Clinical trial NCT03625466
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2018-08-10; Completion date: 2021-10-07
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will explore the impact of lumacaftor/ivacaftor (LUM/IVA) on disease progression in subjects aged 2 through 5 years with cystic fibrosis (CF), homozygous for F508del (F/F).

Detailed description:

Arms: arm 1: Participants received placebo matched to LUM/IVA in placebo-controlled period for 48 weeks. arm 2: Participants weighing less than (\<)14 kilograms (kg) at screening received LUM 100 milligrams (mg)/IVA 125 mg fixed-dose combination (FDC) every 12 hours (q12h) in placebo-controlled period for 48 weeks. Participants weighing greater than or equals to (\>=)14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h in placebo-controlled period for 48 weeks. arm 3: Participants who received either placebo or LUM/IVA in placebo-controlled period administered LUM/IVA (either LUM 100 mg/IVA 125 mg FDC q12h or LUM 150 mg/IVA 188 mg FDC q12h as per their body weight for participants \<6 years of age at week 48 and LUM 200 mg/IVA 250 mg FDC q12h regardless of their body weight for participants \>=6 years of age at week 48) in open-label period for 48 weeks.
Interventions: intervention 1: LUM/IVA intervention 2: LUM/IVA intervention 3: Placebo
Intervention descriptions: intervention 1: FDC tablets or granules for oral administration. intervention 2: FDC granules for oral administration. intervention 3: Placebo matched to LUM/IVA for oral administration.

Protocol documents:
Prot_000.pdf: 
Page 1 of 63 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
An Exploratory Phase 2, 2-part, Randomized, 
Double-blind, Placebo-controlled Study With a 
Long-term, Open-label Period to Explore the Impact 
of Lumacaftor/Ivacaftor on Disease Progression in 
Subjects Aged 2 Through 5 Years With Cystic 
Fibrosis, Homozygous for F508del 
Vertex Study Number: VX16‑809‑121 
 
EudraCT Number: 2017-003761-99 
Date of Protocol: 24 July 2019 (Version 4.0) 
Replaces Version 3.0 (dated 11 June 2018) 
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 






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2 
PROTOCOL SYNOPSIS 
Title An Exploratory Phase 2, 2-part, Randomized, Double-blind, Placebo-controlled 
Study With a Long-term, Open-label Period to Explore the Impact of 
Lumacaftor/Ivacaftor on Disease Progression in Subjects Aged 2 Through 5 Years 
With Cystic Fibrosis, Homozygous for F508del 
  
Brief Title A Study to Explore the Impact of Lumacaftor/Ivacaftor on Disease Progression in 
Subjects Aged 2 Through 5 Years With Cystic Fibrosis, Homozygous for F508del 
  
Clinical Phase and 
Clinical Study Type  
Phase 2, exploratory 
  
Objectives Primary Objective 
To explore the impact of lumacaftor/ivacaftor (LUM/IVA) on disease progression in 
subjects aged 2 through 5 years with cystic fibrosis (CF), homozygous for F508del 
Secondary Objective 
To explore the relationship between lung clearance index (LCI) and imaging 
modalities for LUM/IVA in subjects aged 2 through 5 years with CF, homozygous 
for F508del 
  
Endpoints Primary Endpoint 
Absolute change from baseline in magnetic resonance imaging (MRI) global chest 
score at Week 48 
Secondary Endpoints 
• 
Absolute change from baseline in LCI2.5 through Week 48 
• 
Absolute change from baseline in weight-for-age z-score at Week 48 
• 
Absolute change from baseline in stature-for-age z-score at Week 48 
• 
Absolute change from baseline in body mass index (BMI)-for-age z-score at 
Week 48 


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Number of Subjects Approximately 50 subjects 
  
Study Population Male and female subjects 2 through 5 years of age (inclusive) with CF, homozygous 
for F508del 
  
Investigational Drug Active substance: LUM/IVA fixed-dose combination 
 Activity: CFTR corrector and potentiator (chloride ion [Cl-] secretion) 
 Strength and route of administration: 
• 
LUM 100-mg/IVA 125-mg granules for oral administration 
• 
LUM 150-mg/IVA 188-mg granules for oral administration 
• 
LUM 100-mg/IVA 125-mg tablets for oral administration 
  
 LUM/IVA matching placebo 
 Strength and route of administration: 
LUM 0-mg/IVA 0-mg granules for oral administration 
  
Study Duration Excluding the Screening Period, the planned study duration is 98 weeks (± 4 days) 
(from Day 1 to last day of Safety Follow-up Visit).  
  


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Study Design The study includes the following: 
• 
Screening Period (Day -28 through Day -1) 
• 
Treatment Period  
o 
Part 1 Placebo-controlled Period: Day 1 through Week 48 
o 
Part 2 Open-label Period: Week 48 through Week 96 
• 
Safety Follow-up Visit (Week 98 [2 weeks ± 4 days after the last dose of study 
drug]) 
Subjects will receive LUM 100 mg/IVA 125 mg every 12 hours (q12h) (subjects 
weighing <14 kg at screening), LUM 150 mg/IVA 188 mg q12h (subjects weighing 
≥14 kg at screening), or matching placebo (Part 1 only) during the Treatment Period. 
No downward dose adjustments will be made if a subject’s weight decreases. If a 
subject subsequently weighs ≥14 kg at 2 consecutive visits, the dose will be adjusted 
to LUM 150 mg/IVA 188 mg q12h at the second visit where weight is ≥14 kg. 
Subjects who turn 6 years of age at or after the Week 48 Visit will receive LUM 
200 mg/IVA 250 mg q12h (starting at the Week 48 Visit or the next scheduled visit 
after turning 6 years of age), regardless of weight. 
Subjects who prematurely discontinue study treatment will have an Early 
Termination of Treatment (ETT) Visit as soon as possible.  
The Safety Follow-up Visit is required for 1) subjects who complete their ETT Visit 
<10 days after the last dose of study drug and 2) subjects who interrupt study drug 
treatment and complete their Week 96 Visit <10 days after the last dose of study 
drug. The Safety Follow-up Visit is not required for subjects who continue onto 
commercially available, physician-prescribed LUM/IVA within 2 weeks (± 4 days) 
of completing study drug treatment at the Week 96 or ETT Visit. 
  
Assessments Efficacy 
MRI, multiple-breath washout (MBW), 
, weight, stature, BMI,
 
 
Safety 
Adverse events (AEs), clinical laboratory values, ophthalmologic examinations 
(OEs), physical examinations, and vital signs 
  
Statistical Analyses There is limited information on the primary endpoint of MRI global chest score in 
this specific patient population. Only a small cohort of 17 patients similar to the 
patient population in this study from Heidelberg, Germany has some relevant 
information on this perspective. A vague normal prior distribution with a mean of 
3.0 and an SD of 1000.0 for the mean change of MRI global chest score from 
baseline to the end of Year 1 in the placebo arm is used for the Bayesian sample size 
consideration. 
The proposed sample size of 50 subjects (2:1 randomization: 33 LUM/IVA subjects 
and 17 placebo subjects after adjusting for a dropout rate of 10%) is based on the 
number of potential subjects expected to be available for participation. 
To illustrate potential outcomes, the Bayesian posterior probability that the mean 
change in the primary endpoint is better in the LUM/IVA group than placebo will be 
calculated.  
For this study, a positive mean change of 3.0 points in the placebo arm (consistent 
with Heidelberg data) and a common SD of 5.0 in each arm were assumed. In this 
scenario, a maximum observed positive mean change of approximately 1.66 in the 
LUM/IVA arm would yield 80% Bayesian posterior probability of LUM/IVA being 
superior to placebo.  


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The actual Bayesian posterior probability of LUM/IVA being superior to placebo 
will be calculated using the actual observed mean change in the LUM/IVA arm and 
placebo arm at Week 48, which will serve as the primary analysis for this study. The 
primary endpoint and all secondary 
 specified in the 
protocol will also be analyzed using descriptive summary statistics. The reason for 
using descriptive summary statistics is due to the limited sample size and the 
associated insufficient power from the traditional statistical analysis perspective. 
The primary endpoint of absolute change in MRI global chest score from baseline at 
Week 48 will be analyzed using descriptive summary statistics for both between 
treatment arm difference and within-treatment change.  
The secondary 
 of absolute change in LCI2.5 
 
 from baseline through Week 48 will also be analyzed using descriptive 
summary statistics for both between treatment arm difference and within-treatment 
change. The change from baseline to the average of all post-baseline measures at 
scheduled visits will be used for this analysis. Additional summary of changes from 
baseline at each post-baseline time point (at Week 12, Week 24, Week 36, and 
Week 48 for LCI2.5 
 will be 
provided in a similar way. 
 
 
 
 
 
 
Descriptive summary statistics including number of subjects, mean, median, SD, 
minimum, and maximum, along with the corresponding 95% CIs from the 
descriptive summary statistics will be provided.  
Additional Bayesian summary statistics, including the 95% credible intervals on the 
primary endpoint of absolute change in MRI global chest score from baseline at 
Week 48 
, may be explored. Details and analysis for 
 safety endpoints, along with the details of statistical 
analysis will be provided in the statistical analysis plan. 
IDMC Reviews An independent data monitoring committee (IDMC) will conduct safety reviews of 
study data as outlined in the IDMC charter. 


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3 
SCHEDULE OF ASSESSMENTS 
Table 3-1 
Study VX16-809-121: Screening  
Assessment 
Screening Visit 
Day -28 through Day -1 
Informed consent/assent 
X 
Demographics 
X 
Medical history 
X 
Medications reviewa 
X 
Stature, weight, and vital signsb,c 
X 
OEd 
X 
Full physical examination 
X 
CFTR genotypee,f 
X 
Serum chemistryf 
X 
Hematologyf 
X 
Sweat chlorideh 
X 
MBWi 
X 
Adverse events  
Continuous from signing of ICF through Safety Follow-up Visit (if required) 
BMI: body mass index; CFTR: cystic fibrosis transmembrane conductance regulator gene; 
; 
ICF: informed consent form; MBW: multiple-breath washout; OE: ophthalmological examination 
  
a  
All medications taken within 28 days before the first dose of study drug through the end of the study will be recorded 
(Section 9.5). 
b 
If children can stand unassisted and follow directions, stature should be measured as height; otherwise, stature will be 
measured as length. Stature and weight must be measured with shoes off and while wearing light clothing. BMI will be 
derived from this assessment. Refer to Section 11.5.4 for details. 
c 
The subject should rest for at least 5 minutes before having vital signs measured. 
d 
An OE will be conducted by a licensed ophthalmologist or optometrist. The examination does not need to be repeated if 
there is documentation of an examination meeting protocol criteria that was conducted within 3 months before the Screening 
Visit. Subjects with documentation of bilateral lens removal do not need the OE. Refer to Section 11.5.5 for details. 
e  
Subjects without a documented genotype in their medical record will be tested to assess CFTR genotype (see inclusion 
criterion 6 [Section 8.1]). 
f  
Refer to Section 11.5.2 for details. 
h 
If an eligible historical sweat chloride result is documented in the subject’s medical record, that result alone (and not the 
Screening Visit result) may be used to determine eligibility (see inclusion criterion 5 [Section 8.1]). For subjects using an 
historical sweat chloride value documented in their medical record to determine eligibility, the sweat chloride test at the 
Screening Visit is still required. Refer to Section 11.4.3 for details. 
i 
The MBW assessment may be performed pre- or post-bronchodilator. The assessment will be performed in multiple 
replicates as described in the MBW manual. If the subject cannot perform the MBW assessment at the Screening Visit, this 
assessment may be repeated during the Screening Period. The subject will be considered a screen failure if the MBW 
assessment cannot be performed (i.e., if 2 technically acceptable MBW tests are not achieved) at the Screening Visit or 
during re-testing. Refer to Section 11.4.2 for details. 


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Table 3-2 
Study VX16-809-121: Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Treatment Period 
ETT Visitb 
Safety 
Follow-up 
Visitc 
Part 1: Placebo-controlled Period 
Part 1/ 
Part 2d 
Part 2: Open-label Periode 
Day 
1 
Day 3 
(± 1 Day
) 
Day 15 
(± 3 Days
) 
Weeks 12, 
24, 36 
(± 7 Days) 
Week 48 
(± 7 Days) 
Day 338f 
(± 1 Day) 
Day 350 
(± 3 Days
) 
Weeks 60
, 72, 84 
(± 7 Days
) 
Week 96 
(± 7 Days
) 
As Soon as 
Possible 
After the 
Last Dose  
2 Weeks 
(± 4 Days) 
After the 
Last Dose 
Clinic visit 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Telephone contactg 
 
X 
 
 
 
X 
 
 
 
 
 
Randomizationh 
X 
 
 
 
 
 
 
 
 
 
 
Stature and weighti 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Vital signsj 
Xk 
 
X 
X 
Xk 
 
X 
X 
X 
X 
X 
OEl 
 
 
 
 
Xm 
 
 
 
Xm,n 
Xm,n 
Xm,n 
Full PEo 
X 
 
 
Week 24 
X 
 
 
Week 72 
X 
X 
X 
 
a 
Assessments will be performed before study drug dosing unless noted otherwise (Section 11.1). 
b 
If the ETT Visit occurs 10 days or later after the last dose of study drug, the Safety Follow-up Visit will not be required. Subjects who prematurely discontinue study drug 
treatment for AEs should be followed until the AE is considered resolved. 
c 
The Safety Follow-up Visit is required for 1) subjects who complete their ETT Visit <10 days after the last dose of study drug and 2) subjects who interrupt study drug 
treatment and complete their Week 96 Visit <10 days after the last dose of study drug; it is not required for subjects who continue onto commercially available, 
physician-prescribed LUM/IVA within 2 weeks (± 4 days) of completing study drug treatment at the Week 96 or ETT Visit. 
d  
The first open-label dose of LUM/IVA will be the dose administered at the Week 48 Visit after completion of the predose assessments. 
e  
If the subject’s Week 48 Visit is delayed, all subsequent visits must be delayed accordingly based on the actual Week 48 Visit date. 
f  
The Day 338 Visit (telephone contact) should occur 1 to 3 days after the actual date of the Week 48 Visit, regardless of whether it is Study Day 338.  
g 
Telephone contacts will be made to assess the subject's status, any AEs, medications, treatments, and procedures. 
h 
Randomization must only occur after all inclusion and exclusion criteria are met and before the first dose of study drug. Randomization will be done through IWRS and 
may occur on Day -1. 
i 
If children can stand unassisted and follow directions, stature should be measured as height; otherwise, stature will be measured as length. Stature and weight must be 
measured with shoes off and while wearing light clothing. BMI will be derived from this assessment. Refer to Section 11.5.4 for details. 
j 
The subject should rest for at least 5 minutes before having vital signs measured (Section 11.5.4). 
k 
Vital signs will be measured predose and at 1 hour (± 15 minutes), 2 hours (± 15 minutes), and 4 hours (± 15 minutes) postdose on Day 1 and at Week 48. 
l 
An OE will be conducted by a licensed ophthalmologist or optometrist. Subjects with documentation of bilateral lens removal do not need the OE. Refer to Section 11.5.5 
for details. 
m 
Subjects may complete the OE up to 7 days before the scheduled visit. 
n 
An OE will be conducted at the Week 96 Visit (or the ETT Visit if the subject does not have a Week 96 Visit, unless the discontinuation is due to initiation of treatment 
with commercially-available study drug), or the Safety Follow-up Visit. 
o 
Symptom-directed PEs will occur at any time during the study if triggered by AEs or if deemed necessary by the investigator.  


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Table 3-2 
Study VX16-809-121: Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Treatment Period 
ETT Visitb 
Safety 
Follow-up 
Visitc 
Part 1: Placebo-controlled Period 
Part 1/ 
Part 2d 
Part 2: Open-label Periode 
Day 
1 
Day 3 
(± 1 Day
) 
Day 15 
(± 3 Days
) 
Weeks 12, 
24, 36 
(± 7 Days) 
Week 48 
(± 7 Days) 
Day 338f 
(± 1 Day) 
Day 350 
(± 3 Days
) 
Weeks 60
, 72, 84 
(± 7 Days
) 
Week 96 
(± 7 Days
) 
As Soon as 
Possible 
After the 
Last Dose  
2 Weeks 
(± 4 Days) 
After the 
Last Dose 
Abbreviated PE 
Xp 
 
 
 
Xp 
 
 
 
 
 
 
Serum chemistryq,r 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Hematologyq,r 
 
 
 
X 
X 
 
 
X 
X 
X 
X 
MBWv 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
MRI 
Xw 
 
 
 
Xw,x 
 
 
 
Xw,w  
X 
 
 
p 
An abbreviated PE will be performed 4 hours (± 30 minutes) postdose on Day 1 and at Week 48 (Section 11.5.4).  
q  
Refer to Section 11.5.2 for details. 
r  
If the MRI occurs before the scheduled study visit, this assessment may occur on the same day as the MRI assessment. Blood draws performed on the same day as the MRI 
assessment must be collected before administration of any medications related to MRI procedures. 
v 
The MBW assessment should be performed pre-bronchodilator and before dosing. The assessment will be performed in multiple replicates. Refer to Section 11.4.2 for 
details. 
w  
Subjects may complete the imaging assessment up to 7 days before the scheduled visit. Screening assessments must be completed, inclusion and exclusion criteria must be 
reviewed, and subjects must meet eligibility criteria relevant at the time before participating in the baseline MRI assessment up to 7 days before Day 1. If the MRI is 
performed before the scheduled visit, the blood draws for serum chemistry, hematology, and 
 may be performed on the day of the MRI assessment. Blood 
draws for any assessment performed on the same day as MRI testing must be collected before administration of any medications related to MRI procedures. 
 
 
x  
The MRI at Weeks 48 and/or 96 may be delayed for up to 60 days if the subject is recovering from a PEx. The MRI should be done after the PEx is resolved and at least 
28 days after the last dose of the antibiotic regimen for the treatment of pulmonary infection has been completed. If the 28-day antibiotic-free period is not completed 
before the 60-day extension ends, the MRI should be completed within 1 week of the end of the 60-day extension. If the MRI at Weeks 48 and/or 96 is delayed, all other 
assessments must also be delayed. 


