Clinical trial NCT03068312
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2017-07-18; Completion date: 2018-12-18
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will evaluate the efficacy of ivacaftor treatment in subjects with CF 6 years of age and older who have a 3849 + 10KB C→T or D1152H CFTR mutation.

Detailed description:

Arms: arm 1: Participants received IVA 150 milligram (mg) every 12 hours (q12h) for 8 weeks in treatment period 1 followed by placebo matched to IVA for 8 weeks in treatment period 2. A washout period of 8 weeks was maintained between the 2 treatment periods. arm 2: Participants received placebo matched to IVA for 8 weeks in treatment period 1 followed by IVA 150 mg q12h for 8 weeks in treatment period 2. A washout period of 8 weeks was maintained between the 2 treatment periods.
Interventions: intervention 1: Ivacaftor intervention 2: Placebo
Intervention descriptions: intervention 1: IVA 150 mg tablet. intervention 2: Placebo matched to IVA tablet.

Protocol documents:
Prot_000.pdf: 
Page 1 of 51 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Randomized, Double-blind, Placebo-
controlled, Crossover Study to Evaluate the 
Efficacy of Ivacaftor in Subjects with Cystic 
Fibrosis Who are 6 Years of Age and Older 
and Have Either a 3849 + 10KB C→T or 
D1152H-CFTR Mutation 
Vertex Study Number: VX16-770-127 
 
 
Date of Protocol: 20 October 2016 (Version 1.0)  
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. 


Protocol VX16-770-127, Version 1.0 
Page 2 of 51 
Vertex Pharmaceuticals Incorporated 
 
2 
PROTOCOL SYNOPSIS 
 
Title A Randomized, Double-blind, Placebo-controlled, Crossover Study to Evaluate 
the Efficacy of Ivacaftor in Subjects with Cystic Fibrosis Who are 6 Years of Age 
and Older and Have Either a 3849 + 10KB C→T or D1152H-CFTR Mutation 
Brief Title A Study to Evaluate Efficacy of Ivacaftor in Subjects With Cystic Fibrosis Who 
Have a 3849 + 10KB C→T or D1152H CFTR Mutation  
  
Clinical Phase and 
Clinical Study Type  
Phase 3b, efficacy 
  
Objectives Primary: 
To evaluate the efficacy of ivacaftor treatment in subjects with cystic fibrosis (CF) 
6 years of age and older who have a 3849 + 10KB C→T or D1152H CF 
transmembrane conductance regulator gene (CFTR) mutation. 
  
Endpoints Primary: 
Change from baseline in lung clearance index2.5 (LCI2.5; calculated as lung volume 
turnovers required to reach 2.5% of the starting nitrogen [N2] concentration) 
through 8 weeks of treatment 
  
Number of Subjects Approximately 50 subjects 
  
Study Population Male or female subjects 6 years of age and older weighing ≥25 kg who have CF 
and a 3849 + 10KB C→T or D1152H CFTR mutation on at least 1 allele. 
  
Investigational Drug Active substance: ivacaftor 
 Activity: CFTR potentiator  
 Strength and route of administration: 150 mg film-coated tablets for oral 
administration. 


Protocol VX16-770-127, Version 1.0 
Page 3 of 51 
Vertex Pharmaceuticals Incorporated 
 
  
Study Duration Excluding the Screening Period, each subject will participate in the study for 
approximately 28 weeks (Day 1 through the Safety Follow-up Visit).  
  
Study Design This study is a randomized, double-blind, placebo-controlled, single-center, 
crossover, exploratory study. 
The crossover design includes two 8-week treatment periods separated by an 
8-week (±4 days) washout period. Subjects will be randomized to receive 
Ivacaftor, 150 mg every 12 hours (q12h), in Treatment Period 1 and placebo in 
Treatment Period 2, or placebo in Treatment Period 1 and ivacaftor (150 mg q12h) 
in Treatment Period 2. 
  
Assessments Efficacy: 
Multiple breath washout (MBW); 
 
 
 
 
Safety: 
Adverse events (AEs), clinical laboratory assessments (amylase, lipase, and liver 
function tests [LFTs]), physical examinations and vital signs, and 
ophthalmological examinations (OEs) (for subjects <18 years of age) 
  
Statistical Analyses No formal sample size calculation was conducted. The planned sample size of 
approximately 50 subjects is based on the number of subjects expected to be 
available for participation in this study. 
The Full Analysis Set (FAS) is defined as all randomized subjects who have 
received at least 1 dose of study drug. The FAS will be used for efficacy analyses.  
The Safety Set is defined as all enrolled subjects who received at least 1 dose of 
study drug. The Safety Set will be used for safety analyses. Study baseline is 
defined as the most recent nonmissing measurement collected before the first 
administration of study drug in Treatment Period 1; and all the statistical 
inferences will be based on change from study baseline. 
Efficacy: 
Bayesian analyses will be used to estimate the effect of ivacaftor versus placebo 
on LCI2.5. A non-informative prior distribution (normal distribution with mean 0 
and variance = 106) on the treatment difference will be assumed. The posterior 
distribution of the treatment difference will be obtained using the Markov Chain 
Monte Carlo (MCMC) method. 
Supportive analyses of change from study baseline through 8 weeks of ivacaftor 
treatment versus placebo in LCI2.5 will be performed based on a mixed-effects 
model for repeated measures (MMRM).  
 
 
  
Safety: 
The incidence of treatment-emergent AEs (TEAEs) will be summarized in 
contingency tables (n, percentage) by treatment. For other safety parameters 
(e.g., vital signs), the raw values and changes from baseline will be summarized 


Protocol VX16-770-127, Version 1.0 
Page 4 of 51 
Vertex Pharmaceuticals Incorporated 
 
by treatment. Additionally, all safety data will be presented in subject data 
listings. 
  


Protocol VX16-770-127, Version 1.0 
Page 5 of 51 
Vertex Pharmaceuticals Incorporated 
 
3 
SCHEDULE OF ASSESSMENTS 
Schedules of Assessments are shown in Table 3-1 and Table 3-2. 
Table 3-1 
Study VX16-770-127: Screening Period Assessments 
Event/Assessment 
Screening Period 
(Day -28 through Day-1) 
Informed consent form (ICF) and assent form (when applicable) 
X 
Review inclusion/exclusion criteria 
X 
Demographics 
X 
Medical history (includes CF genotype) 
X 
Prior and concomitant medications 
X 
Ophthalmological history 
X 
Ophthalmologic examinationa 
X 
Physical examination 
X 
Weight and heightb 
X 
Vital signsc 
X 
Multiple breath washoutd 
X 
Spirometryd 
X 
Sweat chloride 
X 
Serum follicle-stimulating hormone (FSH; suspected 
postmenopausal female subjects only)e  
X 
Serum pregnancy test (female subjects of childbearing potential)f 
X 
Hematology 
X 
Serum chemistry 
X 
Adverse events 
Continuous from signing of the ICF and 
Assent (where applicable) through the 
Safety Follow-up Visit 
 
 
a 
OE is required for subjects who are under 18 years of age at the Screening Visit. If there is documentation of an 
OE that met protocol criteria and was conducted within 3 months before the Screening Visit, the subject is not 
required to have another OE during Screening.  
b 
Weight and height will be measured with shoes off. 
c 
Vital signs (blood pressure, pulse rate, respiration rate, and body temperature) will be collected after the subject 
has been at rest (supine) for 5 minutes. Vital sign assessments will be performed before blood draws. 
d 
At Screening, spirometry and MBW may be performed pre- or post-bronchodilator.  
e 
FSH will be measured for any suspected postmenopausal female with at least 12 months of continuous 
spontaneous amenorrhea. Serum FSH levels must be ≥40 mIU/mL to be considered postmenopausal. 
f 
See Section 11.5.6.1 for definition of childbearing potential. 


Protocol VX16-770-127, Version 1.0 
Page 6 of 51 
Vertex Pharmaceuticals Incorporated 
 
Table 3-2 
Study VX16-770-127: Treatment Period and Follow-up Visit Assessments 
Event/Assessment 
Treatment Period 1 
Washout 
Period  
Treatment Period 2 
Early 
Termination of 
Treatment (ETT) 
Safety Follow-up 
4 weeks (± 7 days) after 
last dose of study druga 
Day 1 
Week 4 
(± 4 days) 
Week 8 
(± 4 days) 
8 weeks 
(± 4 days) 
Day 1 
Week 4 
(± 4 days) 
Week 8 
(± 4 days) 
Review of inclusion 
/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Meal(s) or snack(s) 
at sitec 
X 
X 
X 
 
X 
X 
X 
 
 
Vital signsd 
X 
X 
X 
 
X 
X 
X 
X 
X 
Physical 
examination 
X 
 
X 
 
X 
 
X 
X 
X 
Multiple breath 
washoutf 
X 
X 
X 
 
X 
X 
X 
 
 
a 
If the ETT Visit occurs ≥3 weeks after the last dose of study drug, the Follow-up Visit will not be required. 
c 
Fat-containing food such as a standard CF high-fat, high-calorie meal or snack will be provided to subjects at the site after all predose assessments have 
occurred. 
d 
Vital signs (blood pressure, pulse rate, respiration rate, and body temperature) will be collected after the subject has been at rest (supine) for 5 minutes. 
Blood pressure will be measured by sphygmomanometer. Vital sign assessments will be performed before blood draws. 
f 
Multiple breath washout 
 will be performed pre-bronchodilator 
, and must be performed before dosing. 


Protocol VX16-770-127, Version 1.0 
Page 7 of 51 
Vertex Pharmaceuticals Incorporated 
 
Table 3-2 
Study VX16-770-127: Treatment Period and Follow-up Visit Assessments 
Event/Assessment 
Treatment Period 1 
Washout 
Period  
Treatment Period 2 
Early 
Termination of 
Treatment (ETT) 
Safety Follow-up 
4 weeks (± 7 days) after 
last dose of study druga 
Day 1 
Week 4 
(± 4 days) 
Week 8 
(± 4 days) 
8 weeks 
(± 4 days) 
Day 1 
Week 4 
(± 4 days) 
Week 8 
(± 4 days) 
Pregnancy test 
(female subjects of 
childbearing 
potential)h 
X 
X 
X 
 
X 
X 
X 
X 
X 
Liver function tests 
(LFTs)i 
X 
 
X 
 
X 
 
X 
X 
X 
Amylase and lipase 
X 
 
X 
 
X 
 
X 
X 
X 
Ophthalmological 
examinationj 
 
 
 
 
 
 
X 
X 
 
Ivacaftor or placebo 
dosing 
X 
X 
X 
 
X 
X 
X 
 
 
Concomitant 
treatments and 
procedures 
---------------------Continuous from signing of the ICF and Assent (where applicable) through the Safety Follow-up Visit--------------------- 
Adverse events 
---------------------Continuous from signing of the ICF and Assent (where applicable) through the Safety Follow-up Visit--------------------- 
 
h 
A urine β-hCG test will be performed at all visits in Treatment Periods 1 and 2 and will be performed before the first dose of study drug on Day 1 of 
Treatment Periods 1 and 2. A urine β-hCG test will be performed at the ETT visit (as applicable). A serum pregnancy test will be performed at the Safety 
Follow-up Visit.  
i 
ALT, AST, GGT, alkaline phosphatase, and bilirubin 
j 
OE is required for subjects who were under 18 years of age at the Screening Visit. OE will be performed either at the Week 8 Visit of Treatment Period 2 or 
at the ETT Visit. This examination is not required if the subject received study drug for a total of less than 4 weeks. 


Protocol VX16-770-127, Version 1.0 
 Page 8 of 51 
Vertex Pharmaceuticals Incorporated 
 
4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Protocol Synopsis ................................................................................................................... 2 
3 
Schedule of Assessments ........................................................................................................ 5 
4 
Table of Contents ................................................................................................................... 8 
List of Tables ........................................................................................................................... 11 
List of Figures .......................................................................................................................... 11 
List of Abbreviations ............................................................................................................... 12 
5 
Introduction .......................................................................................................................... 14 
5.1 
CF and Ivacaftor Background ........................................................................................ 14 
5.2 
Rationale for Study ......................................................................................................... 14 
6 
Study Objectives .................................................................................................................. 15 
6.1 
Primary Objective ........................................................................................................... 15 
 
 
7 
Study Endpoints ................................................................................................................... 15 
7.1 
Primary Endpoint ............................................................................................................ 15 
 
 
8 
Study Population .................................................................................................................. 15 
8.1 
Inclusion Criteria ............................................................................................................ 16 
8.2 
Exclusion Criteria ........................................................................................................... 16 
9 
Study Implementation ......................................................................................................... 17 
9.1 
Study Design .................................................................................................................. 17 
9.1.1 
Screening ................................................................................................................ 18 
9.1.1.1 
Repetition of Screening Assessments .............................................................. 18 
9.1.1.2 
Rescreening ...................................................................................................... 18 
9.1.1.3 
Extension of the Screening Period Window .................................................... 19 
9.1.2 
Treatment Period .................................................................................................... 19 
9.1.2.1 
Treatment Period 1 ........................................................................................... 19 
9.1.2.2 
Washout Period ................................................................................................ 19 
9.1.2.3 
Treatment Period 2 ........................................................................................... 19 
9.1.3 
Follow-up ................................................................................................................ 20 
9.1.4 
Early Termination of Treatment ............................................................................. 20 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 20 
9.3 
Rationale for Study Design and Study Drug Regimens ................................................. 20 
9.3.1 
Study Design ........................................................................................................... 20 
9.3.2 
Study Drug Dose and Duration .............................................................................. 20 
9.3.3 
Study Assessments ................................................................................................. 21 
9.4 
Study Restrictions ........................................................................................................... 21 
9.5 
Prior and Concomitant Medications ............................................................................... 22 
9.5.1 
Maintenance of Stable Medication Regimen for CF .............................................. 22 
9.6 
Administration ................................................................................................................ 23 
9.7 
Dose Modification for Toxicity ...................................................................................... 23 
9.8 
Removal of Subjects ....................................................................................................... 23 
9.9 
Replacement of Subjects ................................................................................................ 24 
10 Study Drug Information and Management ....................................................................... 24 


Protocol VX16-770-127, Version 1.0 
 Page 9 of 51 
Vertex Pharmaceuticals Incorporated 
 
10.1 Preparation and Dispensing ............................................................................................ 24 
10.2 Packaging and Labeling ................................................................................................. 24 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 24 
10.4 Study Drug Interruption ................................................................................................. 25 
10.5 Drug Accountability ....................................................................................................... 25 
10.6 Disposal, Return, or Retention of Unused Drug ............................................................. 25 
10.7 Compliance ..................................................................................................................... 25 
10.8 Blinding and Unblinding ................................................................................................ 25 
10.8.1 
Blinding .................................................................................................................. 25 
10.8.2 
Unblinding .............................................................................................................. 26 
11 Assessments .......................................................................................................................... 27 
11.1 Timing of Assessments ................................................................................................... 27 
11.2 Subject and Disease Characteristics ............................................................................... 27 
 
