Clinical trial NCT03911713
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2019-04-17; Completion date: 2020-08-20
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy, safety, pharmacodynamic (PD) and pharmacokinetic (PK) effect of VX-561.

Detailed description:

Arms: arm 1: Participants received IVA 150 milligrams (mg) orally every 12 hours (q12h) in the treatment period for 12 weeks. arm 2: Participants received VX-561 25 mg orally daily (qd) in the treatment period for 12 weeks. arm 3: Participants received VX-561 50 mg orally qd in the treatment period for 12 weeks. arm 4: Participants received VX-561 150 mg orally qd in the treatment period for 12 weeks. arm 5: Participants received VX-561 250 mg orally qd in the treatment period for 12 weeks.
Interventions: intervention 1: VX-561 intervention 2: IVA intervention 3: Placebo intervention 4: Placebo
Intervention descriptions: intervention 1: VX-561 tablets for oral administration. intervention 2: 150-mg film-coated tablet for oral administration. intervention 3: Placebo matched to IVA. intervention 4: Placebos matched to VX-561.

Protocol documents:
Prot_000.pdf: 
Page 1 of 52 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 2, Randomized, Double-blind Study to 
Evaluate the Efficacy and Safety of VX-561 in 
Subjects Aged 18 Years and Older With Cystic 
Fibrosis 
Vertex Study Number: VX18-561-101 
 
EudraCT Number: 2018-003970-28 
Date of Protocol: 03 October 2019 (Version 2.0) 
 
 
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 VX18-561-101, Version 2.0 
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Vertex Pharmaceuticals Incorporated 
 
2 
PROTOCOL SYNOPSIS 
Title 
A Phase 2, Randomized, Double-blind Study to Evaluate the Efficacy and Safety 
of VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis 
 
 
Brief Title 
A Study to Evaluate Efficacy and Safety of VX-561 in Subjects Aged 18 Years 
and Older With Cystic Fibrosis  
 
 
Clinical Phase and 
Clinical Study Type  
Phase 2, efficacy and safety  
 
 
Objectives 
Primary Objective 
• To evaluate the efficacy of VX-561  
Secondary Objectives 
• To evaluate the pharmacodynamic (PD) effect of VX-561  
• To evaluate the pharmacokinetics (PK) of VX-561, IVA, and relevant 
metabolites  
• To evaluate the safety and tolerability of VX-561 
 
 
Endpoints 
Primary Endpoint 
• Absolute change in percent predicted forced expiratory volume in 1 second 
(ppFEV1) from baseline at Week 12 
Secondary Endpoints 
• Absolute change in sweat chloride concentrations from baseline at Week 12 
• PK parameters of VX-561, IVA, and relevant metabolites 
• Safety and tolerability, based on the assessment of adverse events (AEs), 
laboratory test results, standard 12-lead ECGs, vital signs, and pulse oximetry 
 
 
Number of Subjects 
Approximately 88 subjects were planned to enroll in 5 treatment arms (25 mg 
once daily [qd] VX-561, 50 mg qd VX-561, 150 mg qd VX-561, 250 mg qd 
VX-561, and IVA 150 mg every 12 hours [q12h]) in a ratio of 1:2:2:2:1 under the 
original protocol. The 25 mg qd VX-561 and 50 mg qd VX-561 treatment arms 
were discontinued; 44 subjects had been enrolled and randomized to the 
5 treatment arms at this point. The remaining subjects planned to enroll will be 
randomized 2:2:1 to 3 treatment arms (250 mg qd VX-561, 150 mg qd VX-561, 
and IVA 150 mg q12h).  
 
 
Study Population 
Male subjects and female subjects with CF who have a gating mutation and were 
previously taking a stable dose of IVA, ages 18 and older 
 
 
Investigational Drugs 
Active substance: VX-561 
Activity: CFTR potentiator (increased Cl− secretion) 
Strength and route of administration: 50-mg and 25-mg VX-561 tablets for oral 
administration  
 
Active substance: IVA (VX-770) 
Activity: CFTR potentiator (increased Cl− secretion) 


Protocol VX18-561-101, Version 2.0 
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Strength and route of administration: 150-mg film-coated tablet for oral 
administration 
 
Study Duration 
Including the Screening Period, each subject will participate in the study for 
approximately 20 weeks 
 
 
Study Design 
This is a Phase 2 study of VX-561 monotherapy. A schematic of the study design 
is shown in Figure 2-1, which is randomized, double-blind, parallel-group, and 
active-controlled. The study will evaluate 4 dose levels of VX-561 in subjects 
with CF who have a gating mutation and were previously taking a stable dose of 
IVA. Randomization will be stratified by ppFEV1 value at screening (<70 versus 
≥70). 
The original protocol included 25 mg qd VX-561 and 50 mg qd VX-561 treatment 
arms; both treatment arms were discontinued in the current protocol (
 
). 
Figure 2-1 
VX18-561-101 Study Design 
a 
Approximately 88 subjects were planned to enroll in 5 treatment arms (25 mg 
qd VX-561, 50 mg qd VX-561, 150 mg qd VX-561, 250 mg qd VX-561, and 
IVA 150 mg q12h) in a ratio of 1:2:2:2:1 under the original protocol. The 
25 mg qd VX-561 and 50 mg qd VX-561 treatment arms were discontinued; 
44 subjects had been enrolled and randomized to the 5 treatment arms at this 
point. The remaining subjects planned to enroll will be randomized 2:2:1 to 
3 treatment arms (250 mg qd VX-561, 150 mg qd VX-561, and IVA 150 mg 
q12h). 
 
 
Study Rationale 
This study is being conducted to evaluate the efficacy and PD effect (i.e., change 
in sweat chloride) for a range of VX-561 doses to support VX-561 dose selection 
for future studies, including studies of VX-561 in triple combination (TC) with 
CFTR correctors, such as VX-121 and TEZ.  
Subjects will be on stable IVA treatment at baseline and will be randomized to 
study drug treatment groups on Day 1 (VX-561 or IVA). Change in ppFEV1 from 
IVA baseline is the primary endpoint. However, dose selection of VX-561 for 
future studies may consider the totality of data, including exposure-response 
analyses for efficacy (ppFEV1) and PD (sweat chloride) endpoints.  
 
 
Assessments 
Safety: AEs, clinical laboratory assessments, clinical evaluation of vital signs, 
ECGs, physical examinations, and pulse oximetry 
Treatment Period 
12 weeks 
Screening  
28 days 
Washout 
Period 
3-5 days 
VX-561 250 mg qd 
VX-561 150 mg qd 
VX-561 50 mg qd 
(treatment arm discontinued) 
IVA 150 mg q12h 
Enroll 
Subjects on 
Stable IVA 
Treatmenta 
Washout 
VX-561 
or 
IVA 
Resume IVA  
Safety Follow-up 
28 days after last 
dose 
VX-561 25 mg qd 
(treatment arm discontinued) 


Protocol VX18-561-101, Version 2.0 
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Efficacy: Spirometry  
PD: Sweat chloride  
PK: VX-561, IVA, and relevant metabolites 
 
 
Statistical Analyses 
The following efficacy analyses will be conducted for ppFEV1 and sweat chloride: 
The analysis of the absolute change in ppFEV1 from baseline at Week 12 will be 
based on a mixed-effects model for repeated measures (including 250 mg qd 
VX-561, 150 mg qd VX-561, and IVA 150 mg q12h treatment arms only). The 
primary results will be the within-group comparison for each VX-561 arm. The 
adjusted mean with a 2-sided 95% CI will be provided. Between-group estimates 
of each VX-561 arm and IVA arm will also be provided. 
The analysis of the absolute change from baseline in sweat chloride at Week 12 
will be conducted similarly to ppFEV1 (including 250 mg qd VX-561, 150 mg qd 
VX-561, and IVA 150 mg q12h treatment arms only).  
A sequential approach will be used to perform the population PK/PD analyses for 
VX-561. Bayesian estimates of individual PK parameters from the final 
population PK model will be used to simulate PK profiles for each subject, which 
will be used in exposure-response models to describe changes in sweat chloride 
and ppFEV1 from baseline.  
Safety analyses for all treatment arms (including the 25 mg qd VX-561 and 50 mg 
qd VX-561 treatment arms that were discontinued) will be conducted to support 
the dose selection. Descriptive analyses will be provided for the safety data 
comprising AEs, clinical laboratory assessments, ECGs, vital signs, and pulse 
oximetry; no statistical hypothesis testing will be performed. The PK results for 
VX-561, IVA, and relevant metabolites will be reported with descriptive statistics. 
Sample size 
Based on the initial study design that included 4 dose groups of VX-561 and an 
IVA 150 mg q12h dose group, assuming a within-group SD of 7 percentage points 
and a 10% dropout rate at Week 12: a sample size of 22 subjects in the 50, 150, 
and 250 mg qd VX-561 arms will provide a 95% CI of ± 3.4 percentage points 
around the observed mean absolute change in ppFEV1 from baseline at Week 12, 
based on 2-sided, 1-sample t statistics; a sample size of 11 subjects in the other 
arms will provide a 95% CI of ± 5.4 percentage points around the observed mean.  
Following discontinuation of the 25 mg qd VX-561 and 50 mg qd VX-561 
treatment arms, the remaining subjects planned to enroll will be randomized in a 
2:2:1 ratio to the 3 current treatment arms with a sample size of approximately 
28 subjects for the 250 mg qd VX-561 treatment arm, approximately 28 subjects 
for the 150 mg qd VX-561 treatment arm, and approximately 14 subjects for the 
IVA 150 mg q12h treatment arm. The total study sample size including 
discontinued arms and current arms is approximately maintained as planned 
(N = 88). Under the same assumption as the original design (within-group SD of 
7 percentage points and 10% dropout rate at Week 12): a sample size of 
28 subjects in the 250 mg qd VX-561 and 150 mg qd VX-561 arms will provide a 
95% CI of ± 2.9 percentage points around the observed mean absolute change in 
ppFEV1 from baseline at Week 12, based on 2-sided, 1-sample t statistics; a 
sample size of 14 subjects in the IVA 150 mg q12h arm will provide a 95% CI of 
± 4.4 percentage points around the observed mean. 
 
 
IDMC Reviews 
An independent data monitoring committee (IDMC) will conduct safety reviews 
of study data as outlined in the IDMC charter. The planned IDMC reviews (with 
reference to number of subjects and duration of study) will be specified in the 
IDMC charter.  


Protocol VX18-561-101, Version 2.0 
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3 
SCHEDULE OF ASSESSMENTS 
The schedule of assessments is provided in Table 3-1. 
Table 3-1 
Study VX18-561-101: Screening Visit, Treatment Period, Washout Visit, and Safety Follow-up Visit  
Event/Assessmenta 
Screening 
Visitb 
Treatment Period 
Washout Visit 
ETT 
Visitc 
Safety 
Follow-up 
28 ( 7) Days 
After Last 
Dose of Study 
Drug 
Day -28 
to Day -1 
Day 1  
Day 15 
( 3 day) 
Week 4 
( 5 days) 
Week 8 
( 5 days) 
Week 12 
( 5 days) 
4 ( 1) Days 
After 
Week 12 Visit 
Outpatient visits 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationd 
 
X 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Weighte 
X 
X 
X 
X 
X 
X 
 
X 
X 
Heighte 
X 
 
 
 
 
 
 
 
 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationg 
Complete 
Abbrev. 
 
Abbrev. 
Abbrev. 
Abbrev. 
 
Abbrev. 
Abbrev. 
Standard 12-lead ECGh 
X 
X 
 
X 
 
 
 
X 
X 
Sweat chloridei, j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a  
All assessments will be performed before dosing, unless noted otherwise. Assessments may be performed in any order when more than 1 assessment is required at a particular 
time point. Assessments that are collected before and after dosing will only be collected once if study drug is not administered on the day of the visit (i.e., premature 
discontinuation of study drug treatment). 
b  
All screening results must be reviewed before randomization, unless noted otherwise. 
c  
If the subject prematurely discontinues study drug, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug treatment. Additional PK 
samples and safety assessments may also be performed at the discretion of the investigator. See Section 9.1.5 for additional details. 
d  
Randomization may occur on the previous day (Day -1) after eligibility has been confirmed. 
e  
Weight and height will be measured with shoes off. 
f  
Vital signs and pulse oximetry will be collected after the subject has been at rest for at least 5 minutes.  
g  
Complete and abbreviated PEs are described in Section 11.5.3.  
h  
Standard 12-lead ECGs will be performed in the supine position after the subject has been at rest for at least 5 minutes. See Section 8.2 for information about the ECG 
assessment for study eligibility. 
i  
Sweat chloride assessments should be performed at approximately the same time at every visit. See Section 8.1 for information about the sweat chloride assessment for study 
eligibility.  
j  
The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred. 


Protocol VX18-561-101, Version 2.0 
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Table 3-1 
Study VX18-561-101: Screening Visit, Treatment Period, Washout Visit, and Safety Follow-up Visit  
Event/Assessmenta 
Screening 
Visitb 
Treatment Period 
Washout Visit 
ETT 
Visitc 
Safety 
Follow-up 
28 ( 7) Days 
After Last 
Dose of Study 
Drug 
Day -28 
to Day -1 
Day 1  
Day 15 
( 3 day) 
Week 4 
( 5 days) 
Week 8 
( 5 days) 
Week 12 
( 5 days) 
4 ( 1) Days 
After 
Week 12 Visit 
Spirometryk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisj 
X 
X 
 
 
 
 
 
X 
X 
β-hCGl 
Serum 
Urine 
 
Urine 
 
 
 
Serum 
Serum 
CFTR genotypem 
X 
 
 
 
 
 
 
 
 
FSHn 
X 
 
 
 
 
 
 
 
 
Serum chemistry and 
hematologyj 
X 
X 
X 
X 
X 
X 
 
X 
X 
Coagulationj 
X 
X 
 
 
 
X 
 
X 
X 
PK samplingo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VX-561 or IVA dosingp 
 
Day 1 through Week 12 
 
 
 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications reviewq 
Continuous from signing of ICF through Safety Follow-up Visit 
Treatment and procedures 
review 
Continuous from signing of ICF through Safety Follow-up Visit 
 
k  
Spirometry may be performed pre- or post-bronchodilator at the Screening Visit. At other study visits, spirometry will be done pre-bronchodilator, before the morning dose of 
study drug, and should be performed at approximately the same time at every visit.  
l  
The serum β-hCG test is to be performed for all female subjects at Screening. Subsequent urine or serum β-hCG tests are to be performed as indicated for women of 
childbearing potential. A definition of non-childbearing potential is provided in Section 11.5.5.1. 
m  
CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before randomization, a previous CFTR genotype laboratory report 
may be used to establish eligibility. Subjects who have been randomized and whose screening genotype does not confirm study eligibility must be discontinued from the 
study. 
n  
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
o  
Blood samples will be collected for PK analysis of VX-561 and metabolites or IVA and metabolites. The sample collected at Screening will be collected without regard to 
 
time of IVA dosing. On Day 1, samples will be collected before dosing (0 hours) and at 4 hours after dosing (relative to the morning dose). At Day 15, Week 4, Week 8, and 
 
Week 12, a predose sample will be collected before the morning dose. In a subset of subjects (up to approximately 20 subjects), additional samples will be collected at the 
 
Week 4 visit at 1, 2, 4, and 6 hours after dosing (relative to the morning dose). At the Washout Visit, a single sample will be collected prior to resumption of IVA. A single 
 
sample will be collected at the Safety Follow-up Visit for analysis of IVA for those subjects who resume IVA therapy. Acceptable PK sampling windows are provided in 
 
Table 11-1. At the ETT Visit, a single blood sample for PK analysis will be collected.  
p  
Study drug will be administered orally twice daily (Section 9.6). The last dose of study drug will be the morning dose on the Week 12 Visit. Subjects may resume their prior 
IVA therapy after the Washout Visit. 
q  
All medications taken from 28 days before the Screening Period through the end of the study will be recorded (Section 9.5). 