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Table 3-2 
Study VX16-809-121: Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Treatment Period 
ETT Visitb 
Safety 
Follow-up 
Visitc 
Part 1: Placebo-controlled Period 
Part 1/ 
Part 2d 
Part 2: Open-label Periode 
Day 
1 
Day 3 
(± 1 Day
) 
Day 15 
(± 3 Days
) 
Weeks 12, 
24, 36 
(± 7 Days) 
Week 48 
(± 7 Days) 
Day 338f 
(± 1 Day) 
Day 350 
(± 3 Days
) 
Weeks 60
, 72, 84 
(± 7 Days
) 
Week 96 
(± 7 Days
) 
As Soon as 
Possible 
After the 
Last Dose  
2 Weeks 
(± 4 Days) 
After the 
Last Dose 
Study drug dosingz 
LUM/IVA q12h or placebo q12h 
LUM/IVA q12h 
 
 
Observation 4 hours 
after the first dose 
X 
 
 
 
X 
 
 
 
 
 
 
Study drug count 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
Medications, 
treatments, and 
procedures review 
Continuous from signing of ICF through Safety Follow-up Visit (if required) 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit (if required) 
AE: adverse event; BMI: body mass index; ETT: Early Termination of Treatment; 
; ICF: informed consent form; 
 
 
; IVA: ivacaftor; IWRS: interactive web response system; LUM: lumacaftor; MBW: multiple-breath washout; MRI: magnetic resonance imaging; 
OE: ophthalmological examination; PE: physical examination; 
; q12h: every 12 hours 
 
z 
Study drug will be administered q12h (± 2 hours) within 30 minutes of consuming fat-containing food. On days of scheduled visits, the dose will be administered at the site 
after predose assessments have been completed. Refer to Section 9.6 for details. If the Treatment Period has been extended to allow for recovery from a PEx and the 
Week 48 and/or Week 96 Visit is delayed (Section 11.1), subjects should continue to take study drug until the Week 48 and/or Week 96 Visit has been completed. 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 4 
3 
Schedule of Assessments ........................................................................................................ 8 
4 
Table of Contents ................................................................................................................. 12 
List of Tables ........................................................................................................................... 15 
List of Figures .......................................................................................................................... 15 
List of Abbreviations ............................................................................................................... 16 
5 
Introduction .......................................................................................................................... 18 
5.1 
Background ..................................................................................................................... 18 
5.2 
Study Rationale .............................................................................................................. 18 
6 
Study Objectives .................................................................................................................. 19 
6.1 
Primary Objective ........................................................................................................... 19 
6.2 
Secondary Objective ....................................................................................................... 19 
7 
Study Endpoints ................................................................................................................... 19 
7.1 
Primary Endpoint ............................................................................................................ 19 
7.2 
Secondary Endpoints ...................................................................................................... 19 
 
 
8 
Study Population .................................................................................................................. 20 
8.1 
Inclusion Criteria ............................................................................................................ 20 
8.2 
Exclusion Criteria ........................................................................................................... 21 
9 
Study Implementation ......................................................................................................... 22 
9.1 
Study Design .................................................................................................................. 22 
9.1.1 
Screening ................................................................................................................ 23 
9.1.1.1 
Repetition of Screening Assessments .............................................................. 23 
9.1.1.2 
Rescreening ...................................................................................................... 23 
9.1.1.3 
Extension of Screening Period Window .......................................................... 24 
9.1.2 
Treatment Period .................................................................................................... 24 
9.1.3 
Follow-up ................................................................................................................ 24 
9.1.4 
Early Termination of Treatment Early Discontinuation ......................................... 24 
9.1.5 
Independent Data Monitoring Committee .............................................................. 25 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 25 
9.3 
Rationale for Study Design and Study Drug Regimens ................................................. 25 
9.3.1 
Study Design ........................................................................................................... 25 
9.3.2 
Study Drug Dose and Duration .............................................................................. 26 
9.3.2.1 
Dose of LUM/IVA ........................................................................................... 26 
9.3.2.2 
Duration of Dosing ........................................................................................... 26 
9.3.3 
Rationale for Study Assessments ........................................................................... 27 
9.4 
Study Restrictions ........................................................................................................... 28 
9.5 
Prior and Concomitant Medications ............................................................................... 29 
9.6 
Administration ................................................................................................................ 29 
9.7 
Dose Modification for Toxicity ...................................................................................... 31 
9.8 
Removal of Subjects ....................................................................................................... 31 
9.9 
Replacement of Subjects ................................................................................................ 32 


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10 Study Drug Information and Management ....................................................................... 32 
10.1 Preparation and Dispensing ............................................................................................ 32 
10.2 Packaging and Labeling ................................................................................................. 32 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 32 
10.4 Drug Accountability ....................................................................................................... 32 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 33 
10.6 Compliance ..................................................................................................................... 33 
10.7 Blinding and Unblinding ................................................................................................ 33 
10.7.1 
Blinding .................................................................................................................. 33 
10.7.2 
Unblinding .............................................................................................................. 34 
11 Assessments .......................................................................................................................... 35 
11.1 Timing of Assessments ................................................................................................... 35 
11.2 Subject and Disease Characteristics ............................................................................... 35 
11.3 Pharmacokinetics ............................................................................................................ 36 
11.4 Efficacy ........................................................................................................................... 36 
11.4.1 
MRI With Perfusion ............................................................................................... 36 
11.4.2 
Multiple-breath Washout ........................................................................................ 36 
 
 
11.4.4 
Weight, Stature, and BMI ....................................................................................... 37 
 
 
 
 
 
 
 
 
 
 
11.5 Safety .............................................................................................................................. 38 
11.5.1 
Adverse Events ....................................................................................................... 39 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 39 
11.5.3 
Elevation of Liver Function Test Parameters ......................................................... 40 
11.5.4 
Physical Examinations and Vital Signs .................................................................. 41 
11.5.5 
Ophthalmologic Examination ................................................................................. 41 
11.5.6 
Contraception and Pregnancy ................................................................................. 41 
12 Statistical and Analytical Plans .......................................................................................... 41 
12.1 Sample Size and Power .................................................................................................. 42 
12.2 Analysis Sets .................................................................................................................. 42 
12.3 Statistical Analysis ......................................................................................................... 42 
12.3.1 
General Considerations ........................................................................................... 43 
12.3.2 
Background Characteristics .................................................................................... 43 
12.3.2.1 Subject Disposition .......................................................................................... 43 
12.3.2.2 Demographics, Medical History, and Baseline Characteristics ....................... 44 
12.3.2.3 Prior and Concomitant Medications ................................................................ 44 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 44 
12.3.2.5 Important Protocol Deviations ......................................................................... 45 
12.3.3 
Efficacy Analysis .................................................................................................... 45 
12.3.3.1 Primary Analysis for the Study ........................................................................ 45 
12.3.3.2 Analysis of Primary Endpoint .......................................................................... 45 


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12.3.3.3 Analysis of Secondary Endpoints .................................................................... 45 
 
12.3.4 
Safety Analysis ....................................................................................................... 49 
12.3.4.1 Adverse Events ................................................................................................ 49 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 50 
12.3.4.3 Vital Signs ........................................................................................................ 50 
12.3.4.4 Ophthalmologic Examination .......................................................................... 50 
12.3.4.5 Physical Examination ....................................................................................... 50 
12.3.4.6 Other Safety Analysis ...................................................................................... 50 
12.3.5 
Interim and IDMC Analyses ................................................................................... 50 
12.3.5.1 Interim Analysis ............................................................................................... 50 
12.3.5.2 IDMC Analysis ................................................................................................ 51 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 51 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 51 
13.1.1 
Adverse Events ....................................................................................................... 51 
13.1.1.1 Definition of an Adverse Event........................................................................ 51 
13.1.1.2 Clinically Significant Assessments .................................................................. 51 
13.1.1.3 Documentation of Adverse Events................................................................... 52 
13.1.1.4 Adverse Event Severity .................................................................................... 52 
13.1.1.5 Adverse Event Causality .................................................................................. 53 
13.1.1.6 Study Drug Action Taken ................................................................................ 53 
13.1.1.7 Adverse Event Outcome .................................................................................. 54 
13.1.1.8 Treatment Given............................................................................................... 54 
13.1.2 
Serious Adverse Events .......................................................................................... 54 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 54 
13.1.2.2 Documentation of Serious Adverse Events ...................................................... 55 
13.1.2.3 Reporting Serious Adverse Events .................................................................. 55 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 56 
13.2 Administrative Requirements ......................................................................................... 56 
13.2.1 
Ethical Considerations ............................................................................................ 56 
13.2.2 
Subject Information and Informed Consent ........................................................... 56 
13.2.3 
Investigator Compliance ......................................................................................... 56 
13.2.4 
Access to Records ................................................................................................... 57 
13.2.5 
Subject Privacy ....................................................................................................... 57 
13.2.6 
Record Retention .................................................................................................... 57 
13.2.7 
Study Termination .................................................................................................. 57 
13.2.8 
End of Study ........................................................................................................... 58 
13.3 Data Quality Assurance .................................................................................................. 58 
13.4 Monitoring ...................................................................................................................... 58 
13.5 Electronic Data Capture ................................................................................................. 58 
13.6 Publications and Clinical Study Report .......................................................................... 59 
 
 
13.6.2 
Clinical Study Report ............................................................................................. 59 
14 Reference .............................................................................................................................. 60 
15 Protocol Signature Pages .................................................................................................... 62 


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15.1 Sponsor Signature Page .................................................................................................. 62 
15.2 Investigator Signature Page ............................................................................................ 63 
 
List of Tables 
Table 3-1 
Study VX16-809-121: Screening ............................................................................ 8 
Table 3-2 
Study VX16-809-121: Treatment Period and Safety Follow-up Visit ................... 9 
Table 9-1 
Study Restrictions ................................................................................................. 29 
Table 9-2 
Study Drug Administration ................................................................................... 30 
Table 10-1 
Study Drug ............................................................................................................ 32 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 39 
Table 13-1 
Grading of AE Severity ........................................................................................ 53 
Table 13-2 
Classifications for AE Causality ........................................................................... 53 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 53 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 54 
List of Figures 
Figure 9-1 
VX16‑809‑121 Study Design .............................................................................. 22 
 


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List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BMI z-score 
BMI-for-age z-score; BMI, adjusted for age and sex 
CF 
cystic fibrosis 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
CI 
confidence interval 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DZL 
Deutsches Zentrum fur Lungenforschung 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, throat 
EMA 
European Medicines Agency 
ETT 
Early Termination of Treatment 
EU 
European Union 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
F508del 
CFTR protein lacking the phenylalanine normally found at position 508 of the 
wild-type protein 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
 
 
FEV1 
forced expiratory volume in 1 second 
GCP 
Good Clinical Practice 
Gd 
Gadolinium 
GGT 
gamma-glutamyl transferase 
GPS 
Global Patient Safety 
height z-score 
height-for-age z-score; height, adjusted for age and sex 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IPD 
important protocol deviation 
IRB 
institutional review board 
 
 
IV 
intravenous 
IVA 
ivacaftor 
IWRS 
interactive web response system 
K-M 
Kaplan-Meier 
LCI 
lung clearance index 


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Abbreviation 
Term 
LCI2.5 
the number of lung turnovers required to reduce the end tidal inert gas 
concentration to 1/40th of its starting value 
LFT 
liver function test 
LS 
least squares 
LUM 
lumacaftor 
MBW 
multiple-breath washout 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effects model for repeated measures 
MRI 
magnetic resonance imaging 
OE 
ophthalmological examination 
P 
probability 
pbo 
placebo 
PE 
physical examination 
PEx 
pulmonary exacerbation 
PI 
pancreatic insufficiency 
PK 
pharmacokinetic, pharmacokinetics 
PT 
Preferred Term 
q12h 
every 12 hours 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
UTE 
ultrashort echo time 
weight z-score 
weight-for-age z-score; weight, adjusted for age and sex 
 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive disease with serious, chronically debilitating 
morbidities and high premature mortality and at present, there is no cure. CF affects 
approximately 70,000 individuals worldwide,1 with approximately 30,000 individuals in the 
US,1, 2 32,000 individuals in the EU,3 4,100 individuals in Canada,4 and 3,200 individuals in 
Australia.5 Despite progress in the treatment of CF with antibiotics and mucolytics, the predicted 
median age of survival for a person with CF is approximately 40 years.2, 6, 7 Although the disease 
affects multiple organs, progressive loss of lung function is the leading cause of mortality.8 
CF is caused by a defect in the gene encoding CFTR, an epithelial chloride (Cl-) ion channel that 
is responsible for aiding in the regulation of salt and water absorption and secretion in various 
tissues.9 This function is defective in patients with CF due to a loss of cell surface expression 
and/or function of CFTR. 
Lumacaftor (LUM; VX-809)/ivacaftor (IVA; VX-770) combination therapy (Orkambi) is the 
first medicine designed to treat the underlying molecular defect and enhance the function of 
CFTR in patients homozygous for F508del. Orkambi is approved in the US, Canada, and EU for 
patients 2 years and older who are homozygous for F508del, in Switzerland, Liechtenstein, and 
Australia for patients 6 years and older who are homozygous for F508del, and in Israel for 
patients 12 years and older who are homozygous for F508del. The LUM/IVA development 
program is designed to support the hypothesis that an oral chronic treatment restoring CFTR 
function can lead to improved pulmonary and extrapulmonary manifestations of CF, prevent 
progressive lung damage, and ultimately prolong survival. 
Details about the LUM/IVA development program can be found in the Investigator’s Brochure. 
5.2 
Study Rationale 
CF greatly affects the pediatric population, as approximately half of the total CF population is 
less than 18 years of age.10 Even before the widespread adoption of newborn screening, the 
majority of patients with CF were diagnosed in infancy or early childhood due to manifestations 
of the disease. Pancreatic destruction leading to pancreatic exocrine insufficiency begins in utero, 
and lung involvement is manifest by pulmonary inflammation and infection that begins shortly 
after birth.  
Pharmacokinetic (PK) and preliminary safety profiles for LUM/IVA combination therapy have 
been established in subjects 2 through 5 years of age who are homozygous for F508del 
(Study VX15-809-115 [Study 115] Part A [completed] and Part B [ongoing]). The present study 
is designed to explore long-term disease progression and efficacy of LUM/IVA in subjects 
2 through 5 years of age, homozygous for F508del. The long-term data will provide information 
about disease progression and the potential for disease modification by early CFTR-targeted 
intervention and will support the efficacy and safety of LUM/IVA in this younger CF population. 


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6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To explore the impact of LUM/IVA on disease progression in subjects aged 2 through 5 years 
with CF, homozygous for F508del 
6.2 
Secondary Objective 
To explore the relationship between lung clearance index (LCI) and imaging modalities for 
LUM/IVA in subjects aged 2 through 5 years with CF, homozygous for F508del 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Absolute change from baseline in magnetic resonance imaging (MRI) global chest score at 
Week 48 
7.2 
Secondary Endpoints 
• 
Absolute change from baseline in LCI2.5 through Week 48 
• 
Absolute change from baseline in weight-for-age z-score at Week 48 
• 
Absolute change from baseline in stature-for-age z-score at Week 48 
• 
Absolute change from baseline in body mass index (BMI)-for-age z-score at Week 48 


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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’s legally appointed and authorized representative (e.g., parent or legal guardian) will 
sign and date an informed consent form (ICF) and the subject will sign and date an assent 
form (if applicable).  
2. Subject’s legally appointed and authorized representative (e.g., parent or legal guardian) is 
willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, and other study procedures. 
3. Subjects (male and female) will be between the ages of 2 and 5 years, inclusive, on the date 
of informed consent (and assent, if applicable). 
4. Subjects who weigh ≥8 kg without shoes and wearing light clothing at the Screening Visit. 
5. Subjects with confirmed diagnosis of CF, defined as: 
• a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis as 
documented in the subject’s medical record OR from the sweat chloride test result 
obtained at the Screening Visit (if an eligible historical sweat chloride result is 
documented in the subject’s medical record, that result alone [and not the Screening Visit 
result] may be used to determine eligibility) 
AND  
• clinical manifestations of CF. 
6. Subjects who are homozygous for F508del (genotype to be confirmed at the Screening Visit 
or as documented in the subject’s medical record).  
7. Subjects with stable CF disease as deemed by the investigator at the Screening Visit. 
8. Subjects who are willing to remain on a stable CF medication regimen through the Safety 
Follow-up Visit, if applicable. 