11.4 Efficacy ........................................................................................................................... 27 
11.4.1 
MBW ...................................................................................................................... 27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.5 Safety .............................................................................................................................. 31 
11.5.1 
Adverse Events ....................................................................................................... 31 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 31 
11.5.3 
Elevation of Liver Function Test Parameters ......................................................... 33 
11.5.4 
Physical Examinations and Vital Signs .................................................................. 33 
11.5.5 
Ophthalmologic Examination ................................................................................. 34 
11.5.6 
Contraception and Pregnancy ................................................................................. 34 
11.5.6.1 Contraception ................................................................................................... 34 
11.5.6.2 Pregnancy and Nursing Mothers ...................................................................... 35 
12 Statistical and Analytical Plans .......................................................................................... 35 
12.1 Sample Size and Power .................................................................................................. 35 
12.2 Analysis Sets .................................................................................................................. 35 
12.3 Statistical Analysis ......................................................................................................... 35 
12.3.1 
General Considerations ........................................................................................... 35 
12.3.2 
Background Characteristics .................................................................................... 36 
12.3.2.1 Subject Disposition .......................................................................................... 36 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 36 
12.3.2.3 Prior and Concomitant Medications ................................................................ 36 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 37 
12.3.3 
Efficacy Analysis .................................................................................................... 37 
12.3.3.1 Change from Baseline in LCI .......................................................................... 37 
 
 


Protocol VX16-770-127, Version 1.0 
 Page 10 of 51 
Vertex Pharmaceuticals Incorporated 
 
 
 
 
 
 
 
 
 
 
 
12.3.5 
Safety Analysis ....................................................................................................... 38 
12.3.5.1 Adverse Events ................................................................................................ 38 
12.3.5.2 Clinical Laboratory Assessments ..................................................................... 39 
12.3.5.3 Vital Signs ........................................................................................................ 39 
12.3.5.4 Physical Examination ....................................................................................... 39 
12.3.5.5 Ophthalmological Examinations ...................................................................... 39 
12.3.6 
Interim and IDMC Analyses ................................................................................... 39 
12.3.6.1 Interim Analysis ............................................................................................... 39 
12.3.6.2 IDMC Analysis ................................................................................................ 39 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 40 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 40 
13.1.1 
Adverse Events ....................................................................................................... 40 
13.1.1.1 Definition of an Adverse Event........................................................................ 40 
13.1.1.2 Clinically Significant Assessments .................................................................. 40 
13.1.1.3 Documentation of Adverse Events................................................................... 40 
13.1.1.4 Adverse Event Severity .................................................................................... 41 
13.1.1.5 Adverse Event Causality .................................................................................. 41 
13.1.1.6 Study Drug Action Taken ................................................................................ 42 
13.1.1.7 Adverse Event Outcome .................................................................................. 42 
13.1.1.8 Treatment Given............................................................................................... 43 
13.1.2 
Serious Adverse Events .......................................................................................... 43 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 43 
13.1.2.2 Documentation of Serious Adverse Events ...................................................... 43 
13.1.2.3 Reporting Serious Adverse Events .................................................................. 44 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 44 
13.2 Administrative Requirements ......................................................................................... 44 
13.2.1 
Ethical Considerations ............................................................................................ 44 
13.2.2 
Subject Information and Informed Consent ........................................................... 45 
13.2.3 
Investigator Compliance ......................................................................................... 45 
13.2.4 
Access to Records ................................................................................................... 45 
13.2.5 
Subject Privacy ....................................................................................................... 45 
13.2.6 
Record Retention .................................................................................................... 45 
13.2.7 
Study Termination .................................................................................................. 46 
13.3 Data Quality Assurance .................................................................................................. 46 
13.4 Monitoring ...................................................................................................................... 46 
13.5 Electronic Data Capture ................................................................................................. 47 
13.6 Publications and Clinical Study Report .......................................................................... 47 
 
 
13.6.2 
Clinical Study Report ............................................................................................. 47 
14 References ............................................................................................................................. 48 


Protocol VX16-770-127, Version 1.0 
 Page 11 of 51 
Vertex Pharmaceuticals Incorporated 
 
15 Protocol Signature Pages .................................................................................................... 50 
15.1 Sponsor Signature Page .................................................................................................. 50 
15.2 Investigator Signature Page ............................................................................................ 51 
List of Tables 
Table 3-1 
Study VX16-770-127: Screening Period Assessments ........................................... 5 
Table 3-2 
Study VX16-770-127: Treatment Period and Follow-up Visit Assessments ......... 6 
Table 9-1 
Prohibited Medications ......................................................................................... 22 
Table 10-1 
Study Drug ............................................................................................................ 24 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 32 
Table 13-1 
Grading of AE Severity ........................................................................................ 41 
Table 13-2 
Classifications for AE Causality ........................................................................... 42 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 42 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 42 
List of Figures 
Figure 9-1 
VX16-770-127 Study Design ............................................................................... 18 
 


Protocol VX16-770-127, Version 1.0 
 Page 12 of 51 
Vertex Pharmaceuticals Incorporated 
 
List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
cAMP 
cyclic adenosine monophosphate 
CF 
cystic fibrosis 
 
 
CFTR 
Cystic fibrosis transmembrane conductance regulator gene 
CFTR 
Cystic fibrosis transmembrane conductance regulator protein 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECFS-CTN 
European Cystic Fibrosis Society - Clinical Trial Network 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ERS 
European Respiratory Society 
ETT 
Early Termination of Treatment 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
 
 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
 
 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IRB 
institutional review board 
IVA 
ivacaftor 
IXRS 
interactive web or voice response system 
LCI 
lung clearance index 
LCI2.5 
LCI calculated as lung volume turnovers required to reach 2.5% of the starting 
nitrogen concentration 
LFT 
liver function test 


Protocol VX16-770-127, Version 1.0 
 Page 13 of 51 
Vertex Pharmaceuticals Incorporated 
 
Abbreviation 
Definition 
MBW 
multiple breath washout 
MCMC 
Markov Chain Monte Carlo method 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effects model for repeated measures 
mRNA 
messenger ribonucleic acid 
N2 
nitrogen 
n 
number 
OE 
Ophthalmologic(al) examination 
PE 
physical examination 
P-gp 
P-glycoprotein 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
q12h 
every 12 hours 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SUSAR 
suspected, unexpected, serious adverse reactions 
TEAE 
treatment-emergent adverse event 
TOBI® 
Tobramycin Inhalation Solution 
ULN 
upper limit of normal 
Vertex 
Vertex Pharmaceuticals Incorporated 


Protocol VX16-770-127, Version 1.0 
 Page 14 of 51 
Vertex Pharmaceuticals Incorporated 
 
5 
INTRODUCTION 
5.1 
CF and Ivacaftor Background 
Cystic fibrosis (CF) is a chronically debilitating autosomal recessive disease with high morbidity 
and premature mortality that affects approximately 70,000 individuals worldwide1, including 
approximately 30,000 individuals in the United States2 and approximately 39,000 in the 
European Union (EU).3 The disease affects predominately Whites4 and is caused by mutations in 
the CF transmembrane conductance regulator gene (CFTR), which results in absent or deficient 
function of the CFTR protein at the cell surface.5 CFTR is an epithelial chloride channel 
responsible for aiding in the regulation of salt and water absorption and secretion in various 
tissues. The failure to regulate chloride transport in these tissues results in the multisystem 
pathology associated with CF.6 In the lungs, obstruction of airways with thick mucus, 
establishment of a chronic bacterial infection in the airways, and damaging inflammatory 
responses are all thought to play a role in causing irreversible structural changes in the lungs and 
respiratory failure. Progressive loss of lung function is the leading cause of mortality.2,4 
Currently, there is no cure for CF, and, despite adjunctive treatments with nutritional 
supplements, antibiotics and mucolytics,7 the median predicted age of survival of individuals 
born today with CF is approximately 40 years of age.2,8 
More than 2000 mutations in the CFTR gene have been identified.9 CFTR mutations are grouped 
into 5 classes depending on the mutation type. This study focuses on the Class V (splice) 
mutation 3849 + 10kb C→T, which has a prevalence of 0.2% to 2% globally and the Class X 
missense mutation D1152H, which has a prevalence of <0.1% globally. Both mutations have 
residual CFTR function: 3849 + 10kb C→T results in a reduced amount of normal CFTR protein 
at the cell surface (average sweat chloride 66 mEq/L; 34% of patients with pancreatic 
insufficiency9), while D1152H results in normal or elevated levels of CFTR protein at the cell 
surface but with reduced levels of CFTR function (average sweat chloride 45 mEq/L; 23% of 
patients with pancreatic insufficiency9). These mutations are described further below.  
Ivacaftor (Kalydeco®), the first CFTR modulator developed by Vertex Pharmaceuticals 
Incorporated, is an orally-administered CFTR potentiator that increases the channel-open 
probability of CFTR protein at the cell surface to enhance chloride transport. Globally, ivacaftor 
is indicated for the treatment of CF in patients as young as 2 years who have the G551D and 
certain other gating (Class III) mutations as well as the R117H mutation in the CFTR gene, 
depending on the country. 
5.2 
Rationale for Study 
Class V CFTR mutations include splicing abnormalities that markedly decrease the amount of 
wild-type CFTR protein at the cell surface.10,11 One of these Class V mutations, 3849 + 10kb 
C→T, is characterized by a partially active splice site in intron 19 that leads to the insertion of a 
new 84 base pair exon that contains an in-frame stop codon between exon 19 and 20.12 With this 
mutation, both correctly and aberrantly spliced CFTR transcripts are produced, and the amounts 
of each may vary between patients.13 CFTR protein translated from any correctly spliced CFTR 
mRNA is thought to be present and functional at the cell membrane. In an in vitro model system, 
ivacaftor increased wild-type CFTR chloride transport, and therefore may increase the function 
of CFTR derived from correctly spliced transcripts available at the cell surface.14 Therefore, this 
study will evaluate ivacaftor treatment in subjects with the 3849 + 10kb C→T CFTR mutation. 


Protocol VX16-770-127, Version 1.0 
 Page 15 of 51 
Vertex Pharmaceuticals Incorporated 
 
D1152H is a missense mutation that results in normal or increased levels of CFTR protein at the 
cell surface but a reduction in CFTR-mediated chloride transport. In vitro, ivacaftor increased 
chloride transport in cells expressing D1152H-CFTR.14 Therefore, this study will also evaluate 
ivacaftor treatment in subjects with the D1152H mutation. 
Study VX12-770-113 (Study 113) demonstrated improvements with ivacaftor treatment in 
subjects with clinical residual CFTR function, and subjects who had a 3849 + 10KB C→T or 
D1152H CFTR mutation were among those included in Study 113.  
 
 
. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the efficacy of ivacaftor treatment in subjects with CF 6 years of age and older who 
have a 3849 + 10KB C→T or D1152H CFTR mutation. 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Change from baseline in lung clearance index2.5 (LCI2.5; calculated as lung volume turnovers 
required to reach 2.5% of the starting nitrogen [N2] concentration) through 8 weeks of treatment. 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 


Protocol VX16-770-127, Version 1.0 
 Page 16 of 51 
Vertex Pharmaceuticals Incorporated 
 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible 
for the study. 
8.1 
Inclusion Criteria 
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
informed consent form (ICF), and, when appropriate, assent form. 
2. Male or female with confirmed diagnosis of CF.15 The subject must have both of the 
following: 
 One or more characteristic phenotypic features, such as chronic cough and sputum 
production, persistent chest radiograph abnormalities, or airway obstruction manifested 
by wheezing and air trapping; or a history of CF in a sibling; or a positive newborn 
screening test result; 
 An increased sweat chloride concentration (≥60 mmol/L) by pilocarpine iontophoresis on 
2 or more occasions; or identification of 2 CF causing mutations; or demonstration of 
abnormal nasal epithelial ion transport. 
3. Six years of age and older and ≥25 kg on the date of the ICF. 
4. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
5. A 3849 + 10KB C→T or D1152H mutation on at least 1 CFTR allele.  
6. FEV1 ≥40% of predicted and ≤105% of predicted at screening, based on the Global Lung 
Function Initiative (GLI)-2012 multi-ethnic all-age reference equations.16 
8.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible: 
1. A G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H 
mutation 
2. 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 study drug to the 
subject. For example: 
o A history of cirrhosis with portal hypertension. 
o An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in 
therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 
(the first dose of study drug). 
3. Ongoing or prior participation in an investigational drug study (including studies 
investigating lumacaftor/ivacaftor or ivacaftor) within 30 days before the Screening Visit.  
o A washout period of 5 terminal half-lives of the previous investigational study drug 
or 30 days, whichever is longer, must elapse before the Screening Visit. The duration 
of the elapsed time may be longer if required by local regulations.  
o Subjects who participated in Vertex Study VX14-661-108 may not be enrolled. 


Protocol VX16-770-127, Version 1.0 
 Page 17 of 51 
Vertex Pharmaceuticals Incorporated 
 
o Ongoing participation in a noninterventional study (including observational studies) 
is permitted. 
4. Any of the following abnormal laboratory values at the Screening Visit: 
 Hemoglobin <10 g/dL 
 Alanine aminotransferase (ALT) or AST >5 × upper limit of normal (ULN) 
 Bilirubin >2 × ULN 
 Glomerular filtration rate ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt 
equation in subjects <18 years of age and the Modification of Diet in Renal Disease 
equation in subjects ≥18 years of age).17,18,19 
5. For subjects <18 years of age at the Screening Visit, evidence of cataract/lens opacity 
determined to be clinically significant by the ophthalmologist or optometrist during the 
ophthalmologic examination (OE) at the Screening Visit. 
6. Use of any moderate or strong inducers or inhibitors of cytochrome P450 (CYP) 3A, 
including consumption of certain herbal medications (e.g., St. John’s Wort) and certain fruit 
and fruit juices, within 14 days before Day 1 (the first dose of the study drug).  
7. Pregnant, breastfeeding, or planning to become pregnant during the study.  
8. Sexually active subjects of reproductive potential must be willing to use appropriate 
contraception.  
9. 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 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a randomized, double-blind, placebo-controlled, single-center, crossover study that 
includes two 8-week treatment periods separated by an 8-week washout period (Figure 9-1). 
There will be 7 study visits, not including the Screening Visit. The total study duration for each 
subject will be approximately 32 weeks, including the Screening and the Follow-up periods.  
 Sequence 1: ivacaftor (150 mg q12h) in Treatment Period 1; washout; placebo in 
Treatment Period 2 
 Sequence 2: placebo in Treatment Period 1; washout; ivacaftor (150 mg q12h) in 
Treatment Period 2 


Protocol VX16-770-127, Version 1.0 
 Page 18 of 51 
Vertex Pharmaceuticals Incorporated 
 
