Conditions: Cystic Fibrosis
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 20
Healthy volunteers: no

Brief summary:
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter, crossover study that will evaluate the efficacy of LUM/IVA in subjects with CF 12 years of age and older who have at least one A455E mutation.

Detailed description:

Arms:
arm 1: LUM/IVA in Treatment Period 1; washout; placebo in Treatment Period 2 arm 2: Placebo in Treatment Period 1; washout; LUM/IVA in Treatment Period 2

Interventions: intervention 1: LUM/IVA intervention 2: Placebo
Intervention descriptions: intervention 1: LUM 400 mg/IVA 250 mg every 12 hours (q12h) intervention 2: No Active Drug

Protocol document:
Prot_000.pdf: 
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Vertex Pharmaceuticals Incorporated 
1
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED
Clinical Study Protocol 
A Phase 2, Randomized, Double-Blind, 
Placebo-Controlled, Crossover Study to 
Evaluate the Efficacy of Lumacaftor/Ivacaftor 
Combination Therapy in Subjects With Cystic 
Fibrosis Who Have an A455E-CFTR Mutation
Vertex Study Number: VX15-809-111
EudraCT Number: 2016-001585-29 
Date of Protocol: 17 February 2017 (Version 2.0) 
Replaces Version 1.0, dated 25 April 2016 
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations. Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 




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2
PROTOCOL SYNOPSIS 
Title A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to 
Evaluate the Efficacy of Lumacaftor/Ivacaftor Combination Therapy in Subjects 
With Cystic Fibrosis Who Have an A455E-CFTR Mutation
Brief Title Lumacaftor/Ivacaftor Combination Therapy in Subjects With CF Who Have an 
A455E-CFTR Mutation
Clinical Phase and 
Clinical Study Type 
Phase 2, double-blind, placebo-controlled, crossover
Objectives Primary Objective
To evaluate the efficacy of lumacaftor/ivacaftor combination therapy (LUM/IVA) in 
subjects with cystic fibrosis (CF) 12 years of age and older who have at least one 
A455E mutation. 
.
Endpoints Primary Endpoint
Absolute change from baseline in percent predicted forced expiratory volume in 
1 second (ppFEV1) through 8 weeks of treatment. 
 
Number of Subjects Approximately 20 subjects.
Study Population Male and female subjects 12 years of age and older with CF, with an A455E
mutation on at least 1 CFTR allele, and with forced expiratory volume in 1 second 
(FEV1) ≥30% of predicted and ≤90% of predicted. 
Investigational Drug Active substance: LUM/IVA fixed-dose combination
Activity: CFTR corrector and potentiator (chloride ion secretion)
Strength and route of administration: 200-mg lumacaftor/125-mg ivacaftor 
(200/125 mg) film-coated tablets for oral administration
Dosage: LUM 400 mg/IVA 250 mg every 12 hours (q12h)
Study Duration The total study duration for each subject will be approximately 32 weeks, including 
the Screening and Follow-up periods.


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Study Design This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter, 
crossover study. The crossover design includes two 8-week treatment periods 
separated by an 8-week (± 7 days) washout period. Subjects will be randomized 
(1:1) to 1 of 2 treatment sequences: LUM/IVA followed by placebo or placebo 
followed by LUM/IVA.
Assessments Efficacy: Spirometry (excluding assessments on Day 2 and the day after the 
Week 16 Visit [if applicable]); 
Safety: Adverse events (AEs), clinical laboratory assessments (liver function tests), 
ophthalmologic examinations (for subjects less than 18 years of age), vital signs, and 
spirometry (on Day 2 and the day after the Week 16 Visit only, for subjects with 
FEV1 <40% of predicted)
Statistical Analyses Sample Size: No formal sample size calculation is to be conducted for this study. 
The planned sample size of approximately 20 subjects is based on the number of 
subjects expected to be available for participation.
Analysis Sets: The Full Analysis Set (FAS) is defined as all randomized subjects 
who have received at least 1 dose of study drug. The FAS will be used for efficacy 
analyses. The Safety Set is defined as all subjects who received at least 1 dose of 
study drug. The Safety Set will be used for safety analyses.
Efficacy Analysis: The analysis of the absolute change from baseline in ppFEV1
through 8 weeks of study drug treatment will be based on a mixed-effects model for 
repeated measures utilizing the FAS. The estimated mean treatment difference 
overall, a 95% CI, and a 2-sided P value will be provided. The estimated mean 
treatment difference at each visit along with the corresponding 95% CI and P value 
will also be presented. Raw values and changes from baseline will be summarized 
by treatment group using descriptive statistics. Paired t-tests for the difference 
between treatments for each subject, as well as Wilcoxon signed-rank tests, may be 
provided.
Safety Analysis: The incidence of treatment-emergent AEs will be summarized in 
contingency tables (n, percentage) by treatment. For other safety parameters 
(e.g., vital signs), the raw values and changes from baseline will be summarized by 
treatment. Additionally, all safety data will be presented in subject data listings.


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3
SCHEDULE OF ASSESSMENTS 
Schedules of Assessments are shown in Table 3-1, Table 3-2, and Table 3-3.
Table 3-1 
Study VX15-809-111: Screening Period Assessments 
Assessment
Screening Period
(Day -28 through Day -1)
Informed consent and assent (when applicable)
X
Review inclusion/exclusion criteria
X
Demographics
X
Medical history
X
CFTR genotypinga
If deemed necessary by investigator
Ophthalmological history
X
Prior and concomitant medications
X
Ophthalmologic examinationb
X
Complete physical examination
X
Weight, heightc
X
Vital signs and pulse oximetryd
X
Spirometrye
X
FSHf
X
Serum pregnancy test (females of childbearing potential)g
X
Hematology 
X
Serum chemistry
X
AEs and SAEs
Continuous from signing of the ICF and 
Assent Form (where applicable) through 
the Follow-up Visit
a  
It is expected that most subjects will have documentation of CFTR genotype in their medical records. If 
documentation of CFTR genotype is not available, or if confirmation of CFTR genotype is deemed 
necessary by the investigator, CFTR genotyping will be performed during the Screening Period. 
b 
Ophthalmologic examination is required for subjects who are less than 18 years of age at the Screening 
Visit. If there is documentation of an ophthalmologic examination that met protocol criteria and was 
conducted within 3 months before the Screening Visit, the subject is not required to have a repeat 
ophthalmologic examination during Screening.  
c 
Weight and height will be measured with shoes off. 
d 
Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) and pulse oximetry will be 
collected after the subject has been at rest (seated or supine) for at least 5 minutes. Blood pressure will be 
measured by sphygmomanometer. 
e 
At Screening, spirometry may be performed pre- or post-bronchodilator.  
f 
FSH will be measured for any suspected postmenopausal female with at least 12 months of continuous 
spontaneous amenorrhea. Serum FSH levels must be ≥40 mIU/mL to be considered postmenopausal. 
g 
See Section 11.6.7.1 for definition of childbearing potential. 


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Table 3-2 
Study VX15-809-111: Treatment Period Assessments 
Treatment Period 1
Washout 
Period 
(No Visit)
Treatment Period 2
Early 
Termina-
tion of 
Treat-
ment 
(ETT)
Event/Assessment 
Day 1
Day 2a
Week 4
(± 4 days)
Week 8
(± 7 days)
8 weeks
(± 7 days)
Week 16
(± 4 days)
Day after 
Week 16
Visita
Week 20
(± 4 days)
Week 24
(± 7 days)
Review inclusion/
exclusion criteriab
X
Randomization
X
Vital signsg
X
X
X
X
X
X
X
X
X
Pulse oximetry
X
X
Spirometryh
X
X
X
X
X
X
X
X
X
Urine pregnancy 
testi
X
X
X
X
X
X
X
a 
These visits will be conducted for subjects whose FEV1 at Screening is <40% of predicted. 
b 
Confirmation of subject eligibility will occur before randomization. 
  
  
  
  
g  
Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be collected after the subject has been at rest (seated or supine) for at least 5 minutes. 
Blood pressure will be measured by sphygmomanometer. 
h 
Spirometry will be performed pre-bronchodilator and must be performed before study drug dosing. 
i
Pregnancy tests will be performed for all female subjects of childbearing potential. The urine β-hCG tests on Day 1 and Week 16 must be negative before the study drug is 
administered. 


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Table 3-2 
Study VX15-809-111: Treatment Period Assessments 
Treatment Period 1
Washout 
Period 
(No Visit)
Treatment Period 2
Early 
Termina-
tion of 
Treat-
ment 
(ETT)
Event/Assessment 
Day 1
Day 2a
Week 4
(± 4 days)
Week 8
(± 7 days)
8 weeks
(± 7 days)
Week 16
(± 4 days)
Day after 
Week 16
Visita
Week 20
(± 4 days)
Week 24
(± 7 days)
Liver function tests 
(LFTs)j
X
X
X
X
X
Ophthalmologic 
examinationk
Xl
Xl
Meal(s) or snack(s) 
at siten
X
X
X
X
X
X
X
X
Study drug dosing
Day 1 through Week 8
(Last dose of study drug will be administered the 
day before the Week 8 Visit)
No study 
drug
Week 16 through Week 24
(Last dose of study drug will be administered the 
day before the Week 24 Visit)
Observation 4 h
after dosingo
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
Concomitant 
treatments and 
procedures
X
X
X
X
X
X
X
X
X
AEs and SAEs
Continuous from signing of the ICF and Assent Form (where applicable) through the Follow-up Visit 
j  
ALT, AST, GGT, alkaline phosphatase, and bilirubin. 
k  
For subjects who were less than 18 years of age at the Screening Visit. 
l 
Ophthalmologic examination will be performed at the Week 24 Visit, the Early Termination of Treatment Visit, or the Follow-up Visit. This examination is not required if the 
subject received the study drug for a total of less than 4 weeks. 
n 
Fat-containing food such as a standard "CF" high-fat, high-calorie meal or snack will be provided to subjects at the site after all predose assessments have occurred. 
o  
Observation 4 h after dosing will be performed for subjects whose FEV1 at Screening is <40% of predicted. 


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Table 3-3 
Study VX15-809-111: Follow-up Visit Assessments 
Event/Assessment
Follow-up
4 weeks (± 7 days) after last dose of study drug
Vital signsa
X
Spirometryd
X
Serum pregnancy teste
X
LFTsf
X
Ophthalmologic examinationg,h
X
Concomitant medications
X
Concomitant treatments and procedures
X
AEs and SAEs
Continuous from signing of the ICF and Assent Form 
(where applicable) through the Follow-up Visit
a  
Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be collected after the 
subject has been at rest (seated or supine) for at least 5 minutes. Blood pressure will be measured by 
sphygmomanometer. 
  
  
d 
Spirometry will be performed pre-bronchodilator. 
e 
Pregnancy tests will be performed for all female subjects of childbearing potential.  
f  
ALT, AST, GGT, alkaline phosphatase, and bilirubin. 
g  
For subjects who were less than 18 years of age at the Screening Visit. 
h  
Ophthalmologic examination will be performed at the Week 24 Visit, the Early Termination of Treatment 
Visit, or the Follow-up Visit. This examination is not required if the subject received study drug for a total 
of less than 4 weeks. 


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4
TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
 
2 
Protocol Synopsis ............................................................................................................. 3 
3 
Schedule of Assessments.................................................................................................. 5 
4 
Table of Contents ............................................................................................................. 9 
List of Tables...................................................................................................................... 13 
List of Figures .................................................................................................................... 13 
5 
Introduction.................................................................................................................... 14 
5.1 
Cystic Fibrosis and Current Treatments ................................................................... 14 
5.2 
Rationale for Study ................................................................................................... 14 
6 
Study Objectives ............................................................................................................ 15 
6.1 
Primary Objective ..................................................................................................... 15 
 
 
7 
Study Endpoints ............................................................................................................. 16 
7.1 
Primary Endpoint ...................................................................................................... 16 
 
 
8 
Study Design ................................................................................................................... 16 
8.1 
Overview of Study Design ....................................................................................... 16 
8.1.1 
Screening .......................................................................................................... 17 
8.1.1.1 
Repetition of Screening Assessments ........................................................ 17 
8.1.1.2 
Rescreening ................................................................................................ 18 
8.1.1.3 
Extension of the Screening Period Window .............................................. 18 
8.1.2 
Treatment Period 1 ........................................................................................... 18 
8.1.3 
Washout Period................................................................................................. 18 
8.1.4 
Treatment Period 2 ........................................................................................... 18 
8.1.5 
Follow-up.......................................................................................................... 19 
8.1.6 
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 ........................................................................ 19 
8.2.2.1 
Dose of LUM and IVA .............................................................................. 19 
8.2.2.2 
Duration of Dosing ..................................................................................... 19 
8.2.2.3 
Washout Period .......................................................................................... 20 
8.2.3 
Rationale for Study Assessments ..................................................................... 20 
9 
Study Population ............................................................................................................ 21 
9.1 
Inclusion Criteria ...................................................................................................... 21 
9.2 
Exclusion Criteria ..................................................................................................... 21 
9.3 
Prior and Concomitant Medications ......................................................................... 22 
9.3.1 
Maintenance of Stable Medication Regimen for CF ........................................ 23 
9.3.2 
Prohibited Medications ..................................................................................... 23 
9.4 
Removal of Subjects from Study Drug Treatment ................................................... 24 
9.5 
Replacement of Subjects .......................................................................................... 24 


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10 Study Drug Administration and Management ........................................................... 24 
10.1 Method of Assigning Subjects to Treatment Groups ............................................... 24 
10.2 Packaging and Labeling ........................................................................................... 25 
10.3 Study Drug Supply, Storage, and Handling ............................................................. 25 
10.4 Preparation and Dispensing ...................................................................................... 25 
10.5 Dosage and Administration ...................................................................................... 25 
10.6 Study Drug Interruption ........................................................................................... 26 
10.7 Drug Accountability ................................................................................................. 26 
10.8 Disposal, Return, or Retention of Unused Drug ....................................................... 26 
10.9 Compliance ............................................................................................................... 26 
10.10 Blinding and Unblinding .......................................................................................... 27 
10.10.1 Blinding ............................................................................................................ 27 
10.10.2 Unblinding ........................................................................................................ 27 
11 Assessments .................................................................................................................... 28 
11.1 Timing of Assessments ............................................................................................. 28 
11.2 Subject Characteristics and Medical History ........................................................... 28 
11.3 Efficacy ..................................................................................................................... 28 
11.3.1 
Spirometry ........................................................................................................ 28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.6 Safety ........................................................................................................................ 31 
11.6.1 
Adverse Events ................................................................................................. 31 
11.6.2 
Clinical Laboratory Assessments ..................................................................... 32 
11.6.3 
Elevation of Liver Function Test Parameters ................................................... 33 
11.6.4 
Physical Examinations and Vital Signs ............................................................ 34 
11.6.5 
Ophthalmologic Examination ........................................................................... 34 
11.6.6 
Ophthalmologic History ................................................................................... 35 
11.6.7 
Contraception and Pregnancy ........................................................................... 35 
11.6.7.1 Contraception ............................................................................................. 35 
11.6.7.2 Pregnancy ................................................................................................... 37 
11.6.8 
Pulse Oximetry ................................................................................................. 37 
11.6.9 
Spirometry ........................................................................................................ 37 
12 Statistical and Analytical Plans .................................................................................... 37 
12.1 Sample Size and Power ............................................................................................ 38 
12.2 Analysis Sets ............................................................................................................ 38 
12.3 Statistical Analysis ................................................................................................... 38 
12.3.1 
General Considerations ..................................................................................... 38 
12.3.2 
Background Characteristics .............................................................................. 39 


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12.3.2.1 Subject Disposition .................................................................................... 39 
12.3.2.2 Demographics and Baseline Characteristics .............................................. 39 
12.3.2.3 Prior and Concomitant Medications........................................................... 39 
12.3.2.4 Study Drug Exposure and Compliance ...................................................... 39 
12.3.3 
Efficacy Analysis .............................................................................................. 40 
12.3.3.1 Change from Baseline in ppFEV1 ............................................................. 40 
 
 
 
 
 
 
 
 
 
 
 
