24 visit. 
Relative change from baseline in duration of sleep time during the night at Week 24 
Defined as average duration of sleep time at Week 24 minus average duration of sleep time at 
baseline, divided by average duration of sleep time at baseline. Baseline is defined as the 
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daily mean of data obtained in the 7 days prior to Day 1 (Day -7 through Day -1).; week 24 is 
defined as the mean of data obtained in the calendar week prior to Week 24 visit. 
Absolute change from baseline in time above sedentary duration at Week 24 
Defined as average time above sedentary duration at Week 24 minus average time above 
sedentary duration at baseline. Baseline is defined as the daily mean of data obtained in the 7 
days prior to Day 1 (Day -7 through Day -1).; week 24 is defined as the mean of data 
obtained in the calendar week prior to Week 24 visit. 
Relative change from baseline in time above sedentary duration at Week 24 
Defined as average time above sedentary duration at Week 24 minus average time above 
sedentary duration at baseline, divided by average time above sedentary duration at baseline. 
Baseline is defined as the daily mean of data obtained in the 7 days prior to Day 1 (Day -7 
through Day -1).; week 24 is defined as the mean of data obtained in the calendar week prior
to Week 24 visit. 
The time unit for duration of sleep and time above sedentary duration will be in hours. 
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9.3.2.2
Analysis of Secondary Endpoints 
9.3.2.2.1 Analysis of Key Secondary Efficacy Endpoints 
Absolute and percentage change from baseline in exercise duration during CPET at 
Week 24 
Analysis of these two variables will be similar to that of the primary analysis of the primary 
efficacy endpoint using a mixed model repeated measures (MMRM) using SAS PROC 
MIXED based on the FAS, with the exception that exercise duration during CPET at baseline 
will replace baseline VO2max value in the MMRM model.  
Absolute and percentage change from baseline in exercise duration measured in the unit of 
seconds at both Week 12 and Week 24 will be derived from the main model based on the 
FAS. The LS means (with 95% CI) at each visit will be plotted by treatment groups.  
In addition, raw changes from baseline in exercise duration measured in the unit of seconds 
as well as raw values at both Week 12 and Week 24 will be summarized using descriptive 
summary statistics.  
9.3.2.2.2 Analysis of Additional Secondary Efficacy Endpoints 
Analysis of the following other secondary endpoints will also be similar to that of the 
primary analysis of the primary efficacy endpoint using a mixed model repeated measures 
(MMRM) using SAS PROC MIXED based on the FAS, with the exception that for each of 
these secondary endpoints, their corresponding value at baseline will replace baseline 
VO2max value in the MMRM model.  
x
Absolute change from baseline in VO2max during cardiopulmonary exercise testing 
(CPET) at Week 24
x
Absolute and relative change from baseline in oxygen consumption (VO2) at anaerobic 
threshold (AT) (the point during exercise at which lactate starts to accumulate) at 
Week 24
x
Absolute and relative change from baseline in percent predicted forced expiratory volume 
in 1 second (ppFEV1) at Week 24. Note: Baseline ppFEV1 will not be included in the 
MMRM model because ppFEV1 at baseline as a stratification factor has already been 
included in the model. 
x
Absolute and relative change from baseline in body mass index (BMI) at Week 24 
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x
Absolute change from baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
respiratory domain score at Week 24 
x
Absolute and relative change from baseline in functional VO2 gain at Week 24
x
Absolute and relative change from baseline in the slope of pulmonary ventilation (VE) 
versus carbon dioxide production (VCO2) at Week 24
Absolute and percentage change from baseline in these other secondary endpoints above at 
both Week 12 and Week 24 will be derived from the main model based on the FAS.  
In addition, raw changes from baseline in these other secondary endpoints above as well as 
raw values at both Week 12 and Week 24 will be summarized using descriptive summary 
statistics.  
Analysis of the following other secondary endpoints will be based on descriptive summary 
