Clinical trial NCT02951182
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2016-10-01; Completion date: 2017-08-01
Enrollment: 74 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, randomized, double-blind, placebo- and active-controlled, parallel group, multicenter study to evaluate the safety, tolerability, and efficacy of VX-440 in dual and triple combination with tezacaftor (TEZ; VX-661) and ivacaftor (IVA; VX-770) in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F508del/F508del), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ and/or IVA therapy (F508del/MF).

Detailed description:

Arms: arm 1: Participants received placebo matched to VX-440/TEZ/IVA as triple combination for 4 weeks. arm 2: Participants received VX-440 200 milligram (mg) every 12 hours (q12h)/TEZ 100 mg once daily (qd)/IVA 150 mg q12h as triple combination for 4 weeks. arm 3: Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks. arm 4: Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks. arm 5: Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received placebo matched to VX-440 and TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period. arm 6: Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received VX-440 600 mg q12h/ TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period.
Interventions: intervention 1: TEZ intervention 2: IVA intervention 3: VX-440 intervention 4: Matched Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_001.pdf: 
Page 1 of 88 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 2, Randomized, Double-blind, Controlled Study to 
Evaluate the Safety and Efficacy of VX-440 Combination 
Therapy in Subjects Aged 12 Years and Older With Cystic 
Fibrosis 
Vertex Study Number: VX15-440-101 
 
EudraCT Number: 2016-000454-36 
Date of Protocol: 16 September 2016 (Version 2.0) 
 
 
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 
















Protocol VX15-440-101, Version 2.0 
Page 9 of 88 
Vertex Pharmaceuticals Incorporated 
 
Statistical Analyses Primary Objectives:  
The primary objectives of the study are the evaluation of safety and tolerability, and 
efficacy of VX-440 in TC with TEZ/IVA (all parts)
 
 
The safety endpoints include AEs, clinical laboratory values, 12-lead ECGs, vital signs, 
and pulse oximetry through the Safety Follow-up Visit (all parts). The safety analysis 
for all treatment groups in all parts will be descriptive only. 
The primary efficacy endpoint is the absolute change from baseline through Day 29 for 
ppFEV1 (Parts 1 and 2), 
 All ppFEV
1 
hypothesis tests will be performed within the mixed-effects model for repeated 
measures (MMRM) framework at a 5% alpha level, with appropriate adjustment for 
covariates including stratification factors at randomization. The null within-group 
hypothesis of no difference in the mean absolute change from baseline through the last 
on-treatment visit (Day 29 or Week 12) for ppFEV
1, in all treatment groups, by part, 
will be tested using a 2-sided 1-sample t test. The adjusted means and 2-sided 95% 
confidence intervals of the average treatment effects through Day 29
, as 
applicable, for all within-group and between-group comparisons will be estimated 
within MMRM. 
Secondary Objectives: 
A secondary objective of the study is the evaluation of the PD effect of VX-440 in TC 
with TEZ/IVA (all parts) 
  
The PD endpoint is the absolute change in sweat chloride from baseline through Day 29 
(Parts 1 and 2) 
 
In Part 1, the null hypothesis of the lack of a decreasing dose-response trend in the 
mean absolute change from baseline through Day 29 for sweat chloride, between the 
TC dose groups and placebo will be tested using a multiple comparisons procedure 
based on the 1-sided maximum t-statistic. In all parts, the null within-group hypothesis 
of no difference in the mean absolute change from baseline through Day 29   
, for sweat chloride in all treatment groups, by Part, will be 
tested using a 2-sided 1-sample t-test. The adjusted means and 2-sided 95% confidence 
intervals of the average treatment effects through Day 29 
, for 
all within-group and between-group comparisons will be estimated within MMRM. 
  
Interim Analyses Separate interim analyses will be performed after: 
• all subjects in Part 1 have completed the Safety Follow-up Visit 
• all subjects in Part 2 have completed the Safety Follow-up Visit 
  
IDMC Reviews The independent monitoring committee (IDMC) will conduct regular planned safety 
reviews of study data from all parts of the study as outlined in the IDMC Charter. 


Protocol VX15-440-101, Version 2.0 
Page 10 of 88 
Vertex Pharmaceuticals Incorporated 
 
3 
SCHEDULE OF ASSESSMENTS 
The schedule of assessments from the Screening Period through the Safety Follow-up Visit are 
provided in Table 3-1 for Part 1 Cohort 1A, Table 3-2 for Part 1 Cohort 1B, Table 3-3 for Part 2, 
 
All visits will be scheduled relative to the Day 1 Visit (first dose of VX-440 or VX-440 matched 
placebo).  
The CFQ-R assessment must be completed before any other assessment at the clinic visits when 
it is required. For remaining assessments, assessments may be performed in any order when 
more than 1 assessment is required at a particular time point. (See Section 11.1.)


Protocol VX15-440-101, Version 2.0 
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Vertex Pharmaceuticals Incorporated 
 
Table 3-1 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1A)
 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Day 8 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Informed consent 
X 
 
 
 
 
 
 
 
Randomizatione 
 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Ophthalmological history 
X 
 
 
 
 
 
 
 
CFQ-Rf,g 
 
X 
 
X 
X 
X 
Xh  
X 
Weighti 
X 
X 
X 
X 
X 
X 
X 
X 
Height
i 
X 
 
 
 
 
 
 
 
Vital signsj 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryj 
X 
X 
X 
X 
X 
X 
X 
X 
 
a  All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once 
if study drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b  To be eligible to continue into the Treatment Period, subjects must have stable CF disease and have remained on stable CF medication regimen during the 
28 days before the Day 1 Visit AND must not have had an acute non-CF illness within 14 days before the Day 1 Visit. See Section 8.1.3. 
c  If the subject prematurely discontinues study treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug 
treatment. Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit. If the ETT Visit occurs 3 weeks or 
later following the last dose of study drug, then the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
d  All screening results must be reviewed by an appropriately qualified member of the investigator’s team before randomization, unless noted otherwise. 
e  Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria have been confirmed. 
f  CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
g  The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred. 
h  Subjects will complete the CFQ-R at the ETT Visit only if it has been 2 weeks or more since their last visit. 
i  Weight and height will be measured with shoes off. 
j  Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 


Protocol VX15-440-101, Version 2.0 
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Vertex Pharmaceuticals Incorporated 
 
Table 3-1 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1A)
 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Day 8 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Physical examinationk 
Complete 
Abbreviated 
 
Abbreviated 
Abbreviated 
 
Abbreviated 
Complete 
Ophthalmologic 
examinationl 
X 
 
 
 
 
 
 
 
Standard 12-lead ECG
m 
X 
X 
X 
X 
X 
X 
X 
X 
Sweat chloride
g,n 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometryo 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis
g 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (all females 
of childbearing potential) 
Serum 
Urine 
 
 
Urine 
 
Serum  
Serum 
CFTR genotypep 
X 
 
 
 
 
 
 
 
FSHq 
X 
 
 
 
 
 