Figure 9-1 
VX16-770-127 Study Design 
 
9.1.1 
Screening 
The Screening Visit will occur within 28 days before the first dose of study drug to confirm that 
the subjects meet the selection criteria for the study. The assessments to be conducted are shown 
in Table 3-1. The investigator (or appropriate authorized designee) will obtain informed consent 
and assent, if applicable, from each subject. 
If there is documentation of an OE that met protocol criteria and was conducted within 3 months 
before the Screening Visit, the subject is not required to have another OE during Screening 
(Section 11.5.5). 
9.1.1.1 
Repetition of Screening Assessments 
Repetition of individual screening assessment(s) that did not meet eligibility criteria is not 
permitted with the following exceptions: 
 If there is clear evidence of a laboratory error (e.g., hemolyzed sample) or equipment 
malfunction, collection of a repeat sample for the appropriate laboratory test or 
assessment may be permitted with the approval of the medical monitor 
 Exclusionary liver function test (LFT) levels, which may be retested within 14 days of 
the original screening date 
 If screening spirometry measurements fail to meet acceptability and repeatability criteria 
as specified by the American Thoracic Society (ATS)/European Respiratory Society 
(ERS) guidelines20, repeat spirometry evaluation may be performed once. 
If repeat values of the individual assessment(s) are within the eligibility criteria and completed 
within the screening window, then the subject is eligible for the study. 
9.1.1.2 
Rescreening 
Subjects may only be rescreened with the approval of the medical monitor. If a subject is 
rescreened, all screening assessments will be repeated except for follicle-stimulating hormone 
(FSH) level (if serum FSH level was ≥40 mIU/mL during prior screening), sweat chloride, and 
OE (if performed within the last 3 months). If a subject is rescreened, the screening window will 
begin once the first rescreening assessment has been initiated. 
Randomization 
(1:1) 
D-28 
to  
D-1 
Screening
IVA 
150 mg q12h 
Placebo 
D1 
Treatment  
Period 2 
Treatment  
Period 1 
D1 
W4 
W8 
IVA  
150 mg q12h 
Placebo 
8-week  
Washout 
W8 
W4 
4 weeks 
after last 
dose 
Safety 
Follow-up 


Protocol VX16-770-127, Version 1.0 
 Page 19 of 51 
Vertex Pharmaceuticals Incorporated 
 
9.1.1.3 
Extension of the Screening Period Window 
A subject may have the Screening Period window extended by 1 week for the following reasons: 
 Repetition of the Screening Period assessments (Section 9.1.1.1) 
 Unexpected operational or logistic delays, or to meet the eligibility criteria 
 Additional time to conduct OEs (Section 11.5.5). 
9.1.2 
Treatment Period 
9.1.2.1 
Treatment Period 1 
Treatment Period 1 will last approximately 8 weeks. Subjects will be randomized to 1 of 
2 sequences, as shown in Section 9.1. 
Study visits during Treatment Period 1 will occur as shown in Table 3-2. Subjects will be 
outpatients during Treatment Period 1. All visits should occur within the windows specified. 
For subjects who are on a stable regimen of inhaled cycling antibiotics, the Day 1 Visit 
(beginning of Treatment Period 1) should be timed to occur at the end of an off-cycle but no less 
than 14 days after the last dose of inhaled antibiotics in the previous on-cycle. The first dose of 
study drug will be administered on Day 1. The first dose of a new cycle of inhaled cycling 
antibiotic should also occur on Day 1. Dosing details are given in Section 9.6. 
Subjects who prematurely discontinue study drug treatment will be asked to come to the study 
site for an Early Termination Visit and a Safety Follow-Up Visit, as described in Section 9.1.4. 
9.1.2.2 
Washout Period 
Subjects will have a Washout Period lasting 8 weeks (± 4 days). No visits are scheduled during 
the Washout Period. If a subject's Washout Period is >8 weeks, the continuation of the subject 
into Treatment Period 2 will be discussed on a case by case basis with the medical monitor.  
9.1.2.3 
Treatment Period 2 
Treatment Period 2 will last approximately 8 weeks. Study visits during Treatment Period 2 will 
occur as shown in Table 3-2. Subjects will be outpatients during Treatment Period 2. All visits 
should occur within the windows specified. 
In order to participate in Treatment Period 2, subjects must not have an acute upper or lower 
respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for 
pulmonary disease within 4 weeks before the Treatment Period 2, Day 1 Visit (first dose of study 
drug in Treatment Period 2) and must not have any significant “non-CF-related” illness within 
2 weeks before the Treatment Period 2, Day 1 Visit. “Significant illness” is defined as an acute 
(serious or nonserious) condition (e.g., gastroenteritis) in the opinion of the investigator. If a 
subject does not meet these criteria, then the continuation of the subject into Treatment Period 2 
will be discussed with the medical monitor (postponed to achieve 28 days from the illness). 
For subjects who are on a stable regimen of inhaled cycling antibiotics, the Treatment Period 2, 
Day 1 Visit should occur at the end of an off-cycle but no less than 14 days after the last dose of 
inhaled antibiotics in the previous on-cycle. The first dose of study drug in Treatment Period 2 
will be administered at the Day 1 Visit. The first dose of a new cycle of inhaled cycling 
antibiotic should also occur on the Day 1 Visit. Dosing details are provided in Section 9.6. 


Protocol VX16-770-127, Version 1.0 
 Page 20 of 51 
Vertex Pharmaceuticals Incorporated 
 
9.1.3 
Follow-up 
Subjects will have a Safety Follow-up Visit approximately 4 weeks after the last study drug dose 
to assess for safety and other outcomes. Safety Follow-up Visit assessments are listed in 
Table 3-2. 
9.1.4 
Early Termination of Treatment 
Subjects who prematurely discontinue study drug treatment will be asked to come to the study 
site for an Early Termination of Treatment (ETT) Visit as soon as possible after stopping study 
drug, and the Safety Follow-up Visit approximately 4 weeks after the last dose of study drug, to 
assess for safety and other outcomes. If the ETT Visit occurs ≥3 weeks after the last dose of 
study drug, the Follow-up Visit will not be required. The ETT Visit assessments are listed in 
Table 3-2. 
9.2 
Method of Assigning Subjects to Treatment Groups 
An interactive web or voice response system (IXRS) will be used to randomize subjects who 
meet the eligibility criteria to 1 of 2 treatment sequences. Subjects will be randomized in a 
1:1 ratio, stratifying for age (6 to 11 years, and ≥12 years) and FEV1 severity (<60%, and ≥60%). 
9.3 
Rationale for Study Design and Study Drug Regimens 
9.3.1 
Study Design 
A crossover design with a 1:1 randomization to the 2 treatment sequences will enable 
within-subject comparison of the effects of ivacaftor for many endpoints, including lung 
clearance index (LCI). In addition to the increased power of a crossover study design in this 
study with a limited population of potential subjects, the design provides periods of both active 
and placebo treatment to allow evaluation of the efficacy and safety of ivacaftor. Given the intent 
to evaluate efficacy with respect to LCI, the use of placebo is necessary in order to provide a 
robust assessment. No subject will be disadvantaged by the use of placebo, as no active therapy 
is withdrawn, and all will have the potential to benefit during the ivacaftor treatment period due 
to the crossover nature of the study design. 
The 8-week crossover period with an 8-week washout period was chosen to accommodate 
cycling inhaled antibiotic needs in this subject population; additionally, this design successfully 
yielded strong efficacy and safety results in Study VX12-770-111 where the impact of ivacaftor 
was evaluated in subjects with CF aged 6 years and older with a CFTR gating mutation.  
An 8-week period was selected as the duration for the Washout Period because, based on 
previous studies, no residual effects of ivacaftor are expected by the end of the 8-week washout 
period. It is expected that some subjects will be on 28-day-on/28-day-off cycles of stable CF 
medication, as discussed in Section 9.5.1. An 8-week washout period is compatible with these 
cycles. 
9.3.2 
Study Drug Dose and Duration 
An ivacaftor regimen of 150 mg every 12 hours (q12h) was selected because it is the approved 
regimen for the treatment of CF in patients with who are 6 years of age and older weighing 
≥25 kg.   


Protocol VX16-770-127, Version 1.0 
 Page 21 of 51 
Vertex Pharmaceuticals Incorporated 
 
The 8-week duration of dosing in each Treatment Period was chosen based on results of the 
ivacaftor program. Clinical studies have shown a clear improvement of ppFEV1 after 8 weeks of 
treatment. 
9.3.3 
Study Assessments 
 
 
 
  
Multiple breath washout (MBW) for LCI values: LCI is a measure of ventilation inhomogeneity 
that is based on tidal breathing techniques that has been evaluated in patients as young as 
infants.21,22 Studies have shown that LCI correlates with FEV1 in its ability to measure airway 
disease in patients with impacted spirometry assessment but can also detect lung disease at an 
earlier stage than spirometry.23,24 Furthermore, data from Study VX10-770-106 (Study 106) in 
CF subjects aged 6 years and older with an FEV1 >90% predicted showed LCI to be a more 
sensitive outcome measure than FEV1. Given the potential advantages of a more sensitive 
measurement of lung function than spirometry, LCI will be used as the primary endpoint in this 
study. LCI2.5 (see Section 11.4.1) will be used for the primary endpoint as it represents an 
optimal balance between time to perform the assessment and sensitivity.25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4 
Study Restrictions 
Certain medications are not allowed from 14 days before the first dose of study drug through the 
end of the treatment period (Table 9-1). A nonexhaustive list of prohibitions and cautions for 
food and medication will be provided in the Study Reference Manual. 


Protocol VX16-770-127, Version 1.0 
 Page 22 of 51 
Vertex Pharmaceuticals Incorporated 
 
Table 9-1 
Prohibited Medications  
Medication 
Study Period 
Screening Period 
Treatment Period 1 Through 
Treatment Period 2 or ETT  
(if applicable) 
Strong and moderate CYP3A 
inducers 
None allowed within 14 days before 
the first dose of study drug 
None allowed 
Strong and moderate CYP3A 
inhibitors 
None allowed within 14 days before 
the first dose of study drug 
None allowed 
Note: The use of restricted medication in subjects with a medical need will be addressed on a case-by-case basis 
with the medical monitor. 
Clinical studies showed that ivacaftor has the potential to inhibit CYP3A and P-glycoprotein 
(P-gp) substrates. In vitro studies suggest that ivacaftor may inhibit CYP2C9 substrates. Each 
investigator should evaluate the benefit-risk ratio of using such drugs concomitantly with 
ivacaftor during this study and should discuss any concerns regarding the use of these substrates 
with the medical monitor. 
9.5 
Prior and Concomitant Medications 
Information regarding all prior and concomitant medications, including the subject’s CF 
medications, other medications, and herbal and naturopathic remedies administered from 30 days 
before the Screening Period through the 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 only be documented 
in the subjects’ source documents. 
Information about bronchodilator use during the study will be collected and documented in the 
subject’s source documents and eCRF.  
9.5.1 
Maintenance of Stable Medication Regimen for CF 
It is recommended that subjects remain on stable CF medication regimens from 4 weeks before 
Day 1 through the end of the study. A stable medication regimen is defined as a medication 
regimen that the subject has been following for at least 4 weeks before Day 1. 
Specific requirements apply to certain CF medications: 
 At the time of study entry, subjects who are on a stable regimen of a single inhaled antibiotic 
that is continuously administered should remain on this antibiotic through the Safety 
Follow-up Visit.  
 At the time of study entry, subjects who are on a stable regimen of a single inhaled cycling 
antibiotic (e.g., Tobramycin Inhalation Solution [TOBI®] regimen), should remain on this 
antibiotic through the Safety Follow-up Visit. Inhaled cycling antibiotics should be 
administered in 28-day-on/28-day-off cycles. Study visits on Day 1 and Week 8 during 
Treatment Periods 1 and 2 should be timed to occur at the end of an off-cycle, but no fewer 
than 14 days after the last dose of inhaled antibiotics in the previous on-cycle.  
 At the time of study entry, subjects who are on an alternating regimen of inhaled cycling 
antibiotics that comprise continuous administration of antibiotics (e.g., TOBI administration 


Protocol VX16-770-127, Version 1.0 
 Page 23 of 51 
Vertex Pharmaceuticals Incorporated 
 
alternating with Cayston®) should remain on these antibiotics according to their alternating 
regimens through the Safety Follow-up Visit. 
9.6 
Administration 
Study drug tablets will be administered orally. During Treatment Period 1 and Treatment 
Period 2 subjects will take 1 tablet (ivacaftor [150 mg] or matching placebo) twice per day.  
Study drug should be administered within 30 minutes of consuming fat-containing food such as a 
standard CF high-fat, high-calorie meal or snack according to the following guidelines: 
 All doses of study drug (morning and evening, as applicable) should be administered at 
approximately q12 h (± 2 hours) on each dosing occasion (e.g., if the morning doses of 
study drug are administered at 08:00 hours on Day 1, all subsequent morning doses 
should be administered between 06:00 hours and 10:00 hours). 
 At study visits during the treatment periods, the morning dose of study drug will be 
administered at the site after predose assessments have been completed. The meal or 
snack will be provided by the site for the morning dose of study drug.  
 If a subject’s scheduled visit is to occur in the afternoon, the following guidelines must be 
used for administering either the morning or evening dose: 
o If the dose in the clinic will be within 6 hours of the subject’s scheduled morning 
dose, the subject should withhold their morning dose of study drug and the morning 
dose will be administered in the clinic.  
o If the dose in the clinic will be more than 6 hours after the subject’s scheduled 
morning dose, the subject should take the morning dose at home and the evening dose 
will be administered in the clinic. In this event, all assessments will be collected 
relative to the evening dose.  
 For the visit at the end of each treatment period, subjects will be instructed to bring all 
used and unused study drug to the site; study drug will be dispensed at each visit, as 
appropriate. 
9.7 
Dose Modification for Toxicity 
If any unacceptable toxicity arises, individual subjects will discontinue dosing (Section 9.8). 
9.8 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons. Study drug 
treatment will be withdrawn for any female subject who has a confirmed pregnancy and for any 
male subject whose female partner has a confirmed pregnancy. A subject may be withdrawn 
from study drug treatment after a discussion between the investigator and the medical monitor 
for any of the following reasons: 
 The subject develops a medical condition that requires prolonged concomitant therapy 
with a prohibited medication or prolonged interruption of the study drug.  
 The subject has an increase in transaminases for which withdrawal of study drug is 
recommended, as described in Section 11.5.3.  


