Clinical trial NCT03601637
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2018-09-07; Completion date: 2021-10-29
Enrollment: 61 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the safety and pharmacokinetics (PK) of lumacaftor (LUM) and ivacaftor (IVA) in participants 1 to less than 2 years of age with cystic fibrosis (CF), homozygous for F508del (F/F).

Detailed description:

Arms: arm 1: Participants weighing 7 to less than (\<)10 kilograms (kg) at screening received LUM 75 milligrams (mg)/IVA 94 mg fixed-dose combination (FDC) every 12 hours (q12h) and those weighing 10 to \<14 kg at screening received LUM 100 mg/IVA 125 mg q12h for 15 days. Participants weighing greater than or equal to (\>=)14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h for 15 days. arm 2: Participants weighing 7 to \<9 kg at screening received LUM 75 mg/IVA 94 mg FDC q12h and those weighing 9 to \<14 kg received LUM 100 mg/IVA 125 mg q12h for 24 weeks. Participants weighing \>=14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h for 24 weeks. Doses were adjusted upwards for changes in weight.
Interventions: intervention 1: LUM intervention 2: IVA
Intervention descriptions: intervention 1: Fixed Dose Combination (FDC) granules (LUM/IVA). intervention 2: FDC granules (LUM/IVA).

Protocol documents:
Prot_000.pdf: 






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2 
PROTOCOL SYNOPSIS 
Title A Phase 3, 2-part, Open-label Study to Evaluate the Safety and Pharmacokinetics of 
Lumacaftor/Ivacaftor in Subjects 1 to Less Than 2 Years of Age With Cystic 
Fibrosis, Homozygous for F508del 
Brief Title Safety and Pharmacokinetic Study of Lumacaftor/Ivacaftor in Subjects 1 to Less 
Than 2 Years of Age With Cystic Fibrosis, Homozygous for F508del 
  
Clinical Phase and 
Clinical Study Type  
Phase 3, safety and pharmacokinetics (PK) 
  
Objectives Primary Objectives 
Part A 
To evaluate the PK of lumacaftor (LUM) and ivacaftor (IVA) in subjects 1 to less 
than 2 years of age with cystic fibrosis (CF), homozygous for F508del 
Part B 
To evaluate the safety of LUM/IVA in subjects 1 to less than 2 years of age with CF, 
homozygous for F508del 
Secondary Objectives 
Part A 
• 
To evaluate the safety of LUM/IVA in subjects 1 to less than 2 years of age with 
CF, homozygous for F508del 
• 
To evaluate the PK of the metabolites of LUM and IVA in subjects 1 to less than 
2 years of age with CF, homozygous for F508del 
Part B 
• 
To evaluate the pharmacodynamics (PD) of LUM/IVA in subjects 1 to less than 
2 years of age with CF, homozygous for F508del 
• 
To evaluate the PK of LUM and IVA and their respective metabolites in subjects 
1 to less than 2 years of age with CF, homozygous for F508del 
  
Endpoints Primary Endpoints 
Part A 
PK parameters of LUM and IVA 
Part B 
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory 
values (serum chemistry and hematology), standard 12-lead ECGs, vital signs, pulse 
oximetry, and ophthalmologic examinations 
Secondary Endpoints 
Part A 
• 
Safety and tolerability assessments based on AEs, clinical laboratory values 
(serum chemistry and hematology), standard 12-lead ECGs, vital signs, and pulse 
oximetry 
• 
PK parameters of the metabolites of LUM and IVA 
Part B 
• 
Absolute change from baseline in sweat chloride at Week 24 
• 
PK parameters of LUM, IVA, and their respective metabolites 
 


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Number of 
Subjects 
Part A 
Approximately 10 subjects are planned for enrollment, including a minimum of 
5 subjects 18 to <24 months of age (Cohort 1) and 5 subjects 12 to <18 months of age 
(Cohort 2). Subjects who participate in Part A may participate in Part B if they meet 
eligibility criteria; participation in Part A is not required for participation in Part B. 
A review of safety, tolerability, and available PK data will be completed after Part A 
to determine the dose(s) and/or weight bounds to be evaluated in Part B. Additional 
subjects or treatment cohorts may be enrolled, if data from the initially planned 
10 subjects are inadequate to make a determination of the dose(s) to be evaluated in 
Part B. 
Part B 
Approximately 30 subjects are planned for enrollment, including a minimum of 
10 subjects 18 to <24 months of age and 10 subjects 12 to <18 months of age.  
  
Study Population Male and female subjects 1 to <2 years of age on Day 1 with CF, homozygous for 
F508del. 
  
Investigational 
Drug 
Active substance: LUM/IVA fixed-dose combination 
 Activity: CFTR corrector and potentiator (Cl- secretion) 
 Strength and route of administration: 
• 
LUM 75-mg/IVA 94-mg granules for oral administration  
• 
LUM 100-mg/IVA 125-mg granules for oral administration 
• 
LUM 150-mg/IVA 188-mg granules for oral administration 
  
 
 


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Study Duration Part A 
The total duration is approximately 53 days (up to 28 days for the Screening Period, 
15 days for the Treatment Period, and 10 days for the Safety Follow-up Period). 
Part B 
The total duration is approximately 30 weeks (up to 28 days for the Screening Period, 
24 weeks for the Treatment Period, and 2 weeks for the Washout and Safety 
Follow-up Periods). 
  
Study Design Part A 
Subjects will be enrolled in Part A sequentially in the following cohorts: 
• 
Cohort 1: subjects aged 18 to <24 months 
• 
Cohort 2: subjects aged 12 to <18 months 
Enrollment in Part A will begin with subjects in Cohort 1. 
Part A includes the following: 
• 
Screening Period (Day -28 through Day -1) 
• 
Treatment Period (Day 1 through Day 15 ± 2 days; the last dose of LUM/IVA in 
Part A is the morning dose on Day 15) 
• 
Safety Follow-up Visit (10 ± 3 days after the last dose of LUM/IVA) 
Dose Regimens Investigated and Dose Adjustment 
• 
LUM 75 mg/IVA 94 mg every 12 hours (q12h) for subjects weighing 7 to <10 kg 
at screening  
• 
LUM 100 mg/IVA 125 mg q12h for subjects weighing 10 to <14 kg at screening 
• 
LUM 150 mg/IVA 188 mg q12h for subjects weighing ≥14 kg at screening 
Doses are based on the subject’s weight at screening. No dose adjustments will be 
made across the duration of treatment.  
Preliminary review of Part A data (e.g., from Cohort 1 and/or Cohort 2) and any 
updated modeling approaches resulting from such data may result in updated dose 
recommendations, e.g., for Part B. Changes to study drug dose(s) will be 
communicated to site personnel through a memorandum entitled “Justification for 
Dose Selection” to ensure clarity and consistency in study conduct. 
A review of safety, tolerability, and available PK data will be completed after each 
Part A Cohort to confirm or adjust the dose(s) and/or weight bounds to be evaluated 
in Part B. Additional subjects or treatment cohorts may be enrolled, if data from the 
initially planned 10 subjects are inadequate to make a determination of the dose(s) to 
be evaluated in Part B. 
Part B 
Part B includes the following: 
• 
Screening Period (Day -28 through Day -1) 
• 
Treatment Period (Day 1 through Week 24 ± 5 days; the last dose of LUM/IVA 
in Part B is the evening dose before the Week 24 Visit) 
• 
Washout Period (Week 24 to Week 26 ± 4 days) 
• 
Safety Follow-up Visit (Week 26 [2 weeks ± 4 days after the last dose of 
LUM/IVA]) 
Dose Regimens Investigated and Dose Adjustment: 
• 
LUM 75 mg/IVA 94 mg q12h for subjects weighing 7 to <10 kg at screening  
• 
LUM 100 mg/IVA 125 mg q12h for subjects weighing 10 to <14 kg at screening 
• 
LUM 150 mg/IVA 188 mg q12h for subjects weighing ≥14 kg at screening 




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IDMC Reviews An independent data monitoring committee (IDMC) is planned for Part B only. The 
IDMC objectives and operational details will be defined in a separate document (the 
IDMC Charter), which will be finalized before the first subject is enrolled in Part B. 
The IDMC will conduct regular planned reviews of study data for the purpose of 
safety monitoring as outlined in the IDMC Charter. 
 












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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 4 
3 
Schedule of Assessments ........................................................................................................ 9 
4 
Table of Contents ................................................................................................................. 14 
List of Tables ........................................................................................................................... 18 
List of Figures .......................................................................................................................... 18 
List of Abbreviations ............................................................................................................... 19 
Glossary of Terms .................................................................................................................... 20 
5 
Introduction .......................................................................................................................... 21 
5.1 
Background ..................................................................................................................... 21 
5.2 
Study Rationale .............................................................................................................. 21 
6 
Study Objectives .................................................................................................................. 21 
6.1 
Primary Objectives ......................................................................................................... 21 
6.2 
Secondary Objectives ..................................................................................................... 22 
7 
Study Endpoints ................................................................................................................... 22 
7.1 
Primary Endpoints .......................................................................................................... 22 
7.2 
Secondary Endpoints ...................................................................................................... 22 
 
 
8 
Study Population .................................................................................................................. 23 
8.1 
Inclusion Criteria ............................................................................................................ 23 
8.2 
Exclusion Criteria ........................................................................................................... 24 
9 
Study Implementation ......................................................................................................... 25 
9.1 
Study Design .................................................................................................................. 25 
9.1.1 
Overview of Study Design ..................................................................................... 25 
9.1.1.1 
Part A ............................................................................................................... 26 
9.1.1.2 
Part B ................................................................................................................ 27 
9.1.2 
Screening ................................................................................................................ 27 
9.1.2.1 
Repetition of Screening Assessments .............................................................. 28 
9.1.2.2 
Rescreening ...................................................................................................... 28 
9.1.2.3 
Extension of Screening Period Window .......................................................... 28 
9.1.3 
Treatment Period .................................................................................................... 29 
9.1.3.1 
Part A ............................................................................................................... 29 
9.1.3.2 
Part B ................................................................................................................ 29 
9.1.4 
Washout Period ....................................................................................................... 29 
9.1.4.1 
Part A ............................................................................................................... 29 
9.1.4.2 
Part B ................................................................................................................ 29 
9.1.5 
Follow-up ................................................................................................................ 29 
9.1.5.1 
Part A ............................................................................................................... 29 
9.1.5.2 
Part B ................................................................................................................ 29 
9.1.6 
Early Discontinuation/Early Termination of Treatment ......................................... 30 
9.1.6.1 
Part A ............................................................................................................... 30 
9.1.6.2 
Part B ................................................................................................................ 30 
9.1.7 
Independent Data Monitoring Committee .............................................................. 30 


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9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 30 
9.3 
Rationale for Study Design and Study Drug Regimens ................................................. 31 
9.3.1 
Study Design ........................................................................................................... 31 
9.3.2 
Study Drug Dose and Duration .............................................................................. 31 
9.3.3 
Rationale for Study Assessments ........................................................................... 33 
9.4 
Study Restrictions ........................................................................................................... 34 
9.5 
Prior and Concomitant Medications ............................................................................... 35 
9.6 
Administration ................................................................................................................ 36 
9.6.1 
Part A ...................................................................................................................... 36 
9.6.2 
Part B ...................................................................................................................... 37 
9.7 
Dose Modification for Toxicity ...................................................................................... 38 
9.8 
Removal of Subjects ....................................................................................................... 38 
9.9 
Replacement of Subjects ................................................................................................ 39 
9.9.1 
Part A ...................................................................................................................... 39 
9.9.2 
Part B ...................................................................................................................... 39 
10 Study Drug Information and Management ....................................................................... 39 
10.1 Preparation and Dispensing ............................................................................................ 39 
10.2 Packaging and Labeling ................................................................................................. 39 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 39 
10.4 Drug Accountability ....................................................................................................... 40 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 40 
10.6 Compliance ..................................................................................................................... 40 
10.7 Blinding and Unblinding ................................................................................................ 41 
11 Assessments .......................................................................................................................... 41 
11.1 Timing of Assessments ................................................................................................... 41 
11.2 Subject and Disease Characteristics ............................................................................... 41 
11.3 Pharmacokinetics ............................................................................................................ 41 
11.3.1 
Blood Sampling ...................................................................................................... 41 
11.3.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 42 
11.3.3 
Bioanalysis .............................................................................................................. 42 
11.4 Pharmacodynamics ......................................................................................................... 42 
11.4.1 
Part A ...................................................................................................................... 42 
11.4.2 
Part B ...................................................................................................................... 42 
11.4.2.1 Sweat Chloride ................................................................................................. 42 
11.5 Efficacy ........................................................................................................................... 45 
11.5.1 
Part A ...................................................................................................................... 45 
11.5.2 
Part B ...................................................................................................................... 45 
11.6 Safety .............................................................................................................................. 45 
11.6.1 
Adverse Events ....................................................................................................... 45 


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11.6.2 
Clinical Laboratory Assessments ........................................................................... 45 
11.6.3 
Elevation of Liver Function Test Parameters ......................................................... 46 
11.6.4 
Physical Examinations and Vital Signs .................................................................. 47 
11.6.5 
Electrocardiograms ................................................................................................. 47 
11.6.6 
Ophthalmologic Examination ................................................................................. 48 
11.6.7 
Contraception and Pregnancy ................................................................................. 48 
12 Statistical and Analytical Plans .......................................................................................... 48 
12.1 Sample Size and Power .................................................................................................. 48 
12.2 Analysis Sets .................................................................................................................. 49 
12.3 Statistical Analysis ......................................................................................................... 49 
12.3.1 
General Considerations ........................................................................................... 50 
12.3.2 
Background Characteristics .................................................................................... 50 
12.3.2.1 Subject Disposition .......................................................................................... 50 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 51 
12.3.2.3 Prior and Concomitant Medications ................................................................ 51 
12.3.2.4 Study Drug Exposure ....................................................................................... 51 
12.3.2.5 Study Drug Compliance ................................................................................... 52 
12.3.3 
Pharmacodynamics Analysis (Part B Only) ........................................................... 52 
12.3.3.1 Analysis of Primary Endpoints ........................................................................ 52 
12.3.3.2 Analysis of Secondary Pharmacodynamic Endpoint ....................................... 52 
 
12.3.4 
Safety Analysis ....................................................................................................... 55 
12.3.4.1 Adverse Events ................................................................................................ 55 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 56 
12.3.4.3 Electrocardiogram ............................................................................................ 57 
12.3.4.4 Vital Signs ........................................................................................................ 57 
12.3.4.5 Pulse Oximetry ................................................................................................. 57 
12.3.4.6 Ophthalmologic Examinations ......................................................................... 57 
12.3.4.7 Physical Examination ....................................................................................... 57 
12.3.5 
Interim and IDMC Analyses ................................................................................... 57 
12.3.5.1 Interim Analysis ............................................................................................... 57 
12.3.5.2 IDMC Analysis ................................................................................................ 57 
12.4 Clinical Pharmacology Analysis .................................................................................... 57 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 57 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 58 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 58 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 58 
13.1.1 
Adverse Events ....................................................................................................... 58 
13.1.1.1 Definition of an Adverse Event........................................................................ 58 
13.1.1.2 Clinically Significant Assessments .................................................................. 58 
13.1.1.3 Documentation of Adverse Events................................................................... 59 
13.1.1.4 Adverse Event Severity .................................................................................... 60 
13.1.1.5 Adverse Event Causality .................................................................................. 60 
13.1.1.6 Study Drug Action Taken ................................................................................ 61 
13.1.1.7 Adverse Event Outcome .................................................................................. 61 


