Conditions: Cystic Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 98
Healthy volunteers: no

Brief summary:
Study VX16-661-114 (Study 114) is a Phase 3b, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in subjects aged 12 years and older with CF who are homozygous for the F508del mutation on the cystic fibrosis transmembrane conductance regulator gene (CFTR) gene and who discontinued treatment with Orkambi due to respiratory symptoms considered related to treatment. This study is designed to evaluate the safety and efficacy of Tezacaftor/Ivacaftor (TEZ/IVA).

Detailed description:

Arms:
arm 1: Participants received placebo matched to TEZ/IVA fixed-dose combination tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 56 days. arm 2: Participants received TEZ 100 milligram (mg)/IVA 150 mg fixed-dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 56 days.

Interventions: intervention 1: Tezacaftor/Ivacaftor intervention 2: Ivacaftor intervention 3: Placebo intervention 4: Placebo
Intervention descriptions: intervention 1: TEZ 100 mg/IVA 150 mg fixed-dose combination tablet. intervention 2: IVA 150 mg tablet. intervention 3: Placebo matched to TEZ/IVA fixed-dose combination tablet. intervention 4: Placebo matched to IVA tablet.

Protocol document:
Prot_000.pdf: 




Protocol VX16-661-114 Version 3.1 US 
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2 
PROTOCOL SYNOPSIS 
Title 
Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Assess 
the Safety, Efficacy, and Tolerability of Tezacaftor/Ivacaftor (TEZ/IVA) in an Orkambi-
experienced Population Who Are Homozygous for the F508del-CFTR Mutation 
Brief Title 
A Study to Evaluate Safety, Efficacy, and Tolerability of TEZ/IVA in Subjects With 
Cystic Fibrosis (CF) Who Have Previously Discontinued Orkambi 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 3b 
 
 
Objectives 
Primary  
 
To evaluate the respiratory safety of TEZ/IVA in subjects with CF homozygous for 
F508del and who discontinued treatment with Orkambi due to respiratory symptoms 
considered related to treatment 
Secondary  
 
To evaluate the efficacy of tezacaftor in combination with ivacaftor (TEZ/IVA) in 
subjects with CF homozygous for F508del and who discontinued treatment with 
Orkambi due to respiratory symptoms considered related to treatment. 
 
To evaluate patient-reported outcomes after treatment with TEZ/IVA in subjects with 
CF homozygous for F508del who discontinued with Orkambi due to respiratory 
symptoms considered related to treatment. 
 
 
Endpoints 
Primary  
 
Incidence of respiratory adverse events (AEs)  
Key Secondary 
 
Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
from baseline to the average of the Day 28 and Day 56 measurements.  
Secondary 
 
Relative change in ppFEV1 from baseline to the average of the Day 28 and Day 56 
measurements. 
 
Absolute change in Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory 
domain score from baseline to the average of the Day 28 and Day 56 measurements 
 
Tolerability based on study drug discontinuation through Day 56 
 
Safety assessments based on AEs, clinical laboratory values (hematology, serum 
chemistry, coagulation studies, and urinalysis), vital signs, pulse oximetry, and 
postdose spirometry 
 
 
Number of 
Subjects 
Approximately 90 (45 per arm) 
 
 
Study Population 
Male and female subjects aged 12 years or older with CF who are homozygous for the 
F508del- Cystic Fibrosis transmembrane conductance regulator (CFTR) mutation and 
who have previously discontinued treatment with Orkambi due to respiratory symptoms 
considered related to treatment. 
 
 
Investigational 
Drug 
Active substance: TEZ and IVA 
 
Activity: CFTR corrector and potentiator (increased chloride ion [Cl−] secretion) 


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Strength and Route of Administration: TEZ 100-mg/IVA 150-mg fixed-dose 
combination (light yellow) film-coated tablet for oral administration 
 
 
 
Active substance: IVA  
 
Activity: CFTR potentiator (increased Cl− secretion) 
 
Strength and Route of Administration: IVA 150-mg (light blue) film-coated tablet for 
oral administration 
 
 
 
Active substance: not applicable 
 
Activity: placebo 
 
Strength and Route of Administration: 0 mg film-coated matching placebo tablets for 
oral administration 
 
 
Study Duration 
Excluding the Screening Period, each subject will participate in the study for 84 (± 3) days 
(from Day 1 through last day of Safety Follow-up Contact). 
 
 
Study Design 
This study includes the following: 
 
Screening Period (Day −28 through Day −1) 
 
Treatment Period (Day 1 through Day 56 ± 5 days) 
 
Safety Follow-up Contact (28 days ± 7 days after the last dose of study drug)  
Subjects will be stratified by age at the Screening Visit (<18 versus ≥18 years of age), sex 
(male versus female), and ppFEV1 severity determined during the Screening Visit (<40% 
versus ≥40% predicted), and then randomized (1:1) to 1 of the following 2 treatment 
arms: 
TEZ/IVA: TEZ 100 mg once daily (qd) + IVA 150 mg every 12 hours (q12h) 
Placebo: Placebo regimen with visually matched tablets 
Subjects who complete the Day 56 Visit will be offered the opportunity to receive 
TEZ/IVA through the Expanded Access Program if they meet the eligibility criteria for 
that program. 
 
 
Schedule of Study 
Visits 
 
 
Screening Period: 
After obtaining consent and assent (where applicable), screening evaluations will be 
completed at any time during a period of 28 days (Day -28 through Day -1) before the 
first dose of the study drug. 
Treatment Period: 
The first dose of the study drug will be administered on Day 1 and after randomization. 
Clinic visits will occur on Day 1, Day 15 (± 3 days), and at Day 28 and Day 56 (± 5 days).  
Safety Follow-up Contact: 
A Safety Follow-up Contact will be performed 28 days (±7 days) after the last dose of 
study drug. The Safety Follow-up Contact may be a telephone interview; however, if 
deemed necessary by the investigator, a Safety Follow-up Visit may be required with 
necessary assessments to be determined by the investigator.  
 
 
Assessments 
Safety: AEs, clinical laboratory assessments (i.e., hematology, serum chemistry, 
coagulation studies, and urinalysis), vital signs, physical examinations, ophthalmologic 
examinations, pulse oximetry, and postdose spirometry (Day 1 only).   
Efficacy: Spirometry and CFQ-R  
Tolerability: discontinuation of study drug 


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Statistical 
Analyses 
Sample Size Consideration  
Sample size calculation is based on the key secondary endpoint of absolute change in  
ppFEV1 from baseline to the average of the Day 28 and Day 56 measurements.  
A Bayesian approach will be used to assess the treatment effect on the change in ppFEV1. 
The study will be considered successful if the posterior probability that the treatment 
difference between TEZ/IVA and placebo is greater than 0 is at least 80%, using a 
noninformative prior distribution. Assuming a 3.0 percentage points mean treatment 
difference between TEZ/IVA and placebo and a standard deviation (SD) of 6.0 percentage 
points, with 42 TEZ/IVA subjects and 42 placebo subjects, the Bayesian power to achieve 
the posterior probability criterion is at least 90% (92.6%). After adjusting for an assumed 
dropout rate of 5% a total sample size of 90 subjects is needed. 
Analyses Sets 
The Full Analysis Set (FAS) is defined as all randomized subjects who have received at 
least 1 dose of study drug. The FAS will be used in efficacy analyses in which subjects 
will be analyzed according to their randomized treatment group. 
The Safety Set is defined as all subjects who received at least 1 dose of study drug. The 
Safety Set is to be used for all safety and tolerability analyses, in which subjects will be 
analyzed according to the treatment they received. 
Safety Analyses 
Respiratory safety of TEZ/IVA is the primary objective of this study and will be assessed 
in terms of AE incidence, including but not limited to the following: 
 
Chest discomfort 
 
Dyspnea (shortness of breath) 
 
Respiration abnormal (chest tightness) 
 
Asthma 
 
Bronchial hyperreactivity 
 
Bronchospasm  
 
Wheezing 
All safety analyses will be based on the TE Period for subjects in the Safety Set.  
The overall safety profile of study treatments will be assessed in terms of the following 
safety endpoints: 
 
Incidence of treatment-emergent adverse events (TEAEs), SAEs, and 
discontinuations due to AEs 
 
Clinical laboratory values 
 
Vital signs 
 
Pulse oximetry 
All safety data will be listed by subject in data listings. 
Summaries of TEAEs will be presented by MedDRA system organ class and preferred 
term.  
 
Efficacy Analysis 
The actual posterior/conditional probability will be calculated for the probability of a 
greater than zero (>0) treatment effect difference in mean ppFEV1 change between 
TEZ/IVA and placebo is greater than or equal to 80%, based on the observed data of the 
efficacy endpoint on the absolute change from baseline in ppFEV1 to the average of the 
Day 28 and Day 56 measurements. This will serve as the primary efficacy analysis 
outcome. 
Additionally, the key efficacy endpoint of the absolute change from baseline in ppFEV1 to 
the average of the Day 28 and Day 56 measurements will be analyzed using a mixed-


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effects model for repeated measures (MMRM) with ppFEV1 at each time point as the 
outcome variable. The MMRM model will include the absolute change from baseline in 
ppFEV1 at each visit as the dependent variable; treatment, visit, and treatment-by-visit 
interaction as fixed effects; and subject as a random effect, with adjustment for sex (male 
versus female), age group at the Screening Visit (<18 versus ≥18 years old), and ppFEV1 
severity determined during the Screening (or baseline) Period (<40% versus ≥40% 
predicted).  
The estimated treatment effect within TEZ/IVA and placebo arm, as well as the estimated 
treatment difference between TEZ/IVA and placebo arm will be provided based on the 
MMRM model along with 95% confidence interval (CI). These results will serve as 
additional efficacy outcomes, which is in addition to the primary actual 
posterior/conditional probability outcome. Furthermore, treatment effect and treatment 
difference at each post-baseline visit, obtained from the model, will also be provided. 
Secondary endpoints including relative change of ppFEV1, CFQ-R respiratory domain 
score will be analyzed in a similar fashion as the analysis for the primary endpoint.  
Tolerability Analysis 
A tolerability analysis will be based on the Safety Set for a standard summary of study 
drug discontinuation rate. Rate will be reported as descriptive statistics in percentages and 
no statistical hypothesis testing will be performed. 
IDMC Reviews 
The independent data monitoring committee (IDMC) will conduct regular planned safety 
reviews of study data as outlined in the IDMC Charter.  


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of Assessments are shown in Table 3-1 and Table 3-2. 
All visits are to be scheduled relative to the Day 1 Visit (first dose of study drug).  
Table 3-1 
Study VX16-661-114: Screening 
Event/Assessment 
Screening Visit 
Day -28 to Day -1 
Informed consent and assent (when applicable) 
X 
Demographics 
X 
Medical history 
X 
CFTR genotypea 
X 
Ophthalmologic examinationb 
X 
Prior and concomitant medicationsc 
X 
Height and weight (measured with shoes off) 
X 
Vital signsd 
X 
Pulse oximetryd 
X 
Physical examination of all body systems 
X 
Serum FSHe (amenorrheic female subjects only) 
X 
Serum pregnancy testf  
X 
Safety labsg 
X 
Spirometryh 
X 
Inclusion/exclusion criteria review 
X 
AEs and SAEs 
Continuous from signing of informed consent 
form (ICF) and assent (where applicable) 
through Safety Follow-up Contact 
AE: adverse event; CFTR: cystic fibrosis transmembrane conductance regulator;; FSH: follicle-stimulating hormone; ICF: 
informed consent form; SAE: serious adverse event  
  a  
Only if the CFTR genotype is not documented in the subject’s medical record. 
b  
An ophthalmologic examination is required for subjects <18 years who did not have an ophthalmologic examination prior to 
starting Orkambi if they have not have one within 6 months before the Screening Period. Subjects who have documentation 
of bilateral lens removal do not need an ophthalmologic examination (Section 11.4.7). 
c  
All medications taken within 28 days before the Screening Period through the end of the study will be recorded.  
d  
Vital signs (pulse rate, blood pressure, and respiration rate) and pulse oximetry will be collected after the subject has been at 
rest in the seated or supine position for at least 5 minutes. 
e  
FSH will be measured for any potentially postmenopausal female with at least 12 months of continuous spontaneous 
amenorrhea.  
f  
Any female subject who does not meet the criteria for non-childbearing potential is considered to be of childbearing 
potential and must have a serum pregnancy test. (Section 11.4.4.1) 
g  
Includes serum chemistry, hematology, coagulation, and urinalysis. 
h  
Spirometry may be performed pre- or post-bronchodilator (Section 11.3.1). Screening spirometry evaluation may be 
repeated, as specified in Section 9.1.1.1. 


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Table 3-2 
Study VX16-661-114: Treatment Period, ETT, and Safety Follow-up Contact 
Assessments 
Event/Assessmenta 
Day 1 
Day 3 
Telephone 
Contactb 
Day 15 
(± 3 
Days) 
Day 28 
(± 5 
Days) 
Day 56 
(± 5 
Days) 
Early 
Termination 
of 
Treatmentc 
Safety 
Follow-up 
Contact 
28 (± 7) Days 
After Last 
Dose of 
Study Drugd 
Inclusion and exclusion 
criteria review 
X 
 
X 
X 
X 
 
 
Randomizatione 
X 
 
 
 
 
 
 
Clinic visit 
X 
 
X 
X 
X 
X 
 
CFQ-Rf 
X 
 
X 
X 
X 
X 
 
Spirometryg 
X 
 
X 
X 
X 
X 
 
Height (<18 years old only) 
X 
 
X 
X 
X 
X 
 
Vital signsh  
X 
 
X 
X 
X 
X 
 
Pulse oximetryh 
X 
 
X 
X 
X 
X 
 
Physical examinationi 
X 
 
 
 
 
X 
 
Pregnancy test  
urine 
 
urine 
urine 
serum 
serum 
 
Safety labsj 
X 
 
X 
 
X 
X 
 
Snack or meal at sitek 
X 
 
X 
X 
X 
 
 
Study drug dosingl 
X 
 
X 
X 
X 
 
 
Study drug count 
X 
 
X 
X 
X 
X  
 
Concomitant medications  
X 
 
X 
X 
X 
X 
X 
Concomitant treatment and 
procedures review 
X 
 
X 
X 
X 
X 
X 
AEs and SAEs 
Continuous from signing of the ICF and assent (where applicable) through the 
Safety Follow-up Contactm 
 a 
All assessments will be performed before dosing unless noted otherwise 
b 
On Day 3, there is a telephone contact to collect AEs. 
c 
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the 
decision to terminate study treatment. Subjects who prematurely discontinue study drug treatment will also be required to 
complete the Safety Follow-up Contact, approximately 28 (± 7) days after their last dose of study drug. If the ETT Visit 
occurs 3 weeks or later following the last dose of study drug, then the ETT Visit will replace the Safety Follow-up Contact, 
and a separate Safety Follow-up Contact will not be required. See Section 9.1.4. 
d 
Telephone contact may be acceptable. A clinic visit may be required at the discretion of the investigator (Section 9.1.3).  
e 
Randomization must occur after all inclusion and exclusion criteria are met and before the first dose of study drug. 
Randomization will be done through IWRS. Randomization may occur on Day -1. 
f 
The CFQ-R must be completed as the first assessment at each visit. 
g 
Predose spirometry must be performed before dosing and should be performed prebronchodilator at all visits. Postdose 
spirometry will be performed at 2 hours (± 30 minutes) and 4 hours (± 30 minutes) after dosing on Day 1 only. 
h 
Vital signs (pulse rate, blood pressure, and respiration rate) and pulse oximetry will be collected after the subject has been at 
rest in the seated or supine position for at least 5 minutes. Vital signs and pulse oximetry will be collected predose at all 
visits.  
i 
In addition to the complete PEs indicated, symptom-targeted PEs may occur at any time during the study if triggered by AEs 
or if deemed necessary by the investigator. 
j  
Includes serum chemistry, hematology, coagulation and urinalysis. 
k 
Fat-containing food such as a "standard CF" high-fat, high-calorie meal or snack will be provided at the site to subjects after 
all predose assessments have occurred. 
l 
On days of scheduled visits, the morning dose of study drug will be administered at the site after predose assessments have 
been completed.  


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 m 
For enrolled subjects who do not have a Safety Follow-up Contact, AEs and SAEs will be collected through the earliest of 
either 28 days after the last dose of study drug, or the ETT Visit (if that visit is 3 weeks or later following the last dose of 
study drug; see Section 9.1.4).  


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 7 
4 
Table of Contents ................................................................................................................. 10 
List of Tables............................................................................................................................ 13 
List of Figures .......................................................................................................................... 13 
List of Abbreviations................................................................................................................ 14 
5 
Introduction.......................................................................................................................... 16 
6 
Study Objectives .................................................................................................................. 17 
6.1 
Primary Objective(s) ...................................................................................................... 17 
6.2 
Secondary Objective(s) .................................................................................................. 17 
7 
Study Endpoints ................................................................................................................... 17 
7.1 
Primary Endpoint ............................................................................................................ 17 
7.2 
Key Secondary Endpoint ................................................................................................ 17 
7.3 
Secondary Endpoints ...................................................................................................... 17 
8 
Study Population .................................................................................................................. 18 
8.1 
Inclusion Criteria ............................................................................................................ 18 
8.2 
Exclusion Criteria ........................................................................................................... 19 
9 
Study Implementation ......................................................................................................... 21 
9.1 
Study Design .................................................................................................................. 21 
 
Screening ................................................................................................................ 21 
9.1.1
9.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 21 
9.1.1.2 
Rescreening ...................................................................................................... 22 
9.1.1.3 
Extension of Screening Period Window .......................................................... 22 
 
Treatment Period .................................................................................................... 22 
9.1.2
 
Safety Follow-up Contact ....................................................................................... 22 
9.1.3
 
Early Termination of Treatment ............................................................................. 23 
9.1.4
 
Independent Data Monitoring Committee .............................................................. 23 
9.1.5
9.2 
Rationale for Study Design and Study Drug Regimens ................................................. 23 
 
Study Design........................................................................................................... 23 
9.2.1
 
Study Drug Dose .................................................................................................... 24 
9.2.2
 
Rationale for Study Assessments ........................................................................... 24 
9.2.3
9.3 
Study Restrictions ........................................................................................................... 24 
9.4 
Prior and Concomitant Medications ............................................................................... 25 
9.5 
Administration ................................................................................................................ 26 
9.6 
Dose Modification for Toxicity ...................................................................................... 27 
9.7 
Study Drug interruption .................................................................................................. 27 
9.8 
Missed Doses .................................................................................................................. 27 
9.9 
Removal of Subjects ....................................................................................................... 27 
9.10 Replacement of Subjects ................................................................................................ 28 
10 Study Drug Information and Management ....................................................................... 28 
10.1 Preparation and Dispensing ............................................................................................ 28 
10.2 Method of Assigning Subjects to Treatment Groups ..................................................... 28 
10.3 Packaging and Labeling ................................................................................................. 29 


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10.4 Study Drug Supply, Storage, and Handling ................................................................... 29 
10.5 Drug Accountability ....................................................................................................... 29 
10.6 Disposal, Return, or Retention of Unused Drug ............................................................. 30 
10.7 Compliance ..................................................................................................................... 30 
10.8 Blinding and Unblinding ................................................................................................ 30 
 
Blinding .................................................................................................................. 30 
10.8.1
 
Unblinding .............................................................................................................. 31 
10.8.2
11 Assessments .......................................................................................................................... 32 
11.1 Timing of Assessments ................................................................................................... 32 
 
Informed Consent/Assent ....................................................................................... 32 
11.1.1
 
Assigning Subject Number ..................................................................................... 32 
11.1.2
11.2 Subject and Disease Characteristics ............................................................................... 32 
11.3 Efficacy ........................................................................................................................... 32 
 
Spirometry .............................................................................................................. 32 
11.3.1
 
Cystic Fibrosis Questionnaire-Revised .................................................................. 33 
11.3.2
11.4 Safety .............................................................................................................................. 34 
 
Adverse Events ....................................................................................................... 34 
11.4.1
 
Clinical Laboratory Assessments ........................................................................... 34 
11.4.2
 
Physical Examinations and Vital Signs .................................................................. 36 
11.4.3
 
Contraception and Pregnancy ................................................................................. 36 
11.4.4
11.4.4.1 Contraception ................................................................................................... 36 
11.4.4.2 Pregnancy ......................................................................................................... 37 
 
Pulse Oximetry ....................................................................................................... 38 
11.4.5
 
Liver Function Test Parameters .............................................................................. 38 
11.4.6
 
Ophthalmologic Examination ................................................................................. 39 
11.4.7
 
Spirometry .............................................................................................................. 39 
11.4.8
12 Statistical and Analytical Plans .......................................................................................... 39 
12.1 Sample Size Consideration ............................................................................................. 39 
12.2 Analysis Sets .................................................................................................................. 40 
12.3 Statistical Analysis ......................................................................................................... 40 
 
General Considerations ........................................................................................... 40 
12.3.1
 
Background Characteristics .................................................................................... 41 
12.3.2
12.3.2.1 Subject Disposition .......................................................................................... 41 
12.3.2.2 Demographics, Medical History, and Baseline Characteristics ....................... 41 
12.3.2.3 Prior and Concomitant Medications................................................................. 42 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 42 
 
Safety Analysis ....................................................................................................... 42 
12.3.3
12.3.3.1 Adverse Events................................................................................................. 43 
12.3.3.2 Clinical Laboratory Assessments ..................................................................... 43 
12.3.3.3 Vital Signs ........................................................................................................ 43 
12.3.3.4 Physical Examination ....................................................................................... 44 
12.3.3.5 Pulse Oximetry ................................................................................................. 44 
12.3.3.6 Postdose Spirometry ........................................................................................ 44 
 
