Clinical trial NCT04599465
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2021-01-15; Completion date: 2022-07-14
Enrollment: 69 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study was evaluate the effect of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) on glucose tolerance in CF participants, 12 years of age and older who are heterozygous for the F508del mutation and a minimal function mutation (F/MF genotypes), with abnormal glucose metabolism.

Detailed description:

Arms: arm 1: Participants received ELX 200 mg /TEZ 100 mg /IVA 150 mg in the morning and IVA 150 mg in the evening.
Interventions: intervention 1: ELX/TEZ/IVA intervention 2: IVA
Intervention descriptions: intervention 1: Fixed dose combination (FDC) tablets for oral administration. intervention 2: Tablets for oral administration.

Protocol documents:
Prot_000.pdf: 


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Summary of Changes to the Protocol 
The previous version of this protocol (Version 2.0, 22 September 2020) was amended to create 
the current version (Version 3.0, 26 April 2021). The protocol history is provided below. 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.1, 24 August 2020 
Original version 
Version 2.0, 22 September 2020 
Removed option for use of remote measures at certain study visits such 
that those visits are to be performed in the clinic; clarified different 
glomerular filtration rates for subjects ≥18 years of age and subjects 
<18 years of age; clarified that during in-clinic visits, spirometry 
assessments may be performed on more than 1 spirometer, as applicable; 
removed sweat chloride assessment at Week 4; added language to allow 
use of remote measures in extenuating circumstances. 
Version 3.0, 26 April 2021 
Current version 
 
Key changes in the current version of the protocol compared to Version 2.0 are summarized 
below. 
Change and Rationale  
Affected Sections  
Updated the following Other Endpoints to clarify oral glucose 
tolerance test (OGTT) values (in mmol/L) and glucose ranges: 
• 
Change from baseline in percent of time spent in target blood 
glucose range of ≥70 to <140 mg/dL (≥3.89 to <7.77 mmol/L) 
as measured by 7-day continuous glucose monitoring (CGM) 
in subjects with cystic fibrosis-related diabetes (CFRD) at 
Week 48 
• 
Change from baseline in selected CGM parameters (including 
but not limited to percent of time spent between ≥140 and 
<200 mg/dL [≥7.77 and <11.10 mmol/L], percent of time spent 
≥200 mg/dL [≥11.10 mmol/L], and maximum amplitude of 
glucose excursions [MAGE]) in subjects with CFRD at 
Week 48 
Synopsis, and Sections 7.3 and 12.3.3.5 
Updated the definition of impaired glucose tolerance (IGT) to 
2-hour post-OGTT blood glucose level ≥140 to <200 mg/dL (≥7.77 
to <11.10 mmol/L) to eliminate a gap in glucose values in previous 
protocol versions, and to clarify both the glucose values (in 
mmol/L) and the dysglycemia categories. 
Section 8.1 
Updated the definition of CFRD to either fasting hyperglycemia 
(blood glucose level ≥126 mg/dL [≥7.00 mmol/L] after an 8-hour 
fast) or 2-hour post-OGTT blood glucose level ≥200 mg/dL 
(≥11.10 mmol/L) to eliminate a gap in glucose values in previous 
protocol versions, and to clarify both the glucose values (in 
mmol/L) and the dysglycemia categories. 
Section 8.1 
Updated text to state that height will be measured for all subjects at 
screening to correct an error in previous protocol versions. 
Table 3-1 and Section 11.3.3 
Added collection windows around the OGTT assessments and 
clarified that post-0 minute collection time points are defined as 
time after the start of ingestion of glucose solution to provide 
additional guidance on the execution of the OGTT assessment. 
Table 3-1 and Table 3-2, and 
Section 11.3.1 


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Change and Rationale  
Affected Sections  
Removed specification that only subjects with CFRD will collect 
an insulin diary, such that any subject who uses insulin will collect 
an insulin diary, to allow for the possibility of both IGT and CFRD 
subjects to be on insulin. 
Synopsis, Table 3-2, and Sections 7.3, 
11.3.4, and 12.3.3.5 
Added a waiver of the Safety Follow-up Visit for subjects who 
complete the Week 48 Visit and transition to a commercially 
available CFTR modulator regimen with 28 days after the last dose 
of study drug, given the possibility of commercial availability of 
ELX/TEZ/IVA in certain countries. 
Section 9.1.3 
Updated text that remote measures may be used for study visits at 
Week 4 and Week 12, but all other visits must be performed in the 
clinic, to provide clarity on the use of remote measures. 
Section 9.1.7 
Removed glyburide, nateglinide, and repaglinide from list of 
OATP1B1 and OATP1B3 substrates that should be used with 
caution to provide clarity and consistency within the protocol. 
Section 9.5 
Removed glimepiride and glipizide from list of CYP2C9 substrates 
that should be used with caution to provide clarity and consistency 
within the protocol. 
Section 9.5 
Added instruction for investigators to counsel subjects on safe 
withholding of insulins prior to each OGTT based on feedback 
from study sites. 
Section 11.3.1 
Added instruction for sites to record insulin use in the 24 hours 
prior to each OGTT, as insulin use may confound OGTT results. 
Section 11.3.1 
 
Typographical and administrative changes were also made to improve the clarity of the 
document. 
 


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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3b Open-label Study to Assess the Effect of Elexacaftor/Tezacaftor/Ivacaftor 
on Glucose Tolerance in Cystic Fibrosis Subjects with Abnormal Glucose 
Metabolism 
  
Brief Title 
A Study to Assess the Effect of ELX/TEZ/IVA on Glucose Tolerance in Subjects 
With Cystic Fibrosis (CF) 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 3b, investigation of glucose tolerance 
 
 
Objective 
Primary Objective 
To evaluate the effect of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) on 
glucose tolerance in CF subjects with impaired glucose tolerance (IGT) or CF-related 
diabetes (CFRD) 
Secondary Objective 
To evaluate the safety and tolerability of ELX/TEZ/IVA 
 
 
Endpoints 
Primary Endpoint 
Change from baseline in 2-hour blood glucose levels following an oral glucose 
tolerance test (OGTT) to the average of Week 36 and Week 48 
Secondary Endpoints 
• 
Proportion of subjects with improvement in dysglycemia categorization (CFRD, 
IGT, normal glucose tolerance [NGT]) at Week 48 
• 
Safety and tolerability of ELX/TEZ/IVA based on adverse events (AEs), clinical 
laboratory values, ECGs, vital signs, and pulse oximetry 
Other Endpoints  
• 
Change from baseline in sweat chloride (SwCl) through Week 48 
• 
Absolute change in body mass index (BMI) from baseline at Week 48 
• 
Absolute change in body weight from baseline at Week 48 
• 
Change from baseline in hemoglobin A1c (HbA1c) and fructosamine at 
Week 48 
• 
Change from baseline in insulin use (dose) at Week 48 in subjects using insulin 
• 
Change from baseline in post-OGTT diabetes-related biomarkers (including 
insulin, C-peptide, glucagon, calculated indices of insulin secretion 
[insulinogenic index], and insulin resistance [HOMA-IR]) at Week 48 
• 
Change from baseline in biomarkers of inflammation (including C-reactive 
protein [CRP]) at Week 48 
• 
Change from baseline in biomarkers of pancreatic function (including fecal 
elastase-1 [FE-1] and serum immunoreactive trypsinogen [IRT]) at Week 48 
• 
Change from baseline in post-OGTT incretin levels (including glucagon-like 
peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) at 
Week 48 
• 
Change from baseline in percent of time spent in target blood glucose range of 
≥70 to <140 mg/dL (≥3.89 to <7.77 mmol/L) as measured by 7-day continuous 
glucose monitoring (CGM) in subjects with CFRD at Week 48 


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• 
Change from baseline in selected CGM parameters (including but not limited to 
percent of time spent between ≥140 and <200 mg/dL [≥7.77 and 
<11.10 mmol/L], percent of time spent ≥200 mg/dL [≥11.10 mmol/L], and 
maximum amplitude of glucose excursions [MAGE]) in subjects with CFRD at 
Week 48. 
 
 
Number of Subjects 
Approximately 60 subjects will be enrolled, of whom approximately 30 subjects will 
have IGT and 30 subjects will have CFRD. 
 
 
Study Population 
Male and female subjects with CF who are 12 years of age or older, heterozygous for 
the F508del mutation and an MF mutation (F/MF genotypes), with abnormal glucose 
tolerance as determined by OGTT at screening (classified as either IGT or CFRD). 
Among all subjects, approximately 50% may be enrolled while using insulin 
(≤0.3 units/kg/day). 
 
 
Investigational Drug 
Active substance: ELX (VX-445)/TEZ (VX-661)/IVA (VX-770) 
Activity: CFTR correctors (ELX and TEZ) and potentiator (IVA) 
Strength and route of administration: ELX 100-mg/TEZ 50-mg/IVA 75-mg 
fixed-dose combination (FDC) tablets, oral 
 
Active substance: IVA (VX-770) 
Activity: CFTR potentiator 
Strength and route of administration: 150-mg tablets, oral 
 
 
Study Duration 
Excluding the Screening Period, the total study duration is approximately 52 weeks 
(48 weeks for the Treatment Period, and 4 weeks for the Safety Follow-up Period). 
 
 
Study Design 
This is a Phase 3b, open-label study in CF subjects 12 years of age and older with 
F/MF genotypes and abnormal glucose tolerance. A schematic of the study design is 
shown in Figure 2-1. 


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Figure 2-1 
VX19-445-117 Study Design 
 
ELX: elexacaftor; CFRD: CF-related diabetes; CGM: continuous glucose monitoring; IVA: 
ivacaftor; N: total sample size; TEZ: tezacaftor 
a 
On Day -7, a CGM sensor will be inserted subcutaneously to assess baseline blood 
glucose levels for 7 days prior to the first dose of study drug in subjects with CFRD.  
b 
Subjects who complete the visits in the Treatment Period, regardless of whether they 
are on a treatment interruption, will be offered the opportunity to enroll in an 
open-label extension safety study evaluating ELX/TEZ/IVA. The Safety Follow-up 
Visit is not required for subjects who complete the Week 48 Visit and have enrolled in 
an open-label study within 28 days after the last dose of study drug. 
Subjects will receive ELX 200 mg once daily (qd)/TEZ 100 mg qd/IVA 150 mg 
every 12 hours (q12h). 
 
 
Assessments 
Efficacy and PD:  
• 
2-hour OGTT 
• 
SwCl 
• 
BMI 
• 
Weight 
• 
Height 
• 
Diabetes-related blood biomarkers collection 
• 
Insulin use diary for subjects using insulin 
• 
CGM (subjects with CFRD only) 
Safety: AEs, clinical laboratory assessments, 12-lead ECGs, vital signs, pulse 
oximetry, ophthalmologic examinations (for subjects <18 years of age on the date of 
informed consent), and physical examinations (PEs) 
 Other: 
• 
Spirometry 
• 
Fecal sample collection 
• 
Other blood biomarkers collection 
 
 
Statistical Analyses 
Statistical analysis details will be provided in the Statistical Analysis Plan (SAP), 
which will be finalized before the clinical database lock. 
 
The primary null hypothesis to be tested is that the mean change from baseline in 
2-hour blood glucose levels following OGTT to the average of Week 36 and 
Week 48 is equal to zero. Assuming a within group SD of 45 mg/dL and a 10% 
dropout rate at Week 48, a sample size of 60 subjects will have more than 95% power 
to detect a mean decrease from baseline of -30 mg/dL in 2-hour blood glucose levels 


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post-OGTT to the average of Week 36 and Week 48, based on a 2-sided, 1-sample 
t-test at a significance level of 0.05 using the EAST software Version 6.4. 
 
The primary analysis will be based on a mixed-effects model for repeated measures 
(MMRM) with change from baseline in 2-hour post-OGTT blood glucose levels at 
Weeks 24, 36, and 48 as the dependent variable. The model will include visit as a 
fixed effect, and will be adjusted for main covariates as appropriate. The primary 
result obtained from the model will be the estimated mean change from baseline to 
the average of Week 36 and Week 48. The estimated change at each visit and the 
mean change to the average of Week 36 and Week 48 along with the 2-sided 95% CI 
and P value will be provided.  


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are in Table 3-1 and Table 3-2. 
Table 3-1 
Study VX19-445-117: Screening 
Event/Assessment 
Screening Visit 
Day -35 to Day -8 
Comments 
Study visit 
X 
The Screening Visit must be performed in the clinic. 
Informed consent (and assent, if 
applicable) 
X 
Electronic or remote consent may be used, if permitted by 
local regulations. 
Demographics 
X 
Section 11.1 
Medical history 
X 
Section 11.1 
Medications review 
X 
Information regarding medications taken within 56 days 
before the Screening Visit will be collected (Section 9.5). 
Height and weight 
X 
Measured with shoes off (Section 11.3.3). 
Vital signs and pulse oximetry 
X 
Collected after the subject has been at rest for at least 
5 minutes (Section 11.4.3). 
Ophthalmologic examination 
X 
Conducted by an ophthalmologist or optometrist for 
subjects <18 years of age on the date of informed consent 
(Section 11.4.5). 
Complete physical examination 
X 
Section 11.4.3 
12-lead ECG 
X 
Performed prior to any procedure that may affect heart rate 
(e.g., blood draws) and after subject has been at rest for at 
least 5 minutes (Section 11.4.4). 
Sweat chloride 
X 
Section 11.3.5 
Spirometry 
X 
Performed pre- or post-bronchodilator (Section 11.2.1) 
CF genotype 
X 
If the CFTR genotype result is not received before the first 
dose of study drug, a previous CFTR genotype laboratory 
report may be used to establish eligibility (Section 8.1). 
Subjects who have been enrolled whose screening 
genotype does not confirm study eligibility must be 
discontinued from the study (Section 9.9). 
Serum pregnancy (all female 
subjects) 
X 
Section 11.4.2 
Serum chemistry (including 
cholesterol and 
thyroid-stimulating hormone) 
X 
Hematology 
X 
Coagulation 
X 
Urinalysis 
X 
Oral glucose tolerance test 
(OGTT) 
X 
If permitted by local regulations, subjects may provide 
informed consent remotely to begin fasting (except water 
and allowed medications other than prednisone and 
prednisolone) at least 8 hours before the OGTT at the 
Screening Visit. Blood glucose levels will be measured at 
0, 30 (±5), 60 (±5), 90 (±5), and 120 (±5) minutes after the 
start of consuming 1.75 g/kg of body weight (maximum of 
75 g total) of glucose solution (Section 11.3.1). 
OGTT blood biomarkers 
collection 
X 
Collected on the same day as the OGTT (Section 11.3.1). 
Fecal sample collection 
X 
Fecal sample may be collected at the site during the 
Screening Visit, or at any time point prior to the first dose 
of study drug (Section 11.2.2). 