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13.1.1.8 Treatment Given............................................................................................... 61 
13.1.2 
Serious Adverse Events .......................................................................................... 61 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 61 
13.1.2.2 Documentation of Serious Adverse Events ...................................................... 62 
13.1.2.3 Reporting Serious Adverse Events .................................................................. 62 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 63 
13.2 Administrative Requirements ......................................................................................... 63 
13.2.1 
Ethical Considerations ............................................................................................ 63 
13.2.2 
Subject Information and Informed Consent ........................................................... 63 
13.2.3 
Investigator Compliance ......................................................................................... 63 
13.2.4 
Access to Records ................................................................................................... 64 
13.2.5 
Subject Privacy ....................................................................................................... 64 
13.2.6 
Record Retention .................................................................................................... 64 
13.2.7 
Study Termination .................................................................................................. 64 
13.2.8 
End of Study ........................................................................................................... 65 
13.3 Data Quality Assurance .................................................................................................. 65 
13.4 Monitoring ...................................................................................................................... 65 
13.5 Electronic Data Capture ................................................................................................. 65 
13.6 Publications and Clinical Study Report .......................................................................... 66 
 
 
13.6.2 
Clinical Study Report ............................................................................................. 66 
14 Reference .............................................................................................................................. 67 
15 Protocol Signature Pages .................................................................................................... 69 
15.1 Sponsor Signature Page .................................................................................................. 69 
15.2 Investigator Signature Page ............................................................................................ 70 
 


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List of Tables 
Table 3-1 
Study VX16-809-122: Part A and Part B Screening .............................................. 9 
Table 3-2 
Study VX16-809-122: Part A Treatment Period and Safety Follow-up Visit ...... 10 
Table 3-3 
Study VX16-809-122: Part B Treatment Period and Safety Follow-up Visit ...... 12 
Table 9-1 
Summary of LUM and IVA Exposures in Subjects With CF Who Are 2 Years of 
Age and Older ....................................................................................................... 32 
Table 9-2 
Study Restrictions: Part A ..................................................................................... 35 
Table 9-3 
Study Restrictions: Part B ..................................................................................... 35 
Table 9-4 
Study Drug Administration: Part A ...................................................................... 36 
Table 9-5 
Study Drug Administration: Planned Doses for Part B ........................................ 37 
Table 10-1 
Study Drug ............................................................................................................ 40 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 45 
Table 12-1 
Probability of Observing Adverse Events in At Least 1 Subject if the Adverse 
Event Incidence is 5% and 10% ............................................................................ 49 
Table 13-1 
Grading of AE Severity ........................................................................................ 60 
Table 13-2 
Classifications for AE Causality ........................................................................... 60 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 61 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 61 
List of Figures 
Figure 9-1 
Schematic of Study Design for Part A (Cohort 1 and Cohort 2) .......................... 26 
Figure 9-2 
Schematic of Study Design for Part B .................................................................. 27 
 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CF 
cystic fibrosis 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
CI 
confidence interval 
Cl- 
chloride ion 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
eGFR 
estimated glomerular filtration rate 
ETT 
Early Termination of Treatment 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon corresponding 
to position 508 of the wild-type protein 
F508del 
CFTR protein lacking the phenylalanine normally found at position 508 of the 
wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
 
 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GPS 
Global Patient Safety 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IRB 
institutional review board 
 
 
IV 
intravenous 
IVA 
ivacaftor 
 
 
LFT 
liver function test 
LLN 
lower limit of normal 
LUM 
lumacaftor 


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Abbreviation 
Definition 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamics(s) 
PE 
physical examination 
PK 
pharmacokinetic(s) 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PT 
Preferred Term 
q12h 
every 12 hours 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QT 
QT interval 
QTc 
QT interval corrected 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SUSAR 
suspected, unexpected, serious adverse reaction 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
WHODD 
World Health Organization Drug Dictionary 
 
Glossary of Terms 
Abbreviated study numbers: In the body of the text, study numbers are abbreviated to the last 
3 digits for lumacaftor studies (e.g., Study VX15-809-115 is Study 115). 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive disease with serious, chronically debilitating 
morbidities and high premature mortality, and at present, there is no cure. CF affects more than 
70,000 individuals worldwide.1 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.2, 3 Although the disease affects multiple organs, progressive loss of lung function is the 
leading cause of mortality.4 
CF is caused by a variant in the gene encoding CFTR, an epithelial Cl- ion channel that is 
responsible for aiding in the regulation of salt and water absorption and secretion in various 
tissues.5 This function is abnormal in patients with CF due to a loss of cell surface expression 
and/or function of CFTR. 
Lumacaftor (LUM; VX-809)/ivacaftor (IVA; VX-770) combination therapy (Orkambi™) is the 
first medicine designed to treat the underlying molecular defect and enhance the function of 
CFTR in patients homozygous for F508del. The LUM/IVA development program is designed to 
support the hypothesis that an oral chronic treatment restoring CFTR function can lead to 
improved pulmonary and extrapulmonary manifestations of CF, prevent progressive lung 
damage, and ultimately prolong survival. 
Details about the LUM/IVA development program can be found in the Investigator’s Brochure. 
5.2 
Study Rationale 
Approximately half of the total CF patient population is <18 years of age.2, 6-8 Even before the 
widespread adoption of newborn screening, the majority of patients with CF were diagnosed in 
infancy or early childhood due to manifestations of the disease. Pancreatic destruction leading to 
pancreatic exocrine insufficiency begins in utero, and lung involvement is manifest by 
pulmonary inflammation and infection that begins shortly after birth.9, 10  
The primary objectives of the present study are to obtain pharmacokinetic (PK) and safety 
information to support a proposed indication expansion of LUM/IVA in subjects 1 to <2 years of 
age with CF, homozygous for F508del.  
6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
Part A 
To evaluate the PK of LUM/IVA in subjects 1 to less than 2 years of age with CF, homozygous 
for F508del 
Part B 
To evaluate the safety of LUM/IVA in subjects 1 to less than 2 years of age with CF, 
homozygous for F508del 


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6.2 
Secondary Objectives 
Part A 
• To evaluate the safety of LUM/IVA in subjects 1 to less than 2 years of age with CF, 
homozygous for F508del 
• To evaluate the PK of the metabolites of LUM and IVA in subjects 1 to less than 2 years of 
age with CF, homozygous for F508del 
Part B 
• To evaluate the pharmacodynamics (PD) of LUM/IVA in subjects 1 to less than 2 years of 
age with CF, homozygous for F508del 
• To evaluate the PK of LUM and IVA and their respective metabolites in subjects 1 to less 
than 2 years of age with CF, homozygous for F508del 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoints 
Part A 
PK parameters of LUM and IVA 
Part B 
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values 
(serum chemistry and hematology), standard 12-lead ECGs, vital signs, pulse oximetry, and 
ophthalmologic examinations  
7.2 
Secondary Endpoints 
Part A 
• Safety and tolerability assessments based on AEs, clinical laboratory values (serum 
chemistry and hematology), standard 12-lead ECGs, vital signs, and pulse oximetry 
• PK parameters of the metabolites of LUM and IVA 
Part B 
• Absolute change from baseline in sweat chloride at Week 24 
• PK parameters of LUM, IVA, and their respective metabolites 


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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 
for the study. 
8.1 
Inclusion Criteria 
Subjects who meet all of the following inclusion criteria will be eligible: 
1. Subject’s legally appointed and authorized representative (e.g., parent or legal guardian) will 
sign and date an informed consent form (ICF). 
2. Subject’s legally appointed and authorized representative (e.g., parent or legal guardian) is 
willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, and other study procedures. 
3. Subjects (male and female) will be 1 to less than 2 years of age on Day 1 of the relevant part 
of the study. 
4. Weight at the Screening Visit must be within the weight limits as defined for the study drug 
dose levels (see Table 9-4 and Table 9-5) or according to the dosing guidelines identified in 
the “Justification for Dose Selection” memorandum effective at the time a subject is 
screened.  


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5. Subjects with confirmed diagnosis of CF11 at the Screening Visit. CF is defined as: 
• 2 CF-causing mutations (all as documented in the subject’s medical record) 
o Subjects must be homozygous for F508del (genotype to be confirmed at the 
Screening Visit): If a genotype test has been performed previously and is documented 
in the subject’s medical record, the subject is not required to be tested for CFTR 
genotype at screening, but the subject’s eligibility must be approved by the Vertex 
medical monitor. If a historic genotype result is not available at the Screening Visit or 
if the historic genotype result is not approved by the Vertex medical monitor, the 
subject will be tested for CFTR genotype at the Screening Visit, and the results must 
be reviewed before the first dose. Note: Newborn screening genotype results are not 
sufficient for eligibility. 
AND (1 of the 2 criteria below) 
• chronic sinopulmonary disease OR gastrointestinal/nutritional abnormalities  
OR 
• a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis as 
documented in the subject’s medical record OR from the sweat chloride test result 
obtained at the Screening Visit. If an eligible historical sweat chloride result is 
documented in the subject’s medical record, that result alone (and not the Screening Visit 
result) may be used to determine eligibility.  
6. Subjects with stable CF disease as deemed by the investigator at the Screening Visit. 
7. Subject’s legally appointed and authorized representative (e.g., parent or legal guardian) are 
willing to have the subject remain on a stable CF medication regimen through the Safety 
Follow-up Visit. 
8.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible:  
1. History of any comorbidity reviewed at the Screening Visit that, in the opinion of the 
investigator, might confound the results of the study or pose an additional risk in 
administering LUM/IVA to the subject. For example, a history of cirrhosis with portal 
hypertension. 
2. Any clinically significant laboratory abnormalities at the Screening Visit that would interfere 
with the study assessments or pose an undue risk for the subject (as deemed by the 
investigator). 
3. Any of the following abnormal laboratory values at the Screening Visit: 
• Hemoglobin <9.5 g/dL 
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin 
>2 × upper limit of normal (ULN) 
• Chronic kidney disease of Stage 3 (estimated glomerular filtration rate [eGFR] 
<60 mL/min/1.73 m2 calculated by the Bedside Schwartz equation12) based on the normal 
range for eGFR in this age group (62 to 191 mL/min/1.73 m2)  


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4. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy 
(including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of 
LUM/IVA).  
5. A standard 12-lead ECG demonstrating QTc >450 msec at the Screening Visit. If QTc 
exceeds 450 msec at the Screening Visit, the ECG should be repeated 2 more times during 
the Screening Period, and the average of the 3 QTc values should be used to determine the 
subject’s eligibility. 
6. History of solid organ or hematological transplantation. 
7. Ongoing or prior participation in an investigational drug study (including studies 
investigating LUM and/or IVA) within 30 days of the Screening Visit.  
• A washout period of 5 terminal half-lives of the previous investigational study drug, or 
30 days, whichever is longer, must elapse before the Screening Visit.  
• The duration of the elapsed time may be longer if required by local regulations.  
Note: Ongoing participation in a noninterventional study (including observational studies) is 
permitted. 
8. Use of restricted medication or food within specified duration before the first dose of 
LUM/IVA as defined in Section 9.4. 
9. An adequate slit-lamp examination could not be conducted at the Screening Visit 
ophthalmologic examination. 
10. History of cataract/lens opacity or evidence of cataract/lens opacity determined to be 
clinically significant by a licensed ophthalmologist during the ophthalmologic examination at 
the Screening Visit. The Screening Visit ophthalmologic examination does not need to be 
repeated if there is documentation of an examination meeting protocol criteria that was 
conducted within 3 months before the Screening Visit (Section 11.6.6).  
11. The subject or a 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. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
9.1.1 
Overview of Study Design 
This is a Phase 3, 2-part, open-label, multicenter study evaluating the PK, safety, and PD of 
multiple doses of LUM/IVA in subjects 1 to <2 years of age with CF, homozygous for F508del. 
Subjects who participate in Part A may participate in Part B if they meet eligibility criteria.  


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9.1.1.1 
Part A 
Figure 9-1 depicts the schematic for the Part A study design.  
Subjects will be enrolled in Part A sequentially in the following cohorts: 
• Cohort 1: subjects aged 18 to <24 months 
• Cohort 2: subjects aged 12 to <18 months 
Enrollment in Part A will begin with subjects in Cohort 1. 
A review of safety, tolerability, and available PK data will be completed after each Part A Cohort 
(e.g., Cohort 1 and Cohort 2) to confirm or adjust the dose(s) and/or weight bounds to be 
evaluated in Part B. Additional subjects or treatment cohorts may be enrolled, if data from the 
initially planned 10 subjects are inadequate to make a determination of the dose(s) to be 
evaluated in Part B. 
Figure 9-1 
Schematic of Study Design for Part A (Cohort 1 and Cohort 2) 
 
 
IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours 
Notes: Approximately 10 subjects are planned for enrollment, including a minimum of 5 subjects 18 to <24 months of age 
(Cohort 1) and 5 subjects 12 to <18 months of age (Cohort 2).  
a 
Doses are based on the subject’s weight at screening in Part A. No dose adjustments will be made across the duration of 
treatment. On Day 15, only the morning dose will be administered. Refer to Section 9.6.1 for additional study drug 
administration details. 


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9.1.1.2 
Part B 
Figure 9-2 depicts the schematic for the Part B study design. 
 
 
Figure 9-2 
Schematic of Study Design for Part B 
 
IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours 
Notes: Approximately 30 subjects are planned for enrollment, including a minimum of 10 subjects 18 to <24 months 
of age and 10 subjects 12 to <18 months of age.  
a 
The doses and weight bounds listed above are those planned for Part B. Doses are based on the subject’s weight 
at screening in Part B. During the Treatment Period, doses will be adjusted upward if the subject's weight is at 
or above the lower weight bound of the next higher dose at 2 consecutive study visits. However, no downward 
dose adjustments will be made if a subject’s weight decreases. Refer to Section 9.6.2 for additional study drug 
administration details. The last dose of LUM/IVA in Part B will be the evening dose before the Week 24 Visit.  
b 
Refer to Sections 9.1.3.2, 9.1.5.2, and 9.6.2 for details. 
c 
At the Safety Follow-up Visit, subjects who complete LUM/IVA treatment and the visits in the Treatment 
Period will be offered the opportunity to enroll in an optional open label Extension Study evaluating LUM/IVA 
(enrollment will be based on eligibility criteria specified in the Extension Study). The Safety Follow-up Visit, if 
applicable, is the last visit for Part B, and should also be the Day 1 Visit in the Extension Study. 
 
9.1.2 
Screening 
Screening Visit assessments are listed in Table 3-1. 
Screening will occur within 28 days before administration of LUM/IVA. The investigator (or an 
appropriate authorized designee at the study site) will obtain informed consent from the subject’s 
parent or legal guardian.  
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.4). 