Efficacy Analysis .................................................................................................... 44 
12.3.4
12.3.4.1 Analysis of Key Efficacy Variables ................................................................. 44 
12.3.4.2 Analysis of Secondary Efficacy Variables ....................................................... 45 


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Tolerability Analysis .............................................................................................. 45 
12.3.5
12.3.5.2 IDMC Analysis ................................................................................................ 45 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 46 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 46 
 
Adverse Events ....................................................................................................... 46 
13.1.1
13.1.1.1 Definition of an Adverse Event........................................................................ 46 
13.1.1.2 Clinically Significant Assessments .................................................................. 46 
13.1.1.3 Documentation of Adverse Events................................................................... 46 
13.1.1.4 Adverse Event Severity .................................................................................... 47 
13.1.1.5 Adverse Event Causality .................................................................................. 47 
13.1.1.6 Study Drug Action Taken ................................................................................ 48 
13.1.1.7 Adverse Event Outcome .................................................................................. 48 
13.1.1.8 Treatment Given............................................................................................... 49 
 
Serious Adverse Events .......................................................................................... 49 
13.1.2
13.1.2.1 Definition of a Serious Adverse Event............................................................. 49 
13.1.2.2 Documentation of Serious Adverse Events...................................................... 49 
13.1.2.3 Reporting Serious Adverse Events................................................................... 50 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 50 
13.2 Administrative Requirements ......................................................................................... 50 
 
Ethical Considerations ............................................................................................ 50 
13.2.1
 
Subject Information and Informed Consent ........................................................... 51 
13.2.2
 
Investigator Compliance ......................................................................................... 51 
13.2.3
 
Access to Records ................................................................................................... 51 
13.2.4
 
Subject Privacy ....................................................................................................... 51 
13.2.5
 
Record Retention .................................................................................................... 51 
13.2.6
 
Study Termination .................................................................................................. 52 
13.2.7
13.3 Data Quality Assurance .................................................................................................. 52 
13.4 Monitoring ...................................................................................................................... 52 
13.5 Electronic Data Capture ................................................................................................. 53 
13.6 Publications and Clinical Study Report .......................................................................... 53 
 
 
 
Clinical Study Report ............................................................................................. 53 
13.6.2
14 Reference .............................................................................................................................. 54 
15 Protocol Signature Pages .................................................................................................... 55 
15.1 Sponsor Signature Page .................................................................................................. 55 
15.2 Investigator Signature Page ............................................................................................ 56 
 


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List of Tables 
Table 3-1 
Study VX16-661-114: Screening ............................................................................ 7 
Table 3-2 
Study VX16-661-114: Treatment Period, ETT, and Safety Follow-up Contact 
Assessments ............................................................................................................ 8 
Table 9-1 
Study Restrictions ................................................................................................. 25 
Table 9-2 
Study Drug Administration - Treatment Period.................................................... 26 
Table 10-1 
Identity of Study Drugs, Dosage, and Storage ...................................................... 29 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 35 
Table 11-2 
Acceptable Methods of Contraception.................................................................. 37 
Table 13-1 
Grading of AE Severity ........................................................................................ 47 
Table 13-2 
Classifications for AE Causality ........................................................................... 48 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 48 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 48 
List of Figures 
Figure 9-1 
Study VX16-661-114 Design ............................................................................... 21 
 


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List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
ALT 
alanine transferase 
AST 
aspartate transaminase 
ATS 
American Thoracic Society 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator gene  
CI 
confidence interval 
Cl- 
chloride ion 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
EDC 
electronic data capture 
ERS 
European Respiratory Society 
ETT 
early termination of treatment 
F508del 
CFTR protein lacking the phenylalanine normally found at position 508 of the wild-type 
protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GPS 
Global Patient Safety 
 
 
ICF 
informed consent form 
ICH 
International Council on Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IRB 
institutional review board 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LFT 
liver function test 
LUM 
lumacaftor 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minutes 
MMRM 
mixed-effects model for repeated measures 
PAP 
pulmonary arterial pressure 
PE 
physical examination 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
q12h 
every 12 hours 


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Abbreviation 
Term 
qd 
daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
TEZ/IVA 
tezacaftor in combination with ivacaftor 
ULN 
upper limit of normal 
 


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5 
INTRODUCTION 
Cystic fibrosis (CF) affects more than 70,000 children and adults worldwide1 and is the most 
common fatal genetic disease in persons of European descent.2 CF is caused by a defect in the 
gene encoding the CF transmembrane conductance regulator (CFTR), an ion channel that 
regulates the flow of chloride and other ions in epithelia of various tissues, including lungs, 
pancreas and other gastrointestinal organs, and sweat glands. Decreased CFTR activity in people 
with CF results in multisystem pathology3, beginning at birth. Despite progress in the treatment 
of CF with antibiotics and mucolytics, the median predicted survival age for a person with CF is 
approximately 40 years.4 More effective treatments are needed for CF. 
To address this medical need, Vertex Pharmaceuticals Incorporated is developing treatment 
regimens that include CFTR modulators to target the underlying cause of CF: the defective 
CFTR protein. Two types of CFTR modulators have been developed: potentiators, which 
increase the channel gating activity of the CFTR protein, and correctors, which increase the 
quantity of CFTR at the cell surface. Potentiators can increase the activity of CFTR protein 
delivered to the cell surface by correctors: therefore, CFTR potentiators and correctors are 
complementary therapeutic approaches. 
Ivacaftor (IVA; Kalydeco®), the first CFTR modulator developed by Vertex, is an orally 
administered CFTR potentiator that increases the channel-open probability of CFTR protein to 
enhance chloride transport. Globally, Kalydeco is indicated for the treatment of CF in patients as 
young as 2 years who have the G551D and certain other gating mutations as well as the R117H 
mutation in the CFTR gene depending on the country. 5 
Lumacaftor (LUM), the second CFTR modulator developed by Vertex, is a CFTR-specific 
corrector that increases the delivery of CFTR protein at the cell surface by improving the 
processing and trafficking of the CFTR protein.  
Orkambi® is a fixed-dose combination pill of LUM/IVA, which increases the quantity and 
function of the CFTR protein at the cell surface. It is indicated for the treatment of CF in patients 
as young as 6 years and older who are homozygous for F508del. 
In clinical trials, LUM/IVA therapy significantly improved lung function and other measures of 
disease and reduced the rate of pulmonary exacerbations in patients with CF who were 
homozygous for F508del. However, in Phase 1 studies with healthy subjects, there was a decline 
in percent predicted forced expiratory volume in 1 second (ppFEV1) observed within 4 hours of 
dosing LUM/IVA. Postdose spirometry was not done in Phase 3 studies with LUM/IVA, but the 
incidence of respiratory symptoms (i.e., chest discomfort, dyspnea, and respiration abnormal) 
was 22.0% in subjects who received the commercialized dose of the LUM/IVA and 13.8% in 
subjects who received placebo. Post-marketing data for Orkambi suggests that patients have 
discontinued treatment due to respiratory events. Therefore, there is an unmet medical need for 
treatment of patients homozygous for F508del and who have discontinued treatment with 
Orkambi due to respiratory symptoms considered related to treatment.  
Tezacaftor (TEZ) is a CFTR corrector being developed by Vertex that is being evaluated in 
several ongoing Phase 3 studies. Phase 2 data indicate that TEZ in combination with IVA 
(TEZ/IVA) showed statistically significant improvements in lung function (ppFEV1) in subjects 
with CF who have at least 1 copy of F508del after 28 days of treatment. In 


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Studies VX11-661-101 (Study 101) and VX15-661-103, no trends in respiratory events were 
observed for subjects who received TEZ (alone or in combination with IVA). In addition, the 
independent data monitoring committee (IDMC) for the Phase 3 program has not identified any 
meaningful trends in postdose spirometry or adverse event (AE) data to suggest that TEZ/IVA is 
associated with respiratory symptoms. Because there is no association of respiratory events with 
TEZ/IVA, it is reasonable to hypothesize that TEZ/IVA may be a treatment for patients who 
have discontinued treatment with Orkambi due to respiratory symptoms considered related to 
treatment.  
6 
STUDY OBJECTIVES 
6.1 
Primary Objective(s) 
 To evaluate the respiratory safety of TEZ/IVA in subjects with CF homozygous for F508del 
and who discontinued treatment with Orkambi due to respiratory symptoms considered 
related to treatment. 
6.2 
Secondary Objective(s) 
 To evaluate the efficacy of TEZ/IVA in subjects with CF homozygous for the F508del-CFTR 
mutation and who discontinued treatment with Orkambi due to respiratory symptoms 
considered related to treatment. 
 To evaluate patient-reported outcomes after treatment with TEZ/IVA in subjects with CF 
homozygous for the F508del-CFTR mutation and who discontinued treatment with Orkambi 
due to respiratory symptoms considered related to treatment. 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
 Incidence of respiratory AEs  
7.2 
Key Secondary Endpoint 
 Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline to the average of the Day 28 and Day 56 measurements. 
7.3 
Secondary Endpoints 
 Relative change in ppFEV1 from baseline to the average of the Day 28 and Day 56 
measurements. 
 Absolute change in Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain score 
from baseline to the average of the Day 28 and Day 56 measurements. 
 Tolerability based on discontinuation of TEZ/IVA through Day 56 
 Safety assessments based on AEs, clinical laboratory values (hematology, serum chemistry, 
coagulation studies, and urinalysis), vital signs, pulse oximetry, and postdose spirometry 


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8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible 
for the study. 
8.1 
Inclusion Criteria 
1. Subject (or subject’s legally appointed and authorized representative) will sign and date an 
informed consent form (ICF) and, where 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. Males or females, aged 12 years or older on the date of informed consent or, where 
appropriate, date of assent. 
4. Prior discontinuation of Orkambi, with at least 1 respiratory sign or symptom considered 
related to therapy, including but not limited to the following:  
 Chest discomfort 
 Dyspnea (shortness of breath) 
 Respiration abnormal (chest tightness) 
 Asthma 
 Bronchial hyperreactivity 
 Bronchospasm  
 Wheezing 
 Asymptomatic reduction in relative change in ppFEV1 of >12% within 2 weeks after 
Orkambi initiation 
Discontinuation from Orkambi should primarily be due to a respiratory event. However, 
concomitant non-respiratory events will not exclude subjects from participation. Documentation 
of specific qualifying signs or symptoms is not required. Investigator attestation will be accepted 
if information is not present in source materials.  
5. Resolution or stabilization of qualifying event(s) >28 days prior to Screening. 
6. Discontinuation of Orkambi therapy must have occurred within approximately 12 weeks from 
the first dose of Orkambi. In the event that the subject reinitiated Orkambi, discontinuation of 
Orkambi therapy must have occurred within approximately 12 weeks from the time of the most 
recent initiation. Investigator attestation will be accepted if information is not present in source 
materials. 


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7. Homozygous for F508del as documented in the subject’s medical record. If genotype 
documentation is not available in the medical record, genotyping will be performed during 
screening. If the screening genotype result is not received by the end of the Screening Period and 
all other eligibility criteria have been met, the subject may be randomized. Note: Subjects who 
have been randomized and whose screening genotype does not confirm study eligibility must be 
discontinued from the study as described in Section 9.9. 
8. FEV1 ≥25% and ≤90% of predicted normal for age, sex, and height (equations of Wang et al. 
or Hankinson et al. 12, 13) at Screening Visit (Section 11.3.1). Spirometry measurements must 
meet American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria for 
acceptability and repeatability (Section 11.3.1). 
9. Stable CF disease as judged by the investigator. 
10. Willing to remain on a stable CF medication regimen from screening through the Safety 
Follow-up Contact. 
8.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible for this study: 
1. History of any comorbidity that, in the opinion of the investigator, might confound the results 
of the study or pose an additional risk in administering study drug to the subject 
Examples of such comorbidities may include, but are not limited to: 
 Respiratory: 
o Massive hemoptysis within the last 12 months 
o Any of the following within the past 12 months and not associated with an acute, resolved 
event: 
 Six-minute walk test distance <400 m 
 Resting arterial blood gas on room air showing PaCO2 >50 mm Hg or PaO2 
<55 mm Hg 
 Systolic pulmonary arterial pressure (PAP) >35 mm Hg on echocardiography or a 
mean PAP >25 mm Hg measured by right heart catheterization, in the absence of a 
hypoxemic exacerbation or with an alternate etiology to explain the findings 
 Non-respiratory: history of cirrhosis with portal hypertension, history of and/or risk factors for 
ventricular arrhythmia (e.g., long QT syndrome, hypokalemia, heart failure, left ventricular 
hypertrophy, bradycardia, myocardial infarction, cardiomyopathy, morbid obesity, acute 
neurologic events [subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular 
accident, and intracranial trauma], autonomic neuropathy, and significant anemia) 
2. Recent rapid or progressive deterioration in respiratory status 
3. Receiving continuous oxygen at >2 L/min or on face-mask ventilation 


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4. Any of the following abnormal laboratory values at Screening: 
 Abnormal liver function defined as any 2 or more of the following: ≥3 × upper limit of 
normal (ULN) aspartate transferase (AST), ≥3 × ULN alanine transferase (ALT), ≥3 × ULN 
gamma-glutamyl transpeptidase, ≥3 × ULN alkaline phosphatase (ALP), or ≥2 × ULN total 
bilirubin.  
 Abnormal liver function defined as any increase of ≥5 × ULN AST or ALT. 
 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) for subjects ≥18 
years of age and ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt equation) for 
subjects aged 12 to 17 years (inclusive). 
5. Child-Pugh Class B or C hepatic impairment 
6. An acute upper or lower respiratory infection, pulmonary exacerbation, or change in therapy 
(including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study 
drug) 
7. Documentation of colonization with organisms associated with a more rapid decline in 
pulmonary status (e.g. Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium 
abscessus) 
8. History of lung transplantation since most recent initiation of Orkambi 
9. History of alcohol or drug abuse in the past year as deemed by the investigator, including but 
not limited to cannabis, cocaine, and opiates 
10. Participation in an investigational drug study or use of a CFTR modulator (including 
Orkambi) within 28 days or 5 terminal half-lives before screening of the previous investigational 
study drug or CFTR modulator, whichever is longer 
 Ongoing participation in a noninterventional study (including observational studies and 
studies requiring assessments without administration of study drug) is permitted. 
11. Use of restricted medications or foods within the specified window before the first dose of 
study drug, or an anticipated need or use of restricted medication or foods after the first dose of 
study drug, as defined in Table 9-1 
12. Pregnant or nursing females: Females of child-bearing potential must have a negative 
pregnancy test at Screening and Day 1 
13. The subject or a close relative of the subject is the investigator or a sub-investigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the 
study. An adult (aged 18 years or older) who is a relative of a study staff member may be 
randomized in the study provided that  
 the adult lives independently of and does not reside with the study staff member, or 
 the adult participates in the study at a site other than the site at which the family member is 
employed. 


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9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
Study VX16-661-114 (Study 114) is a Phase 3b, randomized, double-blind, placebo-controlled, 
parallel group, multicenter study in subjects aged 12 years and older with CF who are 
homozygous for F508del and who discontinued treatment with Orkambi due to respiratory 
symptoms considered related to treatment. This study is designed to evaluate the safety and 
efficacy of TEZ/IVA. 
This study includes a Screening Period (up to 28 days), Treatment Period (approximately 
56 days), and Safety Follow-up Period (approximately 28 days). Approximately 90 subjects will 
be stratified by age at the Screening Visit (<18 versus ≥18 years of age), sex (male versus 
female), and ppFEV1 (determined during the Screening Visit; <40% versus ≥40% predicted) and 
then randomized 1:1 between the 2 study arms. 
Subjects who complete the Day 56 Visit will be offered the opportunity to receive TEZ/IVA 
through the Expanded Access Program if they meet eligibility requirements for that program. 
Figure 9-1 
Study VX16-661-114 Design 
 
 
 
Screening 
9.1.1
Screening Visit assessments are listed in Table 3-1. 
Screening will occur within 28 days before administration of first dose of study drug. The 
investigator (or an appropriate authorized designee at the study site) will obtain informed 
consent/assent from each subject.  
9.1.1.1 
Repetition of Screening Assessment(s) 
Repetition of individual screening assessment(s) that did not meet eligibility criteria is not 
permitted with the following exceptions:  
 If there is clear evidence of a laboratory error (e.g., hemolyzed sample) or equipment 
malfunction, collection of a repeat sample for the appropriate laboratory test or assessment 
may be permitted with the approval of the medical monitor. 
Note: Clinical visits are on Days -28, 1, 15, 28, and 56. A telephone contact on Day 3 collects AEs. The Safety Follow-up 
may be a clinic visit or telephone call. 


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 Exclusionary liver function test (LFT) levels, which may be retested within 14 days of the 
original screening date 
If screening spirometry measurements fail to meet acceptability or repeatability criteria as 
specified by ATS/ERS guidelines6, repeat spirometry evaluation may be performed once. 
If repeat values of the individual assessment(s) are within the eligibility criteria and completed 
within the screening window, then the subject is eligible for the study. 
9.1.1.2 
Rescreening 
Subjects may only be rescreened with the approval of the medical monitor. If a subject is 
rescreened, all screening assessments will be repeated except for CFTR genotyping, 
follicle-stimulating hormone (FSH) level (if serum FSH level was ≥40 mIU/mL during prior 
screening), and ophthalmologic examination. If a subject is rescreened, the screening window 
will begin after the first rescreening assessment has been initiated. 
9.1.1.3 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 4 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 11.4.7) 
 Repetition of spirometry assessment if results are of poor quality 
 
Treatment Period 
9.1.2
The Treatment Period will last approximately 56 days. Subjects will be randomized to 1 of 
2 treatment arms: TEZ/IVA or placebo. The dosing regimen for each treatment arm is shown in 
Figure 9-1 and is as follows: 
 TEZ/IVA: TEZ 100-mg/ IVA 150-mg fixed-dose combination (light yellow) film-coated 
tablet for oral administration (morning dose); IVA 150-mg (light blue) film-coated tablet for 
oral administration (evening dose) 
 Placebo: 0 mg film-coated matching placebo tablets for oral administration (1 light yellow 
for the morning dose and 1 light blue for the evening dose) 
The first dose of study drug will be administered after randomization on Day 1. Dosing details 
are given in Section 9.5. 
Study visits during the Treatment Period will occur as shown in Table 3-2. Subjects will be 
outpatients during the Treatment Period unless hospitalized for illness. All visits should occur 
within the windows specified. 
 
Safety Follow-up Contact 
9.1.3
A Safety Follow-up Contact will be performed for the purpose of collecting information on AEs 
28 days (±7 days) after the last dose of study drug. The assessments performed at the Safety 
Follow-up Contact are listed in Table 3-2. The Safety Follow-up Contact may be a telephone 


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interview; however, if deemed necessary by the investigator, a Safety Follow-up Visit may be 
required with necessary assessments to be determined by the investigator. 
Subjects who prematurely discontinue treatment may not be required to have a Safety Follow-up 
Contact; refer to Section 9.1.4 for details. 
 
Early Termination of Treatment 
9.1.4
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. These subjects will also be required to complete a Safety Follow-up Contact 28 days 
(± 7 days) after their last dose of study drug.  
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Contact, and a separate Safety Follow-up Contact will not be 
required.  
If a subject withdraws consent for the study, no further visits will be required (including an ETT 
or Safety Follow-up Contact), no further evaluations will be performed, and no additional data 
will be collected. Vertex may retain and continue to use any data collected before such 
withdrawal of consent. 
 
Independent Data Monitoring Committee 
9.1.5
An IDMC will be formed for this study. The safety and tolerability data will be reviewed by an 
IDMC to ensure the safety of the subjects in the study. Procedural details of the IDMC's structure 
and function, frequency of meetings, and data planned for review will be included in the IDMC 
charter. The IDMC charter will be finalized before the first subject is screened.  
9.2 
Rationale for Study Design and Study Drug Regimens 
 
Study Design 
9.2.1
A randomized, double-blind study design will avoid observer bias and reduce symptoms or 
outcomes arising from the subjects' knowledge of treatment. 
Subjects will be randomized to receive TEZ in combination with IVA, or a matched placebo 
regimen. All subjects enrolled in the study will continue their normal, stable treatment for CF 
symptoms throughout the study.  
Orkambi is the only therapy approved for subjects homozygous for the F508del-CFTR mutation 
that targets the underlying cause of CF. TEZ, an experimental CFTR corrector, in combination 
with IVA, is currently being evaluated in several Phase 3 studies in subjects who are both 
homozygous for F508del and heterozygous for F508del with other CFTR mutations. Scheduled 
IDMC reviews of each of the TEZ/IVA Phase 3 studies are completed and did not reveal any 
safety signals. Since subjects entering this study are not taking corrector/potentiator therapy, the 
use of placebo in this study is deemed ethical and necessary to adequately assess the benefit of 
treatment with TEZ in combination with IVA.  
Study 114 is designed to compare active treatment with TEZ 100 mg daily (qd)/IVA 150 mg 
every 12 hours (q12h) with a matched placebo treatment for 8 weeks. The 8-week duration was 
selected to allow adequate exposure to TEZ/IVA to assess both the safety and efficacy of the 
treatment. This is appropriate because patients who have respiratory AEs with Orkambi typically 
do so within the first week of exposure, and a significant response in ppFEV1 is expected after 


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14 to 28 days of treatment with TEZ/IVA. In addition, the 8-week duration was selected to allow 
a robust assessment of the durability of response that will be less affected by short-term 
variability in ppFEV1, and to facilitate the demonstration of significant changes in secondary 
endpoints, including CFQ-R.  
 
Study Drug Dose 
9.2.2
The dose regimen of TEZ chosen for continued development in Phase 3 was evaluated in Study 
101, a Phase 2 study in 2 CF populations: one that was homozygous for F508del and one that 
was heterozygous for F508del and G551D. The dose regimen of TEZ 100 mg qd in combination 
with IVA 150 mg q12h provided clinically meaningful and statistically significant improvements 
in ppFEV1 in both populations. Pivotal Phase 3 studies are ongoing; therefore, results are not 
known. 
 