statistics only. Descriptive summary statistics along with 95% confidence interval will be 
provided at both Week 12 and Week 24 by treatment groups. 
x
Absolute change from baseline in overall Patient Health Questionnaire (PHQ-8) and 
Generalized Anxiety Disorder (GAD-7) scores at Week 24
x
Proportion of patients in each severity category of PHQ-8 and GAD-7 scores at both 
baseline and Week 24. 
x
Absolute and relative change from baseline in physical activity as determined by 
actigraphy at Week 24 
x
Absolute and relative change from baseline in duration of sleep time during the night at 
Week 24
x
Absolute and relative change from baseline in time above sedentary duration at Week 24
In addition, raw values from baseline in these other secondary endpoints above as well as raw 
values at both Week 12 and Week 24 will be summarized using descriptive summary 
statistics.  
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9.3.2.3
Correlation analysis 
Correlation analysis using both Pearson’s correlation coefficient and Spearman’s correlation 
coefficient will be evaluated for the following endpoints for their corresponding change from 
baseline to week 24. Correlation analysis will be performed by treatment arms as well as in 
the overall patient population. 
Percentage change of VO2max and percentage change of ppFEV1 
Absolute change of VO2max and absolute change of ppFEV1 
Percentage change of exercise duration and percentage change of ppFEV1 
Absolute change of exercise duration and absolute change of ppFEV1 
Absolute change of VO2 at AT and absolute change of ppFEV1 
Percentage change of VO2 at AT and percentage change of ppFEV1 
Absolute change of functional VO2 gain and absolute change of ppFEV1 
Percentage change of functional VO2 gain and percentage change of ppFEV1 
Absolute change of the slope of pulmonary ventilation (VE) versus carbon dioxide 
production (VCO2) and absolute change of ppFEV1 
Percentage change of the slope of pulmonary ventilation (VE) versus carbon dioxide 
production (VCO2)and percentage change of ppFEV1 
Absolute change of sleeping time and absolute change of ppFEV1      
Absolute change of physical activity and absolute change of ppFEV1 
Absolute change of time above sedentary duration and absolute change of ppFEV1 
9.3.2.4
Multiplicity adjustment 
No multiplicity adjustment will be made in this study. 
9.4
Safety Analysis 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:   
x
Adverse events 
x
Clinical laboratory values (hematology, serum chemistry, urinalysis, and coagulation 
studies) 
Safety endpoints will be analyzed based on the Safety Set. Only descriptive analysis of safety 
will be performed (i.e., no statistical testing will be performed). 
The study period will be divided into 3 segments: 
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x
The pre-treatment period is defined as the period after the informed consent/assent date 
and before the initial dosing of study drug. 
x
The treatment-emergent period is the period at or after the initial dosing (including day 
1) of study drug to 28 days after the last dose of study drug. 
x
The post-treatment period is defined as the period after 28 days after last dose until the 
end of study. 
9.4.1
Adverse Events  
For analysis purpose, AEs will be categorized as pretreatment AEs, treatment-emergent 
adverse events (TEAEs), or post-treatment AEs: 
x
Pretreatment AE: any AE that started before initial dosing of study drug. 
x
TEAE: any AE that increased in severity or that was newly developed at or after the 
initial dosing of study drug to the end of the safety follow up period. 
x
Post-treatment AE: any AE that increased in severity or that was newly developed after 
28 days after the last dose of study drug. 
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.  
As an intermediate step for programming purposes, imputation rules for missing or partially 
missing AE start/end dates are defined below: 
x
If year of the AE start date is missing, then query site with no imputation. 
x
If year of the AE start date is not missing, but both day and month of the AE start date are 
missing  
o
If year of the AE start date = the year of the first dose date, impute the missing day 
and month of the AE start date using the day and month of the first dose date. If this 
leads to a date after the AE end date, then impute the missing day and month of the 
AE start date using the day and month of the AE end date. Note: 