 
12.3.5 
Safety Analysis ................................................................................................. 41 
12.3.5.1 Adverse Events........................................................................................... 41 
12.3.5.2 Clinical Laboratory Assessments ............................................................... 42 
12.3.5.3 Vital Signs .................................................................................................. 42 
12.3.5.4 Physical Examination ................................................................................. 42 
12.3.6 
Interim Analysis ............................................................................................... 42 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ..................... 42 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting .................................................................................................................. 42 
13.1.1 
Adverse Events ................................................................................................. 42 
13.1.1.1 Definition of an Adverse Event.................................................................. 42 
13.1.1.2 Clinically Significant Assessments ............................................................ 42 
13.1.1.3 Documentation of Adverse Events............................................................. 43 
13.1.1.4 Adverse Event Severity .............................................................................. 44 
13.1.1.5 Adverse Event Causality ............................................................................ 44 
13.1.1.6 Study Drug Action Taken .......................................................................... 44 
13.1.1.7 Adverse Event Outcome ............................................................................ 45 
13.1.1.8 Treatment Given......................................................................................... 45 
13.1.2 
Serious Adverse Events .................................................................................... 45 
13.1.2.1 Definition of a Serious Adverse Event....................................................... 45 
13.1.2.2 Documentation of Serious Adverse Events................................................ 46 
13.1.2.3 Reporting Serious Adverse Events............................................................. 47 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ................................ 47 
13.2 Administrative Requirements ................................................................................... 47 
13.2.1 
Ethical Considerations ...................................................................................... 47 
13.2.2 
Subject Information and Informed Consent ..................................................... 47 
13.2.3 
Investigator Compliance ................................................................................... 48 
13.2.4 
Access to Records ............................................................................................. 48 
13.2.5 
Subject Privacy ................................................................................................. 48 
13.2.6 
Record Retention .............................................................................................. 48 
13.2.7 
Study Termination ............................................................................................ 48 
13.3 Data Quality Assurance ............................................................................................ 49 
13.4 Monitoring ................................................................................................................ 49 


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13.5 Electronic Data Capture ........................................................................................... 49 
 
 
 
 
 
14 References ....................................................................................................................... 51 
15 Protocol Signature Pages .............................................................................................. 54 
15.1 Sponsor Signature Page ............................................................................................ 54 
15.2 Investigator Signature Page ...................................................................................... 55 


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List of Tables 
Table 3-1 
Study VX15-809-111: Screening Period Assessments ..................................... 5 
Table 3-2 
Study VX15-809-111: Treatment Period Assessments .................................... 6 
Table 3-3 
Study VX15-809-111: Follow-up Visit Assessments ....................................... 8 
Table 9-1 
Study Restrictions ........................................................................................... 23 
Table 10-1 
Study Drug ...................................................................................................... 25 
Table 11-1 
Safety Laboratory Test Panels ........................................................................ 32 
Table 12-1 
Difference Detectable Under Various Scenarios of Power, Alpha, and N ..... 38 
Table 13-1 
Grading of AE Severity .................................................................................. 44 
Table 13-2 
Classifications for AE Causality ..................................................................... 44 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE ............ 45 
Table 13-4 
Classifications for Outcome of an AE ............................................................ 45 
List of Figures 
Figure 8-1 
Study Design ................................................................................................... 17 


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5
INTRODUCTION 
5.1
Cystic Fibrosis and Current Treatments 
Cystic fibrosis (CF) is an autosomal recessive disease with serious, chronically debilitating 
morbidities and high premature mortality and at present, there is no cure. CF affects an 
estimated 70,000 children and adults worldwide1 and is the most common fatal genetic 
disease in persons of European descent.2 Based on the size of the population, CF qualifies as 
an orphan disease.3,4 Despite progress in the treatment of CF with antibiotics and mucolytics, 
the predicted median age of survival for a person with CF is approximately 40 years.5,6,7
CF is caused by reduced quantity and/or function of the cystic fibrosis transmembrane 
conductance regulator (CFTR) protein due to mutations in the CFTR gene. The CFTR protein 
is an epithelial chloride channel that aids in regulating salt and water absorption and secretion 
and pH balance in multiple organs, including the lungs, pancreas and other gastrointestinal 
organs, and sweat glands.2 In people with CF, decreased CFTR chloride transport results in 
multisystem pathology. Although the disease affects multiple organs, progressive loss of lung 
function is the leading cause of mortality.8
More than 2000 mutations in the CFTR gene have been identified.9 Based on the 
understanding of the molecular defects caused by CFTR mutations, 2 complementary 
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 a CFTR corrector, and ivacaftor (IVA) is a CFTR potentiator. 
Lumacaftor/ivacaftor combination therapy (LUM/IVA) is approved in the US for the 
treatment of CF in patients 6 years of age and older who are homozygous for the F508del
mutation, and in the EU, Canada, Australia, Switzerland, and Israel for the treatment of CF in 
patients 12 years of age and older who are homozygous for the F508del mutation, the most 
common mutation of the CFTR gene. Further information about LUM/IVA can be found in 
the Package Insert and Summary of Product Characteristics.10,11
5.2
Rationale for Study 
The A455E-CFTR mutation is reported to occur in less than 0.1% of patients with CF 
worldwide,12 but large regional differences in prevalence exist. In The Netherlands, it is the 
second most prevalent mutation, occurring in 3.6% of all patients with CF.13 An especially 
high prevalence has been reported in the Southeast and Southwest regions of The 
Netherlands.14 Although it was initially reported that the A455E mutation is associated with 
mild lung disease15, current clinical experience in The Netherlands shows marked differences 


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in clinical disease severity, ranging from relatively mild to severe loss of lung function at 
young adulthood.  
The A455E mutation results in a severe reduction of mature CFTR protein at the cell surface. 
In recent research, it was noted that when both F508del-CFTR and 264del-CFTR were 
transfected into the same cells, the expression of mature F508del-CFTR protein was 
increased. Similarly, when both A455E-CFTR and 264del-CFTR were transfected into the 
same cells, the expression of mature A455E-CFTR protein was increased. Furthermore, 
compounds known to be able to rescue F508del-CFTR were also able to rescue 
A455E-CFTR in vitro. This suggests that A455E-CFTR could be rescued by the same 
strategies as F508del-CFTR. These findings suggested that A455E might be a suitable 
candidate for LUM/IVA treatment.16
6
STUDY OBJECTIVES 
6.1
Primary Objective 
To evaluate the efficacy of LUM/IVA in subjects with CF 12 years of age and older who 
have at least one A455E mutation.  


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. 
7
STUDY ENDPOINTS 
7.1
Primary Endpoint 
Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) through 8 weeks of treatment.  
 
  
8
STUDY DESIGN 
8.1
Overview of Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter, crossover study 
(Figure 8-1). The crossover design includes two 8-week treatment periods separated by an 
8-week (± 7 days) washout period. There will be 7 to 9 study visits, not including the 
Screening Period. The total study duration for each subject will be approximately 32 weeks, 
including the Screening and Follow-up periods.  
Subjects will be randomized 1:1 to receive 1 of 2 treatment sequences: 
x
Sequence 1: LUM/IVA in Treatment Period 1; washout; placebo in Treatment Period 2 
x
Sequence 2: placebo in Treatment Period 1; washout; LUM/IVA in Treatment Period 2 
It is recommended that subjects maintain a stable CF medication regimen, as discussed in 
Section 9.3.1.




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If repeat values of the individual assessment(s) are within the eligibility criteria and 
completed within the screening window, then the subject is eligible for the study. 
8.1.1.2
Rescreening 
Subjects may be rescreened only with the approval of the medical monitor. If a subject is 
rescreened, all screening assessments will be repeated except for CFTR genotyping, 
follicle-stimulating hormone (FSH) level (if serum FSH level was ≥40 mIU/mL during prior 
screening), sweat chloride, rectal biopsy, and ophthalmologic examination (if performed 
within the last 3 months). A subject may be rescreened only once. If a subject is rescreened, 
the screening window will begin once the first rescreening assessment has been initiated. 
8.1.1.3
Extension of the Screening Period Window 
A subject may have the Screening Period window extended by 1 week for the following 
reasons: 
x
Repetition of the Screening Period assessments (Section 8.1.1.1)
x
Additional time to schedule and conduct the ophthalmologic examination 
(Section 11.6.5)
8.1.2
Treatment Period 1 
Study visits and assessments during Treatment Period 1 are listed in Table 3-2. Subjects will 
be outpatients during Treatment Period 1. All visits should occur within the windows 
specified. Subjects will be randomized to 1 of 2 sequences, as shown in Section 8.1.
The first dose of study drug will be administered on Day 1. Dosing details are given in 
Section 10.5. For subjects who are on a stable regimen of inhaled cycling antibiotics, the 
timing of the Day 1 Visit is described in Section 9.3.1.
The last dose of study drug in Treatment Period 1 will be administered the day before the 
Week 8 Visit. 
Subjects who prematurely discontinue study drug treatment will be asked to come to the 
study site for an Early Termination of Treatment (ETT) Visit and a Follow-up Visit as 
described in Section 8.1.6.
8.1.3
Washout Period 
Subjects will have a Washout Period lasting 8 weeks (± 7 days). No visits are scheduled 
during the Washout Period. 
8.1.4
Treatment Period 2 
Study visits and assessments during Treatment Period 2 are listed in Table 3-2. Subjects will 
be outpatients during Treatment Period 2. All visits should occur within the windows 
specified.  
In order to participate in Treatment Period 2, subjects must not have an acute upper or lower 
respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) 
for pulmonary disease within 4 weeks before the Week 16 Visit (first dose of study drug in 
Treatment Period 2) and must not have had a non-CF-related illness within 2 weeks before 


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the Week 16 Visit. “Illness” is defined as an acute (serious or nonserious) condition 
(e.g., gastroenteritis). If a subject does not meet these criteria, then the continuation of the 
subject into Treatment Period 2 will be discussed with the medical monitor. 
The first dose of study drug in Treatment Period 2 will be administered at the Week 16 Visit. 
Dosing details are given in Section 10.5. For subjects who are on a stable regimen of inhaled 
cycling antibiotics, the timing of the Week 16 Visit is described in Section 9.3.1.
The last dose of study drug in Treatment Period 2 will be administered the day before the 
Week 24 Visit. 
Subjects who prematurely discontinue study drug treatment will be asked to come to the 
study site for an ETT Visit and a Follow-up Visit as described in Section 8.1.6.
8.1.5
Follow-up 
Subjects will have a Follow-up Visit 4 weeks after the last study drug dose. Follow-up Visit 
assessments are listed in Table 3-3.
8.1.6
Early Termination of Treatment 
Subjects who prematurely discontinue study drug treatment will be asked to come to the 
study site for an ETT Visit as soon as possible after stopping study drug and to complete the 
Follow-up Visit 4 weeks after the last dose of study drug. The assessments performed at the 
ETT Visit are listed in Table 3-2, and the assessments performed at the Follow-up Visit are 
listed in Table 3-3.
8.2
Rationale for Study Design and Study Drug Regimens 
8.2.1
Study Design 
A crossover design with a 1:1 randomization to the 2 treatment sequences will enable 
within-subject comparison of the effects of placebo and LUM/IVA. The design allows a 
comparison between placebo and LUM/IVA in this study with a limited population of 
potential subjects. The use of placebo is necessary in order to provide a robust assessment.  
8.2.2
Study Drug Dose and Duration 
8.2.2.1
Dose of LUM and IVA 
The LUM 400 mg q12h/IVA 250 mg q12h dose regimen has been approved in the US, EU,
Canada, Australia, Switzerland, and Israel for the treatment of CF in patients 12 years of age 
and older who are homozygous for the F508del mutation.10,11  
8.2.2.2
Duration of Dosing 
The 8-week duration of dosing in each Treatment Period was chosen based on results of the 
pivotal, placebo-controlled, Phase 3 studies VX12-809-103 and VX12-809-104, in which the 
effect of LUM/IVA therapy was assessed in patients with CF homozygous for F508del.
These studies showed a clear improvement of ppFEV1 after 8 weeks of treatment.19,20


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8.2.2.3
Washout Period 
An 8-week period was selected as the duration for the Washout Period. It is expected that 
some subjects will be on 28-day-on/28-day-off cycles of stable CF medication, as discussed 
in Section 9.3.1. An 8-week washout period is compatible with these cycles. 
Washout periods are generally considered adequate if they encompass 5 half-lives of the 
administered compound. The apparent terminal half-life of LUM is 26 hours10,11, and the 
apparent terminal half-life of IVA is 12 hours.21 Thus, after an 8-week washout, levels of 
LUM and IVA are expected to be negligible. Based on data from previous studies of IVA 
and LUM/IVA, no residual effects of study drugs are expected by the end of the 8-week 
washout period. 
8.2.3
Rationale for Study Assessments 


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9
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled.
9.1
Inclusion Criteria 
Subjects who meet all of the following inclusion criteria will be eligible: 
1. Male or female with confirmed diagnosis of CF.23 The subject must have both of the 
following: 
o
One or more characteristic phenotypic features, such as chronic cough and sputum 
production, persistent chest radiograph abnormalities, or airway obstruction 
manifested by wheezing and air trapping; or a history of CF in a sibling; or a
positive newborn screening test result; 
o
An increased sweat chloride concentration by pilocarpine iontophoresis on two or 
more occasions; or identification of two CF mutations; or demonstration of 
abnormal nasal epithelial ion transport. 
2. Age 12 years or older on the date of informed consent. 
3. All subjects must have an A455E mutation on at least 1 CFTR allele. 
4. Forced expiratory volume in one second (FEV1) ≥30% of predicted and ≤90% of 
predicted at the Screening Visit, based on the Global Lung Function Initiative (GLI)-
2012 multi-ethnic all-age reference equations.24
5. Stable CF disease as judged by the investigator. 
6. Willing to remain on a stable medication regimen for CF from 4 weeks before Day 1 
through the Follow-up Visit. 
7. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
8. Subject (or subject’s legally appointed and authorized representative) will sign and date 
an informed consent form (ICF), and where appropriate, assent form. 
9.2
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible: 
1. History of any comorbidity reviewed at the Screening Visit that, in the opinion of the 
investigator, might confound the results of the study or pose an additional risk in 
administering study drug to the subject. For example: 
o
A history of cirrhosis with portal hypertension. 
o
An acute upper or lower respiratory infection, pulmonary exacerbation, or 
changes in therapy (including antibiotics) for pulmonary disease within 28 days 
before Day 1 (the first dose of study drug). 


