Clinical trial NCT02823470
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2016-06-01; Completion date: 2017-08-01
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will evaluate the impact of smart adherence technology for monitoring on lumacaftor/ivacaftor (LUM/IVA) adherence rates among subjects 16 years of age and older with Cystic Fibrosis (CF) who are homozygous for the F508del Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation.

Detailed description:

Arms: arm 1: LUM/IVA: LUM 400 mg q12h/IVA 250 mg q12h through Week 48. arm 2: LUM/IVA: LUM 400 mg q12h/IVA 250 mg q12h through Week 48.
Interventions: intervention 1: LUM/IVA intervention 2: activated smart device intervention 3: de-activated smart device
Intervention descriptions: intervention 1: LUM 400 mg q12h/IVA 250 mg q12h through Week 48. intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
 
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1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 4, Open-label Treatment, Randomized, 
Multicenter, 2-arm, Parallel-group, Pilot Study of 
Adherence to Lumacaftor/Ivacaftor in CF Subjects 
Homozygous for the F508del-CFTR Mutation  
Vertex Study Number: VX15-809-114 
  
Date of Protocol: 19 Oct 2016 (Version 2.0) 
Replaces Version 1.0, dated 18 Dec 2015 
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 4, Open-label Treatment, Randomized, Multicenter, 2-arm, Parallel-
group, Pilot Study of Adherence to Lumacaftor/Ivacaftor in CF Subjects 
Homozygous for the F508del-CFTR Mutation 
  
Brief Title A Pilot Study to Evaluate the Use of Smart Adherence Technology to Measure 
Lumacaftor/Ivacaftor Adherence in CF Subjects Homozygous for the 
F508del-CFTR Mutation 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 4, Adherence 
  
Objectives Primary 
To evaluate the impact of smart adherence technology for monitoring LUM/IVA 
adherence rates among subjects 16 years of age and older with CF who are 
homozygous for the F508del-CFTR mutation 
Secondary 
To collect subject and physician feedback on the use of smart adherence 
technology to monitor LUM/IVA adherence  
  
Endpoints Primary Endpoint 
Mean percentage adherence to LUM/IVA treatment over 48 weeks 
Secondary Endpoints 
 
Mean percentage adherence to LUM/IVA treatment over 24 weeks 
 
Mean percentage adherence to LUM/IVA treatment from Week 25 through 
Week 48 
 
Proportion of subjects with ≥80% LUM/IVA adherence over 24 weeks 
 
Proportion of subjects with ≥80% LUM/IVA adherence over 48 weeks 
 
Proportion of subjects with ≥80% LUM/IVA adherence from Week 25 
through Week 48 
 
Proportion of subjects with a non-physician-directed LUM/IVA interruption 
≥72 hours over 48 weeks 
 
Number of non-physician-directed LUM/IVA interruptions ≥72 hours over 
48 weeks 
 
Time to the first non-physician-directed LUM/IVA interruption ≥72 hours 
over 48 weeks 
 
 
  
 
 
 
 
 
 


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Number of Subjects Approximately 75 subjects will be enrolled. 
  
Study Population Male and female subjects 16 years of age and older with CF who are homozygous 
for the F508del-CFTR mutation 
  
Investigational 
Drug 
Active substance: LUM and IVA (fixed-dose combination [FDC] with LUM and 
IVA) 
Activity: CFTR corrector and potentiator (chloride ion secretion) 
Strength and Route of Administration: 200-mg LUM/125-mg IVA 
(200/125 mg) film-coated tablets for oral administration 
Dose Regimen: LUM 400 mg/IVA 250 mg every 12 hours (q12h) 
  
Smart Adherence 
Technology 
 
Smart Pill Bottle, activated 
 
Smart Pill Bottle (control), de-activated alerts and feedback features 
  
Study Duration The total duration is approximately 56 weeks (up to 28 days for the Screening 
Period, 48 weeks for the Treatment Period, and 28 days (± 7 days) for Safety 
Follow-up Period, if applicable)  
  
Study Design This is a Phase 4, open-label, randomized, multicenter, 2-arm, parallel-group pilot 
study evaluating LUM/IVA adherence. Each study arm will include a smart 
technology with either active or inactive dosing alert features.   
This study includes: 
 
Screening Period (Day −28 through Day −1) 
 
Treatment Period (Day 1 through Week 48)  
 
Safety Follow-up Visit at Week 52 (28 [± 7] days after the final dose of 
LUM/IVA  
Approximately 75 subjects will be enrolled in this study. All subjects will receive 
LUM 400 mg/IVA 250 mg q12h through Week 48. 
Subjects will be stratified by age (<23 versus ≥23 years of age) and forced 
expiratory volume in 1 second (FEV1) severity (<70% versus 70% predicted) 
determined at the Screening Period and then randomized (2:1) to 1 of the 
following 2 smart adherence technology study arms: 
 
Study Arm A: Smart Pill Bottle, activated  
 
Study Arm B: Smart Pill Bottle (control), de-activated alerts and 
feedback features 
Subjects will receive standardized education on the benefit of LUM/IVA, 
LUM/IVA adherence, and training on the use of the assigned smart adherence 
technology. During applicable study visits, subjects will complete adherence and 
technology satisfaction assessments. Physicians will also complete a technology 
satisfaction questionnaire adherence assessments.  
 
 
  


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Assessments Adherence: Smart Adherence Technology-Reported Adherence 
 
 
 
 
Safety: Adverse events, ophthalmologic examinations, clinical laboratory 
assessments, vital signs, physical examinations 
 
 
 
Statistical Analyses Statistical analysis details will be provided in the Statistical Analysis Plan (SAP). 
The primary endpoint is the mean percentage adherence to LUM/IVA treatment 
over 48 weeks. Assuming a standard deviation (SD) of 8, a sample size of 
50 subjects in Study Arm A and 25 in Study Arm B will have 80% power to 
detect a treatment difference of 5.6% between the means of the 2 arms using a 
2-sided, 2-sample t-test at the 0.05 significance level. 
The primary analysis for the primary endpoint variable will be based on an 
analysis of covariance (ANCOVA) with mean percentage adherence over 
48 weeks as the dependent variable, Study arm as a fixed effect with covariates 
for age (<23 versus ≥23 years old), FEV1 (<70% versus ≥70% predicted), 
, and sex (male versus female), at Screening. 
 
 
 
 
 
Summary statistics for each study arm will be provided. Primary and secondary 
analyses of adherence will be performed through smart technology generated data. 
A complementary analysis based on pill count and missing/interruption of dose 
will also be conducted. Summary of weekly adherence data will be provided; 
pattern of adherence over 48 weeks will be plotted and may be modeled using 
mixed effects models. 
No interim analysis is planned for this study.  
  


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of Assessments are shown in Table 3-1 (Screening Period) and Table 3-2 (Treatment 
Period and Safety Follow-up Visit).  
All visits are to be scheduled relative to the Day 1 Visit.  
Table 3-1 
Screening Period Assessments – Study VX15-809-114 
Assessment 
Screening Period 
Day -28 to Day -1 
Informed consent and assent (where applicable) 
X 
Inclusion and exclusion criteria review 
X 
Demographics 
X 
Height, weight, and BMI 
X 
Review of medical history (includes CFTR genotype)a 
X 
Ophthalmologic examinationb 
X 
Prior and concomitant medications 
X 
Vital signsc 
X 
Physical examinationd 
X 
Spirometrye 
X 
Serum pregnancy test (all female subjects of childbearing 
potential)f 
X 
Serum FSHg 
X 
Hematologyh 
X 
Liver Function Testingi  
X 
AEs and SAEs 
Continuous from signing of ICF or assent (where applicable) 
through Safety Follow-up Visit 
AE: adverse event; BMI: body mass index; CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator gene; FSH: 
follicle-stimulating hormone; ICF: informed consent form; IVA: ivacaftor; LUM: lumacaftor; PE: physical examination; 
SAE: serious adverse event; 
  
  a  
Genotype testing will be performed if this is not documented in medical history. CF genotyping can be waived with 
documented CFTR genotype (Section 11.5.2). 
b  
An ophthalmologic examination will be conducted by either a licensed ophthalmologist or an optometrist for all subjects 
<18 years of age. The exam may be waived if there is documentation of an exam within 3 months of the date of informed 
consent (or assent, when applicable). Subjects with documentation of bilateral lens removal do not need the ophthalmologic 
examination (Section 11.5.6). 
c  
Vital signs will be assessed following a 5-minute rest in the seated or supine position. 
d  
Physical examination of all body systems (Section 11.5.4). 
e  
Spirometry may be performed pre- or postbronchodilator (Section 11.5.5).  
f  
Any female subject initiating LUM/IVA combination therapy who is considered to be of childbearing potential should have 
a serum pregnancy test. Women of childbearing potential are defined as: female subjects after puberty unless they are 
postmenopausal for at least 1 year and have documented FSH levels within the postmenopausal reference range of the 
performing laboratory, or are surgically sterile. 
g  
Serum FSH levels will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous 
spontaneous amenorrhea. 
h 
Blood samples will be collected for clinical laboratory assessments (Section 11.5.2).  
i  
Liver function testing (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transpeptidase 
[GGT], alkaline phosphatase [ALP], and total bilirubin) must be performed at the scheduled visits (Section 11.5.2). 


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Table 3-2 
Treatment Period and Safety Follow-up Visit Assessments – Study VX15-809-114 
Event/Assessment 
Day 1 
Week 12 
Week 24 
Week 36 
Week 48 
Safety  
Follow-up  
Week 52a 
Clinic visit 
X 
X 
X 
X 
X 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
Physical examinationc 
 
 
 
 
X 
 Xd 
Liver Function Testinge 
X 
X 
X 
X 
X 
X 
Urine pregnancy test (all female subjects of childbearing potential) 
X 
X 
X 
X 
X 
X 
Randomizationf 
X 
 
 
 
 
 
Standardized education on adherence 
X 
 
 
 
 
 
Concomitant medications, treatments, and procedures 
X 
X 
X 
X 
X 
X 
Smart Adherence Technology-Reported Adherenceg  
 
X 
X 
X 
X 
 
LUM/IVA drug counti 
 
X 
X 
X 
X 
 
Ophthalmologic examinationj 
 
 
 
 
X 
 
AEs and SAEs 
Continuous from signing of ICF or assent (where applicable) 
LUM/IVA resupply 
Every 3 months throughout study 
 
AE: adverse event; ICF: informed consent form; IVA: ivacaftor; IWRS: interactive web response system; LUM: lumacaftor; PE: physical examination; SAE: serious adverse 
event; 
  
  a  
The Safety Follow-up Visit is 28 (± 7) days after the last dose of LUM/IVA (Section 8.1.3). 
b  
Vital signs will be assessed following a 5-minute rest in the seated or supine position. 
c 
Symptom-targeted PEs will occur at any time during the study if triggered by AEs or if deemed necessary by the investigator. 
d  
Required for subjects who do not begin commercial LUM/IVA after Week 48 only. 
e  
Day 1 only blood draws will be collected before the first dose of LUM/IVA. Liver function testing (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
gamma-glutamyl transpeptidase [GGT], alkaline phosphatase [ALP], and total bilirubin) must be performed at the scheduled visits (Section 11.5.2). 
f  
Randomization must occur after all inclusion and exclusion criteria are met and before the first dose of LUM/IVA. Randomization will be done through IWRS. 
g  
Data will be collected for all subjects throughout the study in real-time. Subjects in Study Arm A will review data with physicians at study visits.  
  
 
i  
LUM/IVA drug count will be collected at the end of specified study visits. 
j  
See Section 11.5.6. 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 6 
4 
Table of Contents ................................................................................................................... 8 
List of Tables............................................................................................................................ 11 
List of Figures .......................................................................................................................... 11 
5 
Introduction.......................................................................................................................... 12 
5.1 
Background ..................................................................................................................... 12 
5.2 
Study Rationale .............................................................................................................. 12 
6 
Study Objectives .................................................................................................................. 13 
6.1 
Primary Objective ........................................................................................................... 13 
6.2 
Secondary Objective ....................................................................................................... 13 
7 
Study Endpoints ................................................................................................................... 13 
7.1 
Primary Endpoint ............................................................................................................ 13 
7.2 
Secondary Endpoints ...................................................................................................... 13 
 
 
8 
Study Design ......................................................................................................................... 13 
8.1 
Overview of Study Design ............................................................................................. 13 
8.1.1 
Screening ................................................................................................................ 15 
8.1.2 
Treatment Period .................................................................................................... 15 
8.1.3 
Follow-up................................................................................................................ 16 
8.1.4 
Early Termination of Treatment ............................................................................. 16 
8.2 
Rationale for Study Design and Study Drug Regimens ................................................. 16 
8.2.1 
Study Design........................................................................................................... 16 
8.2.2 
Study Drug Dose and Duration .............................................................................. 17 
8.2.3 
Rationale for Study Assessments ........................................................................... 17 
9 
Study Population .................................................................................................................. 18 
9.1 
Inclusion Criteria ............................................................................................................ 18 
9.2 
Exclusion Criteria ........................................................................................................... 19 
9.3 
Study Restrictions ........................................................................................................... 20 
9.3.1 
Prior and Concomitant Medications and Other Study Restrictions ........................ 20 
9.3.1.1 
Drug Interactions .............................................................................................. 20 
9.4 
Removal of Subjects ....................................................................................................... 20 
9.5 
Replacement of Subjects ................................................................................................ 21 
10 Study Drug and Smart Adherence Technologies Administration and Management.... 21 
10.1 Preparation and Dispensing ............................................................................................ 21 
10.1.1 
LUM/IVA ............................................................................................................... 21 
10.1.2 
Smart Adherence Technologies .............................................................................. 21 
10.2 Administration ................................................................................................................ 21 
10.2.1 
LUM/IVA ............................................................................................................... 21 
10.3 Method of Assigning Subjects to Treatment Groups ..................................................... 22 
10.4 Dose Modification for Toxicity ...................................................................................... 22 
10.5 Missed Doses .................................................................................................................. 22 