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8.2 
Exclusion Criteria  
1. History of any illness or comorbidity reviewed at the Screening Visit that, in the opinion of 
the investigator, might confound the results of the study, interfere with or pose an additional 
risk in conducting the study assessments, or pose an additional risk in administering study 
drug to the subject. For example, a history of cirrhosis with portal hypertension, or prior 
allergic reaction to gadolinium (Gd)-based contrast material, or metallic implants 
incompatible with MRI. 
2. Any clinically significant laboratory abnormalities at the Screening Visit that would interfere 
with the study assessments or pose an undue risk for the subject (as deemed by the 
investigator). 
3. Any of the following abnormal laboratory values at the Screening Visit: 
• Hemoglobin <10 g/dL 
• Alanine transaminase (ALT), aspartate transaminase (AST), or total bilirubin >2 × upper 
limit of normal (ULN) 
• Abnormal renal function defined as glomerular filtration rate ≤45 mL/min/1.73 m2 
(calculated by the Bedside Schwartz equation)11 
4. An acute upper or lower respiratory infection, PEx as defined by the investigator, or changes 
in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first 
dose of study drug). 
5. Any clinically significant "non-CF-related" illness within 2 weeks before Day 1. "Illness" is 
defined as an acute (serious or nonserious) condition (e.g., gastroenteritis). 
6. History of solid organ or hematological transplantation. 
7. Ongoing or prior participation in an investigational drug study (including studies 
investigating LUM and/or IVA) within 30 days of the Screening Visit.  
• A washout period of 5 terminal half-lives of the previous investigational study drug, or 
30 days, whichever is longer, must elapse before the Screening Visit. 
• The duration of the elapsed time may be longer if required by local regulations. 
Note: Ongoing participation in a noninterventional study (including observational studies) is 
permitted. 
8. Use of restricted medication or food within specified duration before the first dose of study 
drug as defined in Section 9.4. 
9. Inability of the subject to perform the multiple-breath washout (MBW) assessment during the 
Screening Period (Section 11.4.2). 
10. History of cataract/lens opacity or evidence of cataract/lens opacity determined to be 
clinically significant by a licensed ophthalmologist during the ophthalmologic examination 
(OE) at the Screening Visit. The Screening Visit OE does not need to be repeated if there is 
documentation of an examination meeting protocol criteria that was conducted within 
3 months before the Screening Visit. Subjects with documentation of bilateral lens removal 
do not need the OE and this criterion does not apply. 


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11. The subject or a close relative of the subject is the investigator or a subinvestigator, research
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of
the study.
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 2, 2-part, randomized, double-blind, placebo-controlled, parallel-group study 
with a long-term open-label period in subjects 2 through 5 years of age with CF, homozygous for 
F508del (Figure 9-1).  
Figure 9-1 
VX16‑809‑121 Study Design 
Screening 1--.. 
LUM/IVA 
(n = 33) 
Pbo 
(n = 17) 
LUM/IV A ql211 
LUM/IVA 
Matching Pbo q 12h 
LUM/IV A ql211 
i-. 
Safety 
Follow-up 
Visit• 
Day -28 
Day -7 
Day I 
Week 48 
Week 96 
Part 1: Pho-controlled Period 
Part 2: Open-label Period 
Screening Period 
Treatment Periodb,c,d 
Safety 
Follow-up 
ETT: Early Termination of Treatment; IVA: ivacaftor; LUM: lumacaftor; pbo: placebo; q12h: every 12 hours. 
• 
The Safety Follow-up Visit is scheduled to occur 2 weeks (± 4 days) after the last dose. The Safety Follow-up Visit 
is required for !) subjects who complete their ETT Visit <10 days after the last dose of study drug and 2) subjects 
who interrupt study drug treatment and complete their Week 96 Visit <10 days after true last dose of study drug; it 
is not required for subjects who continue onto commercially-available, physician-prescribed study drug within 
2 weeks (± 4 days) of completing study drug treatment at the Week 96 or ETT Visit. 
• 
Approximately 50 subjects are planned to be randomized (2:1) to receive LUM/IV A or placebo. Subjects will 
receive LUM 100 mg/IVA 125 mg every 12 hours (q l2h) (subjects weighing <14 kg at screening), 
LUM 150 mg/IVA 188 mg q l2h (subjects weighing 2::14 kg at screening), or matching placebo (Part I only) during 
the Treatment Period. 
No downward dose adjustments will be made if a subject's weight decreases. If a subject subsequently weighs 
2::14 kg at 2 consecutive visits, the dose will be adjusted to LUM 150 mg/IVA 188 mg q l2h, at the second visit 
where weight 2::14 kg. Subjects who tum 6 years of age at or after the Week 48 Visit will receive LUM 
200 mg/IVA 250 mg q12h (starting at the Week 48 Visit or the next scheduled visit after turning 6 years of age), 
regardless of weight. 
• 
Subjects who prematur,ely discontinue study treatment will have an ETT Visit as soon as possible. 


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9.1.1 
Screening  
Screening Visit assessments are listed in Table 3-1. 
Screening will occur within 28 days before administration of study drug. The investigator (or an 
appropriate authorized designee at the study site) will obtain informed consent from each 
subject's parent or legal guardian and the subject must sign an assent form (if applicable) before 
any study-specific procedures can be performed. The ICF (and assent form, if applicable) will 
comply with all applicable regulations governing the protection of human subjects and will be 
approved by Vertex and the site's institutional review board (IRB). 
To prepare for study participation, subjects/caregivers will be instructed on the study restrictions 
(Section 9.4). 
9.1.1.1 
Repetition of Screening Assessments 
Repetition of any individual Screening Visit assessment(s) that did not meet eligibility criteria is 
not permitted, with the following exceptions:  
• If the subject cannot complete the MBW assessment (Section 11.4.2). 
• If there is clear evidence of a laboratory error (e.g., hemolyzed sample), equipment 
malfunction, or technician error, collection of a repeat sample for the appropriate laboratory 
test may be permitted after discussion with the Vertex medical monitor or authorized 
designee. 
• Exclusionary liver function test (LFT) levels, which may be retested within 14 days of the 
original Screening Visit date. 
In these cases, the individual assessment may be repeated during the Screening Period without 
repeating all the other Screening Visit assessments. Repetition of these screening assessments 
will not reset Screening Period window dates; however the Screening Period window may be 
extended by 1 week after approval by the medical monitor or authorized designee 
(Section 9.1.1.3). If repeat values of the individual assessment(s) are within the eligibility criteria 
and completed within the Screening Period window, then the subject is eligible for the study. 
9.1.1.2 
Rescreening 
Subjects may be rescreened after discussion with the Vertex medical monitor or authorized 
designee; all rescreening requires Vertex approval. If a subject is rescreened, all Screening Visit 
assessments will be repeated, except for CFTR genotyping and the OE (if performed within the 
last 3 months before the Screening Visit). For assessments listed in Section 9.1.1.1, the 
individual assessment may be repeated during the Screening Period without repeating all the 
other Screening Visit assessments.  
Subjects may only be rescreened once for entry into Part 1. If a subject is rescreened, the new 
screening window date will begin once the first rescreening assessment has been initiated.  


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9.1.1.3 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 1 week after approval by the 
medical monitor or authorized designee for the following reasons: 
• Repetition of the Screening Period assessments (Section 9.1.1.1) 
• To account for exclusionary events that may not reflect the subject’s true baseline due to 
an acute event, which may resolve 
• Scheduling of OE (Section 11.5.5) 
• Availability or malfunction of required equipment, or technician error. 
9.1.2 
Treatment Period 
The Treatment Period is 96 weeks; study drug will be administered every 12 hours (q12h) from 
Day 1 through Week 96 (Section 9.1). The Treatment Period can be extended up to 60 days in 
the event of a PEx: up to 60 days for the Week 48 MRI, and up to 60 days for the Week 96 MRI, 
for a total of up to 120 days. Antibiotics taken for a pulmonary infection or exacerbation must be 
completed at least 28 days before the MRI scan (Section 11.1). If the 28-day antibiotic free 
period is not completed before the 60-day extension ends, the MRI should be completed within 
1 week of the end of the 60-day extension. If the MRI at Weeks 48 and 96 is delayed, all other 
assessments must also be delayed. 
Study visits during the Treatment Period will occur as shown in Table 3-2. Subjects will be 
outpatients during the Treatment Period.  
Study drug administration and management details are provided in Section 9.6 and Section 10, 
respectively. 
Procedures for subjects who prematurely discontinue treatment are described in Section 9.1.4. 
9.1.3 
Follow-up 
Subjects will have a Safety Follow-up Visit 2 weeks (± 4 days) after the last study drug dose. 
Safety Follow-up Visit assessments are listed in Table 3-2. 
The Safety Follow-up Visit is required for 1) subjects who complete their Early Termination of 
Treatment (ETT) Visit <10 days after the last dose of study drug (Section 9.1.4) and 2) subjects 
who interrupt study drug treatment and complete their Week 96 Visit <10 days after the last dose 
of study drug; it is not required for subjects who continue onto commercially available, 
physician-prescribed LUM/IVA within 2 weeks (± 4 days) of completing study drug treatment at 
the Week 96 or ETT Visit. 
9.1.4 
Early Termination of Treatment Early Discontinuation 
If the subject prematurely discontinues study treatment, an ETT Visit should be scheduled as 
soon as possible after the subject decides to terminate study treatment. Subjects who prematurely 
discontinue treatment may also be required to complete the Safety Follow-up Visit, 
approximately 2 weeks (± 4 days) after their last dose of study drug (Section 9.1.3). The 
assessments performed at the Safety Follow-up Visit are listed in Table 3-2.  
If the ETT Visit occurs ≥10 days following the last dose of study drug, then the ETT Visit will 
replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be required. 


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Subjects who prematurely discontinue study drug treatment for adverse events (AEs) should be 
followed until the AE is considered resolved. 
Subjects who become eligible to receive commercially-available LUM/IVA by prescription of a 
physician, and who choose to continue onto commercially-available LUM/IVA before 
completion of the study, must remain on study-supplied drug through the ETT Visit, and may 
only initiate treatment with commercially-available LUM/IVA after completion of this visit. 
If the subject withdraws consent for the study, no further evaluations should be performed, and 
no additional data should be collected. Vertex may retain and continue to use any data and 
samples collected before such withdrawal of consent. 
9.1.5 
Independent Data Monitoring Committee 
Safety and tolerability data will be reviewed by an independent data monitoring committee 
(IDMC) with the primary goal of evaluating the safety of the study drug regimen to ensure the 
safety of the subjects in the study (Section 12.3.5.2). 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 enrolled. 
9.2 
Method of Assigning Subjects to Treatment Groups 
Part 1 
An interactive web or voice response system (IXRS) will be used to assign subjects to treatment. 
The randomization code will be produced by Vertex Biostatistics or a qualified randomization 
vendor. The Vertex study biostatistician will review and approve the production of the final 
randomization list, which will be reviewed and approved by a designated unblinded 
biostatistician who is not a member of the study execution team (SET).  
Part 2 
Part 2 is open-label. Randomization is not required for Part 2 because all subjects will receive 
LUM/IVA. 
9.3 
Rationale for Study Design and Study Drug Regimens 
9.3.1 
Study Design 
CF is a rare, inherited genetic disease that is life-shortening and seriously debilitating, for which 
there is no cure. CF is caused by a reduction or loss of CFTR activity, with production of highly 
viscous mucus and reduced mucociliary clearance in the lungs clogging the airways and 
promoting inflammation and infection, causing continued lung function decline over time. CF 
pulmonary disease, the major driver of morbidity and mortality in CF, manifests early and 
progresses throughout life. However, it is not uncommon for young patients with CF to have 
well-preserved or even normal lung function as measured by spirometry.12-15 In patients younger 
than 6 years of age, it is also very challenging to measure lung function using spirometry, and 
results are variable. However, through use of imaging techniques (non-invasive and invasive) 
and MBW assessments, it has been shown that patients in this age group with severe CF-causing 
mutations are likely to already have pulmonary structural aberrations and functional 
abnormalities.14, 16-22 
Vertex has established efficacy, safety, and PK profiles for LUM/IVA combination therapy in 
subjects 6 years of age and older, homozygous for F508del (Studies VX12-809-103, 


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VX12-809-104, VX12-809-105, VX13-809-011, and VX14-809-109). In addition, safety and PK 
profiles for LUM/IVA combination therapy have been established in subjects 2 through 5 years 
of age, homozygous for F508del (Study VX15-809-115 [Study 115]). The present study is 
designed to explore efficacy and to obtain safety information in a very young pediatric 
population in a placebo-controlled setting, with a window of opportunity to halt disease 
progression and prevent organ damage by early intervention with therapies that treat the 
underlying cause of CF. The impact of LUM/IVA on lung function will be explored using 
2 methods:1) thoracic MRI, an imaging assessment used to determine structural and functional 
lung abnormalities and to monitor disease progression, and 2) LCI, a measure of ventilation 
inhomogeneity that is based on tidal breathing techniques that have been evaluated in patients as 
young as infants.  
Given the intent to try to demonstrate efficacy with respect to MRI chest score and LCI, which 
are still endpoints under evaluation in this age group, the use of placebo in Part 1 (48-week 
Placebo-controlled Period) is necessary in order to provide a robust assessment. It is considered 
justified since all subjects within the relevant country are expected to be recruited before 
LUM/IVA is approved in this age group or is available commercially. The placebo or active drug 
will be added to subject’s current standard of care, and no therapies are required to be 
withdrawn. Therefore, no subject will be considered disadvantaged by the use of placebo, and all 
will have the potential to benefit in the rollover study when they will receive LUM/IVA. 
Furthermore, this study is randomized 2:1, with twice as many subjects being on active therapy. 
Exploration of the efficacy of LUM/IVA over the course of Part 2 (48-week Open-label Period) 
in this younger CF population will continue to provide information about disease progression 
and the potential for disease modification by early CFTR-targeted intervention. 
9.3.2 
Study Drug Dose and Duration 
9.3.2.1 
Dose of LUM/IVA 
Subjects will be randomized 2:1 to receive LUM/IVA or placebo. The dose regimens of 
LUM 100 mg/IVA 125 mg q12h (subjects weighing <14 kg at screening) and LUM 150 mg/ 
IVA 188 mg q12h (subjects weighing ≥14 kg at screening) were chosen based on Study 115A, a 
safety and PK study of LUM/IVA in subjects 2 through 5 years of age, and an interim analysis of 
confirmatory PK data obtained during Study 115B. Subjects who turn 6 years of age at or after 
the Week 48 Visit will receive LUM 200 mg/IVA 250 mg q12h (starting at the Week 48 Visit or 
the next scheduled visit after turning 6 years of age), regardless of weight. 
No safety issues were identified in prior clinical or nonclinical studies that would preclude the 
dosing regimen proposed for this study. 
9.3.2.2 
Duration of Dosing 
The duration of 48 weeks of placebo-controlled treatment in Part 1, plus an additional 48 weeks 
of open-label LUM/IVA treatment in Part 2, will provide an adequate assessment of efficacy and 
safety, including long-term impact on disease progression, in particular, structural damage 
assessed via MRI. If the Treatment Period has been extended to allow for recovery from a PEx 
and the Week 48 and/or Week 96 Visit is delayed, subjects should continue to take study drug 
until the Week 48 and/or Week 96 Visit has been completed. 


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9.3.3 
Rationale for Study Assessments 
The following efficacy assessments are standard assessments used in studies in the LUM/IVA 
development program: weight, stature, BMI, 
 
 Rationale is provided below for the following efficacy assessments: MRI, MBW for 
the measurement of LCI,
 
 
MRI Assessment: Current imaging technologies have demonstrated potential advantages in the 
evaluation of early lung disease in infants and children with CF. MRI with perfusion provides 
greater sensitivity than computerized tomography (CT) scan for imaging mucous plugging and 
bronchial wall thickening without ionizing radiation exposure and offers an accepted scoring 
system. It is recognized that MRI with ultrashort echo time (UTE) may be more sensitive for 
bronchiectasis than conventional sequences. However, MRI with perfusion is an accepted 
technique that is currently used by the DZL Clinical Network in the clinical care of patients with 
CF with an established, standard, and published protocol, to evaluate lung function and 
morphology, diagnose abnormalities, and to monitor disease progression on an annual basis. 
Data suggest Gd uptake in the brain after repeated use, thus the EMA restrictions.23 However, 
there is currently no evidence that Gd deposition has caused any harm and EMA has 
recommended restrictions for some agents to prevent any risks that could potentially be 
associated with Gd brain deposition.  
A recent analysis from an exploratory imaging substudy in Study VX14-809-109, UTE MRI was 
demonstrated to be a feasible approach for detecting the effect of LUM/IVA in subjects 
6 through 11 years of age with CF, despite the small sample size, short duration of treatment, and 
limitations in image quality. Furthermore, several studies have demonstrated the application of 
MRI for non-invasive monitoring of early CF lung disease in patients including infants and 
young children. For example, recent studies demonstrated: 1) that MRI was able to detect 
abnormalities in lung structure and perfusion, as well as response to treatment for PExs in infants 
and preschool children with CF22; 2) use of an MR-scoring system that can be used in routine 
assessment of lung disease in CF patients, including infants and young children24; 3) UTE MRI 
detected structural lung disease in young CF patients, with imaging data that was well-correlated 
with CT25; and 4) that MRI and MBW may serve as complementary assessments for 
non-invasive monitoring and as quantitative endpoints in trials in children with CF.26  
MBW Assessment: LCI will be derived from MBW testing. LCI is a measure of ventilation 
inhomogeneity that is based on tidal breathing techniques that have been evaluated in patients as 
young as infants.27, 28 Studies have shown that LCI correlates with forced expiratory volume in 
1 second (FEV1) in its ability to measure airway disease in patients with mild to moderate lung 
disease, but can also detect lung disease at an earlier stage than spirometry.20, 21 Furthermore, 
data from Study VX10-770-106 in subjects with CF with an FEV1 >90% showed LCI to be a 
more sensitive outcome measure than FEV1. LCI has also been shown to be a sensitive measure 
of lung function in subjects aged 6 to 11 years with high baseline lung function treated with 
LUM/IVA combination therapy, as shown by the results of Studies VX14-809-109 and 
VX13-809-011B, and has demonstrated that early intervention with LUM/IVA can improve lung 
function in the pediatric CF population. Given the potential advantages of a more sensitive 
measurement during the early stages of disease progression, LCI2.5 will be used as a secondary 
endpoint in this study. LCI2.5 (the number of lung turnovers required to reduce the end tidal inert 
gas concentration to 1/40th of its starting value) represents the most commonly used MBW 


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parameter.29
 
 
The safety assessments are standard parameters for clinical studies in drug development and are 
generally recognized as reliable, accurate, and relevant to the study of subjects with CF. OE 
assessments were added as part of safety monitoring. 
OEs: A juvenile rat toxicity study performed to support dosing of IVA in subjects <2 years of 
age demonstrated lens opacities in some animals.32 Prior studies in rats and dogs of older age did 
not demonstrate similar findings.32 Given substantial differences between human and rat lens 
development, the finding is of unlikely relevance to humans. Periodic OEs for pediatric subjects 
receiving IVA or IVA in combination with a CFTR corrector are being performed to confirm this 
interpretation. The overall data acquired to-date do not suggest an association between IVA 
treatment and cataract development; however, a potential association has not been fully 
excluded.   
9.4 
Study Restrictions 
Study restrictions are summarized in Table 9-1. 
A nonexhaustive list of study prohibitions and cautions for food and medication will be provided 
in the Study Reference Manual. 