 
 
 
k  Complete and abbreviated PEs are described in Section 11.7.3. Symptom-targeted PEs will occur at any time during the study if triggered by AEs or if 
deemed necessary by the investigator or healthcare provider. 
l  The ophthalmological examination can be performed at any time during the Screening Period through the Day 1 Visit (before the first dose of study drug). 
The screening ophthalmological examination does not have to be performed if there is documentation of an examination that met protocol criteria and was 
within 3 months before the date of informed consent, or if there is documentation of bilateral lens removal for the subject. 
m  All standard 12-lead ECGs will be performed after the subject has been seated for at least 5 minutes. On Days 1 and 15, ECGs will be collected before 
dosing and 4 hours (± 1 hour) after dosing. At all other visits, ECGs will be collected before dosing (as applicable). ECGs collected on Day 1 before dosing 
will be performed in triplicate.  
n  Sweat chloride will be measured in all subjects. If the value cannot be determined from the screening test, a sweat chloride value documented in the subject’s 
medical record may be used to establish eligibility. 
o  Spirometry may be performed pre- or post-bronchodilator at the Screening Visit. Spirometry will be performed pre-bronchodilator, before the morning dose 
of study drugs, and should be performed at approximately the same time at every other study visit. On Days 1 and 15, spirometry will also be performed 
pre-bronchodilator 5 hours (± 1 hour) after study drug administration.  
p  CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before randomization, a previous CFTR genotype 
laboratory report may be used to establish eligibility. 
q  FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 


Protocol VX15-440-101, Version 2.0 
Page 13 of 88 
Vertex Pharmaceuticals Incorporated 
 
Table 3-1 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1A)
 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Day 8 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
G6PD activity testr 
X 
 
 
 
 
 
 
 
Serum chemistry and 
hematologyg 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulationg 
X 
X 
 
X 
X 
 
 
X 
PK samplingt 
 
X 
X 
X 
X 
X 
X 
  
Study drug dosingu 
 
Day 1 through Day 29 
 
 
 
AEs, medicationsv, 
treatments, and procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
 
 
r
  Blood samples will be collected for PK analysis of VX-440, TEZ, M1-TEZ, IVA, and M1-IVA. On Day 1, samples will be collected before dosing (0 hours) 
and at 1, 2, 4, and 6 hours after dosing (relative to the morning dose). On Days 8 and 29, a predose sample will be collected before the morning dose of study 
drug. On Day 15, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 8 hours after dosing. At the Day 43 and the ETT Visits, a single 
blood sample for PK analysis will be collected. 
u  The last dose of study drug will be the morning dose on Day 29. 
v  Refer to Section 9.4 for details. 


Protocol VX15-440-101, Version 2.0 
Page 14 of 88 
Vertex Pharmaceuticals Incorporated 
 
Table 3-2 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1B) 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dose 
Days -28 
to -1d 
Day 1  
Day 15 
(± 2 day) 
Day 29 
(± 2 day) 
Informed consent 
X 
 
 
 
 
 
 
Randomizatione 
 
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Ophthalmological history 
X 
 
 
 
 
 
 
CFQ-Rf,g 
 
X 
X 
X 
X 
Xh  
X 
Weighti 
X 
X 
X 
X 
X 
X 
X 
Height
i 
X 
 
 
 
 
 
 
Vital signsj 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryj 
X 
X 
X 
X 
X 
X 
X 
 
a  All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once 
if study drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b  To be eligible to continue into the Treatment Period, subjects must have stable CF disease and have remained on stable CF medication regimen during the 
28 days before the Day 1 Visit AND must not have had an acute non-CF illness within 14 days before the Day 1 Visit. See Section 8.1.3. 
c  If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug 
treatment. Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit. If the ETT Visit occurs 3 weeks or 
later following the last dose of study drug, then the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
d  All screening results must be reviewed by an appropriately qualified member of the investigator’s team before randomization, unless noted otherwise. 
e  Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria have been confirmed. 
f  CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
g  The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred. 
h  Subjects will complete the CFQ-R at the ETT Visit only if it has been 2 weeks or more since their last visit. 
i  Weight and height will be measured with shoes off. 
j  Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 


Protocol VX15-440-101, Version 2.0 
Page 15 of 88 
Vertex Pharmaceuticals Incorporated 
 
Table 3-2 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1B) 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dose 
Days -28 
to -1d 
Day 1  
Day 15 
(± 2 day) 
Day 29 
(± 2 day) 
Physical examinationk 
Complete 
Abbreviated 
Abbreviated 
Abbreviated 
 
Abbreviated 
Complete 
Ophthalmologic 
examinationl 
X 
 
 
 
 
 
 
Standard 12-lead ECG
m 
X 
X 
X 
X 
X 
X 
X 
Sweat chloride
g,n 
X 
X 
X 
X 
X 
X 
X 
Spirometryo 
X 
X 
X 
X 
X 
X 
X 
Urinalysis
g 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (all females 
of childbearing potential) 
Serum 
Urine 
 
Urine 
 
Serum 
Serum 
CFTR genotypep 
X 
 
 
 
 
 
 
FSHq 
X 
 
 
 
 
 
 
 
k  Complete and abbreviated PEs are described in Section 11.7.3. Symptom-targeted PEs will occur at any time during the study if triggered by AEs or if 
deemed necessary by the investigator or healthcare provider. 
l  The ophthalmological examination can be performed at any time during the Screening Period through the Day 1 Visit (before the first dose of study drug). 
The screening ophthalmological examination does not have to be performed if there is documentation of an examination that met protocol criteria and was 
within 3 months before the date of informed consent, or if there is documentation of bilateral lens removal for the subject. 
m  All standard 12-lead ECGs will be performed after the subject has been seated for at least 5 minutes. On Days 1 and 15, ECGs will be collected before 
dosing and 4 hours (± 1 hour) after dosing. At all other visits, ECGs will be collected before dosing (as applicable). ECGs collected on Day 1 before dosing 
will be performed in triplicate.  
n  Sweat chloride will be measured in all subjects. If the value cannot be determined from the screening test, a sweat chloride value documented in the subject’s 
medical record may be used to establish eligibility. 
o  Spirometry may be performed pre- or post-bronchodilator at the Screening Visit. Spirometry will be performed pre-bronchodilator, before the morning dose 
of study drugs, and should be performed at approximately the same time at every other study visit. On Days 1 and 15, spirometry will also be performed 
pre-bronchodilator, 5 hours (± 1 hour) after study drug administration.  
p  CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before randomization, a previous CFTR genotype 
laboratory report may be used to establish eligibility. 
q  FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 


Protocol VX15-440-101, Version 2.0 
Page 16 of 88 
Vertex Pharmaceuticals Incorporated 
 
Table 3-2 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1B) 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dose 
Days -28 
to -1d 
Day 1  
Day 15 
(± 2 day) 
Day 29 
(± 2 day) 
G6PD activity testr 
X 
 
 
 
 
 
 
Serum chemistry and 
hematologyg 
X 
X 
X 
X 
X 
X 
X 
Coagulationg 
X 
X 
X 
X 
 
 
X 
PK samplingt 
 
X 
X 
X 
X 
X 
  
Study drug dosingu 
 
Day 1 through Day 29 
 
 
 
AEs, medicationsv, 
treatments and procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
 
 
r  A single blood sample will be collected for the G6PD activity test. 
  Blood samples will be collected for PK analysis of VX-440, TEZ, M1-TEZ, IVA, and M1-IVA. On Day 1, samples will be collected before dosing (0 hours) 
and at 1, 2, 4, and 6 hours after dosing (relative to the morning dose). On Day 15, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 8 
hours after dosing. On Day 29, a predose sample will be collected before the morning dose of study drug. At the Day 43 and the ETT Visits, a single blood 
sample for PK analysis will be collected. 
u  The last dose of study drug will be the morning dose on Day 29. 
v  Refer to Section 9.4 for details. 