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10.6 Study Drug Interruption ................................................................................................. 22 
10.7 Packaging and Labeling ................................................................................................. 22 
10.8 Study Drug and Smart Adherence Technology Supply, Storage, and Handling ............ 22 
10.9 Drug and Smart Adherence Technology Accountability ............................................... 23 
10.10 Disposal, Return, or Retention of Unused Drug ............................................................. 23 
10.11 Blinding and Unblinding ................................................................................................ 23 
11 Assessments .......................................................................................................................... 23 
11.1 Timing of Assessments ................................................................................................... 23 
11.2 Subject and Disease Characteristics ............................................................................... 24 
11.3 Adherence ....................................................................................................................... 24 
11.3.1 
Smart Adherence Technology-Reported Adherence .............................................. 24 
 
 
 
 
 
 
 
 
 
11.5 Safety .............................................................................................................................. 24 
11.5.1 
Adverse Events ....................................................................................................... 25 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 25 
11.5.3 
Liver Function Test Parameters .............................................................................. 26 
11.5.4 
Physical Examinations and Vital Signs .................................................................. 27 
11.5.5 
Spirometry .............................................................................................................. 27 
11.5.6 
Ophthalmologic Examination ................................................................................. 27 
11.5.7 
Contraception and Pregnancy ................................................................................. 28 
11.5.7.1 Contraception ................................................................................................... 28 
11.5.7.2 Pregnancy ......................................................................................................... 30 
 
 
 
 
 
12 Statistical and Analytical Plans .......................................................................................... 31 
12.1 Sample Size and Power .................................................................................................. 31 
12.2 Analysis Sets .................................................................................................................. 32 
12.3 Statistical Analysis ......................................................................................................... 32 
12.3.1 
General Considerations ........................................................................................... 32 
12.3.2 
Background Characteristics .................................................................................... 33 
12.3.2.1 Subject Disposition .......................................................................................... 33 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 33 
12.3.2.3 Prior and Concomitant Medications................................................................. 33 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 33 
12.3.3 
Important Protocol Deviations ................................................................................ 34 
12.3.4 
Analysis of Endpoints ............................................................................................. 34 
12.3.4.1 Analysis of Primary Endpoints ........................................................................ 34 
12.3.4.2 Analysis of Secondary Endpoints .................................................................... 34 
12.3.4.3 Analysis of Other Endpoints ............................................................................ 35 
12.3.5 
Safety Analysis ....................................................................................................... 36 
12.3.5.1 Adverse Events................................................................................................. 37 


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12.3.5.2 Clinical Laboratory Assessments ..................................................................... 37 
12.3.5.3 Vital Signs ........................................................................................................ 38 
12.3.5.4 Physical Examination ....................................................................................... 38 
12.3.5.5 Other Safety Analysis ...................................................................................... 38 
12.3.6 
Interim and IDMC Analyses ................................................................................... 38 
12.3.6.1 Interim Analysis ............................................................................................... 38 
12.3.6.2 IDMC Analysis ................................................................................................ 38 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 38 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 38 
13.1.1 
Adverse Events ....................................................................................................... 38 
13.1.1.1 Definition of an Adverse Event........................................................................ 38 
13.1.1.2 Clinically Significant Assessments .................................................................. 38 
13.1.1.3 Documentation of Adverse Events................................................................... 39 
13.1.1.4 Adverse Event Severity .................................................................................... 39 
13.1.1.5 Adverse Event Causality .................................................................................. 40 
13.1.1.6 Study Drug Action Taken ................................................................................ 40 
13.1.1.7 Adverse Event Outcome .................................................................................. 41 
13.1.1.8 Treatment Given............................................................................................... 41 
13.1.2 
Serious Adverse Events .......................................................................................... 41 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 41 
13.1.2.2 Documentation of Serious Adverse Events...................................................... 42 
13.1.2.3 Reporting Serious Adverse Events................................................................... 42 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 43 
13.2 Administrative Requirements ......................................................................................... 43 
13.2.1 
Ethical Considerations ............................................................................................ 43 
13.2.2 
Subject Information and Informed Consent ........................................................... 43 
13.2.3 
Investigator Compliance ......................................................................................... 43 
13.2.4 
Access to Records ................................................................................................... 44 
13.2.5 
Subject Privacy ....................................................................................................... 44 
13.2.6 
Record Retention .................................................................................................... 44 
13.2.7 
Study Termination .................................................................................................. 44 
13.3 Data Quality Assurance .................................................................................................. 45 
13.4 Monitoring ...................................................................................................................... 45 
13.5 Electronic Data Capture ................................................................................................. 45 
 
 
 
 
 
14 References ............................................................................................................................. 47 
15 Protocol Signature Pages .................................................................................................... 49 
15.1 Sponsor Signature Page .................................................................................................. 49 
15.2 Investigator Signature Page ............................................................................................ 50 


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List of Tables 
Table 3-1 
Screening Period Assessments – Study VX15-809-114 ......................................... 6 
Table 3-2 
Treatment Period and Safety Follow-up Visit Assessments – Study VX15-809-
114........................................................................................................................... 7 
Table 8-1 
Study VX15-809-114 Smart Adherence Technology Study Arms....................... 16 
Table 10-1 
LUM/IVA Administration .................................................................................... 21 
Table 10-2 
Identity of LUM/IVA, Dosage, and Storage ......................................................... 23 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 25 
  
 
Table 13-1 
Grading of AE Severity ........................................................................................ 40 
Table 13-2 
Classifications for AE Causality ........................................................................... 40 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 41 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 41 
 
List of Figures 
Figure 8-1 
Study Design ......................................................................................................... 14 
 


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5 
INTRODUCTION 
5.1 
Background 
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 
approximately 70,000 individuals worldwide.1 Based on the size of the population, CF qualifies 
as an orphan disease.2,3 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.4,5,6  
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.7 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. LUM/IVA 
combination therapy is approved in the US, European Union, Canada, Australia, and Switzerland 
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.  
5.2 
Study Rationale 
CF is a chronic disease with challenges in long-term disease management. Inadequate treatment 
adherence is one of the most significant challenges in achieving effective health outcomes. An 
estimated 30-50% of medicines are not taken as recommended and adherence tends to decline 
after the first 6 months of treatment.10  
Effective disease management relies on consistent adherence habits, yet adherence is an 
invisible, and often an unmonitored, expectation in routine care.11 Discrepancies in clinical 
studies between objective (e.g., pharmacy refills) and self-reported measures of adherence (e.g., 
surveys, questionnaires) have led to development of smart adherence technology interventions 
(e.g., smart pill bottles). This study is designed to evaluate the impact of smart adherence 
technologies for supporting and monitoring LUM/IVA adherence rates among subjects 16 years 
of age and older with CF who are homozygous for F508del.  


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6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the impact of smart adherence technologies for monitoring of LUM/IVA adherence 
rates among subjects 16 years of age and older with CF who are homozygous for the 
F508del-CFTR mutation 
6.2 
Secondary Objective 
To collect subject and physician feedback on the use of smart adherence technology to monitor 
LUM/IVA adherence 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Mean percentage adherence to LUM/IVA treatment over 48 weeks 
7.2 
Secondary Endpoints 
 Mean percentage adherence to LUM/IVA treatment over 24 weeks 
 Mean percentage adherence to LUM/IVA treatment from Week 25 through Week 48 
 Proportion of subjects with ≥80% LUM/IVA adherence over 24 weeks 
 Proportion of subjects with ≥80% LUM/IVA adherence over 48 weeks 
 Proportion of subjects with ≥80% LUM/IVA adherence from Week 25 through Week 48 
 Proportion of subjects with a non-physician-directed LUM/IVA interruption ≥72 hours over 
48 weeks 
 Number of non-physician-directed LUM/IVA interruptions ≥72 hours over 48 weeks 
 Time to the first non-physician-directed LUM/IVA interruption ≥72 hours over 48 weeks  
 
 
 
 
 
 
 
  
 
 
8 
STUDY DESIGN 
8.1 
Overview of Study Design 
This is a Phase 4, open-label, randomized, multicenter, 2-arm, parallel-group pilot study 
evaluating LUM/IVA adherence. Each study arm will use a smart technology with either active 
or inactive dosing alert and feedback features.   
 




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8.1.1 
Screening 
Screening Visit assessments are listed in Table 3-1. 
Screening will occur within 28 days before administration of LUM/IVA. The investigator (or an 
appropriate authorized designee at the study site) will obtain informed consent or assent from 
each subject. If the time between screening and dosing exceeds 28 days as a result of unexpected 
operational delays (e.g., delayed drug shipment), then subjects do not require rescreening. 
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.3). 
Subjects previously screened for another Vertex study may participate in this study if they meet 
the eligibility criteria. Screening data from the previous study may be used for this study if they 
were obtained within 28 days before administration of LUM/IVA.  
Subjects who do not meet the eligibility criteria may not be rescreened, with the following 
exceptions, all of which require medical monitor approval: 
 Subjects who met all eligibility criteria but had an intercurrent illness (e.g., upper respiratory 
infection with fever) in the 5 days before the first LUM/IVA dose that was properly 
evaluated and which resolved fully 
 Subjects who met all eligibility criteria but are not able to obtain required documentation 
within the allotted screening window 
 Subjects who met all eligibility criteria but transiently (for personal reasons) are unable to 
commit to all study procedures 
 Subjects who met all eligibility criteria but are not randomized for administrative reasons 
(e.g., interactive web response system is temporarily inaccessible or nonfunctional or 
LUM/IVA is not available at the study site) 
Any subject granted approval by the medical monitor for any of the exceptions listed above may 
have the screening window extended by 1 week before needing to undergo any rescreening 
assessments. If more than 35 days have elapsed from screening before first dose of LUM/IVA, 
all screening assessments need to be repeated. Repetition of any screening assessment that did 
not meet eligibility criteria is not permitted, unless there is clear evidence of a laboratory error 
(e.g., hemolysis of sample). In all cases, the medical monitor must authorize retesting. 
8.1.2 
Treatment Period 
Treatment Period visits and assessments are listed in Table 3-2. Additional study visits may also 
occur as determined by the clinical site for routine care.  
Subjects will be randomized at the Day 1 Visit to either Study Arm A or Study Arm B (described 
in Table 8-1). Each subject will be trained on the use of the assigned smart adherence technology 
and will use the technology throughout the Treatment Period. All subjects will receive LUM 
400 mg/IVA 250 mg q12h throughout the Treatment Period.  
Subjects who prematurely discontinue LUM/IVA treatment will complete a Safety Follow-up 
Visit (See Section 8.1.3).  


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Table 8-1 
Study VX15-809-114 Smart Adherence Technology Study Arms 
 
Smart Adherence 
Technology 
 
Activated Features 
Access to LUM/IVA 
Compliance Status 
Number 
(n) 
Smart Pill Bottle  
(Study Arm A) 
Real-time dosing data transfer, 
electronic medication reminders/missed 
dose alerts (audio, visuals, texts, emails, 
phone calls) 
Site staff and physicians, CRO, 
Vertex 
50 
Smart Pill Bottle, Control 
(Study Arm B) 
Real-time dosing data transfer to 
CRO/Vertex only 
CRO/Vertex only 
25 
CRO: contract research organization 
 
The use of active smart adherence technologies (smart pill bottles) will provide subjects with 
objective and real-time feedback on dosing adherence, including reminders of upcoming or 
missed doses. Study physicians will access dosing adherence data and review them with subjects 
in Study Arm A at scheduled study visits. Subjects in Study Arm B will not receive any alerts, 
reminders, or real-time feedback on dosing adherence. Study Arm B will provide objective data 
on dosing adherence without influencing subjects to take a scheduled dose of LUM/IVA. 
8.1.3 
Follow-up 
Subjects will have a Safety Follow-up Visit 28 (± 7) days after the last dose of LUM/IVA. Safety 
Follow-up Visit assessments are listed in Table 3-2. Subjects who begin commercial LUM/IVA 
before this visit do not have to complete the Safety Follow-up Visit. 
8.1.4 
Early Termination of Treatment  
Subjects who prematurely discontinue LUM/IVA treatment for any reason (except withdrawal of 
consent or assent) and who do not begin commercial LUM/IVA will be asked to return to the 
clinical site 28 (± 7) days of their last dose of LUM/IVA for a Safety Follow-up Visit. 
Assessments performed at this visit will be the same for those in the Safety Follow-up Visit 
(Table 3-2). 
If the subject withdraws consent or assent for the study, no further evaluations should be 
performed and no additional data should be collected. Vertex may retain and continue to use any 
data collected before such withdrawal of consent. 
8.2 
Rationale for Study Design and Study Drug Regimens 
8.2.1 
Study Design 
This pilot study is designed to provide information about the effect of smart adherence 
technologies on LUM/IVA treatment adherence. An estimated 30-50% of medicines are not 
taken as recommended and adherence tends to decline after the first 6 months of treatment.11 
Suboptimal adherence results in morbidity, mortality, preventable hospitalizations, a raised 
incidence of secondary complications,9 and therefore societal and economic burdens.  
Effective disease management relies on consistent adherence habits, yet adherence is an 
invisible, and often an unmonitored, expectation in routine care.11 Discrepancies in clinical 
studies between objective (e.g., pharmacy refills) and self-reported measures of adherence (e.g., 
surveys, questionnaires) have led to development of smart adherence technology interventions 


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(e.g., smart pill bottles). These technologies allow patients to self-monitor medication 
adherence10 through real-time electronic feedback via visual and auditory alarms, texts, emails, 
phone calls, and online dashboards. Smart adherence technologies enhance adherence by 
offering a method for CF patients and physicians to objectively monitor medication compliance12 
and to make long-term adherence both manageable and visible in daily routines. 
This study is not designed or powered to assess a relationship between adherence and clinical 
outcomes. 
 