Rationale for Study Assessments 
9.2.3
Safety assessments are standard parameters for clinical studies in drug development. The 
efficacy assessments are widely accepted and generally recognized as reliable, accurate, and 
relevant to the study of patients with CF. 
Spirometry: Since lung disease is the major cause of morbidity and mortality for patients with 
CF, CF lung disease is the desired primary target of TEZ/IVA cotherapy. Spirometry is the most 
widely implemented standardized assessment to evaluate lung function. Predose and postdose 
spirometry assessments must be performed in all subjects according to the Schedule of 
Assessments (Table 3-1 and Table 3-2).  
CFQ-R: The CFQ-R is a frequently used CF-specific instrument that measures the health-related 
quality of life of patients with CF.7-9As both IVA alone and TEZ/IVA are systemic therapies, 
they have the potential to improve not only respiratory symptoms but other extrapulmonary 
manifestations of CF as well. These improvements can be captured by the non-respiratory 
symptoms domains of the CFQ-R. The adolescent/adult version, the parent/caregiver version, 
and the child version measure quality-of-life domains, including respiratory symptoms, digestive 
symptoms, emotion, and health perception. Linguistically validated versions of the CFQ-R10, 11 
are available, thereby allowing consistent interpretation of the results in this global study. The 
CFQ-R will be used to capture and evaluate the impact of TEZ/IVA on patient reports of 
respiratory symptoms and other aspects of health-related quality of life. 
9.3 
Study Restrictions 
Prohibited medications and certain foods are not allowed in this study (Screening Period through 
the Safety Follow-up Contact) (Table 9-1). Both TEZ and IVA are metabolized predominantly 
via the hepatic enzymatic pathway using CYP3A4. Therefore, the use of known moderate and 
strong inducers and inhibitors of CYP3A, which have the potential to significantly alter the 
exposure of TEZ and IVA, will be restricted in this study. 
A non-exhaustive list of study prohibitions and cautions for food and medication will be 
provided in the Study Reference Manual. 


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Table 9-1 
Study Restrictions 
Restricted Medication/Food 
Study Period 
Screening Period 
Treatment Period 
Certain fruits and fruit juices 
(Grapefruit, grapefruit juice, 
Seville oranges, marmalade)  
None allowed within 14 days before 
the first dose of study drug 
None allowed through the Safety 
Follow-up Contact 
Moderate and strong CYP3A 
inducers 
None allowed within 14 days before 
the first dose of study drug 
None allowed through the Safety 
Follow-up Contact 
Moderate and strong CYP3A 
inhibitors (except ciprofloxacin) 
None allowed within 14 days before 
the first dose of study drug 
None allowed through the Safety 
Follow-up Contact 
Commercially available CFTR 
modulators (e.g., Kalydeco, 
Orkambi, or others)  
None allowed within 28 days or 
5 terminal half-lives before screening, 
whichever is longer 
None allowed through the Safety 
Follow-up Contact 
CFTR: cystic fibrosis conductance regulator; CYP: cytochrome P450 
Note: The use of restricted medication by subjects with medical needs will be addressed on a case-by-case basis 
with the medical monitor. 
9.4 
Prior and Concomitant Medications 
Information regarding all prior and concomitant medications, including the subject's CF 
medications, other medications, and herbal and naturopathic remedies administered from 28 days 
before the Screening Visit through the Safety Follow-up Contact, if applicable, will be recorded 
in each subject's source documents. For subjects who are screened but are not subsequently 
randomized in the study, details of prior medication will only be documented in the subjects' 
source documents. 
 Subjects must remain on a stable medication regimen for their CF from screening through the 
Safety Follow-up Contact; this includes supplements and inhaled antibiotics. A stable 
medication regimen is defined as the current medication regimen for CF that subjects have 
been following for at least 28 days before Day 1. Any potential exceptions to this must be 
discussed and approved by the Vertex medical monitor. Guidelines for a stable inhaled 
antibiotic regimen for CF are as follows: 
• 
Subjects who are taking daily inhaled tobramycin or other chronically inhaled 
antibiotics should remain on that drug at the current regimen throughout the study. 
• 
Subjects who are on inhaled cycling antibiotics should continue on their current 
schedule. The timing of the first dose of study drug should be synchronized as closely 
as possible to the first day of inhaled cycling antibiotics. 
• 
Subjects who alternate 2 different antibiotics monthly should remain on the same 
schedule during the study. The timing of the first dose of study drug should be 
synchronized as closely as possible to the first day of either of the inhaled antibiotics. 
 There are no restrictions on the concomitant use of corticosteroids.  
 Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments performed 
according to the guidelines provided in Section 11.3.1. 


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9.5 
Administration 
Study drug tablets will be administered orally. Subjects will swallow the study drug whole, and 
will not chew the drug before swallowing. Study drug tablets will be administered orally. 
Subjects will receive the same number of tablets each day to maintain the blind. Refer to 
Table 9-2. 
Table 9-2 
Study Drug Administration - Treatment Period 
Treatment Arm 
Time 
Drug(s) and Dose(s) Administered 
Route of Administration 
TEZ/IVA 
 
AM 
TEZ 100-mg/IVA 150-mg fixed-dose tablet 
oral 
PM 
IVA 150-mg tablet 
oral 
Placebo 
 
AM 
TEZ/IVA-matching placebo tablet 
oral 
PM 
IVA-matching placebo tablet 
oral 
AM: morning; IVA: ivacaftor; TEZ: tezacaftor; PM: evening. 
Study drug administration guidelines: 
1. Study drug should be administered within 30 minutes after starting a fat-containing meal, 
such as a standard CF high-fat, high-calorie meal or snack. It is recommended that study drug 
be administered after the start of and before the end of a meal, and that the duration of each 
meal associated with study drug intake (i.e., breakfast and dinner/snack, as applicable) should 
not exceed 30 minutes.  
2. On days with no scheduled clinic visits, study drug should be administered q12h (± 2 hours). 
For each subject, all doses (morning [TEZ/IVA] and evening [IVA], or matching placebo) of 
study drugs will be taken at approximately the same time each day. For example, if the 
morning dose is taken at 08:00 every morning, the evening dose should be taken at 20:00 
every evening (but it could be taken between 18:00 and 22:00). 
3. On days of scheduled visits, the morning dose of study drug will be administered at the site 
after predose assessments have been completed. The meal or snack will be provided by the 
site for the morning dose of study drug.  
4. If a subject's scheduled visit is to occur in the afternoon, the following guidelines must be 
used: 
 If the dose in the clinic will be within 6 hours of the subject's scheduled morning dose, 
the subject should withhold their morning dose of study drug and the morning dose will 
be administered in the clinic. 
 If the dose in the clinic will be more than 6 hours after the subject's scheduled morning 
dose, the subject should take the morning dose at home and the evening dose will be 
administered in the clinic. In this event, all assessments will be collected relative to the 
evening dose. 
5. For visits after the Day 1 Visit, subjects will be instructed to bring all used and unused 
materials associated with study drug to the site; study drug will be dispensed at each visit, as 
appropriate. 


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9.6 
Dose Modification for Toxicity 
Dosages of TEZ or IVA cannot be changed, but the investigator can interrupt or stop treatment. 
9.7 
Study Drug interruption 
If study drug dosing must be interrupted for more than 72 hours, the medical monitor must be 
notified. In these instances, study drug dosing may only resume after approval by the medical 
monitor. Specific instructions for interruption due to elevated LFT levels are provided in 
Section 11.4.6. 
It is recommended that study drug should not be interrupted during a pulmonary exacerbation 
unless, in the opinion of the investigator, it would be in the best interest of the subject.  
9.8 
Missed Doses 
If a subject misses a dose and recalls the missed dose within 6 hours, the subject should take 
his/her dose with food. If more than 6 hours have elapsed after his/her usual dosing time, the 
subject should skip that dose and resume his/her normal schedule for the following dose. For 
example, 
 if the morning dose of study drug should have been taken at approximately 08:00, and the 
subject remembers at 12:00 that he/she forgot to take his/her dose, he/she should take the 
dose with food as soon as possible. 
 if the morning dose of study drug should have been taken at approximately 08:00, and more 
than 6 hours have elapsed beyond the scheduled dosing time (i.e., the time is past 14:00), the 
subject would resume dosing with the evening dose at approximately 20:00. 
9.9 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons. If a subject 
has been withdrawn from study drug treatment, the subject should continue to be followed, 
provided the subject has not withdrawn consent. 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document the subject’s 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 an ETT and/or Safety 
Follow-up Contact, if applicable (Section 9.1.3, Section 9.1.4), and follow up with the subject 
regarding any unresolved AEs. 
If the subject withdraws consent, no further visits will be required (including an ETT or Safety 
Follow-up Contact), no further evaluations will be performed, and no additional data will be 
collected. Vertex may retain and continue to use any data collected before such withdrawal of 
consent.  


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The investigator should inquire about the reason for withdrawal of consent. 
Subjects must return all unused study drug. 
A subject will be withdrawn from study drug treatment for any of the following reasons: 
 A female subject or a female partner of a male subject has a confirmed pregnancy.  
 Treatment unblinding by the investigator. 
 Development of a life-threatening AE or a serious AE (SAE) that places him/her at 
immediate risk, and discontinuation of study drug treatment and withdrawal from the study 
are deemed necessary. 
 Following randomization, the screening CFTR genotype results does not confirm study 
eligibility. The subject will undergo ETT and/or Safety Follow-up Contact per Section 9.1.3 
and Section 9.1.4, and will then be discontinued from the study. After discontinuation of 
study drug treatment, the subject will not undergo any further assessments other than those 
performed at the ETT and/or Safety Follow-up Contact. 
A subject may be withdrawn from study drug treatment after a discussion between the 
investigator and the medical monitor for any of the following reasons: 
 Development of a medical condition that requires prolonged concomitant therapy with a 
prohibited medication or prolonged interruption of the study drug. 
 Noncompliance with study requirements. 
 An increase in liver function studies according to evaluations and management described in 
Section 11.4.6. 
 Development of a cataract or lens opacity. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study drug treatment period(s) will not be 
replaced. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
10.2 
Method of Assigning Subjects to Treatment Groups 
An interactive web response system (IWRS) will be used to assign subjects to treatment. 
Randomization may occur on Day -1. Detailed instructions for randomization will be provided 
separately.  


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10.3 
Packaging and Labeling 
Study drug tablets will be supplied in blister cards by Vertex. Study drug cards will be provided 
and replaced via the IWRS. A detailed study drug dispensation plan will be provided in the 
Pharmacy Manual. 
Study drug labeling will be in compliance with applicable local and national regulations. 
Additional details regarding packaging, labeling, and dispensing for TEZ/IVA and IVA will be 
included in the Pharmacy Manual. 
10.4 
Study Drug Supply, Storage, and Handling 
TEZ 100 mg/IVA 150 mg and matching placebo will be supplied as light yellow film-coated 
tablets of similar size and appearance containing TEZ 100 mg/IVA 150 mg and 
TEZ 0 mg/IVA0 mg, respectively.  
IVA (150 mg) and matching placebo will be supplied as light blue film-coated tablets of similar 
size and appearance containing IVA 150 mg and IVA 0 mg, respectively. 
Blister cards must be stored at room temperature according to Table 10-1 and to the instructions 
provided in the Pharmacy Manual. While at the clinical site, the study drug must be stored in a 
secure, temperature-monitored area of limited access and only at the location(s) listed on the 
Form FDA 1572 (or Investigator Statement). While at the clinical site, the investigator, or an 
authorized designee (e.g., a licensed pharmacist), will ensure that all investigational products are 
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 per instructions in Section 10.5. 
Instructions regarding the storage and handling of study drug after dispensation to subjects will 
be provided to sites in the Pharmacy Manual. 
Table 10-1 
Identity of Study Drugs, Dosage, and Storage 
Drug Name 
Strength/Formulation/Route 
Dosage 
Storage Condition 
TEZ/IVA fixed-dose 
tablet 
100-mg/150-mg tablet; oral 
100 mg/150 mg, 
morning dose 
≤25°C (77°F) with 
excursions to 30°C 
(86°F) 
IVA 
150-mg tablet, oral 
150 mg, evening dose 
≤25°C (77°F) with 
excursions to 30°C 
(86°F) 
TEZ/IVA-matching 
placebo 
0-mg/0-mg tablet; oral 
0 mg/0 mg, 
morning dose 
≤25°C (77°F) with 
excursions to 30°C 
(86°F) 
IVA-matching placebo 
0-mg tablet, oral 
0 mg, evening dose 
≤25°C (77°F) with 
excursions to 30°C 
(86°F) 
 
10.5 
Drug Accountability 
The pharmacist or designated site staff will maintain records documenting the dates and amounts 
of study drug received, study drug dispensed to the subjects, and study drug returned by the 
subjects.  


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Subjects will be instructed to return all used, partially used, and full study drug blister cards to 
the site. These materials will be retained at the site according to instructions provided by Vertex 
or its designee until inventoried by the study monitor. The study monitor will review study drug 
records and inventory throughout the study. 
10.6 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. At the end of the study, the study monitor 
will provide instructions as to the disposition of any unused investigational product. If the study 
monitor authorizes destruction at the study site, the investigator will ensure that the materials are 
destroyed in compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Vertex. Destruction will be adequately documented. 
Procedures for destruction or return of the study drug will be detailed in the Pharmacy Manual. 
10.7 
Compliance  
To maximize treatment compliance, the investigator or designee will supervise all study drug 
dosing that occurs at the site. At each visit, site personnel will review subject compliance with 
study drug dosing and remind the subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should contact the medical monitor to discuss potential discontinuation 
of the subject from the study treatment.  
10.8 
Blinding and Unblinding 
This is a double-blind study. 
 
Blinding  
10.8.1
All study personnel will be blinded to subject treatment assignments except for the following 
individuals:  
 Any site personnel for whom this information is important to ensure the safety of the subject 
in the event of a life-threatening medical emergency 
 Any site personnel for whom this information is important to ensure the safety of the subject 
and the fetus in the event of a pregnancy 
 The unblinded site monitor and unblinded trip report reviewer 
 An unblinded pharmacist at the contract research organization (CRO) for dispensing study 
drug 
 Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy SAE 
processing and reporting regulations 
 External vendor (unblinded) statistician preparing the final (production) randomization list 
who is not part of the study team 
 Vertex IXRS Management for IWRS oversight and system administration 
 Vertex Clinical Supply Chain 


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 Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time 
Spirometry Data Blinding 
Despite treatment blinding, knowledge of the spirometry results has the potential to suggest 
whether a subject has been administered active study drug or placebo. Therefore, during the 
conduct of the study, the Vertex study team will have no access to spirometry data. The vendor 
for central reading of the spirometry data will only send the blinded spirometry files (blinded 
treatment group, with real values for screening and baseline, but with dummy values for all the 
spirometry assessment after baseline) to Vertex to be used for developing the statistical 
programs. Furthermore, subjects and their caregivers should not be informed of their study-
related spirometry results during the Treatment Period, regardless of whether the subject has 
prematurely discontinued study drug treatment. 
 
Unblinding 
10.8.2
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the medical monitor, they will use their best 
judgment, based on the nature and urgency of the clinical situation, and may proceed with 
unblinding without having successfully reached and discussed the situation with the medical 
monitor. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center (
) will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If a subject's treatment assignment has been unblinded for a medical emergency or urgent clinical 
situation, the medical monitor will be notified within 24 hours of the unblinding event. The 
reason and the date of the unblinding will be documented clearly in the subject's study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with the sponsor (Vertex), CRO, or 
any site personnel (other than the physician treating the subject). In addition, the investigator will 
consider whether the clinical event that prompted unblinding will be considered a serious 
adverse event (SAE), according to the regulatory definitions or criteria for SAEs, and if so, 
submit an SAE report to Vertex Global Patient Safety (GPS) or designee, per Section 13.1.2. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, unblind 
individual subjects at any time.  


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11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments is shown in Table 3-1 and Table 3-2. 
 
Informed Consent/Assent 
11.1.1
Each subject of age of consent (per local requirements) must sign and date a study-specific ICF 
before any study-specific procedures can be performed. Subjects not of age of consent must 
assent, if applicable per local requirements, to participate in the study, and the subject's parent or 
legal guardian must sign and date a study-specific ICF before any study-specific procedures can 
be performed. The consent forms will comply with all applicable regulations governing the 
protection of human subjects. An ICF and Assent Form, approved by Vertex and the site's 
institutional review board (IRB) or independent ethics committee (IEC), must be used. 
 
Assigning Subject Number 
11.1.2
After a subject has signed an ICF or Assent Form, if applicable, a subject number will be 
assigned. The subject will retain this number for the entire study. Detailed instructions on 
assigning subject numbers will be provided in the Study Reference Manual. If a subject is 
rescreened, the subject retains the original subject number. 
11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include demographics, medical history, height, and weight. 
Medical history will be collected from each subject during screening. The medical history shall 
include a complete review of systems, past medical and surgical histories, and any allergies. 
Based on the medical history, the subject will be assessed for any disqualifying medical 
conditions as specified in the inclusion and exclusion criteria. 
11.3 
Efficacy 
 
Spirometry 
11.3.1
Spirometry will be performed according to the ATS/ERS guidelines6 at the time points noted in 
Table 3-1 and Table 3-2 according to the additional guidelines that follow. 
Prebronchodilator 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 twice-daily, long-acting bronchodilator (e.g., salmeterol) for more than 
12 hours before the spirometry assessment; and 
 withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment 
During the Treatment Period, all spirometry assessments must be performed before dosing, 
except on Day 1, when in addition to the predose assessments, 2 postdose spirometry 
assessments will be performed 2 hours (±30 minutes) and 4 hours (±30 minutes) after dosing. If 
the Day 1 predose spirometry is performed postbronchodilator, the subject should withhold any 


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further bronchodilator use until completion of the 4-hour postdose spirometry assessment on that 
day. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilator. At all the other visits, all spirometry assessments should be performed 
prebronchodilator. 
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 is performed prebronchodilator, but on a subsequent visit the 
subject does not withhold bronchodilator, a postbronchodilator spirometry will be obtained 
for that visit only, and the visit will not be rescheduled. 
 If a subject does not withhold his/her dose of bronchodilator on Day 1, spirometry at that 
visit and at all subsequent visits (according to the schedule of assessments detailed in Table 
3-2) should be performed postbronchodilator. 
 Each spirometry assessment will be recorded in the source documents as pre- or post-
bronchodilator. 
All sites will be provided with spirometers to be used for all study assessments. Spirometry data 
will be transmitted to a centralized spirometry service for quality review. 
Subjects and their parent/caregiver should not be informed of their study-related spirometry 
results from Day 1 through Day 56, regardless of whether the subject prematurely discontinues 
treatment. 
The parameters listed below will be normalized using the standards of Wang et al (for female 
subjects aged 12 to 15 years [inclusive] and male subjects aged 12 to 17 years [inclusive]) or 
Hankinson et al (for female subjects aged 16 years and older and male subjects aged 18 years 
and older)12, 13:  
 FEV1 (L) 
 Forced vital capacity (FVC) (L) 
 FEV1/FVC (ratio) 
 Forced expiratory flow 25% to 75% (L/s) 
Subjects in whom the Wang standard is applied at the Screening Visit will have the Wang 
standard applied throughout the study, even if there is a change in age during the course of the 
study that would otherwise necessitate use of the Hankinson standard. 
 
Cystic Fibrosis Questionnaire-Revised 
11.3.2
Subjects will be asked to complete the CFQ-R in their native language.14 The CFQ-R will be 
completed before the start of any other assessments, as noted in Table 3-2. Subjects who are 
<14 years of age at Day 1 will complete the CFQ-R child version themselves, and their 
parents/caregivers will complete the CFQ-R Parent version, at all visits, regardless of whether 
the subject subsequently turns 14 years of age during the study. Subjects 14 years of age and 
older at Day 1 will complete the adolescent/adult version of the questionnaire themselves at all 
visits. The questionnaires provide information about demographics; general quality of life, 
school, work, or daily activities; and symptom difficulties (pertaining to CF). Copies of the 


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CFQ-R used in this study will be provided in the Study Reference Manual. Validated translations 
of the CFQ-R, if available, will be provided for participating centers in non-English-speaking 
countries.  
11.4 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, pulse oximetry, postdose spirometry, and physical examinations (PEs). 
 
Adverse Events 
11.4.1
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE case report form 
(CRF) completion guidelines for investigators as well as training will be provided. 
 
Clinical Laboratory Assessments 
11.4.2
Blood samples will be collected before dosing and analyzed at a central laboratory unless 
otherwise specified. A local laboratory may be used if a subject cannot return to the clinical 
study site for mandatory liver function testing (Section 11.4.6).  
Blood samples for clinical laboratory assessments will be collected according to the schedule 
shown in Table 3-1 and Table 3-2. Laboratory test results that are abnormal and considered 
clinically significant will be reported as AEs (see Section 13.1.1.2). 
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 nitrogen 
Creatinine 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate 
Inorganic phosphate  
Total bilirubin, direct bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase  
Alanine aminotransferase 
Lactate dehydrogenase 
Gamma-glutamyl transpeptidase 
Total protein 
Albumin 
Creatine kinase 
Amylase 
Lipase 
Hemoglobin 
Erythrocytes 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Reticulocytes 
Platelets 
Leukocytes 
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes  
Monocytes 
Coagulation Studies 
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 
Urine potassium 
Urine sodium  
a 
If urine is positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of urine will be 
performed for leukocytes, erythrocytes, crystals, bacteria, and casts. 
Pregnancy (β-human chorionic gonadotropin) Tests for Females of Childbearing Potential: 
Serum samples will be obtained as specified in Table 3-1 and Table 3-2 and analyzed at the 
central laboratory. Urine pregnancy tests will be performed at the site as specified in Table 3-2. 
The urine pregnancy test on Day 1 must be negative before the first dose of study drug.  
FSH (Screening Period only): Blood sample for FSH will be measured for any potentially 
postmenopausal female. In addition to at least 12 months of continuous spontaneous amenorrhea, 
serum FSH levels must be ≥40 mIU/mL for the subject to be considered postmenopausal. 
CFTR Genotype (Screening Period only): CFTR genotyping will be performed at the Screening 
Visit only if the CFTR genotype is not 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. 
At the discretion of the local investigator, local laboratories may be used for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 


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significant, it should 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. 
 