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Table 3-1 
Study VX19-445-117: Screening 
Event/Assessment 
Screening Visit 
Day -35 to Day -8 
Comments 
Adverse events 
Continuous, From the 
Date of Informed Consent 
through Completion of 
Study Participation 
Section 13.1; completion of study participation is defined 
in Section 9.1.6. 
CF: cystic fibrosis; OGTT: oral glucose tolerance test 
 
  
















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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
Summary of Changes to the Protocol......................................................................................... 2 
2 
Protocol Synopsis ................................................................................................................... 4 
3 
Schedule of Assessments........................................................................................................ 8 
4 
Table of Contents ................................................................................................................. 17 
List of Tables............................................................................................................................ 20 
List of Figures .......................................................................................................................... 20 
List of Abbreviations................................................................................................................ 21 
5 
Introduction.......................................................................................................................... 24 
5.1 
Background ..................................................................................................................... 24 
5.2 
Study Rationale .............................................................................................................. 24 
6 
Study Objectives .................................................................................................................. 25 
6.1 
Primary Objective ........................................................................................................... 25 
6.2 
Secondary Objective ....................................................................................................... 25 
7 
Study Endpoints ................................................................................................................... 25 
7.1 
Primary Endpoint ............................................................................................................ 25 
7.2 
Secondary Endpoints ...................................................................................................... 25 
7.3 
Other Endpoints .............................................................................................................. 25 
8 
Study Population .................................................................................................................. 26 
8.1 
Inclusion Criteria ............................................................................................................ 26 
8.2 
Exclusion Criteria ........................................................................................................... 26 
9 
Study Implementation ......................................................................................................... 28 
9.1 
Study Design .................................................................................................................. 28 
9.1.1 
Screening ................................................................................................................ 29 
9.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 29 
9.1.1.2 
Rescreening ...................................................................................................... 29 
9.1.1.3 
Extension of Screening Period Window .......................................................... 30 
9.1.2 
Treatment Period .................................................................................................... 30 
9.1.3 
Follow-up................................................................................................................ 30 
9.1.4 
Early Termination of Treatment ............................................................................. 30 
9.1.5 
Lost to Follow-up ................................................................................................... 30 
9.1.6 
Completion of Study Participation ......................................................................... 31 
9.1.7 
Use of Remote Measures ........................................................................................ 31 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 32 
9.3 
Rationale for Study Elements ......................................................................................... 32 
9.3.1 
Study Design........................................................................................................... 32 
9.3.2 
Study Population..................................................................................................... 32 
9.3.3 
Study Drug Dose .................................................................................................... 32 
9.3.4 
Rationale for Study Assessments ........................................................................... 32 
9.4 
Study Restrictions ........................................................................................................... 33 
9.5 
Prior and Concomitant Medications ............................................................................... 34 
9.6 
Administration ................................................................................................................ 35 
9.6.1 
Dosing ..................................................................................................................... 35 
9.6.2 
Missed Doses .......................................................................................................... 35 


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9.7 
Dose Modification for Toxicity ...................................................................................... 35 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 35 
9.8.1 
Liver Function Tests ............................................................................................... 36 
9.8.2 
Rash ........................................................................................................................ 37 
9.9 
Removal of Subjects ....................................................................................................... 37 
9.10 Replacement of Subjects ................................................................................................ 37 
10 Study Drug Information and Management ....................................................................... 38 
10.1 Preparation and Dispensing ............................................................................................ 38 
10.2 Packaging and Labeling ................................................................................................. 38 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 38 
10.4 Drug Accountability ....................................................................................................... 38 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 39 
10.6 Compliance ..................................................................................................................... 39 
10.7 Blinding and Unblinding ................................................................................................ 39 
11 Assessments .......................................................................................................................... 39 
11.1 Subject and Disease Characteristics ............................................................................... 39 
11.2 Other Assessments .......................................................................................................... 39 
11.2.1 
Spirometry .............................................................................................................. 39 
11.2.2 
Fecal Sample Collection ......................................................................................... 40 
11.2.3 
Other Blood Biomarker Collection......................................................................... 41 
11.3 Efficacy and Pharmacodynamics ................................................................................... 41 
11.3.1 
Oral Glucose Tolerance Test .................................................................................. 41 
11.3.2 
Continuous Glucose Monitoring ............................................................................ 41 
11.3.3 
Height and Weight .................................................................................................. 41 
11.3.4 
Insulin Use Diary .................................................................................................... 42 
11.3.5 
Sweat Chloride ....................................................................................................... 42 
11.4 Safety .............................................................................................................................. 42 
11.4.1 
Adverse Events ....................................................................................................... 42 
11.4.2 
Clinical Laboratory Assessments ........................................................................... 42 
11.4.3 
Physical Examinations and Vital Signs .................................................................. 44 
11.4.4 
Electrocardiograms ................................................................................................. 44 
11.4.5 
Ophthalmologic Examination ................................................................................. 44 
11.4.6 
Contraception and Pregnancy ................................................................................. 45 
11.4.6.1 Contraception ................................................................................................... 45 
11.4.6.2 Pregnancy ......................................................................................................... 46 
12 Statistical Analysis ............................................................................................................... 47 
12.1 Sample Size and Power .................................................................................................. 47 
12.2 Analysis Sets .................................................................................................................. 47 
12.3 Statistical Analysis ......................................................................................................... 47 
12.3.1 
General Considerations ........................................................................................... 47 
12.3.2 
Background Characteristics .................................................................................... 48 
12.3.3 
Efficacy and Pharmacodynamic Analysis .............................................................. 48 
12.3.3.1 Analysis of Primary Efficacy Endpoint ........................................................... 48 
12.3.3.2 Analysis of Secondary Efficacy Endpoints ...................................................... 48 
12.3.3.3 Multiplicity Adjustment ................................................................................... 49 
12.3.3.4 Missing Data Handling .................................................................................... 49 


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12.3.3.5 Analysis of Other Efficacy Endpoints.............................................................. 49 
12.3.4 
Safety Analysis ....................................................................................................... 49 
12.4 Interim Analysis ............................................................................................................. 50 
12.5 Data Monitoring Committee Analysis ............................................................................ 50 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 50 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 50 
13.1.1 
Adverse Events ....................................................................................................... 50 
13.1.1.1 Definition of an Adverse Event........................................................................ 50 
13.1.1.2 Clinically Significant Assessments .................................................................. 50 
13.1.1.3 Documentation of Adverse Events................................................................... 51 
13.1.1.4 Adverse Event Severity .................................................................................... 51 
13.1.1.5 Adverse Event Causality .................................................................................. 52 
13.1.1.6 Study Drug Action Taken ................................................................................ 52 
13.1.1.7 Adverse Event Outcome .................................................................................. 53 
13.1.1.8 Treatment Given............................................................................................... 53 
13.1.2 
Serious Adverse Events .......................................................................................... 53 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 53 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 54 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 55 
13.2 Administrative Requirements ......................................................................................... 55 
13.2.1 
Product Complaints ................................................................................................ 55 
13.2.2 
Ethical Considerations ............................................................................................ 55 
13.2.3 
Subject Information and Informed Consent ........................................................... 55 
13.2.4 
Investigator Compliance ......................................................................................... 55 
13.2.5 
Access to Records ................................................................................................... 56 
13.2.6 
Subject Privacy ....................................................................................................... 56 
13.2.7 
Record Retention .................................................................................................... 56 
13.2.8 
Study Termination .................................................................................................. 56 
13.2.9 
End of Study ........................................................................................................... 57 
13.3 Data Quality Assurance .................................................................................................. 57 
13.4 Monitoring ...................................................................................................................... 57 
13.5 Electronic Data Capture ................................................................................................. 57 
13.6 Confidentiality and Disclosure ....................................................................................... 58 
13.7 Publications and Clinical Study Report .......................................................................... 58 
13.7.1 
Publication of Study Results ................................................................................... 58 
13.7.2 
Clinical Study Report ............................................................................................. 59 
14 References ............................................................................................................................. 60 
APPENDIX A Eligible MF CFTR Mutations ....................................................................... 62 
15 Protocol Signature Pages .................................................................................................... 65 
15.1 Sponsor Signature Page .................................................................................................. 65 
15.2 Investigator Signature Page ............................................................................................ 66 
 


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List of Tables 
Table 3-1 
Study VX19-445-117: Screening ............................................................................ 8 
Table 3-2 
Study VX19-445-117: Treatment Period and Safety Follow-up Visit ................. 10 
Table 9-1 
Prohibited Medications ......................................................................................... 33 
Table 10-1 
Study Drug ............................................................................................................ 38 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 43 
Table 11-2 
Acceptable Methods of Contraception.................................................................. 46 
Table 13-1 
Grading of AE Severity ........................................................................................ 51 
Table 13-2 
Classifications for AE Causality ........................................................................... 52 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 52 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 53 
List of Figures 
Figure 2-1 
VX19-445-117 Study Design ................................................................................. 6 
Figure 9-1 
VX19-445-117 Study Design ............................................................................... 29 
 


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List of Abbreviations 
Abbreviation 
Definition 
ADL 
activities of daily living 
AEs 
adverse events 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
Aspartate transaminase 
β 
beta, apparent elimination rate constant 
BMI 
body mass index 
CD 
compact disc 
CF 
Cystic Fibrosis 
CFRD 
CF related diabetes 
CFTR 
CF transmembrane conductance regulator protein 
CFTR 
CF transmembrane conductance regulator gene 
CGM 
continuous glucose monitoring 
CI 
confidence interval 
CRF 
case report form 
CRP 
C-reactive protein 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
ELX 
elexacaftor 
ETT 
Early Termination of Treatment 
EU 
European Union 
F/MF 
F508del mutation and a minimal function mutation 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
FE-1 
fecal elastase-1 
FEF25%-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GIP 
glucose-dependent insulinotropic polypeptide 
GLI 
Global Lung Function Initiative 
GLP-1 
glucagon-like peptide 1 
GPP3 
Good Publication Practices 


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Abbreviation 
Definition 
GPS 
Global Patient Safety 
HbA1c 
hemoglobin A1c 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IGT 
impaired glucose tolerance 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) (US) 
IRB 
institutional review board 
IRT 
immunoreactive trypsinogen 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LS 
least squares 
LUM 
lumacaftor 
MAGE 
maximum amplitude of glucose excursions 
max 
maximum value 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
n 
size of subsample 
N 
total sample size (e.g., number of subjects treated) 
NGT 
normal glucose tolerance 
OATP1B1 
organic anion transporting polypeptide 1B1 
OATP1B3 
organic anion transporting polypeptide 1B3 
OGTT 
oral glucose tolerance test 
P 
probability 
PC 
publication committee 
PD 
pharmacodynamic 
PEs 
physical examinations 
P-gp 
P-glycoprotein 
PIs 
principal investigators 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
q12h 
 every 12 hours 
qd 
once daily 
QTcF 
QT interval corrected by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
steering committee 
SD 
standard deviation 
SET 
Study Execution Team 
SUSARs 
suspected, unexpected, serious adverse events 
SwCl 
sweat chloride 


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Abbreviation 
Definition 
TE 
Treatment-emergent 
TEAEs 
treatment emergent adverse events 
TEZ 
tezacaftor 
t-test 
statistical test used when the independent variable is binary and the dependent variable 
is continuous 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
WHO-DD 
World Health Organization-Drug Dictionary 
 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive genetic disease with serious morbidities and 
frequent premature mortality. CF affects more than 70,000 individuals worldwide1 
(approximately 31,000 in the US2 and 48,000 in the EU3). 
CF is caused by decreased quantity and/or function of the CFTR protein due to mutations in the 
CFTR gene.4 CFTR is a channel that regulates the flow of chloride and other anions across 
epithelia in multiple organs and tissues, including the lungs, pancreas and other gastrointestinal 
organs, and sweat glands.5 Despite progress in the treatment of CF with antibiotics and 
mucolytics, the current median age at death among people with CF is approximately 30 years, 
and the predicted median age of survival is approximately 47 years.2, 3 More effective treatments 
are needed for CF. 
The most common disease-causing mutation is F508del: approximately 84.7% of people with CF 
in the US and 81.1% in Europe have at least one F508del allele.2, 3 
At present CF does not have a cure. CFTR modulators (i.e., correctors and potentiators) represent 
a major advancement in the treatment of CF because they are systemic therapies that target the 
underlying cause of the disease and have been shown to improve CF survival by modifying the 
course of disease.6, 7 The clinical testing and regulatory approval of CFTR modulators in certain 
countries for the treatment of people with CF caused by specific CFTR genotypes has established 
the therapeutic value of specific regimens developed by Vertex. These treatment regimens 
include ivacaftor (IVA) monotherapy (Kalydeco™), lumacaftor (LUM)/IVA dual combination 
therapy (Orkambi™), tezacaftor (TEZ)/IVA dual combination therapy (Symdeko™, Symkevi™) 
and elexacaftor (ELX)/TEZ/IVA triple combination therapy. 
The ELX/TEZ/IVA regimen is the first medicine to demonstrate clinical benefit in patients with 
a single F508del allele, regardless of the mutation of the second allele. A pivotal Phase 3 
program in CF subjects 12 years of age or older demonstrated that ELX/TEZ/IVA provides 
substantial improvements in lung function, CFTR function, and nutritional status, and was 
generally safe and well tolerated with a low rate of treatment discontinuation. 
5.2 
Study Rationale 
Abnormal glucose metabolism is a common complication from CF, and CF-related diabetes 
(CFRD) reaches a prevalence of approximately 50% of adults overall and approximately 80% of 
adults with a severe genotype (i.e., heterozygous for F508del and a minimal function mutation 
[F/MF])8. The primary deficiency is one of impaired insulin secretion due to loss of pancreatic 
beta cell (insulin producing) mass and function. Multiple mechanisms contribute to pancreatic 
destruction, including impaired bicarbonate/fluid secretion and thickened mucus 
(mucoviscidosis), which blocks exocrine ducts and results in fatty/fibrotic replacement of the 
majority of the pancreas. Over time, inflammation is believed to further impair the function of 
reduced endocrine islet cell mass and function. Genetics and other as yet unknown mechanisms 
are also believed to play a role in the progression to CFRD, and the need for exogenous insulin 
treatment, which is currently the standard of care. Patients who develop impaired glucose 
tolerance (IGT) or CFRD are known to have faster decline in lung function, higher mortality, and 
overall significantly increased burden of disease8. The present study is designed to evaluate the 


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effect of ELX/TEZ/IVA on impaired glucose homeostasis in CF subjects with abnormal glucose 
metabolism. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the effect of ELX/TEZ/IVA on glucose tolerance in CF subjects with IGT or CFRD 
6.2 
Secondary Objective 
To evaluate the safety and tolerability of ELX/TEZ/IVA 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Change from baseline in 2-hour blood glucose levels following an oral glucose tolerance test 
(OGTT) to the average of Week 36 and Week 48 
7.2 
Secondary Endpoints 
• 
Proportion of subjects with improvement in dysglycemia categorization (CFRD, IGT, 
normal glucose tolerance [NGT]) at Week 48 
• 
Safety and tolerability of ELX/TEZ/IVA based on adverse events (AEs), clinical laboratory 
values, ECGs, vital signs, and pulse oximetry 
7.3 
Other Endpoints 
• 
Change from baseline in sweat chloride (SwCl) through Week 48 
• 
Absolute change in body mass index (BMI) from baseline at Week 48 
• 
Absolute change in body weight from baseline at Week 48 
• 
Change from baseline in hemoglobin A1c (HbA1c) and fructosamine at Week 48 
• 
Change from baseline in insulin use (dose) at Week 48 in subjects using insulin 
• 
Change from baseline in post-OGTT diabetes-related biomarkers (including insulin, 
C-peptide, glucagon, calculated indices of insulin secretion [insulinogenic index], and 
insulin resistance [HOMA-IR]) at Week 48 
• 
Change from baseline in biomarkers of inflammation (including C-reactive protein [CRP]) at 
Week 48 
• 
Change from baseline in biomarkers of pancreatic function (including fecal elastase-1 [FE-1] 
and serum immunoreactive trypsinogen [IRT]) at Week 48 
• 
Change from baseline in post-OGTT incretin levels (including glucagon-like peptide 1 
[GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) at Week 48 
• 
Change from baseline in percent of time spent in target blood glucose range of ≥70 to 
<140 mg/dL (≥3.89 to <7.77 mmol/L) as measured by 7-day continuous glucose monitoring 
(CGM) in subjects with CFRD at Week 48 
• 
Change from baseline in selected CGM parameters (including but not limited to percent of 
time spent between ≥140 and <200 mg/dL [≥7.77 and <11.10 mmol/L], percent of time 


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spent ≥200 mg/dL [≥11.10 mmol/L], and maximum amplitude of glucose excursions 
[MAGE]) in subjects with CFRD at Week 48 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
8.1 
Inclusion Criteria 
1. Subject (or his or her legally appointed and authorized representative) will sign and date an 
informed consent form (ICF), and, when appropriate, an assent form. 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Subjects (male and female) 12 years of age or older on the date of informed consent. 
4. Subjects heterozygous for F508del and an MF mutation (F/MF genotypes, see Appendix A 
for definition and non-exhaustive list of eligible MF mutations). 
a. Genotype should be confirmed at the Screening Visit. 
b. If the screening CFTR genotype result is not received before the first dose of study drug, 
a previous CFTR genotype laboratory report may be used to establish eligibility. 
c. Subjects who have been enrolled and whose screening genotype does not confirm study 
eligibility must be discontinued from the study (Section 9.9). 
5. Forced expiratory volume in 1 second (FEV1) value ≥30% of predicted mean for age, sex, 
and height (equations of the Global Lung Function Initiative [GLI])9 at the Screening Visit 
(spirometry measurements must meet American Thoracic Society/European Respiratory 
Society criteria10 for acceptability and repeatability) and stable CF disease as judged by the 
investigator. 
6. Willing to remain on a stable CF treatment regimen (other than CFTR modulators) through 
completion of study participation. 
7. Abnormal glucose tolerance as determined by an OGTT, classified as either IGT (defined as 
2-hour post-OGTT blood glucose level ≥140 to <200 mg/dL [≥7.77 to <11.10 mmol/L]) or 
CFRD (defined as either fasting hyperglycemia [blood glucose level ≥126 mg/dL 
(≥7.00 mmol/L) after an 8-hour fast] or 2-hour post-OGTT blood glucose level ≥200 mg/dL 
[≥11.10 mmol/L]). 
8.2 
Exclusion Criteria 
1. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study drug(s) to 
the subject. This includes, but is not limited to, the following: 
• Clinically significant liver cirrhosis with or without portal hypertension 
• Solid organ or hematological transplantation 


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• Alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, 
and opiates, as deemed by the investigator 
• Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical 
carcinoma in situ (all 3 with no recurrence for the last 5 years) 
2. Type 1 or Type 2 diabetes. 
3. Duration of CFRD ≥5 years. 
4. 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). 
5. Any of the following abnormal laboratory values at screening: 
• Hemoglobin <10 g/dL 
• Total bilirubin ≥2 × upper limit of normal (ULN) 
• Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase 
(GGT), or alkaline phosphatase (ALP) ≥3 × ULN 
• Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 
(calculated by the Modification of Diet in Renal Disease Study Equation)11, 12 for subjects 
≥18 years of age and ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt 
equation)13 for subjects <18 years of age 
6. 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 study 
drug). 
7. Lung infection with organisms associated with a more rapid decline in pulmonary status 
(including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and 
Mycobacterium abscessus). For subjects who have had a history of a positive culture, the 
investigator will apply the following criteria to establish whether the subject is free of 
infection with such organisms: 
• The subject has not had a respiratory tract culture positive for these organisms within the 
12 months before the date of informed consent. 
• The subject has had at least 2 respiratory tract cultures negative for such organisms 
within the 12 months before the date of informed consent, with the first and last of these 
separated by at least 3 months, and the most recent one within the 6 months before the 
date of informed consent. 
8. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of 
study drug (Day 1). 
9. Ongoing or prior participation in an investigational drug study (including studies 
investigating ELX with or without coadministration of other study drugs) within 28 days of 
the Screening Visit.  
• A washout period of 5 terminal half-lives of the previous investigational study drug, or 
28 days, whichever is longer, must elapse before the Screening Visit.  