 
 
Subjects will be stratified by age (<23 versus ≥23 years of age) and FEV1 severity (<70% versus 
70% predicted) determined at the Screening Period and then randomized (2:1) to 1 of the 
2 study arms described in Table 8-1.  
A sample size of approximately 75 subjects is sufficient to detect a 5.6% difference between the 
study arms with 80% power.  
8.2.2 
Study Drug Dose and Duration 
LUM/IVA Dose Rationale 
Subjects will receive LUM 400 mg/IVA 250 mg q12h during the Treatment Period. This dose 
regimen has been approved in the US, European Union, Canada, and Australia for the treatment 
of CF in patients 12 years of age and older who are homozygous for the F508del mutation. 
Study Duration Rationale 
Treatment adherence to approved medications tends to decline after 6 months.10 The 48-week 
study treatment duration was chosen to provide an adequate assessment of long-term adherence 
to LUM/IVA. 
8.2.3 
Rationale for Study Assessments 
The safety assessments are standard parameters for clinical studies in drug development and are 
generally recognized as reliable, accurate, and relevant to the study of patients with CF. All 
assessments with the exception of the patient- and physician-reported outcomes and use of smart 
adherence technologies were routinely measured in the LUM/IVA combination program. 
Rationales for these assessments, the patient- and physician-reported outcomes, and use of smart 
adherence technologies are provided below. 
Spirometry 
FEV1 as measured by spirometry is the most widely implemented standardized assessment to 
evaluate lung function in CF. This will be performed at the Screening Visit (See Section 11.5.5). 
Ophthalmologic Examinations  
Cases of noncongenital lens opacities have occurred in pediatric patients treated with ivacaftor, a 
component of LUM/IVA. Although other risk factors were present in some cases (such as 
corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be 
excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric 
patients initiating LUM/IVA treatment (See Section 11.5.6) 
 


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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. Subject and/or legally appointed and authorized representative (e.g., parents or legal 
guardian) will sign and date an informed consent form (ICF) and where appropriate, an 
assent form.  


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2. Subject and/or legally appointed and authorized representative (e.g., parent or legal guardian) 
is willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Confirmed diagnosis of CF and homozygous for the F508del-CFTR mutation at Screening. 
4. Subjects (male and female) will be aged 16 years and older on the date of informed consent 
or, where appropriate, assent. 
5. FEV1 ≥40% of predicted normal for age, sex, and height at Screening. 
9.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible. 
1. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering LUM/IVA to the 
subject, e.g., history of advanced liver disease. 
2. Presence of moderate or severe hepatic impairment (Child-Pugh Class B or C). 
3. Subjects currently receiving invasive mechanical ventilation. 
4. Known history of alcohol or drug abuse in the past year, including but not limited to 
cannabis, cocaine, and opiates, as deemed by the investigator. 
5. Any of the following abnormal laboratory values during screening: 
o Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × ULN 
o ALT or AST >3 × ULN with total bilirubin >2 × ULN 
o Glomerular filtration rate ≤30 mL/min/1.73 m2. This will be calculated by the 
Modification of Diet in Renal Disease study equation for subjects ≥18 years of age 
and calculated by the Counahan-Barratt equation for subjects aged 12 to 17 years. 
6. Pregnant or nursing females (females of childbearing potential must have a negative 
pregnancy test at screening and Day 1). 
7. Female subjects and female partners of male subjects who plan to become pregnant during 
Treatment Period or within 90 days following the last dose of LUM/IVA. 
8. Sexually active subjects of reproductive potential who are not willing to follow the 
contraception requirements outlined in Section 11.5.7.1. 
9. History of solid organ or hematological transplantation. 
10. Ongoing or prior participation in an investigational drug study (including studies 
investigating LUM and/or IVA) within 30 days of screening  
 A washout period of 5 terminal half-lives of the previous investigational LUM/IVA 
or 30 days, whichever is longer 
 The duration of the elapsed time may be longer if required by local regulations. 
11. Current use of commercial LUM/IVA combination therapy. 


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12. Subject, or close relative of the subject, is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study at that site. 
9.3 
Study Restrictions 
9.3.1 
Prior and Concomitant Medications and Other Study Restrictions 
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 Safety Follow-up Visit will be recorded in each 
subject’s source documents and electronic case report form (eCRF). For subjects who are 
screened but are not enrolled in the study, details of prior medications will be documented only 
in the subjects’ source documents. 
9.3.1.1 
Drug Interactions 
A nonexhaustive list of established and potentially significant drug interactions, including 
information on dosage adjustment, is provided in the approved product label for LUM/IVA 
(Orkambi®) (see study reference manual).  
LUM is a strong inducer of CYP3A. Administration of LUM/IVA may decrease systemic 
exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic 
effect. Coadministration with sensitive CYP3A substrates or CYP3A substrates with a narrow 
therapeutic index is not recommended.  
IVA is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of LUM/IVA with strong CYP3A 
inducers significantly reduces IVA exposure, which may reduce the therapeutic effectiveness of 
LUM/IVA. Therefore, coadministration with strong CYP3A inducers (e.g., rifampicin, St. John’s 
wort [Hypericum perforatum]) is not recommended.  
9.4 
Removal of Subjects 
Subjects may withdraw from the study at any time at their own request and subjects may be 
withdrawn at any time at the discretion of the treating physician or by Vertex for safety, 
behavior, noncompliance with study procedures, or administrative reasons. LUM/IVA treatment 
will be withdrawn for any female subject who has confirmed pregnancy and for any male subject 
whose female partner has a confirmed pregnancy. A subject may be withdrawn from the 
LUM/IVA treatment after a discussion between the investigator and the medical monitor for any 
of the following reasons:  
 A subject develops a medical condition that requires prolonged concomitant therapy with a 
prohibited medication or prolonged interruption of LUM/IVA combination therapy. 
 A subject develops a life-threatening adverse event or a serious adverse event (SAE) that 
places him/her at immediate risk, and discontinuation of treatment with LUM/IVA and 
withdrawal from the study are deemed necessary 
 A subject is noncompliant with the study requirements 
 A subject has an increase in transaminases (ALT or AST), meeting criteria for interruption of 
LUM/IVA in Section 11.5.3. 
A subject should be discontinued from the study for the following reason: 


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A subject on a transplant list undergoes lung transplantation 
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 LUM/IVA, request that the subject return for a Safety Follow-up Visit, if applicable (see 
Section 8.1.4), 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 or are withdrawn for nonsafety reasons during the LUM/IVA treatment 
period(s) may be replaced at Vertex’s discretion. 
10 
STUDY DRUG AND SMART ADHERENCE TECHNOLOGIES 
ADMINISTRATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
10.1.1 
LUM/IVA 
LUM/IVA may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
Blister pack tablets will be dispensed at the CRU into individual smart pill bottles by 2 operators, 
1 of whom is a qualified pharmacist, and following national and local laws and regulations.  
10.1.2 
Smart Adherence Technologies  
Table 8-1 describes the smart adherence technologies used in this study. Site pharmacists will 
distribute the assigned smart adherence technology to each subject with LUM/IVA.  
Smart Pill Bottles 
Subjects will be trained to use the smart pill bottle. Subjects in Study Arm A will receive 
additional instruction on the activated smart pill bottle monitoring features. A site pharmacist 
will repackage 3 months supply of LUM/IVA from blister packs into 4 Smart Pill Bottles. Three 
bottles will each store a 1-month supply of LUM/IVA. A fourth bottle will store an additional 7 
days supply of LUM/IVA. Only 1 bottle will be activated at a time.  
10.2 
Administration 
10.2.1 
LUM/IVA 
LUM/IVA fixed-dose tablet will be administered orally (Table 10-1). 
Table 10-1 
LUM/IVA Administration 
All Subjects 
Time 
LUM/IVA (200/125 mg per tablet) 
LUM 400 mg/IVA 250 mg q12h 
AM 
2 tablets 
PM 
2 tablets 
IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours 


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LUM/IVA should be administered within 30 minutes of consuming fat-containing food such as a 
standard CF high-fat, high-calorie meal or snack. LUM/IVA should be administered q12h 
(± 4 hours). 
10.3 
Method of Assigning Subjects to Treatment Groups 
Approximately 75 subjects who meet the eligibility criteria will be randomized at 2:1 ratio to 
1 of 2 study arms. All subjects will receive LUM/IVA. Subjects will be stratified by age 
(<23 versus ≥23 years of age) and FEV1 severity (<70% versus 70% predicted) determined at 
the Screening Visit.  
An interactive web response system (IWRS) will be used to assign subjects to study arms. 
Detailed instructions for randomization will be provided separately. 
10.4 
Dose Modification for Toxicity 
If any unacceptable toxicity arises, a dose modification to LUM 200 mg/IVA 125 mg q12h for 
up to 7 days may be permitted after discussion with and approval by the medical monitor. 
Subjects who receive the LUM/IVA dose modification will be administered 1 tablet in the 
morning and 1 tablet in the afternoon and follow administration instructions as described in 
Section 10.2.  
The medical monitor should be contacted before transitioning subjects back to 
LUM 400 mg/IVA 250 mg q12h. 
10.5 
Missed Doses 
If subjects miss a dose and recall the missed dose within 6 hours, they should take their dose 
with food. If more than 6 hours have elapsed after their usual dosing time, they should skip that 
dose and resume their normal schedule for the following dose.  
10.6 
Study Drug Interruption 
If LUM/IVA dosing must be interrupted due to AEs for more than 72 hours, the medical monitor 
must be notified. In these instances, LUM/IVA dosing may resume only after approval by the 
medical monitor. Specific instructions for interruption for elevated liver function test (LFT) 
levels are provided in Section 11.5.3. 
10.7 
Packaging and Labeling 
At the start of the study, Vertex or designee will provide a labeled supply of LUM/IVA 
combination therapy to the central pharmacy via the treating physician’s request. 
LUM/IVA tablets will be supplied in blister cards by Vertex. A detailed dispensation plan, 
including dispensation into Smart Pill Bottles, will be provided in the Reference Manual. 
LUM/IVA 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.  
10.8 
Study Drug and Smart Adherence Technology Supply, Storage, and 
Handling 
LUM/IVA (200 mg/125 mg) will be supplied as pink film-coated tablets containing 200 mg 
LUM/125 mg IVA. 


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Blister cards must be stored under conditions noted in Table 10-2. While at the clinical site, the 
LUM/IVA must be stored in a secure and temperature-monitored area of limited access. 
Instructions regarding the ordering, storage, and handling of LUM/IVA after dispensation to 
subjects will be provided to sites in the Reference Manual. 
The investigator, or an authorized designee (e.g., a licensed pharmacist), will ensure that all 
LUM/IVA is stored in a secured area, under recommended storage conditions, and in accordance 
with applicable regulatory requirements. To ensure adequate records, all LUM/IVA will be 
accounted for via the drug accountability forms as instructed by Vertex. 
Table 10-2 
Identity of LUM/IVA, Dosage, and Storage 
Drug Name 
Strength/Formulation/Route 
Dosage 
Storage Condition 
LUM/IVA 
(200 mg/125 mg) 
200 mg/125 mg tablet; oral 
LUM 400 mg / 
IVA 250 mg q12h 
≤30°C (≤86°F) 
IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours 
10.9 
Drug and Smart Adherence Technology Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) LUM/IVA received, (2) LUM/IVA dispensed to the subjects, (3) LUM/IVA 
returned by the subjects, (4) smart pill bottles received, (5) smart pill bottles dispensed to 
subjects, and (6) smart pill bottles returned by subjects. Subjects will be instructed to return all 
used and unused materials associated with LUM/IVA, including the assigned smart pill bottle, to 
the site. These materials will be retained at the site according to instructions provided by Vertex 
or its designee until inventoried by the study monitor. The study monitor will review LUM/IVA 
records and inventory throughout the study. 
10.10 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. At the end of the study, the study monitor 
will provide instructions as to the disposition of any unused LUM/IVA. If the study monitor 
authorizes destruction at the study site, the investigator will ensure that the materials are 
destroyed in compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Vertex. Destruction will be adequately documented. 
10.11 
Blinding and Unblinding 
This will be a study of adherence with a deactivated smart adherence technology control arm. 
LUM/IVA treatment will be given open-label. 
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments is shown in Table 3-1 and Table 3-2. 
 