Physical Examinations and Vital Signs 
11.4.3
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits (see Table 3-1and Table 3-2). At other visits, symptom-directed PEs and symptom-
directed vital sign assessments can be performed at the discretion of the investigator or 
healthcare provider. 
A PE includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/throat; 
respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and neurological. 
Breast, anorectal, and genital examinations will be performed when medically indicated. After 
screening, any clinically significant abnormal findings in PEs will be reported as AEs. Vital 
signs include blood pressure (systolic and diastolic), pulse rate, and respiration rate. These will 
be collected predose at all visits and will be assessed following at least a 5-minute rest in the 
seated or supine position. 
 
Contraception and Pregnancy 
11.4.4
The effects of TEZ/IVA on conception, pregnancy, and lactation in humans are not known.  
11.4.4.1 
Contraception 
Participation in this study requires a commitment from the subject and his/her partner to use at 
least 1 acceptable method of contraception, which must be used correctly with every act of 
sexual intercourse. Methods of contraception should be in successful use from at least 14 days 
before the first dose of study drug (unless otherwise noted) and until 90 days following the last 
dose of study drug. 
Contraception for the couple is waived for the following: 
 True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented through 
examination of a semen specimen or by demonstration of the absence of the vas deferens by 
ultrasound before the first dose of the study drug. 
 If the female is of non-childbearing potential, per the following: 
o Documented hysterectomy or a bilateral oophorectomy/salpingo-oophorectomy. 
o Postmenopausal: continuous amenorrhea for at least 12 months and serum FSH levels 
≥40 mIU/mL.  
o Has not achieved menarche (has not had her first menstrual period). If a female achieves 
menarche during the study, she will need to follow acceptable methods of contraception 
or abstinence. 


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For subjects for whom contraception methods are not waived due to 1 of the reasons cited above, 
the following are acceptable contraceptive methods for male subjects and their female (non-
study) partners, and for female subjects and their male (non-study) partners: 
Table 11-2 
Acceptable Methods of Contraception 
 Male vasectomy 6 months or more previously, with a negative post-vasectomy semen analysis for sperm. 
 Male or female condom with or without spermicide (either as a single product if commercially available and/or 
allowed according to local regulations; otherwise condom and spermicide as separate products). 
 Female bilateral tubal ligation performed at least 6 months previously. 
 Female diaphragm, cervical cap, or vaginal sponge, each with spermicide (where available). 
 Female continuous use of an intrauterine device (non-hormone releasing or hormone releasing) for at least 90 
days. 
 Female combined (estrogen and progestogen-containing) or progestogen-only hormonal contraception associated 
with inhibition of ovulation if successfully used for at least 60 days. 
 
Important notes: 
 Local requirements may prohibit the use of some of these acceptable methods listed above. 
Please contact the medical monitor with any questions. 
 If applicable, additional contraception requirements may need to be followed according to 
local regulations and/or requirements. 
 Male and female subjects who are not sexually active at the time of screening must agree to 
follow the contraceptive requirements of this study if they become sexually active. 
 Female condom used with male condom (as a double method of contraception) is not an 
acceptable method of contraception due to risk of tearing; a different acceptable method of 
birth control must be used as described in Table 11-2.  
 Male subjects must not donate sperm after the first dose of study drug, throughout the study, 
and for 90 days following the last dose of study drug. 
 Female subjects and female partners of male subjects should not plan to become pregnant 
during the study through 90 days following the last dose of study drug. 
 Female subjects should not nurse a child from the start of study drug dosing through 90 days 
following the last dose of study drug. 
Unique situations that may not fall within the above specifications may be discussed with the 
Vertex medical monitor on an individual basis. 
11.4.4.2 
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(s). 
All pregnancies occurring during the study or within 90 days after discontinuation of study drug 
must be followed until resolution (i.e., birth or voluntary or spontaneous termination of the 
pregnancy). Any subject found to be pregnant at any time during the study will be withdrawn 
from the study immediately. Any pregnancy outcome that meets the criteria for an SAE will be 
reported as an SAE. 


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If a subject or the female partner of a male subject becomes pregnant while participating in the 
study, study drug will be permanently discontinued immediately. The investigator will notify 
Vertex GPS within 24 hours of the site’s knowledge of the subject’s (or partner’s) pregnancy 
using the Pregnancy Information Collection Form. 
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. 
 
Pulse Oximetry 
11.4.5
Pulse oximetry is a noninvasive measure of oxygen delivery to the tissues and has been 
correlated with clinical status and lung function. Arterial oxygen saturation by pulse oximetry 
will be measured at visits noted in Table 3-1 and Table 3-2 and will be assessed following at 
least a 5-minute rest (seated or supine). Pulse oximetry will be collected before study drug 
dosing at all visits.   
 
Liver Function Test Parameters 
11.4.6
Liver Function Testing 
Liver function testing must be performed as noted in Table 3-2 while subjects are receiving study 
drug treatment and at the ETT visit when indicated. These blood samples should be processed 
and shipped immediately per the Laboratory Manual. 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN and clinical 
symptoms must be followed closely, including repeat confirmatory testing performed by the 
central laboratory within 48 to 72 hours of the initial finding and subsequent close monitoring of 
ALT and AST levels, as clinically indicated. In addition, if ALT or AST is >5 × ULN, repeat 
follow-up levels must be obtained within 7 ± 2 days. 
If a subject cannot return to the site for liver function testing, a local laboratory may be used. 
Elevations in LFTs at the local laboratory must be reported immediately to the medical monitor, 
and the subject must have the tests repeated and sent to the central laboratory as soon as possible 
(ideally within 48 to 72 hours). 
Study Drug Interruption 
Study drug administration must be interrupted immediately (prior to confirmatory testing), and 
the medical monitor must be notified, if any of the following criteria is met and confirmed with 
repeat testing: 
 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. 
If no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, or alcohol 
ingestion) for the elevated tests is identified, regardless of whether the levels have improved, 
study drug treatment must be permanently discontinued if repeat testing within 48 to 72 hours 
confirms the initial elevation. Subjects in whom treatment is discontinued for elevated liver tests 
should have them monitored closely until levels normalize or return to baseline.  


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Resumption of Study Drug 
If an alternative, reversible cause of liver test elevation(s) has been identified, study drug may be 
resumed once the levels return to baseline or are ≤2 × ULN, whichever is higher. Approval of the 
medical monitor is required before resumption of study drug. Upon resumption of study drug, 
levels should be assessed weekly for 4 weeks. If a protocol-defined elevation occurs within 
4 weeks of rechallenge with study drug (with confirmation of the initial elevation by repeat 
testing within 48 to 72 hours), then the study drug treatment must be permanently discontinued, 
regardless of the presumed etiology. 
 
Ophthalmologic Examination 
11.4.7
Subjects <18 years of age who did not have an ophthalmological examination prior to starting 
Orkambi will undergo an ophthalmologic examination if they have not had an ophthalmologic 
examination within 6 months before the Screening Period. The examination must be performed 
by a licensed ophthalmologist or optometrist at screening and includes 
 measurement of best corrected distance visual acuity of each eye 
 pharmacologically dilated examination of the lens with a slit lamp 
The screening ophthalmologic examination must be completed before randomization. Subjects 
who have documentation of bilateral lens removal do not need the ophthalmologic examination. 
Additional ophthalmologic examinations may be conducted at the discretion of the investigator. 
The medical monitor should be notified of any abnormal findings from additional 
ophthalmologic examinations. 
 
Spirometry 
11.4.8
Postdose spirometry assessment will be performed 2 hours (± 30 minutes) and 4 hours 
(± 30 minutes) after dosing on Day 1; these assessments will be performed in addition to the 
predose spirometry assessment. If the Day 1 predose spirometry is performed 
postbronchodilator, the subject should withhold any further bronchodilator use until completion 
of the 4-hour postdose spirometry assessment on that day. 
12 
STATISTICAL AND ANALYTICAL PLANS 
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the statistical analysis plan (SAP) which will be finalized before the 
clinical data lock for the study and treatment unblinding. 
12.1 
Sample Size Consideration 
Sample size calculation is based on the key secondary endpoint of absolute change in ppFEV1 to 
the average of the Day 28 and Day 56 measurements. 
A Bayesian approach will be used to assess the treatment effect on the change in ppFEV1. The 
study will be considered successful if the posterior probability that the treatment difference 
between TEZ/IVA and placebo is greater than 0 is at least 80%, using a noninformative prior 
distribution. Assuming a 3.0 percentage points mean treatment difference between TEZ/IVA and 
placebo and a standard deviation (SD) of 6.0 percentage points, with 42 TEZ/IVA subjects and 
42 placebo subjects, the Bayesian power to achieve the posterior probability criterion is at least 


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90% (92.6%). After adjusting for an assumed dropout rate of 5% a total sample size of 
90 subjects is needed. 
 
 
 
  
 
 
 
 
12.2 
Analysis Sets 
Assignment of subjects to analysis sets will be done before the clinical data lock for the study.  
The All Subjects Set is defined as all subjects who have been randomized or have received at 
least 1 dose of study drug. This analysis set will be used in subject listings and disposition 
summary table, unless otherwise specified. 
The Full Analysis Set (FAS) is defined as all randomized subjects who have received at least 
1 dose of study drug. The FAS will be used in efficacy analyses in which subjects will be 
analyzed according to their randomized treatment group. 
The Safety Set is defined as all subjects who received at least 1 dose of study drug. The Safety 
Set is to be used for all safety and tolerability analyses, in which subjects will be analyzed 
according to the treatment they received. 
12.3 
Statistical Analysis 
The primary objective of this study is to evaluate the respiratory safety of TEZ/IVA through 
Day 56 in subjects with CF homozygous for F508del and who discontinued treatment with 
Orkambi due to respiratory symptoms considered related to treatment. 
This section presents a summary of the planned statistical analyses of safety, efficacy, and 
tolerability. The Vertex Biometrics department or a designated CRO will analyze the data 
derived from this study. SAS® Version 9.2 or higher will be used to generate all statistical 
outputs (tables, figures, listings, and data sets). 
Statistical analysis and presentation details will be provided in the SAP for the study. 
 
General Considerations 
12.3.1
All individual subject data for all randomized subjects exposed to study drug will be presented in 
data listings. 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value, and maximum value. The 
precision of the measurement for each continuous variable will be specified in the SAP.  
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 


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Baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the initial administration of study 
drug.  
Change (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. 
The treatment-emergent (TE) period will include the time from the first dose to the Safety 
Follow-up Contact or 28 days after the last dose of the study drug for subjects who do not have a 
Safety Follow-up Contact.  
 
Background Characteristics 
12.3.2
Subject disposition, demographic and baseline characteristics, prior and concomitant 
medications, study drug exposure and compliance, and other background characteristics will be 
summarized. Additionally, all subject data will be presented in subject data listings. All 
summaries will be based on the FAS unless otherwise specified in the SAP for the study. No 
statistical hypothesis testing will be performed. 
12.3.2.1 
Subject Disposition 
The number and percentage of subjects in the following categories will be summarized as 
appropriate: 
 All Subjects Set  
 Randomized 
 Dosed (Safety Set) 
 Randomized, dosed, and carry the intended CFTR mutation (see SAP Appendix 1) (FAS) 
 Completed study drug treatment 
 Prematurely discontinued the study during the Treatment Period and the reasons for 
discontinuation 
 Completed study/Safety Follow-up Contact 
 Prematurely discontinued the study and the reasons for discontinuation 
12.3.2.2 
Demographics, Medical History, and Baseline Characteristics 
Demographics, medical history, and baseline characteristics will be summarized.  
The following demographics and baseline characteristics will be summarized by dose group for 
the FAS: sex, race, ethnicity, age, weight, height, region, baseline ppFEV1, and baseline score of 
CFQ-R respiratory domain.  


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12.3.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization-Drug 
Dictionary Enhanced and categorized as the following:  
 Prior medication: any medication that started before initial dosing of study drug, regardless 
of when it ended 
 Concomitant medication: medication continued or newly received at or after initial dosing 
of study drug through the end of the TE Period 
 Post-treatment medication: medication continued or newly received beyond the TE Period 
A given medication can be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; or 
prior, concomitant, and post-treatment. If a medication has a missing or partial missing start/end 
date or time and cannot be determined whether it was taken before initial dosing, concomitantly, 
or beyond the TE Period, it will be considered as prior, concomitant, and post-treatment. 
Prior medications and concomitant medications will be summarized descriptively based on the 
FAS. Post-treatment medications will be listed for each subject.  
12.3.2.4 
Study Drug Exposure and Compliance 
Exposure to study drug (i.e., duration of treatment) will be summarized for the FAS in terms of 
duration of treatment a subject received (in days), defined as the last day minus the first day of 
study drug plus 1. 
Dosing compliance will be summarized for the FAS and is calculated as the actual number of 
dosing occasions at which study drug was taken (including when administered at study visits), as 
a percentage of the planned number of dosing occasions. 
Duration of treatment and dosing compliance will be summarized by means of descriptive 
summary statistics. 
 
Safety Analysis 
12.3.3
Respiratory safety of TEZ/IVA is the primary objective of this study and will be assessed in 
terms of AE incidence, including but not limited to the following: 
 Chest discomfort 
 Dyspnea (shortness of breath) 
 Respiration abnormal (chest tightness) 
 Asthma 
 Bronchial hyperreactivity 
 Bronchospasm  
 Wheezing 
All safety analyses will be based on the TE Period for subjects in the Safety Set.  
The overall safety profile of study drug will be assessed in terms of the following safety 
endpoints: 


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 Incidence of treatment-emergent AEs, SAEs, and discontinuations due to AEs 
 Clinical laboratory values 
 Vital signs  
 Pulse oximetry 
All safety data will also be presented in individual subject data listings. 
12.3.3.1 
Adverse Events 
AEs will be coded according to MedDRA. The number and percentage of subjects experiencing 
an AE will be summarized by the MedDRA system organ class and preferred term, as well as by 
dose group. AEs will be classified as pretreatment or treatment-emergent. 
Pretreatment AEs are defined as AEs that were reported or worsened after signing the ICF up 
to the start of study drug dosing. 
Treatment-emergent AEs are defined as AEs that were reported or worsened on or after the 
start of study drug dosing through the Safety Follow-up Contact. 
Only TEAEs will be summarized in tables. All summaries of TEAEs will be presented by the 
severity of the AE and relationship to the study drug. Some rules that will apply to the 
summarization of AEs are (1) a subject with multiple occurrences of the same AE or a 
continuing AE will only be counted once; (2) only the maximum severity level will be presented 
in the severity summary; and (3) only the worst relationship level will be presented in the 
relationship summary. 
AEs leading to death, SAEs, dose interruption, and permanent discontinuation will be listed 
separately. All AEs through the Safety Follow-up Contact will be listed in an individual subject 
data listing, including pretreatment AEs.  
12.3.3.2 
Clinical Laboratory Assessments 
For the laboratory measurements, the raw values and change from baseline values of the 
continuous hematology, coagulation, and chemistry results will be summarized in SI units at 
each scheduled time point. 
The number and percentage of subjects with at least 1 assessment meeting threshold criteria 
during the Treatment Period will be summarized. The threshold criteria will be provided in the 
SAP. 
A listing containing individual subject hematology, coagulation, and chemistry values outside 
the reference ranges will be provided. This listing will include data from scheduled and 
unscheduled time points. Results of urinalysis and pregnancy tests will be provided in data 
listings only. 
12.3.3.3 
Vital Signs 
For the on-treatment vital signs measurements, the raw values and change from baseline values 
will be summarized by treatment group at each scheduled time point during the TE Period: 
systolic and diastolic blood pressure (mm Hg), HR (beats per minute), and respiratory rate 
(breaths per minute).  
Additional vital sign analyses will be described in the SAP, if applicable. 


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12.3.3.4 
Physical Examination 
Physical examination findings will be presented as a data listing only. 
12.3.3.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of raw values and change 
from baseline values will be provided by treatment groups at each scheduled time point during 
the TE Period for the percent of oxygen saturation by pulse oximetry. In addition, the mean value 
at each visit will be plotted by treatment groups for the percent of oxygen saturation.  
12.3.3.6 
Postdose Spirometry 
For the 2-hour and 4-hour postdose measurements on Day 1, a summary of raw values for 
percent predicted FEV1 will be provided by treatment at each time point. The absolute change 
from the Day 1 predose value of percent predicted FEV1 will be summarized by treatment at 
each time point. In addition, the number and percentage of subjects with percent predicted FEV1 
decline of ≥10, ≥15, and ≥20 percentage points in the absolute change from the Day 1 predose 
value, and the number and percentage of subjects with percent predicted FEV1 decline of ≥10, 
≥15, and ≥20% in the relative change from Day 1 will be summarized by treatment and by 
assessment time. 
 
Efficacy Analysis 
12.3.4
12.3.4.1 
Analysis of Key Efficacy Variables 
The actual posterior/conditional probability will be calculated for the probability of a greater 
than zero (>0) treatment effect difference in mean ppFEV1 change between TEZ/IVA and 
placebo is greater than or equal to 80%, based on the observed data of the efficacy endpoint on 
the absolute change from baseline in ppFEV1 to the average of the Day 28 and Day 56 
measurements. This will serve as the primary efficacy analysis outcome. 
Additionally, the key efficacy endpoint of the absolute change from baseline in ppFEV1 to the 
average of the Day 28 and Day 56 measurements will be analyzed using a mixed-effects model 
for repeated measures (MMRM) with ppFEV1 at each time point as the outcome variable. The 
MMRM model will include the absolute change from baseline in ppFEV1 at each visit as the 
dependent variable; treatment, visit, and treatment-by-visit interaction as fixed effects; and 
subject as a random effect, with adjustment for sex (male versus female), age group at the 
Screening Visit (<18 versus ≥18 years old), and ppFEV1 severity determined during the 
Screening (or baseline) Period (<40% versus ≥40% predicted).  
The estimated treatment effect within TEZ/IVA and placebo arm, as well as the estimated 
treatment difference between TEZ/IVA and placebo arm will be provided based on the MMRM 
model along with 95% CI. These results will serve as additional efficacy outcomes, which is in 
addition to the primary actual posterior/conditional probability outcome. Furthermore, treatment 
effect and treatment difference at each post-baseline visit, obtained from the model, will also be 
provided. 
 
 


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12.3.4.2 
Analysis of Secondary Efficacy Variables 
 Relative change in ppFEV1 from baseline to the average of the Day 28 and Day 56 
measurements: Analysis of this variable will be similar to the key efficacy analysis using an 
MMRM model but without calculation of the posterior/conditional probability based on this 
variable. 
 Absolute change in the CFQ-R respiratory domain score from baseline to the average 
of the Day 28 and Day 56 measurements: Analysis of this domain will be similar to the key 
efficacy using an MMRM model but without calculation of the posterior/conditional 
probability based on this variable, with the addition of the CFQ-R respiratory domain score 
at baseline as a covariate. 
 
 
 
Tolerability Analysis 
12.3.5
A tolerability analysis will be based on the Safety Set for a standard summary of study drug 
discontinuation rate. Rate will be reported as descriptive statistics in counts and percentages, 
separately by the TEZ/IVA arm and the placebo arm. No statistical hypothesis testing will be 
performed. An additional summary of the tolerability outcome including but not limited to 
study/study drug discontinuation rate by reasons, by AE of special interest, and by time to 
discontinuation will also be reported. 
12.3.5.2 
IDMC Analysis 
An IDMC will be formed for this study before study initiation. The IDMC’s objectives and 
operational details will be defined in a separate document (IDMC Charter), which will be 
finalized before the first subject is screened in the study. The IDMC will conduct regular planned 
safety reviews of study data as outlined in the IDMC Charter. 


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13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
 
Adverse Events 
13.1.1
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, PEs, pulse oximetry, 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., hepatitis). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., elevated ALT). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
 Concomitant signs or symptoms related to the abnormal study assessment 
 Further diagnostic testing or medical/surgical intervention 
 A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF and assent (where applicable) is signed until the 
following time points: 
 For subjects who do not enroll: until time of screen failure or withdrawal of consent 
 For enrolled subjects who complete the study and for subjects who prematurely discontinue 
study drug and have a Safety Follow-up Contact: through the Safety Follow-up Contact 
 For enrolled subjects who prematurely discontinue study drug (including for withdrawal of 
consent) and do not have Safety Follow-up Contact, the earliest of: 
o 28 days after the last dose of study drug, or 


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o the ETT Visit, if that visit is 3 weeks or later following the last dose of study drug 
(see Section 9.1.4) 
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the study 
will be recorded only in the subject's source documents. The following data will be documented 
for each AE: 
 Description of the event 
 Classification of “serious” or “nonserious” 
 Date of first occurrence and date of resolution (if applicable) 
 Severity  
 Causal relationship to study drug(s)  
 Action taken  
 Outcome  
 Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. AEs of CTCAE 
Grades 4 and 5 will be documented as “life-threatening.” In considering the severity of an AE in 
a pediatric subject, the investigator will consider that reference ranges for pediatric clinical 
laboratory parameters may differ from those given in the CTCAE. The severity of an AE that 
does not appear in the CTCAE will be determined according to the definitions in Table 13-1.  
Table 13-1 
Grading of AE Severity  
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories presented in Table 13-2. 