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9.1.3 
Treatment Period 
9.1.3.1 
Part A 
Treatment Period assessments are listed in Table 3-2. Subjects will be outpatients during the 
Treatment Period. All visits should occur within the windows specified. 
The Treatment Period is 15 days; LUM/IVA will be administered every 12 hours (q12h) from 
Day 1 through Day 15. The morning LUM/IVA dose on Day 15 will be the last dose. LUM/IVA 
administration and management details are provided in Section 9.6.1 and Section 10.  
Procedures for subjects who prematurely discontinue LUM/IVA treatment are described in 
Section 9.1.6.1. 
9.1.3.2 
Part B 
Treatment Period assessments are listed in Table 3-3. Subjects will be outpatients during the 
Treatment Period. All visits should occur within the windows specified. 
The Treatment Period is 24 weeks; LUM/IVA will be administered q12h from Day 1 through 
Week 24. The evening LUM/IVA dose before the Week 24 Visit will be the last dose in Part B. 
LUM/IVA administration and management details are provided in Section 9.6.2 and Section 10. 
Procedures for subjects who prematurely discontinue LUM/IVA treatment are described in 
Section 9.1.6.2. 
9.1.4 
Washout Period 
9.1.4.1 
Part A 
Not applicable 
9.1.4.2 
Part B 
A 2-week Washout Period (Week 24 to Week 26 ± 4 days) will be included in order to evaluate 
the off-drug PD response. 
9.1.5 
Follow-up 
9.1.5.1 
Part A 
Table 3-2 lists the Safety Follow-up Visit assessments for Part A. Subjects will have a Safety 
Follow-up Visit 10 (± 3) days after the last dose of LUM/IVA.  
9.1.5.2 
Part B 
Table 3-3 lists the Safety Follow-up Visit assessments for Part B. The Safety Follow-up Visit is 
scheduled to occur 2 weeks (± 4 days) after the last dose of LUM/IVA.  
The Safety Follow-up Visit, if applicable, is the last visit for Part B, and should also be the Day 1 
Visit in the Extension Study. 
The Safety Follow-up Visit is not required for the following: 
• Subjects who permanently discontinue LUM/IVA treatment before or at the Week 16 Visit if 
they return for the Week 24 Visit 


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• Subjects who continue onto commercially available LUM/IVA by prescription of a physician 
within 2 weeks (± 4 days) of completing LUM/IVA treatment at Week 24 or at the Early 
Termination of Treatment (ETT) Visit 
• Subjects who complete their ETT Visit ≥10 days after the last dose of LUM/IVA 
(Section 9.1.6.2) 
9.1.6 
Early Discontinuation/Early Termination of Treatment 
9.1.6.1 
Part A 
Subjects who permanently discontinue LUM/IVA treatment for any reason (except withdrawal 
of consent) will be asked to return to the study site as soon as possible after their last dose of 
LUM/IVA to complete the ETT Visit. The assessments to be completed are shown in Table 3-2. 
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. 
9.1.6.2 
Part B 
Subjects who prematurely discontinue LUM/IVA treatment will be asked to complete the ETT 
Visit as soon as possible after their last dose. The assessments to be completed are shown in 
Table 3-3. If the ETT Visit occurs ≥10 days after the last dose of LUM/IVA, then the ETT Visit 
will replace the Safety Follow-up Visit, if applicable (i.e., the assessments performed will be 
those specified for the ETT Visit), and a Safety Follow-up Visit will not be required. 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. 
Subjects who become eligible to receive commercially available LUM/IVA by prescription of a 
physician, and who choose to continue onto commercially available LUM/IVA before 
completion of Part B, must remain on study-supplied LUM/IVA through the ETT Visit and may 
only initiate treatment with commercially available LUM/IVA after completion of this visit. 
9.1.7 
Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC) is planned for Part B only. The IDMC 
objectives and operational details will be defined in a separate document (the IDMC Charter), 
which will be finalized before the first subject is enrolled in Part B. The IDMC will conduct 
regular planned reviews of study data for the purpose of safety monitoring as outlined in the 
IDMC Charter. 
9.2 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study with weight-based treatment. Randomization is not required. 


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9.3 
Rationale for Study Design and Study Drug Regimens 
9.3.1 
Study Design 
This is a Phase 3, 2-part, open-label, multicenter study evaluating the PK, safety, and PD of 
multiple doses of LUM/IVA in subjects 1 to <2 years of age with CF, homozygous for F508del. 
Part A will evaluate the PK and safety of LUM/IVA over 15 days of dosing. The evaluation of 
LUM/IVA as multiple doses allows for the assessment of the time-dependent induction effect of 
LUM on the metabolism of IVA. The duration of dosing in Part A was selected to evaluate the 
PK and safety endpoints when the induction effect of LUM on the metabolism of IVA was 
anticipated to have reached steady state. Part B is designed to evaluate the safety of LUM/IVA 
dosing over 24 weeks in this pediatric CF population. In addition, the PD effects and PK of 
multiple doses of LUM/IVA over 24 weeks of dosing will be evaluated, and a 2-week Washout 
Period is included in order to evaluate the off-drug PD response in this open-label study.  
Vertex has established efficacy, safety, and PK profiles for LUM/IVA in subjects 6 years of age 
and older with CF, homozygous for F508del (Studies 103, 104, and 109). Because the 
underlying genetic and molecular etiology of the disease is identical between younger and older 
patients, and the outcome of therapy is likely to be comparable, extrapolation of efficacy from 
older to younger patients is appropriate, and PK studies in younger patients, together with safety 
studies, can provide adequate information for use.13  
Safety and PK profiles for LUM/IVA have been established in subjects 2 through 5 years of age 
with CF, homozygous for F508del (Study 115). The present study is designed to obtain PK and 
safety information to support a proposed indication expansion of LUM/IVA in subjects 1 to 
<2 years of age with CF, homozygous for F508del. The open-label design is considered adequate 
to evaluate the PK and safety of LUM/IVA in this pediatric population. 
9.3.2 
Study Drug Dose and Duration 
Rationale for Dose 
Part A of this study is designed to characterize the safety and PK of LUM and IVA in subjects 
1 to <2 years of age. The plasma concentration versus time data from Part A is intended to 
inform the appropriateness or necessary adjustment of planned doses for Part B. A population 
PK model with maturation function and allometric scaling of clearance and volume of 
distribution as a function of weight was used to project exposures of LUM and IVA for 
comparison with clinical experiences with both study drugs and to select doses to be evaluated in 
this study population. The IVA model was coupled to the LUM model to account for the 
induction of CYP3A by LUM, which increases the metabolism of IVA. Thus, the IVA clearance 
is impacted by the weight dependence for the clearance of IVA alone and LUM 
exposure-dependent induction effect. The population PK model is based on data obtained from 
subjects 2 years of age and older across the LUM and IVA combination development program.  
In the combination program, the dose regimen of LUM 400 mg/IVA 250 mg q12h was used in 
the Phase 3 studies (Studies 103 and 104) for subjects 12 years of age and older. In Phase 3 
Studies 109 and 011, the dose regimen of LUM 200 mg/IVA 250 mg q12h was used for subjects 
6 through 11 years of age. In Phase 3 Study 115, the dose regimen of LUM 100 mg/IVA 
125 mg q12h (body weight <14 kg) or LUM 150 mg/IVA 188 mg q12h (body weight ≥14 kg) 
was used for subjects 2 through 5 years of age. The LUM and IVA exposures from these studies 
are summarized in Table 9-1. Based on the initial simulations for subjects 1 to <2 years of age, 


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the LUM doses selected for Part A are expected to yield exposures that are comparable to those 
of subjects 2 years of age and older, in whom LUM/IVA combination therapy has been shown to 
be safe and well tolerated. 
IVA as a single agent was previously investigated and approved for use in pediatric patients with 
CF, 2 to <6 years of age with select mutations. In the Phase 3 study for this population, pediatric 
subjects who weighed <14 kg received oral administration of IVA granules, 50 mg q12h, and 
had a mean AUCss of 10.5 μg∙h/mL; pediatric subjects 2 to <6 years of age who weighed ≥14 kg 
received IVA granules, 75 mg q12h, and had a mean AUCss of 11.3 μg∙h/mL. In the combination 
program, due to the induction effect of LUM on the metabolism of IVA, the IVA exposures are 
lower than that of IVA monotherapy. The IVA AUCss for subjects 2 years of age and older in the 
combination program are summarized in Table 9-1. Based on the initial simulations for subjects 
1 to <2 years of age, the IVA doses selected for Part A are expected to yield IVA exposures that 
are comparable to subjects 6 years of age and older and within prior clinical experience with IVA 
alone and IVA given in combination with LUM.  
Table 9-1 
Summary of LUM and IVA Exposures in Subjects With CF Who Are 
2 Years of Age and Older  
 
LUM AUC0-12h 
(μg∙h/mL) 
IVA AUC0-12h 
(μg∙h/mL) 
Age Group 
Mean (SD) 
Mean (SD) 
2 through 5 years 
(weight <14 kg) 
180 (45.5) 
5.92 (4.61) 
2 through 5 years 
(weight ≥14 kg) 
217 (48.6) 
5.90 (1.93) 
6 through 11 years 
(pediatrics) 
224 (59.1) 
6.17 (2.68) 
12 through 17 years 
(adolescents) 
241 (61.4) 
3.89 (1.56) 
18 years and older (adults) 
217 (47.9) 
3.80 (1.94) 
Source: Report N329 (Tables 7-4 and 7-7)14 
CF: cystic fibrosis; IVA: ivacaftor; LUM: lumacaftor; PK: pharmacokinetic; q12h: every 12 hours 
Notes: PK data are from Study 115 (2 through 5 years of age), Studies 011 Part B and 109 (6 through 11 years of 
age), and Studies 103 and 104 (12 through 17 years of age; 18 years of age and older). Subjects in Study 115 
received LUM 100 mg/IVA 125 mg q12h (body weight <14 kg) or LUM 150 mg/IVA 188 mg q12h (body 
weight ≥14 kg) for 24 weeks, subjects in Studies 011 and 109 received LUM 200 mg/IVA 250 mg q12h for 
24 weeks, and subjects in Studies 103 and 104 received LUM 400 mg/IVA 250 mg q12h for 24 weeks. 
No safety issues were identified in prior clinical or nonclinical studies that would preclude the 
dosing regimen proposed for the current protocol.  
Preliminary data and any updated modeling approaches resulting from such data may result in 
updated dose recommendations. Changes to study drug dose(s) will be communicated to site 
personnel through a memorandum entitled “Justification for Dose Selection” to ensure clarity 
and consistency in study conduct. 
The population PK models for LUM and IVA were updated with the PK data from Part A 
Cohort 1 (subjects 18 to <24 months of age). The following adjustments to the originally planned 




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9.4 
Study Restrictions 
Prohibited medications and certain foods are not allowed as summarized in Table 9-2 (Part A) 
and Table 9-3 (Part B). 
A nonexhaustive list of study prohibitions and cautions for food and medication will be provided 
in the Study Reference Manual. 


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Table 9-2 
Study Restrictions: Part A 
Restricted Medication/Food 
Study Period 
Screening Period 
Treatment Period 
Moderate and strong CYP3A 
inhibitors and inducers 
None allowed within 14 days before 
the first dose of LUM/IVA 
None allowed until after the Safety 
Follow-up Visit 
Grapefruit/grapefruit juice, 
pomelos, star fruit, and Seville 
oranges 
None allowed within 14 days before 
the first dose of LUM/IVA 
None allowed until last PK sample is 
taken 
IVA: ivacaftor; LUM: lumacaftor; PK: pharmacokinetics 
Note: The use of restricted medication in subjects with a medical need will be addressed on a case-by-case basis 
with the medical monitor or authorized designee. 
 
Table 9-3 
Study Restrictions: Part B 
Restricted Medication/Food 
Study Period 
Screening Period 
Treatment Period 
Strong CYP3A inducers 
None allowed within 14 days before 
the first dose of LUM/IVA 
None allowed 
Strong CYP3A inhibitors 
None allowed within 14 days before 
the first dose of LUM/IVA 
Use with caution 
IVA: ivacaftor; LUM: lumacaftor 
Note: The use of restricted medication in subjects with a medical need will be addressed on a case-by-case basis 
with the medical monitor or authorized designee. 
Use of CYP3A substrates is not prohibited, but investigators need to be aware that LUM appears 
to be a strong inducer of CYP3A. Therefore, the efficacy of drugs extensively metabolized by 
CYP3A may be affected.  
Use of CYP2C and CYP2B6 substrates is not prohibited, but investigators need to be aware that 
LUM has been shown in vitro to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition 
of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest 
that IVA may inhibit CYP2C9. Therefore, concomitant use of LUM/IVA with CYP2B6, 
CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates.  
Each investigator should evaluate the benefit-risk ratio of using CYP3A, CYP2B6, CYP2C8, 
CYP2C9, and CYP2C19 substrates with LUM and IVA and discuss their use with the medical 
monitor or authorized designee. 
9.5 
Prior and Concomitant Medications 
Information regarding all prior and concomitant medications, including the subject’s CF 
medications, other medications, and herbal and naturopathic remedies administered from 28 days 
before the first dose through the Safety Follow-up Visit, if applicable, will be recorded in each 
subject’s source documents. In addition, concomitant medication dose(s) may be collected. 
• It is recommended that subjects remain on a stable medication regimen for their CF from 
28 days before Day 1 through the Safety Follow-up Visit, if applicable. Stable medication 


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regimen is defined as the current medication regimen for CF that subjects have been 
following for at least 28 days before Day 1. 
• While the etiology of respiratory events associated with LUM/IVA is not yet known, data 
from healthy subjects in Study 009 Cohort 4 suggest that treatment with short-acting 
bronchodilators may reverse the initial transient decline in percent predicted forced 
expiratory volume in 1 second (ppFEV1) when dosed with LUM/IVA. Subjects may be 
prescribed a short-acting bronchodilator in accordance with local drug labeling (if not already 
prescribed) to ensure constant availability during the study. 
• Information about bronchodilator use during the study will be collected and documented in 
the subject’s source documents.  
9.6 
Administration 
9.6.1 
Part A 
LUM/IVA will be administered orally as shown in Table 9-4.  
Table 9-4 
Study Drug Administration: Part A 
Dosea 
Time 
LUM/IVA 
(Number of stick packs) 
Subject screening weight 7 to <10 kga,b 
LUM 75 mg/IVA 94 mg q12h 
AM 
1 stick pack 
PM 
1 stick pack 
Subject screening weight 10 to <14 kga,b 
LUM 100 mg/IVA 125 mg q12h 
AM 
1 stick pack 
PM 
1 stick pack 
Subject screening weight ≥14 kga,b 
LUM 150 mg/IVA 188 mg q12h 
AM 
1 stick pack 
PM 
1 stick pack 
IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours 
a 
Preliminary review of Part A data (e.g., from Cohort 1 and/or Cohort 2) and any updated modeling approaches resulting from 
such data may result in updated dose recommendations, e.g., for Part B. Changes to study drug dose(s) will be communicated 
to site personnel through a memorandum entitled “Justification for Dose Selection” to ensure clarity and consistency in study 
conduct. 
b 
Doses are based on the subject’s weight at screening; no dose adjustments will be made across the duration of study 
treatment. 
 