 
 
 
 


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11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. Based on the medical history, the subject will be assessed for any disqualifying 
medical conditions as specified in the inclusion and exclusion criteria. The medical history shall 
include a complete review of systems, past medical and surgical histories, and any allergies.  
11.3 
Adherence 
11.3.1 
Smart Adherence Technology-Reported Adherence  
LUM/IVA adherence monitoring will occur throughout the Treatment Period using smart 
adherence technology. This technology will allow for collection of real-time LUM/IVA 
compliance by reporting LUM/IVA dosing times each time the smart pill bottles are opened. 
Only subjects in Study Arm A will review data with study physicians at the study visits listed in 
Table 3-2. 
11.5 
Safety  
Safety evaluations will include AEs, clinical laboratory assessments, ophthalmologic 
examinations (for subjects <18 years of age), clinical evaluation of vital signs, and physical 
examinations (PEs). 


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11.5.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE eCRF 
completion guidelines for investigators as well as training will be provided. 
11.5.2 
Clinical Laboratory Assessments 
Blood samples and urine pregnancy tests will be analyzed at a central laboratory.  
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table 3-1 and Table 3-2. On Day 1, blood draws will be collected before the first dose of 
LUM/IVA. Laboratory test results that are abnormal and considered clinically significant will be 
reported as AEs (Section 13.1.1).  
The safety laboratory test panels are shown in Table 11-1.  
Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Total Bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate aminotransferase  
Alanine aminotransferase  
Gamma-glutamyl transferase 
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 (β-human chorionic gonadotropin) Tests for Females of Childbearing Potential: 
Serum (Screening only) and urine pregnancy tests will be performed at the site as specified in 
Table 3-1 and Table 3-2. The serum and urine pregnancy tests will be analyzed at the central 
laboratory. The urine pregnancy test on Day 1 must be negative before the first dose of 
LUM/IVA. Additional urine pregnancy tests may be required according to local regulations 
and/or requirements  
If a urine pregnancy test is positive, all LUM/IVA dosing will stop and the pregnancy will be 
confirmed with a serum β-human chorionic gonadotropin test. If confirmed, the pregnancy will 
be reported and the subject will be permanently withdrawn from LUM/IVA (Section 11.5.7.2). If 
a pregnancy test is positive, the procedures outlined in Section 11.5.7.2 will be followed. 
Follicle-stimulating hormone (FSH) (Screening Period only): Blood sample for FSH will be 
measured for any suspected postmenopausal female with at least 12 months of continuous 


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spontaneous amenorrhea. Serum FSH levels must be within the postmenopausal reference range 
of the performing laboratory to be considered postmenopausal. 
CFTR genotype (Screening Period only): CFTR genotyping will be performed to confirm the 
subject is homozygous for the F508del-CFTR mutation as documented in the subject’s medical 
record. The results of the genotype must be obtained and reviewed during the Screening Period. 
CF genotyping can be waived if the subject has a documented genotype result from a previous 
Vertex study with a Screening Visit date of 01 June 2010 or later. Specific instructions will be 
provided in the Laboratory Manual.  
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 
becomes aware of the abnormal result. If it is not possible to send a timely specimen to the 
central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base the 
assessment of an AE on the local laboratory value. 
11.5.3 
Liver Function Test Parameters 
Mandatory Liver Function Testing 
Liver function testing (ALT, AST, GGT, ALP, and total bilirubin) must be performed as noted in 
Table 3-1 and Table 3-2. 
It is strongly recommended that subjects with new treatment-emergent ALT or AST elevations 
of >3 × ULN, total bilirubin >2 × ULN, or clinical symptoms be followed closely, including 
repeat confirmatory testing performed by the central laboratory within 48 to 72 hours of the 
initial finding and subsequent close monitoring of ALT, AST and bilirubin levels, as clinically 
indicated. If ALT or AST is >5 × ULN, follow-up levels must be obtained within 7 ± 2 days. 
If a subject cannot return to the site for liver function testing, a local laboratory may be used. 
Elevations in LFTs at the local laboratory must be reported immediately to the medical monitor, 
and the subject must have the tests repeated and sent to the central laboratory as soon as possible 
(ideally within 48 to 72 hours). 
LUM/IVA Interruption 
LUM/IVA administration must be interrupted immediately and the medical monitor must be 
notified if any of the following criteria is met: 
 ALT or AST >5 × ULN  
 ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN 
A thorough investigation of potential causes should be conducted and the subject should be 
followed closely for clinical progression. 
Resumption of LUM/IVA 
LUM/IVA may be resumed when transaminases return to baseline or are ≤2 × ULN, whichever 
is higher. Approval by the medical monitor is required before resumption of LUM/IVA. Upon 


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resumption of LUM/, transaminases should be assessed weekly for 4 weeks. If a protocol-
defined transaminase elevation occurs within 4 weeks of rechallenge with the LUM/IVA, then 
LUM/IVA must be interrupted again as outlined above. 
11.5.4 
Physical Examinations and Vital Signs 
Complete and symptom-directed physical examinations (PE) of body systems and vital signs 
assessment will be performed as listed in Table 3-1 and Table 3-2. Additional symptom-directed 
PEs and symptom-directed vital sign assessments can be performed at the discretion of the 
investigator or healthcare provider. 
A complete PE includes a review of the following systems: head/neck/thyroid; 
eyes/ears/nose/throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; 
musculoskeletal; and neurological. Breast, anorectal, and genital examinations will be performed 
when medically indicated. After screening, any clinically significant abnormal findings in PEs 
will be reported as AEs. 
The abbreviated PE will include an assessment of the following body systems: EENT, 
cardiovascular system, respiratory system, abdomen, and skin 
Vital signs include blood pressure (systolic and diastolic), oral temperature, pulse rate (beats per 
minute [bpm]), and respiration rate (breaths per minute).  These will be assessed following a 5-
minute rest in the seated or supine position. 
11.5.5 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines16 as noted 
in Table 3-1 according to the additional guidelines that follow.    
During the Screening Visit, a spirometry assessment may be performed pre- or 
postbronchodilator. The spirometry assessment will be recorded in the source documents as 
prebronchodilator or postbronchodilator. 
The parameters listed below will be normalized using the standards of Wang et al.,17 (for male 
subjects aged 12 through 17 years) or Hankinson et al.,18 (for female subjects aged 16 years and 
older and male subjects aged 18 years and older).  
 FEV1 (L) 
 Forced vital capacity (FVC) (L) 
 FEV1/FVC (ratio) 
 Forced expiratory flow (FEF25%-75%) (L/s) 
11.5.6 
Ophthalmologic Examination 
Subjects who are <18 years old at Day 1 will undergo an ophthalmologic examination at the 
Screening and Week 48 visits. The exam will be performed by either a licensed ophthalmologist 
or optometrist, as noted in Table 3-1and Table 3-2, and will include: 
 measurement of best corrected distance visual acuity of each eye; 
 pharmacologically dilated examination of the lens with a slit lamp. 


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The screening ophthalmologic examination must be completed and the results reviewed before 
enrollment. This examination does not have to be repeated if there is documentation of an 
examination that met protocol criteria within 3 months before the date of informed consent (or 
assent, when applicable) or if there is documentation of bilateral lens removal for the subject. 
If a cataract or lens opacity is identified and determined to be clinically significant by the 
ophthalmologist or optometrist at the Screening examination, the subject (and the subject’s 
parent or guardian if the subject is a minor) will be notified. Additional ophthalmologic 
examinations may be conducted at the discretion of the investigator. The Vertex medical monitor 
or designee should be notified of any additional ophthalmologic examinations. 
If a cataract or lens opacity is identified and determined to be clinically significant by the 
ophthalmologist or optometrist after dosing, the subject will be notified. After discussion with 
the Principal Investigator and in collaboration with the medical monitor, the subject may elect to 
continue or discontinue LUM/IVA treatment. If the subject discontinues LUM/IVA treatment, 
the subject should complete the Safety Follow-up Visit. If the subject continues IVA treatment, 
more frequent ophthalmologic monitoring should be considered. 
In addition, at screening, the following history will be obtained and documented for all subjects: 
 History of steroid use 
 History or presence of diabetes 
 Any prior ophthalmologic examinations 
 History of trauma to the eye 
 Any family history of glaucoma, congenital cataracts, or cataracts arising later in life 
 Use of corrective lenses (contact lenses or eyeglasses) 
 History of prolonged exposure to sunlight or ultraviolet light and use of sunglasses 
 History of exposure to secondhand smoke 
11.5.7 
Contraception and Pregnancy 
11.5.7.1 
Contraception 
The effects of LUM monotherapy or LUM in combination with IVA on the PK of hormonal 
contraceptives are not known; however, since LUM is a strong 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 LUM/IVA (unless otherwise 
noted) until 90 days following the last dose of LUM/IVA. 
Definition of Childbearing Potential 
All female subjects who have had their first menstrual period, from the time of the screening 
assessment through the Safety Follow-up Visit, including subjects with tubal ligations and 
subjects who do not have a documented hysterectomy, will be considered to be of childbearing 
potential unless: 


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 The subject has had a documented hysterectomy or bilateral oophorectomy/ 
salpingo-oophorectomy 
 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: 
 True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented through 
examination of a semen specimen or by demonstration of the absence of the vas deferens by 
ultrasound before the first dose of LUM/IVA. 
Acceptable Contraceptive Methods 
Acceptable contraceptive methods for male subjects or male partners of female subjects 
include the following:  
 Vasectomy 6 months or more previously, with a negative postvasectomy semen analysis for 
sperm 
 Condom with spermicide (either as a single product if commercially available and/or allowed 
according to local regulations; otherwise, condom and spermicide as separate products). 
Local regulations may require use of an additional acceptable method of contraception. 
Acceptable contraceptive methods for female subjects include the following: 
 Bilateral tubal ligation performed at least 6 months previously 
 Continuous use of an intrauterine device (nonhormone-releasing) for at least 90 days 
 Barrier contraception (such as diaphragm, cervical cap, or female condom) with spermicide. 
Local regulations may require use of an additional acceptable method of contraception. 
 Note: Hormonal contraceptives, including oral, injectable, transdermal, and implantable, will 
not be considered as an effective method; however, female subjects are not required to 
discontinue hormonal contraceptives. 
Acceptable contraceptive methods for female partners of male subjects:  
 Bilateral tubal ligation performed at least 6 months previously 
 Continuous use of an intrauterine device for at least 90 days(nonhormone-releasing and 
hormone-releasing intrauterine devices are permitted) 
 Barrier contraception (such as diaphragm, cervical cap, or female condom) with spermicide. 
Local regulations may require use of an additional acceptable method of contraception. 
 Hormonal contraceptives, if successfully used for at least 60 days  
Additional notes: 
 Female condom cannot be used with male condom (as a double method of contraception) due 
to risk of tearing. 


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 Male and female subjects who are not sexually active at the time of screening must agree to 
follow the contraceptive requirements of this study if they become sexually active with a 
partner of the opposite sex. 
 If applicable, additional contraception requirements may need to be followed according to 
local regulations and/or requirements. 
 Male subjects must not donate sperm after the first dose of LUM/IVA, throughout the study, 
and for 90 days following the last dose of LUM/IVA. 
 Female subjects and female partners of male subjects should not plan to become pregnant 
during the study through 90 days following the last dose of LUM/IVA. 
 Female subjects should not nurse a child from the start of LUM/IVA dosing through 90 days 
following the last dose of LUM/IVA. 
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. 
11.5.7.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of LUM/IVA. 
If a subject or the female partner of a male subject becomes pregnant while participating in the 
study, LUM/IVA will be permanently discontinued immediately. The investigator will notify the 
medical monitor and Vertex Global Patient Safety (GPS) within 24 hours of the site’s knowledge 
of the subject’s (or partner’s) pregnancy using the Pregnancy Information Collection Form. 
If confirmed to be on active drug, the subject or partner will be followed until the end of the 
pregnancy and the infant will be followed for 1 year after the birth, provided informed consent is 
obtained. A separate ICF will be provided to explain these follow-up activities. Pregnancy itself 
does not constitute an AE. 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12 
STATISTICAL AND ANALYTICAL PLANS 
This section presents a summary of the planned statistical analyses for this protocol. Statistical 
analysis details will be provided in the Statistical Analysis Plan (SAP).  
The Vertex Biometrics department or a designated CRO will analyze the data derived from this 
study. SAS® Version 9.2 or later will be used to generate all statistical outputs (tables, figures, 
listings, and data sets). 
12.1 
Sample Size and Power 
A total of approximately 75 subjects will be enrolled and will be randomized at 2:1 ratio to 1 of 2 
study arms: Study Arm A( approximately 50 subjects) and Study Arm B, (approximately 25 
subjects).  
The primary endpoint is the mean percentage adherence to LUM/IVA treatment over 48 weeks. 
Assuming a standard deviation (SD) of 8, a sample size of 50 in Study Arm A and 25 in Study 
Arm B will have 80% power to detect a difference of 5.6% between the means for the 2 study 
arms using a 2-sided, 2-sample t-test at the 0.05 significance level. 
Data from studies VX09-809-102, VX12-809-103, and VX12-809-104 were used for this sample 
size calculation. Sample sizes based on a range of SDs 
.  
 
