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
Phase: PHASE3
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated

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