If the AE ended before first dose date, then the AE will be classified as a pre-
treatment AE. If the AE ended after the first dose date, then there is not enough 
evidence to determine whether the AE is a TEAE or not, and to be conservative, 
the AE will be classified as a TEAE. 
o
If year of the AE start date ≠ the year of the first dose date, impute the missing day 
and month of the AE start date using 1 and Jan. Note:  

If the year is before the year of the first dose date, then by imputing the missing 
day and month of the AE start date January 1, TEAE status will be pre-
treatment.  

If the year is after the year of the first dose date, then by imputing the missing 
day and month of the AE start date January 1, TEAE status will be TEAE if AE 
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start date is on or before the last dose date +28 days; and will be post-treatment 
AE start date is after the last dose date+28 days. 
x
If month and year of the AE start date are not missing, but day of the AE start date is 
missing  
o
If the year of the AE start date = the year of the first dose date = the year of the AE 
end date, and the month of the AE start date = the month of the first dose date = the
month of the AE end date, then impute the missing day of AE start date using the 
smaller non-missing value of (day of the first dose, day of the AE end date). 
o
If (the year of the AE start date = the year of the first dose date, and the month of the 
AE start date = the month of the first dose date), and (the year of the AE start date < 
the year of the AE end date, or the month of the AE start date < the month of the AE 
end date), then impute the missing day of AE start date using the day of the first dose. 
o
Otherwise, impute the missing day of the AE start date as 1. 
x
Missing or partially missing AE stop date will not be imputed. 
An overview of the TEAE profile will be provided with number and percent of subjects 
including the following categories:  
x
Number of TEAEs (total number of TEAEs only) 
x
All TEAEs  
x
TEAEs by relationship 
x
TEAEs by maximum severity 
x
TEAEs leading to treatment discontinuation 
x
TEAEs leading to treatment interruption 
x
Serious TEAEs 
x
Related serious TEAEs 
x
TEAE leading to death  
Adverse events summary tables will be presented for TEAEs only and will include the 
following:   
x
All TEAEs  
x
TEAEs by relationship 
x
TEAEs by maximum severity  
x
TEAEs leading to treatment discontinuation  
x
TEAEs leading to treatment interruption 
x
Serious TEAEs 
x
Related serious TEAEs 
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x
TEAEs leading to death
Summaries will be presented by MedDRA system organ class (SOC) and preferred term (PT) 
using frequency counts and percentages (i.e., number and percentage of subjects with an 
event). When summarizing the number and percentages of subjects, subjects with multiple 
occurrences of the same adverse event or a continuing adverse event will be counted once, 
and only the maximum severity level will be presented in the severity summaries, and the 
worst/highest relationship level in the relationship summaries.   
Additional summary tables will be presented for TEAEs showing number and percentage of 
subjects 
x
Any TEAE by PT 
x
Respiratory TEAE 
x
TEAE with a frequency of ≥5% at the PT level in any treatment group by PT 
x
TEAE with a frequency of ≥5% at the PT level in any treatment group by SOC and PT 
In addition, a listing containing individual subject adverse event data for TEAEs leading to 
treatment discontinuation and treatment interruption, SAEs and all deaths will be provided 
separately, with a flag indicating the TEAE status for SAEs and deaths. 
9.4.2
Clinical Laboratory 
For the laboratory measurements, the raw values and change from baseline values of the 
continuous hematology and chemistry results will be summarized in SI units by treatment 
group at each scheduled time point. For hematology and chemistry, the number and 
percentage of subjects with abnormal low (<LLN) value and with abnormal high (>ULN) 
value at each scheduled time point will be summarized. 
The number and percentage of subjects with at least one potentially clinically significant 
(PCS) event for liver enzyme during the treatment-emergent period will be summarized. The 
PCS criteria are provided in Appendix F.
For all LFT results (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
serum alkaline phosphatase [ALP], Gamma-glutamyl transferase[GGT] and total bilirubin), 
the following analyses will be conducted: 
x
For each of the LFTs, mean values (and 95% confidence interval) will be plotted against 
visit, and box plot of LFT value/ULN will be plotted against visit.  
x
The incidence of PCS LFTs during the treatment-emergent period according to the 
baseline status will also be summarized by treatment group (only worsening of the shift 
from baseline will be presented).   
x
A listing of subjects with elevated LFT results during the treatment-emergent period will 
be presented. The listing will include all parameters of the LFT assessment at all visits. 
Results of urinalysis and the serum pregnancy test will be listed in individual subject data 
listings only. In addition, a listing containing individual subject hematology, chemistry, and 
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coagulation values outside the reference ranges will be provided. This listing will include 
data from scheduled and unscheduled time points. 
9.4.3
Vital Signs 
For the vital signs measurements, the raw values and change from baseline values will be 
summarized by treatment group at each scheduled time point: systolic and diastolic blood 
pressure (mm Hg)  
The number and percentage of subjects with at least one PCS vital signs event during the 
treatment-emergent period will be summarized. The PCS criteria are provided in Appendix   
F 
9.4.4
Pulse Oximetry 
For the on-treatment pulse oximetry measurements taken at each CPET before the start of 
any exercise , a summary of raw values and change from baseline values will be provided by 
treatment groups at each scheduled time point for the percent of oxygen saturation by pulse 
oximetry. In addition, the mean value at each visit will be plotted by treatment groups for the 
percent of oxygen saturation.  
9.4.5
Physical Examination 
PE findings, which are only collected at Screening in the database, will be presented as a data 
listing only. 
9.4.6
Ophthalmologic Examination 
Abnormal ophthalmologic examination findings will be presented as a data listing only. 
9.5
Narratives Listings 
Narratives listings will be provided for subjects with any of the following events that 
occurred by the study cutoff date: 
x
Death 
x
Serious TEAEs 
x
TEAEs leading to treatment discontinuation  
x
TEAEs leading to treatment interruption 
x
Pregnancy 
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10 INTERIM AND DMC ANALYSES 
10.1
Interim Analysis 
No interim analysis is planned. 
10.2
DMC Analysis 
No DMC analysis is planned 
 