 
 
 


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12.2 
Analysis Sets 
The Full Analysis Set (FAS) will include all randomized subjects who received at least 1 dose of 
LUM/IVA. The FAS will be used for all analyses in this study.  
The Safety Set will include all subjects who received at least 1 dose of LUM/IVA. The Safety 
Set will be used for all safety analyses, unless otherwise specified. 
12.3 
Statistical Analysis  
The primary objective of this study is to evaluate the impact of smart adherence technologies on 
LUM/IVA adherence rates among patients aged 16 years of age and older with CF who are 
homozygous for the F508del. The secondary objective is to collect subject and physician 
feedback on the use of smart adherence technology. This section presents a summary of the 
planned statistical analyses to address the endpoints associated with study’s objectives.   
Statistical analysis and presentation details will be provided in the SAP for the study. 
12.3.1 
General Considerations 
All subject data, including those derived will be presented in subject data listings; listings will 
display all subjects who were randomized, regardless of whether or not they received LUM/IVA.  
Continuous variables will be summarized using the following descriptive summary statistics: the 
number of subjects (n), mean, SD, standard error (SE), median, minimum value (min), and 
maximum value (max). The precision of the measurement for each continuous variable will be 
specified in the SAP.  
Categorical data 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 for a variable, unless otherwise specified, will be defined as the most recent nonmissing 
measurement (scheduled or unscheduled) collected at or before Day 1 of the study.  
Change from baseline will be calculated as postbaseline value minus baseline value. 


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Rules for handling missing data will be described in the SAP. 
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 study/Safety Follow-up Visit, and discontinued 
use of smart adherence technology or study with a breakdown of the reasons for discontinuation) 
will be summarized overall and by study arms. 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized using descriptive summary statistics.  
The following demographics and baseline characteristics will be summarized overall and by 
study arm for the FAS and will include (but are not limited to): sex, race, age, baseline weight, 
baseline height, baseline body mass index (BMI), and baseline patient-reported outcomes 
(PROs). 
No statistical tests will be carried out to evaluate any baseline imbalance between study arms. 
12.3.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded using the World Health Organization Drug 
Dictionary-Enhanced and categorized as the following: 
 Prior medication: any medication that started before initial dosing of LUM/IVA, regardless 
of when dosing of the medication ended 
 Concomitant medication: medication received at or after the first dose of LUM/IVA, 
medication that was received before initial dosing and continued after initial dosing of 
LUM/IVA, or medication with missing stop date 
 Post-treatment medication: medication continued or newly received after the 
treatment-emergent period.  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 the first dose of LUM/IVA, concomitantly, or after the 
treatment-emergent period, it will be considered as prior, concomitant, and post-treatment. 
Prior medications and concomitant medications will be summarized by study arms based on the 
FAS. Post-treatment medications will be provided separately in an individual subject data listing.  
12.3.2.4 
Study Drug Exposure and Compliance 
Exposure to LUM/IVA (i.e., duration of treatment in days) will be summarized for the FAS in 
terms of duration of treatment a subject received (in days), defined as the last day minus the first 
day of LUM/IVA plus 1. Exposure will be summarized by study arms for the FAS. 
Primary and secondary analyses of adherence will be performed through smart technology 
generated data. A complementary analysis based on pill count and missing/interruption of dose 


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will be conducted. Information on number of pills and drug interruption will be collected from 
dispensing pharmacy and subjects.  
These pharmacy and subject reported compliance data will be summarized for the FAS and will 
be derived in at least 1 of 2 methods pending data availability:  
(1) based on pill counts calculated as:  
100 × (total number of tablets taken) / (4 × duration of LUM/IVA exposure in days) 
And/or: 
(2) based on medication interruption days using the formula: 
100 × [1 – (total number of days LUM/IVA interrupted ≥72) / (duration of LUM/IVA exposure)] 
Duration of treatment and dosing compliance will be summarized by means of descriptive 
summary statistics. 
12.3.3 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that has the potential to affect the 
interpretation of study results. The rules for identifying an IPD will be described in the SAP. 
All IPDs will be provided in an individual subject data listing  
12.3.4 
Analysis of Endpoints 
12.3.4.1 
Analysis of Primary Endpoints  
The primary endpoint is the mean percentage adherence to LUM/IVA treatment over 48 weeks.  
The primary analysis for the primary endpoint will be based on an ANCOVA with mean 
percentage adherence over 48 weeks as the dependent variable, study arm as a fixed effect with 
covariates for age (<23 versus ≥23 years old), FEV1 (<70% versus 70% predicted), 
  
and sex (male versus female), at screening. 
 
 
   
 
  
Summary statistics for each arm of the study will be provided. Given the exploratory nature of 
this study, no multiplicity adjustment of type I error will be applied for these analyses. 
Summary of weekly adherence data will be provided; pattern of adherence over 48 weeks will be 
plotted and may be modeled using mixed effects models. 
12.3.4.2 
Analysis of Secondary Endpoints 
Mean percentage adherence to LUM/IVA treatment over 24 weeks: Analysis of this variable 
will be similar to that of the primary analysis of the primary endpoint.  
Mean percentage adherence to LUM/IVA treatment from Week 25 through Week 48: 
Analysis of this variable will be similar to that of the primary analysis of the primary endpoint. 
Proportion of subjects with ≥80% LUM/IVA adherence over 24 weeks: This endpoint will 
be analyzed using a logistic regression model with Study Arm as a fixed effect and covariates for 


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age (<23 versus ≥23 years old), FEV1 (<70% versus 70% predicted), 
 and sex (male 
versus female), at the screening. In case of model non-convergence and for sensitivity analysis, a 
2-sided Cochran-Mantel-Haenszel (CMH) test stratified by the same covariates as in the logistic 
regression will be provided. The estimate of odds ratio and the corresponding 95% CI will be 
provided.  
Proportion of subjects with ≥80% LUM/IVA adherence over 48 weeks: Analysis of this 
variable will be similar to that of the proportion of subjects with ≥80% adherence over 24 weeks.  
Proportion of subjects with ≥80% LUM/IVA adherence from Week 25 through Week 48: 
Analysis of this variable will be similar to that of the proportion of subjects with ≥80% 
adherence over 24 weeks.  
Proportion of subjects with a non-physician-directed LUM/IVA interruption ≥72 hours 
over 48 weeks: Analysis of this endpoint will be similar to that of the proportion of subjects with 
≥80% adherence over 24 weeks.  
Number of non-physician-directed LUM/IVA interruptions 72 hours over 48 weeks: For 
number of drug interruptions, comparison between the study arms will be carried out using 
negative binomial regression model with Study Arm as a fixed effect and age group (<23 versus 
23 years old), FEV1 (<70% versus 70% predicted), 
 and sex (male versus female), at 
the screening as covariates.  
The log of time spent in the study will be treated as the offset in this model. 
In addition, a stratified Wilcoxon’s rank-sum test by adjusting for age group, ppFEV1, 
 
and sex may be performed as a sensitivity analysis, if needed.  
Time to the first non-physician-directed LUM/IVA interruption ≥72 hours over 48 weeks: 
Time-to-first LUM/IVA interruption ≥72 hours over 48 weeks will be analyzed using Cox 
regression. A Cox PH regression model will include a main effect of Study Arm and covariates 
for age (<23 versus ≥23 years old), FEV1 (<70% versus 70% predicted), 
 and sex 
(male versus female), at the screening visit. Additionally, Kaplan-Meier method will be used to 
produce graphical presentation of the survival curves. Log-rank test and Wilcoxon test will also 
be summarized.  


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12.3.5 
Safety Analysis 
All safety analyses will be based on the set of data associated with the treatment-emergent period 
for subjects in the Safety Set. 
The overall safety profile of LUM/IVA will be assessed based on the following safety and 
tolerability endpoints: 
 Treatment-emergent adverse events (TEAEs) 
 Clinical laboratory values (i.e., liver function tests) 
 Vital signs 
 Ophthalmological examinations 
All safety data will be presented in individual subject data listings. 


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12.3.5.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
 Pretreatment AE: any AE that started before the first dose of LUM/IVA 
 TEAE: any AE that increased in severity or that was newly developed at or after the first 
dose of LUM/IVA to 28 days after the last dose of LUM/IVA 
 Post-treatment AE: any AE that increased in severity or that was newly developed after 
28 days after the last dose of LUM/IVA 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study treatment, then the AEs will be classified as TEAEs. 
AE summary tables will be presented for TEAEs only and will include the following: 
 All TEAEs  
 TEAEs by relationship  
 TEAEs by maximal severity 
 TEAEs leading to treatment discontinuation 
 Serious TEAEs 
 TEAEs leading to death 
Summaries will be presented by MedDRA System Organ Class and preferred term using 
frequency counts and percentages by study arm (i.e., number and percentage of subjects with an 
event as well as total number of events). When summarizing the number and percentage of 
subjects with an event, subjects with multiple occurrences of the same AE or a continuing AE 
will be counted once; only the maximum severity level will be presented in the severity 
summaries and the worst/highest relationship level presented in the relationship summaries.  In 
addition, summary tables containing individual subject AE data for all deaths and other serious 
and significant AEs will be provided separately. All AEs, including pre- and post-treatment AEs, 
will be presented in individual subject data listings. 
AEs leading to death, SAEs, dose interruption, and permanent discontinuation will be listed 
separately. All AEs through the Safety Follow-up Visit will be listed in an individual subject data 
listing, including pre-treatment AEs.  
12.3.5.2 
Clinical Laboratory Assessments 
For the on-treatment laboratory measurements, the raw values and change from baseline values 
of the liver function test results will be summarized in SI units by study arms at each visit. For 
liver function, the number and percentage of subjects with abnormal low (<LLN) value and with 
abnormal high (>ULN) value at each scheduled time point will be summarized. 
The number and percentage of subjects with at least 1 potentially clinically significant (PCS) 
event during the treatment-emergent period will be summarized. Clinically significant abnormal 
laboratory findings will be reported as AEs.  


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12.3.5.3 
Vital Signs 
The following vital signs will be summarized by study arms at each scheduled time point: 
systolic and diastolic blood pressure (mmHg), oral temperature, pulse rate (beats per minute 
[bpm]), and respiratory rate (breaths per minute). Clinically significant abnormal findings in vital 
signs will be reported as AEs.  
12.3.5.4 
Physical Examination 
PE results will be presented in individual subject data listings only. Clinically relevant results 
identified after screening will be reported as AEs. 
12.3.5.5 
Other Safety Analysis 
Not applicable 
12.3.6 
Interim and IDMC Analyses 
12.3.6.1 
Interim Analysis 
No interim analysis is planned for this study.  
12.3.6.2 
IDMC Analysis 
Not applicable 
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, PEs, and vital signs, will be assessed and those 
deemed a clinically significant worsening from baseline documented as an AE. When possible, a 
clinical diagnosis for the study assessment will be provided, rather than the abnormal test result 
alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, the abnormal study 
assessment itself will be listed as the AE (e.g., bacteria in urine or decreased hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
 Concomitant signs or symptoms related to the abnormal study assessment 
 Further diagnostic testing or medical/surgical intervention 


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 A change in the dose of LUM/IVA or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the clinical status of the subject indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the following time points: 
 For subjects who do not enroll: until time of screen failure (e.g., screen failure, withdrawal of 
consent) 
 For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up Visit 
 For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of: 
o 28 days after the last dose of LUM/IVA or 
o Dosing with commercial LUM/IVA 
All subjects will be queried, using non-leading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the eCRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the study 
will be recorded only in the subject’s source documents. The following data will be documented 
for each AE: 
 Description of the event 
 Classification of “serious” or “nonserious” 
 Date of first occurrence and date of resolution (if applicable) 
 Severity  
 Causal relationship to LUM/IVA(s)  
 Action taken  
 Outcome  
 Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed Month 
year). AEs of CTCAE Grades 4 and 5 should be documented as “life-threatening.” In 
considering the severity of an AE in a pediatric subject, the investigator should consider that 
reference ranges for pediatric clinical laboratory parameters may differ from those given in the 
CTCAE. 