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Table 9-1 
Study Restrictions 
Restricted Medication/Fooda 
Study Period 
Screening Period 
Treatment Period 
Strong CYP3A inducers 
None allowed within 14 days before 
the first dose of study drug 
None allowed 
Strong CYP3A inhibitors 
None allowed within 14 days before 
the first dose of study drug 
Use with caution 
CYP: cytochrome P450  
Note: The use of restricted medication in subjects with a medical need will be addressed on a case-by-case basis 
with the medical monitor or authorized designee. 
a 
See Section 9.5 for guidance for concomitant medications. 
Use of CYP3A substrates is not prohibited, but investigators need to be aware that LUM appears 
to be a strong inducer of CYP3A. Therefore, the efficacy of drugs extensively metabolized by 
CYP3A may be affected.  
Use of CYP2C and 2B6 substrates is not prohibited, but investigators need to be aware that LUM 
has been shown in vitro to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of 
CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest that 
IVA may inhibit CYP2C9. Therefore, concomitant use of LUM/IVA with CYP2B6, CYP2C8, 
CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates.  
Each investigator should evaluate the benefit-risk ratio of using CYP3A, CYP2B6, CYP2C8, 
CYP2C9, and CYP2C19 substrates with LUM and IVA and discuss their use with the medical 
monitor or authorized designee. 
9.5 
Prior and Concomitant Medications 
Information regarding all prior and concomitant medications, including the subject's CF 
medications, other medications, and herbal and naturopathic remedies administered from 28 days 
before the first dose through the Safety Follow-up Visit, if applicable, will be recorded in each 
subject's source documents. In addition, concomitant medication dose(s) may be collected. 
• It is recommended that subjects remain on a stable medication regimen for their CF from 
28 days before Day 1 through the Safety Follow-up Visit, if applicable. Stable medication 
regimen is defined as the current medication regimen for CF that subjects have been 
following for at least 28 days before Day 1. 
• Information about bronchodilator use during the study will be collected and documented 
in the subject's source documents. Subjects who are using a bronchodilator should have 
their MBW assessments performed according to the guidelines provided in 
Section 11.4.2. 
9.6 
Administration 
On Day 1 through the Week 96 Visit (last dose of study drug), granules will be orally 
administered with the approved foods and liquids listed in the study manual (e.g., apple sauce), 
as shown in Table 9-2. Subjects who turn 6 years of age at or after the Week 48 Visit will be 
orally administered tablets as shown in Table 9-2. 


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Table 9-2 
Study Drug Administration 
Treatment Arm 
Time 
LUM/IVA 
(Number of Stick 
Packs/Tablets) 
Placebo 
(Number of Stick Packs) 
LUM/IVA (Part 1) 
 
 
 
Subject screening weight <14 kga 
LUM 100 mg/IVA 125 mg q12h 
AM 
1 stick pack 
None 
PM 
1 stick pack 
None 
Subject screening weight ≥14 kga 
LUM 150 mg/IVA 188 mg q12h 
AM 
1 stick pack 
None 
PM 
1 stick pack 
None 
Placebo (Part 1 Only) 
 
 
 
LUM/IVA matching placebo 
AM 
None 
1 stick pack 
PM 
None 
1 stick pack 
LUM/IVA (Part 2) 
 
 
 
Subject <6 years of age and 
screening weight <14 kga 
LUM 100 mg/IVA 125 mg q12h 
AM 
1 stick pack 
NA 
PM 
1 stick pack 
NA 
Subject <6 years of age and 
screening weight ≥14 kga 
LUM 150 mg/IVA 188 mg q12h 
AM 
1 stick pack 
NA 
PM 
1 stick pack 
NA 
Subjects ≥6 years of ageb 
LUM 200 mg/IVA 250 mg q12h 
AM 
2 tablets 
NA 
PM 
2 tablets 
NA 
IVA: ivacaftor; LUM: lumacaftor; NA: not applicable; q12h: every 12 hours 
a 
Doses are based on the subject’s weight at screening. No downward dose adjustments will be made if a subject’s weight 
decreases. If a subject subsequently weighs ≥14 kg at 2 consecutive visits, the dose will be adjusted to LUM 150 mg/IVA 
188 mg q12h at the second visit where weight ≥14 kg.  
b 
Subjects who turn 6 years of age at or after the Week 48 Visit will receive LUM 200 mg/IVA 250 mg q12h (starting at the 
Week 48 Visit or the next scheduled visit after turning 6 years of age), regardless of weight. 
Study drug will be administered within 30 minutes from the start of consuming fat-containing 
food such as a standard “CF” high-fat, high-calorie meal or snack according to the following 
guidelines: 
1. All doses of study drug (morning and evening, as applicable) should be administered at 
approximately every 12 hours (± 2 hours) on each dosing occasion (e.g., if the morning dose 
is administered at 08:00 on Day 1, all subsequent morning doses should be administered 
between 06:00 and 10:00). 
2. The granule formulation will be dispensed by opening the stick packs containing the granules 
and mixing the granules with the approved foods and liquids listed in the study manual 
(e.g., apple sauce). Each dose will be comprised of the approved food or liquids into which 
the granules from the stick packs are mixed. Details on preparing study drug will be provided 
in the pharmacy manual. 
3. On the Day 1 and Week 48 Visits, all subjects will be observed for 4 hours after the first 
dose.  
4. On days of scheduled visits, with the exception of afternoon visits addressed below, the 
morning dose will be administered at the site after predose assessments have been completed.  


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5. If a subject's scheduled visit is to occur in the afternoon, the following guidelines must be 
used for administering either the morning or evening dose: 
• 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 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. 
6. For visits after the Day 1 Visit, subjects/caregivers will be instructed to bring all used and 
unused study drug materials to the site; study drug will be dispensed at each visit, as 
appropriate. 
7. If the Treatment Period has been extended to allow for recovery from a PEx and the Week 48 
and/or Week 96 Visit is delayed (Section 11.1), subjects should continue to take study drug 
until the Week 48 and/or Week 96 Visit has been completed. 
9.7 
Dose Modification for Toxicity 
If any unacceptable toxicity arises, individual subjects will discontinue dosing (Section 9.1.4). 
9.8 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons. If a subject 
has been withdrawn from study drug treatment, the subject will continue to be followed, 
provided the subject has not withdrawn consent.  
Subjects who discontinue study treatment early should return for study assessments at the ETT 
and Safety Follow-up Visits, if applicable, as noted in Section 9.1.3 and Section 9.1.4.  
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a Safety Follow-up Visit, if 
applicable (see Section 9.1.4), and follow up with the subject regarding any unresolved AEs. 
If the subject withdraws consent for the study, no further evaluations should be performed, and 
no additional data should be collected. Vertex may retain and continue using the study data and 
samples after the study is over, and may use the samples and information in the development of 
the study compound, and for other drugs and diagnostics, in publications and presentations, and 
for education purposes. If the subject withdraws from the study, the study data and samples 
collected will remain part of the study. A subject will not be able to request the withdrawal of 
his/her information from the study data. A subject may request destruction of the samples 
collected from him/her during the study as long as those samples can be identified as his/her 
samples. 


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9.9 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study drug treatment period(s) will not be 
replaced. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee to the subject’s legally appointed and authorized representative (e.g., parent or legal 
guardian) for administration to the study subject. 
10.2 
Packaging and Labeling 
Vertex will supply the granules in stick packs in kits and LUM 100-mg/IVA 125-mg tablets in 
child-resistant weekly blister cards. Study drug labeling will be in compliance with applicable 
local and national regulations. Additional details regarding packaging, labeling, and dispensing 
for study drug will be included in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
Packaging and storage conditions for study drug are described in Table 10-1. The investigator, or 
an authorized designee (e.g., a licensed pharmacist), will ensure that all investigational product is 
stored in a secured area, under recommended storage conditions, and in accordance with 
applicable regulatory requirements. To ensure adequate records, all study drugs will be 
accounted for as described in Section 10.4. 
Table 10-1 
Study Drug  
Drug 
Name 
Formulation/ 
Route 
Packaging (Formulation Strength) 
Storage 
Condition 
LUM/IVA 
Granules/ 
Oral 
Supplied as 100-mg LUM/125-mg IVA granules in 
1 stick pack  
Store at ≤25°C (77°F) with 
excursions to 30°C (86°F) 
LUM/IVA 
Granules/ 
Oral 
Supplied as 150-mg LUM/188-mg IVA granules in 
1 stick pack  
Store at ≤25°C (77°F) with 
excursions to 30°C (86°F) 
LUM/IVA 
matching 
placebo  
Granules/ 
Oral 
Supplied as and 0-mg LUM/0-mg IVA granules in 
1 stick pack  
Store at ≤25°C (77°F) with 
excursions to 30°C (86°F) 
LUM/IVA 
Fixed-dose 
tablet/ 
Oral 
Supplied as 100-mg LUM/125-mg IVA tablets 
Store at ≤25ºC (77ºF) with 
excursions to 30ºC (86ºF) 
IVA: ivacaftor; LUM: lumacaftor 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects/caregivers. Subjects/caregivers will be instructed to return all used and 
unused materials associated with the study drug to the site. These materials will be retained at the 
site according to instructions provided by Vertex or its designee until inventoried by the study 
monitor. The study monitor will review study drug records and inventory throughout the study. 


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10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the 
subjects/caregivers until the study monitor has performed drug accountability. At the end of the 
study, the study monitor will provide instructions as to the disposition of any unused 
investigational product. If the study monitor authorizes destruction at the study site, the 
investigator will ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by Vertex. 
Destruction will be adequately documented. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject/caregiver of study drug dosing requirements. 
Compliance will also be assessed by ongoing study drug count. 
If a subject/caregiver demonstrates continued noncompliance of study drug dosing despite 
educational efforts, the investigator should contact the medical monitor to discuss 
discontinuation of the subject from the study treatment while remaining in the study.  
10.7 
Blinding and Unblinding 
10.7.1 
Blinding  
Part 1 is a double-blind study. The subjects/caregivers and all site personnel, including the 
investigator and the study monitor, and the Vertex study team will remain blinded to treatment 
assignments until database lock for Part 1 (i.e., database lock for data up to and including the 
Week 48 Visit) with the following exceptions: 
• 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 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy serious 
adverse event (SAE) processing and reporting regulations 
• 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 
• Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time 
• Subjects and their parent/caregiver should not be informed of their study-related LCI, 
, and imaging results during Part 1 and Part 2 of the study regardless if the 
subject has prematurely discontinued treatment.  
Imaging Data Blinding 
Despite treatment blinding, knowledge of the imaging data has the potential to suggest whether a 
subject has been administered active study drug or matching placebo. Therefore, during the 
conduct of Part 1 (i.e., up to and including the Week 48 Visit), the Vertex study team will have 


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no access to the postdose imaging data. The central reader of these data will only send the 
blinded files (no treatment group, with real values for baseline, but with dummy values for all the 
assessments after baseline) to Vertex to be used for developing the statistical programs. 
LCI Data Blinding 
Despite treatment blinding, knowledge of the LCI results has the potential to suggest whether a 
subject has been administered active study drug or matching placebo. Therefore, during the 
conduct of Part 1 (i.e., up to and including the Week 48 Visit), the Vertex study team will have 
no access to the post first-dose LCI data. The central reader of these data will only send the 
blinded files (no treatment group, with real values for screening and baseline for LCI, but with 
dummy data for LCI for all the assessment values after baseline) to Vertex to be used for 
developing the statistical programs. 
10.7.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the medical monitor, they will use their best 
judgment, based on the nature and urgency of the clinical situation, and may proceed with 
unblinding without having successfully reached and discussed the situation with the medical 
monitor. In case of emergency, the investigator will have the final decision and unilateral right 
for 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. 


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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 an SAE, 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to 
Vertex GPS or designee, per Section 13.1.2. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, unblind 
individual subjects at any time.  
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The schedule of assessments is shown in Table 3-1 and Table 3-2.  
The following assessments must be performed in the order specified below when more than 
1 assessment is required at a particular time point: 
1. Vital signs should be performed before any other procedures that may affect heart rate 
(e.g., blood draws). 
3. The MRI assessment may be performed up to 7 days before the scheduled visit. If the MRI 
assessment is performed before the scheduled visit, blood draws for serum chemistry, 
hematology, 
 may be performed on the day of the MRI assessment. 
Blood draws for any assessment performed on the same day as MRI testing must be collected 
before administration of any medications related to MRI procedures.
 
• The MRI at Weeks 48 and/or 96 may be delayed for up to 60 days if the subject is 
recovering from a PEx. The last dose of the antibiotic regimen for the treatment of 
pulmonary infection or exacerbation must be completed at least 28 days before the MRI. 
If the 28-day antibiotic-free period is not completed before the 60-day extension ends, the 
MRI should be completed within 1 week of the end of the 60-day extension. If the MRI at 
Weeks 48 and/or 96 is delayed, all other assessments must also be delayed. 
11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, stature, 
and weight. 
Medical history will be elicited from each subject's caregiver during screening. Based on the 
medical history, the subject will be assessed for any disqualifying medical conditions as 


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specified in the inclusion and exclusion criteria. The medical history should include a complete 
review of systems, past medical and surgical histories, and any known allergies. 
11.3 
Pharmacokinetics 
Not applicable. 
11.4 
Efficacy 
11.4.1 
MRI With Perfusion 
The proposed morpho-functional MR-scoring-system is reproducible and applicable for 
semi-quantitative evaluation of a large spectrum of CF lung disease severity. Data from a study 
conducted by the DZL network show that MRI detected abnormalities in lung structure and 
perfusion, and response to therapy for exacerbations in infants and preschool children with CF. 
These results support the development of MRI for non-invasive monitoring and as an endpoint in 
interventional trials for early CF lung disease. This scoring-system is being used routinely in the 
assessment of CF lung disease and as an endpoint for clinical trials by the DZL network and 
other CF Centers in Europe.22, 24 
Children will be sedated according to the established sedation procedure used for diagnostic 
procedures at each site, such as oral or rectal chloral hydrate (100 mg/kg body weight, maximum 
dose of 2 g) (± phenobarbital) or propofol, and monitored during the MRI examination by 
MR-compatible pulse oximetry. 
Detailed procedures for the assessment will be provided in the Imaging Manual. 
11.4.2 
Multiple-breath Washout 
Screening Period 
Subjects must complete the MBW assessment during the Screening Period. If a subject cannot 
perform the MBW assessment at the Screening Visit, this assessment may be repeated during the 
Screening Period (without repeating the other assessments required during the Rescreening 
Visit). The subject will be considered a screen failure if the MBW assessment cannot be 
performed (i.e., if 2 technically acceptable tests are not achieved) during the Screening Visit or 
during re-testing. During the Screening Period, the MBW test may be performed pre- or 
post-bronchodilator.  
Treatment Period 
At all visits after the Screening Period, MBW tests should be performed pre-bronchodilator. 
Each MBW will be performed in multiple replicates at each visit according to the MBW manual.  
LCI will be derived from MBW testing. LCI2.5 represents the number of lung turnovers required 
to reduce the end tidal inert gas concentration to 1/40th of its starting value, 
 
 
 
The mean LCI value at each visit will be calculated using all technically acceptable replicates. 
All LCI replicate values will be provided by a central reader; however, the LCI central reader 
will not perform the calculation for the mean LCI values at visits. The mean LCI value at each 
Treatment Period Visit will be calculated by the sponsor or sponsor designee from the 
technically acceptable values provided by the LCI central reader.  


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Detailed MBW procedures will be supplied in the Study Reference Manual. 
11.4.4 
Weight, Stature, and BMI 
See Section 11.5.4. 