LUM/IVA will be administered approximately 30 minutes from the start of consuming 
fat-containing food such as a standard “CF” high-fat, high-calorie meal or snack according to the 
following guidelines:  
1. The morning LUM/IVA dose will be administered at the study site on Days 1, 8, and 15. 
2. The date, amount taken, time of LUM/IVA administration, including whether food was taken 
with each dose, and occurrence and time of regurgitation within 1 hour after dosing will be 
recorded for each dose. 


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3. LUM/IVA will be administered after all predose safety and PK assessments have been 
performed. 
4. All LUM/IVA doses (morning and evening, as applicable) should be administered at 
approximately every 12 hours (± 1 hour) on each dosing occasion (e.g., if the morning dose 
is administered at 08:00 on Day 1, all subsequent morning doses should be administered 
between 07:00 and 09:00).  
5. The granule formulation will be dispensed by opening the stick packs containing the granules 
and mixing the granules with the approved foods and liquids listed in the Study Reference 
Manual. Each dose will be composed of the approved food or liquids into which the granules 
from the stick packs are mixed. Details on preparing LUM/IVA will be provided in the 
Pharmacy Manual. 
6. At the Day 1 Visit, all subjects will be observed for 4 hours after the morning LUM/IVA 
dose. 
7. The morning dose on Day 15 will be the last LUM/IVA dose. 
9.6.2 
Part B 
A review of safety, tolerability, and available PK data will be completed after Part A to confirm 
or adjust the dose(s) and/or weight bounds to be evaluated in Part B (Section 9.3.2). LUM/IVA 
will be administered orally as shown in Table 9-5.  
Table 9-5 
Study Drug Administration: Planned Doses for Part B 
Proposed Dosesa 
Time 
LUM/IVA 
(Number of stick packs) 
Subject screening weight 7 to <10 kga,b 
LUM 75 mg/IVA 94 mg q12h 
AM 
1 stick pack 
PM 
1 stick pack 
Subject screening weight 10 to <14 kga,b 
LUM 100 mg/IVA 125 mg q12h 
AM 
1 stick pack 
PM 
1 stick pack 
Subject screening weight ≥14 kga,b 
LUM 150 mg/IVA 188 mg q12h 
AM 
1 stick pack 
PM 
1 stick pack 
IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours 
a 
The doses and weight bounds listed above are those planned for Part B. Depending on the results from Part A (e.g., Cohort 1 
and Cohort 2), any changes to study drug dose(s) and/or weight bounds will be communicated to site personnel through a 
memorandum entitled “Justification for Dose Selection” to ensure clarity and consistency in study conduct. 
b 
Doses are based on the subject’s weight at screening. During the treatment period, doses may be adjusted upward based on 
weight gain; however, no downward dose adjustments will be made if a subject’s weight decreases. For example, if a subject 
weighs <14 kg at screening and subsequently weighs ≥14 kg at 2 consecutive study visits, the dose will be adjusted to 
LUM 150 mg/IVA 188 mg q12h at the second visit when the subject’s weight is ≥14 kg. 
LUM/IVA will be administered within 30 minutes from the start of consuming fat-containing 
food such as a standard “CF” high-fat, high-calorie meal or snack according to the following 
guidelines: 
1. All doses of LUM/IVA (morning and evening, as applicable) should be administered at 
approximately every 12 hours (± 2 hours) on each dosing occasion (e.g., if the morning dose 
is administered at 08:00 on Day 1, all subsequent morning doses should be administered 
between 06:00 and 10:00). 


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2. The granule formulation will be dispensed by opening the stick packs containing the granules 
and mixing the granules with the approved foods and liquids listed in the Study Reference 
Manual. Each dose will be composed of the approved food or liquids into which the granules 
from the stick packs are mixed. Details on preparing LUM/IVA will be provided in the 
Pharmacy Manual. 
3. On Day 1 Visit, all subjects will be observed for 4 hours after the LUM/IVA dose.  
4. The date, dose quantity, time of drug administration, including whether food was taken with 
each dose, and occurrence and time of regurgitation within 1 hour after dosing, will be 
recorded for 1 day (i.e., 2 doses) before PK sample collection and on the days of PK sample 
collection. 
5. On days of scheduled study visits (Day 1, Day 15, and during Weeks 4, 8, 12 and 16), with 
the exception of afternoon visits addressed below, the morning dose will be administered at 
the clinic after any predose assessments have been completed.  
6. If the scheduled study visit occurs in the afternoon, the following guidelines must be used for 
administering either the morning or evening dose: 
• If the morning dose occurs within 6 hours of the study visit, the subject should withhold 
the dose at home, and administer the dose at the clinic. 
• If the morning dose occurs more than 6 hours before the study visit, the subject should 
take the morning dose at home, and the evening dose will be administered in the clinic. In 
this event, all assessments will be collected relative to the evening dose. 
7. For visits after the Day 1 Visit, subjects will be instructed to bring all used and unused 
LUM/IVA materials to the site; LUM/IVA will be dispensed at each visit, as appropriate. 
8. At the Week 24 Visit, the LUM/IVA dose will NOT be administered. The last LUM/IVA 
dose in Part B will be the previous dose administered before the Week 24 Visit.  
9.7 
Dose Modification for Toxicity 
Modifications of the LUM/IVA dose are prohibited. Should any unacceptable toxicity arise, 
individual subjects will be withdrawn from the study treatment. 
9.8 
Removal of Subjects  
Subjects may withdraw from the study at any time at the request of the parent or legal guardian. 
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. If a subject has been withdrawn from study drug treatment, the subject 
will continue to be followed as described in Section 9.1.6.1 (Part A) and Section 9.1.6.2 
(Part B), provided that the subject’s parent or legal guardian has not withdrawn consent.  
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject’s parent or legal guardian. 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’s parent or legal guardian 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’s parent or legal guardian regarding any unresolved AEs.   


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If the subject’s parent or legal guardian withdraws consent for the study, no further evaluations 
should be performed, and no additional data should be collected. Vertex may retain and continue 
using the study data and samples after the study is over and may use the samples and information 
in the development of the study compound, and for other drugs and diagnostics, in publications 
and presentations, and for education purposes. If the subject’s parent or legal guardian withdraws 
the subject from the study, the study data and samples collected will remain part of the study. A 
subject’s parent or legal guardian will not be able to request the withdrawal of the subject’s 
information from the study data. A subject’s parent or legal guardian may request destruction of 
the samples collected from the subject during the study as long as those samples can be identified 
as the subject’s samples.   
9.9 
Replacement of Subjects 
9.9.1 
Part A 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug Treatment 
Period may be replaced at Vertex’s discretion. 
9.9.2 
Part B 
Subjects who withdraw or are withdrawn during the study drug Treatment Period will not be 
replaced. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
LUM/IVA 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 
Vertex will supply the LUM/IVA granules in stick packs. Study drug labeling will be in 
compliance with applicable local and national regulations. Additional details regarding 
packaging, labeling, and dispensing for LUM/IVA will be included in the Pharmacy Manual.  
10.3 
Study Drug Supply, Storage, and Handling 
Table 10-1 provides the study drug information. The investigator, or an authorized designee 
(e.g., a licensed pharmacist), will ensure that all investigational product is stored in a secured 
area, under recommended storage conditions, and in accordance with applicable regulatory 
requirements. To ensure adequate records, all study drugs will be accounted for as described in 
Section 10.4. Detailed instructions regarding the storage, handling, and dispensation of 
LUM/IVA will be provided in the Pharmacy Manual. 


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Table 10-1 
Study Drug 
Drug 
Name 
Formulation/ 
Route 
Packaging (Formulation Strength) 
Storage 
Condition 
LUM/IVA 
Granules/ 
Oral 
Supplied as 75-mg LUM/94-mg IVA granules in 1 stick pack 
Store at ≤25°C 
(77°F) with 
excursions to 
30°C (86°F) 
LUM/IVA 
Granules/ 
Oral 
Supplied as 100-mg LUM/125-mg IVA granules in 1 stick pack  Store at ≤25°C 
(77°F) with 
excursions to 
30°C (86°F) 
LUM/IVA  
Granules/ 
Oral 
Supplied as and 150-mg LUM/188-mg IVA granules in 1 stick 
pack  
Store at ≤25°C 
(77°F) with 
excursions to 
30°C (86°F) 
IVA: ivacaftor; LUM: lumacaftor 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subject’s parent or legal guardian. The subject’s parent or legal guardian 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 
regular basis. The study monitor will promptly communicate to Vertex any discrepancies he or 
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 subject’s 
parent or legal guardian 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’s parent or legal guardian of study drug dosing 
requirements. Compliance will also be assessed by ongoing study drug count.  
If there is continued noncompliance of study drug dosing despite educational efforts, the 
investigator should contact the medical monitor to discuss discontinuation of the subject from the 
study treatment. 


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10.7 
Blinding and Unblinding 
This will be an open-label study. However, the site and the subject’s parent or legal guardian 
should not be informed of a subject’s study related sweat chloride (with the exception of results 
that are needed to establish eligibility when an historical sweat chloride measurement is not 
available), 
 results during the study even if the subject 
permanently discontinued treatment. 
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The schedule of assessments is shown in Table 3-1, Table 3-2, and Table 3-3. In Part A, all 
assessments will be performed predose unless noted otherwise. In Part B, all assessments may be 
performed predose or postdose unless noted otherwise. 
11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, length, 
and weight. 
Medical history will be elicited from each subject’s parent or legal guardian during screening. 
Based on the medical history, the subject will be assessed for any disqualifying medical 
conditions as specified in the inclusion and exclusion criteria. The medical history should include 
a complete review of systems, past medical and surgical histories, and any known allergies. In 
addition, the subject's parent or legal guardian will be asked to provide the height of the subject’s 
biological parents, if available. 
See Section 11.4.2.1 for the sweat chloride assessment that will be performed during the 
Screening Visit in Part A (sweat chloride will be assessed during the Screening Visit, the 
Treatment Period, and the Safety Follow-up in Part B). 
11.3 
Pharmacokinetics 
11.3.1 
Blood Sampling 
For the evaluation of plasma concentrations of LUM, IVA, and their respective metabolites, PK 
blood samples will be collected from all subjects, as noted in Table 3-2 (Part A) and Table 3-3 
(Part B). 
Samples from the PK sampling will be kept frozen by Vertex or its designee until all analyses 
have been completed and then disposed of according to Vertex or designee standard operating 
procedures. 
The actual times may change upon agreement of the clinical pharmacologist and investigator, but 
the number of samples will remain the same (Part A only). All efforts will be made to obtain the 
PK samples at the exact nominal time relative to dosing. Samples collected outside of the 
acceptable windows will be considered protocol deviations. For each PK blood draw, a record of 
LUM/IVA administration will be collected as described in Section 9.6. The collection date and 
time that each PK blood sample is drawn will also be recorded. 
If appropriate, these samples may also be used for the evaluation of metabolites that arise during 
treatment, for further evaluation of the bioanalytical method, and/or for analyses that provide 


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information on the metabolic pathways used by, or impacted by, LUM or IVA. These data will 
be used for exploratory purposes and may not be included in the clinical study report.  
Details on sample collection, processing, and shipping will be provided in a separate guideline. 
11.3.2 
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 Laboratory Manual.  
11.3.3 
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. 
11.4 
Pharmacodynamics 
11.4.1 
Part A 
Not applicable 
11.4.2 
Part B  
The assessments described in Section 11.4.2.1 through Section 11.4.2.8 will be performed in 
Part B. 
11.4.2.1 
Sweat Chloride 
Collection of sweat samples will be performed using an approved collection device. Sweat 
samples will be sent to a central laboratory for testing and interpretation of results. Specific 
instructions for collection, handling, processing, and shipping of sweat chloride samples to the 
central laboratory will be provided separately. The sweat chloride test will be conducted at 
approximately the same time as blood collections. At each time point, 2 samples will be 
collected, 1 sample from each arm (left and right). 


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11.5 
Efficacy 
11.5.1 
Part A 
Not applicable 
11.5.2 
Part B  
All efficacy-related assessments are listed in Section 11.4, Pharmacodynamics. 
11.6 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, pulse oximetry, ECGs, physical examinations (PEs), and ophthalmologic examinations 
(Part B only). 
11.6.1 
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 CRF completion 
guidelines for investigators as well as training will be provided. 
11.6.2 
Clinical Laboratory Assessments 
Blood samples will be analyzed at a central laboratory. Although blood samples are to be 
analyzed at a central laboratory, a local laboratory may be used if a subject cannot return to the 
clinical study site for the mandatory liver function testing (Section 11.6.3). 
Blood 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 11-1.  
Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
 
Glucose  
Blood urea nitrogen   
Creatinine  
Sodium 
Potassium 
Calcium 
Total bilirubin, direct bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase 
Alanine aminotransferase 
Lactate dehydrogenase 
Gamma glutamyl transferase (GGT) 
Total protein 
Albumin 
Creatine kinase 
Amylase 
Lipase 
Hemoglobin 
Platelets 
Total white blood cell count  
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes 
Monocytes 
 
 
 