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The severity of an AE that does not appear in the CTCAE scale should be determined according 
to the definitions in Table 13-1. Clinically significant laboratory tests should be recorded as AEs 
in the subject’s source documents and eCRF. 
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 
LUM/IVA. 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 
LUM/IVA, a plausible mechanism for the event to be related to the investigational 
LUM/IVA and causes other than the investigational LUM/IVA have been ruled out, 
and/or the event re-appeared on re-exposure to the investigational LUM/IVA. 
Possibly related 
There is an association between the event and the administration of the 
investigational LUM/IVA and there is a plausible mechanism for the event to be 
related to investigational LUM/IVA, 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 LUM/IVA and likely to be 
related to factors other than investigational LUM/IVA.  
Not related 
The event is related to an etiology other than the investigational LUM/IVA (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 LUM/IVA 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 
LUM/IVA dose not changed in response to an AE 
Dose reduced 
LUM/IVA dose reduced in response to an AE 
Drug interrupted 
LUM/IVA administration interrupted in response to an AE  
Drug withdrawn 
LUM/IVA administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding LUM/IVA 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 LUM/IVA. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, hospitalization, 
surgery, or physical therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
 Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation in the study and is suspected of being a delayed toxicity due to administration of 
LUM/IVA) 
 Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  


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 Inpatient hospitalization or prolongation of hospitalization 
 Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
 Congenital anomaly or birth defect 
 Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, regardless of causality, will be reported by the investigator to Vertex 
GPS. In addition, all SAEs that occur after the Safety Follow-up Visit and are considered related 
to LUM/IVA 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 LUM/IVA 
and possible etiologies. On the SAE Form, relationship to LUM/IVA 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 SAE Form. 
13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the LUM/IVA. The SAE Form will be completed for 
new/initial events as well as to report follow-up information on previously reported events. 
Investigators are asked to report follow-up information as soon as it becomes available to ensure 
timely reporting to health authorities.  


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Please send completed SAE Forms to Vertex GPS 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 LUM/IVA 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 and all applicable laws and regulations and will be subject to approval by Vertex or its 
designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  


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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 eCRFs, 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 eCRFs/SAE forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/EC, may also request access to all study records, including source 
documentation, for inspection. 
For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act and associated regulations (HIPAA), an executed HIPAA 
authorization shall be obtained by the site from each subject (or the legal representative of the 
subject) before research activities may begin. Each HIPAA authorization shall comply with all 
HIPAA requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA and other parties requiring access under the protocol, and statements as to the 
purpose for which such information may be used and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
 Subject or investigator noncompliance 
 Unsatisfactory subject enrollment 
 Lack of adherence to protocol procedures 


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


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


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14 
REFERENCES
 
1 
Australian Cystic Fibrosis Data Registry. Cystic fibrosis in Australia 2009: 12th annual 
report. Baulkham Hills, New South Wales, Australia: Cystic Fibrosis Australia; 2011. 
2 
FDA Office of Orphan Products Development. Developing Products for Rare Diseases & 
Conditions. Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.
htm. Accessed 01 July 2015. 
3 
European Medicines Agency. Committee for Orphan Medicinal Products (COMP). 
Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_
000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30. 
Accessed 01 July 2015. 
4  
Cystic Fibrosis Foundation Patient Registry. 2012 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2013. 
5 
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. 
6 
Cystic Fibrosis Trust. Cystic Fibrosis Trust annual review 2010. London, UK: Cystic 
Fibrosis Trust; 2012. 
7  
Kriendler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125:219-29. 
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. Assessed 15 February 2016. 
10  
Wildman, M J. Moving cystic fibrosis care from rescue to prevention by embedding 
adherence measurement in routine care. Pediatr Respir Rev. 2014;16-18. 
11  
Payer, JZ. Therapeutic adherence to biophosphonates. Biomed Pharmacother. 2007;191-
3. 
12  
Siracusa C, Ryan J, Burns, L, Wang Y, Zhang N, Clancy J, et al. Electronic monitoring 
reveals highly variable adherence patterns in patients prescribed ivacaftor. J Cystic 
Fibrosis.2015;14:621-6 
13  
Risser J, Jacobson TA, Kripalani S. Development and psychometric evaluation of the 
Self-efficacy for Appropriate Medication Use Scale (SEAMS) in low-literacy patients 
with chronic disease. J Nurs Meas. 2007;15:203–19. 
14  
Reynolds NR, Sun J, Nagaraja HN, Gifford AL, Wu AW, Chesney MA. Optimizing 
measurement of self-reported adherence with the AIDS clinical trials group adherence 
questionnaire: A cross protocol analysis. JAIDS. 2007;14:402-9. 


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15  
Chesney MA, Ickovics JR, Chambers DB, Gifford AL, Neidiq J, Zwicki B, et al. Self-
reported adherence to anti-retroviral medications among participants in HIV clinical 
trials: the AACTG adherence instruments. Patient Care Committee and Adherence 
Working Group of the Outcomes Committee of the Adult AIDS Clinical Trials Group 
(AACTG). AIDS Care. 2000; 12:255-266. 
16 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
17 
Wang X, Dockery DQ, Wypij D, Fay ME, Ferris BG. Pulmonary function between 6 and 
18 years of age. Pediatr Pulmonol. 1993;15:75-88. 
18 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general US population. Am J Respir Crit Care Med. 1999;159:179-87. 




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15.2 
Investigator Signature Page 
Protocol #: 
VX15-809-114 
Version #: 
2.0 
Version Date 
19 Oct 2016 
Study Title: A Phase 4, Open-label treatment, Randomized, Multicenter, 2-arm, Parallel-group, 
Pilot Study of Adherence to Lumacaftor/Ivacaftor in CF Subjects Homozygous for the 
F508del-CFTR Mutation 
 
I have read Protocol VX15-809-114, Version 2.0 and agree to conduct the study according to its 
terms. I understand that all information concerning lumacaftor/ivacaftor and this protocol 
supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential.   
 
Printed Name 
 
 
Signature 
 
Date 
 
 

SAP_001.pdf: 




Statistical Analysis Plan (Methods) 
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Appendix E: Coefficients for Hankinson and Wang Methods for Calculating Predicted 
Spirometry Parameters ..........................................................................................24
Appendix F: Patient-reported and Physician-reported Outcomes.....................................28




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3
INTRODUCTION
This statistical analysis plan (SAP) Methods describes the final analysis for 
Study VX15-809-114 and is based on the following:

approved clinical study protocol (Version 2.0, dated 19 October 2016)

approved electronic case report form (eCRF) (Version 2.0, dated 22 December 2016)
Study VX15-809-114 is a Phase 4, open-label treatment, randomized, multicenter, 2-arm, 
parallel-group, pilot study of adherence to lumacaftor/ivacaftor (LUM/IVA) in cystic fibrosis 
(CF) subjects homozygous for F508del.
This study was terminated early by a business decision. The collected data at the time of 
termination are limited and therefore, the planned statistical analyses in the protocol will not 
be performed. Descriptive summary of statistics will be performed. Please refer to Section 8
for details.
4
STUDY OBJECTIVES 
4.1
Primary Objective
To evaluate the impact of smart adherence technology for monitoring of LUM/IVA 
adherence rates among subjects 16 years of age and older with CF who are homozygous for 
the F508del-CFTR mutation
4.2
Secondary Objectives 
To collect subject and physician feedback on the use of smart adherence technology to 
monitor LUM/IVA adherence
4.3
Other Objectives
Not applicable
5
STUDY ENDPOINTS
5.1
Adherence Endpoint
This study was terminated early by a business decision. The data collected at the time of 
termination are limited and premature due to early termination. Therefore, the planned 
adherence endpoints listed in Sections 2 and 7 of the protocol will not be performed. Based 
on the expected available data, a list of applicable adherence endpoints below will be 
analyzed as follows:

Mean percentage adherence to LUM/IVA treatment over any treatment duration for all 
subjects.

Mean percentage adherence to LUM/IVA treatment over 0 through 12 weeks for subjects 
who have at least 12 weeks of eligible smart pill bottle data.


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
Proportion of subjects with ≥80% adherence over 0 through 12 weeks for subjects who 
have at least 12 weeks of eligible smart pill bottle data

Proportion of subjects with ≥90% adherence over 0 through 12 weeks for subjects who 
have at least 12 weeks of eligible smart pill bottle data
6
STUDY DESIGN 
This is a Phase 4, open-label, randomized, multicenter, 2-arm, parallel-group pilot study 
evaluating LUM/IVA adherence. Each study arm will use a smart technology with either 
active or inactive dosing alert features.   
This study includes:

Screening Period (Day −28 through Day −1)

Treatment Period (Day 1 through Week 48 )

Safety Follow-Up Visit (28 [± 7] days after the final dose of study drug). Subjects who 
begin commercially available LUM/IVA combination therapy within 28 (± 7) days of the 
last dose of LUM/IVA do not have to complete the Safety Follow-up Visit.
Figure6-1 depicts a schematic of the study design. Approximately 75 subjects will be 
enrolled in this study. All subjects will receive LUM 400 mg/IVA 250 mg every 12 hours 
(q12h) through Week 48.
Randomization of subjects to the 2 study arms will be stratified by age (<23 versus ≥23 years 
of age) and forced expiratory volume in 1 second (FEV1) severity (<70% versus 70% 
predicted) at the Screening Visit. All subjects will be randomized at 2:1 ratio to 1 of the 
following 2 smart adherence technology study arms:

Study Arm A: Smart Pill Bottle, activated 

Study Arm B: Smart Pill Bottle (control), de-activated alerts and feedback features
Subjects will receive standardized education on the benefit of medication adherence and 
training on the use of the assigned smart adherence technology. During applicable study
visits, subjects will complete adherence and technology satisfaction assessments; and 
physicians will complete technology satisfaction assessments at Week 48. Tables 11-1 and 
11-2 in Appendix A provide a list of assessments by study visit. 
All subjects will be required to complete study assessments for all scheduled visits. Subjects 
who prematurely discontinue study drug treatment will complete a Safety Follow-up Visit.




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6.2
Randomization
Randomization of subjects to the 2 study arms will be stratified by age (<23 versus ≥23 years 
of age) and forced expiratory volume in 1 second (FEV1) severity (<70% versus 70% 
predicted) determined at the Screening Visit. All subjects will be randomized at 2:1 ratio to 
1 of the following 2 smart adherence technology study arms:

Study Arm A: Smart Pill Bottle, activated 

Study Arm B: Smart Pill Bottle (control), de-activated alerts and feedback features
An interactive web response system (IWRS) will be used to assign subjects to study arms
using a list of randomization codes generated by a designated vendor.
6.3
Blinding and Unblinding
This is a study of adherence with a deactivated smart adherence technology as the control 
arm. LUM/IVA treatment is given open-label to all subjects.
7
ANALYSIS SETS
The following analysis sets are defined: 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 Full Analysis Set (FAS) will include all randomized subjects who received at least 
1 dose of LUM/IVA. The FAS will be used for all analyses except the safety analyses in this 
study. Given the nature and objective of this study, the subjects will be grouped and analyzed 
according to the smart technology arm that they actually received and not according to the 
arm that they were randomized to. 
The Safety Set will include all subjects who received at least 1 dose of LUM/IVA. The 
Safety Set will be used for all safety analyses.
8
STATISTICAL ANALYSIS
8.1
General Considerations
The Schedule of Assessments is provided in Appendix A. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (SD), standard error (SE), 
median, minimum value (min), and maximum value (max).
Categorical variables will be summarized using counts and percentages.
Baseline value, unless specified otherwise, will be defined as the most recent non-missing
measurement (scheduled or unscheduled) collected before the first dose of study drug.
Change (absolute change) from baseline will be calculated as postbaseline value minus 
baseline value


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Treatment-emergent (TE) Period will be from the first dose date of the study drug to the 
Safety Follow-up Visit or 28 days after the last dose, whichever is latest. The TE period will 
be used for safety analyses.
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows:

In scheduled visit windows per specified visit windowing rules.

In the derivation of baseline/last on-treatment measurements.

In the derivation of maximum/minimum on-treatment values and maximum/minimum 
change from baseline values for safety analyses.

In individual subject data listings as appropriate.
Visit windowing rules: Day 1 is defined as the day of first dose of study treatment. Relative 
days after Day 1 are calculated as (assessment date – Day 1 date) + 1. Relative days prior to 
Day 1 are calculated as (assessment date – Day 1 date). The day prior to Day 1 is Day -1. The 
analysis visit windows for protocol-defined visits are provided in Appendix B. Visit window 
rules will not apply to the smart technology-reported adherence, which will be collected and 
stored daily and will be summarized at actual date. Visit window rules will apply to other 
visit-dependent assessments, including liver function tests, and patient-reported, as well as, 
physician-reported outcomes.
Incomplete/missing data will not be imputed, unless specified otherwise.
Outliers: No formal statistical analyses will be performed to detect or remedy the presence 
of statistical outliers, unless specified otherwise.
Multiplicity: No multiplicity adjustment will be performed for hypothesis testing.
Malfunction of smart bottle: any subject who got a smart bottle with a malfunction signal and 
never received the alerts who was subsequently switched to the control (Arm B) will be 
considered as a control subject (Arm B).
8.2
Background Characteristics 
8.2.1
Subject Disposition
The number of subjects in the following categories will be summarized overall and by study 
arm: 

Randomized

Safety Set

Full Analysis Set (FAS)


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The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized overall and by study arm:

Completed study drug

Prematurely discontinued study drug and the reason for discontinuation 

Completed study (defined as completed the planned study treatment and Safety Follow-
up Visit)

Prematurely discontinued the study and the reason for discontinuation 
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
Demographics, medical history and baseline characteristics will be summarized overall and 
by study arm based on the FAS.
Demographic data will include the following:

Age at screening (in years)

Age group at screening (16 to <23, and 23 years)

Sex (female and male)

Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations)

Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian, Other Pacific Islander, and Other)
Baseline characteristics will include the following:

Weight (kg) at study baseline

Height (cm) at study baseline

BMI (kg/m2) at study baseline
Other baseline characteristics will include the following:

Percent predicted FEV1 at screening

Percent predicted FEV1 severity (<70% versus 70% predicted) at screening
No statistical tests will be carried out to evaluate any imbalance at enrollment between study 
arms. 
Medical history will be summarized by MedDRA system organ class (SOC) and preferred 
term (PT).