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11.5 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, physical examinations (PEs), and OEs. 


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11.5.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF completion 
guidelines for investigators as well as training will be provided. 
11.5.2 
Clinical Laboratory Assessments 
The safety laboratory test panels are shown in Table 11-1 and will be performed as indicated in 
Table 3-2. The timing of clinical laboratory assessments is described in Section 11.1. Additional 
clinical laboratory evaluations will be performed at other times if judged to be clinically 
appropriate. Laboratory test results that are abnormal and considered clinically significant will be 
reported as AEs (see Section 13.1).  
Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
 
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 transferase  
Total protein 
Albumin 
Creatine kinase 
Amylase 
Lipase 
Hemoglobin 
Erythrocytes: 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelets 
Reticulocytes (absolute) 
Leukocytes 
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes 
Monocytes 
 
 
 
Clinical laboratory assessments from screening will have no clinically significant findings that 
preclude participation in the study, as judged by the investigator, for a subject to receive study 
drug on Day 1. 
CF genotype (Screening Period only): Subjects without a documented genotype in their medical 
record will be tested to assess CFTR genotype. 
For purposes of study conduct and data analysis, samples will be analyzed at a central laboratory. 
However, at the discretion of the local investigator, samples may be analyzed at a local 
laboratory for management of urgent medical issues, including if a subject cannot return to the 
clinical study site for the mandatory liver function testing (Section 11.5.3). If a local laboratory 


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test value is found to be abnormal and clinically significant, it will be verified by the central 
laboratory as soon as possible after the investigator becomes aware of the abnormal result. If it is 
not possible to send a specimen to the central laboratory (e.g., the subject was hospitalized 
elsewhere) ideally within 48 to 72 hours, the investigator may base the assessment of an AE on 
the local laboratory value. 
11.5.3 
Elevation of Liver Function Test Parameters 
Mandatory Liver Function Testing 
Liver function testing ALT, AST, gamma-glutamyl transferase [GGT], alkaline phosphatase 
[ALP], and total bilirubin) must be performed while subjects are receiving study drug treatment 
(see Table 3-2 and Section 11.5.2). These blood samples should be processed and shipped 
immediately per the Laboratory Manual. 
Subjects with new ALT or AST elevations of ≥3 × ULN and clinical symptoms will be followed 
closely, including repeat confirmatory testing performed by the central laboratory within 48 to 
72 hours of the initial finding and subsequent close monitoring of ALT and AST levels, as 
clinically indicated. If a subject cannot return to the site for liver function testing, a local 
laboratory may be used. Elevations in LFTs (ALT or AST ≥3 × ULN) at the local laboratory 
must be reported immediately to the medical monitor AND the subject must have the tests 
repeated and sent to the central laboratory as soon as possible (ideally within 48 to 72 hours). 
Study Drug Interruption 
Study drug administration must be interrupted immediately, and the Vertex medical monitor or 
designee must be notified, if any of the following criteria is met: 
• ALT or AST ≥8 × ULN 
• ALT or AST ≥5 × ULN for more than 2 weeks 
• ALT or AST ≥3 × ULN in association with total bilirubin ≥2 × ULN and/or clinical 
jaundice 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression. 
Resumption of Study Drug 
If a convincing alternative etiology is identified for the LFTs (ALT, AST, and total bilirubin), 
study drug may be resumed when levels return to baseline or are ≤2 × ULN, whichever is higher. 
Approval of the Vertex medical monitor or designee is required before resumption of study drug. 
Upon resumption of study drug, transaminases should be assessed weekly for 4 weeks. If a 
protocol-defined liver test elevation occurs within 4 weeks of rechallenge with study drug, then 
study drug must be discontinued, regardless of the presumed etiology. 
Discontinuation of Study Drug 
If no convincing alternative etiology (e.g., acetaminophen use or viral hepatitis) for the elevated 
transaminases is identified, regardless of whether ALT or AST levels have improved, study drug 
treatment must be discontinued, after consulting with the Vertex medical monitor or authorized 
designee. Subjects in whom treatment is discontinued for elevated transaminases should have 
their transaminases monitored closely until levels normalize or return to baseline. 


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11.5.4 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits (see Table 3-1 and Table 3-2). At other visits, symptom-directed PEs and 
symptom-directed vital sign assessments can be performed at the discretion of the investigator or 
healthcare provider. 
A PE includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/throat 
(EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Anorectal, and genital examinations will be performed when medically indicated. 
After screening, any clinically significant abnormal findings in PEs will be reported as AEs. 
The abbreviated PE will include an assessment of the following body systems: 
head/neck/thyroid, EENT, cardiovascular system, respiratory system, skin, and abdomen.  
Vital signs include blood pressure (systolic and diastolic), temperature (any clinically acceptable 
method may be used [e.g., oral or axillary]; however, the same method should be used at each 
visit]), pulse rate, and respiration rate. The subject should rest for at least 5 minutes before 
having vital signs measured; additional instructions will be included in a separate Study 
Reference Manual. 
Weight and stature will be assessed and BMI will be derived. If subjects can stand unassisted and 
follow directions, stature should be measured as height; otherwise, stature will be measured as 
length. Stature and weight must be measured with shoes off and while wearing light clothing. 
BMI will be calculated using the following equation:  
BMI (kg/m2) = body weight (kg) ÷ stature2 (m2) 
11.5.5 
Ophthalmologic Examination 
Ophthalmologic examinations will be performed by a licensed ophthalmologist or optometrist. 
The OE includes 
• measurement of best corrected distance visual acuity of each eye; and 
• pharmacologically dilated examination of the lens with a slit lamp. 
If a cataract is identified and determined to be clinically significant by the ophthalmologist or 
optometrist, the subject’s caregiver and the Vertex medical monitor will be notified.  
11.5.6 
Contraception and Pregnancy 
Not applicable. 
12 
STATISTICAL AND ANALYTICAL PLANS 
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details for the interim analysis and the final analysis will be provided in the study statistical 
analysis plan (SAP), which will be finalized before the clinical data lock for the study and 
treatment unblinding. Details of analysis for the IDMC will be described in a separate IDMC 
SAP. 


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12.1 
Sample Size and Power 
There is limited information on the primary endpoint of MRI global chest score in this specific 
patient population. Only a small cohort of 17 patients similar to the patient population in this 
study, from Heidelberg, Germany, has some relevant information on this perspective. A vague 
normal prior distribution with a mean of 3.0 and an SD of 1000.0 for the mean change of MRI 
global chest score from baseline to the end of Year 1 in the placebo arm is used for the Bayesian 
sample size consideration.  
The proposed sample size of 50 subjects (2:1 randomization: 33 LUM/IVA subjects and 
17 placebo subjects after adjusting for a dropout rate of 10%) is also based on the number of 
potential subjects expected to be available for participation. 
To illustrate potential outcomes, the Bayesian posterior probability that the mean change in the 
primary endpoint is better in the LUM/IVA group than placebo will be calculated. 
For this study, a positive mean change of 3.0 points in the placebo arm (consistent with 
Heidelberg data) and a common SD of 5.0 in each arm were assumed. In this scenario, a 
maximum observed positive mean change of approximately 1.66 in the LUM/IVA arm would 
yield 80% Bayesian posterior probability of LUM/IVA being superior to placebo. 
The actual Bayesian posterior probability of LUM/IVA being superior to placebo will be 
calculated using the actual observed mean change in the LUM/IVA arm and placebo arm at 
Week 48, which will serve as the primary analysis for this study. The primary endpoint and all 
secondary 
 endpoints specified in the protocol will also be analyzed using 
descriptive summary statistics. The reason for using descriptive summary statistics is due to the 
limited sample size and the associated insufficient power from the traditional statistical analysis 
perspective. 
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 a 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 will 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 explore the impact of LUM/IVA combination therapy 
on disease progression in subjects aged 2 through 5 years with CF, homozygous for F508del. 
The secondary objective is to explore the efficacy of LUM/IVA combination therapy in subjects 
aged 2 through 5 years with CF, homozygous for F508del. 
This section presents a summary of the planned statistical analyses of efficacy and safety. The 
Vertex Biometrics department or a designated CRO will analyze the data derived from this 


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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. 
12.3.1 
General Considerations 
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. 
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 Visit or 14 days after the last dose of the study drug for subjects who do not have a 
Safety Follow-up Visit.
 
12.3.2 
Background Characteristics 
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 (FAS) 


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• Completed study drug treatment 
• Prematurely discontinued the study during the Treatment Period and the reasons for 
discontinuation 
• Completed study/Safety Follow-up Visit 
• 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 initial dose 
group for the FAS: sex, race, ethnicity, age, weight, stature, region, baseline LCI2.5, 
 
 baseline MRI global chest test score, 
 
  
12.3.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using a World Health Organization-Drug 
Dictionary 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. 


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12.3.2.5 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. Protocol deviations will be reviewed throughout the study. The rules 
for identifying an IPD will be described in the SAP. 
All IPDs will be provided in an individual subject data listing, and summarized, as appropriate. 
12.3.3 
Efficacy Analysis 
All efficacy analyses described in this section will be based on the FAS, unless specified 
otherwise. The analysis will include all available measurements through the last scheduled 
on-treatment visit, including measurements after treatment discontinuation. 
12.3.3.1 
Primary Analysis for the Study  
The actual Bayesian posterior probability of LUM/IVA being superior to placebo will be 
calculated using the actual observed mean change in the LUM/IVA arm and placebo arm at 
Week 48, which will serve as the primary analysis for the study.  
The primary endpoint and all secondary 
 specified in the protocol will 
also be analyzed using descriptive summary statistics. The reason for using descriptive summary 
statistics is due to the limited sample size and the associated insufficient power from the 
traditional statistical analysis’s perspective.  
12.3.3.2 
Analysis of Primary Endpoint  
The primary endpoint of absolute change in MRI global chest score from baseline at Week 48 
will be analyzed using descriptive summary statistics for both between treatment arm difference 
and within-treatment change.  
Descriptive summary statistics including number of subjects, mean, median, SD, minimum, and 
maximum, along with the corresponding 95% CIs from the descriptive summary statistics will be 
provided. Additional Bayesian summary statistics including the 95% credible intervals on the 
primary endpoint of absolute change in MRI global chest score from baseline at Week 48 might 
be explored and details will be provided in the SAP. 
12.3.3.3 
Analysis of Secondary Endpoints 
• Absolute change from baseline in LCI2.5 through Week 48  
The secondary endpoint of absolute change in LCI2.5 from baseline through Week 48 will be 
analyzed using descriptive summary statistics for both between treatment arm difference and 
within-treatment arm change. The change from baseline to the average of all post-baseline 
measures at scheduled visits will be used for this analysis. Additional summary of changes from 
baseline at each post-baseline time point (at Week 12, Week 24, Week 36, and Week 48) will be 
provided in a similar way. 
Descriptive summary statistics including number of subjects, mean, median, SD, minimum, and 
maximum, along with the corresponding 95% CIs from the descriptive summary statistics will be 
provided.  
• Absolute change from baseline in weight-for-age z-score at Week 48 


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• Absolute change from baseline in stature-for-age z-score at Week 48 
• Absolute change from baseline in BMI-for-age z-score at Week 48 
For the absolute change from baseline at Week 48, the secondary endpoints above will be 
analyzed using descriptive summary statistics for both between treatment arm difference and 
within-treatment arm change. Additional summary of changes from baseline at each 
post-baseline time point (based on the actual time point of data collection for each of these 
secondary endpoints) will be provided in a similar way. 
Descriptive summary statistics including number of subjects, mean, median, SD, minimum, and 
maximum, along with the corresponding 95% CIs from the descriptive summary statistics will be 
provided.  


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12.3.4 
Safety Analysis 
All safety analyses will be based on the set of data associated with 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 and 
tolerability endpoints:  
• Incidence of treatment-emergent adverse events (TEAEs)  
• Clinical laboratory values (i.e., hematology, serum chemistry)  
• Vital signs 
• OEs 
• PEs 
All safety data will also be presented in individual subject data listings. Safety endpoints will be 
analyzed based on the Safety Set. Only a descriptive analysis of safety will be performed. 
12.3.4.1 
Adverse Events 
AEs will be classified as pretreatment AEs or TEAEs, defined as follows:  
Pretreatment AE: any AE that started before the first dose date of study drug 
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed at 
or after the first dose date of study drug through the end of the TE Period  
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of AEs are described in the SAP. 
AE summary tables will be presented for TEAEs only, overall and by treatment group, and will 
include the following: 
• All TEAEs 
• TEAEs by strongest relationship  
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• Serious TEAEs 
• TEAEs leading to death 
Summaries will be presented by MedDRA System Organ Class (SOC) and Preferred Term (PT) 
using frequency counts and percentages (i.e., number and percentage of subjects with an event). 
When summarizing the number and percentage of subjects with an event, subjects with multiple 


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occurrences of the same AE or a continuing AE will be counted once. Only the maximum 
severity level will be presented in the severity summaries, and the strongest relationship level 
will be presented in the relationship summaries.  
In addition, a listing containing individual subject AE data for TEAEs leading to treatment 
discontinuation, SAEs, and deaths will be provided separately. All AEs, including pretreatment 
AEs, will be presented in an individual subject data listing. 
12.3.4.2 
Clinical Laboratory Assessments 
For the treatment-emergent laboratory measurements, the raw values and change from baseline 
values of the continuous laboratory parameters will be summarized in SI units by treatment 
group at each scheduled time point. In addition, mean value at each visit will be plotted by 
treatment groups for each of the liver function parameters.  
The number and percentage of subjects with at least 1 categorical change during the TE Period 
will be summarized by treatment group. The categorical (post-baseline) shift from baseline will 
also be summarized for selected laboratory parameters. The categorical criteria and the 
parameter selection criteria will be provided in the SAP. In addition, a listing containing 
individual subject laboratory assessment values outside the reference ranges will be provided. 
This listing will include data from scheduled and unscheduled time points.    
12.3.4.3 
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), pulse rate (beats per minute), and respiratory rate 
(breaths per minute).  
Additional vital sign analyses will be described in the SAP, if applicable. 
12.3.4.4 
Ophthalmologic Examination 
OE findings will be presented as a data listing only. 
12.3.4.5 
Physical Examination 
PE findings will be presented as a data listing only. 
12.3.4.6 
Other Safety Analysis 
The above safety analysis will be performed by treatment arm from baseline to Week 48, as well 
as from baseline to Week 96. In addition, a similar safety analysis like the above will be 
performed separately for placeboLUM/IVA arm from Week 48 (before to LUM/IVA dose) 
through the end of the Safety Follow-up after Week 96, where predose measurement at Week 48 
will be used as the baseline value.  
Details of the analysis will be provided in the SAP. 
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analysis 
The primary analysis for Part 1 will be conducted after all subjects have completed Part 1 
(i.e., up to and including the Week 48 Visit). The final analysis for Part 2 will occur after all 


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subjects have completed the study. Statistical analysis details for the interim analysis will be 
provided in the study SAP. 
12.3.5.2 
IDMC Analysis 
An IDMC will be formed. The IDMC’s objectives and operational details will be defined in a 
separate document (the IDMC charter). The IDMC will conduct regular planned safety reviews 
of study data as outlined in the IDMC charter. 
Details of the IDMC analysis will be provided in a separate IDMC SAP. 
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, PEs, and vital signs will be assessed and those 
deemed to have clinically-significant worsening from baseline will be documented as an AE. 
When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 


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13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF is signed until the following time points: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, 
withdrawal of consent) 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up 
Visit 
• For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of 
o 18 days after the last dose of study drug, or 
o the ETT Visit, if that visit is 10 days or later following the last dose of study drug (see 
Section 9.1.4) 
All subjects/caregivers 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 (Accessed 
August 2015). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” In 
considering the severity of an AE in a pediatric subject, the investigator will consider that 
reference ranges for pediatric clinical laboratory parameters may differ from those given in the 
CTCAE. The severity of an AE that does not appear in the CTCAE will be determined according 
to the definitions in Table 13-1.  


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Table 13-1 
Grading of AE Severity  
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening 
(Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories presented in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject's medical record). 
 
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. 
 


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


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


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13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IECs, and 
participating investigators in accordance with ICH Guidelines and/or local regulatory 
requirements, as applicable. In addition, Vertex, or authorized designee, will be responsible for 
the submission of safety letters to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/local IEC 
of all unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki (1996 Version), 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. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, the subject’s legally appointed and authorized 
representative (e.g., parent or legal guardian) will sign and date an ICF and the subject will sign 
and date an assent form (if applicable) before study participation. The method of obtaining and 
documenting the informed consent and assent (if applicable) and the contents of the consent will 
comply with ICH GCP and all applicable laws and regulations and will be subject to approval by 
Vertex or its designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  


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13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers and access to subject names linked to such 
numbers shall be limited to the site and the study physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 


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13.2.8 
End of Study 
The end of study is defined as the last scheduled visit (or contact) of the last subject in the study. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated, web-based electronic data capture (EDC) application. Vertex 
will have read-only access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator's responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject's 
CRF. Source documentation supporting the CRF data will indicate the subject's participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user's identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  


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Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc (CD) or other electronic media will be placed in the investigator's 
study file. 
13.6 
Publications and Clinical Study Report 
13.6.2 
Clinical Study Report  
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in 
accordance with local regulations. 