 
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11 REFERENCES 
1
Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG. Pulmonary function between 
6 and 18 years of age. Pediatr Pulmonol. 1993; 15:75-88. 
2
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. 
3
Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4:1-9.
4
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. 
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12
APPENDICES 
Appendix A Schedule of Assessments 
Table 12-1Study VX15-809-112: Treatment Period and Safety Follow-up Visit 
Event/Assessment
Treatment Period
Early 
Termination 
of Treatmenta
Safety Follow-up
4 Weeks (± 7 Days)
After Last Dosea
Day 1
Week 12
(± 7 Days)
Week 24
(± 7 Days)
Clinic Visit
X
X
X
X
X
Randomization
X
CFQ-R, PHQ-8, and GAD-7
b
X
X
X
X
Height and weightc
X
X
X
X
X
Vital signsd
X
X
X
X
X
Spirometrye
X
X
X
X
Physical examination (PE)f
X
X
Ophthalmologic examination
Xg
Xg
Xg
Cardiopulmonary exercise 
test (CPET)h
X
X
X
X
Urine β-HCGi
X
X
X
X
X
Serum chemistryj
X
X
X
X
X
Hematologyj
X
X
X
X
X
                                                
a  
If the subject prematurely discontinues study drug, an Early Termination of Treatment (ETT) Visit should be scheduled 
as soon as possible after the subject decides to discontinue. If the ETT Visit occurs 3 weeks after the last dose of study drug 
or later, then the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. When the Safety Follow-up Visit is complete, the subject has completed the study. 
b 
All questionnaires must be completed before the start of any other assessments scheduled at that visit. The CFQ-R must 
be completed first, then the PHQ-8 and GAD-7. 
c  
During the Treatment Period and at the Safety Follow-up Visit, height will be collected only for subjects who were 21 
years of age or younger at the Screening Visit. Height and weight will be measured with shoes off. 
d 
Vital signs (systolic and diastolic blood pressure, oral temperature, pulse rate, and respiration rate) will be collected 
before study drug dosing and after the subject has been seated for at least 5 minutes. Blood pressure will be taken using a 
manual sphygmomanometer. 
e 
Spirometry will be assessed before CPET.  
f  
The physical examination includes an assessment of all body systems. Symptom-directed physical examinations will 
occur at any time during the study if triggered by AEs or if deemed necessary by the investigator. 
g  For all subjects <18 years of age at the Screening Visit, except for those who have had bilateral lens removal, an 
ophthalmologic examination will be conducted by a licensed ophthalmologist or optometrist at 1 of the following visits: the 
Week 24 Visit, the ETT Visit, or the Safety Follow-up Visit. 
h  CPET includes pulse oximetry. 
i  
Pregnancy tests will be performed for all female subjects of childbearing potential. A urine β–hCG test will be 
performed on Day 1 (before first dose of study drug) and every 4 weeks thereafter. When there is not a scheduled study visit, 
the pregnancy test will be conducted with a urine home pregnancy test kit provided by the study site. For tests performed at 
home, the site staff will telephone the subject to confirm the test results. 
j  
On Day 1, blood samples for chemistry and hematology tests will be collected before the first dose of study drug. At 
other scheduled visits, these samples may be collected at any time during the visit. 
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Table 12-1Study VX15-809-112: Treatment Period and Safety Follow-up Visit 
Event/Assessment
Treatment Period
Early 
Termination 
of Treatmenta
Safety Follow-up
4 Weeks (± 7 Days)
After Last Dosea
Day 1
Week 12
(± 7 Days)
Week 24
(± 7 Days)
Study drug dispensedk
X
X
Study drug dosing
LUM 400 mg/IVA 250 mg q12h or placebo q12h
Study drug count
X
X
X
Reminder of standard 
exercise recommendationsl
X
X
Activity and sleep tracking 
via actigraphy
Continuous from Day 1 through Week 24 Visit
Recording concomitant 
medications and 
treatments/procedures
Continuous from signing of ICF through Safety Follow-up Visit
Recording AEs
Continuous from signing of ICF through Safety Follow-up Visit
                                                