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2. A G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or 
R117H mutation on at least one CFTR allele.  
3. Ongoing or prior participation in an investigational drug study (including studies 
investigating LUM/IVA or IVA) within 30 days before the Screening Visit.  
o
A washout period of 5 terminal half-lives of the previous investigational study 
drug or 30 days, whichever is longer, must elapse before the Screening Visit. The 
duration of the elapsed time may be longer if required by local regulations.  
o
Subjects who participated in Vertex Study VX14-661-108 may not be enrolled. 
o
Ongoing participation in a noninterventional study (including observational 
studies) is permitted.  
4. Pregnant or breastfeeding. 
5. Any of the following abnormal laboratory values at the Screening Visit: 
x
Hemoglobin <10 g/dL 
x
Any 2 or more of the following:  
o
aspartate aminotransferase (AST) ≥3 × upper limit of normal (ULN)  
o
alanine aminotransferase (ALT) ≥3 × ULN  
o
gamma-glutamyl transpeptidase (GGT) ≥3 × ULN  
o
alkaline phosphatase ≥3 × ULN  
x
ALT or AST >5 × ULN 
x
Bilirubin >2 × ULN 
x
Glomerular filtration rate ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt 
equation).25
6. History of cataract/lens opacity, or evidence of cataract/lens opacity determined to be 
clinically significant by the ophthalmologist or optometrist during the ophthalmologic 
examination at the Screening Visit (if applicable). 
7. Use of strong inhibitors or strong inducers of CYP3A, including consumption of certain 
herbal medications (e.g., St. John’s Wort) and certain fruit and fruit juices, within 14 days 
before Day 1 (the first dose of study drug).  
8. Sexually active subjects of reproductive potential who are not willing to follow the 
contraception requirements outlined in Section 11.6.5.
9.3
Prior and Concomitant Medications 
Information regarding all prior and concomitant medications, including the subject’s CF 
medications, other medications, and herbal and naturopathic remedies administered from 
30 days before the Screening Period through the Follow-up Visit, will be recorded in each 
subject’s source documents and electronic case report form (eCRF). For subjects who are 


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screened but not enrolled, details of prior medications will only be documented in the 
subjects’ source documents.
Information about bronchodilator use during the study will be collected and documented in 
the subject’s source documents and eCRF. 
9.3.1
Maintenance of Stable Medication Regimen for CF 
It is recommended that subjects remain on stable CF medication regimens from 4 weeks
before Day 1 through the Follow-up Visit. A stable medication regimen is defined as a 
medication regimen that the subject has been following for at least 4 weeks before Day 1. 
Specific requirements apply to certain CF medications: 
x
Subjects who, at the time of study entry, are on a stable regimen of a single inhaled 
antibiotic that is continuously administered should remain on this antibiotic through the 
Follow-up Visit.  
x
Subjects who are on a stable regimen of a single inhaled cycling antibiotic 
(e.g., Tobramycin Inhalation Solution [TOBI®] regimen) at the time of study entry should 
remain on this antibiotic through the Follow-up Visit. Inhaled cycling antibiotics should 
be administered in 28-day-on/28-day-off cycles. Study visits on Day 1 and Week 8 
during Treatment Period 1 and on Week 16 and Week 24 during Treatment Period 2 
should be timed to occur at the end of an off-cycle and at least 14 days after the last dose 
of inhaled antibiotics in the previous on-cycle.  
x
Subjects who are on an alternating regimen of inhaled cycling antibiotics that comprise 
continuous administration of antibiotics (e.g., TOBI administration alternating with 
Cayston®) at the time of study entry should remain on these antibiotics according to their 
alternating regimens through the Follow-up Visit. 
9.3.2
Prohibited Medications 
Prohibited medications and certain foods are not allowed while subjects are receiving study 
drug (Table 9-1). A nonexhaustive list of prohibitions and cautions for food and medication 
will be provided in the Study Reference Manual. 
Table 9-1 
Study Restrictions 
Restricted Medication/Food
Study Period
Screening Period
Treatment Period
Strong CYP3A inducers
None allowed within 14 days before 
the first dose of study drug
None allowed
Strong CYP3A inhibitors
None allowed within 14 days 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.
The use of moderate CYP3A inducers and inhibitors is not prohibited. 
Use of CYP2B6 and CYP2C substrates is not prohibited. In vitro studies suggest that LUM 
has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of 


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CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest 
that IVA may inhibit CYP2C9. Therefore, concomitant use of LUM/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 concomitantly 
with LUM/IVA during this study. Investigators should discuss any concerns regarding the 
use of these substrates with the medical monitor. 
9.4
Removal of Subjects from Study Drug Treatment 
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. 
Study drug treatment will be withdrawn for any female subject who has a confirmed 
pregnancy and for any male subject whose female partner has a confirmed pregnancy. 
A subject may be withdrawn from study drug treatment after a discussion between the 
investigator and the medical monitor for any of the following reasons: 
1. The subject develops a medical condition that requires prolonged concomitant therapy 
with a prohibited medication or prolonged interruption of study drug.  
2. The subject has an increase in transaminases for which withdrawal of study drug is 
recommended, as described in Section 11.6.3.
3. The subject develops a cataract.  
If a subject has been withdrawn from study drug treatment, the subject will be followed as 
described in Section 8.1.6, provided the subject has not withdrawn consent. 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. 
The investigator will inquire about the reason for withdrawal, request that the subject return 
all unused investigational product(s), request that the subject return for a Follow-up Visit, if 
applicable (see Section 8.1.6), and follow up 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. 
9.5
Replacement of Subjects 
Subjects who withdraw will not be replaced. 
10
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
10.1
Method of Assigning Subjects to Treatment Groups 
An interactive web or voice response system (IXRS) will be used to assign subjects to 
treatment sequence in a 1:1 ratio to receive either LUM/IVA during Treatment Period 1 and 
placebo during Treatment Period 2, or placebo during Treatment Period 1 and LUM/IVA 
during Treatment Period 2. The randomization code will be produced by Vertex Biostatistics 
or a qualified randomization vendor. 


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10.2
Packaging and Labeling 
Vertex will supply the LUM 200 mg/IVA 125 mg fixed-dose combination tablets in weekly 
blister cards. Study drug labeling will be in compliance with applicable local and national 
regulations. Additional details regarding packaging, labeling, and dispensing for LUM/IVA 
will be included in the Pharmacy Manual. 
10.3
Study Drug Supply, Storage, and Handling 
Table 10-1 provides 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, under recommended 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
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)
10.4
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee to the subject or the subject’s legally appointed and authorized representative 
(e.g., parent or legal guardian) for administration to the subject. Study drug will be dispensed 
at study visits as appropriate. 
For the visit at the end of each treatment period (i.e., the Week 8 and Week 24 Visits) and the 
ETT Visit (if applicable), subjects will be instructed to bring all remaining study drug to the 
site. 
10.5
Dosage and Administration 
Study drug tablets will be administered orally. During Treatment Period 1 and Treatment 
Period 2, subjects will take 2 tablets (LUM/IVA or matching placebo) twice per day.  
Study drug should be administered within 30 minutes of consuming fat-containing food such 
as a standard CF high-fat, high-calorie meal or snack according to the following guidelines: 
1.
All doses of study drug (morning and evening, as applicable) should be administered 
at approximately every 12 hours (± 2 hour) on each dosing occasion (e.g., if the 
morning doses of study drug are administered at 08:00 hours on Day 1, all subsequent 
morning doses should be administered between 06:00 hours and 10:00 hours). 


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2.
At the first visit of each treatment period (i.e., on the Day 1 and Week 16 Visits), 
subjects whose FEV1 at the Screening Visit was <40% of predicted will be observed 
for 4 hours after the morning dose of study drug.  
3.
At study visits during the treatment periods, 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.  
4.
If a subject’s scheduled visit is to occur in the afternoon, the following guidelines 
must be used for administering either the morning or evening dose: 
o
If the dose in the clinic will be within 6 hours of the subject’s scheduled morning 
dose, the subject should withhold their morning dose of study drug and the 
morning dose will be administered in the clinic.  
o
If the dose in the clinic will be more than 6 hours after the subject’s scheduled
morning dose, the subject should take the morning dose at home and the evening 
dose will be administered in the clinic. In this event, all assessments will be 
collected relative to the evening dose.  
10.6
Study Drug Interruption 
If study drug dosing must be interrupted for more than 72 hours, the medical monitor must be 
notified. In these instances, study drug dosing may resume only after approval by the medical 
monitor. Specific instructions for interruption for elevated LFT levels are provided in 
Section 11.6.3.
10.7
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, and study drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site 
according to instructions provided by Vertex or its authorized designee until inventoried by 
the study monitor. The study monitor will review study drug records and inventory 
throughout the study. 
10.8
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. The site monitor will instruct the 
site when it is appropriate to return or destroy study drug. If the site monitor authorizes 
destruction at the study site, the investigator, or authorized designee, will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Vertex. Destruction will be 
adequately documented. Procedures for destruction or return of the study drug will be 
detailed in the Pharmacy Manual. 
10.9
Compliance 
To ensure treatment compliance, the investigator or authorized designee will supervise all 
study drug dosing that occurs at the site. At each visit, site personnel will review the subject’s 


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compliance with study drug dosing and remind the subject of study drug dosing 
requirements. Compliance will also be assessed by ongoing study drug count. 
10.10
Blinding and Unblinding 
10.10.1
Blinding 
This study is double-blind. The subjects and all site personnel, including the investigator, site 
monitor, and study team, will remain blinded to treatment assignments until database lock. 
Exceptions are made for the following personnel:  
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 the 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 who will prepare the final (production) randomization list (this 
statistician is not a part of the study team) 
x
Vertex IXRS Management for IXRS oversight and system administration 
x
Vertex Clinical Supply Chain 
x
The bioanalytical laboratory/vendor personnel managed by Vertex Bioanalysis 
Vertex Quality Assurance Good Clinical Practice (GCP) personnel and all other Vertex 
Bioanalysis laboratory personnel will be blinded to the treatment assignment. 
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. 
10.10.2
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 an electronic process. 
Unblinding of an 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. 


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In addition, the Vertex Medical Information Call Center (MICC) will answer calls 24 hours a 
day, 7 days a week, 365 days of the year, and will triage these calls to the study medical 
monitor or appropriate backup. Contact information for the Vertex medical monitor and 
MICC will be provided in the Study Reference Manual. 
If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding 
event. The reason and the date of the unblinding will be documented clearly in the subject’s 
study file. Information about the treatment assignment obtained from the unblinding will be 
maintained in a secure location with controlled access and will not be shared with the 
sponsor (Vertex), Contract Research Organization (CRO), or any site personnel (other than 
the physician treating the subject). In addition, the investigator will consider whether the 
clinical event that prompted unblinding will be considered an SAE, according to the 
regulatory definitions or criteria for SAEs, and if so, submit an SAE report to Vertex GPS or 
designee, per Section 13.1.2.
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, 
unblind individual subjects at any time.  
11
ASSESSMENTS 
11.1
Timing of Assessments 
The schedule of assessments is shown in Table 3-1, Table 3-2, and Table 3-3.  
  
Spirometry will be performed as described in Section 11.3.1.
Vital sign assessments will be performed before blood draws. 
Liver function testing may be performed predose or postdose. At the Day 1 and Week 16 
Visits, urine pregnancy tests must be negative before study drug is administered. 
11.2
Subject Characteristics and Medical History 
Subject and disease characteristics include demographics, medical history, height, and 
weight. 
Medical history will be elicited from each subject during the Screening Period. Based on the 
medical history, the subject will be assessed for any disqualifying medical conditions as 
specified in the inclusion and exclusion criteria. The medical history will include a complete 
review of systems, past medical and surgical histories, and any allergies.  
11.3
Efficacy 
11.3.1
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines26 at 
the time points noted in Table 3-1, Table 3-2, and Table 3-3 and according to the additional 


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guidelines that follow. (Spirometry on Day 2 and the day after the Week 16 Visit [if 
applicable] will be considered safety assessments and not efficacy assessments.) 
Pre-bronchodilator spirometry is defined as spirometry testing performed for a subject who 
has 
x
withheld their short-acting β-agonist (e.g., albuterol) or anticholinergic (e.g., Atrovent®)
for more than 4 hours before the spirometry assessment; and
x
withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before 
the spirometry assessment; and
x
withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide 
[Spiriva®]) for more than 24 hours before the spirometry assessment. 
At the Screening Visit, spirometry may be performed pre- or post-bronchodilator. During the 
study, all spirometry assessments should be performed pre-bronchodilator. Spirometry 
assessments must be performed before the study drug dose at the visit. In the event that a 
subject forgets to withhold bronchodilators, spirometry should be performed according to the 
following: 
x
If the subject’s Day 1 predose spirometry is obtained pre-bronchodilator, but on a 
subsequent visit the subject forgets to withhold the bronchodilator dose, a 
post-bronchodilator spirometry will be obtained for that visit only and the visit will not be 
rescheduled.  
x
If, at the subject’s Day 1 predose spirometry assessment, the subject forgets to withhold 
the dose of bronchodilator, spirometry should be performed post-bronchodilator and all 
subsequent spirometric measurements during the study should be performed 
post-bronchodilator. 
x
Each spirometry assessment will be recorded in the source documents as 
pre-bronchodilator or post-bronchodilator. 
At study visits that include administration of study drug, spirometry will be performed before 
dosing.  
All sites will be provided with spirometers to be used for all study assessments. 
 
 
 
. Lung 
function equipment in the participating centers will be equally calibrated according to the 
ATS/ERS guidelines for lung function testing.27
Spirometry data will be transmitted to a centralized spirometry service for quality review. 




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11.6
Safety 
11.6.1
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with International 
Conference on Harmonisation (ICH) GCP guidelines. Section 13.1 outlines the definitions, 


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collection periods, criteria, and procedures for documenting, grading, and reporting AEs. A 
separate document that details AE case report form (CRF) completion guidelines as well as 
training for investigators will be provided. 
11.6.2
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, with the exception of urine 
pregnancy tests, which will be analyzed locally. Although blood samples are to be collected 
and analyzed at a central laboratory, a local laboratory may be used if a subject cannot return 
to the study site for the mandatory liver function testing (Section 11.6.3).
Laboratory test results that are abnormal and considered clinically significant will be 
recorded as AEs (see Section 13.1).  
The safety laboratory test panels are shown in Table 11-1.
Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry at Screening
Liver Function Tests
Hematology at Screening
Glucose 
Blood urea nitrogen 
Creatinine 
Sodium
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate 
Phosphate 
Bilirubin, direct bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase
Alanine aminotransferase 
Amylase 
Lactate dehydrogenase
Lipase 
Gamma glutamyl transpeptidase
Protein 
Albumin 
Creatine kinase
Bilirubin, direct bilirubin 
Aspartate aminotransferase
Alanine aminotransferase 
Gamma glutamyl transpeptidase
Alkaline phosphatase 
Hemoglobin 
Erythrocytes: 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration
Mean corpuscular volume
Platelets 
Reticulocytes (absolute) 
Leukocytes 
Differential (absolute and percent):
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes 
Monocytes 
Pregnancy Testing for Female Subjects of Childbearing Potential 
Serum samples will be analyzed at the central laboratory. Urine beta-human chorionic 
gonadotropin tests will be performed at the study site. The urine pregnancy tests at Day 1 
and Week 16 must be negative before the first dose of study drug. 
If a urine pregnancy test is positive, all study drug dosing will stop and the pregnancy will be 
confirmed with a serum beta-human chorionic gonadotropin test. If the subject is pregnant, 
the procedures outlined in Section 11.6.7.2 will be followed. 


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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. 
11.6.3
Elevation of Liver Function Test Parameters 
Study Drug Interruption 
Study drug administration must be interrupted immediately, and the Vertex medical 
monitor or authorized designee must be notified, if any of the following criteria is met: 
x
ALT or AST ≥5 × ULN  
x
ALT or AST ≥3 × ULN in association with 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. 
Resumption of Study Drug 
If a convincing alternative etiology is identified for the elevated transaminases (ALT, AST, 
and 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 authorized 
designee is required before resumption of study drug. Upon resumption of study drug, 
transaminases should be assessed weekly for 4 weeks. If a protocol-defined transaminase 
elevation occurs within 4 weeks of rechallenge with the study drug, then the study drug must 
be discontinued, regardless of the presumed etiology. 
Mandatory Liver Function Testing 
Liver function testing (ALT, AST, gamma glutamyl transpeptidase, alkaline phosphatase, 
and bilirubin) must be performed as shown in Table 3-2 and Table 3-3. These blood samples 
should be processed and shipped immediately 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 


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confirmatory testing performed by the central laboratory within 48 to 72 hours of the initial 
finding and subsequent close monitoring of ALT and AST levels, as clinically indicated. 
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 and the subject must have the tests repeated and sent to the central 
laboratory as soon as possible (ideally within 48 to 72 hours). 
11.6.4
Physical Examinations and Vital Signs 
At the Screening Visit, a PE of all body systems will be performed. At other visits, 
symptom-directed PEs can be performed at the discretion of the investigator or healthcare 
provider. 
A PE of all body systems includes a review of the following systems: head/neck/thyroid,
eyes/ears/nose/throat, respiratory, cardiovascular, lymph nodes, abdomen, skin,
musculoskeletal, and neurological. Breast, anorectal, and genital examinations will be 
performed when medically indicated. Any clinically significant abnormal findings in PEs 
will be reported as AEs. 
Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be 
collected with the subject in a seated position after the subject has been at rest for at least 
5 minutes. Blood pressure will be measured by sphygmomanometer. 
11.6.5
Ophthalmologic Examination 
Subjects who are less than 18 years of age at the Screening Visit will undergo an 
ophthalmologic examination during the Screening Period and at the Week 24 Visit, the ETT 
Visit, or the Follow-up Visit. These ophthalmologic examinations are not required under the 
following circumstances: 
x
If there is documentation of an ophthalmologic examination that met protocol criteria and 
was conducted within 3 months before the Screening Visit, the subject is not required to 
have a repeat ophthalmologic examination during the Screening Period. 
x
If the subject received study drug for a total of less than 4 weeks, the ophthalmologic 
examination at the Week 24, ETT, or Follow-up Visit is not required.  
The ophthalmologic examination will include: 
x
Measurement of best corrected distance visual acuity of each eye 
x
Measurement of lens refracting power (e.g., autorefractor or ophthalmoscopy streak 
following cycloplegia) 
x
Pharmacologically dilated examination of the lens with a slit lamp 
These examinations must be conducted by a licensed ophthalmologist or optometrist. 
If a cataract or lens opacity is identified and determined to be clinically significant by the 
ophthalmologist or optometrist, the subject (and the subject’s parent/guardian if the subject is 
a minor) will be notified.  