Protocol VX18-561-101, Version 2.0 
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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 6 
4 
Table of Contents ................................................................................................................... 8 
List of Tables............................................................................................................................ 11 
List of Figures .......................................................................................................................... 11 
List of Abbreviations................................................................................................................ 12 
5 
Introduction.......................................................................................................................... 14 
5.1 
Background ..................................................................................................................... 14 
5.2 
Study Rationale .............................................................................................................. 15 
6 
Study Objectives .................................................................................................................. 15 
6.1 
Primary Objective ........................................................................................................... 15 
6.2 
Secondary Objectives ..................................................................................................... 15 
7 
Study Endpoints ................................................................................................................... 15 
7.1 
Primary Endpoint ............................................................................................................ 15 
7.2 
Secondary Endpoints ...................................................................................................... 15 
8 
Study Population .................................................................................................................. 15 
8.1 
Inclusion Criteria ............................................................................................................ 15 
8.2 
Exclusion Criteria ........................................................................................................... 16 
9 
Study Implementation ......................................................................................................... 18 
9.1 
Study Design .................................................................................................................. 18 
9.1.1 
Screening ................................................................................................................ 18 
9.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 18 
9.1.1.2 
Rescreening ...................................................................................................... 18 
9.1.1.3 
Extension of Screening Period Window .......................................................... 19 
9.1.2 
Treatment Period .................................................................................................... 19 
9.1.3 
Washout Period....................................................................................................... 19 
9.1.4 
Follow-up................................................................................................................ 19 
9.1.5 
Early Termination of Treatment OR Early Discontinuation .................................. 19 
9.1.6 
Lost to Follow-up ................................................................................................... 20 
9.1.7 
Independent Data Monitoring Committee .............................................................. 20 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 20 
9.3 
Rationale for Study Elements ......................................................................................... 20 
9.3.1 
Study Design........................................................................................................... 20 
9.3.2 
Study Population..................................................................................................... 21 
9.3.3 
Study Drug Dose and Duration .............................................................................. 21 
9.3.4 
Rationale for Study Assessments ........................................................................... 21 
9.4 
Study Restrictions ........................................................................................................... 21 
9.5 
Prior and Concomitant Medications ............................................................................... 22 
9.6 
Administration ................................................................................................................ 22 
9.7 
Dose Modification for Toxicity ...................................................................................... 23 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 23 
9.9 
Removal of Subjects ....................................................................................................... 24 


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9.10 Replacement of Subjects ................................................................................................ 25 
10 Study Drug Information and Management ....................................................................... 25 
10.1 Preparation and Dispensing ............................................................................................ 25 
10.2 Packaging and Labeling ................................................................................................. 25 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 25 
10.4 Drug Accountability ....................................................................................................... 25 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 26 
10.6 Compliance ..................................................................................................................... 26 
10.7 Blinding and Unblinding ................................................................................................ 26 
10.7.1 
Blinding .................................................................................................................. 26 
10.7.2 
Unblinding .............................................................................................................. 27 
11 Assessments .......................................................................................................................... 28 
11.1 Subject and Disease Characteristics ............................................................................... 28 
11.2 Pharmacokinetics ............................................................................................................ 28 
11.2.1 
Blood Sampling ...................................................................................................... 28 
11.2.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 28 
11.2.3 
Bioanalysis.............................................................................................................. 28 
11.3 Pharmacodynamics: Sweat Chloride .............................................................................. 28 
11.4 Efficacy: Spirometry ...................................................................................................... 29 
11.5 Safety .............................................................................................................................. 29 
11.5.1 
Adverse Events ....................................................................................................... 30 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 30 
11.5.3 
Physical Examinations and Vital Signs .................................................................. 31 
11.5.4 
Electrocardiograms ................................................................................................. 31 
11.5.5 
Contraception and Pregnancy ................................................................................. 32 
11.5.5.1 Contraception ................................................................................................... 32 
11.5.5.2 Pregnancy ......................................................................................................... 34 
12 Statistical and Analytical Plans .......................................................................................... 34 
12.1 Sample Size and Power .................................................................................................. 34 
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 and Pharmacodynamic Analyses ............................................................. 37 
12.3.3.1 Efficacy: Spirometry ........................................................................................ 37 
12.3.3.2 Pharmacodynamics: Sweat Chloride................................................................ 37 
 
12.3.4 
Safety Analysis ....................................................................................................... 38 
12.3.4.1 Adverse Events................................................................................................. 38 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 39 
12.3.4.3 Electrocardiogram ............................................................................................ 39 
12.3.4.4 Vital Signs ........................................................................................................ 39 


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12.3.4.5 Pulse Oximetry ................................................................................................. 39 
12.3.4.6 Physical Examination ....................................................................................... 40 
 
 
 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses ........................... 40 
12.3.6.1 Interim Analysis ............................................................................................... 40 
12.3.6.2 Independent Data Monitoring Committee Analysis ........................................ 40 
12.4 Clinical Pharmacology Analysis .................................................................................... 40 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 40 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 40 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 41 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 41 
13.1.1 
Adverse Events ....................................................................................................... 41 
13.1.1.1 Definition of an Adverse Event........................................................................ 41 
13.1.1.2 Clinically Significant Assessments .................................................................. 41 
13.1.1.3 Documentation of Adverse Events................................................................... 41 
13.1.1.4 Adverse Event Severity .................................................................................... 42 
13.1.1.5 Adverse Event Causality .................................................................................. 42 
13.1.1.6 Study Drug Action Taken ................................................................................ 43 
13.1.1.7 Adverse Event Outcome .................................................................................. 43 
13.1.1.8 Treatment Given............................................................................................... 44 
13.1.2 
Serious Adverse Events .......................................................................................... 44 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 44 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 45 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 45 
13.2 Administrative Requirements ......................................................................................... 45 
13.2.1 
Ethical Considerations ............................................................................................ 45 
13.2.2 
Subject Information and Informed Consent ........................................................... 46 
13.2.3 
Investigator Compliance ......................................................................................... 46 
13.2.4 
Access to Records ................................................................................................... 46 
13.2.5 
Subject Privacy ....................................................................................................... 46 
13.2.6 
Record Retention .................................................................................................... 47 
13.2.7 
Study Termination .................................................................................................. 47 
13.2.8 
End of Study ........................................................................................................... 47 
13.3 Data Quality Assurance .................................................................................................. 47 
13.4 Monitoring ...................................................................................................................... 48 
13.5 Electronic Data Capture ................................................................................................. 48 
13.6 Confidentiality and Disclosure ....................................................................................... 48 
13.7 Publications and Clinical Study Report .......................................................................... 49 
 
 
13.7.2 
Clinical Study Report ............................................................................................. 49 
14 References ............................................................................................................................. 50 
15 Protocol Signature Pages .................................................................................................... 51 
15.1 Sponsor Signature Page .................................................................................................. 51 
15.2 Investigator Signature Page ............................................................................................ 52 


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List of Tables 
Table 3-1 
Study VX18-561-101: Screening Visit, Treatment Period, Washout Visit, and 
Safety Follow-up Visit ............................................................................................ 6 
Table 9-1 
Study Restrictions ................................................................................................. 22 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 28 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 30 
Table 11-3 
Acceptable Methods of Contraception.................................................................. 33 
Table 13-1 
Grading of AE Severity ........................................................................................ 42 
Table 13-2 
Classifications for AE Causality ........................................................................... 43 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 43 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 43 
List of Figures 
Figure 2-1 
VX18-561-101 Study Design ................................................................................. 4 
Figure 9-1 
VX18-561-101 Study Design ............................................................................... 18 
 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
AUC 
area under the concentration versus time curve 
AUC0-24h 
AUC from the time of dosing to 24 hours 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
bpm 
beats per minute 
CD 
compact disc 
CF 
cystic fibrosis 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CMC 
chemistry, manufacturing, and controls 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
predose concentration 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ETT 
Early Termination of Treatment 
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 
GI 
gastrointestinal 
GLI 
Global Lung Function Initiative 
GPP 
Good Publication Practices 
GPS 
Global Patient Safety 
HBE 
human bronchial epithelial 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
independent data monitoring committee 


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Abbreviation 
Definition 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IRB 
institutional review board 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LUM 
lumacaftor 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
n 
size of subsample 
PC 
publication committee 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PI 
pancreatic insufficient 
PK 
pharmacokinetic, pharmacokinetics 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval, segment 
PT 
Preferred Term 
q12h 
every 12 hours 
qd 
daily 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QT 
QT interval 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia’s formula 
RNA 
ribonucleic acid 
RR 
interval from the onset of 1 QRS complex to the next 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
steering committee 
SD 
standard deviation 
SET 
study execution team 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SUSAR 
suspected, unexpected, serious adverse reaction 
TC 
triple combination 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor  
ULN 
upper limit of normal 
USA 
United States of America 
WHO-DD 
World Health Organization-Drug Dictionary 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive, chronic disease with serious morbidities and 
frequent premature mortality. At present, there is no cure. CF affects more than 
70,000 individuals worldwide.1 Based on its prevalence, CF qualifies as an orphan disease.2, 3  
CF is caused by reduced quantity and/or function of the CFTR protein due to mutations in the 
CFTR gene. The CFTR protein is an epithelial chloride channel that aids in regulating salt and 
water absorption and secretion and pH balance in sweat glands and multiple organs, including 
the lungs, pancreas, and other gastrointestinal (GI) organs. Despite progress in the treatment of 
CF with antibiotics and mucolytics, the predicted median age of survival for a person with CF is 
approximately 40 years.4, 5 Progressive loss of lung function is the leading cause of mortality.6 
There are more than 2000 variants described in the CFTR gene. The most commonly seen 
variants that are clearly associated with CF have been identified (336 to date), but many rare 
cases remain uncharacterized.7  
Based on the understanding of the molecular defects caused by these CFTR mutations, 
2 complementary approaches have been developed to address the decreased quantity and/or 
function of CFTR in order to enhance chloride transport in patients with CF. Correctors facilitate 
the cellular processing and trafficking to increase the quantity of CFTR at the cell surface. 
Potentiators increase the channel-open probability of the CFTR protein delivered to the cell 
surface to enhance ion transport. Depending on the CFTR genotype of the patient, both 
approaches may be required to ameliorate lung disease in patients with CF.  
The therapeutic activity of CFTR correctors and potentiators has been established with products 
that were developed by Vertex and approved for the treatment of CF: ivacaftor (IVA) 
monotherapy (Kalydeco®), lumacaftor (LUM) in combination with IVA (Orkambi®), and 
tezacaftor (TEZ) in combination with IVA (Symdeko™, Symkevi®). Kalydeco, Orkambi, and 
Symdeko are approved to treat CF in patients with specific CFTR genotypes. TEZ and LUM are 
first-generation CFTR correctors that improve the processing and trafficking of mutated CFTR 
protein, resulting in an increase in the quantity of protein at the cell surface. IVA increases the 
open-channel probability of the mutated CFTR protein that has been delivered to the cell surface, 
thereby enhancing total chloride transport. For the most common CF-causing mutation, F508del, 
the combined effect of either LUM and IVA or TEZ and IVA is increased quantity and function 
of F508del-CFTR at the cell surface. 
VX-561 is a deuterated isotope of IVA with a specific pattern of 9 substituted deuteriums. In 
vitro data indicate similar potency of VX-561 in human bronchial epithelial (HBE) cells relative 
to IVA. Safety pharmacology and nonclinical toxicology studies of VX-561 demonstrate a 
similar safety profile relative to IVA. Phase 1 clinical studies in healthy subjects have shown that 
VX-561 had a reduced rate of clearance, increased exposure, greater plasma levels at 24 hours, 
and a longer half-life compared to IVA, thereby supporting once daily dosing (refer to VX-561 
Investigator’s Brochure). In healthy subject studies to date, the safety profile of VX-561 is 
considered similar to IVA. 


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5.2 
Study Rationale 
This study is being conducted to evaluate the efficacy and pharmacodynamic (PD) effect 
(i.e., change in sweat chloride) for a range of VX-561 doses to support VX-561 dose selection 
for future studies, including studies of VX-561 in triple combination (TC) with CFTR correctors, 
such as VX-121 and TEZ. Subjects will be on stable IVA treatment at baseline and will be 
randomized to study drug treatment groups on Day 1 (VX-561 or IVA). Change in ppFEV1 from 
IVA baseline is the primary endpoint. However, dose selection of VX-561 for future studies may 
consider the totality of data, including exposure-response analyses for efficacy (percent predicted 
forced expiratory volume in 1 second [ppFEV1]) and PD (sweat chloride) endpoints.  
6 
STUDY OBJECTIVES  
6.1 
Primary Objective 
 To evaluate the efficacy of VX-561  
6.2 
Secondary Objectives 
 To evaluate the PD effect of VX-561  
 To evaluate the pharmacokinetics (PK) of VX-561, IVA, and relevant metabolites  
 To evaluate the safety and tolerability of VX-561 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
 Absolute change in ppFEV1 from baseline at Week 12 
7.2 
Secondary Endpoints 
 Absolute change in sweat chloride concentrations from baseline at Week 12 
 PK parameters of VX-561, IVA, and relevant metabolites 
 Safety and tolerability, based on the assessment of adverse events (AEs), laboratory test 
results, standard 12-lead ECGs, vital signs, and pulse oximetry 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
8.1 
Inclusion Criteria 
1. Subject will sign and date an informed consent form (ICF).  
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures.  
3. Subjects (males and females) aged 18 years or older on the date of informed consent. 