k  Study drug will be administered orally, 2 times a day, within 30 minutes of consumption of fat-containing food.. 
l
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Appendix B Precisions of Summary for Continuous Variables  
Continuous Variables  
Table 12-2 Precision of Special Summary Statistics for CF Studies 
Variables
Statistics
Decimal Places
CPET Related variables
Mean, LS mean, 95% CI
1
Percent Predicted FEV1
Mean, LS mean, 95% CI
1
CFQ-R
BMI
PHQ-8/GAD-7
Mean, LS mean, 95% CI
Mean, LS mean, 95% CI
Mean, 95% CI
1
1
1
Demographics
Mean, 95% CI
1
Actigraphy
Mean, 95% CI
1
The precision of the Safety Lab Data will follow the latest standard from the Biometrics 
Standardization Committee. 
The precision of the measurement in raw data for other continuous variables will be used to 
determine the number of decimal places to present in tables, figures, and derived listings. 
Minimum and maximum values will be reported with the same precision as the units of 
measure. The mean and median will be reported to 1 greater decimal place, and the SD and 
SE will be reported to 2 additional decimal places. 
Any values that require transformation to standard units (metric or International System [SI])
will be converted with the appropriate corresponding precision. 
 
 
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Appendix C Analysis Visit Window Mapping Rules for Safety and 
Pharmacodynamic and Actigraphy Measurements  
Table 12-3 Visit Window Mapping Rules for Safety and Pharmacodynamic and 
Actigraphy Measurements 
Assessments
Visit
Target Study Day
Visit Window 
(in study days)
x CPET related
Week 12
85
(1, 92]
x
Week 24
169
[93, 176]
x Spirometry
Safety follow up week 28
197
[177, 204]
x
x CFQ-R/PHQ-8/GAD-7
x
x Weight and Height
x
x Vital Signs
x
x Actigraphy*
x
x Labs – Liver Function Test
* Baseline actigraphy data will be the average of the corresponding actigraphy data 7 days 
prior to the Day 1 visit (Day -7 to Day -1). The same rule applies to actigraphy data collected 
at week 12 and week 24, where the average of the corresponding actigraphy data 7 days prior 
to the target day visit (target study Days 85 and 169 will be used for these two visits). Due to 
a window of ± 7 Days for each of these visits, the actual 7-day interval from which 
actigraphy data is used may vary from subject to subject.  
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Appendix D Coefficients for Hankinson and Wang Methods for Calculating 
Predicted Spirometry Parameters 
Percent predicted FEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a 
percentage. The predicted FEV1 (L) will be calculated using the Hankinson1 and Wang2
standards.  
The Hankinson standard will be applied to male subjects 18 years and older and female 
subjects 16 years and older; the Wang standard will be applied to male subjects 6 to 17 years 
and female subjects 6 to 15 years of age. During the study, the subjects who have a birthday 
that would move them from Wang to Hankinson will use the Wang standard before that 
birthday and the Hankinson standard at or after that birthday. 
Hankinson Normal Values (HNVs) will be calculated for FEV1, forced vital capacity (FVC), 
forced expiratory flow mid expiratory phase (FEF25-75%), and FEV1/FVC% using the 
Hankinson equation:  
Predicted lung function parameter = b0+b1 × age+b2 × age2+ b3 × height2
In the equation, height is given in centimeters, age is given in years, and the coefficients b0,
b1, b2, and b3 are determined based on subject’s sex, race, and age group as shown in Table 
12-4 
Wang Normal Values (WNVs) will be calculated for FEV1, FVC, FEF25-75%, and FEV1/FVC 
using the Wang equation:  
ln(Predicted lung function parameter) = D + βln (height)
Wang Normal Values (WNVs) will be calculated for FEV1, FVC, FEF25-75%, and FEV1/FVC 
using the Wang equation. In the equation, height is given in meters, and the coefficients α 
and β are determined based on subject’s sex, race, and age as shown in Table 12-5 and 
Table 12-6. 
If either height or age is missing, and the spirometry measurement is non-missing, the last 
non-missing value of height and age will be used in the calculation of predicted values. 
  