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


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13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, hospitalization, 
surgery, or physical therapy. “No” indicates the absence of any kind of treatment for an AE. 
 
Serious Adverse Events 
13.1.2
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
 Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation in the study and is suspected of being a delayed toxicity due to administration of 
the study drug) 
 Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
 Inpatient hospitalization or prolongation of hospitalization 
 Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person's ability to conduct normal life functions) 
 Congenital anomaly or birth defect 
 Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject's life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Contact, regardless of causality, will be reported by the investigator to Vertex 


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GPS. In addition, all SAEs that occur after the Safety Follow-up Contact and are considered 
related to study drug(s) will be reported to Vertex GPS within 24 hours. 
SAEs will be recorded on the Vertex Organized Safety Information Collection Form (hereafter 
referred to as the “SAE Form”) using a recognized medical term or diagnosis that accurately 
reflects the event. SAEs will be assessed by the investigator for relationship to the investigational 
study drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be 
assessed only as related (includes possibly related) or not related (includes unlikely related), and 
severity assessment will not be required. For the purposes of study analysis, if the event has not 
resolved at the end of the study reporting period, it will be documented as ongoing. For purposes 
of regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report to Vertex the outcome of the event using the SAE Form. 
13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. The SAE Form will be 
completed for new/initial events as well as to report follow-up information on previously 
reported events. Investigators are asked to report follow-up information as soon as it becomes 
available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email: 
 (preferred choice) 
Fax: 
  
Contact Telephone:
 
13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions involving the study drug(s) to all regulatory authorities and participating investigators 
in accordance with ICH Guidelines and/or local regulatory requirements, as applicable. In 
addition, Vertex, or authorized designee, will be responsible for the submission of safety letters 
to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/local IEC 
of all unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
 
Ethical Considerations 
13.2.1
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will only 
be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator's 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 


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Subject Information and Informed Consent 
13.2.2
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
ICH GCP and all applicable laws and regulations and will be subject to approval by Vertex or its 
designee. 
 
Investigator Compliance 
13.2.3
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
 
Access to Records 
13.2.4
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.  
 
Subject Privacy 
13.2.5
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers and access to subject names linked to such 
numbers shall be limited to the site and the study physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 
 
Record Retention 
13.2.6
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 


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Study Termination 
13.2.7
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
 Subject or investigator noncompliance 
 Unsatisfactory subject enrollment 
 Lack of adherence to protocol procedures 
 Lack of evaluable and/or complete data 
 Potentially unacceptable risk to study subjects 
 Decision to modify drug development plan 
 Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated web-based electronic data capture (EDC) application. Vertex 
will have read-only access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 


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


Protocol VX16-661-114 Version 3.1 US 
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Vertex Pharmaceuticals Incorporated 
 
14 
REFERENCE 
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 09 February 2017. 
2 
Kreindler JL. Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
3 
Sheppard MN, Nicholson AG. The pathology of cystic fibrosis. Curr Diagn Pathol. 
2002;8(1):50-59. 
4 
Cystic Fibrosis Foundation. Patient Registry: 2014 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2015. 
5 
Vertex Pharmaceuticals Incorporated. Ivacaftor (VX-770) Investigator's Brochure, 
Version 13.0. Report date: 16 May 2016. 
6 
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. 
7 
Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life measures 
for children with respiratory conditions. Paediatr Respir Rev. 2008;9(3):220-32. 
8 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 
9 
Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality 
of life for children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45. 
10 
Wenninger K, Aussage P, Wahn U, Staab D, German Cystic Fibrosis Questionnaire study 
group. The revised German Cystic Fibrosis Questionnaire: validation of a disease-
specific health-related quality of life instrument. Qual Life Res. 2003;12(1):77-85. 
11 
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life 
Res. 2003;12(1):63-76. 
12 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general U.S. population. Am J Respir Crit Care Med. 1999;159(1):179-87. 
13 
Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG. Pulmonary function between 6 and 
18 years of age. Pediatr Pulmonol. 1993;15(2):75-88. 
14 
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of 
the Cystic Fibrosis Questionnaire in the United States. Chest. 2005;128(4):2347-54. 
 


Protocol VX16-661-114 Version 3.1 US
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15
PROTOCOL SIGNATURE PAGES
15.1
Sponsor Signature Page
Protocol #:
VX16661114
Version #:
3.1 US
Version Date:
09 June 2017
Study Title: Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to 
Assess the Safety, Efficacy, and Tolerability of Tezacaftor/Ivacaftor (TEZ/IVA) in an Orkambi-
experienced Population Who Are Homozygous for the F508del-CFTR Mutation
This Clinical Study Protocol has been reviewed and approved by the sponsor.


Protocol VX16-661-114 Version 3.1 US 
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Vertex Pharmaceuticals Incorporated 
 
15.2 
Investigator Signature Page 
Protocol #:  
VX16-661-114 Version #: 
3.1 US Version Date: 09 June 2017 
Study Title: Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to 
Assess the Safety, Efficacy, and Tolerability of Tezacaftor/Ivacaftor (TEZ/IVA) in an Orkambi-
experienced Population Who Are Homozygous for the F508del-CFTR Mutation 
I have read Protocol VX16-661-114, Version 3.1 US, and agree to conduct the study according 
to its terms. I understand that all information concerning TEZ and IVA and this protocol supplied 
to me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
Printed Name 
 
 
Signature 
 
Date 
 

SAP_001.pdf: 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan Methods 
Protocol Number VX16-661-114, Version 1.0 
 
A Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel Group 
Study to Assess the Safety, Efficacy, and Tolerability of Tezacaftor/Ivacaftor 
(TEZ/IVA) in an Orkambi-experienced Population Who Are Homozygous for the 
F508del-CFTR Mutation 
 
Author of SAP:  
 
Version: 1.0  
Version Date of SAP: 21 May 2018 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, MA 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) 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ................................................................................................ 2 
List of Tables ....................................................................................................................... 4 
List of Figures ...................................................................................................................... 4 
2 
INTRODUCTION ........................................................................................................... 5 
3 
STUDY OBJECTIVES ................................................................................................... 5 
3.1 
Primary Objective ....................................................................................................... 5 
3.2 
Secondary Objectives ................................................................................................. 5 
4 
STUDY ENDPOINTS ..................................................................................................... 6 
4.1 
Safety Endpoints (Primary Endpoint) ........................................................................ 6 
 
Primary Safety Endpoint .................................................................................... 6 
4.1.1
 
Secondary Safety Endpoints ............................................................................... 6 
4.1.2
4.2 
Efficacy Endpoints (Secondary Endpoints) ................................................................ 6 
 
Key Secondary Efficacy Endpoint ..................................................................... 6 
4.2.1
 
Secondary Efficacy Endpoints ............................................................................ 6 
4.2.2
 
Additional Secondary Endpoint .......................................................................... 7 
4.2.3
5 
STUDY DESIGN ............................................................................................................. 7 
5.1 
Overview of Study Design ......................................................................................... 7 
5.2 
Sample Size and Power .............................................................................................. 8 
5.3 
Randomization ............................................................................................................ 9 
5.4 
Blinding and Unblinding ............................................................................................ 9 
 
Blinding .............................................................................................................. 9 
5.4.1
 
Unblinding ........................................................................................................ 10 
5.4.2
6 
ANALYSIS SETS .......................................................................................................... 11 
7 
STATISTICAL ANALYSIS ......................................................................................... 11 
7.1 
General Considerations ............................................................................................ 11 
7.2 
Background Characteristics ...................................................................................... 13 
 
Subject Disposition ........................................................................................... 13 
7.2.1
 
Demographics and Baseline Characteristics ..................................................... 14 
7.2.2
 
Medical History ................................................................................................ 15 
7.2.3
 
Prior and Concomitant Medications ................................................................. 15 
7.2.4
 
Study Drug Exposure ........................................................................................ 16 
7.2.5
 
Study Drug Compliance ................................................................................... 16 
7.2.6
 
Important Protocol Deviations .......................................................................... 16 
7.2.7
7.3 
Primary Safety Analysis ........................................................................................... 17 
 
Definition of Primary Safety Endpoint ............................................................. 17 
7.3.1
7.3.1.1 
Summaries of RAESI by Treatment Interval ............................................. 17 
7.4 
Primary Efficacy Analysis ........................................................................................ 18 
7.5 
Additional Efficacy Analysis ................................................................................... 18 
 
Key Secondary Efficacy Endpoint ................................................................... 18 
7.5.1
7.5.1.1 
Definition of Key Secondary Efficacy Endpoint ....................................... 18 
7.5.1.2 
Analysis of Key Secondary Efficacy Endpoint .......................................... 18 
 
Secondary Efficacy Endpoints .......................................................................... 19 
7.5.2
7.5.2.1 
Definition of Secondary Efficacy Endpoints ............................................. 19 


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7.5.2.2 
Additional Secondary Endpoint ................................................................. 21 
7.5.2.3 
Analysis of Secondary Efficacy Endpoints ................................................ 21 
7.5.2.4 
Multiplicity adjustment .............................................................................. 22 
7.5.2.5 
Analysis of Additional Secondary Endpoint .............................................. 22 
7.5.2.6 
Additional Analysis of Secondary Endpoints ............................................ 22 
7.6 
Additional Safety Analysis ....................................................................................... 22 
 
Adverse Events ................................................................................................. 23 
7.6.1
7.6.1.1 
Overview of Pre-treatment AEs and Treatment Emergent AEs ................ 24 
7.6.1.2 
TEAEs and TE SAEs by System Organ Class (SOC) and Preferred Term 
(PT) ............................................................................................................ 25 
7.6.1.3 
TEAEs and TE SAEs by Preferred Term (PT) .......................................... 25 
7.6.1.4 
TEAEs and TE SAEs by SOC, PT, and Relationship ................................ 25 
7.6.1.5 
TEAEs and TE SAEs by SOC, PT, and Severity ....................................... 25 
7.6.1.6 
Elevated Transaminase............................................................................... 26 
 
Clinical Laboratory Values ............................................................................... 26 
7.6.2
 
Vital Signs ........................................................................................................ 27 
7.6.3
 
Pulse Oximetry ................................................................................................. 27 
7.6.4
 
Postdose Spirometry on Day 1 ......................................................................... 27 
7.6.5
 
Physical Examination ....................................................................................... 27 
7.6.6
8 
INTERIM AND DMC ANALYSES ............................................................................. 28 
8.1 
Interim Analysis ....................................................................................................... 28 
8.2 
No interim analysis is planned for this study. DMC Analysis ................................. 28 
9 
References ....................................................................................................................... 29 
10  APPENDICES ................................................................................................................ 30 
10.1  Schedule of Assessments .......................................................................................... 30 
10.2  Analysis Visit Window Mapping Rules for Efficacy and Safety Measurements .... 33 
10.3  Coefficients for Hankinson and Wang Methods for Calculating Predicted 
Spirometry Parameters ............................................................................................. 34 
10.5  Threshold Analysis Criteria ...................................................................................... 39 
10.6  Standards for Efficacy and Safety Variable Display in TFLs .................................. 46 
10.7  Imputation Rules for Missing AE Start Date ........................................................... 47 
  
 


Statistical Analysis Plan (Methods) 
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List of Tables 
Table 7-1 
Logic for Determining the Category of a Medication ...................................... 16 
Table 7-2 
CFQ-R for Children Ages 12 and 13 ................................................................ 20 
Table 7-3 
CFQ-R for Adolescents and Adults (Subjects 14 Years and Older) ................ 20 
Table 7-4 
CFQ-R for Parents/Caregivers (Subjects 13 Years and Younger) ................... 21 
Table 10-1 
Study VX16-661-114: Screening ..................................................................... 30 
Table 10-2 
Study VX16-661-114: Treatment Period, ETT, and Safety Follow-up Contact 
Assessments .................................................................................................................... 31 
Table 10-3 
Visit Window Mapping Rules .......................................................................... 33 
Table 10-4 
HNVs Equation Coefficients by Sex, Race, and Age ....................................... 35 
Table 10-5 
WNVs Equation Coefficients by Sex and Age in White Boys and Girls ......... 36 
Table 10-6 
WNVs Equation Coefficients by Sex and Age in Black Boys and Girls ......... 37 
Table 10-7 
Threshold Criteria for Clinical Chemistry and Hematology ............................ 39 
Table 10-8 
Threshold Criteria for Coagulation ................................................................... 44 
Table 10-9 
Threshold Criteria for Vital Signs .................................................................... 45 
Table 10-10 
Precision Standards for Efficacy Variables ................................................ 46 
Table 10-11 
Standard Display Units in Percent Predicted FEV1 ................................... 46 
  
List of Figures 
Figure 5-1 
Schematic of the Study Design for US subjects ................................................. 8 
Figure 5-2 
Schematic of the Study Design for EU subjects ................................................. 8 
 
 
 
 


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2 
INTRODUCTION 
This SAP, which describes the planned final analyses for Study VX16-661-114, is based on 
the following: 
 The approved clinical study protocol (Version 3.1 for USA and Version 3.2 for the EU, 
dated on 09 June, 2017), 
 The approved electronic case report forms (eCRF) (Version 1.5, dated 16 on March, 
2017).  
Study VX16-661-114 is a Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel 
Group Study to Assess the Safety, Efficacy, and Tolerability of Tezacaftor/Ivacaftor 
(TEZ/IVA) in an Orkambi-experienced Population Who Are Homozygous for the 
F508del-CFTR Mutation. 
This SAP (Methods) documents the planned final statistical analyses of efficacy and safety 
endpoints defined in the VX16-661-114 study protocol. 
The Vertex Biometrics Department or a designated CRO will perform the statistical analysis 
of the efficacy and safety data; SAS (Version 9.2, or higher) will be used to generate all 
statistical outputs (tables, figures, listings, and datasets). The SAP will be finalized and 
approved prior to the final clinical data lock and treatment unblinding for the study.  If the 
methods in this SAP differ from the methods described in the protocol, the SAP will prevail. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to evaluate the respiratory safety of Tezacaftor in combination with 
ivacaftor (TEZ/IVA) in subjects with CF homozygous for F508del and who discontinued 
treatment with Orkambi due to respiratory symptoms considered related to treatment 
3.2 
Secondary Objectives 
The secondary objectives of the study are as follows: 
 
To evaluate the efficacy of TEZ/IVA in subjects with CF homozygous for F508del 
and who discontinued treatment with Orkambi due to respiratory symptoms considered 
related to treatment. 
 
To evaluate patient-reported outcomes after treatment with TEZ/IVA in subjects with 
CF homozygous for F508del who discontinued with Orkambi due to respiratory symptoms 
considered related to treatment. 


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4 
STUDY ENDPOINTS 
4.1 
Safety Endpoints (Primary Endpoint) 
 Primary Safety Endpoint 
4.1.1
The primary endpoint is the incidence of respiratory adverse events (AEs) including but not 
limited to the following categories while patients are on treatment: 
 Chest discomfort 
 Dyspnea (shortness of breath) 
 Respiration abnormal (chest tightness) 
 Asthma 
 Bronchial hyperreactivity 
 Bronchospasm  
 Wheezing 
 Secondary Safety Endpoints 
4.1.2
The additional safety endpoints are as follows: 
 Incidence of treatment-emergent AEs, SAEs, and discontinuations due to AEs 
 Clinical laboratory values 
 Physical Examinations 
 Vital signs  
 Pulse oximetry 
 Postdose spirometry on Day 1 
4.2 
Efficacy Endpoints (Secondary Endpoints) 
 Key Secondary Efficacy Endpoint 
4.2.1
The key efficacy endpoint is the absolute change in percent predicted forced expiratory vol-
ume in 1 second (ppFEV1) from baseline to the average of the Day 28 and Day 56 measure-
ments.  
 
 Secondary Efficacy Endpoints 
4.2.2
 Relative change in ppFEV1 from baseline to the average of the Day 28 and Day 56 meas-
urements. 


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 Absolute change in Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain 
score from baseline to the average of the Day 28 and Day 56 measurements 
 Additional Secondary Endpoint 
4.2.3
 Discontinuation rate through Day 56 
5 
STUDY DESIGN  
5.1 
Overview of Study Design 
This study includes the following: 
 Screening Period (Day −28 through Day −1) 
 Treatment Period (Day 1 through Day 56 ± 5 days) 
 Safety Follow-up Contact (28 days ± 7 days after the last dose of study drug) for subjects 
who do not enroll in the long-term, open-label safety study of TEZ/IVA. (Open-label 
study is an option in the EU only.)  
Subjects will be stratified by age at the Screening Visit (<18 versus ≥18 years of age), sex 
(male versus female), and ppFEV1 severity determined during the Screening Visit (<40% 
versus ≥40% predicted), and then randomized (1:1) to 1 of the following 2 treatment arms: 
TEZ/IVA: TEZ 100 mg once daily (qd) + IVA 150 mg every 12 hours (q12h) 
Placebo: Placebo regimen with visually-matched tablets 
Subjects in the United States who complete the Day 56 Visit will be offered the opportunity 
to receive TEZ/IVA through the Expanded Access Program if they meet the eligibility 
criteria for that program. 
A schematic of the study design is shown in Figure 5-1 and Figure 5-2. 


Statistical Analysis Plan (Methods) 
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Figure 5-1 
Schematic of the Study Design for US subjects 
 
 
 
Figure 5-2 
Schematic of the Study Design for EU subjects 
 
 
 
 
5.2 
Sample Size and Power 
Sample size calculation is based on the key secondary endpoint of absolute change in 
ppFEV1 to the average of the Day 28 and Day 56 measurements. 
Note: Clinical visits are on Days -28, 1, 15, 28, and 56. A telephone contact on Day 3 collects AEs. The Safety Follow-
up may be a clinic visit or telephone call. 
a  The Safety Follow-up Contact is scheduled to occur 28 (±7) days after the last dose of study drug. The Safety Follow 
up Contact is not required for subjects who complete the Day 56 Visit and have enrolled in a long-term, open-label 
safety study of TEZ/IVA within 28 days after the last dose of study drug. 
b Subjects who complete the Day 56 Visit will be offered the opportunity to enroll in a long-term, open-label safety 
study of TEZ/IVA if they meet eligibility requirements for the safety study. 
Note: Clinical visits are on Days -28, 1, 15, 28, and 56. A telephone contact on Day 3 collects AEs. The Safety Follow-
up may be a clinic visit or telephone call. 




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 Unblinded statistician preparing the final (production) randomization list who is not part 
of the study team 
 Vertex Clinical Operations IWRS management 
 Vertex Clinical Supply Chain 
 IDMC 
 Vendor preparing the unblinded analysis for the IDMC  
 Vendor preparing the unblinded interim analysis focusing on safety outcomes 
Vertex Medical Monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time. Such unblinding events will be fully documented (see below). 
Spirometry Data Blinding 
Despite treatment blinding, knowledge of the spirometry results has the potential to suggest 
whether a subject has been administered active study drug or placebo. Therefore, during the 
conduct of the study, the Vertex study team will have no access to the post-dose spirometry 
data. The vendor for central reading of the spirometry data will send only blinded spirometry 
files (blinded treatment group, with real values for screening and baseline, but with dummy 
values for all the spirometry assessment after baseline) to Vertex to be used for developing 
the statistical programs. Furthermore, subjects and their caregiver should not be informed of 
their study-related spirometry results during the Treatment Period regardless of whether the 
subject has prematurely discontinued treatment 
 Unblinding 
5.4.2
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment 
is necessary for clinical management. In such cases, investigators should use their best 
judgment as to whether to unblind without first attempting to contact the medical monitor to 
discuss and agree to the need for unblinding. If investigators deem that it is not necessary to 
unblind immediately, they will first attempt to contact the medical monitor to discuss and 
agree to the need for unblinding. If investigators have tried but are unable to reach the 
medical monitor, they should use their best judgment, based on the nature and urgency of the 
clinical situation, and may proceed with unblinding. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center (
) will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If a subject's treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor should be notified within 24 hours of the unblinding 


Statistical Analysis Plan (Methods) 
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event. The reason and the date of the unblinding will be documented clearly in the subject's 
study file. Information about the treatment assignment obtained from the unblinding will be 
maintained in a secure location with controlled access and will not be shared with sponsor 
(Vertex), contract research organization (CRO), or any site personnel (other than the 
physician treating the subject). In addition, the investigator will consider whether the clinical 
event that prompted unblinding will be considered an SAE, according to the regulatory 
definitions or criteria for SAEs, and if so, submit an SAE report to Vertex GPS or designee, 
per Protocol Section13.1.2. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, the Vertex medical monitor may, for matters relating to 
safety concerns, unblind individual subjects at any time. 
6 
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set, Randomized Set, Full Analysis Set 
(FAS), and Safety Set.  
The All Subjects Set is defined as all subjects who have been randomized or have received 
at least 1 dose of study medication. This analysis set will be used in subject listings and the 
disposition summary table, unless otherwise specified. 
The Randomized Set is defined as all subjects who have been randomized. 
The Full Analysis Set (FAS) is defined as all randomized subjects who carry the intended 
CFTR allele mutation and have received at least 1 dose of study drug.  
The Safety Set is defined as all subjects who received at least 1 dose of study drug.   
7 
STATISTICAL ANALYSIS 
7.1 
General Considerations 
All individual subject data in the All Subject Set will be presented in data listings. The 
Schedule of Assessments is provided in Section 10.1. The precision standards are provided in 
Section 10.6. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (SD), median, minimum value 
(min), and maximum value (max).   
Categorical variables will be summarized using counts and percentages.  
Baseline Value, unless otherwise specified, is defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected prior to or on the first dose of study drug.  
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. 