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Additional ophthalmologic examinations may be conducted at the discretion of the 
investigator. The Vertex medical monitor or authorized designee should be notified of any 
additional ophthalmologic examinations. 
11.6.6
Ophthalmologic History 
At the Screening Visit, the following history will be obtained for all subjects: 
x
History of steroid use 
x
History or presence of diabetes 
x
Any prior ophthalmologic or optometric examinations 
x
History of trauma to the eye 
x
Any family history of glaucoma, congenital cataracts, or cataracts arising later in life 
x
Use of corrective lenses (contact lenses or eyeglasses) 
x
History of prolonged exposure to sunlight or ultraviolet light and use of sunglasses 
x
History of exposure to secondhand smoke 
11.6.7
Contraception and Pregnancy 
11.6.7.1
Contraception 
The effects of LUM monotherapy or LUM/IVA on the pharmacokinetics of hormonal 
contraceptives are not known; however, since LUM is an inducer of CYP3A, it may reduce 
the effectiveness of hormonal contraceptives. 
Participation in this study requires a commitment from the subject and his/her partner to use 
at least 1 effective method of birth control as a couple. Acceptable methods of contraception 
for participants of this study and their partners are listed below. Methods of contraception 
should be in successful use from at least 14 days before the first dose of study drug (unless 
otherwise noted) until 90 days following the last dose of study drug. 
Definition of Childbearing Potential
All female subjects who have had their first menstrual period, from the time of the Screening 
Visit through the Follow-up Visit, including subjects with tubal ligations, will be considered 
to be of childbearing potential unless: 
x
The subject has had a documented hysterectomy or bilateral 
oophorectomy/salpingo-oophorectomy. 
x
The subject is postmenopausal, defined as at least 12 months of continuous spontaneous 
amenorrhea with serum FSH levels ≥40 mIU/L.
Contraception for the couple is waived for the following:
x
True abstinence for the subject, when this is consistent with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. 


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x
If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented 
through examination of a semen specimen or by demonstration of the absence of the vas 
deferens by ultrasound before the first dose of study drug. 
x
If the female is of non-childbearing potential, as defined above. 
Acceptable Contraceptive Methods
Acceptable contraceptive methods for male subjects or male partners of female subjects 
include the following:  
x
Vasectomy performed at least 6 months previously, with a negative post-vasectomy 
semen analysis for sperm. 
x
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 subjects include the following: 
x
Bilateral tubal ligation performed at least 6 months previously. 
x
Continuous use of an intrauterine device (non-hormone-releasing) for at least 90 days. 
x
Barrier contraception (such as a diaphragm, cervical cap, or female condom) with 
spermicide. Local regulations may require use of an additional acceptable method of 
contraception. 
x
Note: Hormonal contraceptives will not be considered as an effective method; however, 
female subjects are not required to discontinue hormonal contraceptives. 
Acceptable contraceptive methods for female partners of male subjects:  
x
Bilateral tubal ligation performed at least 6 months previously. 
x
Continuous use of an intrauterine device (hormone-releasing or non-hormone-
releasing) for at least 90 days. 
x
Barrier contraception (such as a diaphragm, cervical cap, or female condom) with 
spermicide. Local regulations may require use of an additional acceptable method of 
contraception. 
x
Hormonal contraceptives, if successfully used for at least 60 days.  
Additional Notes 
x
A female condom cannot be used with a male condom (as a double method of 
contraception) due to risk of tearing. 
x
Male and female subjects who are not sexually active must agree to follow the 
contraceptive requirements of this study if they become sexually active with a partner of 
the opposite sex. 


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x
If applicable, additional contraception requirements may need to be followed according 
to local regulations and/or requirements. 
x
Male subjects must not donate sperm after the first dose of study drug, throughout the 
study, and for 90 days after the last dose of study drug. 
x
Female subjects and female partners of male subjects should not plan to become pregnant 
during the study through 90 days after the last dose of study drug. 
x
Female subjects should not nurse a child from the start of study drug dosing through 
90 days after the 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 designee on an individual basis.
11.6.7.2
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during 
study drug treatment and for 90 days after the last dose of study drug. 
If a subject or the female partner of a male subject becomes pregnant during study 
participation, study drug must be permanently discontinued immediately. The investigator 
must notify the medical monitor and Vertex GPS within 24 hours of the site’s knowledge of 
the subject’s (or partner’s) pregnancy using the Pregnancy Information Collection Form. 
If the subject is confirmed to be on active drug, the subject or partner will be followed until 
the end of the pregnancy and the infant will be followed for 1 year after the birth, provided 
informed consent is obtained. A separate ICF (and assent form, if applicable) will be 
provided to explain these follow-up activities. Pregnancy itself does not constitute an AE.  
11.6.8
Pulse Oximetry 
Arterial oxygen saturation by pulse oximetry will be measured at visits noted in Table 3-1 
and Table 3-2. Pulse oximetry will be assessed after the subject has been at rest (seated or 
supine) for at least 5 minutes and before blood sample collection. The assessments of pulse 
oximetry on Day 2 and the day after the Week 16 Visit will be performed only for subjects 
whose FEV1 at the Screening Visit is <40% of predicted. At these visits, pulse oximetry will 
be collected before the morning dose of study drug.  
11.6.9
Spirometry 
Spirometry assessments other than the assessments on Day 2 and the day after the Week 16 
Visit will be considered efficacy assessments, as discussed in Section 11.3.1. The 
assessments of spirometry on Day 2 and the day after the Week 16 Visit will be considered 
safety assessments and not efficacy assessments. They will be performed only for subjects 
whose FEV1 at the Screening Visit is <40% of predicted. 
12
STATISTICAL AND ANALYTICAL PLANS 
Analyses of efficacy and safety data will be described in a statistical analysis plan (SAP). 
The SAP will be finalized before database lock for the final analysis. 


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12.1
Sample Size and Power 
No formal sample size calculation is conducted for this study of exploratory nature. The 
planned sample size of approximately 20 subjects is based on the number of subjects 
expected to be available for participation. 
Assuming an estimated standard deviation (SD) of the paired differences of 8.00 in ppFEV1,
the available sample size of 20 subjects produces a two-sided 95% CI of the mean treatment 
difference with precision (margin of error) of 3.74 percentage points. In addition, Table 12-1 
displays a list of treatment differences detectable under various scenarios of power and 
significance level, with total sample sizes of 15 and 20.  
Table 12-1 
Difference Detectable Under Various Scenarios of Power, Alpha, and N 
Power
90%
90%
90%
90%
80%
80%
80%
80%
Alpha
10%
10%
5%
5%
10%
10%
5%
5%
N
20
15
20
15
20
15
20
15
Difference 
detectable
5.4
6.4
6.1
7.3
4.6
5.4
5.3
6.3
12.2
Analysis Sets 
The Full Analysis Set (FAS) is defined as all randomized subjects who have received at least 
1 dose of study drug. The FAS will be used for efficacy analyses. 
The Safety Set is defined as all subjects who received at least 1 dose of study drug. The 
Safety Set will be used for safety analyses. 
12.3
Statistical Analysis 
This section summarizes the planned statistical analyses for this study. The Vertex 
Biometrics department or a designated CRO will conduct these analyses. SAS® Version 9.2
or higher will be used to generate all statistical outputs (tables, figures, listings, and data 
sets). 
For each Treatment Period, subjects will be categorized according to the treatment they 
actually received, whether or not it corresponds to the treatment to which they were assigned. 
12.3.1
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, standard error, median, minimum value, and 
maximum value. 
Categorical variables will be summarized using counts and percentages.  
Unless specified otherwise, only descriptive analyses will be performed (i.e., no statistical 
hypothesis testing will be performed). 
Baseline: Study baseline is defined as the most recent nonmissing measurement collected 
before the first administration of study drug in Treatment Period 1. Period baseline is defined 
as the most recent nonmissing measurement collected before the first administration of study 


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drug in each treatment period. For Treatment Period 1, the period baseline will be the study 
baseline; for Treatment Period 2, the period baseline will be from an assessment measured 
after the Washout Period. 
For all efficacy analyses, the statistical inference will be based on change from study 
baseline. However, efficacy analyses based on change from period baseline will also be 
presented. Similarly, summary tables, as applicable, will be presented based on both 
baselines. 
All subject data, including those derived, will be presented in the subject data listings; 
listings will display all subjects who were randomized, regardless of whether or not they 
received study drug. 
12.3.2
Background Characteristics 
12.3.2.1
Subject Disposition 
The number and percentage of subjects in each disposition category (e.g., randomized, 
included in the FAS, included in the Safety Set, completed each treatment period, completed 
the Follow-up Visit, and discontinued study, with reasons for discontinuation) will be 
summarized by treatment sequence and overall. 
12.3.2.2
Demographics and Baseline Characteristics 
The following demographics and baseline characteristics for the FAS will be summarized by 
treatment sequence and overall: age, sex, race, weight, height, BMI, weight z-score, and BMI 
z-score.  
12.3.2.3
Prior and Concomitant Medications 
Medications taken from 30 days before the Screening Visit up to the Follow-up Visit will be 
summarized by preferred term using the World Health Organization-Drug Dictionary 
Enhanced for the FAS as frequency tables in 2 parts: 
x
Prior medication: medication that started before the first dose of study drug, regardless of 
when dosing of the medication ended. 
x
Concomitant medication: medication received at or after the first dose of study drug, 
medication that was received before initial dosing and continued after initial dosing of 
study drug, or medication with missing stop date. 
Medication that started before the first dose of study drug and continued after the first dose of 
study drug will be summarized as prior medication and separately as concomitant 
medication. Medications with a missing start date will be considered to have a start date 
before the first dose of study drug. 
Prior medications will be summarized by treatment sequence, and concomitant medications 
will be summarized by treatment group. 
12.3.2.4
Study Drug Exposure and Compliance 
Exposure to study drug and dosing compliance will be summarized for the FAS by means of 
summary statistics.  


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Dosing compliance will be summarized for each treatment period for the FAS, and is 
calculated as the actual number of dosing occasions at which study drug was administered, as 
a percentage of the planned number of dosing occasions. 
12.3.3
Efficacy Analysis 
Efficacy analyses will be based on the FAS unless noted otherwise. 
All efficacy data will be presented in subject data listings.  
12.3.3.1
Change from Baseline in ppFEV1 
The analysis of absolute change from baseline in ppFEV1 through 8 weeks of study drug 
treatment will be based on a mixed-effects model for repeated measures (MMRM) utilizing 
the FAS. 
The model will include the absolute change from the study baseline in each treatment period 
as the dependent variable; sequence, treatment, treatment period, and visit within treatment 
period as fixed effects; ppFEV1 at study baseline as a covariate; and subject nested within 
sequence as the random effect. An unstructured covariance matrix is further assumed for the 
repeated measurements of the same subject within each treatment period. If there is a 
convergence problem for the unstructured covariance matrix, an appropriate covariance 
matrix structure, such as compound symmetry, will be assumed in the primary analysis. The 
estimated mean treatment difference overall, a 95% CI, and a 2-sided P value will be 
provided. The estimated mean treatment difference at each visit along with the corresponding 
95% CI and P value will also be presented. Raw values and changes from baseline will be 
summarized by treatment group using descriptive statistics. Paired t-tests for difference 
between treatments for each subject, as well as Wilcoxon signed-rank tests, may be provided. 
As a supportive analysis, the analysis will be repeated using change from period baseline 
instead of change from study baseline. 
Summary, plots, and individual listings of efficacy data will be generated. A more detailed 
description of the planned statistical analysis of efficacy endpoints will be presented in the 
SAP. 


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12.3.5
Safety Analysis 
The overall safety profile of LUM/IVA will be assessed in terms of:  
x
Incidence of treatment-emergent adverse events (TEAEs) 
x
Clinical laboratory values (LFTs) 
x
Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) 
Safety analyses will be based on the Safety Set. 
All safety data will be presented in subject data listings.  
12.3.5.1
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
The number and percentage of subjects experiencing an AE will be summarized by the 
MedDRA system organ class and preferred term. AEs will be classified as pre-treatment or 
treatment-emergent.
Pre-treatment AEs are defined as AEs that were reported or worsened after signing the ICF 
up to the start of study drug dosing. 
Treatment-emergent AEs are defined as AEs that were reported or worsened on or after the 
start of study drug dosing through the Follow-up Visit. 
Only TEAEs will be summarized in tables. Some rules that will apply to the summarization 
of AEs are (1) a subject with multiple occurrences of the same AE or a continuing AE will 
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. 
AEs leading to death, SAEs, dose interruption, and permanent discontinuation will be listed 
separately. All AEs through the Follow-up Visit, including pre-treatment AEs, will be listed 
in a subject data listing.  


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12.3.5.2
Clinical Laboratory Assessments 
All statistical summaries of laboratory values will be provided using SI units. LFT results 
will be summarized by treatment group at each scheduled time point. Changes from baseline 
will also be summarized. Maximum shift changes from baseline based on the LFT normal 
ranges will be tabulated by treatment. A subject data listing of abnormal LFT values from 
scheduled and unscheduled time points will be provided. A listing of all laboratory values of 
Grade 3 toxicity or worse will also be provided. Results for hematology and chemistry 
assessments will be listed and summarized. Clinically significant abnormal laboratory 
findings will be reported as AEs.  
12.3.5.3
Vital Signs 
Systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), respiratory rate 
(breaths per minute), and body temperature (degrees C) will be summarized by treatment. 
Changes from baseline will also be summarized. Clinically significant abnormal findings will 
be reported as AEs. 
12.3.5.4
Physical Examination 
PE results performed as part of the Screening Period assessment will be presented in subject 
data listings only. Clinically relevant results identified after screening will be reported as 
AEs. 
12.3.6
Interim Analysis 
No interim analysis is planned. 
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 Section 13.1.2.1.
13.1.1.2
Clinically Significant Assessments 
Study assessments, including laboratory tests and vital signs, will be assessed, and those 
deemed a clinically significant worsening from baseline will be documented as AEs. When 
possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a 
diagnosis, the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine 
or decreased hemoglobin). 


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An abnormal study assessment is considered clinically significant if the subject has 1 or more 
of the following: 
x
Concomitant signs or symptoms related to the abnormal study assessment 
x
Further diagnostic testing or medical/surgical intervention 
x
A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of 
whether the study assessment results are clinically significant will be made by the 
investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory 
value will be an SAE if the clinical status of the subject indicates a life-threatening AE. 
13.1.1.3
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the following time points: 
x
For subjects who do not enroll: until time of screen failure (e.g., screen failure, 
withdrawal of consent) 
x
For enrolled subjects who have a Follow-up Visit: through the Follow-up Visit 
x
For enrolled subjects who do not have a Follow-up Visit, the earliest of: 
o
28 days after the last dose of study drug, or 
o
the ETT Visit, if that visit is 3 weeks or later after the last dose of study drug (see 
Section 8.1.6).
All subjects will be queried, using non-leading questions, about the occurrence of AEs at 
each study visit. When possible, a constellation of signs and/or symptoms will be identified 
as 1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the 
study will be recorded only in the subject’s source documents. The following data will be 
documented for each AE: 
x
Description of the event 
x
Classification of “serious” or “nonserious”
x
Date of first occurrence and date of resolution (if applicable) 
x
Severity 
x
Causal relationship to study drug(s)  
x
Action taken  
x
Outcome  
x
Concomitant medication or other treatment given 


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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), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (accessed 
August 2015). AEs of CTCAE Grade 4 and Grade 5 will be documented as 
“life-threatening.” In considering the severity of an AE in a pediatric subject, the investigator 
will consider that reference ranges for pediatric clinical laboratory parameters may differ 
from those given in the CTCAE. The severity of an AE that does not appear in the CTCAE 
will be determined according to the definitions in Table 13-1.  
Table 13-1 
Grading of AE Severity 
Classification
Definition
Mild (Grade 1)
Mild level of discomfort and does not interfere with regular activities
Moderate (Grade 2)
Moderate level of discomfort and significantly interferes with regular activities
Severe (Grade 3)
Significant level of discomfort and prevents regular activities
Life-threatening 
(Grade 4)
Any adverse drug experience that places the subject, in the view of the 
investigator, at immediate risk of death 
13.1.1.5
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to 
the study drug(s). Causality will be classified using the categories presented in Table 13-2.
Table 13-2 
Classifications for AE Causality 
Classification
Definition
Related
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled 
out, and/or the event 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 record).
13.1.1.6
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action 
taken will be classified according to the categories shown in Table 13-3.  