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4. Receiving IVA treatment with no interruptions for at least 28 days before screening.  
5. Tolerating IVA therapy as judged by the investigator.  
6. Female subjects must have a negative pregnancy test at Screening. 
7. Body weight ≥35 kg. 
8. Subjects must be able to produce a valid (quantity-sufficient) sweat sample at screening. If 
the initial screening collection results in insufficient sweat volume, then the sweat chloride 
collection may be repeated.  
9. Confirmed diagnosis of CF as determined by the investigator. 
10. Has 1 of the following mutations in their CF gene: G551D, G1244E, G1349D, G178R, 
G551S, S1251N, S1255P, S549N, or S549R. If the screening CFTR genotype result is not 
received before randomization, a previous CFTR genotype laboratory report may be used to 
establish eligibility. Subjects who have been enrolled and whose screening genotype does not 
confirm study eligibility must be discontinued from the study (Section 9.9). 
11. Subjects must have a forced expiratory volume in 1 second (FEV1) ≥40% and ≤100% of 
predicted normal for age, sex, and height (equations of the Global Lung Function Initiative 
[GLI])8 at the Screening Visit. Spirometry measurements must meet American Thoracic 
Society/European Respiratory Society criteria9 for acceptability and repeatability. 
12. Stable CF disease as judged by the investigator.  
13. Willing to remain on a stable CF treatment regimen (other than protocol-specified changes in 
CFTR modulator regimen) through the Safety Follow-up Visit (Section 9.5). 
8.2 
Exclusion Criteria 
1. History of any comorbidity 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.  
2. History of clinically significant cirrhosis with or without portal hypertension. 
3. Any of the following abnormal laboratory values at screening: 
 Hemoglobin <10 g/dL 
 Total bilirubin ≥2 × upper limit of normal (ULN) 
 Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase 
(GGT), or alkaline phosphatase (ALP) ≥3 × ULN 
 Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 
(calculated by the Modification of Diet in Renal Disease Study Equation)10,11 for subjects 
≥18 years of age 
4. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy 
(including antibiotics) for sinopulmonary disease within 28 days before the first dose of 
study drug. 
5. Lung infection with organisms associated with a more rapid decline in pulmonary status 
(e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). For 


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subjects who have had a history of a positive culture, the investigator will apply the 
following criteria to establish whether the subject is free of infection with such organisms:  
 The subject has not had a respiratory tract culture positive for these organisms within the 
12 months before the date of informed consent. 
 The subject has had at least 2 respiratory tract cultures negative for such organisms 
within the 12 months before the date of informed consent, with the first and last of these 
separated by at least 3 months, and the most recent 1 within the 6 months before the date 
of informed consent. 
6. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of 
study drug. 
7. Standard 12-lead ECG demonstrating QTcF >450 msec at screening. If QTcF exceeds 
450 msec, the ECG will be repeated 2 more times, and the average of the 3 QTcF values will 
be used to determine the subject’s eligibility. 
8. History of solid organ or hematological transplantation. 
9. History of alcohol or drug abuse in the past year, including, but not limited to, cannabis, 
cocaine, and opiates, as deemed by the investigator. 
10. Ongoing or prior participation in a study of an investigational treatment with the exception of 
the following: 
 Ongoing or prior participation in an investigational study of a Vertex CFTR modulator. A 
washout period of 28 days must elapse before Day 1. 
 For prospective subjects with ongoing or prior participation in all other interventional 
studies, a washout period of 28 days or 5 terminal half-lives (whichever is longer) must 
elapse before screening. The duration of the elapsed time may be longer if required by 
local regulations. 
 Ongoing participation in a noninterventional study (including observational studies and 
studies requiring assessments without administration of study drug or assignment to other 
interventions) is permitted. 
11. Use of prohibited medications as defined in Table 9-1, within the specified window before 
the first dose of study drug. 
12. Pregnant or nursing female subjects. 
13. 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. However, an adult (aged 18 years or older) who is a relative of a study 
staff member may be enrolled in the study provided that: 
 the adult lives independently of and does not reside with the study staff member, and 
 the adult participates in the study at a site other than the site at which the family member 
is employed 


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9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 2 study of VX-561 monotherapy. A schematic of the study design is shown in 
Figure 9-1, which is randomized, double-blind, parallel-group, and active-controlled. The study 
will evaluate 4 dose levels of VX-561 in subjects with CF who have a gating mutation and were 
previously taking a stable dose of IVA. Randomization will be stratified by ppFEV1 value at 
screening (<70 versus ≥70). 
The original protocol included 25 mg once daily (qd) and 50 mg qd VX-561 treatment arms; 
both were discontinued in the current protocol (
).  
Figure 9-1 
VX18-561-101 Study Design 
 
a 
Approximately 88 subjects were planned to enroll in 5 treatment arms (25 mg qd VX-561, 50 mg qd VX-561, 
150 mg qd VX-561, 250 mg qd VX-561, and IVA 150 mg every 12 hours [q12h]) in a ratio of 1:2:2:2:1 under 
the original protocol. The 25 mg qd VX-561 and 50 mg qd VX-561 treatment arms were discontinued; 
44 subjects had been enrolled and randomized to the 5 treatment arms at this point. The remaining subjects 
planned to enroll will be randomized 2:2:1 to 3 treatment arms (250 mg qd VX-561, 150 mg qd VX-561, and 
IVA 150 mg q12h). 
9.1.1 
Screening 
Screening Visit assessments are listed in Table 3-1. 
The Screening Period will occur within 28 days before administration of study drug. Screening 
assessments will be used to confirm that subjects meet eligibility criteria. The investigator (or an 
appropriate authorized designee at the study site) will obtain informed consent from each subject 
before any study procedures takes place.  
9.1.1.1 
Repetition of Screening Assessment(s) 
Screening assessments may be repeated once to establish study eligibility. 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 be rescreened only once. If a subject is rescreened, all screening assessments will 
be repeated except for CFTR genotyping, follicle-stimulating hormone (FSH) level (if serum 
Treatment Period 
12 weeks 
Screening  
28 days 
Washout 
Period 
3-5 days 
VX-561 250 mg qd 
VX-561 150 mg qd 
VX-561 50 mg qd 
(treatment arm discontinued) 
IVA 150 mg q12h 
Enroll 
Subjects on 
Stable IVA 
Treatmenta 
Washout 
VX-561 
or 
IVA 
Resume IVA  
Safety Follow-up 
28 days after last 
dose 
VX-561 25 mg qd 
(treatment arm discontinued) 


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FSH level was ≥40 mIU/mL during prior screening), and sweat chloride level. If a subject is 
rescreened, the new screening window will begin once the first rescreening assessment has been 
initiated. 
9.1.1.3 
Extension of Screening Period Window 
The Screening Period window may be extended by 2 weeks for the following reasons: 
 Repetition of the Screening assessments (Section 9.1.1.1) 
 Unexpected operational or logistic delays, or to meet the eligibility criteria 
 Repetition of spirometry assessment if results are of poor quality 
9.1.2 
Treatment Period 
The Treatment Period will last approximately 12 weeks. Treatment Period assessments are listed 
in Table 3-1. Dosing details are in Section 9.6. 
9.1.3 
Washout Period 
The Washout Period will last approximately 4 days. 
The study visits during the Washout Period will occur as shown in Table 3-1. 
9.1.4 
Follow-up 
Subjects will have a Safety Follow-up Visit 28 (± 7) days after the last dose of study drug. Safety 
Follow-up Visit assessments are listed in Table 3-1. 
9.1.5 
Early Termination of Treatment OR Early Discontinuation 
If a subject prematurely discontinues study treatment, an Early Termination of Treatment (ETT) 
Visit should be scheduled as soon as possible after the subject decides to terminate study 
treatment. Subjects who prematurely discontinue treatment will also be required to complete the 
Safety Follow-up Visit, approximately 28 (± 7) days after their last dose of study drug. The 
assessments performed at the Safety Follow-up Visit are listed in Table 3-1. 
Subjects who discontinue from study drug dosing for any reason (except withdrawal of consent) 
will have a final PK blood sample drawn as soon as possible after the decision to discontinue 
study drug is made. Additional safety assessments may also be performed at the discretion of the 
investigator, including possible consultation with a specialist consultant. The Vertex medical 
monitor will be informed about these additional assessments, and any additional data collected 
(e.g., as the result of an outside consultation) will be considered part of the study record to 
provide the most complete safety profile of the study drug. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required.  
If a subject withdraws consent for the study, no further assessments will be performed, and no 
additional data should be collected. Vertex may retain and continue to use any data and samples 
collected before such withdrawal of consent. 


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9.1.6 
Lost to Follow-up 
A subject will be considered lost to follow-up if both of the following occur: 
 The subject misses 2 consecutive study visits (telephone contact and/or clinic visit) and is 
subsequently unable to be contacted by telephone (3 documented attempts by telephone 
within 2 weeks following the second missed visit). 
 The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 
9.1.7 
Independent Data Monitoring Committee 
Safety and tolerability data will be reviewed by an independent data monitoring committee 
(IDMC) to ensure the safety of the subjects (Section 12.3.6). Procedural details of the IDMC’s 
structure and function, frequency of meetings, and data planned for review will be in the IDMC 
charter. The IDMC charter will be finalized before the first subject is screened.  
9.2 
Method of Assigning Subjects to Treatment Groups 
An interactive web response system (IWRS) will be used to assign subjects to treatment. A 
randomization list will be produced by Vertex Biostatistics or a qualified randomization vendor. 
The Vertex study biostatistician will review and approve the dummy randomization list. The 
final randomization list will be reviewed and approved by a designated unblinded biostatistician 
who is not a member of the study execution team (SET). 
Subjects will be assigned a unique subject number. Only subjects who have completed screening 
assessments and are eligible for participation in the study will be randomized to receive study 
drug during the Treatment Period. Randomization will be stratified by ppFEV1 (<70 versus ≥70) 
determined during screening.  
Approximately 88 subjects were planned to enroll in 5 treatment arms (25 mg qd VX-561, 50 mg 
qd VX-561, 150 mg qd VX-561, 250 mg qd VX-561, and IVA 150 mg q12h) in a ratio of 
1:2:2:2:1 under the original protocol. The 25 mg qd VX-561 and 50 mg qd VX-561 treatment 
arms were discontinued; 44 subjects had been enrolled and randomized to the 5 treatment arms at 
this point. The remaining subjects planned to enroll will be randomized 2:2:1 to 3 treatment arms 
(250 mg qd VX-561, 150 mg qd VX-561, and IVA 150 mg q12h).  
9.3 
Rationale for Study Elements 
9.3.1 
Study Design 
Subjects will continue their stable IVA treatment through screening, and then be randomized to 
study drug treatment groups on Day 1 (VX-561 or IVA). The efficacy and PD of VX-561 will be 
assessed after 12 weeks of randomized treatment. IVA (150 mg every 12 hours [q12h]) is 
included as a reference arm, but with unequal randomization to provide greater information on 
VX-561 dose-ranging. After the Treatment Period, a 3- to 5-day Washout Period where subjects 
will take no CFTR modulators is included to collect additional PK and PD data and enable a 
more thorough evaluation of VX-561 exposure-response relationships.  
Following completion of the Washout Period, subjects will resume their prior therapy with 
commercial IVA. 


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9.3.2 
Study Population 
The study will enroll subjects with CF with a gating mutation (see Section 8.1) to ensure a 
relatively homogenous population to evaluate the efficacy, PK, and PD of VX-561 across a range 
of doses relative to IVA.  
9.3.3 
Study Drug Dose and Duration 
VX-561 
Four dose levels of VX-561 will be evaluated to provide a broad range of exposure for 
exposure-response analyses. The original protocol included 25 mg qd VX-561 and 50 mg qd 
VX-561 treatment arms; both treatment arms were discontinued in the current protocol 
 
. A VX-561 dose regimen of 150 mg qd provides exposure 
similar to IVA 150 mg q12h, including Cmax, AUC0-24h, and Ctrough. Based on the similarity of 
VX-561 and IVA in vitro potency and efficacy in HBE cells, this dose is predicted to provide the 
same effect as IVA on CFTR potentiation, and thus is also expected to result in a similar PD (i.e., 
sweat chloride) and efficacy (i.e., ppFEV1) response. The 250 mg qd dose of VX-561 is included 
to provide a range of exposures to enable a more robust exposure-response analysis.  
The 12-week treatment duration is considered sufficient to avoid any carryover of the efficacy or 
PD effect from stable IVA treatment and avoid the need for an extended washout of IVA before 
the start of the Treatment Period. 
IVA 
The IVA dose regimen of 150 mg q12h is the approved regimen for treatment of CF in subjects 
aged 6 years and older who have 1 mutation in the CFTR gene that is responsive to IVA based 
on clinical and/or in vitro assay data. 
9.3.4 
Rationale for Study Assessments 
The PK assessments and safety assessments are standard measurements for clinical studies in 
drug development.  
The PD and efficacy endpoints being evaluated (sweat chloride and spirometry) are widely 
accepted and generally recognized as reliable, accurate, and relevant to the study of individuals 
with CF. Sweat chloride was evaluated in the registration study of IVA (Kalydeco), and 
spirometry was evaluated in the registration studies of IVA (Kalydeco) and LUM/IVA 
combination therapy (Orkambi). 
9.4 
Study Restrictions 
Study restrictions are summarized in Table 9-1. VX-561 and IVA are metabolized extensively 
via CYP3A. Therefore, use of moderate and strong inducers or inhibitors of CYP3A, which have 
the potential to alter the exposure of VX-561 or IVA will be prohibited.  
A non-exhaustive list of study prohibitions and cautions for medication will be provided in the 
Study Reference Manual. 


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Table 9-1 
Study Restrictions 
Restricted 
Medication/Food/Activity a 
Timing of Restriction 
Start 
Stop 
Moderate and strong CYP3A 
inducers or inhibitors (except 
ciprofloxacin), including 
grapefruit or grapefruit juice 
None allowed within 14 days before 
the first dose of study drug 
None allowed through the Safety 
Follow-up Visit 
CFTR modulators other than 
study drug (e.g., Symdeko/ 
Symkevi)  
None allowed within 28 days before 
first dose of study drug 
None allowed through the Safety 
Follow-up Visit 
a 
See Section 9.5 for guidance on concomitant medications. 
9.5 
Prior and Concomitant Medications 
Subjects will abstain from all concomitant medications as described in the exclusion criteria 
(Section 8.2) and Study Restrictions (Table 9-1). 
All medications taken from 28 days before the Screening Period through the end of the study will 
be recorded with indication, route of administration, and start and stop dates of administration. 
All subjects will be questioned about medications from signing of the ICF through the Safety 
Follow-up Visit. 
 Subjects must remain on a stable CF medication (and supplement) regimen (other than 
protocol-specified changes in CFTR modulator regimen) for their CF from 28 days before 
the Day 1 Visit through the Safety Follow-up Visit. Stable CF medication regimen is defined 
as the current medication regimen for CF that subjects have been following for at least 
28 days before the Day 1 Visit. Subjects must not initiate long-term treatment with new 
medication from 28 days before the Day 1 Visit through the Safety Follow-up Visit unless 
discussed and approved by the medical monitor.  
 Subjects may receive doses of prednisone or prednisolone of up to 10 mg/day or equivalent 
(chronically), or prednisone or prednisolone 60 mg/day for up to 5 days, without prior 
approval of the medical monitor. 
 Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments performed 
according to the guidelines provided in Section 11.4. 
9.6 
Administration 
Study drug will be administered orally twice daily. Subjects will receive the same number of 
tablets each day to maintain the blind. Additional information is provided in the Pharmacy 
Manual. 
Study drug will be administered with a fat-containing meal or snack, consistent with the 
recommendations for administration of Kalydeco12, according to the following guidelines: 
 It is recommended that the dose be taken within 30 minutes of the start of the meal or snack. 
 All study drug doses will be administered q12h to maintain the blind. All doses of study drug 
will be taken at approximately the same time each day. For example, the morning dose could 


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be taken at 08:00 every morning and the evening dose could be taken at 20:00 every evening 
throughout the study. 
 The date, amount taken, and time of study drug administration, including whether food was 
taken with each dose, will be recorded for the 2 doses before PK sample collection and the 
dose received on the morning of PK sample collection. 
 On days of scheduled visits, the morning dose of study drug will be administered at the site 
after predose assessments have been completed. The meal or snack will be provided by the 
site for the morning dose of study drug.  
 A subject’s morning dose can be delayed by up to 6 hours to accommodate predose 
assessments on clinic visit days. 
 For visits after the Day 1 Visit, 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. 
Missed Doses 
 If a subject misses a dose and recalls the missed dose within 6 hours, the subject should take 
the dose with food. If more than 6 hours have elapsed after the usual dosing time, the subject 
should skip that dose and resume the normal schedule for the following dose. 
9.7 
Dose Modification for Toxicity 
If any unacceptable toxicity arises, individual subjects will discontinue dosing (Section 9.1.5). 
No dose modifications for toxicity are allowed. 
9.8 
Study Drug Interruption and Stopping Rules 
The medical monitor should be notified of a discontinuation of study drug or an interruption of 
study drug that lasts >72 hours for any reason and of the resumption of study drug after such 
interruption. 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, or total bilirubin 
>2 × ULN, must be followed closely, including confirmatory testing performed by the central 
laboratory within 48 to 72 hours of the initial finding and subsequent close monitoring of ALT, 
AST, and bilirubin levels, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results 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). 
Study drug administration must be interrupted immediately (prior to confirmatory testing) if 
any of the following criteria are met: 
 ALT or AST >8 × ULN 
 ALT or AST >5 × ULN for more than 2 weeks 
 ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical 
jaundice 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression.  