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8.2.3
Medical History
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). Medical history will be summarized descriptively by system organ class (SOC) 
and preferred term (PT) overall and by study arm based on the FAS. It will also be listed.
8.2.4
Prior and Concomitant Medications
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced (WHODDE) and categorized as the following:
Prior medication: any medication that started before the first dose date of study drug, 
regardless of when the medication ended.
Concomitant medication: medication continued or newly received during the TE period. 
Post-treatment medication: medication continued or newly received after the TE period.
A given medication may be classified as follows: prior, concomitant, post-treatment, both 
prior and concomitant, both concomitant and post-treatment, or 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. Details for imputing missing or partial start and/or stop dates of medication are 
described in Appendix C.
If a medication has a completely missing or partially missing start/stop date and it cannot be 
determined whether it was taken before the first dose date, concomitantly, or after the TE 
period, it will be classified as prior, concomitant, and post-treatment.
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
< first dose date of 
study drug
≥ first dose date and ≤ 
End date of TE period
> End date of TE 
period
< first dose date of study drug
P
PC
PCA
≥ first dose date and 
≤ End date of TE period
-
C
CA
> End date of TE period
-
-
A
P: Prior; C: Concomitant; A: Post-treatment
Summaries of prior and concomitant medications will be based on the FAS. They will also be 
listed by subject.


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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: ≤6 weeks, >6 and ≤12 weeks; >12 and ≤24 weeks; >24 and ≤36 weeks; >36 and 
≤48 weeks; and >48 weeks, for each treatment group.
8.2.6
Study Drug Compliance 
Study drug compliance based on number of tablets will be assessed by calculating the 
percentage of tablets consumed relative to the expected number of tablets administered 
during the subject’s actual time on-study. The expected number of tablets administered 
during the subject’s actual time on-study will be 4 tablets per day multiply the number of 
days in the study. The number of tablets consumed is the difference between the expected 
number of tablets dispensed and the total number of tablets returned. 
These pharmacy and subject reported compliance data will be summarized during the overall 
treatment duration (from first dose to last dose), based on the medication interruption days. 
Compliance rate based on the interruption days will be calculated as follow: 
100 × [1 – (total number of days of any study drug interruption) / (duration of study drug 
exposure)]
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, median, min, and max. They will also be summarized in categories: <80% and 
≥80% using frequency tables.
Study drug compliance summaries will be based on the FAS.


Statistical Analysis Plan (Methods) 
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8.2.7
Important Protocol Deviations 
An important protocol deviation (IPD) is a protocol deviation that has the potential to affect 
the interpretation of study results. IPDs will be identified from the clinical database and/or 
site deviation log. 
The protocol deviations that may be considered as potential IPDs include, but are not limited
to:

Violation of subjects rights, safety or well-being

Subject entered the study despite violation of any inclusion or exclusion criteria

Subject received prohibited concomitant medications

Subject received the wrong treatment or incorrect doses

Subject remained in study despite meeting withdrawal criteria
All IPDs will be presented in an individual subject data listing.
8.3
Adherence Analysis
All analyses described in this section will be based on the FAS, unless specified otherwise. 
The analysis will include all available measurements through the last scheduled on-treatment 
visit (Week 48), including measurements after treatment discontinuation, per the visit 
windowing rules described in Appendix B.
8.3.1
List of Analyzed Adherence Endpoints
This study was terminated early by a business decision. The data collected at the time of 
termination are limited and premature due to early termination. Therefore, we will perform 
the descriptive summary for the following applicable endpoints as described in Section 5.3.1:

Mean percentage adherence to LUM/IVA treatment over any treatment duration for all 
subjects.

Mean percentage adherence to LUM/IVA treatment over 0 through 12 weeks for subjects 
who have at least 12 weeks of eligible smart pill bottle data.

Proportion of subjects with ≥80% adherence over 0 through 12 weeks for subjects who 
have at least 12 weeks of eligible smart pill bottle data

Proportion of subjects with ≥90% adherence over 0 through 12 weeks for subjects who 
have at least 12 weeks of eligible smart pill bottle data


Statistical Analysis Plan (Methods) 
Page 14 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
8.3.2
Analysis of Adherence Endpoints
Mean percentage adherence to LUM/IVA treatment over treatment duration for all 
subjects
The percentage adherence over treatment duration for each subject is defined as:
100 × (total number of smart bottle openings over the eligible treatment duration 
excluding the physician-directed interruption periods of the eligible treatment duration) / 
[2 × (eligible duration of treatment - the number of physician-directed interruption days 
of the eligible treatment duration) 
Note: (1) the physician-directed interruption is defined as the reported interruptions due to 
reasons not being “Non-compliance”; (2) if there are more than 2 smart bottle openings at 
any day, they will be counted as 2 in calculation of the adherence endpoints. (3) the eligible
treatment duration = eligible date of last dose – date of first dose + 1, where the eligible date 
of last dose is defined to be either the CRF collected date of last dose or the last activity date 
of smart bottle data, whichever is earlier.
Descriptive statistics will be provided by the number of subjects (n), mean, SD, SE, median, 
min, and max by treatment arm based on FAS. 
 
The percentage adherence will also be listed.
Mean percentage adherence to LUM/IVA treatment over 0 through 12 weeks for 
subjects who have at least 12 weeks of eligible smart pill bottle data
Subjects who have at least 12 weeks of eligible smart pill bottle data are defined as those 
who have at least 12 weeks of eligible treatment duration = eligible date of last dose – date of 
first dose + 1, where the eligible date of last dose is defined to be either the CRF collected 
date of last dose or the last activity date of smart bottle data, whichever is earlier.
The percentage adherence over 12 weeks for each eligible subject is defined as:
100 × (total number of smart bottle openings over the first 12 weeks excluding the
physician-directed interruption periods of the first 12 weeks) / [2 × ( 12 weeks (ie, 84 
days)- the number of physician-directed interruption days of the first 12 weeks) 
Note: (1) the physician-directed interruption is defined as the reported interruptions due to 
reasons not being “Non-compliance”; (2) if there are more than 2 smart bottle openings at 
any day, they will be counted as 2 in calculation of the adherence endpoints.
Descriptive statistics will be provided by the number of subjects (n), mean, SD, SE, median, 
min, and max by treatment arm based on FAS.
 
The percentage adherence will also be listed.
In addition, the number of smart bottle openings during the physician-directed interruption 
periods will be presented in a by-subject listing. Please note that if there are more than 
2 smart bottle openings at any day, they will be counted as the actual number in this listing. 




Statistical Analysis Plan (Methods) 
Page 16 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed beyond the TE period
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs.
Details for imputing missing or partial start dates of adverse events are described in 
Appendix D.
AE overall summary table, TEAEs by SOC and PTs summary table, TEAEs by PTs 
summary table, related TEAEs by SOC and PTs summary table will be presented by study 
arms and overall. In addition, SAEs, AEs, TEAEs leading to treatment discontinuation, 
TEAEs leading to drug interruption will be listed. 
8.4.2
Clinical Laboratory
For the on-treatment laboratory measurements, the raw values and change from baseline 
values of the liver function test results will be summarized in SI units by study arms at each 
visit. 
The abnormal (high) LFT test results will be listed.
The abnormal (high or low) chemistry and hematology test results will be listed.
The abnormal urine or serum pregnancy test for female subjects of childbearing potential will 
be listed.
8.4.3
Vital Signs
The vital sign results will be listed.
8.4.4
Ophthalmological Examinations
Listings for subjects with abnormal ophthalmological examinations for subjects <18 years 
old at screening will be provided.
Listings for ophthalmological history data for all subjects will be provided.
8.4.5
Physical Examination 
Listings for abnormal physical examination results will be provided. 
9
INTERIM ANALYSES
Not applicable.


Statistical Analysis Plan (Methods) 
Page 17 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
10
REFERENCES
1.
Siracusa, C. M., Ryan, J., Burns, L., Wang, Y., Zhang, N., Clancy, J. P., & Drotar, D. 
(2015). Electronic monitoring reveals highly variable adherence patterns in patients 
prescribed ivacaftor. Journal of Cystic Fibrosis, 14(5), 621-626.
2.
Jonas V. Bilenas. Scatter Plot smoothing using PROC LOESS and Restricted Cubic 
Splines. Available at: http://support.sas.com/resources/papers/proceedings14/1503-
2014.pdf  Accessed 25 January 2016.


Statistical Analysis Plan (Methods) 
Page 18 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
11
LIST OF APPENDICES
Appendix A: Schedule of Assessments
Schedules of Assessments are shown in Table 11-1 and Table 11-2. These tables provide the 
schedule of assessments during the study from the Screening Period through the Safety 
Follow-up Visits. 
All visits are to be scheduled relative to the Day 1 Visit. 


Statistical Analysis Plan (Methods) 
Page 19 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
Table 11-1
Screening Period Assessments – Study VX15-809-114
Assessment
Screening Period
Day -28 to Day -1
Informed consent and assent (where applicable)
X
Inclusion and exclusion criteria review
X
Demographics
X
Height, weight, and BMI
X
Review of medical history (includes CFTR genotype)a
X
Ophthalmologic examinationb
X
Prior and concomitant medications
X
Vital signsc
X
Physical examinationd
X
Spirometrye
X
Serum pregnancy test (all female subjects of childbearing 
potential)f
X
Serum FSHg
X
Hematologyh
X
Liver Function Testingi
X
AEs and SAEs
Continuous from signing of ICF or assent (where applicable) 
through Safety Follow-up Visit
                                               
a
Genotype testing will be performed if this is not documented in medical history. CF genotyping can be waived with 
documented CFTR genotype (Protocol Section Error! Reference source not found.).
b
An ophthalmologic examination will be conducted by either a licensed ophthalmologist or an optometrist for all 
subjects <18 years of age. The exam may be waived if there is documentation of an exam within 3 months of the date 
of informed consent (or assent, when applicable). Subjects with documentation of bilateral lens removal do not need 
the ophthalmologic examination (Protocol Section 11.5.6.).
c
Vital signs will be assessed following a 5-minute rest in the seated or supine position.
d
Physical examination of all body systems (Protocol Section Error! Reference source not found.).
e
Spirometry may be performed pre- or postbronchodilator (Protocol Section 11.5.5)
f
Any female subject initiating LUM/IVA combination therapy who is considered to be of childbearing potential should 
have a serum pregnancy test. Women of childbearing potential are defined as: female subjects after puberty unless they 
are postmenopausal for at least 1 year and have documented FSH levels within the postmenopausal reference range of 
the performing laboratory, or are surgically sterile.
g
Serum FSH levels will be measured for any suspected postmenopausal female subjects with at least 12 months of 
continuous spontaneous amenorrhea.
h
Blood samples will be collected for clinical laboratory assessments (Protocol Section 11.5.2). 
i
Liver function testing (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl 
transpeptidase [GGT], alkaline phosphatase [ALP], and total bilirubin) must be performed at the scheduled visits
(Protocol Section 11.5.2).


Statistical Analysis Plan (Methods) 
Page 20 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
Table 11-2 Treatment Period and Safety Follow-up Visit Assessments – Study VX15-809-
114
Event/Assessment
Day 1
Week 12
Week 24
Week 36
Week 48
Safety 
Follow-up 
Week 52a
Clinic visit
X
X
X
X
X
X
Vital signsb
X
X
X
X
X
X
Physical examinationc
X
Xd
Liver Function Testinge
X
X
X
X
X
X
Urine pregnancy test (all female subjects of 
childbearing potential)
X
X
X
X
X
X
Randomizationf
X
Standardized education on adherence
X
Concomitant medications, treatments, and 
procedures
X
X
X
X
X
X
Smart Adherence Technology-Reported 
Adherenceg
X
X
X
X
LUM/IVA drug counti
X
X
X
X
Ophthalmologic examinationj
X
AEs and SAEs
Continuous from signing of ICF or assent (where applicable)
LUM/IVA resupply
Every 3 months throughout study
                                               
a
The Safety Follow-up Visit is 28 (± 7) days after the last dose of LUM/IVA (Protocol Section 8.1.3).
b
Vital signs will be assessed following a 5-minute rest in the seated or supine position.
c
Symptom-targeted PEs will occur at any time during the study if triggered by AEs or if deemed necessary by the 
investigator.
d
Required for subjects who do not begin commercial LUM/IVA after Week 48 only.
e
Day 1 only blood draws will be collected before the first dose of LUM/IVA. Liver function testing (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transpeptidase [GGT], alkaline 
phosphatase [ALP], and total bilirubin) must be performed at the scheduled visits (Protocol Section 11.5.2).
f
Randomization must occur after all inclusion and exclusion criteria are met and before the first dose of LUM/IVA. 
Randomization will be done through IWRS.
g
Data will be collected for all subjects throughout the study in real-time. Subjects in Study Arm A will review data with 
physicians at study visits. 
.
i
LUM/IVA drug count will be collected at the end of specified study visits.
j
See Protocol Section 11.5.6.