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Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification
Definition
Dose not changed
Study drug dose not changed in response to an AE
Dose reduced
Study drug dose reduced in response to an AE
Drug interrupted
Study drug administration interrupted in response to an AE 
Drug withdrawn
Study drug administration permanently discontinued in response to an AE
Not applicable
Action taken regarding study drug administration does not apply. 
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible.
13.1.1.7
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4.
Table 13-4 
Classifications for Outcome of an AE 
Classification
Definition
Recovered/Resolved
Resolution of an AE with no residual signs or symptoms
Recovered/ Resolved 
With Sequelae
Resolution of an AE with residual signs or symptoms
Not Recovered/Not 
Resolved (Continuing)
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing
Fatal
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE.
Unknown
Outcome of an AE is not known (e.g., a subject lost to follow-up)
13.1.1.8
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was 
given in response to an AE, and may include treatments such as other medications, 
hospitalization, surgery, or physical therapy. “No” indicates the absence of any kind of 
treatment for an AE. 
13.1.2
Serious Adverse Events 
13.1.2.1
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
x
Fatal (death, regardless of cause, that occurs during participation in the study or occurs 
after participation in the study and is suspected of being a delayed toxicity due to 
administration of the study drug) 


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


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13.1.2.3
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an 
SAE, regardless of the presumed relationship to the investigational study drug. The Vertex 
Clinical Trial SAE Form will be completed for new/initial events as well as to report 
follow-up 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 Global Patient Safety via 
Email:
(Preferred Choice) 
Or via 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 
applicable. In addition, Vertex, or authorized designee, will be responsible for the submission 
of safety letters to central independent ethics committees (IECs).  
It is the responsibility of the investigator or designee to promptly notify the local institutional 
review board (IRB)/local IEC of all 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 ICH GCP 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 consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from 
the subject (if applicable), before study participation. The method of obtaining and 
documenting the informed consent and assent (if applicable) and the contents of the consent 
will comply with ICH GCP Guidelines and all applicable laws and regulations and will be 
subject to approval by Vertex or its authorized designee. 


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13.2.3
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator 
and Vertex. Changes that significantly affect the safety of the subjects, the scope of the 
investigation, or the scientific quality of the study (i.e., efficacy assessments) will require 
IRB/IEC notification before implementation, except where the modification is necessary to 
eliminate an apparent immediate hazard to human subjects. Vertex will submit all protocol 
modifications to the required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the 
protocol, the investigator will contact Vertex to discuss the planned course of action. If 
possible, contact will be made before the implementation of any changes. Any departures 
from protocol will be fully documented in the source documentation and in a protocol 
deviation log.  
13.2.4
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit 
and for audits. The records will also be available for direct inspection, verification, and 
copying, as required by applicable laws and regulations, by officials of the regulatory health 
authorities (FDA and others). The investigator will comply with applicable privacy and 
security laws for use and disclosure of information related to the research set forth in this 
protocol.  
13.2.5
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and 
privacy laws and regulations, all CRFs, study reports, and communications relating to the 
study will identify subjects by assigned subject numbers and access to subject names linked 
to such numbers shall be limited to the site and the study doctor and shall not be disclosed to 
Vertex. As required by applicable laws and regulations in the countries in which the study is 
being conducted, the investigator will allow Vertex and/or its representatives access to all 
pertinent medical records to allow for the verification of data gathered in the CRFs/SAE 
forms and the review of the data collection process. The FDA and regulatory authorities in 
other jurisdictions, including the IRB/IEC, may also request access to all study records, 
including source documentation, for inspection. 
13.2.6
Record Retention 
The investigator will maintain all study records according to ICH GCP Guidelines and/or 
applicable local regulatory requirements, 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. 


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Vertex Pharmaceuticals Incorporated 
Conditions that may lead to reasonable cause and warrant termination include, but are not 
limited to: 
x
Subject or investigator noncompliance 
x
Unsatisfactory subject enrollment 
x
Lack of adherence to protocol procedures 
x
Lack of evaluable and/or complete data 
x
Potentially unacceptable risk to study subjects 
x
Decision to modify drug development plan 
x
Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.3
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the 
qualifications of each investigator, inspect clinical study site facilities, and inform the 
investigator of responsibilities and procedures for ensuring adequate and correct study 
documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated web-based electronic data capture (EDC) application. 
Vertex will have read-only access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator 
for resolution. Any changes to study data will be made to the CRF and documented in an 
audit trail, which will be maintained within the clinical database. 
13.4
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness 
and clarity, cross-checking with source documents, and clarification of administrative matters 
will be performed. 
The study will be monitored by Vertex or its authorized designee. Monitoring will be done 
by personal visits from a representative of Vertex, or authorized 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 correct information in the CRFs on the 
subjects for which they are responsible.  


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Vertex Pharmaceuticals Incorporated 
A CRF will be completed for each enrolled study subject. It is the investigator’s 
responsibility to ensure the accuracy, completeness, clarity, and timeliness of the data 
reported in the subject’s CRF. Source documentation supporting the CRF data will indicate 
the subject’s participation in the study and will document the dates and details of study 
procedures, AEs, other observations, and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible 
after information is collected.  
The audit trail entry will show the user’s identification information and the date and time of 
any correction. The investigator will provide formal approval of all the information in the 
CRFs, including any changes made to the CRFs, to endorse the final submitted data for the 
subjects for whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival 
CRF in the form of a CD or other electronic media will be placed in the investigator’s study 
file. 


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14
REFERENCES
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available from:
http://www.cff.org/AboutCF/. Accessed 30 June 2015. 
2  
Kriendler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new 
therapies. Pharmacol Ther. 2010;125:219-29. 
3 
FDA Office of Orphan Products Development. Developing products for rare diseases 
& conditions. Available from:
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/defa
ult.htm. Accessed 01 July 2015. 
4 
European Medicines Agency. Committee for Orphan Medicinal Products (COMP). 
Available from:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_conte
nt_000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30.
Accessed 01 July 2015. 
5  
Cystic Fibrosis Foundation Patient Registry. 2012 Annual Data Report. Bethesda, 
MD: Cystic Fibrosis Foundation; 2013. 
6 
Stern M, Wiedemann B, Wenzlaff P. From registry to quality management: The 
German Cystic Fibrosis Quality Assessment Project 1995-2006. Eur Respir J. 
2008;31(1):29-35. 
7 
Cystic Fibrosis Trust. Cystic Fibrosis Trust Annual Review 2010. London, UK: 
Cystic Fibrosis Trust; 2012. 
8  
Flume PA, Van Devanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
9 
Cystic Fibrosis Mutation Database (CFTR1). Cystic Fibrosis Centre at the Hospital 
for Sick Children in Toronto web site [Internet]. Available from:
http://www.genet.sickkids.on.ca/cftr/StatisticsPage.html. Accessed 15 February 2016. 
10
Orkambi™ (lumacaftor/ivacaftor) Package Insert. Vertex Pharmaceuticals 
Incorporated. Cambridge, MA, USA. Issue date: July 2015. 
11  
Orkambi® (lumacaftor/ivacaftor) Summary of Product Characteristics. Vertex 
Pharmaceuticals (Europe) Limited. London, United Kingdom. Available from:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003954/WC500197611.pdf [Accessed 03 January 
2016]. 
12 
McKone EF, et al. Effect of genotype on phenotype and mortality in cystic fibrosis: a 
retrospective cohort study. Lancet. 2003;361:1671 


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13 
Nederlandse Cystic Fibrosis Registratie. Rapportage over het jaar 2012. 2013 Oct. 
Available from: http://www.cfonderzoek.nl/bestanden/cf-
registratie/rapportage2012.pdf. Accessed 01 July 2015. 
14 
Collee JM, et al. Relative frequencies of cystic fibrosis mutations in The Netherlands 
as an illustration of significant regional variation in a small country. Human Genet. 
1998;102:587. 
15 
Gan KH, et al. A cystic fibrosis mutation associated with mild lung disease. N Engl J 
Med. 1995 Jul 13;333(2):95  
16  
Cebotaru L, Rapino D, Cebotaru V, Guggino WB. Correcting the cystic fibrosis 
disease mutant, A455E CFTR. PLoS ONE [Internet]. 2014 Jan;9(1):e85183. 
Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885674/ [Accessed 
04 March 2016].  
17 
Dekkers JF, et al. A functional CFTR assay using primary cystic fibrosis intestinal 
organoids. Nat Med. 2013 Jul;19(7):939-45. 
18  
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
19  
Vertex Pharmaceuticals Incorporated. Report K060. A Phase 3, randomized, 
double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and 
safety of lumacaftor in combination with ivacaftor in subjects aged 12 years and older 
with cystic fibrosis, homozygous for the F508del-CFTR mutation. Report date: 
08 September 2014; Addendum 1 Date: 17 September 2014. 
20  
Vertex Pharmaceuticals Incorporated. Report K061. A Phase 3, randomized, 
double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and 
safety of lumacaftor in combination with ivacaftor in subjects aged 12 years and older 
with cystic fibrosis, homozygous for the F508del-CFTR mutation. Report date: 
02 September 2014; Addendum 1 Date: 17 September 2014. 
21  
Kalydeco® (ivacaftor) Summary of Product Characteristics. Vertex Pharmaceuticals 
(Europe) Limited. Updated: 16 January 2016. Available from: 
https://www.medicines.org.uk/emc/medicine/27586 [Accessed 04 March 2016]. 
22  
Bellin MD, Laguna T, Leschyshyn J, Regelmann W, Dunitz J, Billings J, et al. Insulin 
secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small 
pilot study. Pediatr Diabetes. 2013;14(6):417-21. 
23  
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. 
Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998;132(4):589-95. 
24  
Stanojevic S, Stocks J, Bountziouka V, Aurora P, Kirkby J, Bourke S, et al. The 
impact of switching to the new global lung function initiative equations on spirometry 
results in the UK CF registry. J Cyst Fibros. 2014;13(3):319-27. 
25 
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 


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Vertex Pharmaceuticals Incorporated 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51:875-8. 
26 
American Thoracic Society. Standardization of spirometry: 1994 update. Am J Respir 
Crit Care Med. 1995;152:1107-36. 
27 
Beydon N, et al. An official American Thoracic Society/European Respiratory 
Society statement: pulmonary function testing in preschool children. Am J Respir Crit 
Care Med. 2007;175(12):1304-45. 
28  
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 
1994;331:637-42. 
29
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR 
potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 
2011;365:1663-72.




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15.2
Investigator Signature Page 
Protocol #:
VX15-809-111
Version #:
2.0
Version Date
17 February 2017
Study Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to 
Evaluate the Efficacy of Lumacaftor/Ivacaftor Combination Therapy in Subjects With Cystic 
Fibrosis Who Have an A455E-CFTR Mutation
I have read Protocol VX15-809-111, Version 2.0 and agree to conduct the study according to 
its terms. I understand that all information concerning LUM/IVA and this protocol supplied 
to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential.  
Printed Name
Signature
Date

SAP_001.pdf: 
Statistical Analysis Plan Methods                                                                                                        Page 1 of 42 
Protocol Number: VX15-809-111
Vertex Pharmaceuticals Incorporated                                                                               
VERTEX PHARMACEUTICALS INCORPORATED 
Final Analysis Statistical Analysis Plan 
(Methods) 
Protocol Number VX15-809-111
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Crossover Study to Evaluate the Efficacy of 
Lumacaftor/Ivacaftor Combination Therapy in Subjects 
With Cystic Fibrosis Who Have an A455E-CFTR Mutation
Author of SAP: 
Version of SAP: 1.0
Date of SAP: 07 September 2017 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
Page 1 of 90


Statistical Analysis Plan Methods                                                                                                                                                                                                                Page 2 of 42 
Protocol Number: VX15-809-111 
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1
TABLE OF CONTENTS 
1 
Table of Contents ................................................................................................................. 2 
 
 
 
 
 
 
3 
Introduction ......................................................................................................................... 4 
4 
Study Objectives .................................................................................................................. 5 
4.1 
Primary Objective .......................................................................................................... 5 
 
 
5 
Study Endpoints .................................................................................................................. 5 
5.1 
Primary Endpoint ........................................................................................................... 5 
 
 
6 
Study Design ........................................................................................................................ 6 
6.1 
Overall Design ............................................................................................................... 6 
6.2 
Sample Size and Power .................................................................................................. 7 
6.3 
Randomization ............................................................................................................... 7 
6.4 
Blinding and Unblinding ................................................................................................ 7 
6.4.1 
Blinding .................................................................................................................. 7 
6.4.2 
Unblinding .............................................................................................................. 9 
7 
Analysis Sets ......................................................................................................................... 9 
8 
Statistical Analysis ............................................................................................................. 10 
8.1 
General Considerations ................................................................................................ 10 
8.2 
Background Characteristics ......................................................................................... 11 
8.2.1 
Subject Disposition .............................................................................................. 11 
8.2.2 
Demographics and Baseline Characteristics ........................................................ 12 
8.2.3 
Medical History .................................................................................................... 13 
8.2.4 
Prior and Concomitant Medications ..................................................................... 13 
8.2.5 
Study Drug Exposure ........................................................................................... 14 
8.2.6 
Study Drug Compliance ....................................................................................... 14 
8.2.7 
Important Protocol Deviations ............................................................................. 15 
8.3 
Efficacy Analysis ......................................................................................................... 15 
8.3.1 
Analysis of Primary Efficacy Variable(s) ............................................................ 15 
8.3.1.1 
Definition of Variable .................................................................................... 16 
8.3.1.2 
Primary Analysis............................................................................................ 16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Safety Analysis ............................................................................................................. 25 
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8.4.1 
Adverse Events ..................................................................................................... 26 
8.4.1.1 
Overview of Treatment Emergent AEs ......................................................... 26 
8.4.1.2 
TEAEs and TE SAEs by System Organ Class and Preferred Term .............. 27 
8.4.1.3 
TEAEs and TE SAEs by PT .......................................................................... 27 
8.4.1.4 
Related TEAEs and TE SAEs by SOC, PT ................................................... 27 
8.4.1.5 
Grade 3/4 TEAEs by SOC, PT ...................................................................... 27 
8.4.2 
Clinical Laboratory .............................................................................................. 27 
8.4.3 
Vital Signs ............................................................................................................ 28 
8.4.4 
Pulse Oximetry ..................................................................................................... 28 
8.4.5 
Physical Examination ........................................................................................... 28 
8.4.6 
Ophthalmologic Examination .............................................................................. 28 
9 
Summary of Interim and IDMC Analyses ...................................................................... 28 
10 References .......................................................................................................................... 29 
11 List of Appendices ............................................................................................................. 30 
11.1 Appendix A: Schedule of Assessments ........................................................................ 30 
11.2 Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments ............. 34 
11.3 Appendix C: Imputation Rules for Missing AE dates ................................................. 35 
11.5 Appendix E: Precisions of Summary Statistics and Derived Variables in TFLs ......... 36 
11.6 Appendix F: Criteria for Potentially Clinically Significant Events (Threshold Analysis 
Criteria) 
 38 
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3
INTRODUCTION 
This SAP describes the planned final analyses for the Study VX15-809-111 data and is based
on the following: 
x
approved clinical study protocol (Version 2.0, dated 17 February 2017) 
x
approved electronic case report form (eCRF) (Version 3.0, dated 06 January 2017)
Study VX15-809-111 is a Phase 2, randomized, double-blind, placebo-controlled, crossover 
study to evaluate the efficacy of LUM/IVA in subjects with cystic fibrosis (CF), 12 years of age 
and older who have at least one A455E mutation.  
 