Protocol VX15-440-101, Version 2.0 
Page 17 of 88 
Vertex Pharmaceuticals Incorporated 
 
Table 3-3 
Study VX15-440-101: Schedule of Assessments for Part 2 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Periodb 
Washout Period 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dosed 
Days -56 
to -29e 
Day -28 
(± 1 day) 
Day -14f 
(± 1 day) 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Randomizationg 
 
 
 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Ophthalmological 
history 
X 
 
 
 
 
 
 
 
 
 
CFQ-Rh,i 
 
 
 
X 
X 
X 
X 
X 
Xj  
X 
Weightk 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Height
k 
X 
 
 
 
 
 
 
 
 
 
Vital signsl 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryl 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
a  All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once 
if study drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b  To be eligible to continue into the Treatment Period, subjects must have stable CF disease and have remained on stable CF medication regimen during the 
28 days before the Day 1 Visit AND must not have had an acute non-CF illness within 14 days before the Day 1 Visit. See Section 8.1.3. 
c  If the subject prematurely discontinues study treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug 
treatment. Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit. If the ETT Visit occurs 3 weeks or 
later following the last dose of study drug, then the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
d  Part 2 subjects who meet criteria specified in Section 8.1.5 will not have a Safety Follow-up Visit. 
e  All screening results must be reviewed by an appropriately qualified member of the investigator’s team before the subject receives the first dose of TEZ/IVA 
in the Run-in Period on Day -28, unless noted otherwise.  
f  The Day -14 Visit is only required for subjects who are naïve to TEZ/IVA treatment. 
g  Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria and criteria for entry into the Treatment Period have been 
confirmed. See Section 8.1.3. 
h  CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
i  The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred. 
j  Subjects will complete the CFQ-R at the ETT Visit only if it has been 2 weeks or more since their last visit. 
k  Weight and height will be measured with shoes off. 
l  Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 


Protocol VX15-440-101, Version 2.0 
Page 18 of 88 
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Table 3-3 
Study VX15-440-101: Schedule of Assessments for Part 2 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Periodb 
Washout Period 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dosed 
Days -56 
to -29e 
Day -28 
(± 1 day) 
Day -14f 
(± 1 day) 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
Physical 
examinationm 
Complete Abbreviated 
 
Abbreviated Abbreviated Abbreviated 
 
Abbreviated Abbreviated Complete 
Ophthalmologic 
examinationn 
X 
 
 
 
 
 
 
 
 
 
Standard 12-lead 
ECGo 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Sweat chloridei,p 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Spirometryq 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis
i 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (all 
females of 
childbearing 
potential) 
Serum 
Urine 
 
Urine 
 
Urine 
 
Urine 
Serum 
Serum 
CFTR genotyper 
X 
 
 
 
 
 
 
 
 
 
FSHs 
X 
 
 
 
 
 
 
 
 
 
 
m  Complete and abbreviated PEs are described in Section 11.7.3. Symptom-targeted PEs will occur at any time during the study if triggered by AEs or if 
deemed necessary by the investigator or healthcare provider. 
n  The ophthalmological examination can be performed at any time during the Screening Period through the Day 1 Visit (before the first dose of study drug). 
The screening ophthalmological examination does not have to be performed if there is documentation of an examination that met protocol criteria and was 
within 3 months before the date of informed consent, or if there is documentation of bilateral lens removal for the subject. 
o  All standard 12-lead ECGs will be performed after the subject has been seated for at least 5 minutes. On Days 1 and 15, ECGs will be collected before 
dosing and 4 hours (± 1 hour) after dosing. At all other visits, ECGs will be collected before dosing (as applicable). ECGs collected on Day 1 before dosing 
will be performed in triplicate.  
p  Sweat chloride will be measured in all subjects. If the value cannot be determined from the screening test, a sweat chloride value documented in the subject’s 
medical record may be used to establish eligibility.  
q  Spirometry may be performed pre- or post-bronchodilator at the Screening Visit. Spirometry will be performed pre-bronchodilator, before the morning dose 
of study drugs, and should be performed at approximately the same time at every other study visit. On Days 1 and 15, spirometry will also be performed 
pre-bronchodilator, 5 hours (± 1 hour) after study drug administration.  
r  CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before Day -28, a previous CFTR genotype 
laboratory report may be used to establish eligibility. 


Protocol VX15-440-101, Version 2.0 
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Vertex Pharmaceuticals Incorporated 
 
Table 3-3 
Study VX15-440-101: Schedule of Assessments for Part 2 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Periodb 
Washout Period 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dosed 
Days -56 
to -29e 
Day -28 
(± 1 day) 
Day -14f 
(± 1 day) 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
G6PD activity testt 
X 
 
 
 
 
 
 
 
 
 
Serum chemistry 
and hematology
i 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Coagulationi 
X 
X 
 
X 
X 
X 
 
 
 
X 
PK samplingv 
 
 
 
X 
X 
X 
X 
 
X 
  
TEZ/IVA dosingw 
 
Day -28 through Day 57 
 
 
VX-440 or placebo 
dosingx 
 
 
 
Day 1 through Day 29 
 
 
 
 
AEs, medicationsy, 
treatments and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
 
s  FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
t  A single blood sample will be collected for the G6PD activity test 
v  Blood samples will be collected for PK analysis of VX-440, TEZ, M1-TEZ, IVA, and M1-IVA. On Day 1, samples will be collected before dosing (0 hours) 
and at 1, 2, 4, and 6 hours after dosing (relative to morning dose). On Day 15, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 8 hours 
after dosing. On Day 29, a predose sample will be collected before the morning dose of study drug. At the Day 43 Visit, a single blood sample for PK 
analysis will be collected before the morning dose of TEZ/IVA. At the ETT Visit, a single blood sample for PK analysis will be collected. 
w  The last dose of TEZ/ivacaftor will be the morning dose on Day 57. 
x  The last dose of VX-440 or placebo will be the morning dose on Day 29. 
y  Refer to Section 9.4 for details. 