Protocol VX16-770-127, Version 1.0 
 Page 24 of 51 
Vertex Pharmaceuticals Incorporated 
 
 The subject develops a cataract.  
If a subject has been withdrawn from study drug treatment, the subject will continue to be 
followed, provided the subject has not withdrawn consent.  
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a Safety Follow-up Visit, if 
applicable (see Section 9.1.4), and follow up with the subject regarding any unresolved adverse 
events (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. 
9.9 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study drug treatment period(s) will not be 
replaced. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee to the subject or the subject’s legally appointed and authorized representative 
(e.g., parent or legal guardian) for administration to the subject. 
10.2 
Packaging and Labeling 
Vertex will supply Ivacaftor and placebo tablets in child-resistant weekly blister cards. Study 
drug labeling will be in compliance with applicable local and national regulations. Additional 
details regarding packaging, labeling, and dispensing will be included in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
Table 10-1 provides the study drug information. The investigator, or an authorized designee 
(e.g., a licensed pharmacist), will ensure that all investigational product is stored in a secured 
area, under recommended storage conditions, and in accordance with applicable regulatory 
requirements. To ensure adequate records, all study drugs will be accounted for as detailed in 
Section 10.5. Detailed instructions regarding the storage, handling, and dispensation of the study 
drug will be provided in the Pharmacy Manual. 
Table 10-1 
Study Drug  
Drug Name 
Formulation/ 
Route 
Packaging (Formulation 
Strength) 
Storage 
Condition 
Ivacaftor  
 
Oral 
Supplied as 150-mg tablets  
25ºC (77ºF) with excursions 
to 30ºC (86ºF) 
 


Protocol VX16-770-127, Version 1.0 
 Page 25 of 51 
Vertex Pharmaceuticals Incorporated 
 
10.4 
Study Drug Interruption 
If study drug dosing must be interrupted for more than 72 hours, the medical monitor must be 
notified. In these instances, study drug dosing may resume only after approval by the medical 
monitor. Specific instructions for interruption for elevated LFT levels are provided in 
Section 11.5.3. 
10.5 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of study drug received, study drug dispensed to the subjects, and study drug returned by 
the subjects. Subjects will be instructed to return all used and unused materials associated with 
the study drug to the site at each visit. These materials will be retained at the site according to 
instructions provided by Vertex or its designee until inventoried by the study monitor. The study 
monitor will review study drug records and inventory throughout the study. 
10.6 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. At the end of the study, the study monitor 
will provide instructions as to the disposition of any unused investigational product. If the study 
monitor authorizes destruction at the study site, the investigator will ensure that the materials are 
destroyed in compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Vertex. Destruction will be adequately documented. 
10.7 
Compliance  
Study drug doses administered during inpatient periods will be administered under the direct 
supervision of the investigator or designee in the clinical research unit to ensure 100% study 
treatment compliance. 
For study drug doses administered during the outpatient periods of the study, drug accountability 
will be assessed at each visit by counting returned dosage units. Discrepancies will be discussed 
with the subject and recorded in the source documents. If subjects demonstrate continued 
noncompliance of study drug dosing despite educational efforts, the investigator will contact the 
medical monitor to discuss discontinuing the subject from the study.  
10.8 
Blinding and Unblinding 
This will be a double-blind study. 
10.8.1 
Blinding  
Subjects and all site personnel, including the investigator, site monitor, and study team, will 
remain blinded to treatment assignments until database lock. The Vertex study team will remain 
blinded to treatment assignments until all subjects have completed the study. Exceptions are 
made for the following personnel:  
 Any site personnel for whom this information is important to ensure the safety of the 
subject in the event of a life-threatening medical emergency 
 Any site personnel for whom this information is important to ensure the safety of the 
subject and the fetus in the event of a pregnancy 


Protocol VX16-770-127, Version 1.0 
 Page 26 of 51 
Vertex Pharmaceuticals Incorporated 
 
 Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy serious 
adverse event (SAE) processing and reporting regulations 
 Unblinded statistician who will prepare the final (production) randomization list (this 
statistician is not part of the study team) 
 Vertex IXRS Management for IXRS oversight and system administration 
 Vertex Clinical Supply Chain 
 The bioanalytical laboratory/vendor personnel managed by Vertex Bioanalysis 
Vertex Quality Assurance GCP personnel and all other Vertex Bioanalysis laboratory personnel 
will be blinded to the treatment assignment. 
10.8.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the medical monitor, they will use their best 
judgment, based on the nature and urgency of the clinical situation, and may proceed with 
unblinding without having successfully reached and discussed the situation with the medical 
monitor. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center (
) will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup.  
If a subject's treatment assignment has been unblinded for a medical emergency or urgent clinical 
situation, the medical monitor will be notified within 24 hours of the unblinding event. The 
reason and the date of the unblinding will be documented clearly in the subject's study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with the sponsor (Vertex), contract 
research organization (CRO), or any site personnel (other than the physician treating the subject). 
In addition, the investigator will consider whether the clinical event that prompted unblinding 
will be considered an SAE, according to the regulatory definitions or criteria for SAEs, and if so, 
submit an SAE report to Vertex GPS or designee, per Section 13.1.2. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, unblind 
individual subjects at any time.  


Protocol VX16-770-127, Version 1.0 
 Page 27 of 51 
Vertex Pharmaceuticals Incorporated 
 
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments is shown in Table 3-1 and Table 3-2.  
  
Vital sign assessments will be performed before blood draws. 
Liver function testing and urine pregnancy testing may be completed predose or postdose. 
11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history 
(includes recording CF genotype), height, and weight. 
11.4 
Efficacy 
11.4.1 
MBW 
LCI is derived from N2 MBW testing and will be conducted at visits specified in Table 3-1 and 
Table 3-2 to evaluate the effect of ivacaftor on lung ventilation inhomogeneity. LCI2.5 represents 
the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of 
its starting value, 
 
.25  
Each MBW will be performed in multiple replicates for each visit, and the mean LCI value at 
each visit will be calculated by the sponsor or sponsor designee using all technically acceptable 
washout replicates provided by the central reader.  
During the Screening Period, the MBW test may be performed pre‑ or post‑bronchodilator. At 
all other visits, all MBW tests should be performed “pre‑bronchodilator” 
 
. MBW testing must be performed before dosing, unless noted otherwise. 
Pre-bronchodilator MBW testing is defined as MBW testing performed for subjects who have 
 withheld their short-acting bronchodilator (e.g., albuterol) or anticholinergic (e.g., Atrovent) 
for more than 4 hours before the MBW testing; AND 
 withheld their long-acting bronchodilator (e.g., salmeterol) more than 12 hours before the 
MBW testing; AND 
 withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the MBW testing. 


Protocol VX16-770-127, Version 1.0 
 Page 28 of 51 
Vertex Pharmaceuticals Incorporated 
 
In the event that a subject forgets to withhold bronchodilator(s), MBW testing should be 
performed according to the following: 
 If the subject's Day 1 (in each treatment period) MBW test is pre-bronchodilator, but on a 
subsequent visit, the subject forgets to withhold bronchodilator use, post-bronchodilator 
MBW testing will be obtained for that visit only, and the visit will not be rescheduled. 
 If at the subject’s Day 1 (in each treatment period) MBW test, the subject forgets to withhold 
his/her dose of bronchodilator, MBW testing should be performed post-bronchodilator and 
all subsequent MBW testing should be performed post-bronchodilator. 
 Each MBW test will be recorded in the source documents as pre-bronchodilator or 
post-bronchodilator. 
Detailed LCI procedures will be supplied in the Study Reference Manual. 
Subjects and their parent/caregiver should not be informed of their study-related LCI results 
during the study regardless if the subject has prematurely discontinued treatment. 






Protocol VX16-770-127, Version 1.0 
 Page 31 of 51 
Vertex Pharmaceuticals Incorporated 
 
11.5 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, and PEs.  
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 and urine samples will be analyzed at a central laboratory with the exception of urine 
pregnancy tests, which will be analyzed locally. On Day 1, blood samples will be collected 
before the first dose of the study drug. At all other scheduled visits, these samples will be 
collected at any time during the visit. 
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table 3-1 and Table 3-2). Laboratory test results that are abnormal and considered clinically 
significant will be reported as AEs (see Section 13.1). 
The safety laboratory test panels are shown in Table 11-1. 


Protocol VX16-770-127, Version 1.0 
 Page 32 of 51 
Vertex Pharmaceuticals Incorporated 
 
Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry at Screening  
Hematology at Screening 
Liver Function Testsa  
Glucose  
Blood urea nitrogen  
Creatinine  
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate aminotransferase 
Alanine aminotransferase  
Amylasea  
Lactate dehydrogenase 
Lipasea  
Gamma glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
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  
 
Bilirubin, direct bilirubin  
Aspartate aminotransferase 
Alanine aminotransferase  
Gamma glutamyl transferase 
Alkaline phosphatase  
 
a 
Amylase, lipase, and LFTs performed at screening and at other Visits as indicated in Table 3-2. 
Pregnancy Testing for Female Subjects of Childbearing Potential 
Serum samples will be analyzed at the central laboratory. Urine beta-human chorionic 
gonadotropin (β-hCG) tests will be performed at the study site. The urine pregnancy test at Day 1 
of each treatment period must be negative before the first dose of study drug. 
If a urine pregnancy test is positive, all study drug dosing will stop and the pregnancy will be 
confirmed with a serum (β-hCG) test. If the subject is pregnant, the procedures outlined in 
Section 11.5.6.2 will be followed. 
Additional Evaluations 
Additional clinical laboratory evaluations will be performed at other times if judged to be 
clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 
becomes aware of the abnormal result. If it is not possible to send a timely specimen to the 
central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base the 
assessment of an AE on the local laboratory value. 


Protocol VX16-770-127, Version 1.0 
 Page 33 of 51 
Vertex Pharmaceuticals Incorporated 
 
11.5.3 
Elevation of Liver Function Test Parameters 
Elevation of LFT Parameters 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN must be followed 
closely, including repeat confirmatory testing performed by the central laboratory within 48 to 
72 hours of the initial finding and subsequent close monitoring of ALT and AST levels, as 
clinically indicated. In addition, if ALT or AST are >5 × ULN, repeat follow-up levels must be 
obtained within 7 ± 2 days and followed up 7 days later. 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). 
LFT Elevations Leading to Study Drug Interruption 
Study drug 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, or 
 ALT or AST >3 × ULN in association with elevation of bilirubin >2 × ULN and/or 
clinical jaundice 
Repeat testing should be performed within 48 to 72 hours to confirm the initial elevation. A 
thorough investigation of potential causes should be conducted and the subject should be 
followed closely for clinical progression. If no convincing alternative etiology for the elevated 
transaminases is identified, regardless of whether ALT or AST levels have improved, the subject 
must be discontinued from the study in consultation with the medical monitor (Section 9.8). 
Subjects in whom treatment is discontinued for elevated transaminases should have their 
transaminases monitored closely until levels normalize or return to baseline. If an alternative 
cause of transaminase elevation has been identified, study drug may be resumed once 
transaminases return to ≤2 × ULN. Approval of the medical monitor is required before 
resumption of study drug. Upon resumption of study drug, transaminases should be assessed 
weekly for 4 weeks. If a protocol-defined transaminase elevation occurs within 4 weeks of 
rechallenge with the study drug (with confirmation of the initial elevation by repeat testing 
within 48 to 72 hours), then the study drug must be permanently discontinued, regardless of the 
presumed etiology. 
11.5.4 
Physical Examinations and Vital Signs 
A physical examination (PE) of all body systems and vital signs assessment will be performed at 
screening and select study visits (Table 3-1 and Table 3-2). At other visits, symptom-directed 
PEs and symptom-directed vital sign assessments can be performed at the discretion of the 
investigator or healthcare provider. 
A PE includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/throat; 
respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and neurological. 
Breast, anorectal, and genital examinations will be performed when medically indicated. After 
screening, any clinically significant abnormal findings in PEs will be reported as AEs. 
Vital signs include blood pressure (systolic and diastolic), body temperature, pulse rate, and 
respiration rate. These will be assessed following at least a 5-minute rest in the supine position. 


Protocol VX16-770-127, Version 1.0 
 Page 34 of 51 
Vertex Pharmaceuticals Incorporated 
 
11.5.5 
Ophthalmologic Examination 
Subjects who are under 18 years of age at the Screening Visit will undergo an OE at the time 
points in Table 3-1 and Table 3-2. The OE will include: 
 measurement of best corrected distance visual acuity of each eye 
 pharmacologically dilated examination of the lens with a slit lamp  
These examinations must be conducted by a licensed ophthalmologist or optometrist. If there is 
documentation of an OE that met protocol criteria and was conducted within 3 months before the 
Screening Visit, the subject is not required to have another OE during Screening. 
If a cataract or lens opacity is identified and determined to be clinically significant by the 
ophthalmologist or optometrist, the subject (and the subject’s parent or guardian if the subject is 
a minor) will be notified.  
Additional OEs may be conducted at the discretion of the investigator. The Vertex medical 
monitor or designee should be notified of any additional OEs. 
In addition, at Screening, the following history will be obtained for all subjects: 
 history of steroid use 
 history of trauma to the eye 
 any family history of glaucoma, congenital cataracts, or cataracts arising later in life 
11.5.6 
Contraception and Pregnancy 
11.5.6.1 
Contraception 
Ivacaftor did not show any genotoxic potential in a standard battery of in vitro and in vivo 
studies. Ivacaftor also did not show any teratogenic potential in developmental and reproductive 
toxicology studies. 
Ivacaftor has been studied with an estrogen/progesterone oral contraceptive and was found to 
have no significant effect on the exposures of the oral contraceptive. Ivacaftor is not expected to 
modify the efficacy of oral contraceptives. Therefore, hormonal contraceptives will be 
acceptable as a means of contraception for female subjects of childbearing potential in this study.  
Definition of Childbearing Potential 
All female subjects who have had their first menstrual period, from the time of the Screening 
Visit through the Follow-up Visit, including subjects with tubal ligations, will be considered to 
be of childbearing potential unless: 
 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. 


Protocol VX16-770-127, Version 1.0 
 Page 35 of 51 
Vertex Pharmaceuticals Incorporated 
 
11.5.6.2 
Pregnancy and Nursing Mothers  
Subjects will be counseled to inform the investigator if they (or their female partner) are 
pregnant or plan to become pregnant or are breastfeeding or planning to breastfeed during study 
treatment and for 90 days after the last dose of study drug. An exception is made for pregnancies 
in the female partners of male subjects when the pregnancy resulted from donated sperm or 
sperm banked before study drug exposure. 
If a female subject or a male subject’s female partner becomes pregnant, the pregnancy must be 
reported to Vertex Global Patient Safety within 24 hours of the site’s knowledge of the 
pregnancy while confirmation is pending. Once the pregnancy is confirmed with a serum 
pregnancy test, study drug will be permanently discontinued. Pregnancy does not constitute an 
AE. 
Once a pregnancy is confirmed, pregnant female subjects or female partners of male subjects 
will be followed until delivery or the end of pregnancy (i.e., delivery, stillbirth, miscarriage), 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. 
12 
STATISTICAL AND ANALYTICAL PLANS 
Analyses of efficacy and safety data will be described in a statistical analysis plan (SAP). The 
SAP will be finalized before database lock for the final analysis. 
12.1 
Sample Size and Power 
No formal sample size calculation was conducted. The planned sample size of approximately 
50 subjects is based on the number of subjects expected to be available for participation. 
Assuming an estimated standard deviation (SD) of the paired differences of 1.00 in LCI2.5, this 
available sample size of 50 subjects will produce a 2-sided 95% confidence interval (CI) of the 
mean treatment difference with precision (margin of error) of 0.28 points. Similarly, the margin 
of error using a 2-sided 80% CI will be 0.18 points. 
12.2 
Analysis Sets 
The Full Analysis Set (FAS) is defined as all randomized subjects who have received at least 
1 dose of study drug.  
The Safety Set is defined as all enrolled subjects who received at least 1 dose of study drug. The 
Safety Set is to be used for all safety analyses in which subjects will be analyzed according to the 
treatment they received and not according to their randomized treatment group. 
12.3 
Statistical Analysis 
This section summarizes the planned statistical analyses of efficacy and safety. The Vertex 
Biometrics department or a designated CRO will conduct these analyses. SAS® Version 9.2 or 
higher will be used to generate all statistical outputs (tables, figures, listings, and data sets).  
12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: the 
number of subjects (n), mean, SD, standard error, median, minimum value, and maximum value. 
Categorical variables will be summarized using counts and percentages.  