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• The duration of the elapsed time may be longer if required by local regulations.  
10. Use of restricted medication (including antidiabetic medication other than insulin, which 
must be at a dose no greater than 0.3 units/kg/day) within specified duration before the first 
dose of study drug as defined in Table 9-1.  
11. BMI ≥30 kg/m2 at the Screening Visit. 
12. Pregnant and breast-feeding females. All female subjects regardless of childbearing potential 
status (Section 11.4.6) must have a negative pregnancy test at the Screening Visit and the 
Day 1 Visit. 
13. 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 at that site. However, an adult (aged 18 years or older) who is a relative of a study 
staff member may be enrolled in the study provided that: 
• the adult lives independently of and does not reside with the study staff member, and 
• the adult participates in the study at a site other than the site at which the family member 
is employed. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3b, open-label study in CF subjects 12 years of age and older with F/MF 
genotypes and abnormal glucose tolerance (Figure 9-1). Approximately 60 subjects (F/MF 
genotypes) will be enrolled, of whom approximately 30 subjects will have IGT and 30 subjects 
will have CFRD. During the Treatment Period, subjects will be administered ELX/TEZ/IVA for 
approximately 48 weeks. All subjects will receive ELX 200 mg once daily (qd)/TEZ 100 mg qd/ 
IVA 150 mg every 12 hours (q12h). 


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Figure 9-1 
VX19-445-117 Study Design 
ELX: elexacaftor; CFRD: CF-related diabetes; CGM: continuous glucose monitoring; IVA: ivacaftor; N: total 
sample size; TEZ: tezacaftor 
a 
On Day -7, a CGM sensor will be inserted subcutaneously to assess baseline blood glucose levels for 7 days 
prior to the first dose of study drug in subjects with CFRD. 
b 
Subjects who complete the visits in the Treatment Period, regardless of whether they are on a treatment 
interruption, will be offered the opportunity to enroll in an open-label extension safety study evaluating 
ELX/TEZ/IVA. The Safety Follow-up Visit is not required for subjects who complete the Week 48 Visit and 
have enrolled in an open-label study within 28 days after the last dose of study drug. 
9.1.1 
Screening 
Screening Visit assessments are listed in Table 3-1. 
Screening will occur within 35 days before administration of study drug. The investigator (or an 
appropriate authorized designee) will obtain informed consent from each subject.  
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.4) and concomitant medications (Section 9.5). 
9.1.1.1 
Repetition of Screening Assessment(s) 
Screening assessments may be repeated once to establish study eligibility. If repeat values of the 
individual assessment(s) are within the eligibility criteria and completed within the screening 
window, then the subject is eligible for the study. 
9.1.1.2 
Rescreening 
Subjects may be rescreened once. If a subject is rescreened, the subject will provide informed 
consent and assent (as applicable), and all screening assessments will be repeated, except for:  
• CFTR genotyping 
• Ophthalmologic examination (if performed within 3 months before the date of informed 
consent) 
If a subject is rescreened, a new screening window will begin when the first rescreening 
assessment has been initiated. 


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9.1.1.3 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 2 weeks for the following 
reasons: 
• Repetition of the Screening Period assessments (Section 9.1.1.1) 
• Unexpected operational or logistic delays, or to meet the eligibility criteria 
• Scheduling of ophthalmologic examination (Section 11.4.5) 
9.1.2 
Treatment Period 
Treatment Period assessments are listed in Table 3-2. 
The Treatment Period will last approximately 48 weeks. Study drug administration details are 
provided in Section 9.6. 
9.1.3 
Follow-up 
The Safety Follow-up Visit is scheduled to occur 28 (± 7) days after the last dose of study drug.  
The Safety Follow-up Visit is not required for subjects who complete the Week 48 Visit and 
enroll in the open-label extension safety study, or who transition to a commercially available 
CFTR modulator regimen, within 28 days after the last dose of study drug. 
9.1.4 
Early Termination of Treatment 
If a subject prematurely discontinues study treatment, an Early Termination of Treatment (ETT) 
Visit should be scheduled as soon as possible after the subject decides to terminate study 
treatment. Subjects who prematurely discontinue treatment will also be required to complete the 
Safety Follow-up Visit.  
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required.  
If a subject withdraws from the study and also withdraws consent or assent, no further 
assessments will be performed. Vertex may retain and continue to use any data and samples 
collected before such withdrawal of consent or assent. 
9.1.5 
Lost to Follow-up 
A subject will be considered lost to follow-up if both of the following occur: 
• The subject misses 2 consecutive study visits (telephone contact, clinic, and/or home health 
visit) and is subsequently unable to be contacted by telephone (3 documented attempts by 
telephone within 2 weeks following the second missed visit) 
• The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 


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9.1.6 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as 1 of the following: 
• For subjects who complete the Treatment Period and enter an open-label extension safety 
study within 28 days of the Week 48 Visit: the Week 48 Visit  
• For subjects who complete the Treatment Period and do not enter an open-label extension 
safety study within 28 days of the Week 48 Visit: the Safety Follow-up Visit 
• For subjects who prematurely discontinue study drug treatment but do not withdraw consent 
(and assent, as applicable): the latest of the ETT Visit or Safety Follow-up Visit (if required) 
• For subjects who withdraw consent or assent: date of withdrawal of consent or assent, 
whichever is earlier (Section 9.9) 
If subjects are lost to follow-up (Section 9.1.5), the date of completion of study participation will 
be defined as the date of the last contact.  
The end of study is defined in Section 13.2.9. 
9.1.7 
Use of Remote Measures 
Remote measures may be used for study visits at Week 4 and Week 12 (see Table 3-2). All other 
visits must be performed in the clinic. 
Whenever local regulations or site practice do not allow remote measures, visits will be 
conducted at the site. However, under extenuating circumstances, remote measures may be 
implemented (e.g., if a subject is unable to travel to the study site due to safety concerns and/or 
local restrictions related to COVID-19 or other emerging events). The decision whether to 
conduct a study visit remotely or in clinic will be at the discretion of the investigator; if the 
investigator determines that study visits will be conducted remotely, the medical monitor should 
be notified. Under extenuating circumstances, the Screening visit (including initial consent) and 
Day 1 visits must still be performed in the clinic. 
The following remote measures may be implemented. Additional details can be found in the 
Study Reference Manual. 
• Consent and reconsent may be obtained electronically (or verbally, with follow-up 
electronic/written confirmation), as allowed by local regulations.  
• Study drug may be shipped directly from the site to the subject, as applicable and as allowed 
by local regulations. 
• Under extenuating circumstances, study visits (except Screening and Day 1) may be 
conducted as in-home visits by qualified personnel. All visits must have a consultation 
between the subject and investigator (i.e., in person, phone, or telemedicine video 
conference) within 1 business day after the home health visit, which can be outside the visit 
window. 
• Study assessments may be performed or overseen by qualified personnel conducting the 
in-home visits. 
• Remote monitoring visits may be implemented as applicable (including remote source data 
verification) and as allowed per local regulations. 


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9.2 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study.  
9.3 
Rationale for Study Elements 
9.3.1 
Study Design 
In patients with CF, IGT (a form of prediabetes) and then CFRD develops progressively, starting 
as early as age 10, and without known remission.14 Once the diagnosis of IGT is made, patients 
have an approximately 4 to 11 × increased risk of developing CFRD over a 3 to 4 year 
observation period15, 16, at which point insulin treatment is often started. Thus, the diagnoses of 
IGT and CFRD are considered robust and clinically relevant categories of disease.16 An 
open-label study design is therefore appropriate to ascertain the effects of ELX/TEZ/IVA 
through within-group comparisons over 48 weeks. A 48-week treatment period is expected to be 
sufficient to determine the maximum treatment effect of ELX/TEZ/IVA on changes in glucose 
tolerance (OGTT) in CF subjects with IGT or CFRD, and follows a similar open-label study 
design in which Orkambi was found to improve glucose tolerance in subjects with IGT and 
CFRD.17 Due to the known variability in the OGTT in patients with IGT and CFRD, 2 OGTTs at 
baseline (Screening and Day 1), 1 OGTT at Week 24, and 2 OGTTs at the end of the study 
(Weeks 36 and 48) will be performed.18 
9.3.2 
Study Population 
This study will enroll CF subjects with F/MF genotypes, 12 years of age and older. A pivotal 
Phase 3 study demonstrated efficacy and safety of ELX/TEZ/IVA in CF subjects with F/MF 
genotypes 12 years of age and older. The F/MF population has the highest incidence of abnormal 
glucose tolerance, as defined by an OGTT, including IGT and CFRD. This is due to stereotypical 
progression of pancreatic disease, including blocked acinar ducts, atrophy of the exocrine 
pancreas, loss of endocrine islets, inflammation, additional genetic factors, and other potential 
mechanisms as described above. Patients with F/MF genotypes therefore offer a population of 
patients who are naive to CFTR modulator treatment and have prevalent endocrine disease 
(IGT/CFRD) that is amenable to investigation. 
This study will utilize both the OGTT and CGM to evaluate the effect of ELX/TEZ/IVA on 
abnormal glucose homeostasis in subjects with CF and F/MF genotypes. 
9.3.3 
Study Drug Dose 
The dose of ELX/TEZ/IVA evaluated in the pivotal Phase 3 study in subjects with F/MF 
genotypes ≥12 years of age (ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h) was generally 
safe and well tolerated and resulted in clinically meaningful improvements compared to placebo 
in endpoints including ppFEV1 (LS mean treatment difference of 14.3 percentage points 
[p<0.0001] for absolute change from baseline) and SwCl (LS mean treatment difference 
of -41.8 mmol/L [p<0.0001] for absolute change from baseline) through 24 weeks. This dose of 
ELX/TEZ/IVA is approved in some regions for the treatment of CF and will be used for all 
subjects enrolled in this study. 
9.3.4 
Rationale for Study Assessments 
The safety assessments are standard parameters for clinical studies in drug development. 


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An OGTT will be performed to assess changes in glucose levels post-oral glucose challenge, 
including the 2-hour time point. The OGTT is a standard procedure recommended annually for 
CF patients by age 10, and any other time CFRD is suspected. CGM will be performed in 
subjects with CFRD only to assess dynamic, free-ranging changes in capillary glucose levels and 
for associations with changes in other biomarkers or parameters. Serum biomarkers of glucose 
homeostasis (insulin, glucagon, incretins) are standard biomarkers for mechanistic studies 
involving patients with diabetes. Changes in ppFEV1 have been correlated with glucose control 
parameters (i.e., CGM)15, and will be useful to establish extrapulmonary (independent of lung) 
efficacy, and also confirm a positive drug effect throughout the study. SwCl is a standard 
pharmacodynamic (PD) assessment for studies involving subjects with CF, and this PD marker 
in skin can be correlated with pulmonary and extrapulmonary (diabetes-related) endpoints in 
order to advance the understanding of systemic efficacy of ELX/TEZ/IVA. 
9.4 
Study Restrictions 
Table 9-1 lists prohibited medications. A non-exhaustive list of study prohibitions and cautions 
for medication will be provided in the Study Reference Manual. 
Table 9-1 
Prohibited Medications 
Medication 
Timing of Restriction 
Rationale 
Start of Restriction 
End of 
Restriction 
Moderate and strong 
CYP3A inducers 
None allowed 
within 14 days 
before the first dose 
of the study drug on 
Day 1 
None allowed 
through 
completion of 
study 
participation 
ELX, TEZ, and IVA are metabolized 
extensively via CYP3A4. Therefore, use 
of moderate and strong inducers and 
inhibitors of CYP3A, which have the 
potential to alter the exposure of ELX, 
TEZ, or IVA, are prohibited. 
Moderate and strong 
CYP3A inhibitors 
(except ciprofloxacin)a 
None allowed 
within 14 days 
before the first dose 
of the study drug on 
Day 1 
None allowed 
through 
completion of 
study 
participation 
CFTR modulators 
(investigational or 
approved), except for 
study drugs 
None allowed 
within 28 days 
before the first dose 
of the study drug on 
Day 1 
None allowed 
until after the last 
dose of study drug 
These agents may confound the results 
of this study. 
Anti-diabetic 
medications, except for 
exogenous 
(subcutaneously 
injected) insulins 
None allowed 
within 28 days 
before the first dose 
of the study drug on 
Day 1 
None allowed 
until after the last 
dose of study drug 
These agents may confound the results 
of this study. 
CYP: cytochrome P450; ELX: elexacaftor; IVA: ivacaftor; TEZ: tezacaftor 
a 
Ciprofloxacin is not a moderate CYP3A inhibitor on the basis of results of a drug-drug interaction study 
conducted with IVA, a sensitive CYP3A substrate (Kalydeco [ivacaftor] US Package Insert). 


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9.5 
Prior and Concomitant Medications 
Information regarding prior and concomitant medications, including CF medications, other 
medications, and herbal and naturopathic remedies, will be collected from each subject’s source 
documentation for medications taken within 56 days before the Screening Visit through 
completion of study participation, as defined in Section 9.1.6. 
For subjects who are screened but are not subsequently enrolled, details of prior medication will 
be documented only in the subjects’ source documents. 
• Subjects should remain on a stable treatment regimen for their CF from 28 days before the 
Day 1 Visit through completion of study participation. Stable treatment regimen is defined as 
the current treatment regimen for CF that subjects have been following for at least 28 days 
before the Day 1 Visit. Subjects should not initiate long-term treatment with new medication 
from 28 days before the Day 1 Visit through completion of study participation. Guidelines 
for stable treatment regimens for CF are as follows: 
o Subjects who are taking inhaled tobramycin or other chronically inhaled antibiotics 
should remain on that regimen throughout the study. 
o Subjects who cycle onto and off of an inhaled antibiotic should continue on their prior 
schedule. The timing of the first dose of study drug on the Day 1 Visit should be 
synchronized as closely as possible (e.g., not more than ± 3 days) to the first day in 
the cycle onto the inhaled antibiotic. 
o Subjects who alternate between 2 different inhaled antibiotics should remain on the 
same cycling schedule during the study. The timing of the first dose of study drug on 
the Day 1 Visit should be synchronized as closely as possible (e.g., not more than 
± 3 days) to the first day in the cycle onto 1 of the inhaled antibiotics. 
• Subjects may receive doses of prednisone or prednisolone of up to 10 mg/day chronically, or 
up to 60 mg daily for up to 5 days; however, these doses may not be administered during a 
pre-OGTT fasting period. 
• ELX may inhibit OATP1B1 and OATP1B3, which may increase the exposure of medicinal 
products that are substrates for these transporters. Substrates such as statins should be used 
with caution.  
• IVA is a weak inhibitor of P-glycoprotein (P-gp). Administration of IVA may increase 
systemic exposure of medicinal products that are sensitive substrates of P-gp, which may 
increase or prolong their therapeutic effect and adverse reactions. Digoxin or other substrates 
of P-gp with a narrow therapeutic index, such as cyclosporine, everolimus, sirolimus, and 
tacrolimus, should be used with caution and appropriate monitoring.  
• IVA may inhibit CYP2C9; therefore, during coadministration with warfarin, additional 
monitoring of the international normalized ratio is recommended. Other medicinal products 
that are CYP2C9 substrates for which exposure may be increased should be used with 
caution. 
• Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator should have their spirometry assessments performed 
according to the guidelines provided in Section 11.2.1. 