 
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Table 12-4 
HNVs Equation Coefficients by Sex, Race, and Age 
Source: Reference 1  
Parameter
Sex
Race
Age
(years)
bo
b1
b2
b3
HNVFEV1
Male
Caucasian
<20
-0.7453
-0.04106
0.004477
0.00014098
≥20
0.5536
-0.01303
-0.000172
0.00014098
African 
American
<20
-0.7048
-0.05711
0.004316
0.00013194
≥20
0.3411
-0.02309
0.00013194
Mexican 
American
<20
-0.8218
-0.04248
0.004291
0.00015104
≥20
0.6306
-0.02928
0.00015104
Female
Caucasian
<18
-0.8710
0.06537
0.00011496
≥18
0.4333
-0.00361
-0.000194
0.00011496
African 
American
<18
-0.9630
0.05799
0.00010846
≥18
0.3433
-0.01283
-0.000097
0.00010846
Mexican 
American
<18
-0.9641
0.06490
0.00012154
≥18
0.4529
-0.01178
-0.000113
0.00012154
HNVFVC
Male
Caucasian
<20
-0.2584
-0.20415
0.010133
0.00018642
≥20
-0.1933
0.00064
-0.000269
0.00018642
African 
American
<20
-0.4971
-0.15497
0.007701
0.00016643
≥20
-0.1517
-0.01821
0.00016643
Mexican 
American
<20
-0.7571
-0.09520
0.006619
0.00017823
≥20
0.2376
-0.00891
-0.000182
0.00017823
Female
Caucasian
<18
-1.2082
0.05916
0.00014815
≥18
-0.3560
0.01870
-0.000382
0.00014815
African 
American
<18
-0.6166
-0.04687
0.003602
0.00013606
≥18
-0.3039
0.00536
-0.000265
0.00013606
Mexican 
American
<18
-1.2507
0.07501
0.00014246
≥18
0.1210
0.00307
-0.000237
0.00014246
HNVFEF25-75%
Male
Caucasian
<20
-1.0863
0.13939
0.00010345
≥20
2.7006
-0.04995
0.00010345
African 
American
<20
-1.1627
0.12314
0.00010461
≥20
2.1477
-0.04238
0.00010461
Mexican 
American
<20
-1.3592
0.10529
0.00014473
≥20
1.7503
-0.05018
0.00014473
Female
Caucasian
<18
-2.5284
0.52490
-0.015309
0.00006982
≥18
2.3670
-0.01904
-0.000200
0.00006982
African 
American
<18
-2.5379
0.43755
-0.012154
0.00008572
≥18
2.0828
-0.03793
0.00008572
Mexican 
American
<18
-2.1825
0.42451
-0.012415
0.00009610
≥18
1.7456
-0.01195
-0.000291
0.00009610
HNVFEV1/FVC%
Male
Caucasian
88.066
-0.2066
African 
American
89.239
-0.1828
Mexican 
American
90.024
-0.2186
Female
Caucasian
90.809
-0.2125
African 
American
91.655
-0.2039
Mexican 
American
92.360
-0.2248
Page 48 of 129