Protocol VX16-770-127, Version 1.0 
 Page 36 of 51 
Vertex Pharmaceuticals Incorporated 
 
Unless specified otherwise, only descriptive analyses will be performed (i.e., no statistical 
hypothesis testing will be performed). 
Baseline: Study baseline is defined as the most recent nonmissing measurement collected before 
the first administration of study drug in Treatment Period 1. Period baseline is defined as the 
most recent nonmissing measurement collected before the first administration of study drug in 
each Treatment Period. For Treatment Period 1, the period baseline will be the study baseline; 
for Treatment Period 2, the period baseline will be from an assessment measured after the 
Washout Period and before the first administration of study drug in Period 2. 
For all efficacy analyses, the statistical inference will be based on change from study baseline. 
However, efficacy analyses based on change from period baseline will also be presented. 
Similarly, summary tables, as applicable, will be presented based on both baselines. 
All subject data, including those derived, will be presented in the subject data listings; listings 
will display all subjects who were randomized, regardless of whether or not they received study 
drug. 
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
The number and percentage of subjects in each disposition category (e.g., randomized, included 
in the FAS, included in the Safety Set, completing treatment period, and discontinuing study, 
with reasons for discontinuation) will be summarized by treatment sequence and overall. 
12.3.2.2 
Demographics and Baseline Characteristics 
The demographics and baseline characteristics summary will be presented by treatment sequence 
for FAS. Background (e.g., medical history) summary will be presented by treatment sequence 
for the FAS. 
12.3.2.3 
Prior and Concomitant Medications 
Medications taken 30 days before the Screening Visit and up to the Safety Follow-up Visit will 
be summarized by preferred term using the World Health Organization-Drug Dictionary 
Enhanced for the FAS as frequency tables in 2 parts: 
 Prior medication: medication that started before the first dose of study drug, regardless of 
when dosing of the medication ended. 
 Concomitant medication: medication received at or after the first dose of study drug, 
medication that was received before initial dosing and continued after initial dosing of 
study drug, or medication with missing stop date. 
Medication that started before the first dose of study drug and continued after the first dose of 
study drug will be summarized as prior medication and separately as concomitant medication. 
Medications with a missing start date will be considered to have a start date before the first dose 
of study drug. 
Prior medications will be summarized by treatment sequence, and concomitant medications will 
be summarized by treatment group. 


Protocol VX16-770-127, Version 1.0 
 Page 37 of 51 
Vertex Pharmaceuticals Incorporated 
 
12.3.2.4 
Study Drug Exposure and Compliance 
Exposure to study drug and dosing compliance will be summarized for the FAS by means of 
summary statistics. 
Dosing compliance will be summarized for each treatment period for the FAS, and is calculated 
as the actual number of dosing occasions at which study drug was administered, as a percentage 
of the planned number of dosing occasions. 
12.3.3 
Efficacy Analysis  
Efficacy analyses will be based on the FAS unless noted otherwise, and the statistical inference 
will be based on change from study baseline. All efficacy data will be presented in subject data 
listings.  
12.3.3.1 
Change from Baseline in LCI 
A Bayesian approach will be used to estimate the effect of ivacaftor versus placebo on change from 
study baseline in LCI2.5. A non-informative prior distribution (normal distribution with mean 0 
and variance = 106) on the treatment difference will be assumed. The posterior distribution of the 
treatment difference will be obtained using the Markov Chain Monte Carlo (MCMC) method. 
The mean of the posterior distribution will be calculated and the 80% credible interval for the 
treatment difference will be provided. Using this Bayesian method, the posterior probability that 
the treatment difference for LCI2.5 is less than zero will be calculated. The study will be 
considered successful if this probability exceeds 80%.  
Supportive analyses of absolute change from study baseline in LCI2.5 through Week 8 of each 
double-blind treatment period based on a mixed-effects model for repeated measures (MMRM) 
using the FAS will be performed. 
The model will include the absolute change from the study baseline in each treatment period as 
the dependent variable; sequence, treatment, treatment period, and visit within treatment period 
as fixed effects; LCI2.5 at study baseline as covariate if deemed necessary; and subject nested 
within sequence as the random effect. An unstructured covariance matrix will be used for the 
repeated measurements of the same subject within each treatment period. If there is a 
convergence problem for the unstructured covariance matrix, an appropriate covariance matrix 
structure, such as compound symmetry, will be assumed in the primary analysis. The estimated 
mean treatment difference overall, and a 80% confidence interval will be provided.  
Carry-over effect will be assessed by the sequence effect in the model, as well as by comparing 
baseline for each treatment period. If there is a clinically or statistically significant unequal 
carry-over effect, then the data from the first period may be used for the analysis.  


Protocol VX16-770-127, Version 1.0 
 Page 38 of 51 
Vertex Pharmaceuticals Incorporated 
 
12.3.5 
Safety Analysis 
The overall safety profile of ivacaftor will be assessed in terms of:  
 Incidence of treatment-emergent adverse events (TEAEs) 
 Clinical laboratory values (e.g., LFTs) 
 Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) and PEs 
 OEs (for subjects less than 18 years of age) 
Safety analyses will be based on the Safety Set. All safety data will be presented in subject data 
listings.  
12.3.5.1 
Adverse Events 
AEs will be coded according to MedDRA. The number and percentage of subjects experiencing 
an AE will be summarized by the MedDRA system organ class and preferred term. AEs will be 
classified as pre-treatment or treatment-emergent. 
Pre-treatment AEs are defined as AEs that were reported or worsened after signing the ICF up 
to the start of study drug dosing. 
Treatment-emergent AEs are defined as AEs that were reported or worsened on or after the 
start of study drug dosing through the Safety Follow-up Visit. 


Protocol VX16-770-127, Version 1.0 
 Page 39 of 51 
Vertex Pharmaceuticals Incorporated 
 
Only TEAEs will be summarized in tables. Some rules that will apply to the summarization of 
AEs are (1) a subject with multiple occurrences of the same AE or a continuing AE will only be 
counted once; (2) only the maximum severity level will be presented in the severity summary; 
and (3) only the worst relationship level will be presented in the relationship summary. 
AEs leading to death, SAEs, dose interruption, and permanent discontinuation will be listed 
separately. All AEs through the Safety Follow-up Visit, including pre-treatment AEs, will be 
listed in a subject data listing.  
12.3.5.2 
Clinical Laboratory Assessments 
All statistical summaries of laboratory values will be performed using SI units. LFT results will 
be summarized by treatment group at each scheduled time point. Changes from baseline will also 
be summarized. Maximum shift changes from baseline based on the LFT normal ranges will be 
tabulated by treatment. A subject data listing of abnormal LFT values from scheduled and 
unscheduled time points will be provided. Results for hematology and for chemistry assessments 
other than LFTs will be listed. Clinically significant abnormal laboratory findings will be 
reported as AEs.   
12.3.5.3 
Vital Signs 
Systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), respiratory rate 
(breaths per minute), and body temperature (degrees C) will be summarized by treatment. 
Changes from baseline will also be summarized. Clinically significant abnormal findings will be 
reported as AEs. 
12.3.5.4 
Physical Examination 
PE results performed as part of the Screening Period assessment will be presented in subject data 
listings only. Clinically relevant results identified after screening will be reported as AEs. 
12.3.5.5 
Ophthalmological Examinations 
Ophthalmological examination will be done for subjects who are under 18 years of age at the 
Screening Visit and then either at the Week 24 Visit or at the ETT Visit. This examination is not 
required if the subject received study drug for a total of less than 4 weeks. 
Ophthalmologic examination findings will be presented as a data listing. Summary tables will be 
provided if deemed necessary and as appropriate. 
12.3.6 
Interim and IDMC Analyses 
12.3.6.1 
Interim Analysis 
No interim analysis is planned. 
12.3.6.2 
IDMC Analysis 
Not applicable. 


Protocol VX16-770-127, Version 1.0 
 Page 40 of 51 
Vertex Pharmaceuticals Incorporated 
 
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a 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 to have clinically-significant worsening from baseline will be documented as an AE. 
When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
 Concomitant signs or symptoms related to the abnormal study assessment 
 Further diagnostic testing or medical/surgical intervention 
 A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF is signed until the following time points: 
 For subjects who do not enroll: until time of screen failure (e.g., screen failure, 
withdrawal of consent) 
 For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up 
Visit 
 For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of: 
o 28 days after the last dose of study drug, or 
o The Early Treatment Termination Visit, if that visit is 3 weeks or later after the last 
dose of study drug (see Section 9.1.4). 


Protocol VX16-770-127, Version 1.0 
 Page 41 of 51 
Vertex Pharmaceuticals Incorporated 
 
All subjects will be queried, using nonleading 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 study drug(s)  
 Action taken  
 Outcome  
 Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed August 
2015). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” In considering 
the severity of an AE in a pediatric subject, the investigator will consider that reference ranges 
for pediatric clinical laboratory parameters may differ from those given in the CTCAE. The 
severity of an AE that does not appear in the CTCAE will be determined according to the 
definitions in Table 13-1.  
Table 13-1 
Grading of AE Severity  
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories presented in Table 13-2. 


Protocol VX16-770-127, Version 1.0 
 Page 42 of 51 
Vertex Pharmaceuticals Incorporated 
 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, such 
as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject's medical record). 
 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories shown in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/Resolved With 
Sequelae 
Resolution of an AE with residual signs or symptoms 
Not Recovered/Not 
Resolved (Continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 


Protocol VX16-770-127, Version 1.0 
 Page 43 of 51 
Vertex Pharmaceuticals Incorporated 
 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, hospitalization, 
surgery, or physical therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
 Fatal (death, regardless of cause, that occurs during participation in the study or occurs 
after participation in the study and is suspected of being a delayed toxicity due to 
administration of the study drug) 
 Life-threatening, such that the subject was at immediate risk of death from the reaction as 
it occurred  
 Inpatient hospitalization or prolongation of hospitalization 
 Persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person's ability to conduct normal life functions) 
 Congenital anomaly or birth defect 
 Important medical event that, based upon appropriate medical judgment, may jeopardize 
the subject or may require medical or surgical intervention to 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 


Protocol VX16-770-127, Version 1.0 
 Page 44 of 51 
Vertex Pharmaceuticals Incorporated 
 
GPS. In addition, all SAEs that occur after the Safety Follow-up Visit and are considered related 
to study drug(s) will be reported to Vertex GPS within 24 hours. 
SAEs will be recorded on the Vertex Organized Safety Information Collection Form (hereafter 
referred to as the “SAE Form”) using a recognized medical term or diagnosis that accurately 
reflects the event. SAEs will be assessed by the investigator for relationship to the investigational 
study drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be 
assessed only as related (includes possibly related) or not related (includes unlikely related), and 
severity assessment will not be required. For the purposes of study analysis, if the event has not 
resolved at the end of the study reporting period, it will be documented as ongoing. For purposes 
of regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report to Vertex the outcome of the event using the SAE Form. 
13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. The SAE Form will be 
completed for new/initial events as well as to report follow-up information on previously 
reported events. Investigators are asked to report follow-up information as soon as it becomes 
available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email:
 (preferred choice) 
Fax:
  
Contact Telephone:
 
13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities and participating 
investigators in accordance with ICH Guidelines and/or local regulatory requirements, as 
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. 


Protocol VX16-770-127, Version 1.0 
 Page 45 of 51 
Vertex Pharmaceuticals Incorporated 
 
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.  
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 physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the eCRFs/SAE forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory 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. 


Protocol VX16-770-127, Version 1.0 
 Page 46 of 51 
Vertex Pharmaceuticals Incorporated 
 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
 Subject or investigator noncompliance 
 Unsatisfactory subject enrollment 
 Lack of adherence to protocol procedures 
 Lack of evaluable and/or complete data 
 Potentially unacceptable risk to study subjects 
 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. 


Protocol VX16-770-127, Version 1.0 
 Page 47 of 51 
Vertex Pharmaceuticals Incorporated 
 
13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the eCRFs on the 
subjects for which they are responsible.  
An eCRF will be completed for each enrolled study subject. It is the investigator's responsibility 
to ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject's 
eCRF. Source documentation supporting the eCRF data will indicate the subject's participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the eCRF as soon as possible after 
information is collected.  
The audit trail entry will show the user's identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the eCRFs, 
including any changes made to the eCRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the eCRF data and corresponding audit trails. A copy of the final archival 
eCRF in the form of a CD or other electronic media will be placed in the investigator's study file. 
13.6 
Publications and Clinical Study Report 
13.6.2 
Clinical Study Report  
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in 
accordance with local regulations. 


Protocol VX16-770-127, Version 1.0 
 Page 48 of 51 
Vertex Pharmaceuticals Incorporated 
 
14 
REFERENCES 
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 03 September 2015. 
2 
Cystic Fibrosis Foundation. Patient Registry: 2014 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2015. 
3 
European Cystic Fibrosis Society. 2013 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: European Cystic Fibrosis Society; 2016. 
4 
O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373(9678):1891-904. 
5 
Rommens J, Iannuzzi M, Kerem B, Drumm M, Melmer G, Dean M, et al. Identification 
of the cystic fibrosis gene: chromosome walking and jumping. Science. 
1989;245(4922):1059-65. 
6 
Sheppard MN, Nicholson AG. The pathology of cystic fibrosis. Curr Diagn Pathol. 
2002;8(1):50-59. 
7 
Konstan MW, VanDevanter DR, Rasouliyan L, Pasta DJ, Yegin A, Morgan WJ, et al. 
Trends in the use of routine therapies in cystic fibrosis: 1995-2005. Pediatr Pulmonol. 
2010;45(12):1167-72. 
8 
Cystic Fibrosis Trust. UK Cystic Fibrosis Registry: Annual Data Report 2009. Bromley, 
Kent, UK: Cystic Fibrosis Trust; 2011. 
9 
The Clinical and Functional Translation of CFTR (CFTR2). Welcome to CFTR2. 
Available at: http://cftr2.org. Accessed September 19, 2016. 
10 
Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992-
2001. 
11 
MacDonald K, McKenzie K, Zeitlin P. Cystic fibrosis transmembrane regulator protein 
mutation: 'class' opportunity for novel drug innovation. Paediatr Drugs. 2007;9:1-10. 
12 
Highsmith WE, Burch LH, Zhou Z, Olsen JC, Boat TF, Spock A, et al. A novel mutation 
in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride 
concentrations. N Engl J Med. 1994;331(15):974-80. 
13 
Chiba-Falek O, Shoshani T, Aviram M, Augarten A, Bentur L, Tal A, et al. The 
molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 
kB C-->T mutation. Genomics. 1998;53(3):276-83. 
14 
Van Goor F, Yu H, Burton B, Hoffman BJ. Effect of ivacaftor on CFTR forms with 
missense mutations associated with defects in protein processing or function. J Cyst 
Fibros. 2014;13(1):29-36. 
15 
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: A consensus statement. J 
Pediatr. 1998;132(4):589-95. 
16 
Stanojevic S, Stocks J, Bountziouka V, Aurora P, Kirkby J, Bourke S, et al. The impact 
of switching to the new global lung function initiative equations on spirometry results in 
the UK CF registry. J Cyst Fibros. 2014;13(3):319-27. 
17 
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51(11):875-78. 
18 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-
70. 