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Study drug administration must be discontinued if subsequent ALT or AST values confirm the 
initial elevation that satisfied the interruption rule (above), and no convincing alternative 
etiology (e.g., acetaminophen use, viral hepatitis, alcohol ingestion) is identified, regardless of 
whether transaminase levels have improved. 
All subjects in whom treatment is discontinued for elevated transaminases and/or bilirubin 
should have these levels monitored closely until levels normalize or return to baseline. 
If an alternative, reversible cause of transaminase elevation and/or increased bilirubin or clinical 
jaundice has been identified, study drug administration may be resumed once transaminases or 
bilirubin return to baseline or are ≤2 × ULN, whichever is higher. Regardless of the duration of 
interruption, the medical monitor should be notified prior to resumption of study drug. Upon 
resumption of study drug, transaminases and bilirubin should be assessed weekly until the Safety 
Follow-up Visit. If a protocol-defined transaminase or bilirubin elevation interruption threshold 
recurs with 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. 
Individuals who develop adverse events (AEs) will be monitored closely; consideration should 
be given to the need for additional safety assessments and possible consultation (e.g., with a 
dermatologist, GI specialist, or other specialist consultant). Any additional data collected (e.g., as 
a result of an outside consultation) will be considered part of the study record to provide the most 
complete safety profile of the study drug. 
9.9 
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. A subject 
who withdraws from study drug treatment will continue to be followed unless the subject 
withdraws consent.  
Subjects who discontinue study treatment early should continue to return for study assessments, 
as noted in Section 9.1.5.  
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 9.1.5), and follow up with the subject regarding any unresolved AEs. 
Subjects who have been enrolled and whose screening CFTR genotype does not confirm study 
eligibility must be discontinued from the study, even if a previous CFTR genotype laboratory 
report was used to establish eligibility. 
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends, and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study, the study data and samples collected will remain part of the study. A subject will 
not be able to request the withdrawal of his/her information from the study data. A subject may 


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request destruction of the samples collected from him/her during the study as long as those 
samples can be identified as his/her samples. 
Stopping rules are presented in Section 9.8. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period(s) may be replaced at Vertex’s discretion. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
Study drug refers to VX-561, IVA, and their matching placebos. 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
10.2 
Packaging and Labeling 
Study drug tablets will be supplied in blister cards by Vertex. 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 
The investigator, or an authorized designee (e.g., a licensed pharmacist), will ensure that all 
investigational product is stored in a secured area, under recommended storage conditions, and in 
accordance with applicable regulatory requirements. To ensure adequate records, all study drugs 
will be accounted for via the drug accountability forms as instructed by Vertex. 
VX-561 and matching placebo will be supplied as light blue film-coated tablets of similar size 
and appearance containing 50 mg VX-561, 25 mg VX-561, and 0 mg VX-561, respectively. 
Following discontinuation of the 25 mg qd VX-561 treatment arm, the 25 mg VX-561 tablet and 
matching placebo will no longer be distributed to subjects. 
IVA and matching placebo will be supplied as light blue film-coated tablets of similar size and 
appearance containing 150 mg IVA and 0 mg IVA, respectively. 
Detailed instructions regarding the storage, handling, and dispensation of the study drug will be 
provided in the Pharmacy Manual. 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information about the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee. The study monitor will review study drug 
records and inventory throughout the study.  
If a site uses a site-specific drug accountability system and/or process, including processes 
associated with the destruction of returned materials, the process must be documented and 
approved by Vertex. The study monitor must review the drug accountability documentation on a 


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regular basis. The study monitor will promptly communicate to Vertex any discrepancies he/she 
is unable to resolve with the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The 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. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count.   
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should consider discontinuing the subject from the study.  
10.7 
Blinding and Unblinding 
This will be a double-blind study. 
10.7.1 
Blinding  
All subjects, site personnel (including the investigator, the site monitor, and the study team), and 
the Vertex study team will be blinded to the treatment codes with the exception of the following:  
 Any site personnel for whom this information is important to ensure the safety of the subject 
in the event of a life-threatening medical emergency 
 Any site personnel for whom this information is important to ensure the safety of the subject 
or the male subject’s partner and her fetus in the event of a pregnancy 
 Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy serious 
adverse event (SAE) processing and reporting regulations 
 Vendor preparing the final (production) randomization list who is not part of the study team 
 Vertex IWRS Manager 
 Vertex Clinical Supply Chain 
 IDMC 
 Vendor performing the unblinded analysis of safety data for the IDMC  
 Bioanalytical contract research organization (CRO) analyzing PK samples and Vertex 
Bioanalytical personnel who are not members of the SET but review raw data from the 
Bioanalytical CRO. The Vertex Bioanalytical SET member will continue to be blinded. 
 Vertex Modeling and Simulation personnel or vendor conducting the population PK and 
PK/PD analyses 


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 Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time   
 Vertex Quality Assurance, for the purposes of any audit or event investigations 
Sweat Chloride and Spirometry Blinding:  
 During the conduct of the study, the Vertex study team will not have access to the spirometry 
results after the morning dose on the Day 1 Visit.  
 Sites, subjects, and their parents/caregivers/companions should not be informed of their 
study-related sweat chloride results during the Treatment Period regardless of whether the 
subject has prematurely discontinued treatment. Sites are blinded to sweat chloride results to 
ensure the study blind in maintained. 
 Subjects and their parents/caregivers/companions should not be informed of their 
study-related spirometry results during the Treatment Period regardless of whether the 
subject has prematurely discontinued treatment. 
A limited Vertex team (non-study members) may be unblinded and have access to safety, PD, 
and efficacy data for the purpose of conducting ongoing data reviews for planning and enabling 
clinical development, regulatory, and chemistry, manufacturing, and controls (CMC) decisions.  
10.7.2 
Unblinding 
At the initiation of the study, study site personnel will be instructed on the method for breaking 
the blind. The unblinding method will be either manual or electronic. 
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 unblinding. 
If investigators deem it unnecessary to unblind immediately, they will first attempt to contact the 
medical monitor to discuss 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. 
Contact information for the medical monitor (or appropriate backup) will be in a separate 
document. 
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 Vertex, the 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, unblind individual 
subjects at any time.  


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11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1.  
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 
11.2 
Pharmacokinetics 
11.2.1 
Blood Sampling 
For the evaluation of plasma concentrations of VX-561 and IVA, blood samples will be collected 
from all subjects according to Table 3-1. These samples may also be used for evaluations of 
metabolites of VX-561 or IVA, for further evaluation of the bioanalytical method, and for 
analyses that provide information on the metabolic pathways used or impacted by VX-561 or 
IVA. 
All efforts should be made to obtain the PK samples at the exact nominal time relative to dosing. 
Acceptable windows for sampling times are shown in Table 11-1. Samples collected outside of 
these acceptable windows will be considered protocol deviations. The exact time of the sample 
collection will be noted. 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Sampling Time 
Time From Scheduled Sampling Allowed 
Predose 
Within 60 minutes before dosing 
Post-dose, up to 6 hours after study drug dosing 
± 15 minutes 
 
11.2.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be provided in the PK Sample Handling Guideline.  
11.2.3 
Bioanalysis 
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee standard operating procedures. A description of the assay and validation data will be 
provided in separate reports. 
11.3 
Pharmacodynamics: Sweat Chloride 
Collection of sweat samples will be performed using an approved collection device. 
Each collection will occur before study drug dosing. At each time point, 2 samples will be 
collected, 1 from each arm (left and right). Additionally, sweat collections will be performed on 
any single day during screening.  
Sweat samples will be sent to a central laboratory for testing and interpretation of results. Sweat 
chloride results for individual subjects will not be disclosed to the study sites. 
Specific instructions for collection, handling, processing, and shipping of sweat chloride samples 
to the central laboratory will be provided in a separate Laboratory Manual. 


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See Section 10.7.1 for information about blinding of sweat chloride results. 
11.4 
Efficacy: Spirometry  
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines.9 
Spirometry will be performed as outlined below: 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
 withheld their short-acting bronchodilators (e.g., albuterol and ipratropium bromide 
[Atrovent®]) for more than 4 hours before the spirometry assessment; 
 withheld their twice daily, long-acting bronchodilator (e.g., salmeterol) for more than 
12 hours before the spirometry assessment; and 
 withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilator. At all other visits, all spirometry assessments should be performed 
“pre-bronchodilator”. During the Treatment Period, spirometry assessments must be performed 
before the morning dose of study drug at approximately the same time at each visit.  
In the event that a subject forgets to withhold bronchodilator(s), spirometry should be performed 
according to the following: 
 If a subject’s Day 1 Visit spirometry assessment is pre-bronchodilator but, on a subsequent 
visit, the subject forgets to withhold bronchodilator use, a post-bronchodilator spirometry 
assessment will be obtained for that visit only, and the visit will not be rescheduled. 
 If, on the Day 1 Visit, the subject forgets to withhold his/her dose of bronchodilator, 
spirometry should be performed post-bronchodilator, and all subsequent spirometric 
measurements (according to the schedule of assessments detailed in Table 3-1) should be 
performed post-bronchodilator. 
 Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator. 
If more than 1 spirometry assessment is required at a visit, bronchodilators will be withheld until 
completion of the last scheduled spirometry assessment. 
All sites will be provided with spirometers to be used for all study assessments. Spirometry data 
will be transmitted to a centralized spirometry service for quality review. The investigator's 
assessment of the spirometry results will be used for the screening assessment and determination 
of eligibility.  
See Section 10.7.1 for information about blinding of spirometry results. 
11.5 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, physical examinations (PEs), and pulse oximetry. 


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11.5.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP Guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE case report form 
(CRF) completion guidelines for investigators as well as training will be provided. 
11.5.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, with the exception of the urine 
pregnancy tests, which will be performed at the site. Blood and urine samples for clinical 
laboratory assessments will be collected as shown in Section 3.  
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 11-2. 
Table 11-2 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Total bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate transaminase 
Alanine transaminase 
Amylase  
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase  
Hemoglobin  
Hematocrit 
Erythrocytes 
Mean corpuscular volume 
Platelets  
Reticulocytes  
Leukocytes  
Differential (absolute and percent): 
Eosinophils 
Basophils  
Neutrophils 
Lymphocytes 
Monocytes  
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
Leukocyte esterase  
Nitrite  
Urobilinogen  
Urine protein  
pH 
Urine blood  
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose  
Note: Glomerular filtration rate will be calculated by the Modification of Diet in Renal Disease Study Equation for 
subjects ≥18 years of age (Section 8.2). 
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be done, and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
b 
If blood urea nitrogen cannot be collected, urea may be substituted. 
 
Additional Tests at Screening: The following additional tests will be performed during screening 
to assess eligibility:  
 Serum beta-human chorionic gonadotropin (β-hCG) for all female subjects  


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 Serum follicle-stimulating hormone (FSH) for suspected postmenopausal female subjects 
only. Levels will be within the laboratories range for postmenopausal for subjects to be 
considered of non-childbearing potential. 
Pregnancy Testing (Female Subjects of Childbearing Potential): 
 Serum and urine β-hCG as described in Table 3-1. 
The pregnancy test at screening and Day 1 must be negative before receiving the first dose of 
study drug. 
If a urine pregnancy test is positive, the pregnancy will be confirmed with a serum β-hCG test. If 
pregnancy is confirmed, the procedures outlined in Section 11.5.5.2 will be followed. 
CFTR Genotype: CFTR genotyping will be performed for all subjects (Sections 8.1 and 9.9). 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 
becomes aware of the abnormal result. If it is not possible to send a timely specimen to the 
central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base the 
assessment of an AE on the local laboratory value. 
11.5.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits. At other visits, symptom-directed PEs and symptom-directed vital signs assessments 
can be performed at the discretion of the investigator or healthcare provider. 
A PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, nose, and 
throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs. 
The abbreviated PE will include an assessment of the following body systems: head, neck, and 
thyroid; EENT; cardiovascular system; respiratory system; skin; and abdomen. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed.  
11.5.4 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines: 
 The subject will be instructed to rest for at least 5 minutes before having an ECG. 
 The test should be performed in the supine position 


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A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. Clinically significant ECG abnormalities occurring during the study 
through the Safety Follow-up Visit will be recorded as AEs.  
See Section 8.2 for information about the ECG assessment for study eligibility. 
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. Further details 
pertaining to ECGs will be provided to sites in the ECG Manual.  
11.5.5 
Contraception and Pregnancy 
11.5.5.1 
Contraception 
Study participation requires compliance with the contraception guidelines outlined below. 
Contraception for the couple is waived for the following: 
 True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. True abstinence must 
be practiced from the Screening Visit through 90 days after the last dose of study drug. 
 If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the first 
dose of study drug (e.g., examination of a semen specimen or by demonstration of the 
absence of the vas deferens by ultrasound). 
 If the female is of non-childbearing potential. To be considered of non-childbearing potential, 
the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH level 
within the laboratory’s reference range for postmenopausal females. 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy. 
Note: All other females (including females with tubal ligations and females who do not have 
a documented bilateral oophorectomy) will be considered to be of childbearing potential. 
 Same sex relationships. 
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used as a couple. Acceptable methods of contraception are listed in Table 11-3.  


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Table 11-3 
Acceptable Methods of Contraception 
Method 
Male Subjects and 
Their Female 
(Non-study) Partners 
Female Subjects and 
Their Male 
(Non-study) Partners 
Vasectomy 6 months or more previously, with a documented 
negative postvasectomy semen analysis for sperm 
Yes 
Yes 
Documented tubal ligation 4 weeks or more previously 
Yes 
Yes 
Male or female condom with or without spermicidea 
Yes 
Yes 
Female barrier contraception (such as diaphragm, cervical 
cap, or sponge) with spermicide 
Yes 
Yes 
Continuous use of an intrauterine device for at least 90 days 
before the first dose of study drug. 
 
 
 Hormone-releasing 
Yes 
Yes 
 Non-hormone releasing 
Yes 
Yes 
Hormonal methods of contraception (oral or patch), if 
successfully used for at least 60 days before the first dose of 
study drug 
Yes 
Yes 
Note: At least 1 acceptable method of contraception must be used by couples not exempt from the contraception 
requirement. Methods of contraception must be in successful use from signing of consent, approximately 28 days 
before the first dose of study drug (unless otherwise noted), and until 90 days following the last dose of study drug. 
Additional contraception requirements may need to be followed according to local regulations and/or requirements. 
a 
A female condom cannot be used with a male condom due to risk of tearing. 
 
Additional notes: 
 Male and female subjects who are not sexually active at the time of screening must agree to 
follow the contraceptive requirements of this study if they become sexually active with a 
partner of the opposite sex. 
 Male subjects must not donate sperm from signing consent, throughout the study, and for 
90 days following the last dose of study drug. 
 Female subjects and female partners of male subjects should not plan to become pregnant 
from signing consent through 90 days following the last dose of study drug. For male 
subjects with a female partner of childbearing potential, the couple should not plan to 
become pregnant during the study or within 90 days after the last dose of study drug, with the 
exception of couples who plan to become pregnant by artificial insemination using sperm 
banked by the male subject before the first dose of study drug or sperm from another source. 
 Male subjects whose female partner becomes pregnant through well-documented in vitro 
fertilization (donated sperm) or banked sperm (collected before the subject received study 
drug), or is otherwise already pregnant before the male subject’s first dose of study drug, 
must be compliant with the contraception requirements. In this scenario, the male subject and 
his female partner must commit to using a male condom (to ensure there is no exposure of 
the fetus to study drug) from signing consent through 90 days after the last dose of study 
drug. 
 Female subjects should not nurse a child from signing consent through 90 days following the 
last dose of study drug. 