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9.6 
Administration 
9.6.1 
Dosing 
Study drug tablets will be administered orally as ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg 
q12h. 
Study drug should be administered with a fat-containing meal or snack, such as a 
standard “CF” meal or snack or a standard meal according to the following guidelines: 
1. It is recommended that the dose be taken within approximately 30 minutes of the start of the 
meal or snack. 
2. All doses of study drug (morning and evening, as applicable) should be administered at 
approximately every 12 hours (± 2 hours) on each dosing occasion (e.g., if the morning doses 
of study drug are administered at 08:00 hour on Day 1, all subsequent morning doses should 
be administered between 06:00 hour and 10:00 hour). 
3. At the Day 1 Visit, all subjects will be observed for 2 hours after the morning dose of the 
study drug. 
4. On days of scheduled visits, the morning dose of study drug will be administered under the 
supervision of site medical staff or a home health nurse after predose assessments have been 
completed. The meal or snack will be provided by the site on in-clinic visit days for the 
morning dose of study drug. 
5. For visits after the Day 1 Visit, subjects will be instructed to return all used and unused study 
drug to the site or the home health nurse; study drug will be dispensed at each visit, as 
appropriate. 
6. At the Week 48 Visit, the morning dose of study drug will NOT be administered. The last 
dose of study drug will be the evening dose administered the day before the Week 48 Visit. 
9.6.2 
Missed Doses 
If 6 hours or less have passed since the missed morning or evening dose, the subject should take 
the missed dose as soon as possible and continue on the original schedule.  
Morning dose: If more than 6 hours have passed since the missed morning dose, the subject 
should take the missed dose as soon as possible and should not take the evening dose. 
Evening dose: If more than 6 hours have passed since the missed evening dose, the subject 
should not take the missed dose. The next scheduled morning dose should be taken at the usual 
time. 
Morning and evening doses should not be taken at the same time. 
9.7 
Dose Modification for Toxicity 
No dose modifications for toxicity are allowed. If any unacceptable toxicity arises, individual 
subjects will discontinue dosing (Section 9.1.4). 
9.8 
Study Drug Interruption and Stopping Rules 
In subjects who have interrupted study drug for >72 hours for any reason, the investigator should 
resume study drug only after a thorough investigation of the cause for interruption. The 
investigator will evaluate the subject’s clinical stability and should consider resumption of study 


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drug only after the subject is clinically stable and there is no comorbidity or condition that, in the 
opinion of the investigator, might confound the results of the study or pose an additional risk in 
administering study drug to the subject. 
The medical monitor should be notified of an interruption of study drug that lasts >72 hours for 
any reason and of the resumption of study drug after such interruption. In subjects for whom 
study drug was previously interrupted, the medical monitor should be notified of any plan to 
discontinue study drug, before the discontinuation has occurred, if possible. 
9.8.1 
Liver Function Tests 
The central laboratory will notify the medical monitor of ALT or AST >3 × ULN and total 
bilirubin >2 × ULN that are derived from centrally submitted samples. 
Subjects with new treatment emergent ALT or AST elevations of >3 × ULN, with or without 
total bilirubin >2 × ULN, must be followed closely, including confirmatory testing performed by 
the central laboratory within 48 to 72 hours of the initial finding and subsequent close 
monitoring of ALT, AST, and bilirubin levels, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results must be reported immediately to the medical monitor, and the subject 
must have the tests repeated and sent to the central laboratory as soon as possible (ideally within 
48 to 72 hours). 
Study drug administration must be interrupted immediately (prior to confirmatory testing) if 
any of the following criteria are met: 
• ALT or AST >8 × ULN 
• ALT or AST >5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical 
jaundice 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression. 
Study drug administration must be discontinued if the following criterion is met: 
• Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral 
hepatitis, alcohol ingestion) is identified, regardless of whether transaminase levels have 
improved. 
All subjects in whom treatment is discontinued for elevated transaminases (and bilirubin, as 
applicable) should have these levels monitored closely until levels normalize or return to 
baseline. 
If an alternative, reversible cause of transaminase elevation with or without increased bilirubin or 
clinical jaundice has been identified, subjects may receive study drug once transaminases return 
to baseline or are ≤2 × ULN, whichever is higher. Regardless of the duration of interruption, the 
medical monitor should be notified prior to resumption of study drug. Upon resumption of study 
drug, transaminases and bilirubin should be assessed weekly for 4 weeks. If a protocol-defined 
transaminase elevation interruption threshold recurs within 4 weeks of rechallenge with the study 


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drug (with confirmation of the initial elevation by repeat testing within 48 to 72 hours), then the 
study drug must be permanently discontinued, regardless of the presumed etiology.  
9.8.2 
Rash 
Individuals who develop a generalized rash will be monitored closely. Study drug dosing should 
be interrupted if a subject develops a generalized rash of Grade 3 or higher (Section 13.1.1.4), or 
a rash that is considered a serious adverse event (SAE). The investigator will notify the medical 
monitor of any rash that results in interruption of study drug, is Grade 3 or higher 
(Section 13.1.1.4), or is an SAE. Investigators should consider additional evaluation including 
laboratory testing (e.g., complete blood count with differential, liver function tests), photographs 
of the rash, and dermatology consultation. The investigator may consider resumption of study 
drug if considered clinically appropriate. 
9.9 
Removal of Subjects 
Subjects (or subjects’ parent/legal guardian) may withdraw from the study at any time at their 
own request. Subjects may be withdrawn from study drug treatment at any time at the discretion 
of the investigator or Vertex for safety, behavior, noncompliance with study procedures, or 
administrative reasons. A subject who withdraws (or is withdrawn by parent/legal guardian) 
from study drug treatment will continue to be followed unless the subject (or parent/legal 
guardian) withdraws consent. 
In addition, a subject must be discontinued from study drug treatment if the subject meets any of 
the following criteria: 
• Has a screening CFTR genotype that does not confirm study eligibility if a previous CFTR 
genotype laboratory report was used to establish eligibility. These subjects must be 
discontinued from the study (Section 8.1) 
• Meets any of the stopping (discontinuation) criteria (Section 9.8) 
• Becomes pregnant (Section 11.4.6.2) 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a Safety Follow-up Visit, if 
applicable (see Section 9.1.4), and follow up with the subject regarding any unresolved AEs. 
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends, and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study, the study data and samples collected will remain part of the study. A subject will 
not be able to request the withdrawal of his/her information from the study data. A subject may 
request destruction of the samples collected from him/her during the study as long as those 
samples can be identified as his/her samples. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study drug treatment period will not be 
replaced. 


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10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. An interactive web response system 
(IWRS) will be used to dispense study drug. 
10.2 
Packaging and Labeling 
Study drug tablets will be supplied in blister cards by Vertex. Study drug labeling will be in 
compliance with applicable local and national regulations. Additional details regarding 
packaging, labeling, and dispensing for study drug will be 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 via the drug 
accountability forms as instructed by Vertex. 
Detailed instructions regarding the storage, handling, and dispensation of the study drug will be 
provided in the Pharmacy Manual. 
Table 10-1 
Study Drug 
Drug Name, Dosing Form, Route 
Tablet Strength 
ELX/TEZ/IVA, FDC tablet, oral 
 
ELX 
 
TEZ 
 
IVA 
 
100 mg 
50 mg 
75 mg 
IVA, tablet, oral 
150 mg 
ELX: elexacaftor; FDC: fixed-dose combination; IVA: ivacaftor; TEZ: tezacaftor 
Note: See Section 9.6 for details on study drug administration. 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information about the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. A central pharmacy may be used for subjects opting to have home 
health visits. Subjects will be instructed to return all used and unused materials associated with 
the study drug to the site or the home health nurse. 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/she 
is unable to resolve with the site. 


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10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
The principal investigator, study site staff, including pharmacy personnel will assist Vertex with 
any recall activities (as applicable) and place impacted investigational medicinal product (IMP) 
in quarantine when requested. 
10.6 
Compliance 
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site or in the subject’s home at required visits. At each visit, site medical 
staff/home health nurses will review that the subject is compliant with study drug dosing and 
remind the subject and their parent or legal guardian of study drug dosing requirements. 
Compliance will also be assessed by ongoing study drug count. 
If a subject’s parent or legal guardian demonstrates continued noncompliance of study drug 
dosing despite educational efforts, the investigator should consider discontinuing the subject 
from the study. 
10.7 
Blinding and Unblinding 
This is an open-label study; however, subjects and their parent/legal guardian should not be 
informed of their study-related CGM, SwCl, spirometry, FE-1, and blood biomarker results 
during the Treatment Period, regardless if the subject permanently discontinues. 
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1 and Table 3-2. 
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 
Medical history will be elicited from each subject and extracted from medical records 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 will 
include a complete review of systems, medical and surgical histories, and any allergies. 
11.2 
Other Assessments 
These data will be used for internal exploratory purposes and may or may not be included in the 
clinical study report (CSR). 
11.2.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines10 and according to the additional guidelines that follow. 


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Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have: 
• withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 
• withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before 
the spirometry assessment; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide 
[Spiriva®]) for more than 24 hours before the spirometry assessment. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilator. At all other visits, all spirometry assessments should be performed 
pre-bronchodilator. During the Treatment Period, spirometry assessments must be performed 
before study drug dosing (Section 9.6.1) at approximately the same time at each visit. In the 
event that a subject forgets to withhold bronchodilator(s), spirometry should be performed 
according to the following: 
• If a subject’s Day 1 spirometry assessment is pre-bronchodilator, but, on a subsequent 
visit, the subject forgets to withhold bronchodilator use, a post-bronchodilator spirometry 
assessment will be obtained for that visit only, and the visit will not be rescheduled. 
• If, on Day 1, the subject forgets to withhold his/her dose of bronchodilator, spirometry 
should be performed post-bronchodilator, and all subsequent spirometric measurements 
(according to the schedule of assessments) should be performed post-bronchodilator. 
• Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator. 
Spirometers will be provided to be used for all study assessments. At scheduled visits, 
spirometry assessments may be performed on more than one spirometer, as applicable. 
Spirometry data will be transmitted to a centralized spirometry service for quality review. The 
investigator’s assessment of the spirometry results will be used for the screening assessment and 
determination of eligibility. 
See Section 10.7 for information about access to spirometry results. 
The measured spirometric values listed below will be converted to percent predicted values using 
the standard equations of GLI.9  
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 
• Forced expiratory flow, midexpiratory phase (FEF25%-75%) (L/s) 
11.2.2 
Fecal Sample Collection 
FE-1 will be measured to assess exocrine pancreatic function. 
Fecal samples may be collected by site medical staff or a home health nurse during the study 
visit; alternatively, at all visits except the Screening Visit, samples may be collected by the 


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subject or the subject’s caregiver up to 48 hours before the study visit at home and brought to the 
study visit. The Day 1 sample must be collected predose; others may be collected pre- or 
postdose. Subjects who provide a fecal sample at the Screening Visit, or at any time point prior 
to the first dose of study drug, do not need to provide a sample on Day 1. 
See Section 10.7 for information about access to FE-1 results. 
Instructions for the collection, processing, storage, and shipment of fecal samples will be 
provided in a separate Laboratory Manual. 
11.2.3 
Other Blood Biomarker Collection 
Pancreatic markers, including but not limited to IRT, will be measured in blood to assess 
exocrine pancreatic function. Inflammatory markers, including but not limited to CRP, will be 
measured in blood to assess inflammation. Blood biomarker samples may be used for additional, 
exploratory analyses that may or may not be included in the CSR. 
See Section 10.7 for information about access to blood biomarkers results. 
Instructions for the collection, processing, storage, and shipment of blood biomarker samples 
will be provided in the Laboratory Manual.  
11.3 
Efficacy and Pharmacodynamics 
11.3.1 
Oral Glucose Tolerance Test 
OGTT will be performed to assess 2-hour glucose levels. Depending on a subject’s weight, 
1.75 g/kg of body weight or 75 g maximum of oral glucose solution will be administered in the 
morning after at least 8 hours of fasting (except water and allowed medications other than 
prednisone and prednisolone). Investigators must counsel subjects on the safe withholding of 
insulins prior to each OGTT. Insulin use in the 24 hours prior to each OGTT will be recorded by 
the site. 
Blood samples will be obtained at 0, 30 (±5), 60 (±5), 90 (±5), and 120 (±5) minutes after the 
start of ingestion of glucose solution. The 0-minute blood sample should be collected 
immediately prior to ingestion of glucose solution. During study visits with OGTTs, a blood 
sample will be collected post-OGTT to measure diabetes-related blood biomarkers, including 
insulin, C-peptide, glucagon, calculated indices of insulin secretion (insulinogenic index), and 
insulin resistance (HOMA-IR), and to measure incretin levels, including GLP-1 and GIP. 
Specific instructions will be provided in the Laboratory Manual 
11.3.2 
Continuous Glucose Monitoring 
CGM will be performed in subjects with CFRD only to assess dynamic, free-ranging changes in 
capillary glucose levels. A CGM sensor will be inserted subcutaneously by site medical staff, a 
home health nurse, or the subject after adequate training, calibrated, and worn for approximately 
7 days (according to Table 3-2). 
See Section 10.7 for information about access to CGM results. 
11.3.3 
Height and Weight 
Height and weight will be measured with shoes off. Following screening, height will be collected 
only for subjects ≤21 years of age on the date of informed consent.  


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11.3.4 
Insulin Use Diary 
At each study visit, subjects who take insulin will provide the diary for documentation of insulin 
use for at least 7 days prior to the visit. Total daily dose of insulin will be recorded in the diary. 
11.3.5 
Sweat Chloride 
The SwCl test is a standard diagnostic tool for CF, serving as a biomarker of CFTR activity. 
Sweat samples will be sent to a central laboratory for testing and interpretation of results. 
Individual SwCl test results will not be disclosed to the study sites. Specific instructions for 
collection, handling, processing, and shipping of SwCl samples to the central laboratory will be 
provided separately. The SwCl test must be conducted predose relative to the morning dose of 
study drug during the Treatment Period. At each time point, 2 samples will be collected, 
1 sample from each arm (left and right). 
11.4 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, and PEs, and ophthalmologic exams. 
11.4.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with current ICH E6 GCP 
Guidelines. Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs.  
11.4.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a local or central laboratory. As described below, 
urine pregnancy tests will either be analyzed by the site or at home using a home kit. All blood 
samples will be collected while subjects are in a seated or supine position. Specific instructions 
for the collection, processing, and shipment of samples will be provided in a separate Laboratory 
Manual. 
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. 


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Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Total bilirubin, direct bilirubin, indirect 
bilirubin  
Alkaline phosphatase  
Aspartate transaminase 
Alanine transaminase 
Amylase  
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Cholesterol  
Hemoglobin  
Erythrocytes 
Mean corpuscular volume 
Platelets  
Reticulocytes  
Leukocytes  
Differential (absolute and percent): 
Eosinophils 
Basophils  
Neutrophils 
Lymphocytes 
Monocytes  
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
Leukocyte esterase  
Nitrite  
Urobilinogen  
Urine protein  
pH 
Urine blood  
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose  
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be done, and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
b 
If blood urea nitrogen cannot be collected, urea may be substituted. 
Pregnancy (β-human chorionic gonadotropin) Tests for all Female Subjects: All female subjects 
must have a serum pregnancy test at screening. Serum pregnancy tests will be performed at the 
by site medical staff or a home health nurse and analyzed at the central laboratory. Urine 
pregnancy tests will either be performed and analyzed at the site or at home by using a home kit 
provided by the site/home health nurse. Results will be reported to the site by telephone. The 
urine pregnancy test on Day 1 must be negative before the first dose of study drug is 
administered to the subject. Additional pregnancy tests may be required according to local 
regulations and/or requirements. 
CF genotype (Screening Period only): CF genotyping will be performed on all subjects to 
confirm the genotype documented in the subject's medical record.  
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 
becomes aware of the abnormal result. If it is not possible to send a timely specimen to the 
central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base the 
assessment of an AE on the local laboratory value. 


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11.4.3 
Physical Examinations and Vital Signs 
A physical examination (PE) of all body systems and vital signs assessment will be performed at 
screening and select study visits. At other visits, symptom-directed PEs and symptom-directed 
vital signs assessments can be performed at the discretion of the investigator or healthcare 
provider. 
A PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, nose, and 
throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed.  
Arterial oxygen saturation by pulse oximetry will be assessed following at least a 5-minute rest 
and before study drug dosing. Pulse oximetry will be collected before study drug dosing. 
11.4.4 
Electrocardiograms 
Twelve-lead ECGs will be performed as indicated in Table 3-1 and Table 3-2. Additional 
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 ECG will be done before any other procedures that may affect heart rate, such as 
blood draws. 
• The subject will be instructed to rest for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position 
ECG traces will undergo safety review by the investigator and be maintained with source 
documentation. 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, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement.  
11.4.5 
Ophthalmologic Examination 
Ophthalmologic examinations will be conducted only for subjects who are <18 years of age on 
the date of informed consent. The examination does not need to be completed if there is 
documentation of bilateral lens removal for the subject. 