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Clinical laboratory assessments from screening will have no clinically significant findings that 
preclude participation in the study, as judged by the investigator, for a subject to receive 
LUM/IVA on Day 1. 
CF Genotype (Screening Period only): If a historic genotype result is not available at screening 
or if the historic genotype result is not approved by the Vertex medical monitor, CF genotyping 
will be performed on a subject to confirm the subject is homozygous for F508del. 
Note: Newborn screening genotype results are not sufficient for eligibility. 
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 
for data analysis. Local laboratories may be used at the discretion of the local investigator for 
management of urgent medical issues. If a local laboratory test value is found to be abnormal and 
clinically significant, it will be verified by the central laboratory as soon as possible after the 
investigator becomes aware of the abnormal result. If it is not possible to send a timely specimen 
to the central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base 
the assessment of an AE on the local laboratory value. 
11.6.3 
Elevation of Liver Function Test Parameters 
Mandatory Liver Function Testing 
Liver function testing (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
gamma-glutamyl transferase [GGT], alkaline phosphatase [ALP], and total bilirubin) must be 
performed while subjects are receiving LUM/IVA treatment (see Table 3-2, Table 3-3, and 
Section 11.6.2). These blood samples should be processed and shipped immediately as per the 
Laboratory Manual. 
Subjects with new ALT or AST elevations of ≥3 × upper limit of normal (ULN) will be followed 
closely, including repeat confirmatory testing performed by the central laboratory within 48 to 
72 hours of the initial finding and subsequent close monitoring of ALT and AST levels, as 
clinically indicated. If a subject cannot return to the site for liver function testing, a local 
laboratory may be used. Elevations in LFTs (ALT or AST ≥3 × ULN) at the local laboratory 
must be reported immediately to the medical monitor, AND the subject must have the tests 
repeated and sent to the central laboratory as soon as possible (ideally within 48 to 72 hours). 
Study Drug Interruption 
LUM/IVA administration must be interrupted immediately, and the Vertex medical monitor or 
designee must be notified if any of the following criteria is 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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Resumption of Study Drug 
If a convincing alternative etiology is identified for the elevated liver tests (ALT, AST, and total 
bilirubin), LUM/IVA may be resumed when levels return to baseline or are ≤2 × ULN, 
whichever is higher. Approval of the Vertex medical monitor or designee is required before 
resumption of LUM/IVA. Upon resumption of LUM/IVA, transaminases should be assessed 
weekly for 4 weeks. If a protocol-defined liver test elevation occurs within 4 weeks of 
rechallenge with LUM/IVA, then LUM/IVA must be discontinued, regardless of the presumed 
etiology. 
Discontinuation of Study Drug 
If no convincing alternative etiology (e.g., acetaminophen use or viral hepatitis) for the elevated 
transaminases is identified, regardless of whether ALT or AST levels have improved, LUM/IVA 
treatment must be discontinued, after consulting with the Vertex medical monitor or authorized 
designee. Subjects in whom treatment is discontinued for elevated transaminases should have 
their transaminases monitored closely until levels normalize or return to baseline. 
11.6.4 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits (see Table 3-1, Table 3-2, and Table 3-3). At other visits, symptom-directed PEs and 
symptom-directed vital sign assessments can be performed at the discretion of the investigator or 
healthcare provider. 
A PE includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/throat 
(EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Anorectal, and genital examinations will be performed when medically indicated. 
After screening, any clinically significant abnormal findings in PEs will be reported as AEs. 
An abbreviated PE will be performed at select study visits (see Table 3-2 and Table 3-3). The 
abbreviated PE will include an assessment of the following body systems: head/neck/thyroid, 
EENT, cardiovascular system, respiratory system, skin, and abdomen.  
Vital signs include blood pressure (systolic and diastolic), temperature (any clinically acceptable 
method may be used, however, the same method should be used at each visit), pulse rate, 
respiration rate, and pulse oximetry. The subject should rest for at least 5 minutes, if possible, 
before vital signs are assessed. 
Weight and length will be assessed; BMI and weight-for-length will be derived. Length and 
weight must be measured with the subject in a dry diaper or dry underclothes only. Length 
should be measured while the subject is supine by measuring from the crown of the head to the 
bottom of the feet, with the hips and legs straightened. BMI will be calculated using the 
following equation: BMI (kg/m2) = body weight (kg) ÷ length2 (m2). 
11.6.5 
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 should rest for at least 5 minutes, if possible, before having an ECG performed. 


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• The ECG will be performed before any other procedures that may affect heart rate, such as 
blood draws. 
The ECG traces will be manually read at the study site at the Screening Visit and Safety 
Follow-up Visit. A printout of the ECG traces will be made for safety review by the investigator 
and maintained with source documentation. All traces will be centrally evaluated by a qualified 
pediatric cardiologist. Clinically significant ECG abnormalities occurring during the study 
through the Safety Follow-up Visit will be recorded as AEs.  
To ensure safety of the subjects, the investigator will make comparisons of the ECG findings to 
baseline measurements. Repeat ECGs will be performed as deemed appropriate. Subject 
eligibility to continue in the study will be evaluated. 
11.6.6 
Ophthalmologic Examination 
Ophthalmologic examinations must be conducted by a licensed ophthalmologist, preferably a 
pediatric ophthalmologist. The ophthalmologic examination includes an examination of the lens 
with a slit lamp. 
The screening ophthalmologic examination must be completed, and the results reviewed before 
enrollment. If cataract/lens opacity is identified and determined to be clinically significant by the 
licensed ophthalmologist at the screening examination, the subject must not be enrolled. The 
screening ophthalmologic examination does not need to be repeated if there is documentation of 
an examination meeting protocol criteria that was conducted within 3 months before the 
Screening Visit.  
11.6.7 
Contraception and Pregnancy 
Not applicable 
12 
STATISTICAL AND ANALYTICAL PLANS 
12.1 
Sample Size and Power 
Part A 
Approximately 10 subjects are planned for enrollment. No formal sample size calculations have 
been performed. The number of subjects in Part A is common in early clinical pharmacology 
studies and is considered sufficient to achieve the PK objectives of Part A. 
Part B 
Approximately 30 subjects are planned for enrollment. Assuming a 10% dropout rate, 
approximately 27 subjects will complete Part B. No formal sample size calculations have been 
performed. The number of subjects in Part B is deemed adequate to meet the primary safety 
objective.  
Table 12-1 displays estimates of the probability for observing AEs in at least 1 subject for the 
given incidence (θ) and sample size. With a total sample size of 27 subjects (completers), there is 
a 75.0% chance of observing AEs in at least 1 subject if the true incidence rate is 5%, and a 
94.2% chance of observing AEs in at least 1 subject if the true incidence rate is 10%.  




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12.3.1 
General Considerations 
For Part A and Part B, all individual subject data based on the All Subjects Set of the 
corresponding part will be presented in data listings. 
Part A data will be summarized overall and by cohort. The Part A primary safety conclusion will 
be based upon the overall group. Part B will be summarized overall.  
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, SE, median, minimum, and maximum. 
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 Part B only: 
• For sweat chloride, the values at each visit will be based on the averaged measurements from 
left and right arms as specified in Section 12.3.3.2.1. The baseline will be defined as the 
average of the values at screening and the pretreatment measurement on Day 1. If only 
1 pre-first dose measurement of sweat chloride is available, that measurement will be 
considered the baseline.  
Change (absolute change) from baseline will be calculated as Postbaseline value − Baseline 
value. 
Relative change from baseline will be calculated and expressed in percentage as 
100% × (Postbaseline value − Baseline value)/Baseline value. 
The Treatment-emergent (TE) Period will include the time from the initial dose in Treatment 
Period in each part to the Safety Follow-up Visit or 14 days after the last dose of the study drug 
in the corresponding part, whichever occurs first. 
12.3.2 
Background Characteristics 
Unless otherwise specified, this section applies to both Part A and Part B. All summaries will be 
based on the Safety Set of the corresponding part overall. No statistical hypothesis testing will be 
performed.  
12.3.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized:  
• All Subjects Set 
• Dosed (Safety Set) 
• Enrolled and dosed (FAS, Part B only) 
The number and percentage (based on Safety Set) of subjects in each of the following disposition 
categories will be summarized: 
• Completed treatment 
• Prematurely discontinued the treatment and the reason for discontinuation  
• Completed study (i.e., completed Safety Follow-up Visit) 






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volumes <15 µL, the values will be considered missing for analysis purposes). If a subject has 
replicated measurements at a postbaseline time point, then the median of the values will be used 
in data analyses. The sweat chloride results for the left and right arms will be averaged and used 
in the analysis if the sweat chloride values for the left and right arms are both ≥15 µL; if only 1 
arm is ≥15 µL, then only that value will be used. Note: Any sweat chloride concentration 
reported as <10 mmol/L or >160 mmol/L will be considered as a missing value. 
Descriptive summary statistics (n, mean, SD, SE, median, minimum, and maximum), along with 
the 95% CI and within-group P value based on Normal approximation, will be provided for 
absolute change from baseline in sweat chloride at Week 24.  
In addition, descriptive summary statistics, along with 95% CI based on Normal approximation, 
will be provided for all other visits.  




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12.3.4 
Safety Analysis 
Unless otherwise specified, this section applies to Part A and Part B. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints: 
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (serum chemistry and hematology) 
• ECGs (standard 12-lead) 
• Vital signs 
• Pulse oximetry 
• Ophthalmologic examinations (Part B only) 
For Part A and Part B, safety endpoints will be analyzed based on the Safety Set for the 
corresponding part. 
Subgroup analysis or any additional analysis will be described in the SAP. 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs for each study part, defined as follows:  
• Pretreatment AE: any AE that started before the first dose date of study drug in a study 
part. 
• TEAE: any AE that increased in severity or that was newly developed at or after the first 
dose of study drug through the end of the TE Period of each corresponding study part. 
• Post-treatment AE: any AE that increased in severity or that newly developed after the 
TE Period of each corresponding study part. 
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of adverse events are described in the SAP. 
For Part A and Part B, TEAE summaries will be presented using number and percentages of 
subjects.  
An overview of the TEAE profile will be provided, including total number of TEAEs, with 
number and percentage of subjects for the following categories: (1) All TEAEs, (2) Grades 3/4 
TEAEs, (3) TEAEs by relationship to study drug, (4) TEAEs by maximum severity, (5) TEAEs 


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leading to treatment interruption, (6) TEAEs leading to treatment discontinuation, (7) serious 
TEAEs, (8) serious TEAEs related to study drug, and (9) TEAEs leading to death. 
AE summary tables will be presented for TEAEs only and will include the following: 
• All TEAEs 
• Grades 3/4 TEAEs 
• TEAEs by relationship to study drug 
• TEAEs by maximum severity 
• TEAEs leading to treatment interruption 
• TEAEs leading to treatment discontinuation 
• Serious TEAEs 
• Serious TEAEs related to study drug 
• TEAEs leading to death 
• Frequently reported TEAEs (Part B only) 
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 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 containing individual subject adverse event data for all TEAEs leading to 
treatment interruption, TEAEs leading to treatment discontinuation, serious adverse event 
(SAEs), and deaths will be provided separately. All AEs, including pre- and post-treatment AEs, 
will be presented 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 will be summarized in SI units at 
each scheduled time point.  
The number and percentage of subjects meeting a threshold analysis criterion during the 
TE Period will be summarized for each part. The threshold analysis criteria and the parameter 
selection criteria will be provided in the SAP.  
For hematology and chemistry, the number and percentage of subjects with abnormal low 
(<lower limit of normal [LLN]) value and with abnormal high (>ULN) value at each scheduled 
time point will be summarized. 
In addition, a listing containing individual subject hematology and chemistry values outside the 
normal reference ranges will be provided. This listing will include data from both scheduled and 
unscheduled visits. 


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12.3.4.3 
Electrocardiogram 
For treatment-emergent ECG measurements, a summary of raw values and change from baseline 
values will be provided at each scheduled time point for the following standard 12-lead ECG 
measurements: RR (msec), HR (beats per minute), PR (msec), QRS duration (msec), QRS axis 
(degrees), QT (msec), and QT corrected for HR intervals. In addition, the mean value (95% CI) 
at each time point will be plotted for QTc. 
The number and percentage of subjects meeting a threshold analysis criterion during the 
TE Period will be summarized. The threshold value criteria will be provided 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 at each visit: systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), pulse rate (beats per minute), respiratory rate (breaths per minute), weight, 
length, and BMI. 
The number and percentage of subjects meeting a threshold analysis criterion during the 
TE Period will be summarized. The threshold value criteria will be provided in the SAP. 
12.3.4.5 
Pulse Oximetry  
For treatment-emergent pulse oximetry measurements, a summary of raw values and change 
from baseline values will be provided at each scheduled time point for the percent of oxygen 
saturation by pulse oximetry.  
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 
Treatment Period will be provided.  
12.3.4.6 
Ophthalmologic Examinations 
Ophthalmologic examination findings will be presented as a data listing for Part A (screening 
only) and Part B.  
12.3.4.7 
Physical Examination 
PE findings will be presented as an individual subject data listing only. 
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analysis 
Interim analyses may take place at any time during the study if deemed necessary by the Vertex 
team. 
12.3.5.2 
IDMC Analysis 
Details of the IDMC (Section 9.1.7) analysis will be provided in the IDMC Analysis Plan. 
12.4 
Clinical Pharmacology Analysis 
12.4.1 
Pharmacokinetic Analysis 
Nonlinear mixed effects modeling will be applied for the PK analysis of LUM and IVA. 
Covariates (e.g., body weight) will be evaluated and included in the final population PK model if 


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including them significantly improves the overall model fit and the accuracy and precision of 
population estimates of PK parameters.  
Preliminary analysis will be performed on the PK data obtained from Part A of the current study. 
The PK analysis, along with safety and tolerability data from Part A (e.g., after Cohort 1 and 
after Cohort 2), will be used to appropriately confirm the dose selection for Part B of the study 
(or adjust the doses if necessary before the start of Part B) based on PK parameters relative to 
historical results in the clinical development program. An interim PK analysis of data collected 
in Part A and Part B may be performed to inform future development of LUM and IVA. This 
interim analysis, if performed, will not affect the conduct of the present study. Plasma 
concentrations for LUM, IVA, and their metabolites will be summarized using descriptive 
statistics by visits and time points. 
Details of the analyses will be provided in the clinical pharmacology analysis plan (CPAP). 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses 
The relationship between the outcome measures (e.g., sweat chloride) and drug concentrations 
may be used in exploratory analysis.  
An interim PK/PD analysis of data collected in Part B (e.g., sweat chloride) may be performed to 
inform future development of LUM and IVA. This interim analysis, if performed, will not affect 
the conduct of the present study.  
Details of methods used will be provided in the CPAP. 
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). 


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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 ICF is signed until the following time points: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, withdrawal of 
consent) 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up Visit 
• For enrolled subjects who do not have a Safety Follow-up Visit in Part A, 13 days after the 
last dose of study drug. 
• For enrolled subjects who do not have a Safety Follow-up Visit in Part B, the earliest of 
o 18 days after the last dose of study drug, or 
o the ETT Visit, if that visit is 10 days or later following the last dose of study drug (see 
Section 9.1.6) 
All subject’s parents or legal guardians 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 in the study will be recorded only in the subject’s source documents. The following data 
will be documented for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 


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For the purposes of study analysis, if the event has not resolved at the end of the study reporting 
period (the Safety Follow-up Visit), it will be documented as ongoing. For purposes of 
regulatory safety monitoring, the investigator is required to follow the AE to symptom resolution 
or until the condition stabilizes. 
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: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
September 2007, Center for Biologics Evaluation and Research, 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/Vaccines/ucm074775.htm (Accessed August 2015). In considering the severity of an AE in 
a pediatric subject, the investigator will consider that reference ranges for pediatric clinical 
laboratory parameters may differ from those given in the vaccine scale. The severity of an AE 
that does not appear in this scale will be determined according to the definitions in Table 13-1. 
Table 13-1 
Grading of AE Severity  
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories presented in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, such 
as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject’s medical record). 
 