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4 
TABLE OF CONTENTS 
1 Title Page 
................................................................................................
................................ 1 
 
2 Protocol Synopsis 
................................................................................................................... 5 
3 Schedule of Assessments...................................................................................................... 10 
4 Table of Contents 
................................................................................................................. 23 
List of Tables............................................................................................................................ 27 
List of Figures 
.......................................................................................................................... 27 
Glossary of Terms 
.................................................................................................................... 28
 
5 Introduction.......................................................................................................................... 30 
5.1 Background 
..................................................................................................................... 30 
5.2 Rationale for the Present Study 
...................................................................................... 31
 
6 Study Objectives 
.................................................................................................................. 31
 
6.1 Primary Objectives 
......................................................................................................... 31
 
6.2 Secondary Objectives 
..................................................................................................... 31
 
7 Study Endpoints 
................................................................................................................... 31
 
7.1 Primary Endpoints 
.......................................................................................................... 31 
7.2 Secondary Endpoints 
...................................................................................................... 32 
 
 
8 Study Design 
......................................................................................................................... 32
 
8.1 Overview of Study Design ............................................................................................. 32 
 Screening 
................................................................................................................ 36
 
8.1.1
8.1.1.1 Repetition of Screening Assessment(s) 
............................................................ 37
 
8.1.1.2 Rescreening 
...................................................................................................... 37
 
8.1.1.3 Extension of Screening Period Window 
.......................................................... 37 
 Run-in Period (Part 2)............................................................................................. 37 
8.1.2
 Treatment Period 
.................................................................................................... 38
 
8.1.3
 Washout Period (Part 2) ......................................................................................... 38 
8.1.4
 Follow-up................................................................................................................ 38 
8.1.5
 Early Termination of Treatment 
............................................................................. 39
 
8.1.6
 Independent Data Monitoring Committee 
.............................................................. 39 
8.1.7
8.2 Rationale for Study Design and Study Drug Regimens 
................................................. 39 
 Study Design........................................................................................................... 39 
8.2.1
 Study Drug Dose and Duration .............................................................................. 40 
8.2.2
 Rationale for Study Population............................................................................... 42 
8.2.3
 Rationale for Study Assessments ........................................................................... 42
 
8.2.4
9 Study Population 
.................................................................................................................. 43
 
9.1 Inclusion Criteria 
............................................................................................................ 43
 
9.2 Exclusion Criteria 
........................................................................................................... 44
 
9.3 Prohibited Medications 
................................................................................................... 46 
9.4 Prior and Concomitant Medications 
............................................................................... 47 
9.5 Removal of Subjects 
....................................................................................................... 47 
9.6 Replacement of Subjects ................................................................................................ 48
 
10 Study Drug Administration and Management 
................................................................. 48
 
10.1 Preparation and Dispensing 
............................................................................................ 48 




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12.1.2.1 Pharmacodynamic Effect (Part 1) 
.................................................................... 64
 
12.2 Analysis Sets .................................................................................................................. 66
 
12.3 Statistical Analysis ......................................................................................................... 66
 
 General Considerations 
........................................................................................... 66 
12.3.1
 Background Characteristics 
.................................................................................... 67
 
12.3.2
12.3.2.1 Subject Disposition 
.......................................................................................... 67
 
12.3.2.2 Demographics and Baseline Characteristics 
.................................................... 67
 
12.3.2.3 Prior and Concomitant Medications................................................................. 67 
12.3.2.4 Study Drug Exposure and Compliance 
............................................................ 67 
12.3.2.5 Important Protocol Deviations 
......................................................................... 68 
 Efficacy Analysis 
.................................................................................................... 68
 
12.3.3
12.3.3.1 Analysis of Primary Efficacy Variables 
........................................................... 68
 
12.3.3.2 Analysis of Secondary Efficacy Variables 
....................................................... 69
 
 
 Pharmacodynamic Analysis ................................................................................... 69
 
12.3.4
12.3.4.1 Pharmacodynamic Effect 
................................................................................. 69
 
 Safety Analysis 
....................................................................................................... 70
 
12.3.5
12.3.5.1 Adverse Events................................................................................................. 70 
12.3.5.2 Clinical Laboratory Assessments 
..................................................................... 71
 
12.3.5.3 Electrocardiogram 
............................................................................................ 71
 
12.3.5.4 Vital Signs 
........................................................................................................ 71
 
12.3.5.5 Pulse Oximetry 
................................................................................................. 72
 
12.3.5.6 Physical Examination 
....................................................................................... 72
 
12.3.5.7 Other Safety Analysis ...................................................................................... 72
 
 Interim and IDMC Analyses 
................................................................................... 72
 
12.3.6
12.3.6.1 Interim Analysis 
............................................................................................... 72
 
12.3.6.2 IDMC Analysis 
................................................................................................ 72
 
12.4 Clinical Pharmacology Analysis 
.................................................................................... 72
 
 Pharmacokinetic Analysis 
...................................................................................... 72
 
12.4.1
 Pharmacokinetic/Pharmacodynamic Analyses 
....................................................... 72
 
12.4.2
13 Procedural, Ethical, Regulatory, and Administrative Considerations 
........................... 73 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting 
........................................................................................................................ 73 
 Adverse Events 
....................................................................................................... 73
 
13.1.1
13.1.1.1 Definition of an Adverse Event........................................................................ 73 
13.1.1.2 Clinically Significant Assessments 
.................................................................. 73
 
13.1.1.3 Documentation of Adverse Events................................................................... 73 
13.1.1.4 Adverse Event Severity 
.................................................................................... 74
 
13.1.1.5 Adverse Event Causality 
.................................................................................. 75
 
13.1.1.6 Study Drug Action Taken 
................................................................................ 75 
13.1.1.7 Adverse Event Outcome .................................................................................. 75 
13.1.1.8 Treatment Given............................................................................................... 76 
 Serious Adverse Events 
.......................................................................................... 76 
13.1.2
13.1.2.1 Definition of a Serious Adverse Event............................................................. 76 
13.1.2.2 Documentation of Serious Adverse Events...................................................... 77 
13.1.2.3 Reporting Serious Adverse Events................................................................... 77 


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13.1.2.4 Expedited Reporting and Investigator Safety Letters 
...................................... 77 
13.2 Administrative Requirements 
......................................................................................... 77
 
 Ethical Considerations 
............................................................................................ 77 
13.2.1
 Subject Information and Informed Consent 
........................................................... 78 
13.2.2
 Investigator Compliance 
......................................................................................... 78 
13.2.3
 Access to Records 
................................................................................................... 78
 
13.2.4
 Subject Privacy 
....................................................................................................... 78
 
13.2.5
 Record Retention 
.................................................................................................... 79
 
13.2.6
 Study Termination 
.................................................................................................. 79
 
13.2.7
13.3 Data Quality Assurance 
.................................................................................................. 79
 
13.4 Monitoring 
...................................................................................................................... 80 
13.5 Electronic Data Capture ................................................................................................. 80
 
13.6 Publications and Clinical Study Report 
.......................................................................... 80 
 
 
 Clinical Study Report 
............................................................................................. 81
 
13.6.2
14 References 
............................................................................................................................. 82
 
APPENDIX A  CFTR Mutations That Are Predicted to Result in a CFTR Protein With 
Minimal Function (Part 1  
 
............................................................................. 84 
15 Protocol Signature Pages .................................................................................................... 87 
15.1 Sponsor Signature Page 
.................................................................................................. 87 
15.2 Investigator Signature Page 
............................................................................................ 88
 
 


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List of Tables 
Table 3-1
 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1A) ............ 11 
Table 3-2
 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1B) 
............. 14 
Table 3-3
 
Study VX15-440-101: Schedule of Assessments for Part 2 
................................. 17 
 
 
Table 8-1 
Key Study Elements by Part 
................................................................................. 33
 
Table 8-2
 
Treatment Arms and Planned Doses by Part 
........................................................ 34
 