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All examinations will be conducted by a licensed ophthalmologist or optometrist and will 
include: 
• measurement of best-corrected distance visual acuity of each eye; and 
• pharmacologically dilated examination of the lens with a slit lamp. 
The screening examination does not need to be conducted if there is documentation of an 
examination meeting the protocol requirements that was conducted within 3 months before the 
date of informed consent. 
In addition to the screening ophthalmologic examination, subjects who are <18 years of age on 
the date of informed consent and who have completed at least 12 weeks of study drug treatment 
will have a single follow-up ophthalmologic examination. This examination should be completed 
at or up to 4 weeks before the Week 48 Visit, unless the subject prematurely discontinues study 
drug, in which case this examination should occur by the Safety Follow-up Visit (or ETT Visit 
for subjects who do not complete a Safety Follow-up Visit), as described in Table 3-2. 
Any clinically significant abnormal findings will be reported as AEs. 
11.4.6 
Contraception and Pregnancy 
The effects of ELX monotherapy or in combination with TEZ/IVA on conception, pregnancy, 
and lactation in humans are not known. ELX, TEZ, and IVA did not show genotoxic potential in 
a standard battery of in vitro (Ames test, chromosomal aberration, or micronucleus in cultured 
mammalian cells) and in vivo (rodent micronucleus) studies. Reproductive toxicology studies of 
ELX, TEZ, and IVA have not shown teratogenicity in rats and rabbits. 
11.4.6.1 
Contraception 
Contraception requirement for a couple is waived for the following: 
• True abstinence for the subject, when this is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
True abstinence must be practiced from the Screening Visit through 90 days after the last 
dose of study drug. 
• If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the 
first dose of study drug (e.g., examination of a semen specimen or by demonstration of 
the absence of the vas deferens by ultrasound). 
• If the female is of non-childbearing potential. To be considered of non-childbearing 
potential, the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH 
level within the laboratory’s reference range for postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
Note: All other females (including females with tubal ligations) will be considered to be of 
childbearing potential. 
• Same-sex relationships 


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For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used as a couple. Methods of contraception must be in successful use from signing of consent 
approximately 28 days before the first dose of study drug (unless otherwise noted), and until 
90 days following the last dose of study drug. Additional contraception requirements may need 
to be followed according to local regulations and/or requirements. Acceptable methods of 
contraception are listed in Table 11-2. 
Table 11-2 
Acceptable Methods of Contraception 
 
Male Subjects and Their 
Female (Non-study) 
Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy performed at least 6 months previously, 
with a documented negative postvasectomy semen 
analysis for sperm 
Yes 
Yes 
Bilateral tubal occlusion (e.g., ligation) performed at 
least 6 months previously 
Yes 
Yes 
Male or female condom with or without spermicidea 
Yes 
Yes 
Female barrier contraception (such as diaphragm, 
cervical cap, or sponge) with spermicide 
Yes 
Yes 
Continuous use of an intrauterine device for at least 
90 days before the first dose of study drug 
Yes 
Yes 
Oral, implanted, injected, or vaginal hormonal 
contraceptives, if successfully used for at least 
60 days before the first dose of study drug 
Yes 
Yes 
a 
A female condom cannot be used with a male condom due to risk of tearing. 
Additional notes: 
• If over the course of the study the subject meets the criteria for waiving the contraception 
requirements, the subject does not need to follow the contraceptive methods listed in 
Table 11-2. 
• Male subjects must not donate sperm during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
• Female subjects should not nurse a child during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
• For male subjects with a female partner of childbearing potential, the couple should not 
plan to become pregnant during the study or within 90 days after the last dose of study 
drug, with the exception of couples who plan to become pregnant by artificial 
insemination using sperm banked by the male subject before the first dose of study drug 
or sperm from another source. 
11.4.6.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a female subject becomes pregnant during study participation, study drug will be permanently 
discontinued immediately. The investigator will notify the medical monitor and Vertex GPS 


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within 24 hours of the site’s knowledge of the subject’s (or partner’s) pregnancy using the 
Pregnancy Information Collection Form. Male subjects with female partners who become 
pregnant during the study must use a male condom to avoid exposure of a potential embryo or 
fetus to study drug via the seminal fluid. 
The subject or partner will be followed until the end of the pregnancy and the infant will be 
followed for 1 year after the birth, provided informed consent is obtained. A separate ICF will be 
provided to explain these follow-up activities. Pregnancy itself does not constitute an AE. 
12 
STATISTICAL ANALYSIS 
12.1 
Sample Size and Power 
The primary efficacy endpoint is change from baseline in 2-hour blood glucose levels following 
an OGTT to the average of Week 36 and Week 48. The primary null hypothesis to be tested is 
that the mean change from baseline in 2-hour blood glucose levels following OGTT to the 
average of Week 36 and Week 48 is equal to zero.  
Assuming a within group SD of 45 mg/dL and a 10% dropout rate at Week 48, a sample size of 
60 subjects will have more than 95% power to detect a mean decrease from baseline 
of -30 mg/dL in 2-hour blood glucose levels post-OGTT to the average of Week 36 and 
Week 48, based on a 2-sided, 1-sample t-test at a significance level of 0.05 using the EAST 
software Version 6.4. 
12.2 
Analysis Sets 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), and Safety 
Set. 
The All Subjects Set will include all subjects who were enrolled. This analysis set will be used 
for all individual subject data listings and disposition summary tables, unless otherwise specified. 
The Full Analysis Set (FAS) is defined as all enrolled subjects who carry the intended CFTR 
allele mutation and have received at least 1 dose of study drug. The FAS is to be used in efficacy 
analyses. 
The Safety Set is defined as all subjects who have received at least 1 dose of study drug. The 
Safety Set is to be used for all safety analyses. 
12.3 
Statistical Analysis 
This section presents a summary of the principal features of the planned statistical analyses. 
Statistical analysis details will be in the statistical analysis plan (SAP) which will be finalized 
before clinical database lock. 
12.3.1 
General Considerations 
All individual subject data for subjects will be presented in individual subject data listings. 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). 
Categorical variables will be summarized using counts and percentages. 


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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. The 
baseline 2-hour blood glucose level from OGTT will be the average of measurements at 
screening and Day 1. 
Change (absolute change) from baseline will be calculated as Post-baseline value − Baseline 
value. 
Relative change from baseline will be calculated and expressed in percentage as 
100% × (Post-baseline value − Baseline value)/Baseline value. 
Treatment-emergent (TE) Period will include the time from the first dose of study drug to 
28 days after the last dose of study drug or to the completion of study participation (as defined in 
Section 9.1.6), whichever occurs first. 
Incomplete/missing data will not be imputed, unless specified otherwise. 
12.3.2 
Background Characteristics 
Subject disposition, e.g., completed treatment, prematurely discontinued the treatment and the 
reason for discontinuation, will be summarized. 
Demographic and baseline characteristics will be summarized.  
Medications used will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) and summarized descriptively. Exposure to study drug in (i.e., duration of treatment) 
and dosing compliance (i.e., percentage of days being compliant to treatment) will be 
summarized descriptively.  
Important protocol deviations will be provided in an individual subject data listing, and 
summarized, as appropriate.  
Additional details will be provided in the SAP. 
12.3.3 
Efficacy and Pharmacodynamic Analysis 
12.3.3.1 
Analysis of Primary Efficacy Endpoint 
The primary analysis will be based on a mixed-effects model for repeated measures (MMRM) 
with change from baseline in 2-hour post-OGTT blood glucose levels at Weeks 24, 36, and 48 as 
the dependent variable. The model will include visit as a fixed effect, and will be adjusted for 
main covariates as appropriate. The primary result obtained from the model will be the estimated 
mean change from baseline to the average of Week 36 and Week 48. The estimated change at 
each visit and the mean change to the average of Week 36 and Week 48 along with the 2-sided 
95% CI and P value will be provided. 
Additional details will be provided in the SAP. 
12.3.3.2 
Analysis of Secondary Efficacy Endpoints 
The secondary endpoints include: 
• Proportion of subjects with improvement in dysglycemia categorization (CFRD, IGT, NGT) 
at Week 48 
The number and proportion of subjects with and without response at Week 48 defined as 
improvement in baseline dysglycemia categorization (i.e. CFRD at baseline to IGT/NGT based 


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on Week 48 OGTT measurement and IGT at baseline to NGT based on Week 48 OGTT 
measurement) will be presented. The 2-sided 95% Clopper-Pearson CI on the proportion of 
responders will also be presented. 
Additional details will be provided in the SAP. 
12.3.3.3 
Multiplicity Adjustment 
No multiplicity adjustment is planned. 
12.3.3.4 
Missing Data Handling 
For the primary analysis of the primary endpoint, missing data will be assumed to be missing at 
random conditional on the observed data and covariate; consequently, no imputation of missing 
data will be performed. 
12.3.3.5 
Analysis of Other Efficacy Endpoints 
Descriptive statistics will be provided for all other efficacy endpoints based on the FAS. 
For the following endpoints, observed values and absolute change from baseline will be 
summarized: 
• SwCl 
• BMI 
• Body weight 
• HbA1c and fructosamine 
• Insulin use (dose) in subjects using insulin 
• Post-OGTT diabetes-related biomarkers (including insulin, C-peptide, glucagon, calculated 
indices of insulin secretion [insulinogenic index], and insulin resistance [HOMA-IR]) 
• Biomarkers of inflammation (including CRP) 
• Biomarkers of pancreatic function (including FE-1 and serum IRT) 
• Post-OGTT incretin levels (including GLP-1 and GIP) 
• Percent of time spent in target blood glucose range of ≥70 to <140 mg/dL (≥3.89 to 
<7.77 mmol/L) as measured by 7-day CGM in subjects with CFRD 
• Selected CGM parameters (including but not limited to percent of time spent between ≥140 
and <200 mg/dL [≥7.77 and <11.10 mmol/L], percent of time spent ≥200 mg/dL 
[≥11.10 mmol/L], and MAGE) in subjects with CFRD 
12.3.4 
Safety Analysis 
The overall safety profile will be assessed in terms of the following safety endpoints: 
• Incidence of treatment emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and 
urinalysis) 
• 12-lead ECG outcomes 


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• Vital signs (including weight and height) 
• Pulse oximetry 
For safety analyses, no statistical hypothesis testing will be conducted. Additional details will be 
provided in the SAP. 
12.4 
Interim Analysis 
Not applicable 
12.5 
Data Monitoring Committee Analysis 
Not applicable 
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1. 
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 


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13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the subject completes study 
participation, as defined in Section 9.1.6 
All subjects and their 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 case report form (CRF) and source document. AEs for subjects who are screened 
but not subsequently enrolled will be recorded only in the subject’s source documents. The 
following data will be documented for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
September 2019). When 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 in the CTCAE. The severity of an AE described by a term that does not appear in the 
CTCAE will be determined according to the definitions in Table 13-1. 
Table 13-1 
Grading of AE Severity  
Classification 
Description 
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 (Moderate) 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADLa 
Grade 3 (Severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADLb 
Grade 4 (Life-threatening) 
Life-threatening consequences; urgent intervention indicated  
Grade 5 (Death) 
Death related to adverse event 


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Table 13-1 
Grading of AE Severity  
Classification 
Description 
Source: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed September 2019) 
ADL: activities of daily living; AE: adverse event 
Note: A semi-colon indicates ‘or’ within the description of the grade. 
a 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational study drug, 
a plausible mechanism for the event to be related to the investigational study drug and causes 
other than the investigational study drug have been ruled out, and/or the event reappeared on 
re-exposure to the investigational study drug. 
Possibly 
related 
There is an association between the event and the administration of the investigational study 
drug and there is a plausible mechanism for the event to be related to investigational study 
drug, but there may also be alternative etiology, such as characteristics of the subject’s clinical 
status or underlying disease. 
Unlikely 
related 
The event is unlikely to be related to the investigational study drug and likely to be related to 
factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the alternative 
etiology will be documented in the subject’s medical record). 
AE: adverse event 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories in Table 13-3. 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classificationa 
Definition 
Dose not 
changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug 
interrupted 
Study drug administration interrupted in response to an AE  
Drug 
withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational treatment 
had been completed before the AE began and no opportunity to decide whether to continue, 
interrupt, or withdraw treatment is possible. 


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Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classificationa 
Definition 
AE: adverse event 
a 
Refer to Sections 9.7 and 9.8 for directions regarding what drug actions are permitted per protocol.  
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not resolved 
(continuing) 
Either incomplete improvement or no improvement of an AE, such that it 
remains ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least 
possibly related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
AE: adverse event 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs 
after participation and is suspected of being a delayed toxicity due to administration of 
the study drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as 
it occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect 


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• Important medical event that, based upon appropriate medical judgment, may jeopardize 
the subject or may require medical or surgical intervention to prevent 1 of the outcomes 
listed above (e.g., an allergic bronchospasm requiring intensive treatment in an 
emergency room or at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious”, which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Reporting and 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) 
within 24 hours of identification. In addition, all SAEs that occur after the Safety Follow-up 
Visit and are considered related to study drug(s) will be reported to Vertex GPS within 24 hours 
of identification.  
For SAEs that occur after obtaining informed consent through the Safety Follow-up Visit, the 
SAE Form will be completed for new/initial events as well as to report follow-up information on 
previously reported events. Investigators are asked to report follow-up information as soon as it 
becomes available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email: globalpatientsafety@vrtx.com (preferred choice) 
Fax: +1-617-341-6159  
For technical issues related to submitting the form, contact telephone: +1-617-341-6677 
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) will 
be recorded on the Vertex Clinical Trial Safety Information Collection Form (hereafter referred 
to as the “SAE Form”) using a recognized medical term or diagnosis that accurately reflects the 
event. SAEs will be assessed by the investigator for relationship to the investigational study 
drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be assessed 
only as related (includes possibly related) or not related (includes unlikely related), and severity 
assessment will not be required. For the purposes of study analysis, if the event has not resolved 
at the end of the study reporting period, it will be documented as ongoing. For purposes of 
regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report the outcome to Vertex using the SAE Form. 


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13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IEC, and 
participating investigators in accordance with current ICH E2A Guidelines and/or local 
regulatory requirements, as applicable. In addition, Vertex, or authorized designee, will be 
responsible for the submission of safety letters to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/ IEC of all 
unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Product Complaints 
A product complaint is defined as any verbal or written communication addressed to Vertex, or 
designee, of inquiry or dissatisfaction with the identity, strength, quality, or purity of a released 
drug product, IMP, or medical device. In addition, suspected counterfeit/falsified product is 
considered a product complaint. 
Product complaints are to be reported to Vertex. 
13.2.2 
Ethical Considerations 
The study will be conducted in accordance with the current ICH E6 GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will be 
conducted only at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(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. 
13.2.3 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
current ICH E6 GCP Guidelines and all applicable laws and regulations and will be subject to 
approval by Vertex or its designee. 
13.2.4 
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.  
13.2.5 
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.  
13.2.6 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all data provided to Vertex, study reports, and communications relating to 
the study will identify subjects by assigned subject numbers, and access to subject names linked 
to such numbers will be limited to the site and the study physician and will not be disclosed to 
Vertex. As required by applicable laws and regulations in the countries in which the study is 
being conducted, the investigator will allow Vertex and/or its representatives access to all 
pertinent medical records to allow for the verification of data gathered and the review of the data 
collection process. The FDA and regulatory authorities in other jurisdictions, including the 
IRB/IEC, may also request access to all study records, including source documentation, for 
inspection. 
For sites participating in the US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will comply with all HIPAA 
requirements including authorization allowing the site access to and use of the subject’s 
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. 
13.2.7 
Record Retention 
The investigator will maintain all study records according to current ICH E6 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. 
13.2.8 
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. 
13.2.9 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. Vertex 
will provide, or assess and approve, any electronic data capture (EDC) tools. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each subject. Data 
collected during the study, including results from screening, will be recorded in a data capture 
system for each enrolled subject. Each subject’s set of captured data records, once complete, will 
be signed and dated by the investigator. 
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 data captured for the study/SAE Forms for 
completeness and clarity, 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 data 
captured for the study/SAE Forms and source documents. The study site monitor will ensure that 
the investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
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The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc (CD) or other electronic media will be placed in the investigator’s 
study file. 
Sites will use an EDC tool to record data for each enrolled subject.  
It is the investigator’s responsibility to ensure the accuracy, completeness, clarity, and timeliness 
of the data reported. The investigator is required to prepare and maintain adequate and accurate 
case histories designed to record all observations and other data pertinent to the study for each 
subject, including the dates and details of study procedures, AEs, other observations, and subject 
status.  
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 data reported to Vertex, including 
any changes made, to endorse the final submitted data for the subjects for whom the investigator 
is responsible.  
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 
13.7.1 
Publication of Study Results 
Vertex is committed to reporting the design and results of all clinical studies in a complete, 
accurate, balanced, transparent, and timely manner, consistent with Good Publication Practices 
(GPP3).19  
Publication Planning: Vertex staff along with the lead principal investigators (PIs), the steering 
committee (SC), and/or the publication committee (PC) will work together to develop a 
publication plan.  


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Authorship: Authorship of publications will be determined based on the Recommendations for 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, which 
states that authorship should be based on the following 4 criteria20: 
1. Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data;  
2. Drafting of the article or revising it critically for important intellectual content;  
3. Final approval of the version to be published; and 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
All authors must meet conditions 1, 2, 3, and 4. All persons designated as authors should qualify 
for authorship, and all those who qualify should be listed. Contributions such as medical writing, 
enrollment of subjects, acquisition of funding, collection of data, or general supervision of the 
research group, alone, do not justify authorship.  
Contributors: Contributors who meet fewer than all 4 of International Committee of Medical 
Journal Editors (ICMJE) criteria for authorship will not be listed as authors, but their 
contribution will be acknowledged and specified either as a group (e.g., “study investigators”) or 
individually (e.g., “served as scientific advisor”).  
Publication Review: As required by a separate clinical study agreement, Vertex must have the 
opportunity to review all publications, including any manuscripts, abstracts, oral/slide 
presentations, and book chapters regarding this study before submission to congresses or journals 
for consideration.  
13.7.2 
Clinical Study Report  
A CSR, written in accordance with the current ICH E3 Guideline, will be submitted in 
accordance with local regulations. 


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14 
REFERENCES 
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 24 March 2019. 
2 
Cystic Fibrosis Foundation. 2018 Patient Registry Annual Data Report. Bethesda, MD: 
2019. 
3 
European Cystic Fibrosis Society. 2017 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: 2019. 
4 
Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, et al. 
Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 
1989;245(4922):1059-65. 
5 
Kreindler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
6 
Konstan MW, McKone EF, Moss RB, Marigowda G, Tian S, Waltz D, et al. Assessment 
of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor 
therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation 
(PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017;5(2):107-18. 
7 
Sawicki GS, McKone E, Pasta DJ, Wagener J, Johnson C, Konstan MW. The effect of 
ivacaftor on the rate of lung function decline in CF patients with a G551D-CFTR 
mutation. J Cyst Fibros. 2014;13:S6. 
8 
Granados A, Chan CL, Ode KL, Moheet A, Moran A, Holl R. Cystic fibrosis related 
diabetes: Pathophysiology, screening and diagnosis. J Cyst Fibros. 2019;18(Suppl 2):S3-
9. 
9 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
10 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
11 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-
70. 
12 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-54. 
13 
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51(11):875-78. 
14 
Lanng S, Hansen A, Thorsteinsson B, Nerup J, Koch C. Glucose tolerance in patients 
with cystic fibrosis: five year prospective study. BMJ. 1995;311(7006):655-9. 
15 
Chan CL, Vigers T, Pyle L, Zeitler PS, Sagel SD, Nadeau KJ. Continuous glucose 
monitoring abnormalities in cystic fibrosis youth correlate with pulmonary function 
decline. J Cyst Fibros. 2018;17(6):783-90. 
16 
Schmid K, Fink K, Holl RW, Hebestreit H, Ballmann M. Predictors for future cystic 
fibrosis-related diabetes by oral glucose tolerance test. J Cyst Fibros. 2014;13(1):80-5. 