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13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories shown in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduceda 
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. 
a 
Study drug dose cannot be reduced in this study (Section 9.7).  
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation in the study and is suspected of being a delayed toxicity due to administration of 
the study drug) 


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• 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’s parent or legal guardian signed the ICF, and the hospitalization or 
procedure was planned before the subject’s parent or legal guardian signed the ICF, the 
hospitalization or procedure will not be considered to indicate an SAE, unless an AE caused the 
hospitalization or procedure to be rescheduled sooner or to be prolonged relative to what was 
planned. In addition, hospitalizations clearly not associated with an AE (e.g., social 
hospitalization for purposes of respite care) will not be considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent through the Safety Follow-up Visit, 
regardless of causality, will be reported by the investigator to Vertex Global Patient Safety 
(GPS). In addition, all SAEs that occur after the Safety Follow-up Visit and are considered 
related to study drug(s) will be reported to Vertex GPS within 24 hours. 
SAEs will be recorded on the Vertex Organized Safety Information Collection Form (hereafter 
referred to as the “SAE Form”) using a recognized medical term or diagnosis that accurately 
reflects the event. SAEs will be assessed by the investigator for relationship to the investigational 
study drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be 
assessed only as related (includes possibly related) or not related (includes unlikely related), and 
severity assessment will not be required. For the purposes of study analysis, if the event has not 
resolved at the end of the study reporting period, it will be documented as ongoing. For purposes 
of regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report to Vertex the outcome of the event using the SAE Form. 
13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. The SAE Form will be 


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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 questions, contact telephone: 
 
13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, 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/local IEC 
of all unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will only 
be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subject’s 
parents or legal guardians (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 
legal representative or guardian before study participation. The method of obtaining and 
documenting the informed consent 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 


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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 shall be limited to the site and the study physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the 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 study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act and associated regulations (“HIPAA”) an executed HIPAA 
authorization shall be obtained by the site from each subject (or the legal representative of the 
subject) before research activities may begin. Each HIPAA authorization shall comply with all 
HIPAA requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 


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• 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 contact) of the last subject in the study. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated, web-based electronic data capture (EDC) application. Vertex 
will have read-only access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its 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 


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the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc (CD) or other electronic media will be placed in the investigator’s 
study file. 
13.6 
Publications and Clinical Study Report 
13.6.2 
Clinical Study Report  
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in 
accordance with local regulations. 


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14 
REFERENCE 
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 07 February 2018. 
2 
Cystic Fibrosis Foundation. Patient Registry: 2016 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2017. 
3 
Cystic Fibrosis Trust. UK Cystic Fibrosis Registry: 2015 Annual Data Report. London, 
UK: Cystic Fibrosis Trust; 2016. 
4 
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
5 
Kreindler JL. Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
6 
Cystic Fibrosis Australia. Cystic Fibrosis in Australia 2014: 17th Annual Report From 
the Australian Cystic Fibrosis Data Registry. North Ryde, NSW, Australia: Cystic 
Fibrosis Australia; 2016. 
7 
Cystic Fibrosis Canada. Canadian Cystic Fibrosis Registry: 2015 Annual Report. 
Toronto, Ontario: Cystic Fibrosis Canada; 2017. 
8 
European Cystic Fibrosis Society. 2015 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: European Cystic Fibrosis Society; 2017. 
9 
O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373(9678):1891-904. 
10 
Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, et 
al. Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after 
newborn screening. J Pediatr. 2009;155(5):623-28. 
11 
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: A consensus statement. J 
Pediatr. 1998;132(4):589-95. 
12 
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New 
equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3):629-37. 
13 
ICH E11. Clinical Investigation of Medicinal Products in the Pediatric Population. 20 
July 2000. 
14 
Vertex Pharmaceuticals Incorporated. Report N329. Population Pharmacokinetics of 
Lumacaftor and Ivacaftor in Subjects 2 Through 5 Years of Age with Cystic Fibrosis, 
Homozygous for F508del. Report date: 10 January 2018. 
15 
Vertex Pharmaceuticals Incorporated. Lumacaftor/Ivacaftor Investigator's Brochure, 
Version 3.0. Report date: 12 May 2017. 


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15.2 
Investigator Signature Page 
Protocol #:  VX16‑809‑122 
Version #: 
2.0  
Version Date: 
04 December 2019 
Study Title: A Phase 3, 2-part, Open-label Study to Evaluate the Safety and Pharmacokinetics of 
Lumacaftor/Ivacaftor in Subjects 1 to Less Than 2 Years of Age With Cystic Fibrosis, 
Homozygous for F508del 
 
 
I have read Protocol VX16-809-122, Version 2.0, and agree to conduct the study according to its 
terms. I understand that all information concerning LUM/IVA and this protocol supplied to me 
by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 
 




Clinical Study Protocol Addendum for Cystic Fibrosis, Addendum Version 3.0 
Page 2 of 8 
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 3.0 summarizes additional measures taken for these ongoing CF clinical 
studies (see table below) to ensure continued safety. 
 













SAP_001.pdf: 
 
Page 1 of 43 
 
 
Vertex Pharmaceuticals Incorporated 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number:  VX16-809-122 
(Final Analysis - Parts A and B) 
 
A Phase 3, 2-part, Open-label Study to Evaluate the Safety and 
Pharmacokinetics of Lumacaftor/Ivacaftor in Subjects 1 to Less Than 
2 Years of Age With Cystic Fibrosis, Homozygous for F508del  
 
Author of SAP:   
  
 
Version:  2.0 
Version Date of SAP:  19 May 2021 
 
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. 


Statistical Analysis Plan (Methods) 
Page 2 of 43 
Protocol VX16-809-122, (Version 2.0, 04 December 2019) 
Vertex Pharmaceuticals Incorporated 
 
2 
TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
2 
Table of Contents ............................................................................................................. 2 
4 
Introduction...................................................................................................................... 5 
5 
Study Objectives .............................................................................................................. 5 
5.1 
Primary Objective ....................................................................................................... 5 
5.2 
Secondary Objectives ................................................................................................. 5 
6 
Study Endpoints ............................................................................................................... 6 
6.1 
Primary Endpoint ........................................................................................................ 6 
6.2 
Secondary Endpoint .................................................................................................... 6 
7 
Study Design ..................................................................................................................... 7 
7.1 
Overall Design ............................................................................................................ 7 
7.1.1 
Part A .................................................................................................................. 7 
7.1.2 
Part B .................................................................................................................. 8 
7.2 
Sample Size and Power .............................................................................................. 8 
7.3 
Randomization ............................................................................................................ 9 
7.4 
Blinding and Unblinding ............................................................................................ 9 
8 
Analysis Sets ..................................................................................................................... 9 
8.1 
All Subjects Set .......................................................................................................... 9 
8.2 
Safety Set .................................................................................................................... 9 
8.3 
Full Analysis Set (for Part B only) ........................................................................... 10 
 
 
9 
Statistical Analysis ......................................................................................................... 10 
9.1 
General Considerations ............................................................................................ 10 
9.2 
Background Characteristics ...................................................................................... 12 
9.2.1 
Subject Disposition ........................................................................................... 12 
9.2.2 
Demographics and Baseline Characteristics ..................................................... 12 
9.2.3 
Prior and Concomitant Medications ................................................................. 13 
9.2.4 
Study Drug Exposure........................................................................................ 14 
9.2.5 
Study Drug Compliance ................................................................................... 14 
9.2.6 
Important Protocol Deviations .......................................................................... 15 
9.3 
Efficacy Analysis ...................................................................................................... 15 
9.4 
Safety Analysis ......................................................................................................... 15 
9.4.1 
Adverse Events ................................................................................................. 16 
9.4.2 
Clinical Laboratory ........................................................................................... 18 
9.4.3 
Electrocardiogram ............................................................................................ 19 
9.4.4 
Vital Signs ........................................................................................................ 19 
9.4.5 
Pulse Oximetry ................................................................................................. 20 
9.4.6 
Ophthalmological Examinations ...................................................................... 20 
9.4.7 
Physical Examination ....................................................................................... 20 


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9.4.8 
Other Safety Analysis ....................................................................................... 21 
9.5 
Pharmacodynamic Analysis (Part B Only) ............................................................... 21 
9.5.1 
Analysis of Primary Endpoints ......................................................................... 21 
9.5.2 
Analysis of Secondary Pharmacodynamic Endpoints ...................................... 21 
9.5.2.1 
Absolute Change From Baseline in Sweat Chloride at Week 24............... 21 
9.6 
Narratives Listings .................................................................................................... 25 
10 Summary of Interim and IDMC Analyses .................................................................. 25 
10.1 Interim Analysis ....................................................................................................... 25 
10.2 IDMC Analysis ......................................................................................................... 26 
11 References ....................................................................................................................... 26 
12 List of Appendices.......................................................................................................... 27 
Appendix A: Schedule of Assessments.............................................................................. 27 
Appendix B: Analysis Visit Window Mapping Rules for Safety and Pharmacodynamic 
Measurements (Part B only) ..................................................................................... 34 
Appendix C: Assessments Imputation Rules for Missing Prior/Concomitant Medication 
Dates ......................................................................................................................... 35 
Appendix D: Imputation Rules for Missing AE dates ....................................................... 36 
Appendix E: Criteria for Threshold Analysis .................................................................... 37 
Appendix F:  Important Protocol Deviation Programming Rules for Part B only (Based on 
the Clinical Database) ............................................................................................... 39 
Appendix G:  Blood Pressure Normal Levels for Boys and Girls by Age and Height 
Percentile .................................................................................................................. 40 
 
 




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4 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis of Study VX16-809-122 Parts A 
and B is based on the  
• approved clinical study protocol, dated  04 December 2019, Version 2.0,  
• approved Justification for Dose Selection Memorandum, dated 23 November 2020, 
• approved eCRF, dated 10 March 2021, Version 15.1. 
Study VX16-809-122 is a phase 3, 2-part, open-label study to evaluate the safety and 
pharmacokinetics of lumacaftor/ivacaftor combination therapy in subjects aged 1 to less than 
2 years with cystic fibrosis, homozygous for the F508del CFTR mutation. 
This SAP (Methods) documents the planned final analyses and data presentation for  VX16-
809-122.  
  
 
 will perform the statistical analysis of the safety data; SAS® Version 9.4 
Software (SAS Institute, Cary, North Carolina, USA) or higher will be used to generate all 
statistical outputs (tables, figures, listings and datasets).   
The SAP methods Version 1.0 was finalized before the interim data snapshot for Part A 
Cohort 1. In this SAP Methods Version 2.0, modifications to the approved SAP Version 1.0 
are made based on the amended protocol (Protocol Version 2.0) along with the Justification 
for Dose Selection Memorandum. 
The analysis addressing the pharmacokinetic (PK) objective of the study will be described in 
the Clinical Pharmacology Analysis Plan (CPAP) which will be developed separately by the 
Clinical Pharmacology department at Vertex Pharmaceuticals Incorporated (Vertex). 
5 
STUDY OBJECTIVES 
5.1 
Primary Objective 
Part A 
To evaluate the PK of lumacaftor (LUM) and ivacaftor (IVA) in subjects 1 to less than 
2 years of age with cystic fibrosis (CF), homozygous for F508del 
Part B 
To evaluate the safety of LUM/IVA in subjects 1 to less than 2 years of age with CF, 
homozygous for F508del 
5.2 
Secondary Objectives 
Part A 
• To evaluate the safety of LUM/IVA in subjects 1 to less than 2 years of age with CF, 
homozygous for F508del 
• To evaluate the PK of the metabolites of LUM and IVA in subjects 1 to less than 2 years 
of age with CF, homozygous for F508del 


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Part B 
• To evaluate the pharmacodynamics (PD) of LUM/IVA in subjects 1 to less than 2 years of 
age with CF, homozygous for F508del 
• To evaluate the PK of LUM and IVA and their respective metabolites in subjects 1 to less 
than 2 years of age with CF, homozygous for F508del 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
Part A 
PK parameters of LUM and IVA 
Part B 
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values 
(serum chemistry and hematology), standard 12-lead ECGs, vital signs, pulse oximetry, and 
ophthalmologic examinations 
6.2 
Secondary Endpoint 
Part A 
• Safety and tolerability assessments based on AEs, clinical laboratory values (serum 
chemistry and hematology), standard 12-lead ECGs, vital signs, and pulse oximetry 
• PK parameters of the metabolites of LUM and IVA 
Part B 
• Absolute change from baseline in sweat chloride at Week 24 
• PK parameters of LUM, IVA, and their respective metabolites 


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7 
STUDY DESIGN  
7.1 
Overall Design  
This is a Phase 3, 2-part, open-label, multicenter study evaluating the PK, safety, and PD of 
multiple doses of LUM/IVA in subjects 1 to <2 years of age with CF, homozygous for 
F508del. Subjects who participate in Part A may participate in Part B if they meet eligibility 
criteria.  
7.1.1 
Part A 
Figure 7-1 depicts the schematic for the Part A study design.  
Approximately 10 subjects are planned for enrollment, including a minimum of 5 subjects 18 
to <24 months of age (Cohort 1) and 5 subjects 12 to <18 months of age (Cohort 2). Subjects 
will be enrolled in Part A sequentially in the following cohorts: 
• Cohort 1: subjects aged 18 to <24 months 
• Cohort 2: subjects aged 12 to <18 months 
Enrollment in Part A will begin with subjects in Cohort 1. 
A review of safety, tolerability, and available PK data will be completed after each Part A 
Cohort (e.g., Cohort 1 and Cohort 2) to confirm or adjust the dose(s) and/or weight bounds to 
be evaluated in Part B. Additional subjects or treatment cohorts may be enrolled, if data from 
the initially planned 10 subjects are inadequate to make a determination of the dose(s) to be 
evaluated in Part B. 
Figure 7-1 
Schematic of Study Design for Part A (Cohort 1 and Cohort 2) 
 
 
IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours 


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Notes: Approximately 10 subjects are planned for enrollment, including a minimum of 5 subjects 18 to <24 months of age 
(Cohort 1) and 5 subjects 12 to <18 months of age (Cohort 2). 
a 
Doses are based on the subject’s weight at screening in Part A. No dose adjustments will be made across the duration of 
treatment. On Day 15, only the morning dose will be administered. Refer to Section 9.6.1 in Protocol Version 2.0 for 
additional study drug administration details. 
7.1.2 
Part B 
Figure 7-2 depicts the schematic for the Part B study design. 
 
 
Approximately 30 subjects are planned for enrollment, including a minimum of 10 subjects 
18 to <24 months of age and 10 subjects 12 to <18 months of age. 
Figure 7-2 
Schematic of Study Design for Part B 
 
IVA: ivacaftor; LUM: lumacaftor; q12h: every 12 hours 
Notes: Approximately 30 subjects are planned for enrollment, including a minimum of 10 subjects 18 to <24 months of age 
and 10 subjects 12 to <18 months of age.  
a 
The doses and weight bounds listed above are those planned for Part B. Doses are based on the subject’s weight at 
screening in Part B. No dose adjustments across the duration of treatment will be made. Refer to Section 9.6.2 in 
Protocol Version 2.0 for additional study drug administration details. The last dose of LUM/IVA in Part B will be the 
evening dose before the Week 24 Visit.  
b 
Refer to Sections 9.1.3.2, 9.1.5.2, and 9.1.6.2 in Protocol Version 2.0 for details. 
c 
At the Safety Follow-up Visit, subjects who complete LUM/IVA treatment and the visits in the Treatment Period will 
be offered the opportunity to enroll in an optional open label Extension Study evaluating LUM/IVA (enrollment will be 
based on eligibility criteria specified in the Extension Study). The Safety Follow-up Visit, if applicable, is the last visit 
for Part B, and should also be the Day 1 Visit in the Extension Study. 
7.2 
Sample Size and Power 
Part A 
Approximately 10 subjects are planned for enrollment. No formal sample size calculations 
have been performed. The number of subjects in Part A is common in clinical pharmacology 
studies and is considered sufficient to achieve the PK objectives of Part A. 