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14 
REFERENCE  
1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed 22 March 2018. 
2 
Cystic Fibrosis Foundation. Patient Registry: 2013 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2014. 
3 
European Cystic Fibrosis Society. 2010 ECFS Patient Registry Annual Data Report. 
Karup, Denmark: European Cystic Fibrosis Society; 2014. 
4 
Cystic Fibrosis Canada. Canadian Cystic Fibrosis Registry: 2013 Annual Report. 
Toronto, Ontario: Cystic Fibrosis Canada; 2015. 
5 
Cystic Fibrosis Australia. Cystic Fibrosis in Australia 2013: 16th Annual Report From 
the Australian Cystic Fibrosis Data Registry. Baulkham Hills, Australia: Cystic Fibrosis 
Australia; 2015. 
6 
Stern M, Wiedemann B, Wenzlaff P. From registry to quality management: the German 
Cystic Fibrosis Quality Assessment project 1995 - 2006. Eur Respir J. 2008;31(1):29-35. 
7 
Cystic Fibrosis Trust. UK Cystic Fibrosis Trust Annual Review 2010. Bromley, Kent, 
UK: Cystic Fibrosis Trust; 2012. 
8 
Flume PA, VanDevanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
9 
Kreindler JL. Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
10 
Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, et 
al. Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after 
newborn screening. J Pediatr. 2009;155(5):623-28. 
11 
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New 
equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3):629-37. 
12 
Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D. Cystic fibrosis adult care: 
consensus conference report. Chest. 2004;125(1 Suppl):1S-39S. 
13 
Corey M. Power considerations for studies of lung function in cystic fibrosis. Proc Am 
Thorac Soc. 2007;4(4):334-7. 
14 
Tiddens HA. Detecting early structural lung damage in cystic fibrosis. Pediatr Pulmonol. 
2002;34(3):228-31. 
15 
Macklem PT. The physiology of small airways. Am J Respir Crit Care Med. 1998;157(5 
Pt 2):S181-3. 
16 
Owens CM, Aurora P, Stanojevic S, Bush A, Wade A, Oliver C, et al. Lung Clearance 
Index and HRCT are complementary markers of lung abnormalities in young children 
with CF. Thorax. 2011;66(6):481-8. 
17 
Ellemunter H, Fuchs SI, Unsinn KM, Freund MC, Waltner-Romen M, Steinkamp G, et 
al. Sensitivity of lung clearance index and chest computed tomography in early CF lung 
disease. Respir Med. 2010;104(12):1834-42. 
18 
de Jong PA, Ottink MD, Robben SG, Lequin MH, Hop WC, Hendriks JJ, et al. 
Pulmonary disease assessment in cystic fibrosis: comparison of CT scoring systems and 
value of bronchial and arterial dimension measurements. Radiology. 2004;231(2):434-9. 
19 
Brody AS, Tiddens HA, Castile RG, Coxson HO, de Jong PA, Goldin J, et al. Computed 
tomography in the evaluation of cystic fibrosis lung disease. Am J Respir Crit Care Med. 
2005;172(10):1246-52. 


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20 
Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection 
of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. 
Thorax. 2007;62(4):341-47. 
21 
Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout 
and spirometry versus structural lung disease in cystic fibrosis. Thorax. 2008;63(2):129-
34. 
22 
Wielputz MO, Puderbach M, Kopp-Schneider A, Stahl M, Fritzsching E, Sommerburg O, 
et al. Magnetic resonance imaging detects changes in structure and perfusion, and 
response to therapy in early cystic fibrosis lung disease. Am J Respir Crit Care Med. 
2014;189(8):956-65. 
23 
Agency EM. EMA's final opinion confirms restrictions on use of linear gadolinium 
agents in body scans: recommendations conclude EMA's scientific reivew of gadolinium 
deposition in brain and other tissues (EMA/457616/2017). London, UK:  
24 
Eichinger M, Optazaite DE, Kopp-Schneider A, Hintze C, Biederer J, Niemann A, et al. 
Morphologic and functional scoring of cystic fibrosis lung disease using MRI. Eur J 
Radiol. 2012;81(6):1321-9. 
25 
Roach DJ, Cremillieux Y, Fleck RJ, Brody AS, Serai SD, Szczesniak RD, et al. 
Ultrashort Echo-Time Magnetic Resonance Imaging Is a Sensitive Method for the 
Evaluation of Early Cystic Fibrosis Lung Disease. Ann Am Thorac Soc. 
2016;13(11):1923-31. 
26 
Stahl M, Wielputz MO, Graeber SY, Joachim C, Sommerburg O, Kauczor HU, et al. 
Comparison of Lung Clearance Index and Magnetic Resonance Imaging for Assessment 
of Lung Disease in Children with Cystic Fibrosis. Am J Respir Crit Care Med. 
2017;195(3):349-59. 
27 
Horsley A. Lung clearance index in the assessment of airways disease. Respir Med. 
2009;103(6):793-99. 
28 
Sinhal S, Galati J, Baldwin DN, Stocks J, Pillow JJ. Reproducibility of multiple breath 
washout indices in the unsedated preterm neonate. Pediatr Pulmonol. 2010;45(1):62-70. 
29 
Stanojevic S, Jensen R, Sundaralingam D, Salazar JG, Yammine S, Singer F, et al. 
Alternative outcomes for the multiple breath washout in children with CF. J Cyst Fibros. 
2015;14(4):490-96. 
32 
Vertex Pharmaceuticals Incorporated. Lumacaftor/Ivacaftor Investigator's Brochure, 


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15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol#: 
VXI6-809-121 I Version#: 4.0 
I Version Date: 
24 July 2019 
· Study Title: An Exploratory Phase 2, 2-part, Randomized, Double-blind, Placebo-controlled 
Study With a Long-term, Open-label Period to Explore the Impact of Lumacaftor/Ivacaftor on 
Disease Progression in Subjects Aged 2 Through 5 years with Cystic Fibrosis, Homozygous 
for F508del 
This Clinical Study Protocol has been reviewed and approved by the sponsor. 
Vertex Pharmaceuticals Incorporated 
 


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Vertex Pharmaceuticals Incorporated 
 
15.2 
Investigator Signature Page 
Protocol #:  
VX16‑809‑121 
Version #: 4.0 
Version Date: 
24 July 2019 
Study Title: An Exploratory Phase 2, 2-part, Randomized, Double-blind, Placebo-controlled 
Study With a Long-term, Open-label Period to Explore the Impact of Lumacaftor/Ivacaftor on 
Disease Progression in Subjects Aged 2 Through 5 years with Cystic Fibrosis, Homozygous 
for F508del 
 
 
I have read Protocol VX16‑809‑121, Version 4.0, and agree to conduct the study according to 
its terms. I understand that all information concerning LUM/IVA and this protocol supplied to 
me by Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
I 
I 

SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 37 
Protocol Number: VX16-809-121 
 
 
Vertex Pharmaceuticals Incorporated 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX16-809-121 Version 4.0 
(Part 1 and Final Analysis) 
 
 
An Exploratory Phase 2, 2-part, Randomized, Double-blind, 
Placebo-controlled Study with a Long-term, Open-label Period to 
Explore the Impact of Lumacaftor/Ivacaftor on Disease Progression 
in Subjects Aged 2 Through 5 Years With Cystic Fibrosis, 
Homozygous for F508del 
 
 
Authors of SAP: 
 
 
Version: 1.0 
Version Date of SAP: 16 October 2020 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods) 
Page 2 of 37 
Protocol Number: VX16-809-121 
 
 
Vertex Pharmaceuticals Incorporated 
 
1 
TABLE OF CONTENTS 
 
1 
Table of Contents ................................................................................................................... 2 
3 
Introduction............................................................................................................................ 5 
4 
Study Objectives .................................................................................................................... 5 
4.1 
Primary Objective ............................................................................................................. 5 
4.2 
Secondary Objectives ....................................................................................................... 5 
5 
Study Endpoints ..................................................................................................................... 5 
5.1 
Efficacy Endpoints for Part 1 Analysis ............................................................................ 5 
5.1.1 
Primary Endpoint ...................................................................................................... 5 
5.1.2 
Secondary Endpoints ................................................................................................ 5 
 
 
 
 
6 
Study Design ........................................................................................................................... 7 
6.1 
Overall Design .................................................................................................................. 7 
6.2 
Sample Size and Power .................................................................................................... 9 
6.3 
Randomization .................................................................................................................. 9 
6.4 
Blinding and Unblinding .................................................................................................. 9 
6.5 
Part 1 and Final Analysis .................................................................................................. 9 
7 
Analysis Sets ........................................................................................................................... 9 
7.1 
All Subjects Set .............................................................................................................. 10 
7.2 
Full Analysis Set ............................................................................................................. 10 
 
 
7.4 
Safety Set ........................................................................................................................ 10 
8 
Analysis Period..................................................................................................................... 10 
8.1 
Part 1 Efficacy Analysis Period ...................................................................................... 10 
8.2 
Part 1 Treatment-Emergent Period ................................................................................. 11 
 
 
8.4 
Part 2 Safety Period ........................................................................................................ 11 
9 
Statistical Analysis ............................................................................................................... 11 
9.1 
General Considerations .................................................................................................. 11 
9.2 
Part 1 Analysis ................................................................................................................ 12 
9.2.1 
Background Characteristics .................................................................................... 12 
9.2.2 
Efficacy Analysis .................................................................................................... 15 
9.2.3 
Safety Analysis ....................................................................................................... 20 
9.3 
Final Analyses ................................................................................................................ 23 
9.3.1 
Background Characteristics .................................................................................... 23 
 
 
9.3.3 
Safety Analysis ....................................................................................................... 26 


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10 DMC ANALYSIS ................................................................................................................. 28 
11 References ............................................................................................................................. 29 
12 List of Appendices................................................................................................................ 30 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessment ........................... 30 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 33 
Appendix C: Imputation Rules for Missing AE dates ............................................................. 34 
Appendix D: Criteria for Threshold Analysis .......................................................................... 35 
 
 




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3 
INTRODUCTION 
This statistical analysis plan (SAP) for the Part 1 (interim) and final analysis is based on the most 
recent approved clinical study protocol (CSP), electronic case report form (eCRF), and eCRF 
completion guidelines.  
This SAP (Methods) documents the planned statistical analyses of efficacy and safety endpoints 
for the Part 1 analysis and the final analysis (FA), which have been pre-defined in the VX16-
809-121 study protocol. It also documents analyses for
safety variables 
not specified in the protocol, which will provide supportive information for the scientific 
understanding of the drug entity.  
The Vertex Biometrics Department will perform the statistical analysis of the efficacy and safety 
data; SAS (Version 9.4 or higher) will be used to generate all statistical outputs (tables, figures, 
listings, and datasets). The SAP will be finalized and approved prior to the Part 1 analysis data-
cut and treatment unblinding for the Part 1 analysis. Any revisions to the approved SAP will be 
documented and approved in an amendment to the SAP prior to the clinical database lock for the 
final analysis. Any changes made to the SAP (Methods) after the clinical database lock has 
occurred will be documented in the clinical study report for this study. 
4 
STUDY OBJECTIVES  
4.1 
Primary Objective 
To explore the impact of Lumacaftor/ivacaftor (LUM/IVA) on disease progression in subjects 
aged 2 through 5 years with CF, homozygous for F508del. 
4.2 
Secondary Objectives  
To explore the relationship between lung clearance index (LCI) and imaging modalities for 
LUM/IVA in subjects aged 2 through 5 years with CF, homozygous for F508del. 
5 
STUDY ENDPOINTS 
5.1 
Efficacy Endpoints for Part 1 Analysis 
5.1.1 
Primary Endpoint 
• Absolute change from baseline in magnetic resonance imaging (MRI) global chest score at 
Week 48 
5.1.2 
Secondary Endpoints 
• Absolute change from baseline in LCI2.5 through Week 48 
• Absolute change from baseline in weight-for-age z-score at Week 48 
• Absolute change from baseline in stature-for-age z-score at Week 48 
• Absolute change from baseline in body mass index (BMI)-for-age z-score at Week 48 


Statistical Analysis Plan (Methods) 
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Statistical Analysis Plan (Methods) 
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6 
STUDY DESIGN  
6.1 
Overall Design  
This is a Phase 2, 2-part, randomized, double-blind, placebo-controlled, parallel-group study 
with a long-term open-label period in subjects 2 through 5 years of age with CF, homozygous for 
F508del. A schematic of the study design is shown in Figure 6-1. 


Statistical Analysis Plan (Methods) 
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Figure 6-1 
Schematic of the Study Design 
In Part 1, subjects will be randomized 2:1 to receive LUM/IVA or placebo. The dose regimens 
of LUM 100 mg/IVA 125 mg q12h (subjects weighing <14 kg at screening) and LUM 150 
mg/IVA 188 mg q12h (subjects weighing ≥14 kg at screening) were chosen as shown in Table 
6-1. If a subject weigh is ≥14 kg at 2 consecutive visits, the dose will be adjusted to LUM 150 
mg/IVA 188 mg q12h at the second visit where weight is ≥ 14 kg. After completing Part 1, all 
subjects who continue to participate the open-label Part 2 will receive LUM/IVA with the 
planned dosages. Subjects who turn 6 years of age at or after the Week 48 Visit will receive 
LUM 200 mg/IVA 250 mg q12h (starting at the Week 48 Visit or the next scheduled visit after 
turning 6 years of age), regardless of weight. 
 


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Table 6-1 
Treatment Arms and Planned Dosages  
Treatment Arm  
 
LUM Dose 
IVA Dose 
LUM/IVA (Weight at Screening <14 kg) 
 
100 mg q12h 
125 mg q12h 
LUM/IVA (Weight at Screening ≥14 kg) 
 
150 mg q12h 
188 mg q12h 
Matching Placebo 
 
0 mg 
0 mg 
LUM/IVA (Age ≥6 years at or after Week 48 
Visit) 
 
200 mg q12h 
250 mg q12h 
LUM: lumacaftor; IVA: ivacaftor; PBO: placebo; q12h: every 12 hours 
6.2 
Sample Size and Power 
The proposed sample size of 50 subjects (2:1 randomization: 33 LUM/IVA subjects and 
17 placebo subjects) is based on the number of potential subjects expected to be available for 
participation. No formal sample size calculation was conducted.  
6.3 
Randomization 
Study Part 1 
The proposed sample size of 50 subjects will be randomized by 2:1 ratio to the LUM/IVA arm 
or placebo arm.  
An interactive web or voice response system (IXRS) will be used to assign subjects to treatment 
or placebo. The randomization code will be produced by Vertex Biostatistics or a qualified 
randomization vendor.  
Study Part 2 
Part 2 is an open-label extension period. Randomization is not applicable. 
6.4 
Blinding and Unblinding 
Refer to the CSP Section 10.7 for details. 
6.5 
Part 1 and Final Analysis 
Part 1 analysis will be conducted after all subjects have completed Part 1 (i.e., up to and 
including the Week 48 Visit) or have prematurely discontinued. The final analysis will occur 
after all subjects have completed the study or have prematurely discontinued.  
7 
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set, Full Analysis Set, 
 
 and Safety Set.  
A summary of analysis sets is presented in Table 7-1. 
Table 7-1 
Summary of Analysis Sets 
Analysis Set 
Target Analyses 
Treatment Group/Sequence  
All Subject Seta 
Individual subject listing and disposition summary for 
Part 1 analysis   
• 
LUM/IVA 
• 
PBO  
Full Analysis Set 
(FAS)a 
Efficacy and baseline demographic for Part 1 analysis 
• 
LUM/IVA 
• 
PBO  
By-visit efficacy summary for FA 
• 
LUM/IVALUM/IVA 
• 
PBOLUM/IVA 


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a Treatment label is based on the treatment the subject was randomly assigned to in the study Part 1 or the 
corresponding treatment sequence from Part 1 to Part 2.  
b Treatment label is based on the treatment that the subject received in the study Part 1 or its corresponding 
treatment sequence from Part 1 to Part 2.  
FA: final analysis; IVA: ivacaftor; LUM: lumacaftor; PBO: placebo 
7.1 
All Subjects Set 
The All Subjects Set will include all subjects who are randomized or receive at least 1 dose of 
study drug. This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified.  
7.2 
 Full Analysis Set  
The Full Analysis Set (FAS) will include all randomized subjects who carry the intended CFTR 
allele mutation and receive at least 1 dose of study drug in the study Part 1. The FAS will be 
used to summarize subject demographics and baseline characteristics, and for all efficacy 
analyses, unless otherwise specified. 
7.4 
Safety Set 
The Safety Set will include all subjects who receive at least 1 dose of study drug. The Safety Set 
will be used for all safety analyses.  
8 
ANALYSIS PERIOD  
The analysis period used for efficacy and safety endpoints in the Part 1 Analysis or FA is 
described below. 
8.1 
Part 1 Efficacy Analysis Period 
The Part 1 Efficacy Analysis Period will include the time from the first dose date of study drug 
until the last efficacy assessment in Part 1, which may be collected up to the Week 48 Visit. 
Safety Setb 
Safety for Part 1 analysis 
• 
LUM/IVA 
• 
PBO 
Part 2 safety analysis, individual subject listing, and 
disposition summary for FA 
• 
Overall LUM/IVA  
OR 
• 
LUM/IVALUM/IVA 
• 
PBOLUM/IVA 