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17 
Misgault B, Chatron E, Reynaud Q, Touzet S, Abely M, Melly L, et al. Effect of one-year 
lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis 
patients [published online ahead of print, 2020 Mar 19]. J Cyst Fibros. 2020;S1569-
1993(20):30073-4. 
18 
Scheuing N, Holl RW, Dockter G, Hermann JM, Junge S, Koerner-Rettberg C, et al. 
High variability in oral glucose tolerance among 1,128 patients with cystic fibrosis: a 
multicenter screening study. PLoS One. 2014;9(11):e112578. 
19 
Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
publication practice for communicating company-sponsored medical research: GPP3. 
Ann Intern Med. 2015;163(6):461-4. 
20 
International Committee of Medical Journal Editors (ICMJE). December 2017. 
Recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals. Available at: http://www.icmje.org/recommendations/. Accessed 03 
August 2018. 
 


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APPENDIX A 
Eligible MF CFTR Mutations 
“MF” mutations are a subset of minimal function mutations that are non-responsive to IVA and 
TEZ/IVA. A mutation is considered an MF mutation if it meets at least 1 of the following 
2 criteria: 
(1) No biological plausibility of translated protein (genetic sequence predicts the complete 
absence of CFTR protein), or 
(2) in vitro testing that supports lack of responsiveness to IVA and TEZ/IVA. 
Inclusion of MF Mutations Based on In Vitro Testing 
Mutations that were considered to be MF mutations based on in vitro testing met the following 
criteria in in vitro experiments: 
• baseline chloride transport that was <10% of wildtype CFTR 
• an increase in chloride transport of <10% over baseline following the addition of IVA and 
TEZ/IVA in the assay 
Eligible MF Mutations 
The mutations below are detectable by an FDA-cleared genotyping assay or other method (e.g., 
sequencing). 
This list does not include every eligible mutation, and investigators should contact the medical 
monitor regarding other mutations that may also meet study eligibility criteria. 


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Non-exhaustive List of Minimal Function CFTR Mutations Eligible for VX19-445-117 
 
 
 
 
 
Q2X 
L218X 
Q525X 
R792X 
E1104X 
S4X 
Q220X 
G542X 
E822X 
W1145X 
W19X 
Y275X 
G550X 
W882X 
R1158X 
G27X 
C276X 
Q552X 
W846X 
R1162X 
Q39X 
Q290X 
R553X 
Y849X 
S1196X 
W57X 
G330X 
E585X 
R851X 
W1204X 
E60X 
W401X 
G673X 
Q890X 
L1254X 
R75X 
Q414X 
Q685X 
S912X 
S1255X 
L88X 
S434X 
R709X 
Y913X 
W1282X 
E92X 
S466X 
K710X 
Q1042X 
Q1313X 
Q98X 
S489X 
Q715X 
W1089X 
Q1330X 
Y122X 
Q493X 
L732X 
Y1092X 
E1371X 
E193X 
W496X 
R764X 
W1098X 
Q1382X 
W216X 
C524X 
R785X 
R1102X 
Q1411X 
 
 
 
185+1G>T 
711+5G>A 
1717-8G>A 
2622+1G>A 
3121-1G>A 
296+1G>A 
712-1G>T 
1717-1G>A 
2790-1G>C 
3500-2A>G 
296+1G>T 
1248+1G>A 
1811+1G>C 
3040G>C (G970R) 
3600+2insT 
405+1G>A 
1249-1G>A 
1811+1.6kbA>G 
3850-1G>A 
405+3A>C 
1341+1G>A 
1811+1643G>T  
3120G>A 
4005+1G>A 
406-1G>A 
1525-2A>G 
1812-1G>A 
3120+1G>A 
4374+1G>T 
621+1G>T 
1525-1G>A 
1898+1G>A 
3121-2A>G 
711+1G>T 
1898+1G>C 
 
 
 
 
182delT 
1119delA 
1782delA 
2732insA 
3791delC 
306insA 
1138insG 
1824delA 
2869insG 
3821delT 
365-366insT 
1154insTC 
1833delT 
2896insAG 
3876delA 
394delTT 
1161delC 
2043delG 
2942insT 
3878delG 
442delA 
1213delT 
2143delT 
2957delT 
3905insT 
444delA 
1259insA 
2183AA>G a 
3007delG 
4016insT 
457TAT>G 
1288insTA 
2184delA 
3028delA 
4021dupT 
541delC 
1343delG 
2184insA 
3171delC 
4022insT 
574delA 
1471delA 
2307insA 
3171insC 
4040delA 
663delT 
1497delGG 
2347delG 
3271delGG 
4279insA 
849delG  
1548delG 
2585delT 
3349insT 
4326delTC 
935delA 
1609del CA 
2594delGT 
3659delC 
1078delT 
1677delTA 
2711delT 
3737delA 
 
 
 
 


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Non-exhaustive List of Minimal Function CFTR Mutations Eligible for VX19-445-117 
 
 
 
 
 
CFTRdele1 
CFTRdele16-17b 
991del5 
CFTRdele2 
CFTRdele17a,17b 
1461ins4 
CFTRdele2,3 
CFTRdele17a-18 
1924del7 
CFTRdele2-4 
CFTRdele19 
2055del9>A 
CFTRdele3-10,14b-16 
CFTRdele19-21 
2105-2117del13insAGAAA 
CFTRdele4-7 
CFTRdele21 
2372del8 
CFTRdele4-11 
CFTRdele22-24 
2721del11 
CFTR50kbdel 
CFTRdele22,23 
2991del32 
CFTRdup6b-10 
124del23bp 
3121-977_3499+248del2515 
CFTRdele11 
306delTAGA 
3667ins4 
CFTRdele13,14a 
602del14  
4010del4 
CFTRdele14b-17b 
852del22 
4209TGTT>AA 
 
 
 
 
A46D 
V520F 
Y569D 
N1303K 
 
G85E 
A559T 
L1065P 
 
R347P 
R560T 
R1066C 
 
L467P 
R560S 
L1077P 
 
I507del 
A561E 
M1101K 
 
 
 
 
CFTR: cystic fibrosis transmembrane conductance regulator gene 
Source: CFTR2.org. Clinical and functional translation of CFTR. The Clinical and Functional Translation of CFTR (CFTR2), 
US Cystic Fibrosis Foundation, Johns Hopkins University, the Hospital for Sick Children. Available at: 
http://www.cftr2.org. Accessed 15 February 2016. 
a 
Also known as 2183delAA>G. 
 




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15.2 
Investigator Signature Page 
Protocol #: 
VX19-445-117 
Version #: 
3.0 
Version Date: 
26 April 2021 
Study Title: A Phase 3b Open-label Study to Assess the Effect of 
Elexacaftor/Tezacaftor/Ivacaftor on Glucose Tolerance in Cystic Fibrosis Subjects with 
Abnormal Glucose Metabolism 
 
 
I have read Protocol VX19-445-117, Version 3.0, and agree to conduct the study according to its 
terms. I understand that all information concerning elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor 
(IVA) and this protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is 
confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 

SAP_001.pdf: 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
Statistical Analysis Plan (Methods) 
Page 1 of 31 
Protocol Number: VX19-445-117 
 
 
 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
 
Statistical Analysis Plan 
(Methods) 
Protocol Number VX19-445-117 Version 3.0 
(Final Analysis) 
 
 
A Phase 3b Open-label Study to Assess the Effect of 
Elexacaftor/Tezacaftor/Ivacaftor on Glucose Tolerance in Cystic Fibrosis 
Subjects with Abnormal Glucose Metabolism 
 
Authors of SAP: 
 
Version: 1.0 
Version Date of SAP: 19 July 2022 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations. Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods) 
Protocol Number: VX19-445-117 
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1 
TABLE OF CONTENTS 
1 
Table of Contents .................................................................................................................... 2 
2 
Modifications ........................................................................................................................... 4 
2.1 
Modifications to the Approved Clinical Study Protocol .................................................... 4 
2.2 
Modifications to the Approved Statistical Analysis Plan .................................................. 4 
3 
Introduction ............................................................................................................................. 5 
4 
Study Objectives ...................................................................................................................... 5 
4.1 
Primary Objective .............................................................................................................. 5 
4.2 
Secondary Objectives ......................................................................................................... 5 
5 
Study Endpoints ...................................................................................................................... 5 
5.1 
Efficacy and Pharmacodynamic Endpoints ....................................................................... 5 
5.1.1 
Primary Endpoint ....................................................................................................... 5 
5.1.2 
Secondary Endpoint ................................................................................................... 5 
5.1.3 
Other Endpoints ......................................................................................................... 5 
6 
Study Design ............................................................................................................................ 6 
6.1 
Overall Design ................................................................................................................... 6 
6.2 
Sample Size and Power ...................................................................................................... 7 
6.3 
Randomization ................................................................................................................... 7 
6.4 
Blinding and Unblinding.................................................................................................... 7 
7 
Analysis Sets ............................................................................................................................ 7 
7.1 
All Subjects Set .................................................................................................................. 8 
7.2 
Full Analysis Set ................................................................................................................ 8 
7.3 
Safety Set ........................................................................................................................... 8 
8 
Statistical Analysis .................................................................................................................. 8 
8.1 
General Considerations ...................................................................................................... 8 
8.2 
Background Characteristics ............................................................................................... 9 
8.2.1 
Subject Disposition .................................................................................................... 9 
8.2.2 
Demographics and Baseline Characteristics .............................................................. 9 
8.2.3 
Medical History ....................................................................................................... 10 
8.2.4 
Prior and Concomitant Medications ........................................................................ 10 
8.2.5 
Study Drug Exposure ............................................................................................... 11 
8.2.6 
Study Drug Compliance ........................................................................................... 11 
8.2.7 
Important Protocol Deviations ................................................................................. 11 
8.3 
Efficacy Analysis ............................................................................................................. 11 
8.3.1 
Analysis of Primary Efficacy Variable .................................................................... 11 
8.3.2 
Analysis of Secondary Variable ............................................................................... 12 
8.3.3 
Analysis of Other Variables ..................................................................................... 13 
8.4 
Safety Analysis ................................................................................................................ 14 
8.4.1 
Adverse Events ........................................................................................................ 14 
8.4.2 
Clinical Laboratory .................................................................................................. 16 
8.4.3 
Electrocardiogram .................................................................................................... 16 
8.4.4 
Vital Signs ............................................................................................................... 17 


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8.4.5 
Pulse Oximetry ........................................................................................................ 17 
8.4.6 
Physical Examination ............................................................................................... 17 
8.4.7 
Ophthalmology Examination ................................................................................... 17 
8.4.8 
COVID-19 Impacted Visits ..................................................................................... 17 
8.5 
Additional Analysis ......................................................................................................... 17 
9 
Interim and DMC Analyses.................................................................................................. 18 
9.1 
Interim Analysis ............................................................................................................... 18 
9.2 
DMC analysis .................................................................................................................. 18 
10 References .............................................................................................................................. 19 
11 List of Appendices ................................................................................................................. 20 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments ........................... 20 
Appendix B: Details of GLI Equations for Calculating ppFEV1 ...................................................................... 23 
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates .................. 24 
Appendix D: Imputation Rules for Missing AE dates ............................................................... 25 
Appendix E: Adverse Events of Special Interest ...................................................................... 26 
Appendix F: Criteria for Threshold Analysis ............................................................................ 27 


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2 
MODIFICATIONS 
 
2.1 
Modifications to the Approved Clinical Study Protocol 
Not Applicable. 
2.2 
Modifications to the Approved Statistical Analysis Plan 
Not Applicable. This is the 1st version of Statistical Analysis Plan. 


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3 
INTRODUCTION 
 
Study VX19-445-117 is a Phase 3b open-label study evaluating the effect of elexacaftor (ELX, 
VX-445) in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) on glucose 
tolerance in cystic fibrosis (CF) subjects who are 12 years of age and older, heterozygous for 
F508del and a minimal function mutation (F/MF), and with abnormal glucose metabolism. 
This statistical analysis plan (SAP) is based on the most recent approved clinical study protocol 
(CSP), the most recent approved electronic case report form (eCRF), and the most recent 
approved eCRF completion guidelines. 
This SAP (Methods) version 1.0 documents the planned statistical analyses of efficacy and safety 
endpoints for final analysis. It also documents analyses for additional efficacy and safety 
variables not specified in the protocol, which will provide supportive information for the 
scientific understanding of the drug entity. 
The Vertex Biometrics Department will perform the statistical analysis of efficacy and safety 
data. SAS (Version 9.4 or higher) will be used to generate all statistical outputs (tables, figures, 
listings, and datasets). The SAP (version 1.0) will be finalized and approved prior to the clinical 
database lock for the study. Any revisions to the approved SAP will be documented and 
approved in an amendment to the SAP. 
 
4 
STUDY OBJECTIVES 
 
4.1 
Primary Objective 
To evaluate the effect of ELX/TEZ/IVA on glucose tolerance in CF subjects with impaired 
glucose tolerance (IGT) or CF-related diabetes (CFRD) 
4.2 
Secondary Objectives 
To evaluate the safety and tolerability of ELX/TEZ/IVA 
 
5 
STUDY ENDPOINTS 
 
5.1 
Efficacy and Pharmacodynamic Endpoints 
5.1.1 
Primary Endpoint 
Change from baseline in 2-hour blood glucose levels following an oral glucose tolerance test 
(OGTT) to the average of Week 36 and Week 48 
5.1.2 
Secondary Endpoint 
• 
Proportion of subjects with improvement in dysglycemia categorization (CFRD, IGT, 
normal glucose tolerance [NGT]) at Week 48 
• 
Safety and tolerability of ELX/TEZ/IVA based on adverse events (AEs), clinical laboratory 
values, ECGs, vital signs, and pulse oximetry 
5.1.3 
Other Endpoints 
• 
Change from baseline in sweat chloride (SwCl) through Week 48 
• 
Absolute change in body mass index (BMI) from baseline at Week 48 


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• 
Absolute change in body weight from baseline at Week 48 
• 
Change from baseline in hemoglobin A1c (HbA1c) and fructosamine at Week 48 
• 
Change from baseline in insulin use (dose) at Week 48 in subjects using insulin 
• 
Change from baseline in post-OGTT diabetes-related biomarkers (including insulin, 
C-peptide, glucagon, calculated indices of insulin secretion [insulinogenic index], and 
insulin resistance [HOMA-IR]) at Week 48 
• 
Change from baseline in biomarkers of inflammation (including C-reactive protein [CRP]) at 
Week 48 
• 
Change from baseline in biomarkers of pancreatic function (including fecal elastase-1 [FE-1] 
and serum immunoreactive trypsinogen [IRT]) at Week 48 
• 
Change from baseline in post-OGTT incretin levels (including glucagon-like peptide 1 
[GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) at Week 48 
• 
Change from baseline in percent of time spent in target blood glucose range of ≥70 to 
<140 mg/dL (≥3.89 to <7.77 mmol/L) as measured by 7-day continuous glucose monitoring 
(CGM) in subjects with CFRD at Week 48 
• 
Change from baseline in selected CGM parameters (including but not limited to percent of 
time spent between ≥140 and <200 mg/dL [≥7.77 and <11.10 mmol/L], percent of time 
spent ≥200 mg/dL [≥11.10 mmol/L], and mean amplitude of glycemic excursion* [MAGE]) 
in subjects with CFRD at Week 48 
*Note: definition corrected for MAGE (originally defined as maximum amplitude of glucose 
excursions in the study protocol). 
 
6 
STUDY DESIGN 
 
6.1 
Overall Design 
This is a Phase 3b, open-label study in CF subjects 12 years of age and older with F/MF 
genotypes and abnormal glucose tolerance as shown in Figure 7-1. 
Approximately 60 subjects (F/MF genotypes) will be enrolled, of whom approximately 30 
subjects will have IGT, and 30 subjects will have CFRD. During the Treatment Period, subjects 
will be administered ELX/TEZ/IVA for approximately 48 weeks. All subjects will receive ELX 
200 mg once daily (qd)/TEZ 100 mg qd/ IVA 150 mg every 12 hours (q12h). 


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Figure 7-1 
Schematic of the Study Design 
 
ELX: elexacaftor; CFRD: CF-related diabetes; CGM: continuous glucose monitoring; IVA: ivacaftor; N: total 
sample size; TEZ: tezacaftor 
a 
On Day -7, a CGM sensor will be inserted subcutaneously to assess baseline blood glucose levels for 7 days 
prior to the first dose of study drug in subjects with CFRD. 
b 
Subjects who complete the visits in the Treatment Period, regardless of whether they are on a treatment 
interruption, will be offered the opportunity to enroll in an open-label extension safety study evaluating 
ELX/TEZ/IVA. The Safety Follow-up Visit is not required for subjects who complete the Week 48 Visit and 
have enrolled in an open-label study within 28 days after the last dose of study drug. 
 