Table 9-1
 
Prohibited Medications 
......................................................................................... 46 
Table 10-1
 Study Drug 
............................................................................................................ 51
 
Table 11-1
 Acceptable Pharmacokinetic Sampling Windows 
................................................ 54 
Table 11-2 Safety Laboratory Test Panels 
.............................................................................. 59
 
Table 11-3 Contraceptive Requirements 
................................................................................. 62
 
Table 12-1 Probability of Observing an Adverse Event 
......................................................... 63 
Table 12-2 Power for Within-group Difference for Mean Absolute Change From Baseline in 
ppFEV1 
.................................................................................................................. 64
 
Table 12-3 Contrast Coefficients for the Multiple Comparisons Procedure in Part 1, Cohort 
1B 
.......................................................................................................................... 65 
Table 12-4 Power to Detect a Dose-response Trend Based on Change From Baseline in Sweat 
Chloride in Part 1, Cohort 1B 
............................................................................... 65 
Table 12-5 Power for Within-group Difference for Mean Absolute Change From Baseline in 
Sweat Chloride 
...................................................................................................... 65 
Table 13-1
 Grading of AE Severity ........................................................................................ 74
 
Table 13-2
 Classifications for AE Causality 
........................................................................... 75
 
Table 13-3
 Classifications for Study Drug Action Taken With Regard to an AE 
.................. 75 
Table 13-4
 Classifications for Outcome of an AE 
.................................................................. 75
 
 
List of Figures 
Figure 8-1 
Schematic of the Study Design for Parts 1 and 2 
.................................................. 35 
 
 


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Glossary of Terms 
Abbreviation 
Term 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransaminase 
BMI 
body mass index 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator protein 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CYP 
cytochrome P450 
 
 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ETT 
early termination of treatment 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein (make italics) 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
G6PD 
glucose-6-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
GPS 
Global Patient Safety 
HBE 
human bronchial epithelial 
HMA 
Heads of Medicines Agencies 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
 
 
 
 
INN 
international nonproprietary name 
IPD 
important protocol deviation 
IRB 
institutional review board 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LFT 
liver function test 
LUM 
lumacaftor 
max 
maximum value 


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Abbreviation 
Term 
MBW 
multiple-breath washout 
MCP 
multiple comparisons procedure 
MF 
minimum function 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
N 
total sample size (e.g., number of subjects treated) 
NA 
not applicable 
OATP1B1 
organic anion transporting polypeptide 1B1 
OATP1B3 
organic anion transporting polypeptide 1B3 
P 
probability 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PK 
pharmacokinetic, pharmacokinetics 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
q12h 
every 12 hours 
qd 
daily 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
TBD 
to be determined 
TC 
triple combination 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
ULN 
upper limit of normal 
USAN 
United States adopted name 
Vertex 
Vertex Pharmaceuticals Incorporated 
 
 
 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) affects more than 70,000 children and adults worldwide1 and is the most 
common fatal genetic disease in persons of European descent.
2 Based on its prevalence, CF 
qualifies as an orphan disease.
3,4  CF is caused by a defect in the gene encoding the CF 
transmembrane conductance regulator (CFTR), an ion channel that regulates the flow of chloride 
and other ions in epithelia of various tissues, including lungs, pancreas and other gastrointestinal 
organs, and sweat glands.
2 Decreased CFTR activity in people with CF results in multisystem 
pathology5, beginning at birth. Despite progress in the treatment of CF with antibiotics and 
mucolytics, the median predicted survival age for a person with CF is approximately 40 years.
2, 6 
More effective treatments are needed for CF. 
To address this medical need, Vertex Pharmaceuticals Incorporated is developing treatment 
regimens that include CFTR modulators to target the underlying cause of CF: the defective 
CFTR protein. Two types of CFTR modulators have been developed: potentiators, which 
increase the channel gating activity of the CFTR protein, and correctors, which increase the 
quantity of CFTR at the cell surface. Because potentiators can increase the activity of CFTR 
protein delivered to the cell surface by correctors, CFTR potentiators and correctors are 
complementary therapeutic approaches. 
Ivacaftor (IVA; Kalydeco
®), the first CFTR modulator developed by Vertex, is an orally 
administered CFTR potentiator that increases the channel-open probability of CFTR protein to 
enhance chloride transport. Globally, Kalydeco is indicated for the treatment of CF in patients as 
young as 2 years who have the G551D and certain other gating mutations, as well as the R117H 
mutation in the CFTR gene in certain regions.
7 
Lumacaftor (LUM; VX-809) and tezacaftor (TEZ; VX-661) are orally administered 
first-generation CFTR correctors developed by Vertex that act directly on CFTR to improve its 
cellular processing and trafficking, thereby increasing the quantity of functional F508del-CFTR 
protein at the cell surface. F508del, the most prevalent mutation in people with CF, occurs in 
about 83% of CF patients of European descent, and results in a decreased quantity of CFTR 
protein at the cell surface. Orkambi™ (LUM/IVA combination therapy) is approved in the US, 
EU, Canada, and Australia for patients 12 years and older who are homozygous for F508del. 
Phase 3 studies of TEZ/IVA combination therapy are ongoing in populations that are 
homozygous or heterozygous for F508del. 
VX-440 is a second-generation CFTR corrector that acts through a different site of the CFTR 
protein than LUM and TEZ. In vitro, VX-440 improves the processing and trafficking of 
F508del-CFTR, thereby increasing the quantity of functional F508del-CFTR protein at the cell 
surface. VX-440 has been studied in vitro in combination with the first generation corrector TEZ. 
Consistent with different mechanisms of action, the effects of VX-440 and TEZ are additive. The 
activity of the CFTR protein delivered to the cell surface by VX-440, alone or in combination 
with TEZ, is potentiated by IVA. In human bronchial epithelial (HBE) cells derived from CF 
patients homozygous for F508del, the triple combination (TC) of VX-440, TEZ, and IVA 
increased CFTR-mediated chloride transport more than the dual combinations (VX-440 and 
TEZ; VX-440 and IVA; TEZ and IVA) or individual agents (VX-440; TEZ; IVA). These data, as 


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well as the nonclinical pharmacokinetic (PK) and safety profile, support the development of 
VX-440 in combination with other CFTR modulators for the treatment of CF.  
5.2 
Rationale for the Present Study 
The present study is the first clinical study of VX-440 in subjects with CF and is designed to 
evaluate the safety and efficacy of VX-440 in  
 triple combination with TEZ and IVA. 
VX-440 has been studied in vitro and in vivo, and the safety profile in the nonclinical toxicology 
studies supports continued development of VX-440 with appropriate measures given the 
potential for teratogenicity.
8,9  
The safety, tolerability, and PK of VX-440 as monotherapy or in TC with TEZ/IVA are being 
evaluated in healthy subjects (Study VX15-440-001 [Study 001] and VX16-440-002 [Study 
002]). Single doses of VX-440 up to 1600 mg and multiple doses of VX-440 up to 600 mg q12h 
have been generally safe and well tolerated. Multiple doses of VX-440 up to 600 mg q12h in TC 
with TEZ (100 mg qd) and IVA (up to 300 mg q12h) were also safe and well tolerated.  
Based on the data from nonclinical and clinical studies of VX-440, TEZ, and IVA to date and the 
current unmet medical need for new treatments for CF, there is potential for benefit to CF 
patients from the development of this treatment. Therefore, the overall risk-benefit balance for 
this study is considered to be acceptable. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
• To evaluate the safety and tolerability of VX-440 in  
 triple combination with TEZ 
and IVA 
• To evaluate the efficacy of VX-440 in  
 triple combination with TEZ and IVA 
6.2 
Secondary Objectives 
• To evaluate the pharmacodynamic (PD) effect of VX-440 in  
 triple combination with 
TEZ and IVA on sweat chloride concentrations 
• To evaluate the PK of VX-440 when administered in  
 triple combination with TEZ 
and IVA 
• To evaluate the PK of TEZ, IVA, and their respective metabolites when administered with 
VX-440 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoints 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
standard 12-lead electrocardiograms (ECGs), vital signs, and pulse oximetry 
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
baseline through Day 29 (Parts 1 and 2) 
 