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Part B 
Approximately 30 subjects are planned for enrollment. Assuming a 10% dropout rate, 
approximately 27 subjects will complete Part B. No formal sample size calculations have 
been performed. The number of subjects in Part B is deemed adequate to meet the primary 
safety objective.  
Table 7-1 displays estimates of the probability for observing AEs in at least 1 subject for the 
given incidence () and sample size. With a total sample size of 27 subjects (completers), 
there is a 75.0% chance of observing AEs in at least 1 subject if the true incidence rate is 5%, 
and a 94.2% chance of observing AEs in at least 1 subject if the true incidence rate is 10%.  
Table 7-1 
Probability of Observing Adverse Events in At Least 1 Subject if the 
Adverse Event Incidence () is 5% and 10% 
Sample Size 
 = 5% 
 = 10% 
27a 
75.0% 
94.2% 
a 
27 reflects the sample size of the completers. 
7.3 
Randomization 
This is an open-label study with weight-based treatment dosing. Randomization is not 
required. 
7.4 
Blinding and Unblinding 
This will be an open-label study. However, the site and the subject’s parent or legal guardian 
should not be informed of a subject’s study related sweat chloride (with the exception of 
results that are needed to establish eligibility when a historical sweat chloride measurement is 
not available),
 
 
8 
ANALYSIS SETS 
8.1 
All Subjects Set 
All Subjects Set is defined as all subjects who have signed informed consent and enrolled, or 
dosed, in Part A or Part B respectively.  
This analysis set will be used for all individual subject data listings and the disposition 
summary table, unless specified otherwise. 
8.2 
Safety Set 
Safety Set for Part A will include all subjects who received at least 1 dose of study drug in 
Part A. The Part A safety analyses will be based on the Safety Set overall and by cohort, 
unless otherwise specified.  
Safety Set for Part B will include all subjects who received at least 1 dose of study drug in 
Part B. The safety analyses will be based on the Safety Set overall, unless otherwise 
specified.  


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8.3 
Full Analysis Set (for Part B only) 
Full Analysis Set (FAS) will include all enrolled subjects in Part B who are exposed to any 
amount of study drug in Part B. PD analyses (except LCI) will be based on the FAS. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Appendix A.   
For Part A and Part B, all individual subject data based on All Subjects Set will be presented 
in the corresponding data listings separately. 
Part A data will be summarized overall and by Cohort for the final clinical study report. The 
Part A primary safety conclusions will be based upon the overall group. Part B data will be 
summarized overall. 
Separate interim analyses (IA) will be performed after: 
• IA 1: all subjects in Cohort 1 have completed the last visit in Part A 
• IA 2: all subjects in Cohort 2 have completed the last visit in Part A. 
Interim analysis 1 for Cohort 1 will summarize safety data for Cohort 1 subjects only in a 
single column. Interim analysis 2 for Cohort 2 will summarize safety data for Cohort 2 
subjects only in a single column. Details for the interim analyses are described in Section 
10.1. 
Continuous variables will be summarized using the following descriptive summary 
statistics: number of subjects (n), mean, standard deviation (SD), standard error (SE), 
median, minimum (min), and maximum (max). The precision standards are provided in an 
internal Biometrics document that specifies the programming rules including the precision 
for derived variables. 
Categorical variables will be summarized using counts and percentages. 
Treatment-emergent Period will include the time from the initial dose in Treatment Period 
in each part to the Safety Follow-up Visit or 14 days after the last dose of the study drug in  
the corresponding part, whichever occurs first.  
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 in each 
part. 


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For sweat chloride, the values at each visit will be based on the averaged measurements from 
left and right arms. The baseline will be defined as the average of the values at screening and 
the pretreatment measurement on Day 1. If only 1 pre-first dose measurement of sweat 
chloride is available, that measurement will be considered the baseline. 
Change (absolute change) from baseline will be calculated as postbaseline value - baseline 
value. 
Relative change from baseline: will be calculated and presented in percentage as 
100 × (postbaseline value - baseline value)/baseline value. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
• In the derivation of baseline measurements or last on-treatment visit. 
• In individual subject data listings as appropriate. 
• In the derivation of maximum/minimum values and maximum/minimum changes from 
baseline values. 
• In scheduled visit windows per specified visit windowing rules (for Part B only). 
Visit windowing rules:  
For Part A, the majority of assessments are anticipated to be on schedule. Visit windowing 
will not add significant value to the analysis and will not be applied. Nominal visit will be used 
for all assessments.  
For Part B: 
Appendix B defines the visit window mapping rules to derive the analysis visits for Part B. 
Repeated observations within the same visits window: 
• For all PD parameters, if there are multiple measurements within a visit window, the record 
at the scheduled visit will be used. If there are no measurements at the scheduled visit, then 
1) the record closest to the target day will be used; or 2) if there are multiple records with 
the same distance to the target day, the latest record will be used.   
• For all safety parameters, if there are multiple measurements within a visit window, then 
1) the record closest to the target day will be used; or 2) if there are multiple records with 
the same distance to the target day, the latest record will be used. 
BMI, weight, and length 
 
 they will follow safety parameter visit window rules when evaluated as safety 
endpoints. 
 
  
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. 


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Multiplicity: No multiplicity adjustment will be performed and there is no hypothesis testing. 
Unless otherwise specified, the analysis will be performed using descriptive summary 
statistics. All summaries will be based on the Safety Set and FAS.   
9.2 
Background Characteristics  
Unless otherwise specified, this section applies to both Part A and Part B. All summaries will 
be provided based on the safety set of the corresponding Part, overall and by Cohort for Part 
A, and overall for Part B, unless otherwise specified. No statistical hypothesis testing will be 
performed. 
9.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized :  
• All Subjects Set 
• Dosed (Safety Set) 
• Enrolled but not dosed 
• Enrolled and dosed (FAS, Part B only) 
The numbers and percentages (based on the Safety Set) of subjects in the following disposition 
categories will be summarized 
• Completed study drug treatment 
• Prematurely discontinued the treatment and the reasons for discontinuations 
• Completed study (i.e., completed Safety Follow-up Visit) 
• Prematurely discontinued the study and the reasons for discontinuations 
• Enrolled in a rollover extension study (for Part B only) 
 
A listing will be provided for subjects who discontinued treatment or who discontinued the 
study with reasons for discontinuation. A listing of subjects enrolled in each part will be 
provided. 
9.2.2 
Demographics and Baseline Characteristics 
Demographics, medical history and baseline characteristics will be summarized overall and by 
cohort for Part A, overall for Part B based on the Safety Set. 
Demographic data will include the following: 
• Age at baseline 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 


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• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, and Other) 
Baseline characteristics for Part A and Part B will include the following: 
• Weight (kg) 
•  Length (cm) 
• BMI (kg/m2) 
Baseline characteristics for Part B only will include the following: 
• Sweat Chloride 
Sweat chloride at screening will be listed for Part A. 
Medical history will be summarized by MedDRA system organ class (SOC) and preferred term 
(PT).  
9.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary WHODrug, Global B3 format and categorized as the following: 
• Prior medication: any medication that started before initial dosing of study drug, 
regardless of when it ended. 
• Concomitant medication: medication continued or newly received on or after the first 
dose date of study drug of a study part through the end of the TE Period of the 
corresponding study part. 
• Post-treatment medication: medication continued or newly received after the TE period 
in each study part.  


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A given medication can be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; 
or prior, concomitant, and post-treatment.  
If a medication has a missing or partially missing start/end date or time and it cannot be 
determined whether it was taken before initial dosing, concomitantly, or after 14 days after the 
last dose of study drug, it will be considered as prior, concomitant, and post-treatment. 
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix C. 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by preferred name based on the Safety Set for each part. 
Post-treatment medications will be listed for each subject.  
9.2.4 
Study Drug Exposure  
Part A 
Duration of study drug exposure is defined as follows: last dose date − first dose date + 1 day, 
regardless of any interruptions in dosing. If the last dose date of study drug is missing and the 
ETT visit is available, use the ETT visit as the last dose date. Otherwise, if there is no ETT 
visit, the Safety Follow-up visit is used for analysis purposes. 
Study drug exposure will be summarized descriptively in days overall and by Cohort based on 
Part A Safety Set.  
Study drug exposure duration will be presented in an individual subject data listing to indicate 
whether the study drug was taken or not. 
Part B 
Duration of Part B study drug exposure is defined as follows: Part B last dose date − Part B 
first dose date + 1 day, regardless of any interruptions in dosing. If the last dose date of Part B 
study drug is missing and the ETT visit is available, use the ETT visit as the last dose date. 
Otherwise, if there is no ETT visit, the Safety Follow-up visit is used for analysis purposes. 
Study drug exposure duration will be summarized overall based on the Part B Safety Set and 
descriptively as a quantitative variable. 
Additionally, the cumulative duration of treatment exposure, defined as the sum of the 
subject’s duration of treatment exposure and expressed in subject-years, will be provided. 
Duration of exposure will also be summarized as a categorical variable (>0 to ≤2 weeks, >2 
to ≤4 weeks, >4 to ≤8 weeks, >8 to ≤16 weeks, >16 to ≤24 weeks, and >24 weeks). 
9.2.5 
Study Drug Compliance 
Part A 
A listing of exposure, with the first/last dose date/time, as well as the number of stick packs 
dispensed and returned will be provided to indicate the drug compliance. 
Part B 


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Study drug compliance will be assessed by calculating as follows:  
100 × (1 − [total number of days of study drug interruption] / [duration of study drug 
exposure + total number of days study drug interrupted after last dose, if any]).  
The total number of days of study drug interruption is defined as the sum of (number of days 
of each study drug interruption), where number of days of each study drug interruption is 
defined as the interruption end date − the corresponding interruption start date + 1. 
In calculating the total number of days of study drug being interrupted, only the interruptions 
with duration of ≥3 days will be considered. An interruption with duration of < 3 days will not 
be considered in the calculation. 
Percent of stick packs taken will be calculated as follows: 
100 × (total number of stick packs administered) / (2 × [duration of study drug exposure in 
days + total number of days study drug interrupted after last dose, if any]). Subjects who have 
a calculated percent of stick packs taken >100% will be considered as having taken 100% of 
stick packs. 
Treatment compliance percentages and percent of stick packs taken will be summarized 
descriptively as quantitative variables overall based on Safety Set. The number and percentage 
of subjects whose compliance is <80% or ≥80% and the number and percentage of subjects 
whose percent of stick packs taken is <80% or ≥80% will be summarized. 
Compliance will be presented in an individual subject data listing. 
9.2.6 
Important Protocol Deviations  
An important protocol deviation (IPD) is a PD (any change, divergence, or departure from 
the study design or procedures defined in the protocol) that may significantly impact the 
completeness, accuracy and/or reliability of the study data or that may significantly affect a 
subject’s rights, safety, or well-being. IPDs will be identified by the PD review team 
according to PD plan.  
The programmable rules for identifying important protocol deviations based on the clinical 
database are defined in Appendix F.  
All IPDs will be summarized and presented in an individual subject data listing. 
9.3 
Efficacy Analysis  
Not Applicable.  
9.4 
Safety Analysis 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (serum chemistry and hematology) 
• ECGs (standard 12-lead) 
• Vital signs 


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• Pulse oximetry 
Safety analyses will be performed overall and by cohort for Part A, overall for Part B  based 
on Safety Set. Safety data will be presented in the individual subject data listings based on the 
All Subjects Set. Only descriptive summary statistics of safety data will be provided (i.e., no 
statistical hypothesis testing will be performed). 
9.4.1 
Adverse Events  
AEs will be classified as pretreatment AEs, TEAEs, or post-treatment AEs for each study part, 
defined as follows. 
• Pretreatment AE: any AE that started before initial dosing of study drug in each 
corresponding study part. 
• TEAE: any AE that increased in severity or that was newly developed at or after the first 
dose of study drug through the end of the TE Period of each corresponding study part. 
• Post-treatment AE: any AE that increased in severity or that newly developed after the 
TE Period of each corresponding study part. 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study treatment, then the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of adverse events are described in Appendix 
D. 
TEAE summaries will be presented overall and by cohort for Part A, overall for Part B  using 
number and percentages of subjects. 
An overview of TEAE profile will be provided, including total number of TEAEs, with number 
and percentage of subjects for the following categories: (1) All TEAEs, (2) Grades  3/4 TEAEs, 
(3) TEAEs by strongest relationship to study drug, (4) TEAEs by maximum severity, (5) 
TEAEs leading to treatment interruption, (6) TEAEs leading to treatment discontinuation, (7) 
Serious TEAEs, (8) Serious TEAEs related to study drug, and (9) TEAEs leading to death.  
AE summary tables will be presented for TEAEs only and will include the following: 
• All TEAEs  
• Grades 3/4 TEAEs 
• TEAEs by strongest relationship to study drug  
• TEAEs by maximum severity 
• TEAEs leading to treatment interruption 
• TEAEs leading to treatment discontinuation 
• Serious TEAEs 
• Serious TEAEs related to study drug 
• TEAEs leading to death 


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• Frequently reported TEAEs ≥5% at the preferred term level (Part B only) 
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 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 in the relationship summaries. 
Separate tables will be provided summarizing the number of subjects, the number of events, 
and the number of related events by SOC and PT (as per EudraCT requirement) for each part 
for the following: 
• Treatment-emergent Serious AEs 
• Treatment-emergent Non-Serious AEs 
Note that if an event increases in its severity, it will be reported as a separate event in the 
clinical database and thus may be counted more than once. 
Analysis of AEs of special interest (AESI) categories (Part B only):  
The following AESIs are defined: 
1.  Elevated Transaminases 
The AESI of elevated transaminases is defined by the AEs whose PTs fall into any of the 
following:  
• Alanine aminotransferase abnormal  
• Alanine aminotransferase increased  
• Aspartate aminotransferase abnormal 
• 
Aspartate aminotransferase increased 
• 
Transaminases abnormal 
• 
Transaminases increased 
• 
Liver function test abnormal 
• 
Liver function test increased 
• 
Hypertransaminasaemia 
• 
Hepatic enzyme increased 
• 
Hepatic enzyme abnormal 
2. Respiratory Symptom AESI 
The respiratory symptoms AESI is defined by the AEs whose PTs fall into any of the 
following: 
• Chest Discomfort 


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• Dyspnoea 
• Respiration abnormal 
3. Respiratory Event AESI (including respiratory symptoms or reactive airways) 
The respiratory AESI of respiratory symptoms or reactive airways is defined by the AEs 
whose PTs fall into any of the following: 
• Asthma 
• Bronchial hyperreactivity 
• Bronchospasm  
• Chest Discomfort 
• Dyspnoea 
• Respiration abnormal 
• Wheezing 
Treatment-emergent AESIs will also be summarized 
1. Showing number and percentage of subjects by PT; 
2. Showing number and percentage of subjects by maximum severity; 
3. Summary of duration of events (days) with descriptive statistics; 
4. Summary of time-to-onset of the first event in days (relative to first dose date).  
5. Showing number and percentage of subjects with TEAE leading to treatment 
discontinuation; with TEAE leading to treatment interruption; with serious TEAEs; with 
related serious TEAEs; and with TEAE leading to death. 
In addition, listings that contain individual subject data for all TEAEs leading to treatment 
interruption, TEAEs leading to treatment discontinuation, serious AEs (SAEs) and deaths will 
be provided separately. All AEs, including pre- and post-treatment AEs, will be presented in 
individual subject data listings. 
9.4.2 
Clinical Laboratory 
For treatment-emergent laboratory measurements, the raw values and change from baseline 
values of the continuous hematology and chemistry results will be summarized overall and by 
cohort for Part A, overall for Part B in SI units at each scheduled time point. Laboratory tests 
done in the local laboratory may be used in data analyses if data from the central laboratory 
are not available. 
The number and percentage of subjects meeting a threshold analysis criterion during the 
TE Period will be summarized overall and by cohort for Part A, overall for Part B. The 
threshold analysis criteria are provided in Appendix E. 