This SAP (Methods) documents the planned final statistical analyses for efficacy and safety
endpoints defined in the VX15-809-111 protocol , and describes the corresponding data 
presentations. Analyses for additional efficacy and safety variables not specified in the protocol 
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that will provide supportive information to enhance the scientific understanding of the study 
drug entity are also described. 
The Vertex Biometrics Department will oversee the statistical analysis of the efficacy and 
safety data; 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 before the clinical 
database lock and treatment unblinding for the study.If methods in this SAP differ from the 
methods described in the protocol, the SAP prevails. 
4
STUDY OBJECTIVES  
4.1 
Primary Objective 
To evaluate the efficacy of LUM/IVA in subjects with CF 12 years of age and older who have 
at least one A455E mutation.  
5
STUDY ENDPOINTS 
5.1 
Primary Endpoint 
Absolute change from baseline in percent predicted forced expiratory volume in 1 second 
(ppFEV1) through 8 weeks of treatment. 
  
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Table 6-1
Study Drug 
Drug Name
Formulation/
Route
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)
6.2 
Sample Size and Power 
No formal sample size calculation is conducted for this study of exploratory nature. The 
planned sample size of approximately 20 subjects is based on the number of subjects expected 
to be available for participation. 
Assuming an estimated standard deviation (SD) of the paired differences of 8.00 in ppFEV1,
the available sample size of 20 subjects produces a 2-sided 95% CI of the mean treatment 
difference with precision (margin of error) of 3.74 percentage points. In addition, Table 6-2
displays a list of treatment differences detectable under various scenarios of power and 
significance level, with total sample sizes of 15 and 20.  
Table 6-2
Difference Detectable Under Various Scenarios of Power, Alpha, and N
Power
90%
90%
90%
90%
80%
80%
80%
80%
Alpha
10%
10%
5%
5%
10%
10%
5%
5%
N
20
15
20
15
20
15
20
15
Difference 
detectable
5.4
6.4
6.1
7.3
4.6
5.4
5.3
6.3
6.3 
Randomization 
Approximately 20 subjects who meet eligibility criteria will be randomized (1:1) to 1 of the 
2 treatment sequences ( Figure 1).
An interactive web or voice response system (IXRS) will be used to assign subjects to 
treatment sequence in a 1:1 ratio to receive either LUM/IVA during Treatment Period 1 and 
placebo during Treatment Period 2, or placebo during Treatment Period 1 and LUM/IVA 
during Treatment Period 2.
The IXRS will use a list of randomization codes generated by a designated vendor 
. 
6.4 
Blinding and Unblinding 
This is a double-blind study. 
6.4.1 
Blinding 
This study is double-blind. The subjects and all site personnel, including the investigator, site 
monitor, and study team, will remain blinded to treatment assignments until database lock. 
Exceptions are made for the following personnel:  
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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 the 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 who will prepare the final (production) randomization list (this 
statistician is not a part of the study team) 
x
Vertex IXRS Management for IXRS oversight and system administration 
x
Vertex Clinical Supply Chain 
x
The bioanalytical laboratory/vendor personnel managed by Vertex Bioanalysis 
Vertex Quality Assurance Good Clinical Practice (GCP) personnel and all other Vertex 
Bioanalysis laboratory personnel will be blinded to the treatment assignment. 
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. 
Spirometry  Data  Blinding 
Despite treatment blinding, knowledge of the spirometry results has the potential to suggest 
whether a subject has received active study drug or placebo. Therefore, during the conduct of 
the study, the Vertex study team will have no access to the postdose spirometry data. The 
vendor for central reading of the spirometry data will only send the blinded spirometry files 
(blinded treatment group, with real values for screening and baseline, but with dummy values 
for all the spirometry assessments after baseline) to Vertex to be used for developing the 
statistical programs. Furthermore, subjects and their caregivers should not be informed of their 
study-related spirometry results during the Treatment Period, regardless of whether the subject 
has prematurely discontinued treatment. 
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Statistical Analysis Plan Methods                                                                                                                                                                                                                Page 9 of 42 
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6.4.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or an electronic process. 
Unblinding of an 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. 
If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding event. 
The reason and the date of the unblinding will be documented clearly in the subject’s study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in 
a secure location with controlled access and will not be shared with the sponsor (Vertex), CRO, 
or any site personnel (other than the physician treating the subject). In addition, the investigator 
will consider whether the clinical event that prompted unblinding will be considered an SAE, 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to 
Vertex GPS or designee, per Section 13.1.2 of the protocol. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex medical monitor may, for matters relating to safety 
concerns, unblind individual subjects at any time. 
7
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), and Safety 
Set. 
The All Subjects Set is defined as all subjects who have been randomized or have received at 
least one dose of study drug. This analysis set will be used for all individual subject data 
listings and the disposition summary table, unless specified otherwise.
The FAS is defined as all randomized subjects who have at least one A455E mutation and have 
received at least 1 dose of study drug. The FAS will be used for efficacy analyses. 
The Safety Set is defined as all subjects who received at least 1 dose of study drug. The Safety 
Set will be used for safety analyses. 
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8
STATISTICAL ANALYSIS 
8.1 
General Considerations 
All individual subject data for those randomized or exposed to study drug will be presented in 
data listings. Summary and plots of efficacy data will be generated. The Schedule of 
Assessments is provided in Appendix A. The precision standards are provided in Appendix E. 
Continuous variables will be summarized using the following descriptive summarystatistics: 
the number of subjects (n), mean, standard deviation (SD), standard error (SE), median, 
minimum value (min), and maximum value (max). 
Categorical variables will be summarized using counts and percentages. 
Treatment Emergent (TE) Period: 
x
TE period for Treatment Period 1 will be from the first dose of study drug in the first period 
to 28 days after the last dose of Period 1 or the safety evaluation visit (Safety Follow-up 
Visit, if subject discontinues treatment in Period 1), whichever is latest.  
x
The TE period for Treatment Period 2 will be from the first dose of study drug in the 
second period to 28 days after the last dose of Period 2 or the Safety Follow-up Visit , 
whichever is latest. 
Baseline Value: For this crossover study, 2 types of baseline will be defined.  
x
The study baseline is defined as the most recent non-missing measurement (scheduled or 
unscheduled) collected prior to the first dose of study drug in the study. The definition will 
be applied to all demographics, background, and baseline characteristics and also to data 
analyses, including the primary endpoint analysis.  
x
The period baseline is defined as the most recent non-missing measurement (scheduled or 
unscheduled) collected before the first dose of study drug in each Treatment Period. For 
Treatment Period 2, the period baseline should be from an assessment measured after the 
end of the TE period for Treatment Period 1.  
Absolute change from study baseline will be calculated as postbaseline value – study baseline 
value. 
Absolute change from period baseline will be calculated as postbaseline value – period 
baseline value. 
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Unscheduled Visits: Unscheduled visit measurements will be included in the following:  
(1) derivations of measurements at scheduled visits per specified visit windowing rules below; 
(2) derivations of baseline/last on-treatment measurements; 
(3) derivations of the maximum/minimum on-treatment values and maximum/minimum 
changes from baseline values for safety analyses; 
(4) subject data listings where appropriate. 
Visit Windowing Rules: Appendix B defines the windows for protocol-defined visits. The 
windows will be applied using the following rules for both scheduled and unscheduled visits:  
(1) If no measurement is available within a visit window, the assessment will be considered 
missing for the visit; 
(2) If there is more than one measurement available within the same visit window, use the 
following rules: 
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: 
o the record closest to the target day will be used.
o If there are multiple records with the same distance to the target day, the latest record will 
be used. 
o Assessments at early treatment termination (ETT) visit will follow the windowing 
rules for regular visits up to Week 24. 
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; 2) if there are multiple records within the same 
distance from the target day, the latest record will be used; 3) Safety Follow-up Visit will not be 
windowed, instead, used per nominal visit in relevant analyses.   
Incomplete/Missing data will not be imputed, unless otherwise specified. 
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless otherwise specified. 
8.2 
Background Characteristics  
8.2.1 
Subject Disposition 
Number and percentage of subjects in the following categories will be presented by treatment 
sequence and overall using All Subjects Set (randomized or dosed), as appropriate:  
x
 All Subjectes Set (randomized or dosed) 
x
Randomized 
x Full Analysis Set (FAS)
x
Safety Set
x
Completed treatment period 1 
x Prematurely discontinued the treatment period 1, and the reasons for discontinuations
x
Completed treatment period 2 
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x Prematurely discontinued the treatment period 2, and the reasons for discontinuations
x
Completed study (defined as completed Safety Follow-up Visit) 
x Prematurely discontinued the study and the reasons for discontinuations
A listing will be provided for subjects who discontinued treatment or who discontinued study, 
along with reasons for discontinuations. 
8.2.2 
Demographics and Baseline Characteristics 
Demographic, background (e.g. medical history), and baseline characteristics will be 
summarized by treatment sequence and overall. Protocol deviations/violations will be provided 
as a subject data listing only.  Important protocol deviations/violations will be identified for 
analysis purposes. 
Demographic data will include but not limited to the following: 
x
Age at screening  
x Age group at screening (>= 12  to < 18, and t18 years) 
x Sex 
x Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
x Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, and Other) 
x
Country 
Baseline characteristics will include the following: 
x Weight (kg) at study baseline 
x
Height (cm) at study baseline 
x BMI (kg/m2) at study baseline 
x Mutation genotype 
x ppFEV1 at study baseline 
x ppFEV1 category at study baseline (<40, ≥40 to <70,  ≥70 to ≤90, and  >90) 
x Sweat chloride at study baseline 
x
CFQ-R at study baseline 
x
FEV1 (L) at study baseline 
x FVC (L) at study baseline 
x Percent predicted FVC at study baseline 
x
FEF25-75% (L/sec) at study baseline 
x Percent predicted FEF25-75% at study baseline 
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x
FEV1/FVC at study baseline 
In addition, subject data listings will also be provided for: 
x Informed consent 
x Inclusion/Exclusion criteria violation (for subjects with any such violations) 
8.2.3 
Medical History 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities
(MedDRA). 
For the FAS, medical history will be summarized descriptively by treatment sequence, system 
organ class (SOC) and preferred term (PT) for each treatment sequence and overall. It will be 
listed too. 
8.2.4 
Prior and Concomitant Medications  
Medications taken during this study will be coded using the World Health Organization Drug 
Dictionary Enhanced (WHO-DDE) and categorized as follows: 
x
Prior medication: any medication that started prior to the first dose of study drug, 
regardless of when it ended. 
x
Concomitant medication: medication continued or newly received during the TE period 
for Treatment Period 1 or Treatment Period 2. If a subject took a medication during a 
specific Treatment Period, this medication will be attributed to the treatment the subject 
received during this Treatment Period. As a result, 1 medication could be attributed to more 
than 1 study drug for an individual subject. 
x
Post-treatment medication: medication continued or newly received after the TE period 
for Treatment Period 2, or between the TE periods for Treatment Period 1 and Treatment 
Period 2, or after the TE period for Treatment Period 1 for subjects who do not have 
Treatment Period 2. 
A given medication can be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; or 
prior, concomitant, and post-treatment. If a medication has a missing or partial missing 
start/end date or time and it cannot be determined whether the medication was taken before 
initial dosing, concomitantly, or post-treatment, it will be considered as prior, concomitant, and 
post-treatment. 
For medications with partial start dates, missing month will be imputed with January and 
missing day will be imputed with 1.  For medications with partial stop dates, missing month 
will be imputed with December and missing day will be imputed with the last day of the month. 
For the missing years, 2000 will be used for the start dates and 2050 will be used for the end 
dates. 
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The logic to decide the category of a medication is presented in Table 8-1.
Table 8-1  
Logic for Determining the Category of a Medication 
Medication start date
Medication end date
< Start date 
ofTE 
Period 1
≥ Start date of TE 
Period 1 and ≤ End 
date of TE Period 1
> End date of TE 
Period 1 and < Start 
date of TE Period 2
≥ Start date of TE 
Period 2 and ≤ End 
date of TE Period 2
> End date of 
TE Period 2
< Start date of TE 
Period 1
P
PC1
PC1A
PC1C2A
PC1C2A
≥ Start date of TE 
Period 1 and ≤ End date 
of TE Period 1
-
C1
C1A
C1C2A
C1C2A
> End date of TE Period 
1 and < Start date of TE 
Period 2
-
-
A
C2A
C2A
≥ Start date of TE 
Period 2 and ≤ End date 
of TE Period 2
-
-
-
C2
C2A
> End date of TE Period 
2
-
-
-
-
A
P – Prior; C1 – Concomitant for the Treatment in Period 1; C2 – Concomitant for the Treatment in Period 2; A –
 Post-Treatment. 
Prior medication summary will be presented by treatment sequence and concomitant 
medication summary will be presented by treatment. Both prior and concomitant medication 
will be based on FAS. Medications will be listed by subject. 
8.2.5 
Study Drug Exposure  
Exposure summaries will be based on the FAS and presented by treatment group. 
Duration of study drug exposure is defined as follows: last dose date – first dose date + 1 day 
within the treatment period, regardless of any interruption in dosing between the first and the 
last dose. 
If the last dose date of study drug is missing, the subject’s discontinuation or completion date 
will be used for analysis purposes.  
Exposure will be summarized as a continuous variable in weeks, and also in the following 
categories: ≤2 weeks; >2 and ≤4 weeks;>4 and ≤8 weeks; and >8 weeks, for each treatment 
group. 
8.2.6 
Study Drug Compliance  
Study drug compliance will be measured by the compliance rate; summarized based on the 
FAS and presented by treatment group. 
Compliance rate will be calculated as follows: 
100 × [1 - (Total number of days study drug interrupted) / (Duration of study drug 
exposure)]. 
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The total number of days study drug interrupted is defined as the total of number of days the
study drug was interrupted in each interruption interval, where number of days study drug 
interrupted in each interval is defined as the interruption end date - the corresponding 
interruption start date + 1.
Study drug compliance will be summarized descriptively by the number of subjects (n), mean, 
SD, SE, median, min, and max and into the categories of <80% and ≥80%.
A list of subjects with <80% compliance rate will be provided.
8.2.7 
Important Protocol Deviations  
Important protocol deviations (IPDs) are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of the study data or that may significantly
affect a subject's rights, safety, or well-being. IPDs will be identified from the clinical database 
and/or site deviation log, and IPD rules will be developed and finalized before database lock. 
The protocol deviations that may be considered as potential IPDs include, but are not limited 
to:
x Violation of subjects rights, safety or well-being 
x Subject entered the study despite violation of any inclusion or exclusion criteria 
x Subject was less than 80% compliant with study medications 
x Subject received prohibited concomitant medications 
x Subject received the wrong treatment or incorrect doses 
x Subject remained in study despite meeting withdrawal criteria 
Occurrence of any of these events should be considered as potential IPDs, but the blinded team 
should categorize them as IPDs only if they have the potential to affect interpretation of study 
results. 
IPDs (from the clinical database or from the site deviation log) will be presented in an 
individual subject data listing. 
8.3 
Efficacy Analysis  
The primary objective of this study is to evaluate the efficacy of LUMA/IVA. For efficacy 
analysis, the statistical inference will be based on change from study baseline. Unless otherwise 
defined, all efficacy analyses described in this section will use the FAS. The efficacy analyses 
will be performed according to the treatment to which the subject was actually assigned in each 
period. Data for a period will be used provided that the subject received at least one dose of 
study drug in that treatment period. 
8.3.1 
Analysis of Primary Efficacy Variable(s) 
The analysis will include all available measurements up to Week 8 [inclusive] during each 
treatment period, both on-treatment measurements and measurements after treatment 
discontinuation, per the visit windowing rules (Appendix B). 
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8.3.1.1 
Definition of Variable 
The primary efficacy endpoint is the absolute change in ppFEV1 from study baseline through 8 
weeks of treatment. 
ppFEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a percentage. The 
predicted FEV1 will be calculated based on the Global Lung Function Initiative (GLI)-2012 
multi-ethnic all-age reference equations3; details are provided in Appendix D. 
8.3.1.2 
Primary Analysis  
The primary efficacy analysis will be based on a mixed effects model using SAS procedure 
MIXED. The null hypothesis to be tested is that the mean absolute change from study baseline 
in ppFEV1 through 8 weeks of treatment is the same for LUMA/IVA and placebo. 
The primary efficacy variable/endpoint is the absolute change from baseline in percent 
predicted FEV1 through Week 8 in each Treatment Period. 
The primary analysis for the primary efficacy variable will be based on a mixed-effects model 
for repeated measures (MMRM). The model will include the absolute change from the study 
baseline in each Treatment Period as the dependent variable, with sequence, treatment, period, 
visit within period, and treatment-by-visit interaction as fixed effects, study baseline percent 
predicted FEV1 as covariate, and subject nested within sequence as the random effect. In the 
model, visit will be treated as a class variable. An unstructured covariance matrix is assumed 
for the repeated measurements of the same subject within each treatment period. If there is a 
convergence problem for the unstructured covariance matrix, an appropriate covariance matrix 
structure, such as compound symmetry, will be assumed in the primary analysis.  Denominator 
degrees of freedom for the F-test for fixed effects will be estimated using the Kenward-Roger 
approximation1. With a mixed-effects model as the primary analysis model based on maximum 
likelihood estimation and assuming that data are missing at random conditional on fixed and 
random effects, no imputation of missing data will be done. 
With a mixed-effects model based on a restricted maximum likelihood estimation used for the 
primary analysis and assuming that, conditional on fixed and random effects, data are missing 
at random, no imputation of missing data will be performed. 
The estimated mean treatment difference overall, a 95% CI, and a 2-sided P value will be 
provided. The estimated mean treatment difference at each visit along with the corresponding 
95% CI and P value will also be presented.  
As a supportive sensitivity analysis, the above MMRM analysis will be repeated using change 
from period baseline instead of change from study baseline. 
The raw values and changes from study baseline will be summarized by treatment group using 
descriptive statistics at each scheduled visit. In addition, raw values and changes from period 
baseline will be also summarized by treatment group using descriptive statistics at each 
scheduled visit.  The subgroup summary by mutation groups will also be performed. 
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8.4 
Safety Analysis 
All safety analyses will be based on the set of data associated with the TE period for Treatment 
Period 1 and the TE period for Treatment Period 2. Safety analyses will use the Safety Set. 
Subjects will be analyzed according to the treatment they actually received in a given treatment 
period. For safety analysis, the period baseline will be used, as applicable. 
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 data (liver function tests) 
x
Vital signs 
x
Pulse oximetry 
x
Physical examination 
x
Ophthalmologic examination 
Only descriptive analysis of safety will be performed; no statistical testing is planned.  All safety 
data will be presented in individual subject data listings. 
For the purpose of safety analysis, the study period will be further divided into 3 segments per 
the definition of the treatment emergent (TE) period (Section 8.1): 
x
The pre-treatment period is the period after the informed consent/assent date and before the 
initial dosing of study drug in the study. 
x
The treatment-emergent period (TE period) is defined in Section 8.1.
x
The post-treatment period is the period after the last date of TE period for Treatment 
Period 2 to the date of the last study record in the clinical database or the period between the 
end of TE period for Treatment Period 1 and the start of TE period for Treatment Period 2. 
For subjects who do not have Treatment Period 2, the period after the last date of TE period 
for Treatment Period 1 to the date of the last study record in the clinical database will be 
considered as post-treatment period.  
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8.4.1 
Adverse Events  
For analysis purposes, 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 in the study. 
x
TEAE: any AE that increased in severity or that was newly developed during the TE period 
for Treatment Period 1 or Treatment Period 2. If an AE started (or increased in severity) 
during a specific Treatment Period, this AE will be attributed to the treatment the subject was 
receiving during the Treatment Period. 
x
Post-treatment AE: any AE that increased in severity or that was newly developed during 
the post-treatment period. 
For AEs with missing or partial start date, if there is no clear evidence that the AEs started (or 
increased in severity) before the first dose, the start date will be imputed to the first dosing date 
and the AE assigned to the treatment in Treatment Period 1. As an intermediate step for 
programming purposes, imputation rules for missing or partially missing AE start/end dates are 
defined in Appendix C.
By relationship to the study drug regimen, TEAEs will be classified into 4 categories, as defined 
in Section 13.1.1.5 of the protocol: 
x Not related 
x Unlikely related 
x Possibly related 
x Related 
By severity, TEAEs will be classified into 4 categories, as defined in Section 13.1.1.4 of the 
protocol: 
x Mild or Grade 1 
x Moderate or Grade 2 
x Severe or Grade 3 
x Life-threatening or Grade 4 or 5 
8.4.1.1 
Overview of Treatment Emergent AEs 
An overview of all TEAEs will be summarized in the following categories: 
x
Any TEAEs 
x
TEAEs by relationship 
x
Related TEAEs 
x
TEAEs by severity
x
Grade 3/4 TEAEs 
x
Serious TEAEs
x
Related Serious TEAEs 
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x
TEAEs leading to treatment discontinuation 
x
TEAEs leading to treatment interruption  
x
TEAEs leading to death 
8.4.1.2 
TEAEs and TE SAEs by System Organ Class and Preferred Term 
The number and percentage of subjects with TEAEs will be summarized by treatment group, 
MedDRA system organ class (SOC) and preferred term (PT), where multiple occurrences of the 
same AE or a continuing AE for the same subject will be counted only once. The summary table 
will be presented in descending order of frequencies in the LUMA/IVA treatment group. TE
SAEs will be summarized similarly. 
8.4.1.3 
TEAEs and TE SAEs by PT 
The number and percentage of subjects with TEAEs will be summarized by treatment group 
and PT, where multiple occurrences of the same AE or a continuing AE for the same subject 
will be counted only once. TE SAEs will be summarized similarly. 
8.4.1.4 
Related TEAEs and TE SAEs by SOC, PT 
The number and percentage of subjects with related TEAEs will be summarized by treatment 
group, SOC, and PT, where multiple occurrences of the same AE or a continuing AE for the 
same subject will be counted only once. The summary table will be presented in descending 
order of frequencies in the LUMA/IVA treatment group. TEAEs in the following relationship to 
study drug regimen categories will be considered as related: Related, Possibly Related and 
Missing. Missing relationships will be summarized separately, as well.  TE SAEs will be 
summarized similarly. 
8.4.1.5 
Grade 3/4 TEAEs by SOC, PT 
The number and percentage of subjects with Grade 3/4 TEAEs will be summarized by 
treatment group, SOC, and PT, where multiple occurrences of the same AE or a continuing 
AE for the same subject will be counted only once. The summary table will be presented in 
descending order of frequencies in the LUMA/IVA treatment group. Grade 3/4 TEAEs include 
severe and life-threatening adverse events. 
8.4.2 
Clinical Laboratory 
For treatment-emergent liver function measurements, the raw values and change from period
baseline values will be summarized in SI units by treatment group at each scheduled time point.  
The number and percentage of subjects with liver function values meeting the defined threshold
criteria during the overall TE period will be summarized. The threshold analysis criteria are 
provided in Appendix F. 
For all LFT results (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline 
phosphatase [ALP], direct bilirubin, total bilirubin, and gamma-glutamyl transferase [GGT]), a 
listing of subjects with elevated LFT results during the TE period will be presented. 
The hematology and chemistry lab results at screening will be listed.
Results of urinalysis and the urine/serum pregnancy test will be listed in individual subject data 
listings only. 
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8.4.3 
Vital Signs 
For treatment-emergent vital signs measurements, the raw values and change from period
baseline values will be summarized by treatment group at each scheduled time point: systolic 
and diastolic blood pressure (mm Hg), body temperature (oC), HR (beats per minute), and 
respiratory rate (breaths per minute). In addition, the mean value at each time point will be 
plotted by treatment group for systolic and diastolic blood pressure. 
8.4.4 
Pulse Oximetry 
Arterial oxygen saturation by pulse oximetry will be measured at visits noted in Schedule of 
Assessments.  The assessments of pulse oximetry on Day 2 and the day after the Week 16 Visit 
will be performed only for subjects whose FEV1 at the Screening Visit is <40% of predicted.  
For treatment-emergent pulse oximetry measurements, a listing of raw values and change from 
baseline will be provided.   
8.4.5 
Physical Examination  
Abnormal physical examination results performed as part of the Screening Period assessment 
will be presented in subject data listings only. Clinically relevant results identified after 
screening will be reported as AEs. 
8.4.6 
Ophthalmologic Examination 
The subjects with abnormal ophthalmological examinations for subjects < 18 years old at 
screening will be presented in an individual subject data listing. 
In addition, the ophthalmological history data for all subjects will be listed. 
9
SUMMARY OF INTERIM AND IDMC ANALYSES 
No formal interim or IDMC analyses are planned for this study. 
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10
REFERENCES 
1.
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics. 1997;53:983-97. 
2.
Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm.
3.
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 
Regression Equations and Lookup Tables. Version 7 April 2013. Available at: 
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/quanjer-gli-
2012-regression-equations-and-lookup-tables.aspx. 
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11
LIST OF APPENDICES 
11.1 
Appendix A: Schedule of Assessments 
Table 11-11-1   Study VX15-809-111: Screening Period Assessments 
Assessment
Screening Period
(Day -28 through Day -1)
Informed consent and assent (when applicable)
X
Review inclusion/exclusion criteria
X
Demographics
X
Medical history
X
CFTR genotypinga
If deemed necessary by investigator
Ophthalmological history
X
Prior and concomitant medications
X
Ophthalmologic examinationb
X
Complete physical examination
X
Weight, heightc
X
Vital signs and pulse oximetryd
X
Spirometrye
X
FSHf
X
Serum pregnancy test (females of childbearing potential)g
X
Hematology 
X
Serum chemistry
X
AEs and SAEs
Continuous from signing of the ICF and 
Assent Form (where applicable) through the 
Follow-up Visit
a  
It is expected that most subjects will have documentation of CFTR genotype in their medical records. If 
documentation of CFTR genotype is not available, or if confirmation of CFTR genotype is deemed necessary 
by the investigator, CFTR genotyping will be performed during the Screening Period. 
b 
Ophthalmologic examination is required for subjects who are less than 18 years of age at the Screening Visit. If 
there is documentation of an ophthalmologic examination that met protocol criteria and was conducted within 
3 months before the Screening Visit, the subject is not required to have a repeat ophthalmologic examination 
during Screening.  
c 
Weight and height will be measured with shoes off. 
d 
Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) and pulse oximetry will be 
collected after the subject has been at rest (seated or supine) for at least 5 minutes. Blood pressure will be 
measured by sphygmomanometer. 
e 
At Screening, spirometry may be performed pre- or post-bronchodilator.  
f 
FSH will be measured for any suspected postmenopausal female with at least 12 months of continuous 
spontaneous amenorrhea. Serum FSH levels must be ≥40 mIU/mL to be considered postmenopausal. 
g 
See Section 11.6.7.1 of the protocol for definition of childbearing potential. 
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Table 11-11-2Study VX15-809-111: Treatment Period Assessments 
Treatment Period 1
Washout 
Period 
(No Visit)
Treatment Period 2
Early 
Termina-
tion of 
Treat-
ment 
(ETT)
Event/Assessment 
Day 1
Day 2a
Week 4
(± 4 days)
Week 8
(± 7 days)
8 weeks
(± 7 days)
Week 16
(± 4 days)
Day after 
Week 16
Visita
Week 20
(± 4 days)
Week 24
(± 7 days)
Review inclusion/
exclusion criteriab
X
Randomization
X
Vital signsg
X
X
X
X
X
X
X
X
X
Pulse oximetry
X
X
Spirometryh
X
X
X
X
X
X
X
X
X
Urine pregnancy 
testi
X
X
X
X
X
X
X
a 
These visits will be conducted for subjects whose FEV1 at Screening is <40% of predicted. 
b 
Confirmation of subject eligibility will occur before randomization. 
  