Statistical Analysis Plan Methods 
Page 49 of 55
Protocol Number: VX15-809-112 
Vertex Pharmaceuticals Incorporated 
Table 12-5 
WNVs Equation Coefficients by Sex and Age in White Boys and Girls 
FEV1
FVC
FEF25-75%
FEV1/FVC
Sex
Age
α
β
α
β
α
β
α
β
Male
6
-0.109
2.252
-0.024
2.470
-0.078
-0.248
7
-0.104
2.270
-0.018
2.489
-0.086
-0.220
8
-0.089
2.257
0.005
2.443
0.264
1.505
-0.091
-0.199
9
-0.063
2.197
0.017
2.426
0.308
1.443
-0.086
-0.206
10
-0.057
2.212
0.030
2.407
0.290
1.557
-0.081
-0.209
11
-0.093
2.324
0.009
2.468
0.242
1.738
-0.101
-0.147
12
-0.161
2.512
-0.061
2.649
0.165
1.982
-0.101
-0.133
13
-0.292
2.843
-0.175
2.924
0.007
2.396
-0.116
-0.085
14
-0.329
2.983
-0.219
3.060
0.014
2.483
-0.106
-0.087
15
-0.141
2.709
-0.079
2.859
0.241
2.163
-0.060
-0.155
16
0.062
2.409
0.104
2.591
0.503
1.764
-0.045
-0.178
17
0.262
2.099
0.253
2.374
0.762
1.368
0.008
-0.272
Female
6
-0.109
1.949
-0.013
2.007
-0.097
-0.055
7
-0.144
2.243
-0.062
2.385
-0.084
-0.132
8
-0.137
2.239
-0.055
2.381
0.247
1.668
-0.079
-0.152
9
-0.123
2.222
-0.039
2.351
0.254
1.710
-0.084
-0.128
10
-0.161
2.364
-0.068
2.458
0.195
1.933
-0.092
-0.097
11
-0.223
2.558
-0.120
2.617
0.161
2.091
-0.102
-0.061
12
-0.264
2.709
-0.174
2.776
0.185
2.120
-0.090
-0.067
13
-0.153
2.535
-0.061
2.576
0.294
1.976
-0.093
-0.040
14
0.046
2.178
0.139
2.208
0.450
1.711
-0.096
-0.026
15
0.148
2.008
0.210
2.099
0.581
1.486
-0.062
-0.093
Source: Reference 1
Page 49 of 129


Statistical Analysis Plan Methods 
Page 50 of 55
Protocol Number: VX15-809-112 
Vertex Pharmaceuticals Incorporated 
Table 12-6 
WNVs Equation Coefficients by Sex and Age in Black Boys and Girls 
FEV1
FVC
FEF25-75%
FEV1/FVC
Sex
Age
α
β
α
β
α
β
α
β
Male
6
-0.166
1.723
-0.088
1.961
-0.091
-0.152
7
-0.122
1.846
-0.040
2.040
-0.091
-0.153
8
-0.225
2.271
-0.094
2.323
0.097
1.544
-0.118
-0.104
9
-0.142
2.059
-0.074
2.308
0.255
1.248
-0.079
-0.218
10
-0.157
2.117
-0.110
2.417
0.230
1.428
-0.047
-0.303
11
-0.176
2.166
-0.138
2.453
0.256
1.438
-0.048
-0.263
12
-0.307
2.548
-0.224
2.710
0.085
1.936
-0.084
-0.162
13
-0.486
2.962
-0.342
2.975
-0.121
2.476
-0.141
-0.018
14
-0.472
3.010
-0.337
3.035
-0.115
2.536
-0.123
-0.050
15
-0.318
2.789
-0.226
2.889
0.170
2.120
-0.070
-0.140
16
0.074
2.140
0.058
2.425
0.663
1.299
0.018
-0.289
17
0.053
2.223
0.148
2.310
0.505
1.618
-0.095
-0.087
Female
6
-0.288
2.182
-0.172
2.117
-0.109
0.059
7
-0.250
2.158
-0.135
2.132
-0.104
-0.030
8
-0.276
2.295
-0.176
2.362
-0.283
2.990
-0.103
-0.066
9
-0.294
2.330
-0.200
2.452
0.025
2.062
-0.097
-0.104
10
-0.344
2.507
-0.230
2.571
0.051
2.028
-0.120
-0.043
11
-0.308
2.460
-0.204
2.526
0.078
2.006
-0.089
-0.105
12
-0.219
2.312
-0.107
2.342
0.225
1.804
-0.115
-0.021
13
-0.117
2.196
-0.042
2.294
0.418
1.504
-0.051
-0.148
14
0.041
1.920
0.105
2.021
0.574
1.257
-0.063
-0.103
15
0.203
1.662
0.253
1.787
0.599
1.281
-0.043
-0.139
Source: Reference 2 (Tables 4 and 5)
Page 50 of 129