6.2 
Sample Size and Power 
The primary efficacy endpoint is change from baseline in 2-hour blood glucose levels following 
an OGTT to the average of Week 36 and Week 48. The primary null hypothesis to be tested is 
that the mean change from baseline in 2-hour blood glucose levels following OGTT to the 
average of Week 36 and Week 48 is equal to zero. 
Assuming a within group standard deviation (SD) of 45 mg/dL and a 10% dropout rate at Week 
48, a sample size of 60 subjects will have more than 95% power to detect a mean decrease from 
baseline of -30 mg/dL in 2-hour blood glucose levels post-OGTT to the average of Week 36 and 
Week 48, based on a 2-sided, 1-sample t-test at a significance level of 0.05. 
All power calculations were based on EAST software Version 6.4. 
6.3 
Randomization 
Not applicable. 
6.4 
Blinding and Unblinding 
This is an open-label study. Refer to Section 10.7 of the CSP for details. 
 
7 
ANALYSIS SETS 
 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), Safety Set 


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7.1 
All Subjects Set 
The All Subjects Set will include all subjects who were enrolled (defined as subjects having data 
in the clinical database for this study). This analysis set will be used for all individual subject 
data listings and disposition summary tables, unless otherwise specified. 
7.2 
Full Analysis Set 
The Full Analysis Set (FAS) will include all enrolled subjects who carry the intended CFTR 
allele mutation and have received at least 1 dose of study drug. The FAS will be used to 
summarize subject demographics and baseline characteristics, and for analyses of all efficacy 
endpoints, unless otherwise specified. 
7.3 
Safety Set 
The Safety Set will include all subjects who have received at least 1 dose of study drug. The 
Safety Set is to be used for all safety analyses. 
 
8 
STATISTICAL ANALYSIS 
 
8.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). 
Categorical variables will be summarized using counts and percentages. 
Baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
Treatment Period. The baseline 2-hour post-OGTT blood glucose level will be the average of 
pre-dose measurements at Screening and Day 1 visits (if both measurements are not available, 
use one measurement). 
Absolute change from baseline will be calculated as post-baseline value – baseline value. 
Relative change from baseline will be calculated as (post-baseline value – baseline 
value)/baseline value. 
Treatment-emergent (TE) Period will include the time from the first dose of study drug to 
28 days after the last dose of study drug or to the completion of study participation, whichever 
occurs first. Refer to Section 9.1.6 of the CSP for the definition of completion of study 
participation. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
1) In scheduled visit windows per specified visit windowing rules 
2) In the derivation of baseline and last on-treatment measurements 
3) In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values during TE period for safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix A. 


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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. 
8.2 
Background Characteristics 
8.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized based on the All Subjects 
Set: 
• All Subject Set 
• FAS 
• Safety Set 
The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized: 
• Completed study drug treatment 
• Prematurely discontinued treatment (i.e., discontinued all study drugs) and the reason for 
discontinuation 
• Completed study 
• Prematurely discontinued the study and the reason for discontinuation 
• Rollover to the open-label study 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. 
8.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the FAS. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other, and not collected per local regulations) 
• Country 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 


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Disease characteristics will include the following: 
• ppFEV1 at baseline (<30, ≥30 to <40, ≥40 to <70, ≥70 to ≤90, and >90) 
• ppFEV1 at baseline (continuous) 
• Sweat chloride at baseline (continuous) 
• 2-hour post-OGTT blood glucose levels at baseline (continuous) 
• Dysglycemia categorization at screening (IGT, CFRD) 
• Insulin use at baseline (Yes, No) 
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 
• Prior use of bronchodilator (Yes, No) 
• Prior use of inhaled bronchodilator (Yes, No) 
• Prior use of inhaled hypertonic saline (Yes, No) 
• Prior use of inhaled corticosteroids (Yes, No) 
In addition, data listings will also be provided for: 
• Informed consent; 
• Inclusion/Exclusion criteria violation for subjects with any such violations. 
The predicted FEV1 will be calculated using the Global Lung Function Initiative (GLI); details 
are provided in Appendix B. 
8.2.3 
Medical History 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). Medical history will be summarized descriptively by System Organ Class (SOC) 
and Preferred Term (PT) for the FAS. The corresponding data listing will also be provided. 
8.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD) 
and categorized as follows: 
Prior medication: any medication that was administered during the 56 days before the first dose 
of study drug. 
Concomitant medication: medication continued or newly received during the TE period 
Post-treatment medication: medication continued or newly received after the TE period 
A given medication may be classified as prior, concomitant, or post treatment; both prior and 
concomitant; both concomitant and post treatment; or prior, concomitant, and post treatment. 
If a medication has a missing or partially missing start/end date or time and if it cannot be 
determined whether it was taken before the first dose of study drug, concomitantly during the TE 


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Period, or after the TE Period, it will be considered in all 3 categories of prior, concomitant, and 
post treatment medication. 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: 1) preferred name (PN); and 2) anatomic class (ATC) level 1, ATC level 2, 
and PN for FAS. All medications will be listed for each subject. 
The number of subjects who used hormonal therapy concomitantly during the Treatment Period 
will be summarized based on the Safety Set. 
8.2.5 
Study Drug Exposure 
Study drug exposure will be summarized based on the Safety Set. 
Duration of study drug exposure (in weeks) will be calculated as: (last dose date of study drug – 
first dose date of study drug + 1)/7, regardless of study drug interruption. 
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max. It will also be summarized by intervals, using counts and 
percentages. 
8.2.6 
Study Drug Compliance 
Study drug compliance will be summarized based on the FAS. 
Study drug compliance will be calculated as: 100 × [1 - (total number of days of study drug 
interruption) / (duration of study drug exposure in days)]. A study drug interruption on a given 
day is defined as an interruption of any study drugs on that day. A study drug interruption that 
continues through the end of the study participation (i.e., subject does not resume study drug 
before the end of the study participation) will not be included in the compliance calculation. 
Study drug compliance will be summarized descriptively by the number of subjects (n), mean, 
SD, median, min, and max. It will also be summarized in categories: <80% and ≥80% using 
frequency tables. 
8.2.7 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. A protocol deviation review team will categorize IPDs according to 
the Protocol Deviation Plan during the study. 
IPDs will be only provided in an individual subject data listing. 
8.3 
Efficacy Analysis 
Unless otherwise defined, all efficacy analyses described in this section will be based on the 
FAS. 
8.3.1 
Analysis of Primary Efficacy Variable 
8.3.1.1 
Definition of Variable 
The primary efficacy endpoint is change from baseline in 2-hour glucose levels following an 
OGTT to the average of Week 36 and Week 48. 


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2-hour blood glucose levels following an OGTT: OGTT will be performed to assess 2-hour 
glucose levels. Depending on a subject’s weight, 1.75 g/kg of body weight or 75 g maximum of 
oral glucose solution will be administered in the morning after at least 8 hours of fasting. Blood 
samples will be obtained at 0, 30 (±5), 60 (±5), 90 (±5), and 120 (±5) minutes after the start of 
ingestion of glucose solution. OGTT results are considered valid only when the subject was 
fasting for at least 8 hours. Any non-fasting OGTT results will be disregarded and data for that 
assessment will be considered missing. 
8.3.1.2 
Primary Analysis 
The primary analysis will be performed using a mixed-effects model for repeated measures 
(MMRM) with the change from baseline in 2-hour post-OGTT blood glucose levels at each post- 
baseline visit as the dependent variable. The model will include visit as a fixed effect, with 
continuous baseline 2-hour post-OGTT blood glucose level as covariate. The model will be 
estimated using restricted maximum likelihood. Denominator degrees of freedom for the F-test 
for fixed effects will be estimated using the Kenward-Roger approximation1. An unstructured 
covariance structure will be used to model the within-subject errors. If the model estimation does 
not converge, a compound symmetry covariance structure will be used instead. Conditional on 
the observed data and covariates, missing data will be assumed to be missing at random and 
therefore will be handled by MMRM model. 
The primary result obtained from the model will be the estimated change from baseline to the 
average of Week 36 and Week 48. Data obtained from Week 24, Week 36, and Week 48 visits 
will be included in the model. The least square (LS) mean estimate along with the corresponding 
2-sided 95% confidence interval (CI) and P value will be provided. The LS mean change from 
baseline at each post-baseline visit with 95% CI, obtained from the model, will also be provided. 
Furthermore, the LS mean change from baseline (with SE) at each post-baseline visit, obtained 
from the model, will be plotted. 
In addition, the post-baseline raw values and the change from baseline at each post-baseline visit 
up to Week 48 will be summarized descriptively (n, mean, SD, median, minimum, and 
maximum). 
8.3.2 
Analysis of Secondary Efficacy Variable 
8.3.2.1 
Definition of Variable 
Dysglycemia categorization: abnormal or normal glucose tolerance as determined by an OGTT, 
classified as either: 
• CFRD: 2-hour post-OGTT blood glucose level ≥200 mg/dL [≥11.10 mmol/L]) or fasting 
hyperglycemia [blood glucose level ≥126 mg/dL (≥7.00 mmol/L) after an 8-hour fast] 
• IGT: 2-hour post-OGTT blood glucose level ≥140 to <200 mg/dL [≥7.77 to 
<11.10 mmol/L] and fasting blood glucose level <126 mg/dL (<7.00 mmol/L) 
• NGT: 2-hour post-OGTT blood glucose level <140 mg/dL [<7.77 mmol/L] and fasting 
blood glucose level <126 mg/dL (<7.00 mmol/L) 
Improvement in dysglycemia categorization: response at Week 48 compared to baseline (i.e. 
CFRD at baseline to IGT or NGT at Week 48, or IGT at baseline to NGT at Week 48 OGTT). 


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OGTT results are considered valid only when the subject was fasting for at least 8 hours. Any 
non-fasting OGTT results will be disregarded and data for that assessment will be considered 
missing. 
8.3.2.2 
Analysis Method 
The number and proportion of subjects with and without response at Week 48, defined as 
improvement from baseline dysglycemia categorization (i.e. CFRD at baseline to IGT or NGT 
based on Week 48 OGTT measurement, and IGT at baseline to NGT based on Week 48 OGTT 
measurement), will be presented for patients with abnormal glucose (CFRD or IGT) at baseline. 
The exact, 2-sided 95% Clopper-Pearson CI of the proportion of subjects with improvement will 
also be presented. In addition, the number and proportion of subjects in each dysglycemia 
category at baseline and each post-baseline visit will be presented. 
8.3.3 
Analysis of Other Variables 
8.3.3.1 
Definition of Variables 
Sweat chloride (SwCl): the SwCl value for a given visit will be calculated as the mean of the 
non-missing sweat chloride measurements obtained on the left and right arms at that visit. If one 
of the two arm measurements at a time point is missing, the other will be used as the mean. A 
volume ≥15 μL is required for an accurate determination of sweat chloride. Any results reported 
as having volume <15 μL will be considered missing. Any sweat chloride values reported as <10 
mmol/L or >160 mmol/L will be considered missing. 
Body mass index (BMI): the BMI at each visit is calculated using the weight and height at each 
visit as follows: 
BMI = Weight (kg) / [Height (m)]2 
Continuous glucose monitoring (CGM): CGM will be performed in subjects with CFRD at 
screening to assess dynamic, free-ranging changes in capillary glucose levels. A CGM sensor 
will be inserted subcutaneously by site medical staff, a home health nurse, or the subject after 
adequate training, calibrated, and worn for approximately 7 days. The CGM sensor records 
glucose values every 5 minutes. 
CGM glucose values are considered valid between 39 and 401 mg/dL. Any values reported as 
<39 mg/dL or >401 mg/dL are considered missing. The daily CGM assessment is considered 
valid when at least 202 values are obtained and valid (at least 70% of 288 5-minute records). For 
each analysis visit, the CGM parameters will be calculated for each valid daily assessment and 
then averaged, provided that there are at least 4 valid daily assessments. 
8.3.3.2 
Analysis Method 
For the following other endpoints, the raw values and change from baseline will be summarized 
descriptively (n, mean, SD, standard error [SE], median, minimum, and maximum): 
• 
Change from baseline in sweat chloride (SwCl) through Week 48 
• 
Absolute change in body mass index (BMI) from baseline at Week 48 
• 
Absolute change in body weight from baseline at Week 48 


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• 
Change from baseline in percent of time spent in target blood glucose range of ≥70 to 
<140 mg/dL (≥3.89 to <7.77 mmol/L) as measured by 7-day CGM in subjects with CFRD at 
Week 48 
• 
Change from baseline in percent of time spent between ≥140 and <200 mg/dL [≥7.77 and 
<11.10 mmol/L] and percent of time spent ≥200 mg/dL [≥11.10 mmol/L] as measured by 7- 
day CGM in subjects with CFRD at Week 48 
The raw values and change from baseline at each post-baseline visit up to Week 48 will also be 
summarized descriptively (n, mean, SD, SE, median, minimum, and maximum). 
8.4 
Safety Analysis 
All safety analyses will be based on data from the TE period based in the Safety Set, unless 
otherwise specified. 
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 
• ECGs 
• Vital signs 
• Pulse oximetry 
Only descriptive analysis of safety will be performed, and no statistical testing will be 
performed. 
8.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, and post-treatment 
AEs, defined as follows: 
Pretreatment AE: any AE that occurred before the first dose date of study drug 
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed at 
or after the first dose date of study drug through the end of the TE period 
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was newly 
developed after the TE period 
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs are pre-treatment or TEAE, the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of adverse events are described in Appendix D. 
An overview of all TEAEs will be summarized in the following categories: 
• Number of TEAEs 
• Subjects with any TEAEs 
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 


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• Subjects with TEAEs leading to study drug discontinuation 
• Subjects with TEAEs leading to study drug interruption 
• Subjects with Grade 3/4/5 TEAEs 
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAEs leading to death 
The following summary tables of TEAEs 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): 
• All TEAEs 
• Grade 3/4/5 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Related TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to death 
When summarizing the number and percentages of subjects, subjects with multiple occurrences 
of the same adverse event or a continuing adverse event will be counted once, and only the 
maximum severity level will be presented in the severity summaries, and the strongest 
relationship level in the relationship summaries. 
All AEs, including pretreatment AEs, TEAEs, and post-treatment AEs, will be presented in an 
individual subject data listing based on the All Subjects Set. In addition, separate listings 
containing individual subject adverse event data for TEAEs leading to treatment discontinuation, 
TEAEs leading to treatment interruption, Grade 3/4/5 TEAEs, SAEs, and all deaths will be 
provided. Listings for SAEs and deaths will include a flag indicating the TEAE status. 
8.4.1.1 
Adverse Events of Special Interest 
For this study, elevated transaminase events and rash events, as determined by MedDRA 
preferred terms in Appendix E, are considered as adverse events of special interest. 
For treatment-emergent elevated transaminase events and rash events, the following categories 
will be summarized by treatment group: 
• Subjects with events 


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• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 
• Subjects with serious events 
• Subjects with related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event 
In addition, for treatment-emergent rash events, these categories will be summarized for the 
following subgroups: 
• Sex (male, female) 
• Female subjects with concomitant hormonal therapy (Yes, No) 
8.4.2 
Clinical Laboratory 
For the treatment-emergent laboratory measurements, the observed values and change from 
baseline values of the continuous hematology, serum chemistry, and coagulation results will be 
summarized in SI units at each visit. 
The number and percentage of subjects meeting the threshold analysis criterion at least once 
during the TE period will be summarized for select LFT parameters. The threshold analysis of 
shift from baseline will also be summarized for selected LFT laboratory parameters. The 
threshold analysis criteria are provided in Appendix F. 
For selected LFT laboratory tests (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase [ALP], and total bilirubin), a scatter plot of the maximum treatment- 
emergent value versus the baseline value corresponding to ×ULN (upper limit of normal) will be 
presented. Further, a scatter plot of the maximum treatment-emergent value of ALT and AST, 
separately, versus the maximum treatment-emergent value of total bilirubin corresponding to 
×ULN will also be presented. 
Results of urinalysis and positive urine/serum pregnancy test will be listed in individual subject 
data listings only. For positive serum pregnancy listing, subjects with serum HCG which are 
above non-pregnant levels will be selected. 
In addition, a listing containing individual subject hematology, chemistry, and coagulation values 
will be provided. This listing will include data from both scheduled and unscheduled visits. 
8.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided at each visit and time point for the following ECG 
measurements (in msec): RR interval, PR interval, QT interval, QTcF interval, QRS duration, 
and Heart Rate (beats per minute). 