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 Unique situations that may not fall within the above specifications may be discussed with the 
Vertex medical monitor or authorized designee on an individual basis. 
11.5.5.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a subject, or the female partner of a male subject, becomes pregnant while participating in the 
study, the study drug will be permanently discontinued immediately. The investigator will 
1) notify the medical monitor and Vertex GPS within 24 hours of the site’s knowledge of the 
subject’s (or partner’s) pregnancy, and 2) send the Pregnancy Information Collection Form to 
Vertex GPS. 
A subject (or their partner, if relevant) who becomes pregnant while on study will be followed 
until the end of the pregnancy only if on blinded treatment, or if they have been unblinded and 
have received active drug. The infant will be followed for 1 year after birth, provided informed 
consent is obtained. A separate ICF will be provided to explain these follow-up activities. 
Pregnancy itself is not an AE.  
12 
STATISTICAL AND ANALYTICAL PLANS 
This section presents a summary of the planned analyses of safety, efficacy, and clinical 
pharmacology results. Statistical analysis details on safety and efficacy will be provided in the 
statistical analysis plan (SAP), clinical pharmacologic analysis details will be provided in the 
clinical pharmacology analysis plan (CPAP), and population PK-PD analysis details will be 
provided in the Modeling and Simulation Plan, all of which will be finalized before clinical 
database lock. 
Final analyses will take place after all subjects have completed the study, all data have been 
entered in the clinical study database, and the database has been locked. 
12.1 
Sample Size and Power 
The primary objective is to evaluate efficacy of VX-561. The primary efficacy endpoint is the 
absolute change in ppFEV1 from baseline at Week 12. Based on the initial study design that 
included 4 dose groups of VX-561 and an IVA 150 mg q12h dose group, assuming a 
within-group SD of 7 percentage points and a 10% dropout rate at Week 12: a sample size of 
22 subjects in the 50, 150, and 250 mg qd VX-561 arms will provide a 95% CI of 
± 3.4 percentage points around the observed mean absolute change in ppFEV1 from baseline at 
Week 12, based on 2-sided, 1-sample t statistics; a sample size of 11 subjects in the other arms 
will provide a 95% CI of ± 5.4 percentage points around the observed mean.  
Following discontinuation of the 25 mg qd VX-561 and 50 mg qd VX-561 treatment arms, the 
remaining subjects planned to enroll will be randomized in a 2:2:1 ratio to the 3 current treatment 
arms with a sample size of approximately 28 subjects for the 250 mg qd VX-561 treatment arm, 
approximately 28 subjects for the 150 mg qd VX-561 treatment arm, and approximately 
14 subjects for the IVA 150 mg q12h treatment arm. The total study sample size including 
discontinued arms and current arms is approximately maintained as planned (N = 88). Under the 
same assumption as the original design (within-group SD of 7 percentage points and 10% 
dropout rate at Week 12): a sample size of 28 subjects in the 250 mg qd VX-561 and 150 mg qd 


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VX-561 arms will provide a 95% CI of ± 2.9 percentage points around the observed mean 
absolute change in ppFEV1 from baseline at Week 12, based on 2-sided, 1-sample t statistics; a 
sample size of 14 subjects in the IVA 150 mg q12h arm will provide a 95% CI 
of ± 4.4 percentage points around the observed mean. 
12.2 
Analysis Sets 
The study will include the following analysis sets: 
 The All Subjects Set is defined as all subjects who were randomized or received at least 1 
dose of study drug. The All Subjects Set will be used for individual subject data listings and 
disposition summary tables, unless otherwise specified. 
 The Full Analysis Set (FAS) will include all randomized subjects who carry the intended 
CFTR allele mutation and have received at least 1 dose of study drug in the Treatment 
Period. The FAS will be used for all PD and efficacy analyses in which subjects will be 
analyzed according to their randomized treatment group, unless otherwise specified. 
 The Safety Set will include all subjects who received at least 1 dose of study drug. All safety 
and study drug exposure will be summarized for the Safety Set. 
 The PK Set will include all subjects who received at least 1 dose of study drug and for whom 
the primary PK data are considered sufficient and interpretable. 
12.3 
Statistical Analysis 
This section summarizes the statistical analysis of safety and efficacy data. The Vertex 
Biometrics Department or designee will analyze the safety and efficacy data. Methodological 
and related details will be in the SAP. 
12.3.1 
General Considerations 
The precision standards for reporting safety and efficacy variables are provided in an internal 
Biometrics document that specifies the programming rules, including the precision for derived 
variables. 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). 
Categorical variables will be summarized using counts and percentages. 
Baseline value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug. For ECG, 
baseline will be defined as the most recent pretreatment measurement (or the average of triplicate 
measurements, if the most recent pretreatment measurement is obtained in triplicate) before the 
first dose of study drug. Further details on baseline definition will be provided in SAP. 
Absolute change from baseline will be calculated as Post-baseline value − Baseline value. 
Relative change from baseline will be calculated and expressed in percentage as 
100% × (Post-baseline value − Baseline value)/Baseline value. 
Treatment-emergent (TE) Period will include the time period starting from the date of the first 
dose of study drug to 28 days after the last dose date of study drug taken in the treatment period, 


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or the completion date of study participation, whichever comes earlier. The TE Period will be 
used for safety analyses unless specified otherwise. 
Visit windowing rules: The analysis visit windows for protocol-defined visits will be in the 
SAP. 
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
The number of subjects in each category (including All Subjects Set, Randomized, FAS, Safety 
Set) will be summarized overall and by treatment group.  
The number and percent (based on the FAS) of subjects in each disposition category (including 
completed treatment, completed study, and discontinued treatment or study with a breakdown of 
the reasons for discontinuation) will be summarized overall and by treatment group. 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. A randomization listing of subjects will be provided. 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographics, medical history, and baseline characteristics will be summarized overall and by 
treatment group based on the FAS. No statistical tests will be done to evaluate baseline 
imbalances between groups.  
Demographic and baseline characteristics will include, but are not limited to age (in years), sex, 
ethnicity, race, weight (kg), height (cm), body mass index (BMI, in kg/m2), baseline ppFEV1, 
and baseline sweat chloride. 
Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT). 
12.3.2.3 
Prior and Concomitant Medications 
Medications used will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) and categorized as the following: 
Prior medication: any medication that started before the date of the first dose of study drug, 
regardless of when the medication ended. 
Concomitant medication: medication continued or newly received on or after the date of the 
first dose of study drug through the end of the TE Period. 
Post-treatment medication:medication continued or newly received after the TE Period. 
A given medication may be classified as a prior, concomitant medication, or post-treatment 
medication; both prior and concomitant; both concomitant and post-treatment; or prior, 
concomitant, and post-treatment. If a medication has a missing or partially missing start/end date 
or time and if it cannot be determined whether it was taken before the first dose of study drug, 
concomitantly during the TE Period, or after the TE Period, it will be considered in all 
3 categories of prior, concomitant, and post-treatment medication. 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by Preferred Name based on the FAS. Post-treatment medications will be 
provided separately in an individual subject data listing. 


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Details for imputing missing or partial start and/or stop dates of medication will be in the SAP. 
12.3.2.4 
Study Drug Exposure and Compliance 
Study drug exposure will be summarized overall and by treatment, based on the Safety Set in 
terms of duration of treatment a subject received (in days), defined as: last dose date – first dose 
date + 1 day, regardless of study drug interruption.  
Study drug compliance will be summarized overall and by treatment group based on the FAS, 
and will be calculated as: 100  [1 − (total number of days of study drug interruption)/(duration 
of study drug exposure in days)]. 
In addition, percentage of tablets taken will also be summarized overall and by treatment group 
based on the FAS, and will be calculated as: 100  [(total number of tablets dispensed) – (total 
number of tablets returned)]/(total number of tablets planned to be taken per day  duration of 
study drug exposure in days).  
12.3.3 
Efficacy and Pharmacodynamic Analyses 
All efficacy and PD analyses described in this section will be based on the FAS, unless specified 
otherwise. 
12.3.3.1 
Efficacy: Spirometry 
The efficacy data from the discontinued arms (25 mg qd VX-561 and 50 mg qd VX-561) will not 
be included in the model and will be summarized descriptively. 
The primary efficacy endpoint is the absolute change in ppFEV1 from baseline at Week 12. The 
primary analysis (described below) is based on the within group mean of absolute change from 
baseline for 250 mg qd VX-561, 150 mg qd VX-561, and IVA 150 mg q12h treatment arms. 
The primary analysis will be based on a mixed effects model for repeated measures (MMRM) 
using restricted maximum likelihood. The model will include the absolute change from baseline 
in ppFEV1 at Day 15, Week 4, Week 8, and Week 12 from the current treatment arms (250 mg 
qd VX-561, 150 mg qd VX-561, and IVA 150 mg q12h) as the dependent variable; treatment 
group, visit, and treatment by visit as fixed effects; with continuous baseline ppFEV1 as 
covariates; and an unstructured covariance structure for the within-subject errors. If the model 
estimation does not converge, a compound symmetry covariance structure will be used. 
The primary results obtained from the model will be the within-group treatment effect estimate at 
Week 12 for each treatment arm. The adjusted mean with a 2-sided 95% CI will be presented in 
a table. 
In addition, the adjusted mean and 95% CI of the treatment effect difference between each 
VX-561 arm and the IVA arm obtained from the MMRM model will be provided.  
12.3.3.2 
Pharmacodynamics: Sweat Chloride  
The secondary endpoint is the absolute change from baseline in sweat chloride at Week 12 and 
will be analyzed similarly to ppFEV1 for 250 mg qd VX-561, 150 mg qd VX-561, and IVA 
150 mg q12h treatment arms. Adjusted means and 95% CIs of the average treatment effects at 
Week 12 will be obtained for within-group (for each arm) and between-group comparisons 
(between each VX-561 arm and the IVA arm). Details will be provided in the SAP. 


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12.3.4 
Safety Analysis 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
 AEs 
 Clinical laboratory values (hematology, serum chemistry, coagulation studies, and urinalysis) 
 Standard 12-lead ECGs 
 Vital signs  
 Pulse oximetry 
Safety endpoints will be analyzed based on the Safety Set (including the 25 mg qd VX-561 and 
50 mg qd VX-561 treatment arms that were discontinued). Only a descriptive analysis of safety 
will be performed.  
All safety data from the TE period will be summarized by treatment group and overall. All safety 
data will be presented in individual subject data listings.  
12.3.4.1 
Adverse Events 
AEs will be classified as pretreatment AEs, treatment-emergent adverse events (TEAEs), or post-
treatment AEs defined as follows:  
Pretreatment AE: any AE that started before the first dose date of study drug. 
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed on 
or after the first dose date of study drug through the end of the TE Period.  
Post-treatment AE: any AE that worsened or that was newly developed beyond the TE Period. 
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of AEs are in the SAP. 
AE summary tables will be presented for TEAEs only, overall and by treatment group, and will 
include the following: 
 All TEAEs 
 TEAEs by strongest relationship  
 TEAEs by maximum severity 
 TEAEs leading to treatment discontinuation 
 Serious TEAEs 
 TEAEs leading to death 


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Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same AE or a 
continuing AE will be counted once. Only the maximum severity level will be presented in the 
severity summaries, and the strongest relationship level will be presented in the relationship 
summaries.  
In addition, a listing of individual subject AE data for TEAEs leading to treatment 
discontinuation, SAEs, and deaths will be provided separately. All AEs, including pretreatment 
AEs, will be in an individual subject data listing. 
12.3.4.2 
Clinical Laboratory Assessments 
For treatment-emergent laboratory measurements, the raw values and change from baseline 
values of the continuous hematology and chemistry results, including coagulation results will be 
summarized in SI units by treatment group and visit.  
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized overall and by treatment group. The threshold analysis criterion shift 
from baseline will also be summarized for selected laboratory parameters. The threshold criteria 
will be provided in the SAP. 
Results of urinalysis and the urine/serum pregnancy test will be in individual subject data listings 
only.  
12.3.4.3 
Electrocardiogram 
For treatment-emergent ECG measurements, a summary of raw values and change from baseline 
values will be provided overall and by treatment group at each scheduled visit for the following 
standard 12-lead ECG measurements: RR (msec), HR (beats per minute [bpm]), PR (msec), QRS 
duration (msec), QT (msec), and QT corrected for HR intervals (QTc [msec]).  
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized overall and by treatment group. The threshold value criteria will be in 
the SAP. 
12.3.4.4 
Vital Signs 
For treatment-emergent vital signs measurements, the raw values and change from baseline 
values will be summarized by overall and by treatment group at each scheduled visit: systolic 
and diastolic blood pressure (mm Hg), body temperature (°C), pulse rate (bpm), and respiratory 
rate (breaths per minute). 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized overall and by treatment group. The threshold value criteria will be in 
the SAP. 
12.3.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided overall and by treatment group for each part, at 
each scheduled visit for the percent of oxygen saturation by pulse oximetry. 


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The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
Period will be summarized overall and by treatment group. 
12.3.4.6 
Physical Examination 
PE findings will be presented in individual subject data listings only. Clinically relevant results 
identified after screening will be reported as AEs. 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses 
12.3.6.1 
Interim Analysis 
Not applicable 
12.3.6.2 
Independent Data Monitoring Committee Analysis 
The IDMC will conduct safety reviews of study data. IDMC analyses will be conducted as 
outlined in the IDMC Charter. The planned IDMC reviews (with reference to number of subjects 
and duration of study) will be specified in the IDMC charter.  
IDMC review will include relevant unblinded safety data. The IDMC may recommend stopping 
the study at any time. The IDMC may also recommend stopping individual dose groups, if there 
are increased safety findings in those groups.  
12.4 
Clinical Pharmacology Analysis 
12.4.1 
Pharmacokinetic Analysis 
The PK of VX-561 and IVA will be described using summary statistics. Preliminary review and 
analyses of the drug concentrations may be done before database lock under the conditions of 
masked identifications of the subject concentrations. 
Details of the analyses will be in the CPAP. 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses 
A sequential approach will be used to perform the population PK/PD analyses for VX-561. The 
Bayesian estimates of individual PK parameters from the final population PK model will be used 
to simulate PK profiles for each subject. The simulated VX-561 plasma concentrations will be 
used in the response models to describe changes in sweat chloride and ppFEV1 from baseline. 
Fixed- and random-effect parameter estimates and the associated asymptotic standard error will 
be estimated. Descriptive statistics will be used to summarize Bayesian estimates of individual 
PK/PD parameters obtained from the population PK/PD model. 
Details of the analyses will be described in the Modeling and Simulation Plan. 


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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, ECGs, 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. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the following times: 
 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 35 days after the last dose of study drug, or 
o the ETT Visit, if that visit is 3 weeks or later following the last dose of study drug 
(see Section 9.1.5) 


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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 CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled 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 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
July 2018). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” The 
severity of an AE described by a term 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 in Table 13-2. 


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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 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 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 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) 


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Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
 
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, 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 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.  


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13.1.2.2 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, regardless of causality, will be reported by the investigator to Vertex 
GPS within 24 hours of identification. 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 of identification.  
For SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, 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: 
  
For technical issues related to submitting the form, contact telephone:
 
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) will 
be recorded on the Vertex Clinical Trial 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 the outcome to Vertex using the SAE Form. 
13.1.2.3 
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, IECs, 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 IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/ 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 be 
conducted only 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 


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(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject 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 CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers, and access to subject names linked to such 
numbers will be limited to the site and the study physician and will not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE Forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 
For sites participating in the US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will comply with all HIPAA 
requirements including authorization allowing the site access to and use of the subject’s 


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personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP Guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
 Subject or investigator noncompliance 
 Unsatisfactory subject enrollment 
 Lack of adherence to protocol procedures 
 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. 
13.2.8 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
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 subject. Study 
data for each enrolled subject will be entered into a CRF by study site personnel using a secure, 
validated, web-based electronic data capture (EDC) application. Vertex will have read-only 
access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 


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13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP Guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc (CD) or other electronic media will be placed in the investigator’s 
study file. 
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator's employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 


Protocol VX18-561-101, Version 2.0 
Page 49 of 52 
Vertex Pharmaceuticals Incorporated 
 
13.7 
Publications and Clinical Study Report 
13.7.2 
Clinical Study Report  
A clinical study report (CSR), written in accordance with the ICH E3 Guideline, will be 
submitted in accordance with local regulations. 