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Key study elements of each part are summarized in Table 8-1. The treatment arms and 
randomization ratios for each part are summarized in Table 8-2. A schematic of the study design 
is shown in Figure 8-1 (Parts 1 and 2) 
 
Interim analyses are described in Section 12.3.6.1. 
All parts of this study will include a Screening Period, Treatment Period, and Safety Follow-up 
Visit. Part 2 will also include a 4-week Run-in Period and a 4-week Washout Period after the 
Treatment Period.  
Table 8-1 
Key Study Elements by Part 
 
Part 1a 
Part 2 
Genotype 
F508del/MF 
F508del/F508del 
Age 
≥18 years 
≥18 years 
ppFEV1 criteria 
≥40 to ≤90  
≥40 to ≤90 
Number of subjects Approximately 42a 
Approximately 24 
Stratification c 
ppFEV1
d 
• ≥70  
• <70 
ppFEV1  
• ≥70 
• <70 
Study design 
Parallel 
Parallel 
Comparator 
Placebo 
TEZ/IVA 
VX-440 treatment 
duration 
4 weeks 
4 weeks 
IVA: ivacaftor; MF: minimal function; ppFEV
1: percent predicted forced expiratory volume in 1 second; q12h: 
every 12 hours; TC: triple combination; TEZ: tezacaftor 
a Part 1 consists of Cohort 1A and Cohort 1B. Approximately 10 subjects will be in Cohort 1A and 
approximately 32 subjects will be in Cohort 1B 
c Additional stratification information is provided in Section 8.1.3. 
d 
Stratification will be conducted for Cohort 1B subjects only. 
 


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Table 8-2 
Treatment Arms and Planned Doses by Part 
Part 
Randomization ratio 
 
Treatment Arm 
VX-440 Dosage 
TEZ 
Dosage 
IVA 
Dosage 
Part 1 Cohort 1A 
TC-1A 
200 mg q12h 
100 mg qd 
150 mg q12h 
4:1 
Triple placebo 
Placebo 
Placebo 
Placebo 
Part 1 Cohort 1B 
TC-1B-high 
600 mg q12ha 
50 mg q12h 
300 mg q12ha 
2:1:1 
TC-1B-low 
200 mg q12h 
50 mg q12h 
150 mg q12h 
 
Triple placebo 
Placebo 
Placebo 
Placebo 
Part 2b 
TC-2 
 600 mg q12ha 
50 mg q12h 
300 mg q12ha  
3:1 
TEZ/IVA 
Placebo 
100 mg qd 
150 mg q12h 
In the “TC-1B-high” and “TC-2” treatment arms, the dosage of VX-440 will be determined based on safety and 
PK data from Cohort 1A. The planned dose is shown, but may be reduced to 400 mg q12h.  
b In Part 2, all subjects will also receive TEZ 100 mg qd/IVA 150 mg q12h during the Run-in Period and the 
Washout Period. 
 






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8.1.1.1 
Repetition of Screening Assessment(s) 
Repetition of individual screening assessment(s) that did not meet eligibility criteria is not 
permitted with the following exceptions:  
• If there is clear evidence of a laboratory error (e.g., hemolyzed sample) or equipment 
malfunction, collection of a repeat sample for the appropriate laboratory test or assessment 
may be permitted with the approval of the medical monitor. 
• Exclusionary liver function test (LFT) levels, which may be retested once within 14 days of 
the original screening date, with approval of the medical monitor. 
If screening spirometry measurements fail to meet acceptability and repeatability criteria as 
specified by American Thoracic Society/European Respiratory Society guidelines
10, repeat 
spirometry evaluation may be performed once. 
If repeat values of the individual assessment(s) are within the eligibility criteria and completed 
within the screening window, then the subject is eligible for the study. 
8.1.1.2 
Rescreening 
Subjects may only be rescreened with the approval of the medical monitor. If a subject is 
rescreened, all screening assessments will be repeated except for CFTR genotyping, 
follicle-stimulating hormone (FSH) level (if serum FSH level was ≥40 mIU/mL during prior 
screening), G6PD activity test (if total bilirubin level was <2 × upper limit of normal [ULN] 
during prior screening), sweat chloride level, and the ophthalmologic examination (if 
documentation shows it was performed within the last 3 months). If a subject is rescreened, the 
new screening window will begin once the first rescreening assessment has been initiated. 
8.1.1.3 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 2 weeks, without medical monitor 
approval, for the following reasons: 
• Repetition of the Screening Period assessments (Section 8.1.1.1) 
• Unexpected operational or logistic delays, or to meet the eligibility criteria 
• Scheduling of ophthalmologic examination (Section 11.7.6) 
• Repetition of spirometry assessment if results are of poor quality 
A subject may have the Screening Period window extended by 4 weeks, without medical monitor 
approval, for the following reason: 
• For Parts 1  
 subjects, washout of TEZ/IVA during the Screening Period if enrolling 
from Study VX14-661-110 (Study 661-110) 
 
Run-in Period (Part 2) 
8.1.2
The Run-in Period will have a total duration of 4 weeks and is designed to establish a reliable on-
treatment (TEZ/IVA) baseline for the Treatment Period. Subjects will receive TEZ 100 mg 
qd/IVA 150 mg q12h during the Run-in Period. The first dose of TEZ/IVA will be administered 
at the Day -28 Visit. The last dose of TEZ/IVA within the Run-in Period will be administered on 
Day -1 (1 day before the Day 1 Visit).  