  
  
  
g  
Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be collected after the subject has been at rest (seated or supine) for at least 5 minutes. 
Blood pressure will be measured by sphygmomanometer. 
h 
Spirometry will be performed pre-bronchodilator and must be performed before study drug dosing. 
i
Pregnancy tests will be performed for all female subjects of childbearing potential. The urine β-hCG tests on Day 1 and Week 16 must be negative before the study drug is 
administered. 
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Statistical Analysis Plan Methods                                                                                                                                                                                                                  Page 32 of 42 
Protocol Number: VX15-809-111 
Vertex Pharmaceuticals Incorporated                                                                                                                     
Table 11-11-2Study VX15-809-111: Treatment Period Assessments 
Treatment Period 1
Washout 
Period 
(No Visit)
Treatment Period 2
Early 
Termina-
tion of 
Treat-
ment 
(ETT)
Event/Assessment 
Day 1
Day 2a
Week 4
(± 4 days)
Week 8
(± 7 days)
8 weeks
(± 7 days)
Week 16
(± 4 days)
Day after 
Week 16
Visita
Week 20
(± 4 days)
Week 24
(± 7 days)
Liver function tests 
(LFTs)j
X
X
X
X
X
Ophthalmologic 
examinationk
Xl
Xl
Meal(s) or snack(s) 
at siten
X
X
X
X
X
X
X
X
Study drug dosing
Day 1 through Week 8
(Last dose of study drug will be administered the 
day before the Week 8 Visit)
No study 
drug
Week 16 through Week 24
(Last dose of study drug will be administered the 
day before the Week 24 Visit)
Observation 4 h
after dosingo
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
Concomitant 
treatments and 
procedures
X
X
X
X
X
X
X
X
X
AEs and SAEs
Continuous from signing of the ICF and Assent Form (where applicable) through the Follow-up Visit 
j  
ALT, AST, GGT, alkaline phosphatase, and bilirubin. 
k  
For subjects who were less than 18 years of age at the Screening Visit. 
l 
Ophthalmologic examination will be performed at the Week 24 Visit, the Early Termination of Treatment Visit, or the Follow-up Visit. This examination is not required if the 
subject received the study drug for a total of less than 4 weeks. 
n 
Fat-containing food such as a standard "CF" high-fat, high-calorie meal or snack will be provided to subjects at the site after all predose assessments have occurred. 
o  
Observation 4 h after dosing will be performed for subjects whose FEV1 at Screening is <40% of predicted. 
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Statistical Analysis Plan Methods                                                                                                        Page 33 of 42 
Protocol Number: VX15-809-111
Vertex Pharmaceuticals Incorporated
Table 11-11-3Study VX15-809-111: Follow-up Visit Assessments 
Event/Assessment
Follow-up
4 weeks (± 7 days) after last dose of study drug
Vital signsa
X
Spirometryd
X
Serum pregnancy teste
X
LFTsf
X
Ophthalmologic examinationg,h
X
Concomitant medications
X
Concomitant treatments and procedures
X
AEs and SAEs
Continuous from signing of the ICF and Assent Form 
(where applicable) through the Follow-up Visit
a  
Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be collected after the 
subject has been at rest (seated or supine) for at least 5 minutes. Blood pressure will be measured by 
sphygmomanometer. 
  