Protocol VX18-561-101, Version 2.0 
Page 50 of 52 
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 22 March 2018. 
2 
United States Department of Health and Human Services. Food and Drug Administration. 
Office of Orphan Products Development. Developing Products for Rare Diseases & 
Conditions. Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.
htm. Accessed 19 September 2016. 
3 
European Medicines Agency [Internet]. Committee for Orphan Medicinal Products 
(COMP). Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_
000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30. 
Accessed 19 September 2016. 
4 
Cystic Fibrosis Foundation. Patient Registry: 2016 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2017. 
5 
Cystic Fibrosis Trust. UK Cystic Fibrosis Registry: 2015 Annual Data Report. London, 
UK: Cystic Fibrosis Trust; 2016. 
6 
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
7 
CFTR2.org. Clinical and functional translation of CFTR. The Clinical and Functional 
TRanslation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins 
University, the Hospital for Sick Children. Available at: http://www.cftr2.org. Accessed 
25 October 2018. 
8 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
9 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
10 
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. 
11 
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. 
12 
Kalydeco (ivacaftor) Prescribing Information. Vertex Pharmaceuticals Incorporated. 
Boston, MA, USA. Revised: August 2018. 
13 
Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
publication practice for communicating company-sponsored medical research: GPP3. 
Ann Intern Med. 2015;163(6):461-4. 
14 
International Committee of Medical Journal Editors (ICMJE). December 2017. 
Recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals. Available at: http://www.icmje.org/recommendations/. Accessed 03 
August 2018. 
 


Protocol
Version 2.0
Page 51 of 52
15
PROTOCOL SIGNATURE PAGES
15.1
Sponsor Signature Page
#:
VX18-561-101
Version #:
2.0
Date:
03
2019
Study Title: A Phase 2, Randomized, Double-blind Study to
the Efcacy and Safety of
VX—561 in
Aged 18 Years and Older With Cystic Fibrosis
This clinical study protocol has been reviewed and approved by the sponsor.
Vertex Pharmaceuticals Incorporated


Protocol VX18-561-101, Version 2.0 
Page 52 of 52 
Vertex Pharmaceuticals Incorporated 
 
15.2 
Investigator Signature Page 
Protocol #:  
VX18-561-101 Version #: 
2.0 
Version Date: 
03 October 2019 
Study Title: A Phase 2, Randomized, Double-blind Study to Evaluate the Efficacy and Safety of 
VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis 
 
 
I have read Protocol VX18-561-101, Version 2.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-561, IVA, and this protocol supplied to 
me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 




Page 1 of 7 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol Addendum  
for Cystic Fibrosis  
Cystic Fibrosis Studies for the Following Programs 
Ivacaftor (VX-770) 
 
 
 
 
VX-561 
Version and Date of Protocol Addendum: Version 2.0, 15 May 2020 
Replaces Version 1.0, dated 24 April 2020  
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. 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 2.0 
Page 2 of 7 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes to Cystic Fibrosis Clinical Study Protocols 
Vertex is currently evaluating several CFTR modulators in clinical studies for the treatment of 
cystic fibrosis (CF), a serious and life-threatening disease. In completed studies, treatment with 
these CFTR modulators has generally resulted in rapid, robust, clinically meaningful, and 
statistically significant improvements in clinical measures, and are generally safe and well 
tolerated. Adverse events (AEs) seen with these treatments are mostly consistent with common 
manifestations of CF disease or with common illnesses in CF subjects.  
During this COVID-19 pandemic, the safety of the subjects, investigators, and site personnel 
participating in these clinical studies is Vertex’s first priority, thus it is important to minimize 
any unnecessary risk to COVID-19 exposure through travel to study sites. This addendum 
summarizes the measures taken for ongoing CF clinical studies. These operational adjustments 
were implemented to align with Health Authority guidance ensuring the protection of subjects, 
investigators, and site personnel while maintaining compliance with GCP and minimizing impact 
to the integrity of the studies. Overall, the benefit-risk of these studies remains favorable. 
Vertex recommends that subjects and sites refer to local guidance regarding travel restrictions. 
There are no operational changes to the study protocols for subjects who can travel to the study 
sites for their visits. However, to ensure continued safety of subjects who cannot travel to the 
study sites for their visits (for any reason due to COVID-19), specific alternative measures are 
being implemented to minimize the risk of exposure to COVID-19 (see table below). As the 
COVID-19 pandemic evolves, Vertex will continue to assess the need for additional actions to 
ensure the safety of all involved in these clinical studies. 
Addendum Version 2.0 summarizes additional measures taken for these ongoing CF clinical 
studies (see table below) to ensure continued safety. In addition, administrative changes were 
made to provide clarifications (e.g., changed Addendum 1 to Addendum Version 1.0) and to 
provide examples of qualified personnel (e.g., personnel from site or qualified health care 
agency) who may conduct safety assessments, as indicated per protocol, during in-home visits. 
 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 2.0 
Page 3 of 7 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Rationale for Change 
Study Number 
Addendum Version 2.0, dated 15 May 2020 
Assessments 
 
Weight and height/length/stature may be assessed by subjects or their 
caregivers using medical grade scales and stadiometers, as indicated per 
protocol and per local regulation. Sites and subjects will receive training and 
guidance as needed on these devices.  
 
Subjects or caregivers will provide these measurements to site personnel by 
telephone or video call. Investigators will review results and contact subjects 
for follow-up as needed. All data will continue to be retained in the subject’s 
source files. 
To allow for collection of key data to assess safety and/or 
efficacy while maintaining study integrity and the safety 
of subjects and site personnel. 
 
Addendum 1 allowed for these assessments to be 
performed by qualified personnel conducting the in-home 
visits. Addendum 2 allows for these assessments to be 
performed by subjects or caregivers. 
VX18-561-101 
 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 2.0 
Page 4 of 7 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Consenting of Subjects 
ICFs may be provided electronically or by post mail to subjects (and/or caregivers, as 
indicated per protocol). The subjects and/or caregivers will review the ICF with an 
appropriately qualified member of the investigator’s team via telephone contact or video call. 
After this review, subjects and/or caregivers will consent (or assent, if applicable), and/or 
reconsent verbally and by signing and dating the ICF and returning it to the site via post mail. 
The signed and dated ICF will then be signed and dated by the investigator.  
 
Subjects participating in select studies may have the opportunity to enroll in longterm 
extension studies. Informed consent (or assent, if applicable), and/or reconsent for subjects 
(and/or caregivers, as indicated per protocol) may be obtained per the same process described 
above, as applicable. 
To provide alternative methods of 
obtaining reconsent or consent, as 
applicable, while ensuring subject 
safety. 
VX18-561-101 
Study Drug Shipping 
Study drug may be shipped directly from the site to the subject, as applicable, and if permitted 
by local regulations; subject protected health information will not be released to Vertex.  
 
Reconciliation, return, and destruction of study drug will continue to occur at the clinical site 
as indicated per protocol and in adherence to local regulations. 
To ensure subjects can continue 
treatment with study drug without 
interruption while ensuring their safety. 
 
To clarify that despite these alternative 
measures, reconciliation, return, and 
destruction of study drug will remain as 
indicated per protocol. 
In-home Visits and/or Telephone Contact 
Study visits may be conducted as in-home visits by qualified personnel as requested by 
participating sites on a per-subject basis. In addition, all subjects may be contacted by site 
personnel by telephone or video call, irrespective of in-home visits. 
To provide subjects the opportunity to 
continue participation in the clinical 
studies while ensuring their safety by 
minimizing the risk to COVID-19 
exposure through travel. 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 2.0 
Page 5 of 7 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Safety Assessments and Reporting 
Safety assessments, as indicated per protocol, may be performed by qualified personnel 
conducting the in-home visits (e.g., personnel from site or qualified health care agency). These 
assessments may include the following, as indicated per protocol, and per local regulation:  
• vital signs 
• pulse oximetry 
• height/length/stature 
• weight 
• physical examination 
(complete or abbreviated) 
• pregnancy test  
(serum or urine) 
• urinalysis 
• blood draws for safety test panels 
(chemistry, LFT panel, lipid panel, 
hematology, coagulation).  
Blood and/or urine samples for safety assessments are analyzed as indicated per protocol for 
subjects who have in-home visits. 
Blood and/or urine samples for safety assessments may be collected and analyzed at local 
laboratories for subjects who do not have in-home visits, but do not complete the assessment 
at the site. 
In addition, safety assessents will be evaluated by telephone. These assessments may include 
the review of the following:  
• AEs 
• signs and symptoms/systems for CF 
• medications 
• planned or unplanned hospitalizations for CF 
• study drug administration 
• outcomes related to PEx  
• outcomes related to antibiotic treatment 
Investigators will review results (in-home and telephone) and contact subjects for follow-up as 
needed. 
All data will continue to be retained in the subject’s source files. 
Any clinically significant finding (e.g., AE, SAE, laboratory abnormalities) will continue to be 
reported as indicated per protocol. 
To assess the safety and tolerability of 
the CFTR modulator evaluated in the 
specific clinical study while ensuring 
subject safety. These safety 
assessments will continue to provide 
safety data while minimizing burden to 
subjects and site personnel.  
 
To clarify that despite these alternative 
measures, all adverse events and 
serious adverse events should be 
reported as indicated per protocol. 
VX18-561-101 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 2.0 
Page 6 of 7 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Efficacy and Other Assessments 
Efficacy and other assessments, as indicated per protocol, may be performed by qualified 
personnel conducting the in-home visits. These assessments may include the following, as 
indicated per protocol, and per local regulation. 
In-home Spirometry Assessment 
A spirometry device may be provided to subjects for in-home assessments of lung function as 
indicated per protocol. Sites and subjects will receive training and guidance as needed. 
Patient Reported Outcome 
CFQ-R questionnaires may be provided to subjects (electronically or post mail) to be 
completed at home as indicated per protocol. Subjects will return these questionnaires to the 
site via post mail. 
Other Assessments  
• ECGs  
• sweat chloride 
• blood samples for CFTR genotype testing, 
, PK, FSH, 
, 
  
 
 
To be able to assess safety, treatment 
effectiveness, and quality of life 
measures of the CFTR modulator 
evaluated in the specific clinical study 
while ensuring subject safety. 
 
All Efficacy and 
Other 
Assessments 
VX18-561-101 
Note: CFQ-R 
does not apply for 
 
 
VX18-561-101 
Other Outcomes 
Only 
VX18-561-101 


Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 2.0 
Page 7 of 7 
Vertex Pharmaceuticals Incorporated 
 
Summary of Changes in Ongoing CF Clinical Studies for Subjects Who Cannot Travel to the Study Site 
Protocol Change 
Protocol Change 
Protocol Change 
Addendum Version 1.0, dated 24 April 2020 
Remote Monitoring 
Vertex has implemented remote monitoring visits where applicable, including remote source 
data verification, as allowed per local regulations. Remote monitoring will focus on collection 
of safety data, and data supporting primary and key secondary endpoints. 
To allow for review of key data to 
inform on the safety of subjects 
receiving treatment. 
 
To allow for review of other key data 
to inform on the objectives of the study 
while maintaining study integrity and 
the safety of subjects and site 
personnel. 
VX18-561-101 
AE: adverse event; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; ECG: electrocardiogram; 
 
FSH: follicle-stimulating hormone; GCP: Good Clinical Practice; ICF: informed consent form; 
; LFT: liver function test; 
PEx: pulmonary exacerbation; PK: pharmacokinetic; SAE: serious adverse event; 
; 
 
 
 

SAP_001.pdf: 
 
 
Vertex Pharmaceuticals Incorporated 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX18-561-101 Version 2.0 
(Final Analysis) 
 
A Phase 2, Randomized, Double-blind Study to 
Evaluate the Efficacy and Safety of VX-561 in 
Subjects Aged 18 Years and Older With Cystic Fibrosis 
 
Authors of SAP: 
 
 
Version: Version 1.0 
Version Date of SAP: 24 Jan 2020 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods) Final Analysis 
Page 2 of 30 
Protocol Number: VX18-561-101 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
1 
TABLE OF CONTENTS 
1 
Table of Contents ................................................................................................................... 2 
 
 
 
 
 
 
 
3 
Introduction............................................................................................................................ 5 
4 
Study Objectives .................................................................................................................... 5 
4.1 
Primary Objective ............................................................................................................. 5 
4.2 
Secondary Objectives ....................................................................................................... 5 
5 
Study Endpoints ..................................................................................................................... 5 
5.1 
Primary Endpoint .............................................................................................................. 5 
5.2 
Secondary Endpoints ........................................................................................................ 6 
6 
Study Design ........................................................................................................................... 6 
6.1 
Overall Design .................................................................................................................. 6 
6.2 
Sample Size and Power .................................................................................................... 6 
6.3 
Randomization .................................................................................................................. 7 
6.4 
Blinding and Unblinding .................................................................................................. 7 
7 
Analysis Sets ........................................................................................................................... 7 
7.1 
All Subjects Set ................................................................................................................ 7 
7.2 
Full Analysis Set ............................................................................................................... 7 
7.3 
Safety Set .......................................................................................................................... 7 
8 
Statistical Analysis ................................................................................................................. 7 
8.1 
General Considerations .................................................................................................... 7 
8.2 
Background Characteristics .............................................................................................. 8 
8.2.1 
Subject Disposition ................................................................................................... 8 
8.2.2 
Demographics and Baseline Characteristics ............................................................. 9 
8.2.3 
Medical History ...................................................................................................... 10 
8.2.4 
Prior and Concomitant Medications ....................................................................... 10 
8.2.5 
Study Drug Exposure.............................................................................................. 10 
8.2.6 
Study Drug Compliance ......................................................................................... 11 
8.2.7 
Important Protocol Deviations ................................................................................ 11 
8.3 
Efficacy and Pharmacodynamic Analyses ..................................................................... 11 
8.3.1 
Analysis of Primary Efficacy Variable ................................................................... 11 
8.3.1.1 
Definition of Variables ..................................................................................... 11 
8.3.1.2 
Primary Analysis .............................................................................................. 11 
8.3.1.3 
Sensitivity Analysis .......................................................................................... 12 
8.3.1.4 
Subgroup Analysis ........................................................................................... 12 
8.3.2 
Analysis of Secondary Variable ............................................................................. 12 
8.3.2.1 
Definition of Variables ..................................................................................... 12 
8.3.2.2 
Analysis of Pharmacodynamics Variable: Sweat Chloride ............................. 12 
 
 
8.4 
Safety Analysis ............................................................................................................... 13 
8.4.1 
Adverse Events ....................................................................................................... 14 
8.4.2 
Clinical Laboratory ................................................................................................. 15 


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Vertex Pharmaceuticals Incorporated 
 
8.4.3 
Electrocardiogram .................................................................................................. 15 
8.4.4 
Vital Signs .............................................................................................................. 16 
8.4.5 
Pulse Oximetry ....................................................................................................... 16 
8.4.6 
Physical Examination ............................................................................................. 16 
 
 
 
9 
Interim and DMC Analyses ................................................................................................ 17 
9.1 
Interim Analysis ............................................................................................................. 17 
9.2 
DMC Analysis ................................................................................................................ 17 
10 References ............................................................................................................................. 18 
11 List of Appendices................................................................................................................ 19 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments ......................... 19 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 21 
Appendix C: Details of GLI Equations for Calculating ppFEV1 ............................................. 22 
Appendix D: Imputation Rules for Missing AE dates ............................................................. 23 
Appendix E: Criteria for Threshold Analysis .......................................................................... 24 
 
 