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patients relative to the highest exposure evaluated in healthy subjects, if an effect similar to LUM 
is observed for VX-440. If VX-440 exposures in Cohort 1A are higher than that in healthy 
subjects at a comparable dose, then the high dose of VX-440 will be reduced from 600 mg q12h 
to 400 mg q12h.  
Dose- and exposure-response information obtained from Part 1 (subjects with the F508del/MF 
genotype) is expected to be applicable to other populations with an F508del mutation, including 
subjects with the F508del/F508del genotype, based on similar in vitro potency for the TC in 
HBE cells with 1 or 2 copies of F508del.
8  
TEZ Dose 
In Cohort 1A, TEZ will be administered as 100 mg qd, which is the same dose currently under 
evaluation in Phase 3 studies of TEZ/IVA. This dose of TEZ is appropriate for evaluation in the 
TC based on in vitro experiments with VX-440 which evaluated similar levels of TEZ exposure 
after correction for protein-binding. In Cohort 1B and Part 2, the dose of TEZ, when 
administered in the TC, will be 50 mg q12h so that all components of the TC are administered 
q12h; the total daily dose of TEZ (100 mg) will be the same as that under evaluation in Phase 3 
studies of TEZ/IVA. 
IVA Dose 
In vitro data indicate that maintaining adequate IVA exposure in vivo will be important for 
maximizing efficacy of the TC. When administered in combination with VX-440 200 mg, the 
dose of IVA will be the same as the recommended dose for IVA monotherapy for patients aged 
12 years and older (150 mg q12h). Preliminary data from Study 002 indicate that VX-440 is a 
moderate to strong inducer of CYP3A4. Because IVA is a sensitive CYP3A substrate, the dose 
of IVA will be increased from 150 mg q12h to 300 mg q12h when it is administered with 
VX-440 at a dose level of 600 mg q12h. These dose levels were evaluated in Study 002 and were 
safe and well tolerated. At these dose levels, IVA exposure was approximately 50% lower 
relative to IVA 150 mg q12h monotherapy based on historical data.
12 If the high dose of VX-440 
is reduced to 400 mg q12h, the IVA dose will remain 300 mg q12h, as VX-440 induction is 
predicted to be similar in magnitude at this dose relative to 600 mg q12h. Phase 3 and post-
approval data for IVA monotherapy have not revealed any systemic exposure-related safety 
findings and indicate a wide therapeutic margin for safety. Use of a higher IVA dose when 
coadministering IVA with a CYP3A inducer is consistent with the approach for combination 
therapy with LUM (a strong CYP3A inducer). In that combination therapy, the IVA dose is 250 
mg q12h. 
Treatment Duration 
The 4-week treatment duration in Parts 1 and 2 is based on previous experience with CF 
correctors and potentiators in clinical studies of subjects with CF. Based on preliminary data 
from Studies 001 and 002, and data from previous studies of TEZ and IVA, all components of 
the TC reach steady-state levels of exposure by 2 to 3 weeks. In previous studies of TEZ and 
IVA, PD effects were observed within 4 weeks of treatment. In Study VX06-770-101, treatment 
with IVA for 28 days resulted in statistically significant within-group changes from baseline in 
ppFEV1 as well as a trend toward clinically meaningful improvements in the respiratory domain 
of the CFQ-R; differences in biomarkers of CFTR activity (sweat chloride) between IVA and 
placebo groups were also demonstrated. Furthermore, in Study VX11-661-101 dose-dependent 






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9.2 
Exclusion Criteria 
1. History of any comorbidity that, in the opinion of the investigator, might confound the results 
of the study or pose an additional risk in administering study drug to the subject.  
2. History of cirrhosis with portal hypertension. 
3. Risk factors for Torsade de Pointes, including but not limited to, history of any of the 
following: familial long QT syndrome, chronic hypokalemia, heart failure, left ventricular 
hypertrophy, chronic bradycardia, myocardial infarction, cardiomyopathy, history of 
arrhythmia (ventricular or atrial fibrillation), obesity, acute neurologic events (subarachnoid 
hemorrhage, intracranial hemorrhage, cerebrovascular accident, or intracranial trauma), or 
autonomic neuropathy. 
4. History of hemolysis. 
5. G6PD deficiency, defined as G6PD activity less than the lower limit of normal (LLN) or 
70% of the mean of the LLN and the ULN, whichever is greater. 
6. Any of the following abnormal laboratory values at screening: 
• Hemoglobin <10 g/dL 
• Total bilirubin ≥2 × ULN 
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl 
transpeptidase (GGT), or alkaline phosphatase (ALP) ≥3 × ULN 
• Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m
2 
(calculated by the Modification of Diet in Renal Disease Study Equation)
14, 15 for subjects 
≥18 years of age and ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt 
equation)
16 for subjects aged 12 to 17 years (inclusive) 
7. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy 
(including antibiotics) for pulmonary disease within 28 days before the first dose of study 
drug (Day 1 for Parts 1  
 Day -28 for Part 2). 
8. Lung infection with organisms associated with a more rapid decline in pulmonary status 
(e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). For 
subjects who have had a history of a positive culture in the past, the investigator will apply 
the following criteria to establish whether the subject is free of infection with such 
organisms:  
• The subject has had 2 respiratory tract cultures negative for these organisms within the 
past 12 months, with no subsequent positive cultures. 
• These 2 respiratory tract cultures were separated by at least 3 months, and 1 of them was 
obtained within the past 6 months. 
9. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of 
study drug (Day 1 for Parts 1  
 Day -28 for Part 2). 


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10. A standard digital ECG demonstrating QTc >450 msec at screening. If QTc exceeds 
450 msec for the screening ECG, the ECG should be repeated 2 more times during the 
Screening Period, and the subject will be excluded if the average of the 3 QTc values is >450 
msec. 
11. History of solid organ or hematological transplantation. 
12. History or evidence of cataract or lens opacity determined to be clinically significant by the 
ophthalmologist or optometrist based on the ophthalmologic examination during the 
Screening Period. If there is documentation of an examination meeting protocol criteria that 
was conducted within 3 months before the date of informed consent (or assent, when 
applicable), then the ophthalmologic examination does not need to be repeated during the 
Screening Period. This criterion does not apply to subjects with documentation of bilateral 
lens removal, and the ophthalmologic examination is not required for these subjects at 
screening. 
13. History of alcohol or drug abuse in the past year, including but not limited to, cannabis, 
cocaine, and opiates, as deemed by the investigator. 
14. Ongoing or prior participation in an investigational drug study with the exception of the 
following: 
• Ongoing or prior participation in an investigational study of TEZ/IVA, IVA, LUM/IVA, 
or other CFTR modulator. For Parts 1  
 a washout period of 28 days must elapse 
before Day 1. Subjects participating in Study 661-110 may have the Part 1 
 
Screening Period extended by 4 weeks (Section 8.1.1.3). For Part 2, a washout period 
before Day -28 is not required, and subjects participating in Study 661-110 will transition 
directly from their prior treatment to the TEZ/IVA Run-in Period providing that they 
meet eligibility criteria. For all parts, subjects participating in Study 661-110 may have 
their screening assessments performed while continuing to participate in Study 661-110. 
• For prospective subjects with ongoing or prior participation in all other interventional 
studies, a washout period of 28 days or 5 terminal half-lives, whichever is longer, must 
elapse before screening. The duration of the elapsed time may be longer if required by 
local regulations.  
• Ongoing participation in a noninterventional study (including observational studies and 
studies requiring assessments without administration of study drug or assignment to other 
interventions) is permitted. 
15. Use of commercially available CFTR modulator (e.g., Kalydeco, Orkambi) within 14 days 
before screening (Parts 1  
).  
16. Use of restricted medications as defined in Table 9-1, within the specified window before the 
first dose of study drug (Day 1 in Parts 1  
, Day -28 in Part 2). 
17. Pregnant or nursing females: Females of childbearing potential must have a negative 
pregnancy test at screening and Day 1. 
18. 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 