  
d 
Spirometry will be performed pre-bronchodilator. 
e 
Pregnancy tests will be performed for all female subjects of childbearing potential.  
f  
ALT, AST, GGT, alkaline phosphatase, and bilirubin. 
g  
For subjects who were less than 18 years of age at the Screening Visit. 
h  
Ophthalmologic examination will be performed at the Week 24 Visit, the Early Termination of Treatment 
Visit, or the Follow-up Visit. This examination is not required if the subject received study drug for a total 
of less than 4 weeks. 
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Statistical Analysis Plan Methods                                                                                                                                                                                                                  Page 34 of 42 
Protocol Number: VX15-809-111 
Vertex Pharmaceuticals Incorporated                                                                                                                 
11.2 
Appendix B: Analysis Visit Windows for Safety and Efficacy 
Assessments 
Table 11-4
Visit Window Mapping Rules (within Period)
Assessments
Period -
Visit
Analysis 
Visit
Target 
Study 
Day
Visit Window 
(in study days)
Vital signs (excluding weight, BMI), and 
spirometry, 
per Schedule of Assessments
1 – Day 1
Day 1
1
[1, 1]
1 – Day 2
Day 2
2
Remain as the nominal visit
1 – Week 
4
Week 4
29
[study day of Day 2 visit +1, 43]
1 – Week 
8
Week 8
57
[44, 71]
2 – Week 
17
Day 1
1
[1, 1] of period 2
2 – Week 
17-2
Day 2
2
Remain as the nominal visit
2 – Week 
20
Week 4
29
[study day of Day 2 visit in period 2 +1, 
, 43 of period 2] 
2 – Week 
24
Week 8
57
[44, 71] of period 2
Safety 
Follow-up
Visit
Safety 
Follow-up
Visit
NA
For Vital Signs, remain as the nominal 
visit.
For Spirometry, follow the individual 
visit window to be mapped to individual 
visits if measured before / on Day 71 or 
remain as SFU if otherwise. 
Height
1 - Day 1
Day 1
1
[1, 1]
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Statistical Analysis Plan Methods                                                                                                                                                                                                                  Page 35 of 42 
Protocol Number: VX15-809-111 
Vertex Pharmaceuticals Incorporated                                                                                                                 
Safety 
Follow-up
Visit 
Safety 
Follow-up
Visit 
NA
Remain as the nominal visit
Other clinical chemisty and hemotology 
lab except LFTs, urine prenanancy test, 
pulse oximetry, ophthalmologic 
examination, physical examination
Any
Any
NA
Remain as the nominal visit
Note: 
1. For measurements taken on Day 2 of each treatment period, no visit windowing rule shall 
be applied. Instead, nominal visit will be used. 
2. For all “efficacy” parameters, if there are multiple measurements within a visit window, 
the record at the scheduled visit will be used. 
x  If there are no measurements at the scheduled visit, then the record closest to the target 
day will be used; 
x If there are multiple records with the same distance to the target day, the latest record 
will be used. 
3. For all “safety” parameters, such as liver function tests, if there are multiple 
measurements within a visit window, then 
x
the record closest to the target day will be used; or  
x
if there are multiple records within the same distance from the target day, the latest
record will be used. 
4. Spirometry, 
 will follow the efficacy 
windowing rules. 
5. For prenanancy test, pulse oximetry, ophthalmologic examination, physical examination,  
there is no need to derive the mapped analysis visit as they will be listed only.  
11.3 
Appendix C: Imputation Rules for Missing AE dates 
Imputation rules for missing or partial AE start date are defined below: 
If only Day of AE start date is missing:  
If the AE start year and month are the same as that for the first dose date, then: 
x
If the full (or  partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start day as the day of first dose date; otherwise, impute the 
AE start day as 1. 
x
Otherwise, impute the AE start day as 1. 
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
If Day and Month of AE start date are missing: 
If AE start year = first dose year, then: 
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Statistical Analysis Plan Methods                                                                                                                                                                                                                  Page 36 of 42 
Protocol Number: VX15-809-111 
Vertex Pharmaceuticals Incorporated                                                                                                                 
x
If the full (or partial) AE end date is NOT before the first dose date or AE end date is
missing, then impute the AE start Month and Day as the Month and Day of first dose 
date; otherwise, impute the AE start Month as January and the Day as 1. 
x
Otherwise, impute the AE start MONTH as January and the DAY as 1. 
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site with 
no imputation. Also compare the full (or partial) AE end date to the first dose date. If the AE 
end date is before the first dose date then the AE should be considered as a pretreatment AE. 
Otherwise, the AE will be considered as TEAE. 
The imputation rule will be applied with respect to treatment start date for both periods, as 
necessary and applicable,  and preference will be given to treatment in period 1 in case the 
AE is assigned to treatments in both periods. Missing or partially missing AE end date will 
not be imputed.
11.5 
Appendix E: Precisions of Summary Statistics and Derived 
Variables in TFLs  
Continuous Variables  
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Statistical Analysis Plan Methods                                                                                                                                                                                                                  Page 37 of 42 
Protocol Number: VX15-809-111 
Vertex Pharmaceuticals Incorporated                                                                                                                 
Table 11-5
Precision of special summary statistics for CF studiesj
Variables
Statistics
Decimal Places
ppFEV1
Mean, LS 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, median, SD and SE will be reported to 1 greater decimal place. 
Any values that require transformation to standard units (metric or SI) will be converted with 
the appropriate corresponding precision. 
Categorical Variables: Percentages will be presented to 1 decimal place. 
j The precisions will be reflected in the TFLs.  
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Statistical Analysis Plan Methods                                                                                                                                                                                                                  Page 38 of 42 
Protocol Number: VX15-809-111 
Vertex Pharmaceuticals Incorporated                                                                                                                 
11.6 
Appendix F: Criteria for Potentially Clinically Significant Events 
(Threshold Analysis Criteria) 
Please use relevant threshold analysis criteria from the following tables as it applies to this study.
Table 11-6
Threshold Criteria for Laboratory Tests
Parameter
Criteria
Comments
Clinical Chemistry
CPK
>ULN - ≤ 2.5 x ULN
>2.5 - ≤ 5 x ULN
>5 - ≤ 10x ULN 
>10 x ULN
CTCAE grades 1-4
Creatinine
>ULN - ≤ 1.5 x ULN
>1.5 - ≤ 3.0 x ULN
>3.0 - ≤ 6.0 x ULN
>6.0 x ULN
CTCAE grades 1-4
Blood Urea 
Nitrogen
>ULN - ≤ 1.5 x ULN
>1.5 - ≤ 3.0 x ULN
>3.0 - ≤ 6.0 x ULN
>6.0 x ULN
Same criteria as creatinine 
No CTCAE 
Sodium
Hyponatremia
<LLN - ≥130 mmol/L
<130 – ≥120 mmol/L 
<120 mmol/L 
CTCAE grade 1, 3, 4
(No CTCAE grade 2)
Hypernatremia
>ULN - ≤ 150 mmol/L
>150 mmol/L- ≤155 mmol/L 
>155 mmol/L - ≤ 160 mmol/L
>160 mmol/L
CTCAE grade 1-4
Potassium
Hypokalemia
<LLN – ≥ 3.0 mmol/L
<3.0 – ≥ 2.5 mmol/L
<2.5 mmol/L
CTCAE grade 1&2, 3, 4
(Grade 1 and 2 are the same)
Hyperkalemia
>ULN – ≤ 5.5 mmol/L
>5.5 – ≤ 6.0 mmol/L 
>6.0 – ≤ 7.0 mmol/L 
>7.0 mmol/L
CTCAE grade 1-4
Total Cholesterol
>ULN – ≤ 7.75 mmol/L
>7.75 – ≤ 10.34 mmol/L 
>10.34 – ≤ 12.92 mmol/L
>12.92 mmol/L
CTCAE grade 1-4
Triglycerides
>1.71 – ≤ 3.42 mmol/L 
>3.42 – ≤ 5.7 mmol/L 
>5.7 – ≤ 11.4 mmol/L 
>11.4 mmol/L
CTCAE grade 1-4
Glucose
Hypoglycemia
<3.0 – ≥ 2.2 mmol/L 
<2.2 - ≥ 1.7 mmol/L
<1.7 mmol/L
CTCAE grade 1-4
Hyperglycemia 
>ULN - ≤ 8.9 mmol/L
CTCAE grade 1-4
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Statistical Analysis Plan Methods                                                                                                                                                                                                                  Page 39 of 42 
Protocol Number: VX15-809-111 
Vertex Pharmaceuticals Incorporated                                                                                                                 
>8.9 – ≤ 13.9 mmol/L
>13.9 – ≤ 27.8 mmol/L 
>27.8 mmol/L
Albumin
<35 - ≥ 30 g/L
<30 – ≥ 20 g/L
<20 g/L 
CTCAE grade 1-3
Amylase
>ULN - ≤ 1.5 x ULN
>1.5 – ≤ 2.0 x ULN 
>2.0 – ≤ 5.0 x ULN
>5.0 x ULN
CTCAE grade 1-4
Lipase
>ULN - ≤ 1.5 x ULN
>1.5 – ≤ 2.0 x ULN 
>2.0 – ≤ 5.0 x ULN
>5.0 x ULN
CTCAE grade 1-4
Direct bilirubin
>ULN - ≤ 1.5 x ULN
>1.5 – ≤ 2 x ULN
>2 – ≤ 3 x ULN 
>3 – ≤ 10 x ULN
>10 x ULN
Same Criteria as Total Bilirubin
No CTCAE 
Not in DILI Guidance
GGT 
>ULN - ≤ 2.5 x ULN
>2.5 – ≤ 5.0 x ULN
>5.0 – ≤ 20.0 x ULN 
>20.0 x ULN
CTCAE grade 1-4
Calcium
Hypercalcemia
>ULN - ≤ 2.9 mmol/L 
>2.9 – ≤ 3.1 mmol/L 
>3.1 – ≤ 3.4 mmol/L 
>3.4 mmol/L
CTCAE grade 1-4
Hypocalcemia
<LLN - ≥ 2.0 mmol/L
<2.0 – ≥1.75 mmol/L 
<1.75 – ≥ 1.5 mmol/L 
<1.5 mmol/L 
CTCAE grade 1-4
Magnesium
Hypermagnesemia
>ULN - ≤ 1.23 mmol/L
>1.23 – ≤ 3.30 mmol/L
>3.30 mmol/L
CTCAE grade 1, 3, 4
No CTCAE grade 2
Hypomagnesemia
<LLN - ≥ 0.5 mmol/L
<0.5 – ≥ 0.4 mmol/L
<0.4 – ≥ 0.3 mmol/L 
<0.3 mmol/L 
CTCAE grade 1-4
Bicarbonate
<LLN
>ULN
No CTCAE
Inorganic 
phosphate
Hypophosphatemia
<0.74 – ≥ 0.6mmol/L
<0.6 – ≥ 0.3 mmol/L
<0.3 mmol/L
CTCAE grade 1-4
ALT
>ULN - ≤  3 xULN
>3 – ≤  5 xULN
>5 – ≤  8 xULN
>8 – ≤  20.0 xULN
>20.0 x ULN
Per FDA DILI Guidance Jul 2009 and 
CTCAE
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Statistical Analysis Plan Methods                                                                                                                                                                                                                  Page 40 of 42 
Protocol Number: VX15-809-111 
Vertex Pharmaceuticals Incorporated                                                                                                                 
AST
>ULN - ≤  3 xULN
>3 – ≤  5 xULN
>5 – ≤  8 xULN
>8 – ≤  20.0 xULN
>20.0 x ULN
FDA DILI Guidance and CTCAE
ALT or AST
(ALT>ULN and ALT ≤  3 xULN) or 
(AST>ULN and AST≤  3 xULN)
(ALT>3 xULN and ALT ≤  5 xULN) or 
(AST>3xULN and AST≤  5 xULN)
(ALT>5 xULN and ALT ≤  8 xULN) or 
(AST>5xULN and AST≤  8 xULN)
(ALT>8 xULN and ALT ≤  20 xULN) or 
(AST>8xULN and AST≤  20 xULN)
ALT>20 xULN or AST> 20 xULN
FDA DILI Guidance
Alkaline 
Phosphatase
>ULN - ≤ 1.5xULN
>1.5 – ≤ 2.5 xULN
>2.5 – ≤ 5.0 x ULN
>5.0 – ≤ 20.0 x ULN 
>20.0 x ULN 
FDA DILI Guidance and CTCAE
Total Bilirubin
>ULN - ≤ 1.5 x ULN
>1.5 – ≤ 2 x ULN
>2 – ≤ 3 x ULN 
>3 – ≤ 10 x ULN
>10 x ULN
FDA DILI Guidance and CTCAE
ALT and Total 
Bilirubin
ALT>3xULN and TBILI>2xULN
FDA DILI Guidance Jul 2009 
AST and Total 
Bilirubin
AST>3xULN and TBILI>2xULN
FDA DILI Guidance Jul 2009
(ALT or AST) and 
Total Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN
FDA DILI Guidance Jul 2009 
Hematology
WBC
WBC decreased
<LLN - ≥ 3.0 x 10e9 /L
<3.0 – ≥ 2.0 x 10e9 /L 
<2.0 – ≥ 1.0 x 10e9 /L 
<1.0 x 10e9 /L
CTCAE grade 1-4
Leukocytosis
>100 x 10e9 /L
CTCAE grade 3 (only Grade available) 
Lymphocytes
Lymphocyte decreased
<LLN - ≥ 0.8 x10e9 /L
<0.8 – ≥ 0.5 x10e9 /L 
<0.5 – ≥ 0.2 x10e9 /L 
<0.2 x10e9 /L
CTCAE grade 1-4
Lymphocyte increased
>4 – ≤ 20 x10e9/L 
>20 x10e9/L 
CTCAE grade 2, 3 (only Grades available)
Neutrophils
Neutrophil decreased
<LLN - ≥ 1.5 x10e9 /L
<1.5 – ≥ 1.0 x10e9 /L 
<1.0 – ≥ 0.5 x10e9 /L 
<0.5 x10e9 /L
CTCAE grade 1-4
Hemoglobin
Hgb decreased (anemia)
<LLN - ≥ 100 g/L
<100 – ≥ 80 g/L 
< 80 g/L
CTCAE grade 1-3
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Statistical Analysis Plan Methods                                                                                                                                                                                                                  Page 41 of 42 
Protocol Number: VX15-809-111 
Vertex Pharmaceuticals Incorporated                                                                                                                 
Hgb increased
>ULN - ≤ 20 g/L above ULN
>20 g/L above ULN - ≤ 40 g/L above ULN
>40 g/L above ULN 
CTCAE grade 1-3
Platelets
Platelet decreased
<LLN - ≥ 75.0 x 10e9 /L
<75.0 – ≥ 50.0 x 10e9 /L 
<50.0 – ≥ 25.0 x 10e9 /L 
<25.0 x 10e9 /L
CTCAE grade 1-4
Table 11-7 Threshold Criteria for Vital Signs
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT VITAL SIGNS
Parameter
Threshold Criteria
Comments
SBP
SBP increased
>140 mmHg
>160 mmHg
>10 mmHg increase from baseline
>20 mmHg increase from baseline
>140 mmHg & >10 mmHg increase from baseline
>140 mmHg & >20 mmHg increase from baseline
>160 mmHg & >10 mmHg increase from baseline
>160 mmHg & >20 mmHg increase from baseline
809/770 analyses
SBP decrease
<90 mmHg
<80 mmHg
>10 mmHg decrease from baseline
>20 mmHg decrease from baseline
<90 mmHg and >10 mmHg decrease from baseline
<90 mmHg and >20 mmHg decrease from baseline
<80 mmHg and >10 mmHg decrease from baseline
<80 mmHg and >20 mmHg decrease from baseline
Per HV grade 1, 3, plus shift change
DBP
DBP increased
>90 mmHg
>100 mmHg
>5 mmHg increase from baseline
>10 mmHg increase from baseline
>90 mmHg and >5 mmHg increase from baseline
>90 mmHg and >10 mmHg increase from baseline
>100 mmHg and >5 mmHg increase from baseline
>100 mmHg and >10 mmHg increase from baseline
809/770 analyses
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Statistical Analysis Plan Methods                                                                                                                                                                                                                  Page 42 of 42 
Protocol Number: VX15-809-111 
Vertex Pharmaceuticals Incorporated                                                                                                                 
DBP decreased
<60 mmHg
<45 mmHg
>5 mmHg decrease from baseline
>10 mmHg decrease from baseline
<60 mmHg and >5 mmHg decrease from baseline
<60 mmHg and >10 mmHg decrease from baseline
<45 mmHg and >5 mmHg decrease from baseline
<45 mmHg and >10 mmHg decrease from baseline
Weight
Weight gain 
≥5 % increase from baseline  
≥10 % increase from baseline 
≥ 20% increase from baseline 
CTCAE grade 1-3
Weight loss 
≥5 % decrease from baseline  
≥10 % decrease from baseline 
≥ 20% decrease from baseline 
CTCAE grade 1-3
Page 42 of 90