Protocol VX16-770-127, Version 1.0 
 Page 49 of 51 
Vertex Pharmaceuticals Incorporated 
 
19 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-54. 
20 
Miller MR. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
21 
Horsley A. Lung clearance index in the assessment of airways disease. Respir Med. 
2009;103(6):793-99. 
22 
Sinhal S, Galati J, Baldwin DN, Stocks J, Pillow JJ. Reproducibility of multiple breath 
washout indices in the unsedated preterm neonate. Pediatr Pulmonol. 2010;45(1):62-70. 
23 
Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout 
and spirometry versus structural lung disease in cystic fibrosis. Thorax. 2007;63(2):129-
34. 
24 
Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection 
of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. 
Thorax. 2007;62(4):341-47. 
25 
Stanojevic S, Jensen R, Sundaralingam D, Salazar JG, Yammine S, Singer F, et al. 
Alternative outcomes for the multiple breath washout in children with CF. J Cyst Fibros. 
2015;14(4):490-96. 
28 
American Thoracic Society. Standardization of spirometry: 1994 update. Am J Respir 
Crit Care Med. 1995;152(1107-36. 
29 
Beydon N, Davis SD, Lombardi E, Allen JL, Arets HGM, Aurora P, et al. An Official 
American Thoracic Society/European Respiratory Society Statement: Pulmonary 
Function Testing in Preschool Children. Am J Respir Crit Care Med. 2007;175(12):1304-
45. 
30 
Centers for Disease Control and Prevention. CDC Growth charts [Internet]. Available 
from: http://www.cdc.gov/growthcharts/cdc_charts.htm. Accessed 12 October 2016. 


Protocol VX16-770-127, Version 1.0 
 Page 50 of 51 
Vertex Pharmaceuticals Incorporated 
 
15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol #: 
VX16-770-127 
Version #: 
1.0 
Version Date: 
20 October 2016 
Study Title:A Randomized, Double-blind, Placebo-controlled, Crossover Study to Evaluate the 
Efficacy of Ivacaftor in Subjects with Cystic Fibrosis Who are 6 Years of Age and Older and 
Have Either a 3849 + 10KB C→T or D1152H-CFTR Mutation 
This Clinical Study Protocol has been reviewed and approved by the sponsor. 
Printed Name 
 
Title 
Signature 
 
Date 


Protocol VX16-770-127, Version 1.0 
 Page 51 of 51 
Vertex Pharmaceuticals Incorporated 
 
15.2 
Investigator Signature Page 
Protocol #:  VX16-770-127 
Version #: 
1.0 
Version Date: 
20 October 2016 
Study Title:A Randomized, Double-blind, Placebo-controlled, Crossover Study to Evaluate the 
Efficacy of Ivacaftor in Subjects with Cystic Fibrosis Who are 6 Years of Age and Older and 
Have Either a 3849 + 10KB C→T or D1152H-CFTR Mutation 
 
 
I have read Protocol VX16-770-127, Version 1.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-770 and this protocol supplied to me by 
Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
 
Vertex Pharmaceuticals Incorporated 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan (Methods) 
Protocol Number VX16-770-127 Version 1.0 
 
A Randomized, Double-blind, Placebo-controlled, Crossover Study to 
Evaluate the Efficacy of Ivacaftor in Subjects with Cystic Fibrosis Who are 6 
Years of Age and Older and Have Either a 3849 + 10KB C→T or D1152H-
CFTR Mutation 
 
Author of SAP: 
 
Version: Version 1.0 
Version Date of SAP: 19 October 2018 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods) 
Page 2 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
1 
TABLE OF CONTENTS 
1 
Table of Contents ............................................................................................................. 2 
 
 
 
 
 
 
 
 
3 
Introduction ...................................................................................................................... 6 
4 
Study Objectives .............................................................................................................. 6 
4.1 
Primary Objective ....................................................................................................... 6 
 
 
5 
Study Endpoints ............................................................................................................... 6 
5.1 
Efficacy Endpoint ....................................................................................................... 6 
5.1.1 
Primary Efficacy Endpoint ................................................................................. 6 
 
 
5.1.3 
Pharmacodynamic Endpoint ............................................................................... 7 
6 
Study Design ..................................................................................................................... 7 
6.1 
Overall Design ............................................................................................................ 7 
6.2 
Sample Size and Power .............................................................................................. 8 
6.3 
Randomization ............................................................................................................ 8 
6.4 
Blinding and Unblinding ............................................................................................ 8 
6.4.1 
Blinding .............................................................................................................. 8 
6.4.2 
Unblinding .......................................................................................................... 9 
7 
Analysis Sets ..................................................................................................................... 9 
7.1 
All Subjects Set .......................................................................................................... 9 
7.2 
Full Analysis Set ....................................................................................................... 10 
7.3 
Safety Set .................................................................................................................. 10 
8 
Statistical Analysis ......................................................................................................... 10 
8.1 
General Considerations ............................................................................................ 10 
8.2 
Background Characteristics ...................................................................................... 11 
8.2.1 
Subject Disposition ........................................................................................... 11 


Statistical Analysis Plan (Methods) 
Page 3 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
8.2.2 
Demographics and Baseline Characteristics ..................................................... 12 
8.2.3 
Prior and Concomitant Medications ................................................................. 13 
8.2.4 
Study Drug Exposure ........................................................................................ 14 
8.2.5 
Study Drug Compliance ................................................................................... 14 
8.2.6 
Important Protocol Deviations .......................................................................... 14 
8.3 
Efficacy Analysis ...................................................................................................... 15 
8.3.1 
Primary Efficacy Variable ................................................................................ 15 
8.3.1.1 
Primary Analysis of the Primary Efficacy Variable .................................. 15 
8.3.1.2 
Supportive Analysis of the Primary Efficacy Variable .............................. 16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Safety Analysis ......................................................................................................... 25 
8.4.1 
Adverse Events ................................................................................................. 25 


Statistical Analysis Plan (Methods) 
Page 4 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
8.4.2 
Clinical Laboratory ........................................................................................... 26 
8.4.3 
Vital Signs ........................................................................................................ 27 
8.4.4 
Physical Examination ....................................................................................... 27 
8.4.5 
Ophthalmology Examination (age <18 years at screening) .............................. 27 
9 
Interim and IDMC Analyses ......................................................................................... 27 
9.1 
Interim Analysis ....................................................................................................... 27 
9.2 
IDMC Analysis ......................................................................................................... 27 
10 References ....................................................................................................................... 28 
11 List of Appendices .......................................................................................................... 29 
Appendix A: Schedule of Assessments.............................................................................. 29 
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments ................... 32 
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates ........... 35 
Appendix D: Important Protocol Deviation Programming Rules (Based on the Clinical 
Database) .................................................................................................................. 36 
Appendix E: Details of GLI Equations for Calculating ppFEV1 ....................................... 37 
 
 
Appendix H: Imputation Rules for Missing AE dates ....................................................... 42 
Appendix I: Criteria for Threshold Analysis ..................................................................... 43 
 
 




Statistical Analysis Plan (Methods) 
Page 6 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
3 
INTRODUCTION 
This statistical analysis plan (SAP) for the final analysis is based on the approved clinical 
study protocol (CSP), Version 1.0, dated 20 October 2017, approved electronic case report 
form (eCRF), Version 1.0, dated 12 April 2017, and approved eCRF completion guidelines, 
Version 1.0, dated 25 May 2017.  
This is a Phase 3b, randomized, double-blind, placebo-controlled, single-center, crossover 
study that includes two 8-week treatment periods separated by an 8-week washout period to 
evaluate the efficacy of ivacaftor treatment in subjects with CF 6 years of age and older who 
have a 3849 + 10KB C→T or D1152H-CFTR mutation, 
 
 
 
 
This SAP (Methods) documents the planned statistical analyses of efficacy and safety 
endpoints, 
 
Vertex Biometrics will perform the statistical analysis for the final analysis. SAS® 
Version 9.2 or higher software (SAS Institute, Cary, North Carolina, USA) will be used to 
generate all statistical outputs (tables, figures, listings, and datasets).  
The SAP (Methods) will be finalized and approved prior to the data lock for the final 
analysis. Any changes made to the SAP Methods after the data lock has occurred will be 
documented in the clinical study report for this study.  
4 
STUDY OBJECTIVES  
4.1 
Primary Objective 
To evaluate the efficacy of ivacaftor treatment in subjects with CF 6 years of age and older 
who have a 3849 + 10KB C→T or D1152H CFTR mutation. 
5 
STUDY ENDPOINTS 
5.1 
Efficacy Endpoint 
5.1.1 
Primary Efficacy Endpoint 
 Change from baseline in lung clearance index2.5 (LCI2.5; calculated as lung volume 
turnovers required to reach 2.5% of the starting nitrogen [N2] concentration) through 
8 weeks of treatment. 


Statistical Analysis Plan (Methods) 
Page 7 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
6 
STUDY DESIGN  
6.1 
Overall Design  
This is a randomized, double-blind, placebo-controlled, single-center, crossover study that 
includes two 8-week treatment periods separated by an 8-week washout period (Figure 6-1). 
There are 7 study visits, not including the Screening Visit. The total study duration for each 
subject is approximately 32 weeks, including the Screening and the Follow-up periods.  
 Sequence 1: ivacaftor (150 mg q12h) in Treatment Period 1; washout; placebo in 
Treatment Period 2 
 Sequence 2: placebo in Treatment Period 1; washout; ivacaftor (150 mg q12h) in 
Treatment Period 2 
Figure 6-1 
VX16-770-127 Study Design 
 
 
Randomization 
(1:1) 
D-28 
to  
D-1 
Screening 
IVA 
150 mg q12h 
Placebo 
D1 
Treatment  
Period 2 
Treatment  
Period 1 
D1 
W4 
W8 
IVA  
150 mg q12h 
Placebo 
8-week  
Washout 
W8 
W4 
4 weeks 
after last 
dose 
Safety 
Follow-up 


Statistical Analysis Plan (Methods) 
Page 8 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
6.2 
Sample Size and Power 
No formal sample size calculation was conducted. The planned sample size of approximately 
50 subjects is based on the number of subjects expected to be available for participation. 
Assuming an estimated standard deviation (SD) of the paired differences of 1.00 in LCI2.5, 
this available sample size of 50 subjects will produce a 2-sided 95% confidence interval (CI) 
of the mean treatment difference with precision (margin of error) of 0.28 points. Similarly, 
the margin of error using a 2-sided 80% CI will be 0.18 points. 
6.3 
Randomization 
An interactive web or voice response system (IXRS) is used to randomize subjects who meet 
the eligibility criteria to 1 of 2 treatment sequences. Subjects are randomized in a 1:1 ratio, 
stratifying for age (6 to 11 years, and ≥12 years) and FEV1 severity (<60%, and ≥60%). 
6.4 
Blinding and Unblinding 
This is a double-blind study. 
6.4.1 
Blinding  
Subjects and all site personnel, including the investigator, site monitor, and study team, will 
remain blinded to treatment assignments until database lock. The Vertex study team 
will remain blinded to treatment assignments until all subjects have completed the study. 
Exceptions are made for the following personnel:  
 Any site personnel for whom this information is important to ensure the safety of the 
subject in the event of a life-threatening medical emergency 
 Any site personnel for whom this information is important to ensure the safety of the 
subject and the fetus in the event of a pregnancy 
 Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy 
serious adverse event (SAE) processing and reporting regulations 
 Unblinded statistician who will prepare the final (production) randomization list (this 
statistician is not part of the study team) 
 Vertex IXRS Management for IXRS oversight and system administration 
 Vertex Clinical Supply Chain 
 The bioanalytical laboratory/vendor personnel managed by Vertex Bioanalysis 
Vertex Quality Assurance GCP personnel and all other Vertex Bioanalysis laboratory 
personnel will be blinded to the treatment assignment. 
LCI, 
: During the conduct of the study, the 
Vertex study team will not have access to the LCI, 
 after 
the morning dose on Day 1. Furthermore, sites, subjects, and their caregivers will not be 
informed of their study-related LCI, 
 results during the study 
regardless of whether the subject prematurely discontinued treatment. 


Statistical Analysis Plan (Methods) 
Page 9 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
6.4.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment 
is necessary for clinical management. In such cases, investigators will use their best 
judgment as to whether to unblind without first attempting to contact the medical monitor to 
discuss and agree to the need for unblinding. If investigators deem it not necessary to unblind 
immediately, they will first attempt to contact the medical monitor to discuss and agree to the 
need for unblinding. If investigators have tried but are unable to reach the medical monitor, 
they will use their best judgment, based on the nature and urgency of the clinical situation, 
and may proceed with unblinding without having successfully reached and discussed the 
situation with the medical monitor. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center (
) will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup.  
If a subject's treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding 
event. The reason and the date of the unblinding will be documented clearly in the subject's 
study file. Information about the treatment assignment obtained from the unblinding will be 
maintained in a secure location with controlled access and will not be shared with the 
sponsor (Vertex), contract research organization (CRO), or any site personnel (other than the 
physician treating the subject). In addition, the investigator will consider whether the clinical 
event that prompted unblinding will be considered an SAE, according to the regulatory 
definitions or criteria for SAEs, and if so, submit an SAE report to Vertex GPS or designee, 
per Section 13.1.2 of clinical study protocol. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, 
unblind individual subjects at any time. 
7 
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set, Full Analysis Set and Safety Set.  
7.1 
All Subjects Set 
The All Subjects Set will include all subjects who were randomized or received at least 
1 dose of study drug. This analysis set will be used for all individual subject data listings and 
disposition summary tables, unless otherwise specified.  


Statistical Analysis Plan (Methods) 
Page 10 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
7.2 
Full Analysis Set  
The Full Analysis Set (FAS) will be defined as all randomized subjects who carry the 
intended CFTR allele mutation and have received at least 1 dose of study drug. The FAS will 
be used to summarize subject demographics and baseline characteristics, and for efficacy 
 
, unless specified otherwise. Subjects will be analyzed according to the 
treatment they were randomized to. 
7.3 
Safety Set 
The Safety Set will include all subjects who received at least 1 dose of study drug. The 
Safety Set will be used for all safety analyses, unless otherwise specified. Subjects will be 
analyzed according to the treatment they received.  
8 
STATISTICAL ANALYSIS 
8.1 
General Considerations 
The treatment sequences will be defined as ivacaftor  placebo and placebo  ivacaftor, 
and the treatment groups will be defined as ivacaftor and placebo. The results of the 
statistical analysis will be presented by treatment group, unless specified otherwise. 
The Schedule of Assessments is provided in Appendix A. The precision standards for 
reporting safety and efficacy variables are provided in an internal Biometrics document that 
specifies the programming rules including the precision for derived variables.  
All individual subject data for those randomized or dosed with any amount of study drug will 
be presented in data listings. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, SD, standard error (SE), median, minimum value 
(min), and maximum value (max). SE may not be reported for safety summary tables.  
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline value will be defined as follows.  
The Study Baseline will be defined as the most recent non-missing measurement (scheduled 
or unscheduled) collected prior to the first dose of study drug on Day 1 of Treatment Period 
1. The study baseline will be used to summarize demographics, background, and baseline 
characteristics and for all efficacy analyses.  
The Period Baseline will be defined as the most recent non-missing measurement (scheduled 
or unscheduled) collected before the first dose of study drug on Day 1 of each Treatment 
Period. For Treatment Period 2, the baseline should be from an assessment measured after 
the treatment emergent period (described below) for Treatment Period 1. The period baseline 
will be used for all safety analyses.  