Statistical Analysis Plan (Methods) 
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Treatment Emergent (TE) Period will be defined in the following way: 
 For patients who complete the Safety Follow-up Contact, the TE period will include the 
time from the first dose of the study drug to the Safety Follow-up Contact.  
 For subjects who discontinue and have an ETT Visit but no Safety Follow-up Contact, 
the TE period will include the time from the first dose of the study drug until the ETT 
visit. 
 For subjects who withdraw consent, the TE period includes the time from the first dose of 
the study drug until withdrawal. 
 For subjects who enroll in Study VX14-661-110 (EU only) or in the EAP (US only), the 
TE period in this study (Study 114) will include the time from the first dose of study drug 
in this study until the earlier of last study participation day OR until 28 days after the last 
dose of the study drug in Study 114. 
 For all other subjects, including those who do not have a Safety Follow-up Contact, the 
TE period includes the time from the first dose of the study drug until the earlier of last 
study participation day OR until 28 days after the last dose of the study drug.  
Unscheduled Visits: Unscheduled visit measurements will be included in the following: 
1. derivations of measurements at scheduled visits per specified visit windowing rules 
below; 
2. derivations of baseline/last on-treatment measurements; 
3. derivations of the maximum/minimum on-treatment values and maximum/minimum 
changes from baseline values for safety analyses; 
4. data listings where appropriate. 
Visit Windowing Rules: Section 10.2 defines the windows for protocol-defined visits. The 
windows will be applied using the following rules for both scheduled and unscheduled visits: 
1. If no measurement is available within a visit window, the assessment will be 
considered missing for the visit; 
2. If there is more than one measurement available within the same visit window, use 
the following rules:  
o For all efficacy parameters, if there are multiple measurements within a visit window, 
the record at the scheduled visit will be used. Otherwise, 
o The record closest to the target day will be used;  
o If there are multiple records with the same distance to the target day, the latest 
record will be used.   
o Assessments at early treatment termination (ETT) visit will follow the 
windowing rules for regular visits up to Day 56.  
o Assessments at safety follow-up (SFU) visit will follow the windowing rules 
for regular visits if they fall within the upper boundary of the window for Day 
56, or remain as SFU if they go beyond the upper boundary of the window for 
Day 56. 


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o For all safety parameters, if there are multiple measurements within a visit window, 
then 1) the record closest to the target day will be used; 2) if there are multiple 
records within the same distance from the target day, the latest record will be used; or 
3) SFU visit will not be windowed; instead, it will be used according to the nominal 
visit in relevant analyses. 
Note: spirometry assessments (other than Day 1 postdose spirometry) will be used for both 
efficacy and safety purposes. The measurements will follow the visit windowing rules for 
efficacy parameters. Day 1 postdose spirometry assessments will be used for safety purposes 
only. 
Incomplete/Missing data will not be imputed, unless otherwise specified.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence 
of statistical outliers, unless otherwise specified. 
7.2 
Background Characteristics  
 Subject Disposition 
7.2.1
In the summary table of subject disposition, the number of subjects in the following 
categories will be presented by treatment and overall:  
 All Subjects Set (randomized or dosed) 
 Randomized Set 
 Full Analysis Set (FAS) 
 Safety Set 
The number and percentage of subjects in each of the following disposition categories will be 
presented by treatment and overall based on the Safety Set: 
 Completed treatment through Day 56 
 Prematurely discontinued treatment (any tablet) and the reason for discontinuation and 
day at discontinuation 
  Completed study 
 Prematurely discontinued the study and the reasons for discontinuations  
A listing will be provided for subjects who discontinued treatment or who discontinued from 
the study, along with reason for discontinuation.  
The number and percentage of randomized subjects will be summarized by stratification 
factor, and by country and by site, using the number of subjects being randomized to each 
treatment group as the denominator. A randomization listing will be provided with subjects 
ordered by randomization date. 


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 Demographics and Baseline Characteristics 
7.2.2
The following demographic data will be summarized by treatment and overall based on the 
FAS: 
 Age at Baseline 
 Sex  
 Ethnicity (Hispanic or Latino, not Hispanic or Latino, not collected per local regulations) 
 Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other) 
 Country (USA, France, Germany) 
The following baseline characteristics will be summarized: 
 Height (cm) (subjects < 18 years old only) 
Stratification categories (in addition to sex) will also be summarized: 
 Age groups at screening (< 18, 18 years) 
 Percent predicted FEV1 at screening (<40, ≥40) 
Disease characteristics at baseline will include the following: 
 Percent predicted FEV1 category (<40, ≥40-<70, ≥70) 
 Percent predicted FEV1  
 CFQ-R Respiratory Symptoms domain  
 FEV1 (L)  
 
FVC (L)  
 
Percent predicted FVC  
 
FEF25-75% (L/sec)  
 
Percent predicted FEF25-75%   
 
FEV1/FVC  
 Use of dornase alfa  
 Use of inhaled antibiotic 
 Use of azithromycin 
 Use of any bronchodilator (inhaled or oral) 
 Use of inhaled bronchodilator Use of inhaled hypertonic saline  
 Use of inhaled corticosteroids  


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In addition, data listings will also be provided for: 
 Informed consent; 
 Inclusion/Exclusion criteria violation (for subjects with any such violations); 
 Medical History 
7.2.3
Medical history will be coded by using the Medical Dictionary for Regulatory 
Activities (MedDRA).  For the FAS, medical history will be summarized descriptively by 
system organ class (SOC) and preferred term (PT). The corresponding data listing will also 
be provided. 
 Prior and Concomitant Medications 
7.2.4
Medications taken during this study will be coded using the World Health Organization Drug 
Dictionary Enhanced (WHO-DDE) and categorized as the following: 
 Prior medication: any medication that started before the first dose of study drug, 
regardless of when the medication ended. 
 Concomitant medication: medication continued or newly received at or after the first 
dose of study drug through the end of TE period. 
 Post-treatment medication: medication continued or newly received after the TE period. 
A given medication can be classified as a prior, a concomitant, or a post-treatment 
medication; both prior and concomitant; both concomitant and post-treatment; or prior, 
concomitant, and post-treatment. If a medication has a missing or partially missing start/end 
date and it cannot be determined whether it was taken before the first dose, concomitantly, or 
beyond the TE period, it will be considered as prior, concomitant, and post-treatment. 
For the FAS, prior medications and concomitant medications will be summarized 
descriptively by: 1) preferred name; and 2) anatomic class (ATC) level 1, ATC level 2, and 
preferred name. Frequent (≥5% in any treatment group) prior medications and concomitant 
medications will be summarized descriptively by preferred name. Post-treatment medications 
will be listed by subject.  
As an intermediate step for programming purposes, medications with missing or partially 
missing start dates will use 2000 to impute a missing year, January for a missing month, and 
1 for a missing day. Medications with missing or partially missing stop dates will use 2050 to 
impute for a missing year, December for a missing month, and the last day of the month for a 
missing day. The logic to decide the category of a medication is presented in Table 7-1: 


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Table 7-1 
Logic for Determining the Category of a Medication 
Medication start date 
Medication end date 
< first dose date of 
study drug 
≥ first dose date and 
≤ End date of TE 
period
> End date of TE 
period 
< first dose date of study drug 
P 
PC 
PCA 
≥ first dose date and  
≤ End date of TE period 
- 
C 
CA 
> End date of TE period 
- 
- 
A 
P: Prior; C: Concomitant; A: Post  
 Study Drug Exposure 
7.2.5
Exposure summaries will be based on the FAS. 
Duration of study drug exposure is defined as follows: last dose date – first dose date + 1 day, 
regardless of any interruption in dosing between the first and the last dose. 
Duration of study drug exposure expressed in weeks will be summarized descriptively 
(number, mean, SD, median, minimum, and maximum) and also into the following 
categories: ≤1 weeks, >1-≤4 weeks, >4-≤8 weeks and > 8 weeks. Additionally, the total 
duration of study drug exposure, defined as the sum of all subjects’ duration of treatment 
exposure and expressed in patient years, will be provided. 
 Study Drug Compliance 
7.2.6
Study drug compliance will be measured by the compliance rate and be summarized based on 
the FAS. 
Compliance rate will be calculated as follows:  
100 × [1 - (Total number of days study drug interrupted) / (Duration of study drug exposure)]. 
The total number of days of study drug interrupted is defined as the sum of (number of 
unique days of study drug interrupted in each interruption interval), where number of days of 
study drug interrupted in each interval is defined as the interruption end date - the 
corresponding interruption start date + 1.  
The Compliance rate will be summarized descriptively by the number of subjects (n), mean, 
SD, median, min, and max and into the categories of <80% or ≥80%. 
A list of subjects with <80% of compliance rate will be provided. 
 Important Protocol Deviations 
7.2.7
Important protocol deviations (IPD) are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of the study data or that may 


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significantly affect a subject's rights, safety, or well-being. IPDs rules will be developed and 
finalized before database lock. 
The protocol deviations that should be considered as potential IPDs include, but are not 
limited to: 
 Subject entered the study despite violation of any inclusion or exclusion criteria 
 Subject was less than 80% compliant with study medications 
 Subject received excluded concomitant medications 
 Subject received the wrong treatment or incorrect doses  
 Subject remained in study despite meeting withdrawal criteria 
Occurrence of any of these events should be considered as potential IPDs, but the blinded 
team should categorize them as IPDs only if they have the potential to affect interpretation of 
study results.  
IPDs (from the clinical database or from the site deviation log) will be summarized 
descriptively based on the FAS and presented by treatment. Additionally, IPDs will be 
provided as a subject data listing. 
7.3 
Primary Safety Analysis 
 Definition of Primary Safety Endpoint 
7.3.1
Respiratory safety of TEZ/IVA is the primary objective of this study and will be assessed in 
terms of incidence, including the following respiratory adverse events of special interest 
(RAESI) while patients are on treatment: 
 Chest discomfort 
 Dyspnea (shortness of breath) 
 Respiration abnormal (chest tightness) 
 Asthma 
 Bronchial hyperreactivity 
 Bronchospasm  
 Wheezing 
A summary of RAESI will be presented by PT, relationship and severity. 
Treatment Emergent (TE) Period will follow the definition in Section 7.6 
7.3.1.1 Summaries of RAESI by Treatment Interval 
RAESI will also be summarized by PT for the following treatment intervals: 
• 
0 -1  Week: [Day 1, Day 7] 


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• 
>1 -4 Weeks: [Day 8, Day 28] 
• 
>4 -8 Weeks:  [Day 29, Day 56] 
• 
> 8 Weeks: [Day 57, End of TE period] 
Separate listings will be presented for RAESI leading to treatment discontinuation, treatment 
interruption and deaths. 
7.4 
Primary Efficacy Analysis 
The actual Bayesian posterior probability will be calculated for a greater than zero (>0) 
treatment effect difference in mean ppFEV1 change between TEZ/IVA and placebo, based on 
the observed absolute change from baseline in ppFEV1 to the average of Day 28 and Day 56. 
95% credible intervals will be provided along with the actual Bayesian posterior probability. 
7.5 
Additional Efficacy Analysis 
Unless otherwise defined, all efficacy analyses described in this section will be based on the 
FAS. The FAS will be used in the summary of demographics and baseline characteristics and 
analyses of the efficacy data; subjects will be analyzed according to their randomized 
treatment assignment. 
 Key Secondary Efficacy Endpoint 
7.5.1
7.5.1.1 Definition of Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is the absolute change in ppFEV1 from baseline to the 
average of the Day 28 and Day 56 measurements.  
ppFEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a percentage. The 
predicted FEV1 will be calculated using the Wang and Hankinson standards; details are in 
Section 10.3. 
7.5.1.2 Analysis of Key Secondary Efficacy Endpoint 
Descriptive summary statistics including: 
• 
Number of subjects (n) 
• 
Mean 
• 
Standard deviation (SD) 
• 
Median 
• 
Minimum and Maximum (Min, Max) 
will be provided for the observed values at each study time-point for the absolute of ppFEV1 
from baseline at each post-baseline visit (Day 15, Day 28 and Day 56) as well as to the 
average of Day 28 and Day 56.  


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Descriptive summary statistics will be reported for both the within-treatment arm change and 
the between-treatment arm difference of change.  
 Secondary Efficacy Endpoints 
7.5.2
The following are the secondary efficacy endpoints: 
 Relative change in ppFEV1 from baseline to the average of Day 28 and Day 56 measure-
ments 
 Absolute change in the CFQ-R respiratory domain score from baseline to the average of 
Day 28 and Day 56 measurements 
7.5.2.1 Definition of Secondary Efficacy Endpoints 
Relative change in percent predicted FEV1 from baseline to the average of Day 28 and 
Day 56 measurements 
Relative change in ppFEV1 from baseline to post-baseline measurements will be calculated 
and expressed in percentage as 100×(Post-baseline ppFEV1- Baseline ppFEV1) / Baseline 
ppFEV1  
Relative change in ppFEV1 from baseline to the average of Day 28 and Day 56 
measurements is defined as the average of relative change in percent predicted FEV1 at Day 
28 and Day 56  
Absolute change in the CFQ-R respiratory domain score from baseline to the average 
of Day 28 and Day 56 measurements 
Defined as the average of CFQ-R respiratory domain score at Day 28 and Day 56 minus 
CFQ-R respiratory domain score at baseline 
The CFQ-R1,2,3is a valid CF-specific instrument that measures quality-of-life domains. This 
study uses three different versions of CFQ-R forms in this study:  
 CFQ-R for Children Ages 12 and 13 has a total of 35 questions to form 8 domains. All 
questions are scored 1, 2, 3, or 4. 
 CFQ-R for Adolescents and Adult (subjects 14 years and older) has a total of 50 
questions to form 12 domains. Question 43, which is scored 1, 2, 3, 4, or 5, is not used in 
calculating any domain; all the other 49 questions are scored 1, 2, 3, or 4. 
 CFQ-R for Parents/Caregivers (subjects 13 years and younger) has a total of 44 questions 
to form 11 domains. Question 37, which is scored 1, 2, 3, 4, or 5, is not used in 
calculating any domains; all the other 43 questions are scored 1, 2, 3, or 4. 
For all 3 CFQ-R versions, to calculate the score for each domain, the response scores on the 
negatively phrased questions are reversed (reversed scores = 5 – response scores) so that 1 
always represents the worst condition and 4 always represents the best condition.  
The scaled score for each domain ranges from 0 (worst condition) to 100 (best condition). It 
is calculated as follows: 


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Scaled score for a domain = 100 × (mean(scores of all questions in that domain) - 1)/3 
The scaled score for a specific domain will not be calculated if more than half of the 
questions in the domain have missing scores. 
Table 7-2, Table 7-3, and Table 7-4 provide the questions included in each domain, the 
questions with the reversed scores, as well as the maximum number of missing questions for 
the CFQ-R for Children Ages 12 and 13, the CFQ-R for Adolescents and Adults, and the 
CFQ-R for Parents/Caregivers respectively. 
 
 
Table 7-2 
CFQ-R for Children Ages 12 and 13 
Domain 
Questions 
 
Reversed questions 
Maximum number of 
missing questions 
Total 
Individual 
Physical 
6 
1, 2, 3, 4, 5, 6 
1, 2, 3, 4, 5 
3 
Emotion 
8 
7, 8, 9, 10, 11, 12, 13, 14 
14 
4 
Social 
7 
20, 21, 22, 23, 24, 25, 26 
20, 22, 24, 26 
3 
Body 
3 
27, 28, 29 
- 
1 
Eat 
3 
15, 17, 19 
19 
1 
Treatment burden 
3 
16, 18, 30 
18 
1 
Respiration 
4 
31, 32, 33, 34 
- 
2 
Digestion 
1 
35 
- 
0 
 
 
Table 7-3 
CFQ-R for Adolescents and Adults (Subjects 14 Years and Older) 
Domain 
Questions 
 
Reversed questions 
Maximum number of 
missing questions 
Total 
Individual 
Physical 
8 
1, 2, 3, 4, 5, 13, 19, 20 
13 
4 
Role 
4 
35, 36, 37, 38 
35 
2 
Vitality 
4 
6, 9, 10, 11 
6, 10 
2 
Emotion 
5 
7, 8, 12, 31, 33 
- 
2 
Social 
6 
22, 23, 27, 28, 29, 30 
23, 28, 30 
3 
Body 
3 
24, 25, 26 
- 
1 
Eat 
3 
14, 21, 50 
- 
1 
Treatment burden 
3 
15, 16, 17 
15, 17 
1 
Health perceptions 
3 
18, 32, 34 
18, 32, 34 
1 
Weight 
1 
39 
- 
0 
Respiration* 
6 
40, 41, 42, 44, 45, 46 
43 
3 
Digestion 
3 
47, 48, 49 
- 
1 
*: Question 43 not used to calculate a domain. 
 


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Table 7-4 
CFQ-R for Parents/Caregivers (Subjects 13 Years and Younger) 
Domain 
Questions 
 
Reversed questions 
Maximum number of 
missing questions 
Total 
Individual 
Physical 
9 
1, 2, 3, 4, 5, 13, 14, 15, 16
15 
4 
Vitality 
5 
8, 9, 10, 11, 12 
10, 12 
2 
Emotion 
5 
6, 7, 23, 25, 26 
6 
2 
School 
3 
27, 28, 29 
28 
1 
Body 
3 
19, 20, 21 
- 
1 
Eat 
2 
17, 44 
- 
0 
Treatment burden 
3 
18, 30, 31 
31 
1 
Health perceptions 
3 
22, 24, 32 
22, 24, 32 
1 
Weight 
1 
33 
- 
0 
Respiration* 
6 
34, 35, 36, 38, 39, 40 
37 
3 
Digestion 
3 
41, 42, 43 
- 
1 
*: Question 37 not used to calculate a domain. 
7.5.2.2 Additional Secondary Endpoint 
Discontinuation rate based on study drug discontinuation through Day 56 
Discontinuation rate based on study drug discontinuation through Day 56 is defined (in 
percentage) as 100 × [the number of subjects who permanently discontinued study drug 
before Day 56 visit / by the number of subjects in the FAS set].   
7.5.2.3 Analysis of Secondary Efficacy Endpoints 
Relative change in ppFEV1 from baseline to the average of Day 28 and Day 56 meas-
urements 
Analysis for the relative change in ppFEV1 through from baseline to the average of Day 28 
and Day 56 measurements will be similar to that for the key secondary endpoint analysis by 
providing the following descriptive summary statistics: 
– Number of subjects (n) 
– Mean 
– Standard deviation (SD) 
– Median 
– Minimum and Maximum (Min, Max) 
These descriptive summary statistics will be provided for the observed values at each study 
time-point for the relative change of ppFEV1 from baseline at each post-baseline visit (Day 
15, Day 28 and Day 56) as well as to the average of Day 28 and Day 56.  


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Descriptive summary statistics will be reported for both the within-treatment arm change and 
the between-treatment arm difference of change.  
Absolute change in the CFQ-R respiratory domain score from baseline to the average 
of Day 28 and Day 56 measurements 
Analysis for the absolute change in CFQ-R respiratory domain score (Pooled 'Children Ages 
12 and 13' Version and 'Adolescents and Adults' Version) will be similar to that for the key 
secondary endpoint analysis by providing the following descriptive summary statistics: 
– Number of subjects (n) 
– Mean 
– Standard deviation (SD) 
– Median 
– Minimum and Maximum (Min, Max) 
These descriptive summary statistics will be provided for the observed values at each study 
time-point for the absolute change in CFQ-R respiratory domain score (Pooled 'Children 
Ages 12 and 13' Version and 'Adolescents and Adults' Version) from baseline at each post-
baseline visit (Day 15, Day 28 and Day 56) as well as to the average of Day 28 and Day 56.  
Descriptive summary statistics will be reported for both the within-treatment arm change and 
the between-treatment arm difference of change.  
7.5.2.4 Multiplicity adjustment 
No multiplicity adjustment will be made for the analysis of secondary endpoints.  
7.5.2.5 Analysis of Additional Secondary Endpoint 
Discontinuation rate based on study drug discontinuation through Day 56 
Discontinuation rate based on study drug discontinuation through Day 56 will be summarized 
by the proportions by treatment arms as well as in the overall population. 
7.6 
Additional Safety Analysis 
All safety analyses will be based on the Safety Set. Subjects will be analyzed according to 
the treatment they actually received if they took the same study drug during the entire study 
period. For subjects receiving study drug from more than one treatment group by error, the 
treatment group allocation will be TEZ/IVA.  
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:   


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 Adverse events 
 Clinical laboratory values (hematology, serum chemistry, coagulation studies and 
urinalysis) 
 Vital signs  
 Pulse oximetry 
 Postdose spirometry on Day 1. 
Safety endpoints will be analyzed using data during the treatment emergent period. Only 
descriptive summaries will be presented and no statistical testing is planned.  
Treatment Emergent (TE) Period will be defined in the following way: 
 For patients who complete the Safety Follow-up Contact, the TE period will include the 
time from the first dose of the study drug to the Safety Follow-up Contact.  
 For subjects who discontinue and have an ETT Visit but no Safety Follow-up Contact, 
the TE period will include the time from the first dose of the study drug until the ETT 
visit. 
 For subjects who withdraw consent, the TE period includes the time from the first dose of 
the study drug until withdrawal. 
 For subjects who enroll in Study VX14-661-110 (EU only) or in the EAP (US only), the 
TE period in this study (Study 114) will include the time from the first dose of study drug 
in this study until the earlier of last study participation day OR until 28 days after the last 
dose of the study drug in Study 114. 
 For all other subjects, including those who do not have a Safety Follow-up Contact, the 
TE period includes the time from the first dose of the study drug until the earlier of last 
study participation day OR until 28 days after the last dose of the study drug.  
For the purpose of safety analyses, the entire study period will then be further divided into 3 
segments: 
 
The pre-treatment period is the period after the informed consent/assent date and before 
the start date of the TE period. 
 