Statistical Analysis Plan (Methods) Final Analysis 
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Protocol Number: VX18-561-101 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
3 
INTRODUCTION 
This statistical analysis plan (SAP) for the final analysis is based on the approved clinical study 
protocol (CSP), Version 2.0, dated 03 Oct 2019, and most recent approved electronic case report 
form (eCRF), and approved eCRF completion guidelines.  
This is a Phase 2, randomized, double-blind study to evaluate the efficacy and safety of VX-561 
in subjects aged 18 years and older with cystic fibrosis. 
The planned statistical analyses will contribute to evaluation of VX-561 doses based on totality 
of data, along with PK analysis and PK/PD analysis.  
Per Protocol Version 2.0, the VX-561 25 mg qd and 50 mg qd treatment arms were discontinued 
(
). Most of the subjects randomized to the 
two dropped dose arms did not complete treatment. Therefore, the statistical analysis should be 
interpreted with caution.  
This SAP (Methods) documents the planned statistical analyses of efficacy and safety endpoints 
for the final analysis.  
The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of VX-561 will also be 
evaluated in the study. Selected analyses related to sweat chloride will be documented in this 
SAP, other PK and PD analyses will be documented separately in the clinical pharmacology 
analysis plan (CPAP) and the Modeling and Simulation Plan for the study.  
This SAP (Methods) will be finalized and approved prior to data lock and treatment unblinding 
for the final analysis.  
The Vertex Biometrics Department will perform the statistical analysis within the scope of the 
SAP.  SAS® Version 9.4 or higher software (SAS Institute, Cary, North Carolina, USA) will be 
used to generate all statistical outputs (tables, figures, listings, and datasets).   
4 
STUDY OBJECTIVES  
4.1 
Primary Objective 
 To evaluate the efficacy of VX-561 
4.2 
Secondary Objectives  
 To evaluate the PD effect of VX-561  
 To evaluate the PK of VX-561, IVA, and relevant metabolites 
 To evaluate the safety and tolerability of VX-561  
5 
STUDY ENDPOINTS 
5.1 
Primary Endpoint 
 Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline at Week 12 


Statistical Analysis Plan (Methods) Final Analysis 
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Protocol Number: VX18-561-101 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
5.2 
Secondary Endpoints 
 Absolute change in sweat chloride concentrations from baseline at Week 12 
 PK parameters of VX-561, IVA, and relevant metabolites 
 Safety and tolerability, based on the assessment of adverse events (AEs), laboratory test 
results, standard 12-lead ECGs, vital signs, and pulse oximetry 
6 
STUDY DESIGN  
6.1 
Overall Design  
This is a Phase 2 study of VX-561 monotherapy. A schematic of the study design is shown in 
Figure 6-1, which is randomized, double-blind, parallel-group, and active-controlled. The study 
was planned to evaluate 4 dose levels of VX-561 in subjects with CF who have a gating mutation 
and were previously taking a stable dose of IVA. Randomization will be stratified by ppFEV1 
value at Screening (<70 versus ≥70). Per Protocol Version 2.0, the VX-561 25 mg qd and 50 mg 
qd treatment arms were discontinued (
); 44 
subjects had been enrolled and randomized to the 5 treatment arms at that point. The remaining 
subjects planned to enroll will be randomized 2:2:1 to 3 treatment arms (VX-561 250 mg qd, 
VX-561 150 mg qd, and IVA 150 mg q12h).  
Figure 6-1 
VX18-561-101 Study Design 
 
6.2 
Sample Size and Power 
The primary objective is to evaluate efficacy of VX-561. The primary efficacy endpoint is the 
absolute change in ppFEV1 from baseline at Week 12. Following discontinuation of the VX-561 
25 mg qd and VX-561 50 mg qd treatment arms, the remaining subjects planned for enrollment 
will be randomized in a 2:2:1 ratio to the 3 current treatment arms. Assuming a within-group SD 
of 7 percentage points and a 10% dropout rate at Week 12: a sample size of 22 to 28 subjects in 
the VX-561 150, and 250 mg qd  arms will provide a 95% CI of ± 3.4 to ± 2.9 percentage points 
around the observed mean absolute change in ppFEV1 from baseline at Week 12, based on 2 
sided, 1-sample t statistics; a sample size of 11 to 14 subjects in the IVA 150 mg q12h arm will 
provide a 95% CI of ± 5.4 to ± 4.4 percentage points around the observed mean.  


Statistical Analysis Plan (Methods) Final Analysis 
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Protocol Number: VX18-561-101 Version 1.0 
 
Vertex Pharmaceuticals Incorporated 
 
6.3 
Randomization 
An interactive web response system (IWRS) will be used to assign subjects to treatment. A 
randomization list will be produced by Vertex Biostatistics or a qualified randomization vendor.  
Subjects will be assigned a unique subject number. Only subjects who have completed screening 
assessments and are eligible for participation in the study will be randomized to receive study 
drug during the Treatment Period. Randomization will be stratified by ppFEV1 (<70 versus ≥70) 
determined during screening. 
6.4 
Blinding and Unblinding 
Please refer to Section 10.7 of the CSP for details. 
7 
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set, Full Analysis Set and Safety Set.  
7.1 
All Subjects Set 
The All Subjects Set is defined as all subjects who were randomized or received at least 1 dose 
of study drug. The All Subjects Set will be used for individual subject data listings and 
disposition summary tables, unless otherwise specified.  
7.2 
Full Analysis Set  
The Full Analysis Set (FAS) will include all randomized subjects who carry the intended CFTR 
genotype and have received at least 1 dose of study drug in the Treatment Period. The FAS will 
be used for all PD and efficacy analyses in which subjects will be analyzed according to their 
randomized treatment group, unless otherwise specified. 
7.3 
Safety Set 
The Safety Set will include all subjects who received at least 1 dose of study drug. The Safety 
Set will be used for all safety analyses and study drug exposure, unless otherwise specified. 
Subjects will be analyzed according to the treatment they received.  
If a subject received doses from multiple treatment groups, the subject will be analyzed in the 
group with the highest priority, according to the order (from low priority to high priority) of 
IVA, VX-561 25 mg, VX-561 50 mg, VX-561 150 mg, VX-561 250 mg.  
8 
STATISTICAL ANALYSIS 
8.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of the protocol. The precision standards 
for reporting safety and efficacy variables are provided in an internal Biometrics document that 
specifies the programming rules including the precision for derived variables.   
All individual subject data for those randomized or dosed with any amount of study drug will be 
presented in data listings. 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max).  


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Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Treatment-emergent (TE) period will include the time period starting from the date of the first 
dose of study drug to 28 days after the date of the last study drug taken in the treatment period, 
or the completion date of study participation, whichever comes earlier. The TE Period will be 
used for safety analyses unless specified otherwise. 
Baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug. For ECG, 
baseline will be defined as the most recent non-missing pretreatment measurement (or the 
average of triplicate measurements, if the most recent non-missing pretreatment measurement is 
obtained in triplicate), before the first dose of study drug. 
Absolute change from baseline will be calculated as postbaseline value – baseline value. 
Relative change from baseline will be calculated as (postbaseline value – baseline 
value)/baseline value. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
 In scheduled visit windows per specified visit windowing rules 
 In the derivation of baseline and last on-treatment measurements 
 In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values for safety analyses 
 In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix A.  
Incomplete/missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
Multiplicity: There will be no multiplicity adjustment for performing multiple hypothesis tests, 
unless specified otherwise. 
8.2 
Background Characteristics  
8.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized by treatment groups 
(IVA 150 mg q12h, VX-561 25 mg qd, VX-561 50 mg qd, VX-561 150 mg qd, VX-561 250 mg 
qd), VX-561 total (pooling all VX-561 arms) and overall (pooling all 5 arms):  
 All Subjects Set 
 Full Analysis Set   
 Safety Set 
 Randomized 
 Randomized but not dosed in the Treatment Period 


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The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized: 
 Completed study drug treatment  
 Prematurely discontinued treatment and the reason for discontinuation 
 Completed study (i.e., completed Safety Follow-up Visit) 
 Prematurely discontinued the study and the reason for discontinuation  
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation.  
8.2.2 
Demographics and Baseline Characteristics 
Demographics, medical history and baseline characteristics will be summarized based on the 
FAS, and presented by treatment groups, VX-561 total and overall. 
Demographic data will include the following: 
 Age at baseline (in years) 
 Sex (female or male) 
 Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
 Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other, and not collected per local regulations) 
Baseline characteristics will include the following: 
 Weight (kg) 
 Height (cm) 
 BMI (kg/m2) 
Stratification categories will include the following: 
 ppFEV1 at the Screening Visit (<70, ≥70) 
Disease characteristics will include the following: 
 ppFEV1 at baseline (<40, ≥ 40 to <70, ≥70 to ≤100, >100) 
 ppFEV1 at baseline (continuous)  
 Sweat Chloride at baseline (continuous) 
 Prior use of dornase alfa (Yes, No) 
 Prior use of azithromycin (Yes, No) 
 Prior use of inhaled antibiotic (Yes, No) 
 Prior use of any bronchodilator (Yes, No) 
 Prior use of any inhaled bronchodilator (Yes, No) 


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 Prior use of any inhaled hypertonic saline (Yes, No) 
 Prior use of any inhaled corticosteroids (Yes, No) 
 Infection with Pseudomonas aeruginosa with 2 years prior to screening (Positive, 
Negative) 
In addition, number (%) of subjects (based on the FAS) will be summarized by genotype 
category (F508del/Gating, Gating/Gating and Gating/Other) in a total column. 
Data listings will also be provided for: 
 Informed consent; 
 Inclusion/Exclusion criteria violation for subjects with any such violations. 
 
8.2.3 
Medical History 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). For the FAS, medical history will be summarized descriptively by system organ 
class and preferred term. The corresponding data listing will also be provided. 
8.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHODD, version March 2019, format B3 or the most updated version) and categorized as 
follows: 
Prior medication: any medication that started before the date of first dose of study drug. 
Concomitant medication: medication continued or newly received during the TE Period. 
Post-treatment medication: medication continued or newly received after the TE period. 
A given medication may be classified as a prior, concomitant medication, or post-treatment 
medication; both prior and concomitant; both concomitant and post-treatment; or prior, 
concomitant, and post-treatment. If a medication has a missing or partially missing start/end date 
or time and if it cannot be determined whether it was taken before the first dose of study drug, 
concomitantly during the TE Period, or after the TE Period, it will be considered in all 
3 categories of prior, concomitant, and post-treatment medication. 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by Preferred Name based on the FAS, and presented by treatment groups, VX-
561 total and overall. 
All medications (including post-treatment medications) will be provided in an individual subject 
data listing. Details for imputing missing or partial start and/or stop dates of medication are 
described in Appendix B. 
8.2.5 
Study Drug Exposure  
Study drug exposure (in days) will be calculated as: last dose date of study drug – first dose 
date of study drug + 1 day, regardless of study drug interruption. Exposure will be summarized 
descriptively by the number of subjects (n), mean, SD, median, min, and max. It will also be 


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summarized in categories: ≤4 weeks, >4 to ≤8 weeks, >8 to ≤12 weeks, and >12 weeks, using 
counts and percentages.  
Exposure summaries will be based on the Safety Set, and presented by treatment groups.  
8.2.6 
Study Drug Compliance  
Study drug compliance will be calculated as: 100 x [1 - (total number of days of study drug 
interruption) / (duration of study drug exposure in days)]. A study drug interruption on a given 
day is defined as an interruption of any study drug on that day.  
Percentage of study drug compliance will be summarized based on the FAS, and presented by 
treatment groups. Percentage of study drug compliance will be summarized descriptively by the 
number of subjects (n), mean, SD, median, min, and max. It will also be summarized in 
categories: <80% and ≥80% using frequency tables. 
In addition, percentage of tablets taken will be calculated using the following formula:  
100 x [(total number of tablets dispensed) – (total number of tablets returned)] / (total number of 
tablets planned to be taken per day x duration of study drug exposure in days). Summary similar 
to those for the study drug compliance will be produced based on the FAS. Due to 
discontinuation of the VX-561 25 mg qd and VX-561 50 mg qd treatment arms, the VX-561 25 
mg tablet and its matching placebo were not dispensed following approval of Protocol v2.0; the 
calculations of drug compliance will not be conducted for the VX-561 25 mg tablet and its 
matching placebo.  
8.2.7 
Important Protocol Deviations  
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. A blinded protocol deviation review team will categorize IPDs 
according to the protocol deviation plan.  
IPDs (from the clinical database or from the site deviation log) will be provided in an individual 
subject data listing. 
8.3 
Efficacy and Pharmacodynamic Analyses 
All efficacy and PD analyses described in this section will be based on the FAS, unless otherwise 
specified. 
8.3.1 
Analysis of Primary Efficacy Variable 
8.3.1.1 
Definition of Variables 
The primary efficacy variable is the absolute change in ppFEV1 from baseline at Week 12. 
Percent predicted FEV1 is the ratio of FEV1 (L) and predicted FEV1 (L), expressed as a 
percentage. See Appendix C for more details 
 
8.3.1.2 
Primary Analysis 
The primary efficacy endpoint is the absolute change in ppFEV1 from baseline at Week 12. Per 
Protocol Version 2.0, the lower dose VX-561 arms (VX-561 25 mg qd and 50 mg qd) were 
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mg qd) did not complete study treatment. Due to the large proportion of missing assessments of 
lower dose arms, they are not included in MMRM analysis. The primary analysis (described 
below) is based on the within group mean of absolute change from baseline for VX-561 150 mg 
qd, VX-561 250 mg qd, and IVA 150 mg q12h treatment arms. 
The primary analysis will be based on a mixed effects model for repeated measures (MMRM) 
using restricted maximum likelihood. The model will include the absolute change from baseline 
in ppFEV1 at Day 15, Week 4, Week 8, and Week 12 from the current treatment arms (VX-561 
150 mg qd, VX-561 250 mg qd, and IVA 150 mg q12h) as the dependent variable; treatment 
group, visit, and treatment by visit as fixed effects; with continuous baseline ppFEV1 as 
covariates; and an unstructured covariance structure for the within-subject errors. If the model 
estimation does not converge, a compound symmetry covariance structure will be used. The 
efficacy data from the discontinued arms (VX-561 25 mg qd and VX-561 50 mg qd) will not be 
included in the model. 
The primary results obtained from the model will be the within-group treatment effect estimate at 
Week 12 for each treatment arm. The adjusted mean with a 2-sided 95% CI will be presented in 
a table. 
In addition, the adjusted mean and 95% CI of the treatment effect difference between each 
VX-561 arm and the IVA arm obtained from the MMRM model will be provided.  
The ppFEV1 values and absolute change from baseline values will be summarized descriptively 
(n, mean, SD, median, minimum and maximum) at each scheduled visit by treatment groups (in 
one table including IVA, VX-561 25 mg qd, VX-561 50 mg qd, VX-561 150 mg qd, VX-561 
250 mg qd).  
8.3.1.3 
Sensitivity Analysis 
No sensitivity analysis for the primary efficacy variable has been planned. 
8.3.1.4 
Subgroup Analysis 
No subgroup analysis for the primary efficacy variable has been planned. 
8.3.2 
Analysis of Secondary Variable  
8.3.2.1 
Definition of Variables 
Sweat chloride (SwCl): the SwCl value for a given visit will be calculated as the mean of the 
non-missing sweat chloride measurements obtained on the left and right arms at that visit.  If one 
of the two arm measurements at a time point is missing, the other will be used as the mean.  A 
volume ≥15 μL is required for an accurate determination of sweat chloride.  Any results reported 
as having volume <15 μL will be considered missing. Any sweat chloride values reported as <10 
mmol/L or >160 mmol/L will be considered missing. 
 
8.3.2.2 
Analysis of Pharmacodynamics Variable: Sweat Chloride  
The secondary endpoint is the absolute change from baseline in sweat chloride at Week 12 and 
will be analyzed similarly to ppFEV1, including VX-561 150 mg qd, VX-561 250 mg qd, and 
IVA 150 mg q12h treatment arms only. The model will include treatment group, visit, and 
treatment by visit as fixed effects; with continuous baseline ppFEV1 as covariates. Adjusted 


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means and 95% CIs of the average treatment effects at Week 12 will be obtained for within-
group (for each arm) and between-group comparisons (between each VX-561 arm and the IVA 
arm).  
In addition, the sweat chloride raw values and change from baseline values will be summarized 
descriptively and similar to ppFEV1 analysis. 
 