Statistical Analysis Plan (Methods) 
Page 11 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
For sweat chloride, the study baseline value will be the mean of assessment values on the left 
and the right arm at the most recent time point prior to the first dose of study drug on Day 1 
of the study. If the result from only one of the arms is available then the result from that arm 
will be considered as baseline.   
Absolute change from baseline will be calculated as postbaseline value – baseline value. 
Treatment Emergent (TE) Period for Treatment Period 1 (TE Period 1) will correspond to 
data from the first dose of study drug in Treatment Period 1 to the Safety Follow-up (SFU) 
visit, if the subject discontinues treatment in Treatment Period 1 or 28 days after the last dose 
in Treatment Period 1 for subjects who continue to Treatment Period 2 or subjects who 
discontinue in Treatment Period 1 and do not have an SFU visit. Similarly, the TE period for 
Treatment Period 2 (TE Period 2) will correspond to data from the first dose of study drug in 
Treatment Period 2 to the SFU visit or 28 days after the last dose in Treatment Period 2 for 
subjects who do not have an SFU visit.  
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 and last on-treatment measurements 
 In the derivation of maximum and minimum on-treatment values, and maximum and 
minimum change from baseline values for safety analyses 
 In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided 
in Appendix B.  
Incomplete/missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence 
of statistical outliers, unless specified otherwise. 
Multiplicity: There will be no multiplicity adjustment for performing multiple hypothesis 
tests, unless specified otherwise. 
8.2 
Background Characteristics  
8.2.1 
Subject Disposition 
Subject disposition will be summarized as follows. 
The number of subjects in the following categories will be summarized by treatment 
sequence and overall:  
 All Subjects Set (randomized or dosed) 
 Randomized 
 Full Analysis Set (FAS) 
 Safety Set  


Statistical Analysis Plan (Methods) 
Page 12 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized by treatment sequence and overall as follows: 
 Completed treatment period 1 
 Prematurely discontinued treatment period 1 and the reason for discontinuation  
 Completed treatment period 2 
 Prematurely discontinued treatment period 2 and the reason for discontinuation  
 Completed study (i.e., completed 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 
with reasons for discontinuation. A randomization listing of subjects will also be provided. 
8.2.2 
Demographics and Baseline Characteristics 
Demographics, medical history and baseline characteristics will be summarized based on the 
FAS, and presented by treatment sequence and overall. 
Demographic data will include the following: 
 Age at baseline (in 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 or Other Pacific Islander, and Other) 
Baseline characteristics will include the following: 
 Weight at baseline (kg) 
 Height at baseline (cm) 
 BMI at baseline (kg/m2) 
 BMI z-score at baseline (subjects <21 years old at screening) 
 CFTR genotype for Mutation 1 (3849 + 10KB C→T and D1152H) 
Note: For subjects who may have both CFTR mutations, the priority order will be to choose 
3849+10KB C→T as allele 1 mutation and D1152H as allele 2 mutation, even though this 
case is unlikely to occur. 
Stratification categories will include the following: 
 ppFEV1 at screening (<60 and ≥60) 
 Age group at screening (6 - 11 years and ≥12 years) 


Statistical Analysis Plan (Methods) 
Page 13 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
Disease characteristics will include the following: 
 ppFEV1 at baseline (<40, ≥40 to <70, ≥70 to ≤90, >90) 
 ppFEV1 at baseline (continuous)  
 LCI2.5 at baseline (continuous) 
 Sweat Chloride at baseline (continuous) 
 FEV1 (L) at baseline (continuous) 
A summary of medical history will be provided by MedDRA system organ class (SOC) and 
preferred term (PT) by treatment sequence and overall for the FAS. Further, the CFTR 
genotype for all mutations for each subject will be provided in an individual subject data 
listing.   
8.2.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHODDE) and categorized as follows: 
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 on or after the first dose 
date of study drug through the end of the TE period for Treatment Period 1 or 2. 
Post-treatment medication: medication continued or newly received after the TE period for 
Treatment Period 1 or 2. 
A given medication may be classified as follows: prior, concomitant, post-treatment, both 
prior and concomitant, both concomitant and post-treatment, or prior, concomitant, and 
post-treatment.  
If a medication has a completely missing or partially missing start/stop date and it cannot be 
determined whether it was taken before the first dose date of study drug, concomitantly, or 
after the TE period, it will be classified as prior, concomitant, and post-treatment. 
Prior medications and concomitant medications, separately, will be summarized descriptively 
using frequency stables by preferred name. The summary of prior medications will be based 
on the FAS and presented by treatment sequence and overall. The summary of concomitant 
medications will be based on the FAS and presented by treatment group.  
An individual subject data listing will be provided for all prior medications, concomitant 
medications and post-treatment medications.  
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix C. 


Statistical Analysis Plan (Methods) 
Page 14 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
8.2.4 
Study Drug Exposure  
Study drug exposure (in days) will be calculated as: last dose date of study drug – first dose 
date of study drug + 1 day, regardless of study drug interruption, and will be summarized 
descriptively by treatment group.  
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects 
(n), mean, SD, SE, median, min, and max. It will also be summarized in categories: ≤2 
weeks, >2- ≤4 weeks, >4 - ≤8 weeks, and >8 weeks, using counts and percentages. 
Additionally, the total study drug exposure, defined as the sum total of the study drug 
exposure across all subjects (in patient-weeks), will be provided. 
Exposure summaries will be based on the Safety Set, and presented by treatment group.  
8.2.5 
Study Drug Compliance 
Percentage of tablets taken will be calculated as: 100  [(total number of tablets dispensed) – 
(total number of tablets returned)]/( total number of tablets planned to be taken per 
day  duration of study drug exposure in days). The maximum percentage of tablets taken 
will be 100%.  
Study drug compliance will be calculated as: 100  [1 - (total number of days of study drug 
interruption) / (duration of study drug exposure in days)].   
Percentage of tablets taken and study drug compliance will be summarized descriptively by 
the number of subjects (n), mean, SD, SE, median, min, and max. It will also be summarized 
in categories: <80% and ≥80% using frequency tables.  
Percentage of tablets taken and study drug compliance summaries will be based on the FAS, 
and presented by treatment group. 
8.2.6 
Important Protocol Deviations  
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a 
subject’s rights, safety, or well-being. IPD rules will be developed and finalized before 
database lock. 
The protocol deviations that should be considered as potential IPDs include, but are not 
limited to: 
 Subject was enrolled in the study despite the violation of inclusion/exclusion criteria 
 Subject was less than 80% compliant with study drug based on number of tablets taken 
 Subject received prohibited concomitant medications 
 Subject received the wrong treatment or incorrect doses  
 Subject remained in the study despite meeting withdrawal criteria 


Statistical Analysis Plan (Methods) 
Page 15 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
Occurrence of any of these events should be considered as potential IPDs, but a blinded team 
should categorize them as IPDs only if they have the potential to significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a 
subject’s rights, safety, or well-being.  
IPDs will be provided in an individual subject data listing. Details of the IPD rules are 
provided in Appendix D. 
8.3 
Efficacy Analysis  
All efficacy analyses will be based on the FAS and will use the study baseline, unless 
otherwise specified.  Further, all efficacy analyses will be performed according to the 
treatment to which the subject was assigned in each period. Data for a period will be used 
provided that the subject received at least one dose of study drug in that treatment period.  
The analysis will include all available measurements through the last scheduled on-treatment 
visit, per the visit windowing rules described in Appendix B.  
8.3.1 
Primary Efficacy Variable 
The primary efficacy variable is the absolute change in LCI2.5 (calculated as lung volume 
turnovers required to reach 2.5% of the starting N2 concentration) from study baseline 
through Week 8 in each treatment period.  
8.3.1.1 
Primary Analysis of the Primary Efficacy Variable 
The hypothesis is that the average decrease from study baseline through Week 8 in LCI2.5 is 
greater for ivacaftor versus placebo. A test of the hypothesis will be based on the Bayesian  
approach to statistical inference. If the posterior probability exceeds 80% that the difference 
in the average change from study baseline between ivacaftor and placebo is less than zero, 
then that will be considered as sufficient statistical evidence in favor of the hypothesis, and 
the study will be considered successful.  
The primary analysis will be performed using a Bayesian approach. The change from study 
baseline to each post-baseline visit through Week 8 in each treatment period will be 
calculated for each subject and modeled using a repeated measures regression model with 
mean response for each sequence by treatment period by visit cell modeled as a cell-specific 
effect with continuous study baseline LCI2.5 as a covariate.  A UN@CS direct product 
covariance matrix will be used to model the correlation between the repeated measurements 
by treatment period and visit within an individual subject. This covariance matrix assumes an 
unstructured covariance between treatment period-specific repeated measures, and a 
compound symmetry covariance between visit-specific repeated measures within a treatment 
period. A non-informative prior distribution (normal distribution with mean = 0 and variance 
= 106) will be assumed for each of the unrestricted cell-specific effects and covariate effect in 
the model, and a flat distribution (unrestricted for UN covariance parameters and CS 
covariance parameters) will be assumed for each of the variance-covariance parameters of 
the covariance matrix.  


Statistical Analysis Plan (Methods) 
Page 16 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
The average treatment difference will be defined as the mean of the average change in LCI2.5 
from study baseline through Week 8 for ivacaftor versus placebo. This average treatment 
difference will be obtained using an appropriate contrast of the cell means by averaging over 
visits within a period and across sequences, assuming no carryover effect from Treatment 
Period 1 to Treatment Period 2 due to the 8-week washout period between treatment periods, 
and will be estimated using the Markov Chain Monte Carlo (MCMC) method via PROC 
MCMC in SAS. If the model does not converge, a reduced model with a compound 
symmetry covariance matrix will be used for sequential visits across both treatment periods 1 
and 2 within an individual subject. The posterior probability that the average treatment 
difference is less than zero (lower lung clearance index values are better) will be calculated. 
Further, the posterior mean of the average treatment difference, with the posterior median, 
25th percentile, and 75th percentile will be provided, and the posterior distribution of the 
average treatment difference will be plotted.  
8.3.1.2 
Supportive Analysis of the Primary Efficacy Variable 
A supportive analysis of the primary efficacy variable will be performed using a frequentist 
confidence interval estimation approach based on a mixed-effects model for repeated 
measures (MMRM) with change in LCI2.5 from study baseline as the dependent variable. The 
model will include treatment group, visit (treatment period), treatment group by visit (within 
treatment period) interaction, and treatment period as fixed effects and subject as a random 
effect, with the continuous study baseline LCI2.5 as a covariate, and will include data from 
each treatment group and visit through Week 8 in each treatment period. No sequence effect 
(alias for carryover effect) is included in the model due to the 8-week washout period 
between the treatment periods. A UN@CS direct product covariance matrix will be used to 
model the correlation between the repeated measurements by treatment period and visit 
(within treatment period) within an individual subject. The model will be estimated using 
restricted maximum likelihood. Denominator degrees of freedom for the F test for fixed 
effects will be estimated using the Kenward-Roger approximation. If the model does not 
converge, a reduced model with a compound symmetry covariance matrix will be used for 
sequential visits across both treatment periods 1 and 2 within an individual subject. 
Conditional on the observed data and covariates, missing data due to treatment or study 
discontinuation will be assumed to be missing at random resulting in no imputation 
performed for missing data.  
The least squares (LS) mean and 95% confidence interval (CI) of the average treatment 
difference through Week 8 will be estimated within MMRM using PROC MIXED in SAS, 
for both within-treatment and between-treatment. Further, the LS mean and 95% CI of the 
treatment difference at each post-baseline visit through Week 8 will be provided for both 
within-treatment and between-treatment.  
The LS mean (with 95% CI) of the treatment difference at each post-baseline visit through 
Week 8 will be plotted by treatment group. In addition, a waterfall plot showing the subject-
level placebo-corrected change in LCI2.5 from study baseline at Week 8 will be presented for 
the ivacaftor group.  


Statistical Analysis Plan (Methods) 
Page 17 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
Further, a descriptive analysis of the change from study baseline will be performed by post-
baseline visit through Week 8, for each treatment group. 
















Statistical Analysis Plan (Methods) 
Page 25 of 48 
Protocol Number: VX16-770-127 Version 1.0 
Vertex Pharmaceuticals Incorporated 
 
8.4 
Safety Analysis 
All safety analyses will be based on data from the TE Period for treatment periods 1 and 2, 
for all subjects in the Safety Set.  
All change from baseline analyses will use the period baseline as the baseline value. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
 Treatment-emergent adverse events (TEAEs) 
 Clinical laboratory values (liver function, amylase, lipase) 
 Vital signs 
 Physical Examination 
 Ophthalmology Examination 
All safety data will be summarized by treatment group and overall. 
All safety data will be presented in individual subject data listings. 
8.4.1 
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 date of study drug 
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed 
at or after the first dose date of study drug through the end of the TE period for treatment 
periods 1 or 2 
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed beyond the TE period for treatment periods 1 or 2 
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 in treatment periods 1 or 2, the AEs will 
be classified as TEAEs. 
Details for imputing missing or partial start dates of adverse events are described in 
Appendix H. 


Statistical Analysis Plan (Methods) 
Page 26 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
AE summary tables will be presented for TEAEs only, for the TE period for treatment 
periods 1 and 2, by treatment group and overall, for the following:  
 Number of TEAEs (total number of TEAEs only) 
 Subjects with any TEAEs  
 Subjects with TEAEs by Strongest Relationship 
 Subjects with TEAEs by Maximum Severity 
 Subjects with TEAEs Leading to Study Drug Discontinuation (Discontinuation of all 
study drug) 
 Subjects with TEAEs Leading to Study Drug Interruption (Interruption of all study drug) 
 Subjects with Serious TEAEs 
 Subjects with TEAE Leading to Death  
Summaries will be presented by MedDRA system organ class (SOC) and preferred term (PT) 
using frequency counts and percentages (i.e., number and percentage of subjects with an 
event). When summarizing the number and percentages of subjects, subjects with multiple 
occurrences of the same adverse event or a continuing adverse event will be counted once, 
and only the maximum severity level will be presented in the severity summaries, and the 
strongest relationship level in the relationship summaries.   
All AEs, including pre-treatment AEs, TEAEs, and post-treatment AEs, will be presented in 
an individual subject data listing based on the All Subjects Set.  
8.4.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments, the observed values and change from 
period baseline values of liver function, amylase and lipase test results will be summarized in 
SI units at each scheduled visit, by treatment group.  
The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
during the TE period will be summarized by treatment group and overall. The threshold 
analysis criteria for clinical lab results are provided in Appendix I.  
For liver function laboratory tests (ALT, AST, ALP, GGT, and total bilirubin), a scatter plot 
of the maximum treatment-emergent value versus the period baseline value corresponding to 
xULN will be presented. Further, a scatter plot of the maximum treatment-emergent value of 
ALT and AST, separately, versus the maximum treatment-emergent value of total bilirubin 
corresponding to xULN will also be presented by treatment group.  
In addition, a listing containing all individual subject laboratory test results including liver 
function, amylase and lipase test result values outside the normal reference ranges will be 
provided. This listing will include data from both scheduled and unscheduled visits.  