The treatment-emergent period (TE period) is defined as above. 
 
The post-treatment period is the period after the end of the TE period to the date of the 
last study record in the clinical database. 
 Adverse Events  
7.6.1
For analysis purposes, AEs will be categorized as pretreatment AEs, treatment-emergent 
adverse events (TEAEs), or post-treatment AEs: 
 Pre-treatment AE: any AE that started before the first dose of study drug. 
 TEAE: any AE that increased in severity or that was newly developed at or after the first 
dose of study drug through the end of TE period. 


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 Post-treatment AE: any AE that increased in severity or that was newly developed after 
the TE period. 
For AEs with a missing or partial start date, if there is no clear evidence that the AEs started 
(or increased in severity) before or after the first dose date, the start date will be imputed to 
be the first dose date and the AE will be considered to be a TEAE (see Section 10.7). 
Similarly, if there is no clear evidence that the AEs started (or increased in severity) before or 
after the start of the post-treatment period, the start date will be imputed to be the earliest 
possible time in the TEAE period and the AE will be considered to be a TEAE. As an 
intermediate step for programming purposes, imputation rules for missing or partially 
missing AE start/end dates are defined in Section 10.7. 
Based on the reported severity and relationship to study drugs, TEAEs can be categorized as 
follows: 
By relationship to the study drugs, treatment emergent adverse events (TEAEs) will be 
classified into the 4 categories: 
 
Not related 
 
Unlikely related 
 
Possibly related 
 Related. 
By severity, TEAEs will be classified into the 4 categories: 
 Mild (Grade 1): Mild level of discomfort and does not interfere with regular 
activities 
 Moderate (Grade 2): Moderate level of discomfort and significantly interferes with 
regular activities 
 Severe (Grade 3): Significant level of discomfort and prevents regular activities 
 Life-threatening (Grade 4 and 5): Any adverse drug experience that places the 
subject, in the view of the investigator, at immediate risk of death. 
7.6.1.1 Overview of Pre-treatment AEs and Treatment Emergent AEs 
An overview of the pre-treatment AEs will be summarized in the following categories: 
 Any pre-treatment AEs 
 Grade 3/4 pre-treatment AEs 
 Pre-treatment SAEs by severity. 
An overview of all TEAEs will be summarized in the following categories: 
 Any TEAEs  
 Grade 3/4 TEAEs 
 TEAEs by relationship 
 TEAEs by severity 


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 TEAEs leading to treatment discontinuation (this category will capture TEAEs leading to 
discontinuation of either the morning or the evening tablets) 
 TEAEs leading to treatment interruption (this category will capture TEAEs leading to 
interruption of either the morning or the evening tablets) 
 Related TEAEs 
 Serious TEAEs (TE SAEs) 
 TE SAEs by relationship 
 TE SAEs by severity 
 Related serious TEAEs 
 TEAE leading to death  
7.6.1.2 TEAEs and TE SAEs by System Organ Class (SOC) and Preferred Term 
(PT) 
The number and percentage of subjects with TEAEs will be summarized by treatment group, 
MedDRA system organ class (SOC), and preferred term (PT), where multiple occurrences of 
the same AE for the same subject will be counted only once. The summary table will be 
presented in descending order of frequencies in the TEZ/IVA treatment group. TE SAEs will 
be summarized similarly. 
7.6.1.3 TEAEs and TE SAEs by Preferred Term (PT) 
The number and percentage of subjects with TEAEs will be summarized by treatment group 
and PT, where multiple occurrences of the same AE for the same subject will be counted 
only once. The summary table will be presented in descending order of frequencies in the 
TEZ/IVA treatment group. TE SAEs will be summarized similarly. 
7.6.1.4 TEAEs and TE SAEs by SOC, PT, and Relationship 
The number and percentage of subjects with TEAEs will be summarized by treatment group, 
SOC, PT, and relationship, where multiple occurrences of the same AE for the same subject 
will be counted only once according to the worst relationship to study drug. The summary 
table will be presented in descending order of frequencies in the TEZ/IVA treatment group. 
TE SAE will be summarized similarly. 
7.6.1.5 TEAEs and TE SAEs by SOC, PT, and Severity 
The number and percentage of subjects with TEAEs will be summarized by treatment group, 
SOC, PT, and severity, where multiple occurrences of the same AE for the same subject will 
be counted only once according to the worst severity. The summary table will be presented in 
descending order of frequencies in the TEZ/IVA treatment group. TE SAE will be 
summarized similarly. 


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7.6.1.6 Elevated Transaminase 
The following AE preferred terms will be selected for elevated transaminase: 
 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. 
A summary of elevated transaminase will be presented by preferred term. 
Separate listings will be presented for TEAEs leading to treatment discontinuation, treatment 
interruption, TE SAEs, and all deaths. 
For all AEs, the CRF captures the action taken for TEZ/IVA pills separately from the AE ac-
tion taken for IVA monotherapy pills. As a result, it is possible that, in the final database (af-
ter DBL), the AE actions taken for the two agents (fixed dose TEZ/IVA and IVA monothera-
py) are different.  The summaries and listings of “AE Leading to Treatment Discontinuation” 
and “AE Leading to Treatment Interruption” account for discontinuation and interruptions 
for either agent.  
 Clinical Laboratory Values 
7.6.2
For treatment emergent laboratory measurements, the raw values and change from baseline 
values for the continuous hematology, chemistry, and coagulation results will be summarized 
in SI units by treatment group at each scheduled time point. For hematology, chemistry, and 
coagulation, the number and percentage of subjects with an abnormal low (<LLN) value and 
with an abnormal high (>ULN) value at each scheduled time point will be summarized. 
The number and percentage of subjects with hematology, chemistry and coagulation values 
meeting the defined threshold criterion will be summarized by treatment, lab parameters, and 
visit. The threshold criteria are provided in Section 10.5, Table 10-8 and Table 10-9. 
In addition, a listing containing individual subject hematology, chemistry, and coagulation 
values outside the reference ranges will be provided. This listing will include data from 


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scheduled and unscheduled time points. Subjects with positive pregnancy test results will be 
listed. Abnormal urinalysis results also will be listed by treatment and subject. 
 Vital Signs 
7.6.3
For treatment emergent vital signs measurements, the raw values and changes from baseline 
will be summarized by treatment group at each scheduled time point for systolic and diastolic 
blood pressure (mmHg), HR (beats per minute), and respiratory rate (breaths per minute). In 
addition, the mean value at each time point will be plotted by treatment group for systolic 
and diastolic blood pressure. 
The number and percentage of subjects with vital signs meeting threshold criteria during the 
treatment-emergent period will be summarized by treatment, vital signs parameters, and visit. 
The threshold criteria are provided in Section 10.5, Table 10-7. 
 Pulse Oximetry 
7.6.4
A summary of raw values and change from baseline values will be provided by treatment 
group at each scheduled time point for the percent of oxygen saturation by pulse oximetry. In 
addition, the mean value at each visit will be plotted by treatment group for the percent of 
oxygen saturation.  
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the 
treatment-emergent period will be tabulated by treatment groups. 
 Postdose Spirometry on Day 1 
7.6.5
For the 2-hour and 4-hour postdose measurements on Day 1, a summary of raw values and 
absolute change from predose percent predicted FEV1 will be provided by treatment at Day 1. 
The absolute change from the Day 1 predose value of percent predicted FEV1 will be 
summarized by treatment at each time point. In addition, the number and percentage of 
subjects with percent predicted FEV1 decline of ≥10, ≥15, and ≥20 percentage points in the 
absolute change from the Day 1 predose value will be summarized by treatment and by 
assessment time. Subjects with percent predicted FEV1 decline ≥10 percentage points will be 
listed.   
 
 Physical Examination 
7.6.6
Abnormal PE findings will be presented in a data listing only. 


Statistical Analysis Plan (Methods) 
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8 
INTERIM AND DMC ANALYSES 
8.1 
Interim Analysis 
8.2 
No interim analysis is planned for this study. DMC Analysis 
An independent data monitoring committee (IDMC) was formed before study initiation. The 
IDMC’s objectives and operational details were defined in a separate document (IDMC 
Charter) which was finalized before the first subject was screened in the study. The IDMC 
conducted regular planned safety reviews of study data as outlined in the IDMC Charter and 
IDMC Analysis Plan. The first DMC analysis will be performed when approximately 50% of 
subjects have completed their Day 56 visit at the same time of the planned interim analysis. 
 


Statistical Analysis Plan (Methods) 
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9 
REFERENCES
                                                 
1 Quittner AL, Modi A, Cruz I. Systematic review of health-related quality of life measure 
for children with respiratory conditions. Pediatr Respir Rev. 2008;9:220-32. 
2 Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
3 Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of 
life for children with cystic fibrosis. J Pediatr Psychol. 2003;28(8):535-45.  
4 Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general U.S. population. Am J Respir Crit Care Med. 1999; 159:179-87. 
5 Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG. Pulmonary function between 6 and 
18 years of age. Pediatr Pulmonol. 1993; 15:75-88. 
  


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10 APPENDICES 
10.1 Schedule of Assessments 
Table 10-1 
Study VX16-661-114: Screening 
Event/Assessment 
Screening Visit 
Day -28 to Day -1 
Informed consent and assent (when applicable) 
X 
Demographics 
X 
Medical history 
X 
CFTR genotypea 
X 
Ophthalmologic examinationb 
X 
Prior and concomitant medicationsc 
X 
Height and weight (measured with shoes off) 
X 
Vital signsd 
X 
Pulse oximetryd 
X 
Physical examination of all body systems 
X 
Serum FSHe (amenorrheic female subjects only) 
X 
Serum pregnancy testf  
X 
Safety labsg 
X 
Spirometryh 
X 
Inclusion/exclusion criteria review 
X 
AEs and SAEs 
Continuous from signing of informed consent 
form (ICF) and assent (where applicable) 
through Safety Follow-up Contact 
AE: adverse event; CFTR: cystic fibrosis transmembrane conductance regulator;; FSH: follicle-stimulating hormone; ICF: 
informed consent form; SAE: serious adverse event  
  
 
 
 
 
                                                 
a  Only if the CFTR genotype is not documented in the subject’s medical record. 
b  An ophthalmologic examination is required for subjects <18 years who did not have an ophthalmologic examination prior to 
starting Orkambi if they have not have one within 6 months prior to the Screening Period. Subjects who have documentation 
of bilateral lens removal do not need an ophthalmologic exam (protocol section 11.4.7). 
c  
All medications taken within 28 days before the Screening Period through the end of the study will be recorded.  
d  Vital signs (pulse rate, blood pressure, and respiration rate) and pulse oximetry will be collected after the subject has been at 
rest in the seated or supine position for at least 5 minutes. 
e  
FSH will be measured for any potentially postmenopausal female with at least 12 months of continuous spontaneous 
amenorrhea.  
f  
Any female subject who does not meet the criteria for non-childbearing potential is considered to be of childbearing potential 
and must have a serum pregnancy test (See protocol section 11.4.4.1).  
g  Includes serum chemistry, hematology, coagulation and urinalysis. 
h  Spirometry may be performed pre- or post-bronchodilator (See protocol section 11.3.1). Screening spirometry evaluation may 
be repeated, as specified in protocol section 9.1.1.1. 


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Table 10-2 
Study VX16-661-114: Treatment Period, ETT, and Safety Follow-up 
Contact Assessments 
Event/Assessmenti 
Day 1 
Day 3 
Telephone 
Contactj 
Day 15 
(± 3 
Days) 
Day 28 
(± 5 
Days) 
Day 56 
(± 5 
Days) 
Early 
Termination 
of 
Treatmentk 
Safety 
Follow-up 
Contact 
28 (± 7) Days 
After Last 
Dose of 
Study Drugl 
Inclusion and exclusion 
criteria review 
X 
 
X 
X 
X 
 
 
Randomizationm 
X 
 
 
 
 
 
 
Clinic visit 
X 
 
X 
X 
X 
X 
 
CFQ-Rn 
X 
 
X 
X 
X 
X 
 
Spirometryo 
X 
 
X 
X 
X 
X 
 
Height (<18 years old 
only) 
X 
 
X 
X 
X 
X 
 
Vital signsp  
X 
 
X 
X 
X 
X 
 
Pulse oximetryh 
X 
 
X 
X 
X 
X 
 
Physical examinationq 
X 
 
 
 
 
X 
 
Pregnancy test  
urine 
 
urine 
urine 
serum 
serum 
 
Safety labsr 
X 
 
X 
 
X 
X 
 
                                                 
i      All assessments will be performed before dosing unless noted otherwise 
j  
On Day 3, there is a telephone contact to collect AEs. 
k 
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after 
the decision to terminate study treatment. Subjects who prematurely discontinue study drug treatment will also be required 
to complete the Safety Follow-up Contact, approximately 28 (± 7) days after their last dose of study drug. If the ETT Visit 
occurs 3 weeks or later following the last dose of study drug, then the ETT Visit will replace the Safety Follow-up Contact, 
and a separate Safety Follow-up Contact will not be required. See protocol section 9.1.4. 
l 
Telephone contact may be acceptable. A clinic visit may be required at the discretion of the investigator. The Safety 
Follow up Visit is not required for subjects who complete the Day 56 Visit and enroll in a long-term, open-label safety study 
of TEZ/IVA within 28 days after the last dose of study drug. 
m 
Randomization must occur after all inclusion and exclusion criteria are met and before the first dose of study drug. 
Randomization will be done through IWRS. Randomization may occur on Day -1. 
n 
The CFQ-R must be completed as the first assessment at each visit. 
o     Predose spirometry must be performed before dosing and should be performed prebronchodilator at all visits. Postdose 
spirometry will be performed at 2 hours (± 30 minutes) and 4 hours (± 30 minutes) after dosing on Day 1 only. 
p 
Vital signs (pulse rate, blood pressure, and respiration rate) and pulse oximetry will be collected after the subject has 
been at rest in the seated or supine position for at least 5 minutes. 
q 
In addition to the complete PEs indicated, symptom-targeted PEs may occur at any time during the study if triggered by 
AEs or if deemed necessary by the investigator. 
r  
Includes serum chemistry, hematology, coagulation and urinalysis. 


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Table 10-2 
Study VX16-661-114: Treatment Period, ETT, and Safety Follow-up 
Contact Assessments 
Event/Assessmenti 
Day 1 
Day 3 
Telephone 
Contactj 
Day 15 
(± 3 
Days) 
Day 28 
(± 5 
Days) 
Day 56 
(± 5 
Days) 
Early 
Termination 
of 
Treatmentk 
Safety 
Follow-up 
Contact 
28 (± 7) Days 
After Last 
Dose of 
Study Drugl 
Snack or meal at sites 
X 
 
X 
X 
X 
 
 
Study drug dosingt 
X 
 
X 
X 
X 
 
 
Study drug count 
X 
 
X 
X 
X 
X  
 
Concomitant 
medications  
X 
 
X 
X 
X 
X 
X 
Concomitant treatment 
and procedures review 
X 
 
X 
X 
X 
X 
X 
AEs and SAEs 
Continuous from signing of the ICF and assent (where applicable) through the 
Safety Follow-up Contactu 
                                                 
s 
Fat-containing food such as a "standard CF" high-fat, high-calorie meal or snack will be provided at the site to subjects 
after all predose assessments have occurred. 
t 
On days of scheduled visits, the morning dose of study drug will be administered at the site after predose assessments 
have been completed. At the discretion of the Investigator, subjects may be asked to remain at the site for up to 6 hours after 
receiving the first dose of study drug on Day 1. 
u 
For enrolled subjects who do not have a Safety Follow-up Contact, AEs and SAEs will be collected through the earliest 
of either 28 days after the last dose of study drug, or the ETT Visit (if that visit is 3 weeks or later following the last dose of 
study drug). For subjects who complete the study and enroll in a long-term, open-label safety study of TEZ/IVA, AEs and 
SAEs will be collected through before the first dose of study drug in the safety study. 


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10.2 Analysis Visit Window Mapping Rules for Efficacy and Safety 
Measurements 
Table 10-3 
Visit Window Mapping Rules  
Assessments 
Visit 
Target Study Day 
Visit Window  
(in study days) 
 Height (<18 years 
only) 
 CFQ-R 
 Pregnancy test 
 Vital signs 
 Pulse oximetry 
 Spirometry 
 Safety Labs 
 
Baseline  
1 
[screening visit, pre-
dose Day 1] 
Day 1 Predose and Postdose (only 
for Spirometry) 
1 
 [1,1] 
Day 15  
15 
[2, 22] 
Day 28 (safety labs not collected) 
29 
[23,43] 
Day 56  
57 
[44,78] 
ETT 
 
N/A 
 
Follow the individual 
visit window to be 
mapped to individual 
visits 
 
 
Safety Follow-up (SFU) 
N/A 
Nominal 
 
Note:  
1. 
To apply the above visit windows, please first determine the baseline measurements 
based on the first dose of study medication and then label Day 1 for the date of the first 
dose of study drug, and use the nominal visit names to label SFU (for safety). 
2. 
After baseline, and SFU (only for concomitant medications and treatments) 
measurements are determined; the above visit windows will be applied to determine the 
analysis visit names for all remaining measures at scheduled or unscheduled visits.  
3. 
If there is no scheduled Day 1 post dose visit, any assessments on Day 1 after the first 
dose will be considered for the window of next visit. 
4. 
For all efficacy parameters, if there are multiple measurements within a visit window, 
the record at the scheduled visit will be used.  
 
If there are no measurements at the scheduled visit, then the record closest to the 
target day will be used;  
 
If there are multiple records with the same distance to the target day, the latest 
record will be used.   
5. 
For all safety parameters, if there are multiple measurements within a visit window, then 
1) the record closest to the target day will be used; or 2) if there are multiple records 
within the same distance from the target day, the latest record will be used. 
6. 
Spirometry are following the efficacy windowing rules. 


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10.3 Coefficients for Hankinson and Wang Methods for Calculating Predicted 
Spirometry Parameters 
Percent predicted FEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a 
percentage. The predicted FEV1 (L) will be calculated using the Hankinson1 and Wang2 
standards.  
The Hankinson standard will be applied to male subjects 18 years and older and female 
subjects 16 years and older; the Wang standard will be applied to male subjects 6 to 17 years 
and female subjects 6 to 15 years of age. Subjects in whom the Wang standard is applied at 
the Screening Visit will have the Wang standard applied throughout the study, even if there is 
a change in age during the course of the study that would otherwise necessitate use of the 
Hankinson standard. 
 
Hankinson Normal Values (HNVs) will be calculated for FEV1, forced vital capacity (FVC), 
forced expiratory flow mid expiratory phase (FEF25-75%), and FEV1/FVC% using the 
Hankinson equation:  
Predicted lung function parameter = b0+b1 × age+b2 × age2+ b3 × height2 
In the equation, height is given in centimeters, age is given in years, and the coefficients b0, 
b1, b2, and b3 are determined based on subject’s sex, race, and age group as shown in Table 
10-4. 
Wang Normal Values (WNVs) will be calculated for FEV1, FVC, FEF25-75%, and FEV1/FVC 
using the Wang equation:  
ln(Predicted lung function parameter) =  + βln (height) 
Wang Normal Values (WNVs) will be calculated for FEV1, FVC, FEF25-75%, and FEV1/FVC 
using the Wang equation. In the equation, height is given in meters, and the coefficients α 
and β are determined based on subject’s sex, race, and age as shown in Table 10-5 and Table 
10-6. 
If either height or age is missing, and the spirometry measurement is non-missing, the last 
non-missing value of height and age will be used in the calculation of predicted values. 
  