Statistical Analysis Plan Methods 
Page 52 of 55
Protocol Number: VX15-809-112 
Vertex Pharmaceuticals Incorporated 
Appendix F Criteria for Potentially Clinically Significant Events 
Table 12-7 
Criteria for Potentially Clinically Significant Laboratory Tests 
Parameter
PCS
Comments
Clinical Chemistry
ALT
≤3xULN*(Not a PCS criteria)
>3x - ≤ 5xULN
>5x - ≤ 8xULN
>3xULN
>5xULN
>8xULN
FDA DILI Guidance Jul 2009. 
AST
≤3xULN*(Not a PCS criteria)
>3x - ≤ 5xULN
>5x - ≤ 8xULN
>3xULN
>5xULN
>8xULN
FDA DILI Guidance Jul 2009.
ALT or AST
ALT>3xULN or AST>3xULN
Vertex LFT working group 2014
Alkaline 
Phosphatase
>1.5xULN
FDA DILI Guidance Jul 2009. 
Total Bilirubin
>1.5x - ≤2xULN
>2xULN
FDA DILI Guidance Jul 2009.
ALT and Total 
Bilirubin
ALT>3xULN and TBILI>2xULN
FDA DILI Guidance Jul 2009. 
To be counted within a same treatment phase, 
whatever the interval between measurement.
AST and Total 
Bilirubin
AST>3xULN and TBILI>2xULN
FDA DILI Guidance Jul 2009. 
To be counted within a same treatment phase, 
whatever the interval between measurement.
(ALT or AST) and 
Total Bilirubin
(ALT>3xULN or AST>3xULN) and TBILI>2×ULN Vertex LFT working group 2014
Page 52 of 129


Statistical Analysis Plan Methods 
Page 53 of 55
Protocol Number: VX15-809-112 
Vertex Pharmaceuticals Incorporated 
 
 
Table 12-8 
Criteria for Potentially Clinically Significant Vital Signs 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT VITAL SIGNS
Parameter
PCS
Comments
HR
≤50 bpm and decrease from baseline ≥20 bpm
≥120 bpm and increase from baseline≥20 bpm
To be applied for all positions (including 
missing) except STANDING.
SBP
>140 mmHg at least once
>160 mmHg at least once
>140 mmHg at least twice
>10 mmHg increase from Baseline at least once
>20 mmHg increase from Baseline at least once
To be applied for all positions (including 
missing) except STANDING.
DBP
>90 mmHg at least once
>100 mmHg at least once 
>90 mmHg at least twice
>5 mmHg increase from Baseline at least once
>10 mmHg increase from Baseline at least once
To be applied for all positions (including 
missing) except STANDING.
Page 53 of 129


Statistical Analysis Plan Methods 
Page 54 of 55
Protocol Number: VX15-809-112 
Vertex Pharmaceuticals Incorporated 
                                                                                                                                                      
Appendix G Important Protocol Deviation Programming Rules (Based on the 
Clinical Database) 
Important protocol deviations before first dose 
1.
Individual screening assessment(s) that did not meet eligibility criteria, excluding the exceptions that 
are permitted per protocol, were repeated 
2.
Screening visit performed outside of the -28 to -1 day window 
3.
Subject randomized and screening ophthalmologic examination greater than 3 months prior to 
Screening Visit 
4.
Height not collected for subjects who were 21 years of age or younger at the Screening Visit. 
Important protocol deviations during treatment period 
5.
ETT visit was less than 3 weeks after the last dose of study drug but no Safety Follow-up Visit was 
performed. 
6.
After subject study completion/early discontinuation, prior study visits not done 
7.
Subject who prematurely discontinues study drug treatment did not complete the ETT visit 
8.
CPET not performed per protocol schedule 
9.
Prohibited medication taken during study 
10. Initial dose of study drug not administered on Day 1. 
 
Page 54 of 129