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For hematology and chemistry, the number and percentage of subjects with abnormally low 
(<lower limit of normal [LLN]) value and with abnormally high (>ULN) values at each 
scheduled time point will be summarized overall and by cohort for Part A, overall for Part B. 
Results of urinalysis will be listed in individual subject data listings only.  
In addition, a listing containing individual subject hematology and chemistry values outside 
the normal reference ranges will be provided. This listing will include data from both scheduled 
and unscheduled visits. 
9.4.3 
Electrocardiogram 
For treatment-emergent ECG measurements, a summary of raw values and change from 
baseline values will be provided at each scheduled time point for the following standard 12-
lead ECG measurements: RR (ms), HR (bpm), PR (ms), QRS duration (ms), QT (ms), and 
QT corrected for HR intervals [Fridericia's correction QTcF (ms) =QT/RR1/3]. In addition, 
the mean value at each time point will be plotted for QTcF. 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during 
the TE period will be summarized overall and by cohort for Part A, overall for Part B. The 
threshold analysis criteria are provided in Appendix E. 
9.4.4 
Vital Signs 
For treatment-emergent vital signs measurements, the raw values and change from baseline 
values will be summarized overall and by cohort for Part A, overall for Part B at each 
scheduled time point: systolic and diastolic blood pressure (mm Hg), body temperature (°C), 
pulse rate (beats per minute), and respiratory rate (breaths per minute), weight (kg), length 
(cm), and BMI (kg/m2). 
 
In addition, for both Part A and Part B, vital signs measurements at predose and the 
corresponding postdose timepoints (1 to 2 hours, and 4 to 6 hours) on Day 1 and Day 15 will 
be summarized, absolute change from predose to the corresponding postdose (1 to 2 hours, 
and 4 to 6 hours) on Day 1 and Day 15 will also be summarized. 
The number and percentage of subjects with at least 1  potential abnormal SBP and DBP 
during the Treatment period will be summarized separately. The potential abnormal criteria 
are provided in Appendix G. 
Potential abnormal SBP and DBP by their percentiles adjusted for sex, age and length will be 
provided, including 
• Number and percentage of subjects with categories ≥90%-<95%, ≥95%-<99% + 5 
mmHg and ≥99% + 5 mmHg)  
• Number and percentage of subjects with SBP and DBP percentiles ≥95% once and twice 
during the treatment-emergent period will be provided. 
• Number and percentage of subjects with SBP and DBP percentiles ≥95% at each visit 
will also be provided.  


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The length adjustment will be based on length-for-age-z-scores and their corresponding 
percentiles using the standard normal distribution. The length percentiles will be further 
mapped per the following rules: 
Table 9-1    Grouped Percentiles for Length-for-age Z-scores 
Calculated Percentiles (%) 
Grouped Percentiles (%) 
0 – <7.5  
5 
7.5 – <17.5 
10 
17.5 – <37.5 
25 
37.5 – <62.5 
50 
62.5 – <82.5 
75 
82.5 – <92.5 
90 
92.5 – 100 
95 
The sex- and age-adjusted normal range for SBP and DBP for each grouped height 
percentiles is based on the SBP/DBP table provided in the National Heart, Lung, and Blood 
Institute (NHLBI) website  
(http://www.nhlbi.nih.gov/health-pro/guidelines/current/hypertension-pediatric-jnc-4/blood-
pressure-tables). A listing of subjects with potentially abnormal SBP or DBP will be 
provided.  
A listing of all vital signs parameters with their values at every visit (or time point) will be 
provided for each Part to be included in the CSR appendix.  
9.4.5 
Pulse Oximetry 
For treatment-emergent pulse oximetry measurements, a summary of raw values and change 
from baseline values will be provided at each scheduled time point for the percent of oxygen 
saturation by pulse oximetry overall and by cohort for Part A, overall for Part B.  
In addition, for both Part A and Part B, oxygen saturation at predose and the corresponding 
postdose timepoints will be summarized (1 to 2 hours, and 4 to 6 hours) on Day 1 and Day 
15, absolute change from predose to the corresponding postdose (1 to 2 hours, and 4 to 6 
hours) on Day 1 and Day 15 will also be summarized. 
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 provided. 
9.4.6 
Ophthalmological Examinations 
Ophthalmological examination findings will be presented as a data listing for Part A (screening 
only) and Part B .  
9.4.7 
Physical Examination 
Physical examination findings will be presented as a data listing only.  










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9.6 
Narratives Listings 
Narratives listings will be provided for subjects with any of the following events that 
occurred by the study cutoff date: 
• Death 
• Serious AEs 
• TEAEs leading to treatment discontinuation  
• LFT elevations meeting at least 1 of the following criteria: 
o ALT or AST > 5xULN, or  
o ALT>3xULN and total bilirubin>2xULN, or  
o AST>3xULN and total bilirubin>2xULN  
during the treatment-emergent period 
10 
SUMMARY OF INTERIM AND IDMC ANALYSES 
10.1 
Interim Analysis 
Separate interim analyses (IA) will be performed after: 
• IA 1: all subjects in Cohort 1 have completed the last visit in Part A 
• IA 2: all subjects in Cohort 2 have completed the last visit in Part A. 
The objective of the IAs is to confirm the dose selection for Part B and conduct the safety 
review. 
The tables and listings will be generated as follows:  
1. Disposition 
2. Demographic 


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3. Baseline Characteristics 
4. Exposure 
5. Overall TEAE summary table 
6. Incidence of TEAE by SOC and PT 
7. Listing of Exposure 
8. Listing of all SAEs 
9. Listing of all AEs 
10. Listing of Out of Normal Range (>ULN or <LLN) Chemistry 
11. Listing of Out of Normal Range (>ULN or <LLN) Hematology 
12. Listing of ECGs with Interpretation and findings 
13. Listing of vital signs. 
Safety data for each IA will be summarized in one column as an overall group only for 
Cohorts 1 and 2 respectively. Interim analysis 1 for Cohort 1 will report Cohort 1 subjects 
only. Interim analysis 2 for Cohort 2 subjects will report Cohort 2 subjects only. 
 
10.2 
IDMC Analysis 
There will be no IDMC analysis for Part A. IDMC analyses are planned for Part B.  
The IDMC’s objectives and operational details were defined in a separate document (IDMC 
Charter) which was finalized before the first subject was dosed in the study. The IDMC’s 
planned safety reviews of study data are outlined in the IDMC Charter. The details of the 
IDMC Statistical Analysis will be provided in the DMC Analysis Plan.  
11 
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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12 
LIST OF APPENDICES 
Appendix A: Schedule of Assessments 
Schedules of Assessments are shown in Table 12-1, Table 12-2 and Table 12-3.


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Table 12-1 
Study VX16-809-122: Part A and Part B Screening 
Assessment 
Screening Visit 
Day -28 through Day -1 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Length, weight, and vital signsa,b 
X 
Pulse oximetryb 
X 
Ophthalmologic examinationc 
X 
Full physical examination 
X 
Standard 12-lead ECGd 
X 
CFTR genotypee 
X 
Serum chemistryf 
X 
Hematologyf 
X 
Sweat chlorideh 
X 
Medications review 
Continuous from signing of ICF through Safety Follow-up Visit 
Adverse events  
Continuous from signing of ICF through Safety Follow-up Visit 
BMI: body mass index; 
 ICF: informed consent form;
 
 
 
a 
Length and weight must be measured with the subject in a dry diaper or dry underclothes only (Section 11.6.4 of the 
protocol). BMI will be derived from this assessment.  
b 
The subject should rest for at least 5 minutes, if possible, before having vital signs and pulse oximetry measured 
(Section 11.6.4 of the protocol).  
c 
An ophthalmologic examination will be conducted by a licensed ophthalmologist, preferably a pediatric 
ophthalmologist (Section 11.6.6 of the protocol). The examination does not need to be repeated if there is 
documentation of an examination meeting protocol criteria that was conducted within 3 months before the Screening 
Visit.  
d 
A standard 12-lead ECG will be performed (Section 11.6.5 of the protocol). The subject should rest for at least 5 
minutes, if possible, before having an ECG performed. The ECG will be performed before any other procedures that 
may affect heart rate, such as blood draws.  
e  
If a genotype test has been performed previously and is documented in the subject’s medical record, the subject is not 
required to be tested for CFTR genotype at screening but the subject’s eligibility must be approved by the Vertex 
medical monitor. If a historic genotype result is not available at screening or if the historic genotype result is not 
approved by the Vertex medical monitor, subjects will be tested for CFTR genotype, and the results must be reviewed 
before the first dose. Note: Newborn screening genotype results are not sufficient for eligibility. 
f 
The results must be received and reviewed before the first dose. Refer to Section 11.6.2 of the protocol for details.  
h 
If a historical sweat chloride result (≥60 mmol/L by quantitative pilocarpine iontophoresis) is documented in the 
subject’s medical record, that result alone (and not the Screening Visit result) may be used to determine eligibility. For 
subjects using a historical sweat chloride value documented in their medical record to determine eligibility, the sweat 
chloride test at the Screening Visit is still required in Part B. At screening, 2 samples will be collected, 1 sample from 
each arm (left and right).  












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Appendix B: Analysis Visit Window Mapping Rules for Safety and 
Pharmacodynamic Measurements (Part B only) 
 
Table 12-4 Visit Window Mapping Rules for Safety and Pharmacodynamic 
Measurements 
Assessments 
Visit 
Target Study 
Day 
Visit Window  
(in study days) 
  
Vital Signs 
Pulse oximetry 
LFT Chemistry 
Day 15* 
Week 4  
Week 8  
Week 12 
Week 16 
Week 24 
Safety Follow up  
15 
29 
57 
85 
113 
169 
 
(1, 22]  
[23, 43] 
[44, 71] 
[72, 99] 
[100, 141] 
[142, 183] 
Use nominal visit 
Sweat Chloride 
Non-LFT Chemistry 
Standard 12-lead ECG 
 
Hematology 
Week 4 
Week 12 
Week 24 
Safety Follow up 
29 
85 
169 
 
(1, 57]  
[58, 127] 
[128, 183] 
Use nominal visit 
Microbiology Cultures 
Week 12 
Week 24 
85 
169 
(1, 127]  
[128, 183] 
Ophthalmologic exam 
Week 24 
169 
 (1, 183] 
*Use predose nominal visit for vital signs/pulse oximetry at Day 15 
Special handling for VS/Pulse Oximetry (for the change from predose to postdose 
analysis only): 
For the change from predose to postdose VS/Pulse Oximetry analysis, no windowing rules 
are used. 
1. The predose VS/ Pulse Oximetry on Day 1 and Day 15: analysis visit = nominal visit for 
Day 1 and Day 15, Predose correspondingly. 
2. The post-dose VS/ Pulse Oximetry on Day 1 and Day 15: analysis visit = nominal 
postdose visits (1 to 2 hours, and 4 to 6 hours) on Day 1 and Day 15 correspondingly. 
 
 


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Appendix C: Assessments 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. 
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 summary, the prior, concomitant or post categorization of a medication is described below. 
Table 12-5 
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 
Treatment-emergent  
Period 
> End Date of 
Treatment-emergent  
Period 
< First dose date of study drug 
P 
PC 
PCA 
≥ First dose date and  
≤ End date of Treatment-
emergent period 
- 
C 
CA 
> End date of Treatment-
emergent period 
- 
- 
A 
A: Post; C: Concomitant; P: Prior 
 
 


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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 only Day of AE start date is missing:  
If the AE start year and month are the same as that for the first dose date, then: 
• If the full (or  partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start day as the day of first dose date; otherwise, impute 
the AE start day as 1. 
• Otherwise, impute the AE start day as 1. 
Compare the imputed AE start date with Treatment-Emergent period to determine whether 
the AE is pretreatment AE, TEAE or post-treatment AE. 
If Day and Month of AE start date are missing: 
If AE start year = first dose year, then: 
• If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start Month and Day as the Month and Day of first dose 
date; otherwise, impute the AE start Month as January and the Day as 1. 
• Otherwise, impute the AE start MONTH as January and the DAY as 1. 
Compare the imputed AE start date with Treatment-Emergent period to determine whether 
the AE is pretreatment AE, TEAE or post-treatment AE. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site with 
no imputation. Also compare the full (or partial) AE end date to the first dose date. If the AE 
end date is before the first dose date then the AE should be considered as a pretreatment AE. 
Otherwise, the AE will be considered as TEAE. 
 
 
 


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Appendix E: Criteria for Threshold Analysis 
Table 12-5 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry 
ALT 
≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>3xULN 
>5xULN 
>8xULN 
FDA DILI Guidance Jul 2009.  
AST 
≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>3xULN 
>5xULN 
>8xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
ALT>3xULN or AST>3xULN 
ALT>5xULN or AST>5xULN 
ALT>8xULN or AST>8xULN 
Vertex LFT working group 2014 
 
Alkaline 
Phosphatase 
>1.5xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>1.5x - ≤2xULN 
>2xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total 
Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
To be counted within a same treatment phase, 
whatever the interval between measurements. 
AST and Total 
Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
To be counted within a same treatment phase, 
whatever the interval between measurements. 
(ALT or AST) and 
Total Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
Vertex LFT working group 2014 
CPK 
>3x - ≤ 10xULN 
>10xULN 
FDA criteria Feb 2005. 
Am J Cardiol April 2006. 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Blood Urea 
Nitrogen 
≥17 mmol/L 
 
Sodium 
≤129 mmol/L 
≥150 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 


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Table 12-5 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
Albumin 
≤25 g/L 
 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count 
available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) International Consensus meeting on drug-
induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline 
are more relevant than based on absolute 
value. Other categories for decrease from 
baseline can be used (≥30 g/L, ≥40 g/L, 
≥50 g/L). 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 
 
 
Table 12-6 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
≤70 bpm   
≥150  bpm 
 
PR 
≥150 ms   
 
QRS 
≥80 ms 
 
QTcF 
  
  
Absolute values (ms) 
  
Prolonged: >450 ms (Male and female) 
To be applied to any kind of QT correction 
formula.  
 
 
 


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Appendix F:  Important Protocol Deviation Programming Rules for Part B only 
(Based on the Clinical Database) 
Important protocol deviations before first dose 
• Inclusion criteria: Subjects (males and females) will be 1 to less than 1 years of age 
on Day 1 of the relevant par of study. 
Important protocol deviation during the treatment period 
• Compliance < 80% 
 
 
 


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Appendix G:  Blood Pressure Normal Levels for Boys and Girls by Age and 
Height Percentile 
Child_SBP_DBP.pdf