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8.2 
Part 1 Treatment-Emergent Period  
The Part 1 Treatment-Emergent (TE) Period will include the time from the first dose of study 
drug (including the matched placebo) until 14 days after the last dose of study drug of Part 1 or 
the completion of study participation of Part 1, whichever occurs first.  
Completion of study participation of Part 1 is defined as the following:  
 For subjects who complete Part 1 and enter Part 2: the day prior to the first dose of study 
drug of Part 2 
 For subjects who prematurely discontinue study drug treatment during the Part 1 treatment 
period but do not withdraw consent (and assent, as applicable): the latest of the Week 48 
Visit, ETT or Safety Follow-up Visit (if required) 
 For subjects who withdraw consent or assent: date of withdrawal of consent or assent, 
whichever is earlier. 
8.4 
Part 2 Safety Period  
The Part 2 Safety Period will include the time from the first dose of study drug of Part 2 until 
14 days after the last dose of LUM/IVA or the completion of study participation, whichever 
occurs first.  
Completion of study participation is defined as: 
 For subjects who complete the study, the latest of the ETT Visit or Safety Follow-up Visit (if 
required).  
 For subjects who prematurely discontinue study drug treatment during the study but do not 
withdraw consent (and assent, as applicable): the latest of ETT or Safety Follow-up Visit (if 
required). 
 For subjects who withdraw consent or assent: date of withdrawal of consent or assent, 
whichever is earlier. 
The Part 2 Safety Period will be used for analysis of safety data in the FA.  
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations  
As summarized in Table 7-1, the 2 treatment groups in Part 1 are  
• LUM/IVA  
• Placebo (PBO) 
and the 2 treatment sequences from Part 1 to Part 2 are as follows: 


Statistical Analysis Plan (Methods) 
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• LUM/IVA  LUM/IVA 
• PBO  LUM/IVA 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max).  
Categorical variables will be summarized using counts and percentages.  
Unless otherwise specified,  
 the Study Baseline value is defined as the most recent non-missing measurement (scheduled 
or unscheduled) collected before the first dose of study drug (including the matched placebo). 
The study baseline will be used to calculate the absolute and relative change from baseline 
for efficacy analyses, unless otherwise specified. 
 the LUM/IVA Baseline value is defined as the most recent non-missing measurement 
(scheduled or unscheduled) collected before the first dose of study drug of Part 1 if the 
subject actually received at least one dose of LUM/IVA in Part 1, or before the first dose of 
study drug of Part 2 if the subject did not actually receive at least one dose of LUM/IVA in 
Part 1. The LUM/IVA baseline will be used to calculate the change from baseline in safety 
analysis in the FA, unless otherwise specified.  
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. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
1) In scheduled visit windows per specified visit windowing rules 
2) In the derivation of baseline and last on-treatment measurements 
3) In the derivation of maximum and minimum values, and maximum and minimum change 
from baseline values during analysis period for safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix A. 
Incomplete/missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
9.2 
Part 1 Analysis 
The Part 1 analysis will be conducted after all subjects have completed the study Part 1 or have 
discontinued prematurely. The efficacy analysis and safety analysis will be based on the efficacy 
and safety data from study Part 1 only.  
9.2.1 
Background Characteristics  
9.2.1.1 
Subject Disposition 
A disposition table will be provided for Part 1 with the number of subjects in:  
• All Subjects Set 


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• Randomized 
• Randomized but not dosed 
• Full Analysis Set 
• Safety Set  
The number and percentage (based on the FAS) of subjects in each of the following disposition 
categories will be summarized by treatment group and overall: 
• Completed Part 1 treatment 
• Prematurely discontinued Part 1 treatment and the reason for discontinuation 
• Completed Part 1 study participation 
• Prematurely discontinued Part 1 study participation and the reason for discontinuation  
• Continued to study Part 2 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
participation with reasons for discontinuation during Part 1.  
9.2.1.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics at study baseline will be summarized based on the 
FAS and presented by treatment group and overall. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Age group at baseline (<3 and ≥3 years) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, and not collected per local regulations) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Weight group (<14 kg and ≥14 kg) 
• Weight-for-age z-score 
• Stature (cm) 
• Stature-for-age z-score 
• BMI (kg/m2) 
• BMI-for-age z-score 
Disease characteristics will include the following: 
• LCI2.5 at baseline  


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• MRI global chest score at baseline 
In addition, data listings will also be provided for: 
• Informed consent; 
• Inclusion/Exclusion criteria violation for subjects with any such violations. 
9.2.1.3 
Medical History 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). For the FAS, medical history will be summarized descriptively by system organ 
class (SOC) and preferred term (PT). The corresponding data listing will also be provided. 
9.2.1.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD) 
and categorized as follows: 
Prior medication: any medication that was administered during the 28 days before the first dose 
of study drug (including the matched placebo) in the treatment period.  
Concomitant medication during the Part 1 TE period: medication continued or newly 
received during the Part 1 TE period. 
A given medication may be classified as follows: prior, concomitant, and both prior and 
concomitant.  
If a medication has a completely missing or partially missing start/end date and it cannot be 
determined whether it was taken before the first dose date of study drug, concomitantly during the 
Part 1 TE period, or after the Part 1 TE period, it will be considered as prior and concomitant. 
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix B. 
For FAS, prior medications and concomitant medications during the Part 1 TE period will be 
summarized descriptively by:  
1) treatment group and overall, preferred name (PN) 
2) treatment group and overall, anatomic class (ATC) level 1, ATC level 2, and PN 
9.2.1.5 
Study Drug Exposure  
Study drug exposure summaries will be based on the Safety Set for the study Part 1 and 
presented by treatment group. 
Duration of study drug exposure is defined as last dose date of Part 1 – first dose date of Part 
1 + 1 day, regardless of any interruptions in dosing.  
Duration of study drug exposure period (in weeks) will be summarized descriptively by the 
number of subjects (n), mean, SD, median, min, and max. It will also be summarized as a 
categorical variable by intervals using counts and percentages. 


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9.2.1.6 
Study Drug Compliance 
Percentage of study drug compliance during the study Part 1 will be summarized descriptively 
based on the FAS and will be presented by treatment group and overall.   
Study drug compliance will be calculated as: 100 × (1 − [total number of days of study 
drug interrupted prior to the date of last dose in Part 1] / [duration of drug exposure in Part 1]). A 
study drug interruption on a given day is defined as an interruption of any study drug on that day. 
A study drug interruption that continues through the end of the study participation (i.e., subject 
does not resume study drug before the end of the study participation) will not be included in the 
compliance calculation. 
Descriptive summary statistics include number of subjects (n), mean, SD, median, min, and max. 
It will also be summarized in categories: <80% and ı80% using frequency tables.  
In addition, percentage of stick packs taken will be calculated using the following formula: 100 x 
[(total number of stick packs dispensed during Part 1) – (total number of stick packs returned 
during Part 1)] / (total number of stick packs planned to be taken per day during Part 1 x duration 
of Part 1 drug exposure in days). Summary similar to those for the study drug compliance will be 
produced based on the FAS. 
9.2.1.7 
Important Protocol Deviations  
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. IPD rules will be developed and finalized before database cut/lock.  
The protocol deviations that should be considered as potential IPDs include, but are not limited 
to:  
¾ Subject was enrolled in the study despite the violation of inclusion/exclusion criteria  
¾ Subject was less than 80% compliant with study drug for non-safety reasons 
¾ Subject received prohibited concomitant medications  
¾ Subject received the wrong treatment or incorrect doses  
¾ Subject remained in the study despite meeting withdrawal criteria  
Occurrence of any of these events should be considered as potential IPDs, but a blinded team 
should categorize them as IPDs only if they have the potential to significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being.  
IPDs (from the clinical database or from the site deviation log) will be summarized descriptively 
based on the FAS and presented by treatment group and overall. Additionally, IPDs will be 
provided in an individual subject data listing.  
9.2.2 
Efficacy Analysis  
Unless otherwise specified, all efficacy analyses described in this section will be based on the 
FAS and presented by treatment group. The study baseline will be used to calculate the change 
from baseline for continuous efficacy endpoints. 


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9.2.2.1 
Analysis of Primary Variable 
9.2.2.1.1 
Definition of Variable 
The primary efficacy variable is the absolute change from baseline in MRI global chest score at 
Week 48. 
MRI Chest Scores: MRI scans will be assessed semi-quantitatively via a standardized chest MRI 
scoring system8,9. Each subject will have 6 lobes scored with the lingula treated as a separate 
lobe. The scoring parameters, score aggregation, and global score calculations are described as 
below. 
After scans are reviewed, MRI scores will be captured using the following 7 scoring parameters 
for each of the 6 lobes: 
1. Bronchiectasis / Wall thickening 
2. Mucus plugging 
3. Abscesses / Sacculations 
4. Consolidations 
5. Special findings 
6. Mosaic pattern 
7. Perfusion abnormalities 
Scores assigned to each parameter: 
• 0 = normal 
• 1 = < 50% of lobe involved 
• 2 = ≥ 50% of lobe involved 
The primary variable of MRI Global Chest Score is defined as: 
• MRI Global Score = Sum of parameters 1 – 7 
9.2.2.1.2 
Primary Analysis  
The primary analysis will be performed using Bayesian methods. Specifically, the actual 
Bayesian posterior probability of LUM/IVA being superior to Placebo in the MRI global chest 
score at Week 48 will be calculated using a vague normal prior distribution. Bayesian summary 
statistics including the Bayesian posterior mean difference and corresponding 95% credible 
intervals will also be provided. 
In addition, descriptive summary statistics for both between treatment arm difference and within-
treatment change at Week 48 will be presented. Descriptive summary statistics including number 
of subjects (n), mean, median, SD, minimum, and maximum, along with the corresponding 95% 
CIs will be provided.  


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9.2.2.2 
Analysis of Secondary Variables  
9.2.2.2.1 
Definition of Variables 
Lung clearance index (LCI): LCI assessments are derived from N2-multiple-breath washout
(MBW) testing. LCI2.5 represents the number of lung turnovers required to reduce the end tidal 
inert gas concentration to 1/40th of its starting value,
 
 
 Refer to Section 11.4.2 of the CSP for details. 
Body mass index (BMI): the BMI at each visit is calculated using the weight and height at each 
visit as follows:  
BMI = Weight (kg) / [Height (m)]2 
BMI z-score: the BMI score, adjusted for age and sex, will be referred to as BMI-for-age z-score 
(BMI z-score). The BMI z-score will be calculated by using Centers for Disease Control and 
Prevention (CDC) growth charts7, with the age (in months) used for the calculation defined in 
Appendix A.  
Stature z-score: stature, adjusted for age and sex, will be referred to as stature-for-age z-score 
(stature z-score). The calculation of stature z-score is similar to that of BMI z-score. 
Weight z-score: weight, adjusted for age and sex, will be referred to as weight-for-age z-score 
(weight z-score). The calculation of weight z-score will be exactly the same as stature z-score.  
9.2.2.2.2 
Analysis Method 
Both within-treatment arm change and between treatment arm difference will be analyzed for 
secondary variables, subject to the considerations described below.  
Absolute change from baseline in LCI2.5 through Week 48:  
Analysis of within-treatment arm change will be based on descriptive summary statistics. The 
change from baseline to the average of all post-baseline measures at scheduled visits through 
Week 48 (defined as the average of Week 12, 24, 36, 48) will be used for this analysis. 
Descriptive summary statistics include number of subjects (n), mean, median, SD, minimum, and 
maximum, along with the corresponding 95% CIs will be provided.  
If the LUM/IVA treatment group or the placebo group demonstrates a within-treatment arm 
change with 95% CI excluding 0, and the variability of this variable is within expectation, the 
analysis of between-treatment difference may also be performed based on the descriptive 
summary statistics with the corresponding 95% CIs. 
In addition, the summary of raw values and the absolute change from baseline at each post-
baseline visit up to Week 48 will be provided. 
Absolute change in Weight z-score from baseline at Week 48:  
Absolute change in Stature z-score from baseline at Week 48; 
Absolute change in BMI z-score from baseline at Week 48; 
Analyses of within-treatment arm change will be based on descriptive summary statistics. The 
change from baseline at Week 48 will be used for this analysis. Descriptive summary statistics 
including number of subjects (n), mean, median, SD, minimum, and maximum, along with the 
corresponding 95% CIs will be provided. 


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If the LUM/IVA treatment group or the placebo group demonstrates a within-treatment arm 
change with 95% CI excluding 0, and the variability of this variable is within expectation, the 
analysis of between-treatment difference may also be performed based on the descriptive 
summary statistics with the corresponding 95% CIs.  
Additional summary of raw values and absolute changes from baseline at each post-baseline visit 
up to Week 48 will also be provided. 


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9.2.3 
Safety Analysis 
Unless otherwise specified, all safety analyses of Part 1 analysis will be based on data from the 
Part 1 TE period for all subjects in the Safety Set. Subjects will be analyzed according to the 
treatment they actually received in the study Part 1. For subjects who have received study drug 
from more than one treatment, i.e. received both LUM/IVA and Placebo study drug, the 
treatment group allocation will be the LUM/IVA. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability assessments:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values 
• Vital signs 
• Ophthalmologic examinations (OEs) 
• Physical examinations (PEs) 
Only descriptive analysis will be performed for safety, and no confidence interval will be 
computed.  
9.2.3.1 
Adverse Events  
For analysis purposes, AEs will be classified as pre-treatment AEs and TEAEs during the Part 1 
TE Period in Part 1 analysis, defined as follows:  
Pretreatment AE: any AE that occurred before the first dose date of study drug (including the 
matched placebo) 
TEAE during the Part 1 TE Period: any AE that worsened (either in severity or seriousness) 
or that was newly developed at or after the first dose date of study drug (including the matched 
placebo) through the end of the Part 1 TE period 
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs are pretreatment or post-treatment, the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of adverse events are described in Appendix C. 


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An overview of all TEAEs during Part 1 TE period will be summarized by treatment group and 
overall in the following categories: 
• Number of TEAEs  
• Subjects with any TEAEs  
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation  
• Subjects with TEAEs leading to study drug interruption  
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with TEAE leading to death  
The following summary tables of TEAEs during Part 1 TE period will be presented by MedDRA 
System Organ Class (SOC) and Preferred Term (PT) using frequency counts and percentages 
(i.e., number and percentage of subjects with an event), and by treatment group:  
• All TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Related TEAEs 
• Serious TEAEs 
• TEAEs leading to death 
When summarizing the number and percentages of subjects, subjects with multiple occurrences 
of the same adverse event or a continuing adverse event will be counted once, and only the 
maximum severity level will be presented in the severity summaries, and the strongest 
relationship level in the relationship summaries.  
All AEs, including pretreatment AEs and TEAEs during the Part 1 TE period will be presented 
in an individual subject data listing based on the All Subjects Set. In addition, separate listings 
containing individual subject adverse event data for TEAEs leading to treatment discontinuation, 
TEAEs leading to treatment interruption, SAEs and all deaths will be provided separately, with a 
flag indicating the TEAE status for SAEs and deaths. 
The AEs of special interest (AESI) of elevated transaminases and respiratory event are defined as 
the following.  
1. Elevated transaminases 


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The AESI of elevated transaminases is defined by the AEs whose PTs fall into any of the 
following:  
• Alanine aminotransferase abnormal  
• Alanine aminotransferase increased  
• Aspartate aminotransferase abnormal 
• Aspartate aminotransferase increased 
• Transaminases abnormal 
• Transaminases increased 
• Liver function test abnormal 
• Liver function test increased 
• Hypertransaminasaemia 
• Hepatic enzyme increased 
• Hepatic enzyme abnormal 
2. Respiratory event AESI  
The respiratory event AESI is defined by the AEs whose PTs fall into any of the following: 
• Asthma 
• Bronchial hyperreactivity 
• Bronchospasm  
• Chest Discomfort 
• Dyspnoea 
• Respiration abnormal 
• Wheezing 
Treatment-emergent AESIs will be summarized by treatment group in the following categories:   
• Subjects with events 
• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 
• Subjects with serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event 
 


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9.2.3.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments during the Part 1 TE period, the observed 
values and change from study baseline of the continuous hematology and chemistry results will 
be summarized in SI units at each visit by treatment group.  
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
Part 1 TE period will be summarized by treatment group. The threshold analysis criteria are 
provided in Appendix D.  
In addition, a listing containing individual subject hematology and chemistry values during the 
Part 1 TE period will be provided with a column indicating outside reference range or not. This 
listing will include data from both scheduled and unscheduled visits.  
9.2.3.3 
Vital Signs 
For the treatment-emergent vital signs measurements during the Part 1 TE period, the observed 
values and change from study baseline will be summarized at each visit by treatment group. The 
following vital signs parameters will be summarized: systolic and diastolic blood pressure 
(mm Hg), body temperature (C), pulse rate (beats per minute), and respiratory rate (breaths per 
minute). 
In addition, a listing containing individual subject vital signs values during the Part 1 TE period 
will be provided. This listing will include data from both scheduled and unscheduled visits.  
9.2.3.4 
Ophthalmologic Examination  
The OE results during Part 1 TE period will be presented in individual subject data listings. 
9.2.3.5 
Physical Examination  
Abnormal PE findings will be presented as an individual subject data listing only as appropriate. 
9.3 
Final Analyses 
The final analysis will be conducted after all subjects have completed the study or have 
prematurely discontinued.  
9.3.1 
Background Characteristics  
9.3.1.1 
Subject Disposition 
A disposition table will be provided for the study Part 2 with the number of subjects in: 
• FAS, Part 2 (dosed during the study Part 2) 
• Safety Set, Part 2 (dosed during the study Part 2) 
The number and percentage (based on the FAS, Part 2) of subjects in each of the following 
disposition categories will be summarized for the study Part 2 by treatment sequence from Part 1 
to Part 2:   
• Completed Part 2 treatment  
• Completed study  
• Prematurely discontinued treatment during Part 2 and the reason for discontinuation  


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• Prematurely discontinued study participation during Part 2 and the reason for discontinuation  
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation during Part 2.  
9.3.1.2 
Study Drug Exposure  
Duration of study drug exposure on LUM/IVA during the study Part 2 is defined as last 
LUM/IVA dose date of Part 2 – first LUM/IVA dose date of Part 2 + 1 day, regardless of any 
interruptions in dosing. 
Duration of study drug exposure on LUM/IVA during the Part 2 Safety Period (in weeks) will be 
summarized descriptively based on the Safety Set, Part 2 for overall LUM/IVA treatment group 
by the number of subjects (n), mean, SD, median, min, and max. It will also be summarized as a 
categorical variable by intervals using counts and percentages. 
9.3.1.3 
Study Drug Compliance 
Percentage of study drug compliance during the study Part 2 will be summarized descriptively 
based on the FAS, Part 2 and presented by overall LUM/IVA treatment group.  
Study drug compliance will be calculated as: 100 × (1 − [total number of days of 
LUM/IVA interrupted prior to the date of last dose of LUM/IVA in Part 2] / [duration of 
LUM/IVA exposure in Part 2]). A study drug interruption on a given day is defined as an 
interruption of any study drug on that day. A study drug interruption that continues through the 
end of the study participation (i.e., subject does not resume study drug before the end of the 
study participation) will not be included in the compliance calculation. 
Descriptive summary statistics include the number of subjects (n), mean, SD, median, min, and 
max. It will also be summarized in categories: <80% and ≥80% using frequency tables. A listing 
containing subjects with study drug interruptions will be provided. 
In addition, percentage of stick packs/tablets taken will be calculated using the following 
formula: 100 x [(total number of stick packs/tablets dispensed during Part 2) – (total number of 
stick packs/tablets returned during Part 2)] / (total number of stick packs/tablets planned to be 
taken per day during Part 2 x duration of  Part 2 drug exposure in days). Summary similar to 
those for the study drug compliance will be produced based on the FAS, Part 2. 
9.3.1.4 
Important Protocol Deviations  
IPDs (from the clinical database or from the site deviation log) during Part 2 will be summarized 
descriptively based on the FAS, Part 2 and presented by treatment sequence from Part 1 to Part 
2. Additionally, IPDs will be provided in an individual subject data listing.  