8.4 
Safety Analysis 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
 AEs 
 Clinical laboratory values (hematology, serum chemistry, coagulation, and urinalysis) 
 Standard 12-lead ECGs 


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 Vital signs 
 Pulse oximetry 
Safety endpoints will be analyzed based on the Safety Set. Only a descriptive analysis of safety 
will be performed.  
All safety data from the TE period will be summarized by treatment groups (including IVA, VX-
561 25 mg qd, VX-561 50 mg qd, VX-561 150 mg qd, and VX-561 250 mg qd). 
8.4.1 
Adverse Events  
AEs will be classified as pretreatment AEs, treatment-emergent adverse events (TEAEs), or 
post-treatment AEs, defined as follows:  
Pretreatment AE: any AE that started before the first dose date of study drug. 
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed on 
or after the first dose date of study drug through the end of the TE Period.  
Post-treatment AE: any AE that worsened or that was newly developed beyond the TE Period. 
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs during 
the Treatment Period. 
Details for imputing missing or partial start dates of adverse events are described in Appendix D. 
An overview of all TEAEs will be summarized in the following categories and presented by 
treatment groups and VX-561 total:  
 Number of TEAEs (total number of TEAEs only) 
 Subjects with any TEAEs  
 Subjects with TEAEs by strongest relationship 
 Subjects with TEAEs by maximum severity 
 Subjects with TEAEs leading to treatment discontinuation (discontinuation of any study 
drug) 
 Subjects with Grade 3/4 TEAEs 
 Subjects with related TEAEs 
 Subjects with TEAEs leading to treatment interruption (interruption of any study drug) 
 Subjects with serious TEAEs 
 Subjects with related serious TEAEs 
 Subjects with TEAE leading to death  
The following summary tables of TEAEs will be presented by treatment groups: 
 All TEAEs 
 TEAEs by strongest relationship 


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  TEAEs by maximum severity 
 TEAEs leading to treatment discontinuation 
 TEAEs leading to treatment interruption 
 Related TEAEs 
 Serious TEAEs 
 Related serious TEAEs 
 TEAEs leading to death 
 Grade 3/4 TEAEs 
Summaries will be presented by MedDRA System Organ Class (SOC) and Preferred Term (PT) 
using frequency counts and percentages (i.e., number and percentage of subjects with an event). 
When summarizing the number and percentages of subjects, subjects with multiple occurrences 
of the same adverse event or a continuing adverse event will be counted once, and only the 
maximum severity level will be presented in the severity summaries, and the strongest 
relationship level in the relationship summaries.   
All AEs, including pre-treatment AEs, TEAEs, and post-treatment AEs, will be presented in an 
individual subject data listing based on the All Subjects Set.  
8.4.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments, the observed values and change from 
baseline values of the continuous hematology, chemistry, and coagulation results will be 
summarized in SI units at each scheduled visit by treatment groups.  
The number and percentage of subjects with continuous hematology, chemistry and coagulation 
test values meeting at least 1 threshold analysis criterion event, during the TE period, will be 
summarized by treatment groups. The threshold analysis criteria are provided in Appendix E. 
Results of urinalysis and positive urine/serum pregnancy tests will be listed in individual subject 
data listings only. For positive serum pregnancy listing, subjects with serum HCG which are 
abnormally high will be selected. 
In addition, a listing containing individual subject hematology, chemistry, and coagulation values 
will be provided. This listing will include data from both scheduled and unscheduled visits.  
8.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided at each scheduled visit by treatment groups, for the following 
ECG interval measurements (in msec): RR, PR, QT, and QT corrected for HR intervals (QTcF), 
QRS duration, and HR (beats per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period, will be summarized by treatment groups. The threshold analysis criteria are provided 
in Appendix E. 
In addition, a listing containing individual subject ECG values will be provided. This listing will 
include data from both scheduled and unscheduled visits.  


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8.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized by treatment groups. The following vital signs parameters 
will be summarized: systolic and diastolic blood pressure (mm Hg), body temperature (C), pulse 
rate (beats per minute), respiratory rate (breaths per minute), Weight (kg), and Body Mass Index 
(kg/m2). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period will be summarized by treatment groups. The threshold analysis criteria are provided 
in Appendix E. 
In addition, a listing containing individual subject vital signs values will be provided. This listing 
will include data from both scheduled and unscheduled visits.  
8.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each scheduled visit, for the percent of oxygen 
saturation, by treatment groups. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
Period will be summarized by treatment groups. 
In addition, a listing containing individual subject pulse oximetry values will be provided for 
each part. This listing will include data from both scheduled and unscheduled visits.  
8.4.6 
Physical Examination  
PE findings will be presented as an individual subject data listing only. 


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9 
INTERIM AND DMC ANALYSES 
9.1 
Interim Analysis 
No interim analysis is planned. 
9.2 
DMC Analysis  
The DMC’s objectives and operational details are defined in a separate document (DMC 
Charter) which was finalized before the first subject was screened in the study. The DMC’s 
planned safety reviews of study data are outlined in the DMC Charter and DMC Statistical 
Analysis Plan.  
 
 


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10 
REFERENCES 
1Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 
 
 


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11 
LIST OF APPENDICES 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 11-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days) 2,3, 4 
Safety Analysis 
Serum Chemistry 
Hematology 
Weight/BMI 
Day 1 (Baseline)  
Day 15  
Week 4 
Week 8 
Week 12 
Safety Follow-up 
1 
15 
29 
57 
85 
Not applicable 
1 Pre-dose 
[1, 22] Day 1 post dose 
(22, 43] 
(43, 71] 
(71, 99] 
Use nominal visit 
Coagulation 
Day 1 (Baseline; before dosing) 
Week 12 
Safety Follow-up 
1 
Not applicable  
Not applicable 
Use nominal visit for all post-
baseline visits 
Vital Signs  
Pulse Oximetry  
Day 1 (Baseline)  
Day 15  
Week 4 
Week 8 
Week 12 
Washout Visit 
Safety Follow-up 
1 
15 
29 
57 
85 
Not applicable  
Not applicable 
1 Pre-dose 
[1, 22] Day 1 post dose 
(22, 43] 
(43, 71] 
(71, Week 12 visit date5] 
Use nominal visit  
Use nominal visit 
Standard 12-Lead 
ECG 
Day 1 (Baseline; before dosing) 
Week 4 
Safety Follow-up 
1 
Not applicable  
Not applicable 
 
Use nominal visit for all post-
baseline visits 
Efficacy and Pharmacodynamic Analysis 
Spirometry6 
Sweat Chloride6 
 
Day 1 (Baseline)  
Day 15  
Week 4 
Week 8 
Week 12 
Washout Visit 
Safety Follow-up 
1 
15 
29 
57 
85 
Not applicable 
Not applicable 
1 Pre-dose 
(1, 22]  
(22, 43] 
(43, 71] 
(71, Week 12 visit date5] 
Use nominal visit  
Use nominal visit 
Notes:  
1 Visit name for analysis purpose is used to report data in tables and figures. 
 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered 
missing for the visit. 
b. If there is more than 1 numerical measurement available within the same visit window, use the following 
rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements within the same distance from the target day, the latest 
measurement will be used. 
 
3 For measurements collected on the date of first dose of study drug, if it cannot be determined whether the 
measurements are before or after the first dose:  
a. 
Scheduled measurement will be treated as pre-dose observation. 
b. Unscheduled measurement will be treated as post-dose observation. 


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Table 11-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days) 2,3, 4 
 
4. When the ETT visit replaces the Safety Follow-up visit,  it will be mapped to the Safety Follow-up visit. Other 
ETT visits will be mapped according to the analysis visit windowing rule for safety analysis.  
 
5. If the week 12 visit is not available, then no assessment will be mapped to the Week 12 analysis visit. 
 
6. Except for safety follow-up visit (or ETT replacing safety follow-up visit) and washout visit (given that Week 12 
visit is completed), spirometry and sweat chloride assessments after last dose date will not be mapped to analysis 
visits. 
 
Derived Variables 
1. Age (in years) at first dose date and nominal visit (for demographics, listing and the calculation of [percent] 
predicted spirometry variable) 
Obtain age at informed consent (in days) in “yy, mm” format (e.g., 24 years, 6 months) from Vital Signs page at 
the Screening Visit, and add 0.5 month to convert to days. 
Obtain informed consent date. 
Then age (in years) at first dose date or nominal visit = [(first dose date or nominal visit date – informed consent 
date) in days + age at informed consent (in days)]/365.25. 
   
2. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date to impute. 
If the last dose date is missing or partial date is reported, the last dose date will be imputed based on, in 
descending order priority, the Early Treatment Termination (ETT) visit date, last visit date before the Safety 
Follow-up, or the last study drug administration date from EX SDTM domain, as appropriate, The imputation 
algorithm will ensure the imputed last dose date does not exceed the study participation end date. 
3. Sweat Chloride: 
Non-missing sweat chloride concentrations from the left arm and right arm with the assessment end date/time for 
a given arm up to 30 minutes after first dose time in treatment period will be considered for baseline.  
4. Electrocardiogram: 
Baseline is defined as the most recent pretreatment measurement before the first dose of study drug in the 
Treatment Period (or the average of triplicate measurements, if the most recent non-missing measurement is 
obtained in triplicate at screening).  If multiple ECG measurements are obtained on the same visit during the TE 
period,  
o 
For summary purpose, the nominal scheduled ECG will be used as the ECG value for the visit; 
o 
For threshold analysis purpose, all reported ECG values will be used. 
 
 
 


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Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month.  
b. If DAY and Month are both missing, use the first day of the year.  
c. If DAY, Month and Year are all missing, use a date before the first dose date (in 
practical, use the informed consent date to impute). 
2. Missing or partial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month and year are all missing, assign ‘continuing’ status to stop date (in 
practical, use the end of study date to impute). 
In summary, the prior, concomitant or post categorization of a medication is described below. 
Table 11-2 
Prior, Concomitant, and Post Categorization of a Medication  
Medication Start Date 
Medication Stop Date 
< First Dose Date of Study 
Drug 
≥ First Dose Date and ≤ 
End Date of TE Period 
> End Date of TE Period 
< First dose date of study drug 
P 
PC 
PCA 
≥ First dose date and  
≤ End date of TE period 
- 
C 
CA 
> End date of TE period 
- 
- 
A 
P: Prior; C: Concomitant; A: Post 
 
 


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Appendix C: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, 
 
 using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Quanjer GLI-2012 Regression Equations and Lookup Tables. Philip H. Quanjer, Sanja 
Stanojevic, Tim J. Cole, Janet Stocks. Version 7 April 2013. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/quanjer-gli-2012-
regression-equations-and-lookup-tables.aspx.  
[Accessed January 05, 2019].  
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Implementing GLI-2012 regression equations. Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, 
Janet Stocks. Version 19 July 2015. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/spirometry-tools/it-
engineers-and-manufacturers.aspx 
[Accessed January 05, 2019].   
GLI-2012 - SAS Macro. Sanja Stanojevic. Version 2, 7 April 2013. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/sas-macro.aspx 
[Accessed January 5, 2019]. 
Data handling rule for spirometry is as follows:  
 Input age with at least 2 decimal places. 
  Use height at screening regardless if height is collected at study visit. 
 For race, map CRF black or African American to black, all other races in CRF (except 
white) are mapped to 'other'; multiple checks for race in CRF are also mapped to 'other'; 
white is a reference race in the equations and assumes 0 values for all race coefficients in 
the GLI equations. 
 
 


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Appendix D: Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date are defined below. If the imputed AE start 
date is before the study informed consent date, the AE start date will be imputed using the study 
informed consent date. 
 If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year and month are equal to the month and year of first dose date 
of the Treatment Period, then impute the AE start day as the day of first dose 
date of the Treatment Period;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
 If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Treatment Period;  
 else impute the AE start month as January and day as 1.  
o else impute the AE start month as January and day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
 If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site with 
no imputation.  
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then the AE will be considered as TEAE for the 
Treatment Period.  
o else the AE will be considered as a pretreatment AE. 
 
Imputation rules for partial AE end date are defined below:  
If partial end date, then impute as min (the last day of the month, end of study) if day is missing, 
or min (Dec, end of study) if month is missing. 
 
 


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Appendix E: Criteria for Threshold Analysis 
Table 11-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤  3xULN) or 
(AST>ULN - ≤  3xULN) 
(ALT>3x - ≤  5xULN) or  (AST>3x 
- ≤  5xULN) 
(ALT>5x- ≤  8xULN) or  (AST>5x - 
≤    8xULN) 
(ALT>8x - ≤  20xULN) or (AST>8x 
- ≤ 20xULN) 
ALT>20xULN or AST> 20 xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5 xULN 
>2.5 – ≤ 5.0 x ULN 
>5.0 – ≤ 20.0 x ULN 
>20.0 x ULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and Total Bilirubin (ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 


Statistical Analysis Plan (Methods) - DMC 
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Protocol Number: VX18-561-101 Version 1.0 
 
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Table 11-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
GGT 
>ULN - ≤ 2.5xULN 
>2.5 –  ≤ 5.0xULN 
>5.0 –  ≤ 20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>1x -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤ 1.5xULN 
>1.5 - ≤ 3.0xULN 
>3.0 - ≤ 6.0xULN 
>6.0xULN 
CTCAE grades 1-4 
Lipase 
>ULN -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
CPK 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L  
< 80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L 
above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L  
<50.0 – ≥ 25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 


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Protocol Number: VX18-561-101 Version 1.0 
 
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Table 11-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Reticulocytes/Erythrocytes (%)    <LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated Partial thromboplastin 
time  (PPT) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
 
CTCAE grade 1-3 
 
Prothrombin time (PT) 
International Normalized Ratio 
(INR) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
 
 


Statistical Analysis Plan (Methods) - DMC 
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Protocol Number: VX18-561-101 Version 1.0 
 
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Vertex Pharmaceuticals Incorporated 
 
Table 11-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
 
Per HV grade 2, 3, plus shift change 
 
 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
QTc 
Borderline 
Prolonged 
Additional 
 
 
>450 ms (Male) and <500ms; >470 ms and 
<500ms (Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
 
To be applied to any kind of QT correction 
formula.  
 
 
 
 
 
 
 
 


Statistical Analysis Plan (Methods) - DMC 
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Protocol Number: VX18-561-101 Version 1.0 
 
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Table 11-5 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
HR 
Same as above in ECG category 
 
 
SBP increased 
 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg and >10 mmHg increase from 
baseline 
>140 mmHg and >20 mmHg increase from 
baseline 
>160 mmHg and >10 mmHg increase from 
baseline 
>160 mmHg and >20 mmHg increase from 
baseline 
 
809/770 analyses 
SBP decrease 
 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from 
baseline 
<90 mmHg and >20 mmHg decrease from 
baseline 
<80 mmHg and >10 mmHg decrease from 
baseline 
<80 mmHg and >20 mmHg decrease from 
baseline 
 
Per HV grade 1, 3, plus shift change 


Statistical Analysis Plan (Methods) - DMC 
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Protocol Number: VX18-561-101 Version 1.0 
 
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Vertex Pharmaceuticals Incorporated 
 
Table 11-5 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
DBP increased 
 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from 
baseline 
>90 mmHg and >10 mmHg increase from 
baseline 
>100 mmHg and >5 mmHg increase from 
baseline 
>100 mmHg and >10 mmHg increase from 
baseline 
 
 
DBP decreased 
 
 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from 
baseline 
<60 mmHg and >10 mmHg decrease from 
baseline 
<45 mmHg and >5 mmHg decrease from 
baseline 
<45 mmHg and >10 mmHg decrease from 
baseline 
 
 
 
 
Weight   
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
 
CTCAE grade 1-3 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
 
CTCAE grade 1-3