 
 


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Table 10-4 
HNVs Equation Coefficients by Sex, Race, and Age 
Parameter 
Sex 
Race 
Age 
(years) 
bo 
b1 
b2 
b3 
HNVFEV1 
Male 
Caucasian 
<20 
-0.7453 
-0.04106 
0.004477 
0.00014098 
≥20 
0.5536 
-0.01303 
-0.000172 
0.00014098 
African 
American 
<20 
-0.7048 
-0.05711 
0.004316 
0.00013194 
≥20 
0.3411 
-0.02309 
 
0.00013194 
Mexican 
American 
<20 
-0.8218 
-0.04248 
0.004291 
0.00015104 
≥20 
0.6306 
-0.02928 
 
0.00015104 
Female 
Caucasian 
<18 
-0.8710 
0.06537 
 
0.00011496 
≥18 
0.4333 
-0.00361 
-0.000194 
0.00011496 
African 
American 
<18 
-0 9630 
0.05799 
 
0.00010846 
≥18 
0.3433 
-0.01283 
-0.000097 
0.00010846 
Mexican 
American 
<18 
-0 9641 
0.06490 
 
0.00012154 
≥18 
0.4529 
-0.01178 
-0.000113 
0.00012154 
HNVFVC 
Male 
Caucasian 
<20 
-0.2584 
-0.20415 
0.010133 
0.00018642 
≥20 
-0.1933 
0.00064 
-0.000269 
0.00018642 
African 
American 
<20 
-0.4971 
-0.15497 
0.007701 
0.00016643 
≥20 
-0.1517 
-0.01821 
 
0.00016643 
Mexican 
American 
<20 
-0.7571 
-0.09520 
0.006619 
0.00017823 
≥20 
0.2376 
-0.00891 
-0.000182 
0.00017823 
Female 
Caucasian 
<18 
-1.2082 
0.05916 
 
0.00014815 
≥18 
-0.3560 
0.01870 
-0.000382 
0.00014815 
African 
American 
<18 
-0.6166 
-0.04687 
0.003602 
0.00013606 
≥18 
-0.3039 
0.00536 
-0.000265 
0.00013606 
Mexican 
American 
<18 
-1 2507 
0.07501 
 
0.00014246 
≥18 
0.1210 
0.00307 
-0.000237 
0.00014246 
HNVFEF25-75% 
Male 
Caucasian 
<20 
-1.0863 
0.13939 
 
0.00010345 
≥20 
2.7006 
-0.04995 
 
0.00010345 
African 
American 
<20 
-1 1627 
0.12314 
 
0.00010461 
≥20 
2.1477 
-0.04238 
 
0.00010461 
Mexican 
American 
<20 
-1 3592 
0.10529 
 
0.00014473 
≥20 
1.7503 
-0.05018 
 
0.00014473 
Female 
Caucasian 
<18 
-2.5284 
0.52490 
-0.015309 
0.00006982 
≥18 
2.3670 
-0.01904 
-0.000200 
0.00006982 
African 
American 
<18 
-2 5379 
0.43755 
-0.012154 
0.00008572 
≥18 
2.0828 
-0.03793 
 
0.00008572 
Mexican 
American 
<18 
-2 1825 
0.42451 
-0.012415 
0.00009610 
≥18 
1.7456 
-0.01195 
-0.000291 
0.00009610 
HNVFEV1/FVC% 
Male 
Caucasian 
 
88.066 
-0.2066 
 
 
African 
American 
 
89.239 
-0.1828 
 
 
Mexican 
American 
 
90.024 
-0.2186 
 
 
Female 
Caucasian 
 
90.809 
-0.2125 
 
 
African 
American 
 
91.655 
-0.2039 
 
 
 
 
Mexican 
American 
 
92.360 
-0.2248 
 
 
Source: Reference 4. (Tables 4, 5 and 6) 
 


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Table 10-5 
WNVs Equation Coefficients by Sex and Age in White Boys and 
Girls 
 
 
FEV1 
FVC 
FEF25-75%
FEV1/FVC
Sex 
Age 
α 
β 
α 
β 
α 
β 
α 
β 
Male 
6 
-0.109 
2.252 
-0.024 
2.470 
 
 
-0.078 
-0.248 
7 
-0.104 
2.270 
-0.018 
2.489 
 
 
-0.086 
-0.220 
8 
-0.089 
2.257 
0.005 
2.443 
0.264 
1.505 
-0.091 
-0.199 
9 
-0.063 
2.197 
0.017 
2.426 
0.308 
1.443 
-0.086 
-0.206 
10 
-0.057 
2.212 
0.030 
2.407 
0.290 
1.557 
-0.081 
-0.209 
11 
-0.093 
2.324 
0.009 
2.468 
0.242 
1.738 
-0.101 
-0.147 
12 
-0.161 
2.512 
-0.061 
2.649 
0.165 
1.982 
-0.101 
-0.133 
13 
-0.292 
2.843 
-0.175 
2.924 
0.007 
2.396 
-0.116 
-0.085 
14 
-0.329 
2.983 
-0.219 
3.060 
0.014 
2.483 
-0.106 
-0.087 
15 
-0.141 
2.709 
-0.079 
2.859 
0.241 
2.163 
-0.060 
-0.155 
16 
0.062 
2.409 
0.104 
2.591 
0.503 
1.764 
-0.045 
-0.178 
17 
0.262 
2.099 
0.253 
2.374 
0.762 
1.368 
0.008 
-0.272 
Female 
6 
-0.109 
1.949 
-0.013 
2.007 
 
 
-0.097 
-0.055 
7 
-0.144 
2.243 
-0.062 
2.385 
 
 
-0.084 
-0.132 
8 
-0.137 
2.239 
-0.055 
2.381 
0.247 
1.668 
-0.079 
-0.152 
9 
-0.123 
2.222 
-0.039 
2.351 
0.254 
1.710 
-0.084 
-0.128 
10 
-0.161 
2.364 
-0.068 
2.458 
0.195 
1.933 
-0.092 
-0.097 
11 
-0.223 
2.558 
-0.120 
2.617 
0.161 
2.091 
-0.102 
-0.061 
12 
-0.264 
2.709 
-0.174 
2.776 
0.185 
2.120 
-0.090 
-0.067 
13 
-0.153 
2.535 
-0.061 
2.576 
0.294 
1.976 
-0.093 
-0.040 
14 
0.046 
2.178 
0.139 
2.208 
0.450 
1.711 
-0.096 
-0.026 
15 
0.148 
2.008 
0.210 
2.099 
0.581 
1.486 
-0.062 
-0.093 
Source: Reference 5. (Tables 2 and 3) 
 


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Table 10-6 
WNVs Equation Coefficients by Sex and Age in Black Boys and 
Girls 
 
 
FEV1 
FVC 
FEF25-75%
FEV1/FVC 
Sex 
Age 
α 
β 
α 
β 
α 
β 
α 
β 
Male 
6 
-0.166 
1.723 
-0.088 
1.961 
 
 
-0.091 
-0.152 
7 
-0.122 
1.846 
-0.040 
2.040 
 
 
-0.091 
-0.153 
8 
-0.225 
2.271 
-0.094 
2.323 
0.097 
1.544 
-0.118 
-0.104 
9 
-0.142 
2.059 
-0.074 
2.308 
0.255 
1.248 
-0.079 
-0.218 
10 
-0.157 
2.117 
-0.110 
2.417 
0.230 
1.428 
-0.047 
-0.303 
11 
-0.176 
2.166 
-0.138 
2.453 
0.256 
1.438 
-0.048 
-0.263 
12 
-0.307 
2.548 
-0.224 
2.710 
0.085 
1.936 
-0.084 
-0.162 
13 
-0.486 
2.962 
-0.342 
2.975 
-0.121 
2.476 
-0.141 
-0.018 
14 
-0.472 
3.010 
-0.337 
3.035 
-0.115 
2.536 
-0.123 
-0.050 
15 
-0.318 
2.789 
-0.226 
2.889 
0.170 
2.120 
-0.070 
-0.140 
16 
0.074 
2.140 
0.058 
2.425 
0.663 
1.299 
0.018 
-0.289 
17 
0.053 
2.223 
0.148 
2.310 
0.505 
1.618 
-0.095 
-0.087 
Female 
6 
-0.288 
2.182 
-0.172 
2.117 
 
 
-0.109 
0.059 
7 
-0.250 
2.158 
-0.135 
2.132 
 
 
-0.104 
-0.030 
8 
-0.276 
2.295 
-0.176 
2.362 
-0.283 
2.990 
-0.103 
-0.066 
9 
-0.294 
2.330 
-0.200 
2.452 
0.025 
2.062 
-0.097 
-0.104 
10 
-0.344 
2.507 
-0.230 
2.571 
0.051 
2.028 
-0.120 
-0.043 
11 
-0.308 
2.460 
-0.204 
2.526 
0.078 
2.006 
-0.089 
-0.105 
12 
-0.219 
2.312 
-0.107 
2.342 
0.225 
1.804 
-0.115 
-0.021 
13 
-0.117 
2.196 
-0.042 
2.294 
0.418 
1.504 
-0.051 
-0.148 
14 
0.041 
1.920 
0.105 
2.021 
0.574 
1.257 
-0.063 
-0.103 
15 
0.203 
1.662 
0.253 
1.787 
0.599 
1.281 
-0.043 
-0.139 
Source: Reference 5. (Tables 4 and 5) 
 




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10.5 Threshold Analysis Criteria 
Table 10-7 
Threshold Criteria for Clinical Chemistry and Hematology 
Parameter 
Threshold Criteria 
Comments 
Clinical Chemistry 
CPK 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
CTCAE grades 1-4 
Creatinine 
>ULN - ≤ 1.5 x ULN 
>1.5 - ≤ 3.0 x ULN 
>3.0 - ≤ 6.0 x ULN 
>6.0 x ULN 
CTCAE grades 1-4 
Blood Urea Nitrogen >ULN - ≤ 1.5 x ULN 
>1.5 - ≤ 3.0 x ULN 
>3.0 - ≤ 6.0 x ULN 
>6.0 x ULN 
Same criteria as creatinine  
 
No CTCAE  
Sodium 
Hyponatremia 
<LLN - ≥130 mmol/L 
<130 – ≥120 mmol/L  
<120 mmol/L  
CTCAE grade 1, 3, 4 
 
(No CTCAE grade 2) 
 
Hypernatremia 
>ULN - ≤ 150 mmol/L 
>150 mmol/L- ≤155 mmol/L  
>155 mmol/L - ≤ 160 mmol/L 
>160 mmol/L 
CTCAE grade 1-4 
Potassium 
Hypokalemia 
 <LLN – ≥ 3.0 mmol/L 
 <3.0 – ≥ 2.5 mmol/L 
 <2.5 mmol/L 
CTCAE grade 1&2, 3, 4 
  
(Grade 1 and 2 are the same) 
 
Hyperkalemia 
>ULN – ≤ 5.5 mmol/L 
>5.5 –  ≤ 6.0 mmol/L  
>6.0 – ≤ 7.0 mmol/L  
>7.0 mmol/L 
CTCAE grade 1-4 
Glucose 
Hypoglycemia 
<3.0 – ≥ 2.2 mmol/L  
<2.2 - ≥ 1.7 mmol/L 
<1.7 mmol/L 
CTCAE grade 1-4 
 
Hyperglycemia  
>ULN - ≤ 8.9 mmol/L 
>8.9 – ≤ 13.9 mmol/L 
>13.9 – ≤ 27.8 mmol/L  
>27.8 mmol/L 
CTCAE grade 1-4 
Albumin 
<35 - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L  
CTCAE grade 1-3 
 


Statistical Analysis Plan (Methods) 
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Table 10-7 
Threshold Criteria for Clinical Chemistry and Hematology 
Amylase 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.0 x ULN  
>2.0 – ≤ 5.0 x ULN 
>5.0 x ULN 
CTCAE grade 1-4 
Lipase 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.0 x ULN  
>2.0 – ≤ 5.0 x ULN 
>5.0 x ULN 
CTCAE grade 1-4 
Direct bilirubin 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2 x ULN 
>2 – ≤ 3 x ULN  
>3 – ≤ 10 x ULN 
>10 x ULN 
Same Criteria as Total Bilirubin 
 
No CTCAE  
Not in DILI Guidance 
 
GGT  
>ULN - ≤ 2.5 x ULN 
>2.5 –  ≤ 5.0 x ULN 
>5.0 –  ≤ 20.0 x ULN  
>20.0 x ULN 
CTCAE grade 1-4 
Calcium 
Hypercalcemia 
>ULN - ≤ 2.9 mmol/L  
>2.9 – ≤ 3.1 mmol/L  
>3.1 – ≤ 3.4 mmol/L  
>3.4 mmol/L 
CTCAE grade 1-4 
 
Hypocalcemia 
<LLN - ≥ 2.0 mmol/L 
<2.0 – ≥1.75 mmol/L  
<1.75 – ≥ 1.5 mmol/L  
<1.5 mmol/L  
CTCAE grade 1-4 
Magnesium 
 
Hypermagnesemia 
>ULN - ≤ 1.23 mmol/L 
>1.23 – ≤ 3.30 mmol/L 
>3.30 mmol/L 
CTCAE grade 1, 3, 4 
 
No CTCAE grade 2 
Hypomagnesemia 
<LLN - ≥ 0.5 mmol/L 
<0.5 – ≥ 0.4 mmol/L 
<0.4 – ≥ 0.3 mmol/L  
<0.3 mmol/L  
CTCAE grade 1-4 
CPK 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
CTCAE grades 1-4 
Creatinine 
>ULN - ≤ 1.5 x ULN 
>1.5 - ≤ 3.0 x ULN 
>3.0 - ≤ 6.0 x ULN 
>6.0 x ULN 
CTCAE grades 1-4 
Blood Urea Nitrogen >ULN - ≤ 1.5 x ULN 
>1.5 - ≤ 3.0 x ULN 
>3.0 - ≤ 6.0 x ULN 
>6.0 x ULN 
Same criteria as creatinine  
 
No CTCAE  


Statistical Analysis Plan (Methods) 
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Table 10-7 
Threshold Criteria for Clinical Chemistry and Hematology 
Sodium 
Hyponatremia 
<LLN - ≥130 mmol/L 
<130 – ≥120 mmol/L  
<120 mmol/L  
CTCAE grade 1, 3, 4 
 
(No CTCAE grade 2) 
Hypernatremia 
>ULN - ≤ 150 mmol/L 
>150 - ≤155 mmol/L  
>155 - ≤ 160 mmol/L 
>160  
CTCAE grade 1-4 
Potassium 
Hypokalemia 
 <LLN – ≥ 3.0 mmol/L 
 <3.0 – ≥ 2.5 mmol/L 
 <2.5 mmol/L 
CTCAE grade 1&2, 3, 4 
  
(Grade 1 and 2 are the same) 
Hyperkalemia 
>ULN – ≤ 5.5 mmol/L 
>5.5 –  ≤ 6.0 mmol/L  
>6.0 – ≤ 7.0 mmol/L  
>7.0 mmol/L 
CTCAE grade 1-4 
Glucose 
Hypoglycemia 
<3.0 – ≥ 2.2 mmol/L  
<2.2 - ≥ 1.7 mmol/L 
<1.7 mmol/L 
CTCAE grade 1-4 
Hyperglycemia  
>ULN - ≤ 8.9 mmol/L 
>8.9 – ≤ 13.9 mmol/L 
>13.9 – ≤ 27.8 mmol/L  
>27.8 mmol/L 
CTCAE grade 1-4 
Albumin 
<35 - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L  
CTCAE grade 1-3 
 
Amylase 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.0 x ULN  
>2.0 – ≤ 5.0 x ULN 
>5.0 x ULN 
CTCAE grade 1-4 
Lipase 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.0 x ULN  
>2.0 – ≤ 5.0 x ULN 
>5.0 x ULN 
CTCAE grade 1-4 
Direct bilirubin 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2 x ULN 
>2 – ≤ 3 x ULN  
>3 – ≤ 10 x ULN 
>10 x ULN 
Same Criteria as Total Bilirubin 
 
No CTCAE  
Not in DILI Guidance 
 
GGT  
>ULN - ≤ 2.5 x ULN 
>2.5 –  ≤ 5.0 x ULN 
>5.0 –  ≤ 20.0 x ULN  
>20.0 x ULN 
CTCAE grade 1-4 


Statistical Analysis Plan (Methods) 
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Table 10-7 
Threshold Criteria for Clinical Chemistry and Hematology 
Calcium 
Hypercalcemia 
>ULN - ≤ 2.9 mmol/L  
>2.9 – ≤ 3.1 mmol/L  
>3.1 – ≤ 3.4 mmol/L  
>3.4 mmol/L 
CTCAE grade 1-4 
Hypocalcemia 
<LLN - ≥ 2.0 mmol/L 
<2.0 – ≥1.75 mmol/L  
<1.75 – ≥ 1.5 mmol/L  
<1.5 mmol/L  
CTCAE grade 1-4 
Magnesium 
 
Hypermagnesemia 
>ULN - ≤ 1.23 mmol/L 
>1.23 – ≤ 3.30 mmol/L 
>3.30 mmol/L 
CTCAE grade 1, 3, 4 
 
No CTCAE grade 2 
Hypomagnesemia 
<LLN - ≥ 0.5 mmol/L 
<0.5 – ≥ 0.4 mmol/L 
<0.4 – ≥ 0.3 mmol/L  
<0.3 mmol/L  
CTCAE grade 1-4 
 
 
 
Inorganic phosphate 
Hypophosphatemia 
 
<0.74 – ≥ 0.6mmol/L 
<0.6 – ≥ 0.3 mmol/L 
<0.3 mmol/L 
CTCAE grade 1-4 
ALT 
>ULN - ≤  3 xULN 
>3 – ≤  5 xULN 
>5 – ≤  8 xULN 
>8 – ≤  20.0 xULN 
>20.0 x ULN 
Per FDA DILI Guidance Jul 2009 and CTCAE 
 
AST 
>ULN - ≤  3 xULN 
>3 – ≤  5 xULN 
>5 – ≤  8 xULN 
>8 – ≤  20.0 xULN 
>20.0 x ULN 
FDA DILI Guidance and CTCAE 
 
ALT or AST 
(ALT>ULN and ALT ≤  3 xULN) or (AST>ULN 
and AST≤  3 xULN) 
(ALT>3 xULN and ALT ≤  5 xULN) or 
(AST>3xULN and AST≤  5 xULN) 
(ALT>5 xULN and ALT ≤  8 xULN) or 
(AST>5xULN and AST≤  8 xULN) 
(ALT>8 xULN and ALT ≤  20 xULN) or 
(AST>8xULN and AST≤  20 xULN) 
ALT>20 xULN or AST> 20 xULN 
FDA DILI Guidance  
Alkaline Phosphatase >ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5 xULN 
>2.5 – ≤ 5.0 x ULN 
>5.0 – ≤ 20.0 x ULN  
>20.0 x ULN  
FDA DILI Guidance and CTCAE 
 


Statistical Analysis Plan (Methods) 
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Table 10-7 
Threshold Criteria for Clinical Chemistry and Hematology 
Total Bilirubin 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2 x ULN 
>2 – ≤ 3 x ULN  
>3 – ≤ 10 x ULN 
>10 x ULN 
FDA DILI Guidance and CTCAE 
 
 
ALT and Total 
Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009  
 
AST and Total 
Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009 
 
(ALT or AST) and 
Total Bilirubin  
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009  
 
Hematology 
 
 
WBC 
WBC decreased 
<LLN - ≥ 3.0 x 10e9 /L 
<3.0 – ≥ 2.0 x 10e9 /L  
<2.0 – ≥ 1.0 x 10e9 /L  
<1.0 x 10e9 /L 
CTCAE grade 1-4 
Leukocytosis 
>100 x 10e9 /L 
CTCAE grade 3 (only Grade available)  
Lymphocytes 
Lymphocyte decreased 
<LLN - ≥ 0.8 x10e9 /L 
<0.8 – ≥ 0.5 x10e9 /L  
<0.5 – ≥ 0.2 x10e9 /L  
<0.2 x10e9 /L 
CTCAE grade 1-4 
Lymphocyte increased 
>4 – ≤ 20 x10e9/L  
>20 x10e9/L  
CTCAE grade 2, 3 (only Grades available) 
Neutrophils 
Neutrophil decreased 
<LLN - ≥ 1.5 x10e9 /L 
<1.5 –  ≥ 1.0 x10e9 /L  
<1.0 –  ≥ 0.5 x10e9 /L  
<0.5 x10e9 /L 
CTCAE grade 1-4 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L  
< 80 g/L 
CTCAE grade 1-3 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L above ULN 
>40 g/L above ULN  
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L  
<50.0 – ≥ 25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 


Statistical Analysis Plan (Methods) 
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Table 10-8 
Threshold Criteria for Coagulation 
Parameter 
Threshold 
Comments 
Activated partial 
thromboplastin 
time  (PTT)  
 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
 
CTCAE grade 1-3 
Prothrombin 
time (PT) 
International 
Normalized 
Ratio (INR) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
 
CTCAE grade 1-3 
 
 
 


Statistical Analysis Plan (Methods) 
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Table 10-9 
Threshold Criteria for Vital Signs 
Parameter 
Threshold Criteria 
Comments 
HR 
 
Same PCS as above in ECG category 
 
SBP 
SBP increased 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg and >10 mmHg increase from baseline 
>140 mmHg and >20 mmHg increase from baseline 
>160 mmHg and >10 mmHg increase from baseline 
>160 mmHg and >20 mmHg increase from baseline 
809/770 analyses 
 
SBP decrease 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from baseline 
<90 mmHg and >20 mmHg decrease from baseline 
<80 mmHg and >10 mmHg decrease from baseline 
<80 mmHg and >20 mmHg decrease from baseline 
Per HV grade 1, 3, plus shift change 
 
DBP 
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 
809/770 analyses 
 
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 
 
 
 
 


Statistical Analysis Plan (Methods) 
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10.6 Standards for Efficacy and Safety Variable Display in TFLs 
Table 10-10 Precision Standards for Efficacy Variables 
Variable 
 
Statistics 
Number of Decimal Places 
ppFEV1 (%, absolute or relative change) 
 
Mean, LS mean, 95% CI 
 
1 
CFQ-R 
 
Mean, LS mean, 95% CI 
 
1 
Number of events  
0 
Event rate 
2 
Number of decimal places for standard error and standard deviation will be the same as that for the 
corresponding mean. 
 
Table 10-11 Standard Display Units in Percent Predicted FEV1 
Variable 
Unit 
Displayed Unit 
ppFEV1 
percent 
N/A 
Absolute change in ppFEV1 
percent 
Percentage points 
Relative change in ppFEV1 
percent 
% 
 


Statistical Analysis Plan (Methods) 
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10.7 Imputation Rules for Missing AE Start Date 
For missing or partial AE start date, use the imputation rules below. 
If only Day of AE start date is missing:  
If the AE start year and month are the same as that for the first dose date, then: 
If the full (or  partial) AE end date is NOT prior to the first dose date or AE end date is 
missing, then impute the AE start day as the day of first dose date; otherwise, impute the AE 
start day as 1. 
Otherwise, impute the AE start day as 1. 
Compare the imputed AE start date with TE period to determine whether the AE is pre-
treatment AE, TEAE or post-treatment AE. 
If Day and Month of AE start date are missing: 
If AE start year = first dose year, then: 
If the full (or partial) AE end date is NOT prior to the first dose date or AE end date is 
missing, then impute the AE start Month and Day as the Month and Day of first dose date; 
otherwise, impute the AE start Month as January and the Day as 1. 
Otherwise, impute the AE start Month as January and the Day as 1. 
Compare the imputed AE start date with TE period to determine whether the AE is pre-
treatment AE, TEAE or post-treatment AE. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site with 
no imputation. Also compare the full (or partial) AE end date to the first dose date. If the AE 
end date is prior to the first dose date then the AE should be considered as a pre-treatment 
AE. Otherwise, the AE will be considered as TEAE.