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9.3.3 
Safety Analysis 
Safety analyses specified for the Part 1 analysis (Section 9.2.3) will be performed similarly for 
the Part 2 Safety Period based on the Safety Set, Part 2 in FA.  
Unless otherwise specified, analyses of adverse events and threshold analysis for clinical 
laboratory and vital signs will be summarized for the Part 2 Safety Period and presented for 
overall LUM/IVA treatment group. Analyses on change from LUM/IVA baseline of clinical 
laboratory and vital signs will be summarized at each Part 2 visit and presented by treatment 
sequence from Part 1 to Part 2.   
9.3.3.1 
Adverse Events  
For analysis purpose, AEs in FA will be classified as TEAE during the Part 2 Safety Period and 
Post-treatment AEs, defined as follows:  
TEAE during the Part 2 safety period: any AE that worsened (either in severity or 
seriousness) or that was newly developed at or after the first dose date of study drug in Part 2 
through the end of the Part 2 Safety Period. 
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was newly 
developed after the Part 1 TE period if subjects who did not receive study drug in Part 2 or after 
the Part 2 Safety Period if subjects received study drug in Part 2. 
For the overview of all TEAEs during the Part 2 Safety Period (as defined in Section 9.2.3.1), the 
frequency counts and percentages will be summarized. 


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For the summary tables of TEAEs during the Part 2 Safety Period, the frequency counts and 
percentages will be presented by MedDRA SOC and PT.  
In addition, TEAEs during the Part 2 Safety Period and post-treatment AEs will be presented in 
an individual subject data listing based on the Safety Set, Part 2. 
Similar as the Part 1 analysis of AESIs, the treatment-emergent elevated transaminases events 
and respiratory events during the Part 2 Safety Period will be summarized.   
9.3.3.2 
Clinical Laboratory and Vital Signs 
For the treatment-emergent laboratory and vital sign assessments during the Part 2 Safety Period, 
the observed values and change from the LUM/IVA baseline values will be summarized at each 
Part 2 visit and presented by treatment sequence.   
For the treatment-emergent clinical laboratory, the number and percentage of subjects meeting at 
least 1 threshold analysis criterion during the Part 2 Safety Period will be summarized. The 
threshold analysis criteria are provided in Appendix D. 
In addition, a listing containing individual subject hematology and chemistry values and a listing 
containing individual subject vital signs values during the study Part 2 will be provided. Both 
listings will include data from both scheduled and unscheduled visits. 
9.3.3.3 
Ophthalmologic Examination  
The OE results during the Part 2 Safety Period will be presented in individual subject data 
listings. 
9.3.3.4 
Physical Examination  
Abnormal PE findings will be presented as an individual subject data listing only as appropriate. 


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10 
DMC ANALYSIS 
An independent data monitoring committee (DMC) was formed before initiation of this study.  
The DMC’s objectives and operational details are described in a separate document (DMC 
Charter) which was finalized before the first subject was screened in the study. The DMC will 
conduct planned safety reviews of study data as outlined in the DMC Charter and DMC 
Statistical Analysis Plan.  
 


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11 
REFERENCES 
1 Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 
2  Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 
3 Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
4 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. 
5 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. 
6 Rubin, DB. and Schenker, N.. Interval estimation from multiply-imputed data: a case study 
using agriculture industry codes. Journal of the American Statistical Association. 1987; 81: 
366–374. 
7 Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
   http://www.cdc.gov/growthcharts/percentile_data_files.htm.  
8 Eichinger M, Optazaite DE, Kopp-Schneider A, et al. Morphologic and functional scoring of 
cystic fibrosis lung disease using MRI. Eur J Radiol 2012; 81(6) : 1321-1329. 
9 Leutz-Schmidt P, Stahl M, Sommerburg O, Eichinger M, et al. Non-contrast enhanced 
magnetic resonance imaging detects mosaic signal intensity in early cystic fibrosis lung disease. 
Eur J Radiol 2018; 101: 178-183. 
 
 
 
 
 


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12 
LIST OF APPENDICES 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessment
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3, 4, 5 
(in study Part 1 or 2 days) 
Safety Assessment 
Serum Chemistry  
 
Day 1 (Study Baseline)  
Day 15 
Week 12  
Week 24 
Week 36  
Week 48 
1 
15 
85 
169 
253 
337 
 
1 Pre-dose 
[1, 49] 
[50, 126] 
[127, 210] 
[211, 294] 
[295, min(337+67, 1st dose of 
Part 2)] 
Day 350 
Week 60  
Week 72 
Week 84 
Week 96 
Safety Follow-up 
Part 2 Day 15 
Part 2 Day 85 
Part 2 Day 169 
Part 2 Day 253 
Part 2 Day 337 
N/A 
[1st dose of Part 2, 49] 
[50, 126] 
[127, 210] 
[211, 294] 
[295, 337+67] 
Use nominal visit 
Hematology 
 
Day 1 (Study Baseline)  
Week 12  
Week 24 
Week 36  
Week 48 
 
1 
85 
169 
253 
337 
 
1 Pre-dose 
[1, 126] 
[127, 210] 
[211, 294] 
[295, min(337+67, 1st dose of 
Part 2)] 
Week 60  
Week 72 
Week 84 
Week 96 
Safety Follow-up 
Part 2 Day 85 
Part 2 Day 169 
Part 2 Day 253 
Part 2 Day 337 
N/A 
[1st dose of Part 2, 126] 
[127, 210] 
[211, 294] 
[295, 337+67] 
Use nominal visit 
Vital signs (excluding  
Weight and Stature) 
 
Day 1 (Study Baseline)  
Day 15 
Week 12  
Week 24 
Week 36  
Week 48 
1 
15 
85 
169 
253 
337 
 
1  
[1, 49] 
[50, 126] 
[127, 210] 
[211, 294] 
[295, min(337+67, 1st dose of 
Part 2)] 
Day 350 
Week 60  
Week 72 
Week 84 
Week 96 
Safety Follow-up 
Part 2 Day 15 
Part 2 Day 85 
Part 2 Day 169 
Part 2 Day 253 
Part 2 Day 337 
N/A 
[1st dose of Part 2, 49] 
[50, 126] 
[127, 210] 
[211, 294] 
[295, 337+67] 
Use nominal visit 
Efficacy Assessment  


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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3, 4, 5 
(in study Part 1 or 2 days) 
MRI  
 
Day 1 (Study Baseline) 
Week 48 
 
1 
337 
 
1 Pre-dose 
(1, min(337+67, 1st dose of Part 
2] 
Week 96 
Part 2 Day 337 
[1st dose of Part 2, 337+67] 
MBW 
 
 
 
Day 1 (Study Baseline)  
Week 12  
Week 24 
Week 36  
Week 48  
 
1 
85 
169 
253 
337 
 
1 Pre-dose 
(1, 126] 
[127, 210] 
[211, 294] 
[295, min(337+67, 1st dose of 
Part 2)] 
Week 60  
Week 72 
Week 84 
Week 96 
Part 2 Day 85 
Part 2 Day 169 
Part 2 Day 253 
Part 2 Day 337 
[1st dose of Part 2, 126] 
[127, 210] 
[211, 294] 
[295, 337+67] 
Weight and Stature 
 
Day 1 (Study Baseline)  
Day 15 
Week 12  
Week 24 
Week 36  
Week 48 
1 
15 
85 
169 
253 
337 
 
1 Pre-dose 
[1, 49] 
[50, 126] 
[127, 210] 
[211, 294] 
[295, min(337+67, 1st dose of 
Part 2)] 
Day 350 
Week 60  
Week 72 
Week 84 
Week 96 
Part 2 Day 15 
Part 2 Day 85 
Part 2 Day 169 
Part 2 Day 253 
Part 2 Day 337 
[1st dose of Part 2, 49] 
[50, 126] 
[127, 210] 
[211, 294] 
[295, 337+67] 
Notes: 
 1Visit name for analysis purpose is used to report data in tables and figures. 
 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered 
missing for the visit. 
b. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. 
 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX16-809-121 
 
 
Vertex Pharmaceuticals Incorporated 
 
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window2,3, 4, 5 
(in study Part 1 or 2 days) 
3 For lab and vital sign measurement collected on the date of first dose of study drug in Treatment Period (Part 1 
or Part 2 of study), if it cannot be determined whether the measurement is before or after the first dose:  
a. 
Scheduled measurement will be treated as pre-dose observation. 
b. Unscheduled measurement will be treated as post-dose observation. 
 
4 For safety assessment, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a 
subject doesn’t have a nominal Safety Follow-up visit but has an ETT visit with study day >680, then the ETT 
visit will be mapped into Safety Follow-up analysis visit.  
Derived Variables: 
1. Age (in years) at first dose date and nominal visit (for demographics and listing variables): 
Obtain the age at informed consent (in days) in “yy, mm” format (e.g., 24 years, 6 months) from the Vital 
Signs (VS) page at the Screening Visit and add 0.5 month to convert to days. 
Obtain the informed consent date. 
Then age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed consent 
date) in days + age at informed consent (in days)]/365.25. 
2. Age (in months) at nominal visit (for use in calculation of BMI, stature z-score, and weight z-score): 
Obtain the age at informed consent (in months) in “yy, mm” format (e.g., 24 years, 6 months) from Vital 
Signs (VS) page at the Screening Visit. 
Obtain the informed consent date. 
Then age (in months) at nominal visit = integer part of {[(age at informed consent (in months) + 0.5 + 
diff(first dose date or nominal visit date, informed consent date) in months]} + 0.5. 
3. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date to impute. 
If the last dose date is missing or partial date is reported, the last dose date will be imputed based on, in 
descending order priority, the Early Treatment Termination (ETT) visit date, last visit date before the Safety 
Follow-up, or the last study drug administration date from EX SDTM domain, as appropriate.  The 
imputation algorithm will ensure the imputed last dose date does not exceed the study participation end date. 
5. The 1st dose of Part 2: 
The analysis visit window of the study Part 1 is ended at the day of Week 48 visit before the 1st dose of Part 
2. The analysis visit window of the study Part 2 is started from the day of Week 48 visit after the 1st dose of 
Part 2. 
6. Post-dose Vital signs: 
The analysis window for post-dose vital sign measures will be1 hour (± 15 minutes), 2 hours (± 15 minutes), 
and 4 hours (± 15 minutes). Any measures after the last post-dose analysis window will be allocated to the 
next analysis window.   
 
 


Statistical Analysis Plan (Methods) 
Page 33 of 37 
Protocol Number: VX16-809-121 
 
 
Vertex Pharmaceuticals Incorporated 
 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month.  
b. If DAY and Month are both missing, use the first day of the year.  
c. If DAY, Month and Year are all missing, use a date before the first dose date (in 
practical, use Jan. 01, 2000 to impute). 
2. Missing or partial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month and year are all missing, assign ‘continuing’ status to stop date (in 
practical, use Dec. 31, 2050 to impute). 
In summary, the prior, concomitant, or post categorization of a medication is described below. 
Medication Start Date 
Medication Stop Date 
< First Dose Date of 
Study Drug 
≥ First Dose Date and  
≤ End Date of Part 1 TE 
Period 
< First dose date of study drug 
P 
PC 
≥ First dose date and  
≤ End date of Part 1 TE period 
- 
C 
P: Prior; C: Concomitant during the Part 1 TE period 
Imputation rules for missing and/or partial dates of non-pharmacological treatment/procedure 
will follow the same imputation rule. 
 
 


Statistical Analysis Plan (Methods) 
Page 34 of 37 
Protocol Number: VX16-809-121 
 
 
Vertex Pharmaceuticals Incorporated 
 
Appendix C: Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date are defined below. If the imputed AE start 
date is before the informed consent date, the AE start date will be imputed using the study 
informed consent date. 
• If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year and month are equal to the month and year of first dose date 
of the Treatment Period, then impute the AE start day as the day of first dose 
date of the Treatment Period;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with Part 1 TE period or cumulative safety period to 
determine whether the AE is pretreatment AE, TEAE during the Part 1 TE Period, TEAE 
during the Cumulative Safety Period, or post-treatment AE. 
• If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Treatment Period;  
 else impute the AE start month as January and day as 1.  
o else impute the AE start month as January and day as 1.  
Compare the imputed AE start date with Part 1 TE period or cumulative safety period to 
determine whether the AE is pretreatment AE, TEAE during the Part 1 TE Period, TEAE 
during the Cumulative Safety Period, or post-treatment AE. 
• If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site and 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the date of first 
dose date of the Treatment Period.  
o else impute AE date as the informed consent date. 
The imputation should ensure the imputed AE start date is not before the informed consent date. 
• Imputation rules for partial AE end date are defined below:  
If partial end date, then impute as min (the last day of the month, end of study participation (of 
Part 1)) if day is missing, or min (Dec, end of study participation (of Part 1)) if month is missing. 


Statistical Analysis Plan (Methods) 
Page 35 of 37 
Protocol Number: VX16-809-121 
 
 
Vertex Pharmaceuticals Incorporated 
 
Appendix D: Criteria for Threshold Analysis 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Categorical change 
Comments 
Clinical Chemistry (LFT) 
ALT 
≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>3xULN 
>5xULN 
>8xULN 
FDA DILI Guidance Jul 2009.  
AST 
≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>3xULN 
>5xULN 
>8xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
ALT>3xULN or AST>3xULN 
Vertex LFT working group 2014 
 
ALT>5xULN or AST>5xULN 
 
 
ALT>8xULN or AST>8xULN 
 
Alkaline Phosphatase 
>1.5xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>1.5x - ≤2xULN 
>2xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
To be counted within a same treatment 
phase, whatever the interval between 
measurements. 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
To be counted within a same treatment 
phase, whatever the interval between 
measurements. 
(ALT or AST) and Total 
Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
Vertex LFT working group 2014 
GGT 
>ULN - ≤ 2.5xULN 
>2.5 – ≤ 5.0xULN 
>5.0 – ≤ 20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (Non-LFT) 
CPK (Creatine kinase) 
>3x - ≤ 10xULN 
>10xULN 
FDA criteria Feb 2005. 
Am J Cardiol April 2006. 
Albumin 
≤25 g/L 
 


Statistical Analysis Plan (Methods) 
Page 36 of 37 
Protocol Number: VX16-809-121 
 
 
Vertex Pharmaceuticals Incorporated 
 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Categorical change 
Comments 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<85 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥150 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Amylase 
>1x -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Lipase 
>ULN -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L 
(fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
Hematology 
WBC (Leukocytes) 
<3.0 Giga/L (Non-Black); <2.0 Giga/L 
(Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential 
count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L 
(Black) 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from 
baseline are more relevant than based on 
absolute value. Other categories for 
decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 


Statistical Analysis Plan (Methods) 
Page 37 of 37 
Protocol Number: VX16-809-121 
 
 
Vertex Pharmaceuticals Incorporated 
 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Categorical change 
Comments 
Reticulocytes/Erythrocytes 
(%)    
<LLN 
>ULN 
No CTCAE