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The number and percentage of subjects meeting the threshold analysis criterion at least once 
during the TE period for selected parameters will be summarized. The threshold analysis criteria 
are provided in Appendix F. 
In addition, a listing containing individual subject ECG values will be provided. This listing will 
include data from both scheduled and unscheduled visits. 
8.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each visit. The following vital signs parameters will be 
summarized: height (cm), systolic and diastolic blood pressure (mm Hg), body temperature (°C), 
pulse rate (beats per minute), and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting the threshold analysis criterion at least once 
during the TE period for selected parameters will be summarized. The threshold analysis criteria 
are provided in Appendix F. 
In addition, a listing containing individual subject vital signs values will be provided. This listing 
will include data from both scheduled and unscheduled visits. 
8.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each visit for the percent of oxygen saturation. 
The number and percentage of subjects with shift from baseline (normal/missing and low 
according to the reference range) to the lowest percent of oxygen saturation during the TE period 
will be summarized. The reference range for normal oxygen saturation is specified as >95%, and 
<=95% for low oxygen saturation. 
8.4.6 
Physical Examination 
Abnormal PE findings will be presented as an individual subject data listing only. 
8.4.7 
Ophthalmology Examination 
Ophthalmology examination results will be provided in a data listing. 
8.4.8 
COVID-19 Impacted Visits 
A listing containing subjects’ visits impacted due to COVID-19 will be provided. 
8.5 
Additional Analysis 
Analyses related to the additional endpoints of change from baseline at Week 48 in hemoglobin 
A1c (HbA1c) and fructosamine, insulin use (dose) in subjects using insulin, post-OGTT 
diabetes-related biomarkers, biomarkers of inflammatory, biomarkers of pancreatic function, 
post-OGTT incretin levels and glucose-dependent insulinotropic polypeptide, and some selected 
CGM parameters (including MAGE, which was originally defined as “maximum amplitude of 
glucose excursions” in study protocol, but is corrected to “mean amplitude of glycemic 
excursion” in this SAP) will be discussed in a separate document and thus are out of the scope of 
this SAP. 


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9 
Interim and DMC Analyses 
 
9.1 
Interim Analysis 
Not applicable. 
9.2 
DMC analysis 
Not applicable. 


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10 
REFERENCES 
 
1 Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 


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11 
LIST OF APPENDICES 
 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments 
 
Table 11-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3, 4, 5 
Safety Assessment 
Serum Chemistry 
Hematology 
Day 1 (Baseline) 
Week 4 
Week 12 
Week 24 
Week 36 
Week 48 
Safety Follow-up 
1 
29 
85 
169 
253 
337 
Not applicable 
≤1 Pre-dose 
[1, 57] 
(57, 127] 
(127, 211] 
(211, 295] 
(295, 351] 
Use nominal visit 
Standard 12-lead ECG 
Day 1 (Baseline) 
Week 24 
Week 48 
Safety Follow-up 
1 
169 
337 
Not applicable 
≤1 Pre-dose 
[1, 253] 
(253, 351] 
Use nominal visit 
Vital signs (excluding BMI, 
Weight, and Height) and 
pulse oximetry 
Day 1 (Baseline) 
Week 4 
Week 12 
Week 24 
Week 36 
Week 48 
Safety Follow-up 
1 
29 
85 
169 
253 
337 
Not applicable 
≤1 
[1, 57] 
(57, 127] 
(127, 211] 
(211, 295] 
(295, 351] 
Use nominal visit 
Coagulation 
Day 1 (Baseline) 
Week 24 
Week 48 
Safety Follow-up 
1 
169 
337 
Not applicable 
≤1 Pre-dose 
[1, 253] 
(253, 351] 
Use nominal visit 
Efficacy Assessment and Pharmacodynamic Assessment 
Weight, Height, and BMI 
Day 1 (Baseline) 
Week 4 
Week 12 
Week 24 
Week 36 
Week 48 
Safety Follow-up 
1 
29 
85 
169 
253 
337 
Not applicable 
≤1 
(1, 57] 
(57, 127] 
(127, 211] 
(211, 295] 
(295, 351] 
> 351 
Sweat Chloride 
Day 1 (Baseline) 
Week 24 
Week 48 
1 
169 
337 
≤1 Pre-dose 
(1, 253] 
(253, 351] 
Oral glucose tolerance test 
(OGTT)6 
Baseline 
Week 24 
Week 36 
Week 48 
1 
169 
253 
337 
≤1 Pre-dose 
(1, 211] 
(211, 295] 
(295, 351] 


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Table 11-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3, 4, 5 
Continuous glucose 
monitoring (CGM) 
Day -7 (Baseline) 
Week 1 
Week 12 
Week 24 
Week 36 
Week 48 
-7 
1 
85 
169 
253 
337 
<1 Pre-dose 
[1, 43] 
(43, 127] 
(127, 211] 
(211, 295] 
(295, 362] 
Notes: 
1 Visit name for analysis purpose is used to report data in tables and figures. 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
b. If there is more than 1 numerical measurement available within a visit window, use the following rules: 
i. The measurement closest to the target day will be used; or 
ii. If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. If the latest measurement cannot be determined, then unscheduled visit will be selected 
3 For measurements collected on the date of first dose of study drug, if it cannot be determined whether the 
measurement is before or after the first dose: 
a. 
Scheduled measurement will be treated as pre-dose observation. 
b. Unscheduled measurement will be treated as post-dose observation. 
4 For safety assessment, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a subject 
doesn’t have a nominal Safety Follow-up visit but has an ETT visit with study day >351, then the ETT visit will be 
mapped into Safety Follow-up analysis visit. 
5 For efficacy assessments and nutrition variables (BMI, Weight, Height and their Z-scores), if there are multiple 
assessments >351, then nominal Safety Follow-up visit will be mapped to Safety Follow-up visit. If there is only 
ETT assessment > 351, the ETT visit will be mapped to the Safety Follow-up visit; else if there are multiple 
assessments with >351 then select the earliest record. 
Derived Variables: 
1. Age (in years) at first dose date and nominal visit (for demographics, listing and the calculation of [percent] 
predicted spirometry variables): 
Obtain the age at informed consent (in days) in “yy, mm” format (e.g., 24 years, 6 months) from the Vital Signs 
(VS) page at the Screening Visit, and add 0.5 month to convert to days. 
Obtain the informed consent date. 
Then age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed consent 
date) in days + age at informed consent (in days)]/365.25. 
2. Age (in months) at nominal visit (for use in calculation of BMI, height and weight z-score): 
Obtain the age at informed consent (in months) in “yy, mm” format (e.g., 24 years, 6 months) from Vital Signs 
(VS) page at the Screening Visit. 
Obtain the informed consent date. 


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Table 11-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3, 4, 5 
Then age (in months) at nominal visit = integer part of {[(age at informed consent (in months) + 0.5 + diff(first 
dose date or nominal visit date, informed consent date) in months]} + 0.5. 
3. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date to impute. 
If the last dose date is missing or partial date is reported, the last dose date will be imputed based on, in 
descending order priority, the Early Treatment Termination (ETT) visit date, last visit date before the Safety 
Follow-up, or the last study drug administration date from EX SDTM domain, as appropriate. The imputation 
algorithm will ensure the imputed last dose date does not exceed the study participation end date. 
4. Sweat Chloride: 
Non-missing sweat chloride concentrations from the left arm and right arm with assessment end date/time for a 
given arm up to 30 minutes after first dose time in treatment period will be considered for baseline. 
5. Electrocardiogram: 
Baseline is defined as the most recent pretreatment measurement before the first dose of study drug in the 
Treatment Period. If multiple ECG measurements are obtained on the same calendar day during the TE period, 
o 
For summary purpose, the calculated average ECG will be used as the ECG value on that day; 
o 
For threshold analysis purpose, all reported ECG values will be used. 
6 For the primary endpoint, the baseline 2-hour post-OGTT blood glucose level will be the average of pre-dose 
measurements at Screening and Day 1 visits (if both measurements are not available, use one measurement). For the 
secondary endpoint, the baseline dysglycemia category will be defined as the most recent non-missing measurement 
(scheduled or unscheduled) collected before the first dose of study drug in the Treatment Period. 


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Appendix B: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 Regression 
Equation and Lookup Tables (Version 7 April 2013). Global Lung Function Initiative. [online] 
Available at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138978 
[Accessed Mar 26, 2018]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] Available 
at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138979 [Accessed Mar 
26, 2018]. 
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: http://www.ers-education.org/home/browse-all- 
content.aspx?idParent=138988 [Accessed Mar 26, 2018]. 
Data handling rule for spirometry is as follows: 
 
• Input age with at least 2 decimal place 
• Use height at screening regardless if height is collected at other study visits for subjects 
whose age at informed consent is >21 years. For subjects with age <=21 years, height 
collected at the respective visit should be used; if the height at the respective visit is not 
available, the last non-missing record will be used. 
• For race, map the CRF reported Black or African American to Black, all other races in 
CRF (except White) are mapped to 'other'; multiple checks for race in CRF are also 
mapped to 'other'; white is a reference race in the equations and assumes 0 values for all 
race coefficients in the GLI equations. 


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


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Appendix D: Imputation Rules for Missing AE dates 
Imputation rules for missing or partial AE start date are defined below. If the imputed AE start 
date is before the informed consent date, the AE start date will be imputed using the study 
informed consent date. 
• If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then 
 if AE start year and month are equal to the month and year of first dose date 
of the Treatment Period, then impute the AE start day as the day of first dose 
date of the Treatment Period; 
 else impute the AE start day as 1. 
o else impute the AE start day as 1. 
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then 
 if AE start year is equal to the year of first dose date of the Treatment Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Treatment Period; 
 else impute the AE start month as January and day as 1. 
o else impute the AE start month as January and day as 1. 
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site and 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the first dose date 
of the Treatment Period; 
o else impute the AE start date as the informed consent/assent date. 
 
Imputation rules for partial AE end date are defined below: 
• Impute the AE end date as min (the last day of the month, end of study participation) if day is 
missing, or min (Dec, end of study participation) if month is missing. 


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Appendix E: Adverse Events of Special Interest 
 
Table 11-7 
MedDRA Preferred Terms for Event of Special Interest 
Adverse event of special interest 
MedDRA preferred terms 
Elevated transaminases 
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 abnormal, Hepatic enzyme increased 
Rash 
Rash, Rash erythematous, Rash macular, Rash maculo-papular, 
Rash maculovesicular, Rash vesicular, Rash pruritic, Rash 
follicular, Rash pustular, Nodular rash, Drug eruption, Fixed 
eruption, Urticaria, Urticaria papular, Urticaria vesiculosa, 
Urticarial dermatitis, Rash morbilliform, Rash papular, Rash 
papulosquamous, Rash rubelliform, Rash scarlatiniform , Drug 
hypersensitivity, Type IV hypersensitivity reaction, Dermatitis, 
Dermatitis atopic, Epidermolysis, Skin toxicity, Dermatitis 
allergic, Dermatitis exfoliative, Dermatitis exfoliative 
generalised, Erythema multiforme, Exfoliative rash, 
Mucocutaneous rash, Acute generalised exanthematous 
pustulosis, Cutaneous vasculitis, Urticarial vasculitis, Dermatitis 
bullous, Drug reaction with eosinophilia and systemic 
symptoms, Epidermal necrosis, Oculomucocutaneous syndrome, 
Skin exfoliation, Skin necrosis, Stevens-Johnson syndrome, 
Toxic epidermal necrolysis, Toxic skin eruption, Perioral 
dermatitis, Vasculitic rash, Immune-mediated dermatitis, Penile 
rash, SJS-TEN overlap, Erythrodermic atopic dermatitis, Scrotal 
dermatitis, Anal Rash, generalised bullous fixed drug eruption, 
Severe cutaneous adverse reaction 
Note: the preferred terms listed in the table is based on the MedDRA version applicable at the time of 
finalization of the SAP. If the MedDRA version is upgraded at the time of the analysis, the 
corresponding preferred terms based on the upgraded version, including adding, removing and 
renaming the preferred terms, will be used in the analysis of adverse events of special interest. 


Statistical Analysis Plan (Methods) 
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Appendix F: Criteria for Threshold Analysis 
 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
FDA DILI Guidance Jul 2009. 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
AST 
>ULN - ≤3xULN 
FDA DILI Guidance Jul 2009. 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
ALT or AST 
(ALT>ULN - ≤ 3xULN) or 
(AST>ULN - ≤ 3xULN) 
FDA DILI Guidance 
(ALT>3x - ≤ 5xULN) or (AST>3x - ≤ 
5xULN) 
(ALT>5x- ≤ 8xULN) or (AST>5x - ≤ 
8xULN) 
(ALT>8x - ≤ 20xULN) or (AST>8x - 
≤ 20xULN) 
ALT>20xULN or AST> 20 xULN 
Alkaline Phosphatase 
>ULN - ≤ 1.5xULN 
FDA DILI Guidance Jul 2009. 
>1.5 – ≤ 2.5 xULN 
>2.5 – ≤ 5.0 x ULN 
>5.0 – ≤ 20.0 x ULN 
>20.0 x ULN 
Total Bilirubin 
>ULN - ≤ 1.5xULN 
FDA DILI Guidance Jul 2009. 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN 
>3 – ≤ 10xULN 
>10xULN 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
FDA DILI Guidance Jul 2009. 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN 
>3 – ≤ 10xULN 
>10xULN 
Indirect Bilirubin 
>ULN - ≤ 1.5xULN 
FDA DILI Guidance Jul 2009. 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN 
>3 – ≤ 10xULN 
>10xULN 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009. 
 


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Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
 
Parameter 
Threshold Analysis 
Comments 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009. 
(ALT or AST) and Total Bilirubin (ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 
GGT 
>ULN - ≤ 2.5xULN 
CTCAE grade 1-4 
>2.5 – ≤ 5.0xULN 
>5.0 – ≤ 20.0xULN 
>20.0xULN 
Clinical Chemistry (NON-LFT) 
Albumin 
<LLN - ≥ 30 g/L 
CTCAE grade 1-3 
<30 – ≥ 20 g/L 
<20 g/L 
Amylase 
>1x - ≤ 1.5xULN 
Criteria based upon CTCAE 
>1.5x - ≤ 2xULN 
>2x - ≤ 5xULN 
>5xULN 
Creatinine 
>ULN - ≤ 1.5xULN 
CTCAE grades 1-4 
>1.5 - ≤ 3.0xULN 
>3.0 - ≤ 6.0xULN 
>6.0xULN 
Lipase 
>ULN - ≤ 1.5xULN 
Criteria based upon CTCAE 
>1.5x - ≤ 2xULN 
>2x - ≤ 5xULN 
>5xULN 
Total protein 
<LLN 
No CTCAE 
>ULN 
Creatine kinase 
>ULN - ≤ 2.5 x ULN 
CTCAE grades 1-4 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN 
>10 x ULN 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
CTCAE grade 1-3 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L 
< 80 g/L 
Hgb increased 
CTCAE grade 1-3 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L above 
ULN 
>40 g/L above ULN 


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Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
 
Parameter 
Threshold Analysis 
Comments 
Platelets 
Platelet decreased 
CTCAE grade 1-4 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L 
<50.0 – ≥ 25.0 x 10e9 /L 
<25.0 x 10e9 /L 
Platelet increased 
No CTCAE available 
>ULN 
Reticulocytes/Erythrocytes (%) 
<LLN 
No CTCAE 
>ULN 
Coagulation 
Activated partial thromboplastin 
time (PTT) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
CTCAE grade 1-3 
>2.5 x ULN 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
 
 
Table 12-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
Per HV grade 2, 3, plus shift change 
<50 bpm 
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
Tachycardia 
Per HV grade 1, 2, 3, plus shift change 
>100 bpm 
>115 bpm 
>130 bpm 
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm 
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 


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Table 12-4 
Threshold Analysis Criteria for ECGs 
 
Parameter 
Threshold Analysis 
Comments 
QTc 
>450 to <500ms (Male) or >470 to <500ms 
(Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction 
formula. 
 
 
 
Table 12-5 
Threshold Analysis Criteria for Vital Signs 
 
Parameter 
Threshold Analysis 
Comments 
Pulse Rate 
Same as above in ECG category 
SBP increased 
>140 mmHg 
809/770 analyses 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
>140 mmHg & >10 mmHg increase from 
baseline 
>140 mmHg & >20 mmHg increase from 
baseline 
>160 mmHg & >10 mmHg increase from 
baseline 
>160 mmHg & >20 mmHg increase from 
baseline 
SBP decrease 
<90 mmHg 
<80 mmHg 
Per HV grade 1, 3, plus shift change 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
<90 mmHg and >10 mmHg decrease from 
baseline 
<90 mmHg and >20 mmHg decrease from 
baseline 
<80 mmHg and >10 mmHg decrease from 
baseline 
<80 mmHg and >20 mmHg decrease from 
baseline 


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Table 12-
Threshold Analysis Criteria for Vital Signs 
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Parameter 
Threshold Analysis 
Comments 
DBP increased 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
>90 mmHg and >5 mmHg increase from 
baseline 
>90 mmHg and >10 mmHg increase from 
baseline 
>100 mmHg and >5 mmHg increase from 
baseline 
>100 mmHg and >10 mmHg increase from 
baseline 
DBP decreased 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
<60 mmHg and >5 mmHg decrease from 
baseline 
<60 mmHg and >10 mmHg decrease from 
baseline 
<45 mmHg and >5 mmHg decrease from 
baseline 
<45 mmHg and >10 mmHg decrease from 
baseline 
Weight 
Weight gain 
CTCAE grade 1-3 
≥5 % increase from baseline 
≥10 % increase from baseline 
≥ 20% increase from baseline 
Weight loss 
CTCAE grade 1-3 
≥5 % decrease from baseline 
≥10 % decrease from baseline 
≥ 20% decrease from baseline 
 
 
Table 11-6 
Threshold Analysis Criteria for Laboratory Tests (for labeling purpose) 
 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT or AST 
>3xULN 
>5xULN 
>8xULN 
For labeling purpose