Statistical Analysis Plan (Methods) 
Page 21 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
Appendix B: Analysis Visit Windows for Safety and Adherence/PROs
Assessments
Table 11-3
Analysis Visit Windows for Study Assessments
Assessment
Analysis Visita
Target Study Dayb
Analysis Visit Window
(in study days)
Safety Assessment
LFTs;
Vital Signs;
Baseline
Day 1
1
Week 12
Day 85
[2, 127]
Week 24
Day 169
[128, 211]
Week 36
Day 253
[212, 295]
Week 48
Day 337
[296, 379]
Safety Follow-up (Week 52)
Day 364
Use nominal visit
Adherence 
Subject Satisfaction with Smart 
Adherence Technology
Baseline
Day 1
1
Week 12
Day 85
[2, 127]
Week 24
Day 169
[128, 211]
Week 36
Day 253
[212, 295]
Week 48
Day 337
[296, 379]
Notes: 
The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits:
1.
If no numerical measurement is available within a visit window, the measurement will be considered missing for 
the visit.
2.
If there is more than 1 numerical measurement available within the same visit window, use the following rules: 
a.
For Adherence 
: if there are multiple measurements within a visit window, the 
measurement at the scheduled visit will be used. Otherwise,
i.
If there are no measurements at the scheduled visit, then the measurement closest to the target day will 
be used; or
ii.
If there are multiple measurements with the same distance to the target day, the latest measurement will 
be used.  
b.
For safety parameters: if there are multiple measurements within a visit window,  
i.
The measurement closest to the target day will be used; or 
ii.
If there are multiple measurements within the same distance from the target day, the latest measurement 
will be used.
                                               
a
Analysis Visit is used to report data in tables and figures, but not listings.
b
Target day time point per protocol is predose.


Statistical Analysis Plan (Methods) 
Page 22 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates
Imputation rules for missing or partial medication start/stop dates are defined below:
1. Missing or partial medication start date:
a.
If only DAY is missing, use the first day of the month. 
b. If DAY and Month are both missing, use the first day of the year. 
c.
If DAY, Month and Year are all missing, use a date before the first dose date
(in practical, use Jan. 01, 2000 to impute or other equivalent method).
2. Missing or partial medication stop date:
a.
If only DAY is missing, use the last day of the month.
b. If DAY and Month are both missing, use the last day of the year.
c.
If DAY, Month and year are all missing, assign ‘continuing’ status to stop 
date (in practical, use Dec. 31, 2050 to impute or other equivalent method).
In summary, the prior, concomitant or post categorization of a medication is described below.
Table 11-4
Prior, Concomitant, and Post Categorization of a Medication
Medication Start Date
Medication Stop Date
< First Dose Date of 
Study Drug
≥ First Dose Date 
and ≤ End Date of 
TE Period
> End Date of TE 
Period
< First dose date of study drug
P
PC
PCA
≥ First dose date and 
≤ End date of TE period
-
C
CA
> End date of TE period
-
-
A
A: Post; C: Concomitant; P: Prior


Statistical Analysis Plan (Methods) 
Page 23 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
Appendix D: Imputation Rules for Missing AE dates
Imputation rules for missing or partial AE start date are defined below:
If only Day of AE start date is missing: 
If the AE start year and month are the same as that for the first dose date, then:

If the full (or  partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start day as the day of first dose date; otherwise, impute 
the AE start day as 1.

Otherwise, impute the AE start day as 1.
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE.
If Day and Month of AE start date are missing:
If AE start year = first dose year, then:

If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start Month and Day as the Month and Day of first dose 
date; otherwise, impute the AE start Month as January and the Day as 1.

Otherwise, impute the AE start MONTH as January and the DAY as 1.
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE.
If Year of AE start date is missing:
If the year of AE start is missing or AE start date is completely missing then query site with 
no imputation. Also compare the full (or partial) AE end date to the first dose date. If the AE 
end date is before the first dose date then the AE should be considered as a pretreatment AE. 
Otherwise, the AE will be considered as TEAE.


Statistical Analysis Plan (Methods) 
Page 24 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
Appendix E: Coefficients for Hankinson and Wang Methods for Calculating Predicted 
Spirometry Parameters
Percent predicted FEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a 
percentage. The predicted FEV1 (L) will be calculated using the Hankinson and Wang 
standards. 
The Hankinson standard will be applied to male patients 18 years and older and female 
patients 16 years and older; the Wang standard will be applied to male patients 6 to 17 years 
and female patients 6 to 15 years of age. During the study, the patients who have a birthday 
that would move them from Wang to Hankinson will use the Wang standard before that 
birthday and the Hankinson standard at or after that birthday.
Hankinson Normal Values (HNVs) will be calculated for FEV1, forced vital capacity (FVC), 
forced expiratory flow mid expiratory phase (FEF25-75%), and FEV1/FVC% using the 
Hankinson equation: 
Predicted lung function parameter = b0+b1 × age+b2 × age2+ b3 × height2
In the equation, height is given in centimeters, age is given in years, and the coefficients b0, 
b1, b2, and b3 are determined based on patient’s sex, race, and age group as shown in Table 4. 
Wang Normal Values (WNVs) will be calculated for FEV1, FVC, FEF25-75%, and FEV1/FVC 
using the Wang equation: 
ln (Predicted lung function parameter) = + βln (height)
Wang Normal Values (WNVs) will be calculated for FEV1, FVC, FEF25-75%, and FEV1/FVC 
using the Wang equation. In the equation, height is given in meters, and the coefficients α 
and β are determined based on patient’s sex, race, and age as shown in Table 11-8 and 
Table 11-9.
If either height or age is missing, and the spirometry measurement is non-missing, the last 
non-missing value of height and age will be used in the calculation of predicted values.


Statistical Analysis Plan (Methods) 
Page 25 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
Table 11-7
HNVs Equation Coefficients by Sex, Race, and Age
Parameter
Sex
Race
Age 
(years)
bo
b1
b2
b3
HNVFEV1
Male
Caucasian
<20
-0.7453
-0.04106
0.004477
0.00014098
≥20
0.5536
-0.01303
-0.000172
0.00014098
African 
American
<20
-0.7048
-0.05711
0.004316
0.00013194
≥20
0.3411
-0.02309
0.00013194
Mexican 
American
<20
-0.8218
-0.04248
0.004291
0.00015104
≥20
0.6306
-0.02928
0.00015104
Female
Caucasian
<18
-0.8710
0.06537
0.00011496
≥18
0.4333
-0.00361
-0.000194
0.00011496
African 
American
<18
-0.9630
0.05799
0.00010846
≥18
0.3433
-0.01283
-0.000097
0.00010846
Mexican 
American
<18
-0.9641
0.06490
0.00012154
≥18
0.4529
-0.01178
-0.000113
0.00012154
HNVFVC
Male
Caucasian
<20
-0.2584
-0.20415
0.010133
0.00018642
≥20
-0.1933
0.00064
-0.000269
0.00018642
African 
American
<20
-0.4971
-0.15497
0.007701
0.00016643
≥20
-0.1517
-0.01821
0.00016643
Mexican 
American
<20
-0.7571
-0.09520
0.006619
0.00017823
≥20
0.2376
-0.00891
-0.000182
0.00017823
Female
Caucasian
<18
-1.2082
0.05916
0.00014815
≥18
-0.3560
0.01870
-0.000382
0.00014815
African 
American
<18
-0.6166
-0.04687
0.003602
0.00013606
≥18
-0.3039
0.00536
-0.000265
0.00013606
Mexican 
American
<18
-1.2507
0.07501
0.00014246
≥18
0.1210
0.00307
-0.000237
0.00014246
HNVFEF25-75%
Male
Caucasian
<20
-1.0863
0.13939
0.00010345
≥20
2.7006
-0.04995
0.00010345
African 
American
<20
-1.1627
0.12314
0.00010461
≥20
2.1477
-0.04238
0.00010461
Mexican 
American
<20
-1.3592
0.10529
0.00014473
≥20
1.7503
-0.05018
0.00014473
Female
Caucasian
<18
-2.5284
0.52490
-0.015309
0.00006982
≥18
2.3670
-0.01904
-0.000200
0.00006982
African 
American
<18
-2.5379
0.43755
-0.012154
0.00008572
≥18
2.0828
-0.03793
0.00008572
Mexican 
American
<18
-2.1825
0.42451
-0.012415
0.00009610
≥18
1.7456
-0.01195
-0.000291
0.00009610
HNVFEV1/FVC%
Male
Caucasian
88.066
-0.2066
African 
American
89.239
-0.1828
Mexican 
American
90.024
-0.2186
Female
Caucasian
90.809
-0.2125
African 
American
91.655
-0.2039
Mexican 
American
92.360
-0.2248


Statistical Analysis Plan (Methods) 
Page 26 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
Table 11-8   WNVs Equation Coefficients by Sex and Age in White Boys and Girls
FEV1
FVC
FEF25-75%
FEV1/FVC
Sex
Age
α
β
α
β
α
β
α
β
Male
6
-0.109
2.252
-0.024
2.470
-0.078
-0.248
7
-0.104
2.270
-0.018
2.489
-0.086
-0.220
8
-0.089
2.257
0.005
2.443
0.264
1.505
-0.091
-0.199
9
-0.063
2.197
0.017
2.426
0.308
1.443
-0.086
-0.206
10
-0.057
2.212
0.030
2.407
0.290
1.557
-0.081
-0.209
11
-0.093
2.324
0.009
2.468
0.242
1.738
-0.101
-0.147
12
-0.161
2.512
-0.061
2.649
0.165
1.982
-0.101
-0.133
13
-0.292
2.843
-0.175
2.924
0.007
2.396
-0.116
-0.085
14
-0.329
2.983
-0.219
3.060
0.014
2.483
-0.106
-0.087
15
-0.141
2.709
-0.079
2.859
0.241
2.163
-0.060
-0.155
16
0.062
2.409
0.104
2.591
0.503
1.764
-0.045
-0.178
17
0.262
2.099
0.253
2.374
0.762
1.368
0.008
-0.272
Female
6
-0.109
1.949
-0.013
2.007
-0.097
-0.055
7
-0.144
2.243
-0.062
2.385
-0.084
-0.132
8
-0.137
2.239
-0.055
2.381
0.247
1.668
-0.079
-0.152
9
-0.123
2.222
-0.039
2.351
0.254
1.710
-0.084
-0.128
10
-0.161
2.364
-0.068
2.458
0.195
1.933
-0.092
-0.097
11
-0.223
2.558
-0.120
2.617
0.161
2.091
-0.102
-0.061
12
-0.264
2.709
-0.174
2.776
0.185
2.120
-0.090
-0.067
13
-0.153
2.535
-0.061
2.576
0.294
1.976
-0.093
-0.040
14
0.046
2.178
0.139
2.208
0.450
1.711
-0.096
-0.026
15
0.148
2.008
0.210
2.099
0.581
1.486
-0.062
-0.093


Statistical Analysis Plan (Methods) 
Page 27 of 35
Protocol Number: VX15-809-114
Vertex Pharmaceuticals Incorporated
Table 11-9
WNVs Equation Coefficients by Sex and Age in Black Boys and Girls
FEV1
FVC
FEF25-75%
FEV1/FVC
Sex
Age
α
β
α
β
α
β
α
β
Male
6
-0.166
1.723
-0.088
1.961
-0.091
-0.152
7
-0.122
1.846
-0.040
2.040
-0.091
-0.153
8
-0.225
2.271
-0.094
2.323
0.097
1.544
-0.118
-0.104
9
-0.142
2.059
-0.074
2.308
0.255
1.248
-0.079
-0.218
10
-0.157
2.117
-0.110
2.417
0.230
1.428
-0.047
-0.303
11
-0.176
2.166
-0.138
2.453
0.256
1.438
-0.048
-0.263
12
-0.307
2.548
-0.224
2.710
0.085
1.936
-0.084
-0.162
13
-0.486
2.962
-0.342
2.975
-0.121
2.476
-0.141
-0.018
14
-0.472
3.010
-0.337
3.035
-0.115
2.536
-0.123
-0.050
15
-0.318
2.789
-0.226
2.889
0.170
2.120
-0.070
-0.140
16
0.074
2.140
0.058
2.425
0.663
1.299
0.018
-0.289
17
0.053
2.223
0.148
2.310
0.505
1.618
-0.095
-0.087
Female
6
-0.288
2.182
-0.172
2.117
-0.109
0.059
7
-0.250
2.158
-0.135
2.132
-0.104
-0.030
8
-0.276
2.295
-0.176
2.362
-0.283
2.990
-0.103
-0.066
9
-0.294
2.330
-0.200
2.452
0.025
2.062
-0.097
-0.104
10
-0.344
2.507
-0.230
2.571
0.051
2.028
-0.120
-0.043
11
-0.308
2.460
-0.204
2.526
0.078
2.006
-0.089
-0.105
12
-0.219
2.312
-0.107
2.342
0.225
1.804
-0.115
-0.021
13
-0.117
2.196
-0.042
2.294
0.418
1.504
-0.051
-0.148
14
0.041
1.920
0.105
2.021
0.574
1.257
-0.063
-0.103
15
0.203
1.662
0.253
1.787
0.599
1.281
-0.043
-0.139