Statistical Analysis Plan (Methods) 
Page 27 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
8.4.3 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
period baseline values will be summarized by treatment group, at each scheduled visit. The 
following vital signs parameters will be summarized: systolic and diastolic blood pressure 
(mm Hg), body temperature (C), HR (beats per minute), and respiratory rate (breaths per 
minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during 
the TE period will be summarized by treatment group and overall. The threshold analysis 
criteria are provided in Appendix I. 
In addition, a listing containing all individual subject vital signs measurements will be 
provided. This listing will include data from both scheduled and unscheduled visits. 
8.4.4 
Physical Examination  
Abnormal physical examination findings will be presented as an individual subject data 
listing only. 
8.4.5 
Ophthalmology Examination (age <18 years at screening) 
Ophthalmology examination findings will be presented as an individual subject data listing 
only. 
9 
INTERIM AND IDMC ANALYSES 
9.1 
Interim Analysis 
Not applicable. 
9.2 
IDMC Analysis  
Not applicable. 
 


Statistical Analysis Plan (Methods) 
Page 28 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
10 
REFERENCES 
1Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 
2Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life measure for 
children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32. 
3Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
4Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of 
life for children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45. 


Statistical Analysis Plan (Methods) 
Page 29 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
11 
LIST OF APPENDICES 
Appendix A: Schedule of Assessments 
Table 11-1 
Study VX16-770-127: Treatment Period and Follow-up Visit Assessments 
Event/Assessment 
Treatment Period 1 
Washout 
Period  
Treatment Period 2 
Early 
Termination of 
Treatment (ETT) 
Safety Follow-up 
4 weeks (± 7 days) after 
last dose of study druga 
Day 1 
Week 4 
(± 4 days) 
Week 8 
(± 4 days) 
8 weeks 
(± 4 days) 
Day 1 
Week 4 
(± 4 days) 
Week 8 
(± 4 days) 
Review of inclusion 
/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Meal(s) or snack(s) 
at sitec 
X 
X 
X 
 
X 
X 
X 
 
 
Vital signsd 
X 
X 
X 
 
X 
X 
X 
X 
X 
Physical 
examination 
X 
 
X 
 
X 
 
X 
X 
X 
                                                 
a 
If the ETT Visit occurs ≥3 weeks after the last dose of study drug, the Follow-up Visit will not be required. 
c 
Fat-containing food such as a standard CF high-fat, high-calorie meal or snack will be provided to subjects at the site after all predose assessments have 
occurred. 
d 
Vital signs (blood pressure, pulse rate, respiration rate, and body temperature) will be collected after the subject has been at rest (supine) for 5 minutes. 
Blood pressure will be measured by sphygmomanometer. Vital sign assessments will be performed before blood draws. 


Statistical Analysis Plan (Methods) 
Page 30 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
Table 11-1 
Study VX16-770-127: Treatment Period and Follow-up Visit Assessments 
Event/Assessment 
Treatment Period 1 
Washout 
Period  
Treatment Period 2 
Early 
Termination of 
Treatment (ETT) 
Safety Follow-up 
4 weeks (± 7 days) after 
last dose of study druga 
Day 1 
Week 4 
(± 4 days) 
Week 8 
(± 4 days) 
8 weeks 
(± 4 days) 
Day 1 
Week 4 
(± 4 days) 
Week 8 
(± 4 days) 
Multiple breath 
washoutf 
X 
X 
X 
 
X 
X 
X 
 
 
Pregnancy test 
(female subjects of 
childbearing 
potential)h 
X 
X 
X 
 
X 
X 
X 
X 
X 
Liver function tests 
(LFTs)i 
X 
 
X 
 
X 
 
X 
X 
X 
Amylase and lipase 
X 
 
X 
 
X 
 
X 
X 
X 
Ophthalmological 
examinationj 
 
 
 
 
 
 
X 
X 
 
                                                 
f 
Multiple breath washout 
 will be performed pre-bronchodilator 
, and must be performed before dosing. 
h 
A urine β-hCG test will be performed at all visits in Treatment Periods 1 and 2 and will be performed before the first dose of study drug on Day 1 of 
Treatment Periods 1 and 2. A urine β-hCG test will be performed at the ETT visit (as applicable). A serum pregnancy test will be performed at the Safety 
Follow-up Visit.  
i 
ALT, AST, GGT, alkaline phosphatase, and bilirubin 


Statistical Analysis Plan (Methods) 
Page 31 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
Table 11-1 
Study VX16-770-127: Treatment Period and Follow-up Visit Assessments 
Event/Assessment 
Treatment Period 1 
Washout 
Period  
Treatment Period 2 
Early 
Termination of 
Treatment (ETT) 
Safety Follow-up 
4 weeks (± 7 days) after 
last dose of study druga 
Day 1 
Week 4 
(± 4 days) 
Week 8 
(± 4 days) 
8 weeks 
(± 4 days) 
Day 1 
Week 4 
(± 4 days) 
Week 8 
(± 4 days) 
Ivacaftor or placebo 
dosing 
X 
X 
X 
 
X 
X 
X 
 
 
Concomitant 
treatments and 
procedures 
---------------------Continuous from signing of the ICF and Assent (where applicable) through the Safety Follow-up Visit--------------------- 
Adverse events 
---------------------Continuous from signing of the ICF and Assent (where applicable) through the Safety Follow-up Visit--------------------- 
                                                                                                                                                                                                                         
j 
OE is required for subjects who were under 18 years of age at the Screening Visit. OE will be performed either at the Week 8 Visit of Treatment Period 2 or 
at the ETT Visit. This examination is not required if the subject received study drug for a total of less than 4 weeks. 


Statistical Analysis Plan (Methods) 
Page 32 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
C
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 11-2 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Treatnent Period 
Dayb 
Analysis Visit Window 
(in treatment period 
days) 
Safety Assessment (Treatment Period 1) 
Vital Signs
 
Day 1 (Baseline)  
Week 4 
Week 8 
 
1 
29 
57 
 
1  
[2, 43] 
[44, 71] 
 
Liver Function Tests 
Amylase 
Lipase 
 
Day 1 (Baseline)  
Week 8 
1 
57 
1  
[2, 71] 
Safety Assessment (Treatment Period 2) 
Vital Signs
 
Day 1 (Baseline)  
Week 4 
Week 8 
Safety Follow-up 
1 
29 
57 
NA 
1  
[2, 43] 
[44, 71] 
Nominal visit 
Liver Function Tests 
Amylase 
Lipase 
 
Day 1 (Baseline)  
Week 8 
Safety Follow-up 
1 
57 
NA 
1  
[2, 71] 
Nominal visit 
Efficacy Assessment (Treatment Period 1) 
MBW (LCI) 
Week 8 
57 
[44, 71] 
Efficacy Assessment (Treatment Period 2) 
MBW (LCI) 
Week 8 
57 
[44, 71] 
                                                 
a  Visit name is used to report data in tables, listings and figures. 
 
b  Target day time point per protocol is predose. 


Statistical Analysis Plan (Methods) 
Page 33 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
C
Table 11-2 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Treatnent Period 
Dayb 
Analysis Visit Window 
(in treatment period 
days) 
aVisit name is used to report data in tables and figures.  
bTarget day time point is predose. 
 
Note:  
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 efficacy parameters: 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. 
iii. For tables of the extreme lab measurement based on ULN or LLN, convert the lab measurements 
into times of ULN or LLN first, and then select the extreme measurement. 
 
Derived Variables: 
1. Age (in years) at first dose date  
Obtain age at screening (in days) in yy mm format (e.g., 24 years, 6 months) from screening vital signs page, and add 
0.5 month to convert to days. 
Obtain screening date from Date of Visit (DOV) page. 
Then age (in years) at first dose date = integer part of {[(first dose date-screening date) in days + age at screening (in 
days)]/365.25}. 
Correspondingly, age (in months) at first dose date = integer part of 12*{[(first dose date-screening date) in days + age 
at screening (in days)]/365.25}. 
2. Age (in years) at post-baseline visit (for use in calculation of percent predicted spirometry variables) 


Statistical Analysis Plan (Methods) 
Page 34 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
C
Table 11-2 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Treatnent Period 
Dayb 
Analysis Visit Window 
(in treatment period 
days) 
Age (in years) at post-baseline visit = integer part of {[(post-baseline visit date – screening date) in days + age at 
screening (in days)]/365.25} 
3. Missing First Dose Date or Last Dose Date 
If the first dose date is missing, use Day 1 visit date. 
If the last dose date is missing at final analysis, use maximum of Early Treatment Termination (ETT) visit date and 
last study drug administration date from EX SDTM domain. When a subject is lost to follow up without ETT, impute 
the last dose date as the last on-treatment visit date. 
 
 


Statistical Analysis Plan (Methods) 
Page 35 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
C
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). 
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). 
In summary, the prior, concomitant in TE Period 1or post categorization of a medication in TE 
Period 1 is described in Table 11-3 below. 
Table 11-3 
Prior, Concomitant, and Post Categorization of a Medication in TE Period 1 
Medication Start Date 
Medication Stop Date 
< Start date of TE Period 1 
≥ Start date of TE Period  1 
and ≤ End Date of TE Period 1 
> End Date of TE Period  1 and 
< Start date of TE Period  2  
< Start date of TE Period 1 
P 
PC1 
PC1A1 
≥ Start date of TE Period 1and  
≤ End date of TE Period 1 
- 
C1 
C1A1 
> End date of TE Period 1 
- 
- 
A1 
P: Prior; C1: Concomitant in Treatment Period 1; A1: Post in Treatment Period 1 
 
A similar categorization is described in Table 11-4 below for TE Period 2. 
Table 11-4 
 Concomitant, and Post Categorization of a Medication in TE Period 2 
Medication Start Date 
Medication Stop Date 
≥ Start date of TE Period 2 and 
≤ End Date of TE Period 2 
> End Date of TE Period 2 
≥ Start date of TE Period 2 and  
≤ End date of TE Period 2 
C2 
C2A2 
> End date of TE Period 2 
- 
A2 
 
 


Statistical Analysis Plan (Methods) 
Page 36 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
C
Appendix D: Important Protocol Deviation Programming Rules (Based on the 
Clinical Database) 
Important programmable protocol deviations before first dose 
1. Inclusion criteria: 
a) I3: Six years of age and older and ≥25 kg on the date of the ICF. 
b) I6: FEV1 ≥40% of predicted and ≤105% of predicted at screening, based on the Global 
Lung Function Initiative (GLI)-2012 multi-ethnic all-age reference equations. 
2. Exclusion criteria: 
a) E4: Any of the following abnormal laboratory values at the Screening Visit: 
o Hemoglobin <10 g/dL 
o Alanine aminotransferase (ALT) or AST >5 × upper limit of normal (ULN) 
o Bilirubin >2 × ULN 
o Glomerular filtration rate ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt 
equation in subjects <18 years of age and the Modification of Diet in Renal Disease 
equation in subjects ≥18 years of age). 
 
 


Statistical Analysis Plan (Methods) 
Page 37 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
C
Appendix E: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, 
 using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 predicted 
values are available in: 
Quanjer GLI-2012 Regression Equations and Lookup Tables. Philip H. Quanjer, Sanja Stanojevic, 
Tim J. Cole, Janet Stocks. Version 7 April 2013. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/quanjer-gli-2012-
regression-equations-and-lookup-tables.aspx.  
Accessed March 13, 2017.  
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Implementing GLI-2012 regression equations. Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, 
Janet Stocks. Version 19 July 2015. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/gli-2012-explained.aspx. 
Accessed March 13, 2017 .   
GLI-2012 - SAS Macro. Sanja Stanojevic. Version 2, 7 April 2013. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/sas-macro.aspx 
Accessed March 13, 2017. 
 
 










Statistical Analysis Plan (Methods) 
Page 42 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
C
Appendix H: Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date are defined as follows. 
 If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year and month are equal to the month and year of first dose date of 
the Treatment Period, then impute the AE start day as the day of first dose date 
of the Treatment Period;  
 else impute the AE start day as 1.  
o else 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: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment Period, 
then impute the AE start month and day as the month and day of first dose date 
of the Treatment Period;  
 else impute the AE start month as January and day as 1.  
o else impute the AE start month as January and 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.  
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then the AE will be considered as TEAE for the 
Treatment Period.  
o else the AE will be considered as a pretreatment AE. 
Imputation rules for partial AE end date are defined as follows:  
If partial end date, then impute as min (the last day of the month, end of study) if day is missing, or 
min (Dec, end of study) if month is missing. 
 
 


Statistical Analysis Plan (Methods) 
Page 43 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
C
Appendix I: Criteria for Threshold Analysis 
Table 11-9 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3 - ≤ 5xULN 
>5 - ≤ 8xULN 
>8 - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3 - ≤ 5xULN 
>5 - ≤ 8xULN 
>8 - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤  3xULN) or (AST>ULN - ≤  
3xULN) 
(ALT>3 - ≤  5xULN) or  (AST>3 - ≤  5xULN) 
(ALT>5- ≤  8xULN) or  (AST>5 - ≤    8xULN) 
(ALT>8 - ≤  20xULN) or (AST>8 - ≤ 20xULN) 
ALT>20xULN or AST> 20 xULN 
FDA DILI Guidance 
Alkaline 
Phosphatase 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5 xULN 
>2.5 – ≤ 5.0 x ULN 
>5.0 – ≤ 20.0 x ULN 
>20.0 x ULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total 
Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
AST and Total 
Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and 
Total Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 


Statistical Analysis Plan (Methods) 
Page 44 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
C
Table 11-9 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
GGT 
>ULN - ≤ 2.5xULN 
>2.5 –  ≤ 5.0xULN 
>5.0 –  ≤ 20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Amylase 
>1 -  ≤  1.5xULN 
>1.5 -  ≤  2xULN 
>2 -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Lipase 
>ULN -  ≤  1.5xULN 
>1.5 -  ≤  2xULN 
>2 -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
 
Table 11-10 Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
HR 
Bradycardia 
 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
 
Per HV grade 2, 3, plus shift change 
 
 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 


Statistical Analysis Plan (Methods) 
Page 45 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
C
Table 11-10 Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
SBP increased 
 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg and >10 mmHg increase from 
baseline 
>140 mmHg and >20 mmHg increase from 
baseline 
>160 mmHg and >10 mmHg increase from 
baseline 
>160 mmHg and >20 mmHg increase from 
baseline 
 
809/770 analyses 
SBP decrease 
 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from 
baseline 
<90 mmHg and >20 mmHg decrease from 
baseline 
<80 mmHg and >10 mmHg decrease from 
baseline 
<80 mmHg and >20 mmHg decrease from 
baseline 
 
Per HV grade 1, 3, plus shift change 


Statistical Analysis Plan (Methods) 
Page 46 of 48 
Protocol Number: VX16-770-127 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
C
Table 11-10 Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
DBP increased 
 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from 
baseline 
>90 mmHg and >10 mmHg increase from 
baseline 
>100 mmHg and >5 mmHg increase from 
baseline 
>100 mmHg and >10 mmHg increase from 
baseline 
 
 
DBP decreased 
 
 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from 
baseline 
<60 mmHg and >10 mmHg decrease from 
baseline 
<45 mmHg and >5 mmHg decrease from 
baseline 
<45 mmHg and >10 mmHg decrease from 
baseline 
 
 
Weight   
Weight gain  
≥5% increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
 
CTCAE grade 1-3 
 
 
Weight loss  
≥5% decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
 
CTCAE grade 1-3