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the study. An adult (aged 18 years or older) who is a relative of a study staff member may be 
randomized in the study provided that 
• the adult lives independently of and does not reside with the study staff member, and 
• the adult participates in the study at a site other than the site at which the family member 
is employed. 
9.3 
Prohibited Medications 
Medications that are prohibited in this study (Screening Period through the Safety Follow-up 
Visit) are shown in Table 9-1. VX-440, TEZ, and IVA are metabolized extensively via CYP3A4. 
VX-440 is also metabolized extensively by CYP2C9 and to a lesser extent by CYP2C19. 
Therefore, the use of moderate and strong inducers of CYP3A or CYP2C9 and strong and 
moderate inhibitors of CYP3A, which have the potential to alter the exposure of VX-440, TEZ, 
or IVA, will be restricted in this study. Preliminary results from Study 002 indicate that VX-440 
is a moderate to strong inducer of CYP3A4 at higher doses; therefore, sensitive CYP3A 
substrates with a narrow therapeutic index should be used with caution during the study. VX-440 
was shown in vitro to be an inhibitor of the hepatic transporter organic anion transporting 
polypeptide 1B1 (OATP1B1). Therefore, sensitive substrates of OATP1B1, such as HMG Co-A 
Reductase Inhibitors (i.e., “statins”), are restricted during treatment with VX-440 or placebo. As 
VX-440 has demonstrated the potential for inhibition of CYP2C9 in vitro, warfarin is also 
prohibited during treatment with VX-440 or placebo. 
A non-exhaustive list of study prohibitions and cautions for medication will be provided in the 
Study Reference Manual. 
Table 9-1 
Prohibited Medications 
Medication 
Timing of Restriction 
Start of Restriction 
End of Restriction 
Moderate and strong CYP3A 
or CYP2C9 inducers 
None allowed within 14 days before the 
first dose of the study drug on Day 1 (Parts 
1  
 or Day -28 (Part 2) 
None allowed through the Safety 
Follow-up Visit 
Moderate and strong CYP3A 
inhibitors (except 
ciprofloxacin) 
None allowed within 14 days before the 
first dose of the study drug on Day 1 (Parts 
1  
or Day -28 (Part 2) 
None allowed through the Safety 
Follow-up Visit 
Sensitive OATP1B1 
substrates 
None allowed within 14 days before the 
first dose of VX-440 or placebo on Day 1 
None allowed until after last dose of 
VX-440 or placebo 
Warfarin 
None allowed within 14 days before the 
first dose of VX-440 or placebo on Day 1 
None allowed until after last dose of 
VX-440 or placebo 
Commercially available 
CFTR modulators (e.g., 
Kalydeco, Orkambi)  
Parts 1 
 None allowed within 
14 days before screening 
Part 2: None allowed from the start of the 
Run-in Period 
Parts 1 
 None allowed through 
the Safety Follow-up Visit 
Part 2: None allowed through end of 
the Washout Period  
CFTR: Cystic fibrosis transmembrane conductance regulator; CYP: cytochrome P450; OATP1B1: organic anion 
transporting polypeptide 1B1 
Note: The use of restricted medication by subjects with medical needs will be addressed on a case-by-case basis 
with the medical monitor. 




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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 8.1.6), and follow up with the subject regarding any unresolved AEs. 
If the subject withdraws consent for the study, no further evaluations will be performed and no 
additional data will be collected. Vertex may retain and continue to use any data collected before 
such withdrawal of consent. 
9.6 
Replacement of Subjects 
Subjects who withdraw or are withdrawn before the first dose of study drug on Day 1 may be 
replaced.  
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period may be replaced at Vertex
's discretion. 
10 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
Study drug refers to VX-440, TEZ/IVA, TEZ, IVA, and their matching placebos. 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
10.2 
Administration 
Study drug will be administered orally. Subjects will receive the same number of tablets each 
day to maintain the blind. Additional information is provided in the Pharmacy Manual. 
Study drug will be administered with a fat-containing meal or snack, such as a standard "CF" 
high-fat, high-calorie meal or snack or a standard meal, according to the following guidelines: 
1. It is recommended that the dose be taken within 30 minutes of the start of the meal or snack. 
2. Study drug will be administered q12h (± 2 hours). For each subject, all doses of study drugs 
will be taken at approximately the same time each day. For example, the morning dose could 
be taken at 08:00 every morning and the evening dose could be taken at 20:00 every evening 
throughout the study. 
3. The date, amount taken, and time of study drug administration, including whether food was 
taken with each dose, will be recorded for the 2 doses before PK sample collection and the 
dose received on the morning of PK sample collection. 
4. On days of scheduled visits, the morning dose of study drug will be administered at the site 
after predose assessments have been completed. The meal or snack will be provided by the 
site for the morning dose of study drug.  


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5. If a subject's scheduled visit is to occur in the afternoon, the following guidelines must be 
used: 
• If the dose in the clinic will be within 6 hours of the subject
's scheduled morning dose, 
the subject should withhold their morning dose of study drug and the morning dose will 
be administered in the clinic. 
• If the dose in the clinic will be more than 6 hours after the subject
's scheduled morning 
dose, the subject should take the morning dose at home and the evening dose will be 
administered in the clinic. In this event, all assessments will be collected relative to the 
evening dose. 
6. Subjects will be instructed to bring all used and unused study drug to the site; study drug will 
be dispensed at each visit, as appropriate. 
 
Missed Doses 
10.2.1
If a subject misses a dose and recalls the missed dose within 6 hours, the subject should take 
his/her dose with food. If more than 6 hours have elapsed after his/her usual dosing time, the 
subject should skip that dose and resume his/her normal schedule for the following dose. For 
example, 
• if the morning dose of study drug should have been taken at approximately 08:00, and the 
subject remembers at 12:00 that he/she forgot to take his/her dose, he/she should take the 
dose with food as soon as possible. 
• if the morning dose of study drug should have been taken at approximately 08:00, and more 
than 6 hours have elapsed beyond the scheduled dosing time (i.e., the time is past 14:00), the 
subject would resume dosing with the evening dose at approximately 20:00. 
10.3 
Method of Assigning Subjects to Treatment Groups 
Treatment arms, randomization ratios, and stratification factors for each part are described in 
Table 8-1. An interactive web response system (IWRS) will be used to assign subjects to 
treatment. The randomization code list will be produced by Vertex Biometrics or a qualified 
randomization vendor. 
10.4 
Study Drug Interruption and Stopping Rules  
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, or total bilirubin 
>2 × ULN, must be followed closely, including confirmatory testing performed by the central 
laboratory within 48 to 72 hours of the initial finding and subsequent close monitoring of ALT, 
AST, and bilirubin levels, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results must be reported immediately to the medical monitor, and the subject 
must have the tests repeated and sent to the central laboratory as soon as possible (ideally within 
48 to 72 hours). 
Study drug administration must be interrupted immediately (prior to confirmatory testing), and 
the medical monitor must be notified, if any of the following criteria are met: 
• ALT or AST >8 × ULN 
• ALT or AST >5 × ULN for more than 2 weeks 


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• ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical jaundice 
• Indirect bilirubin >2 × ULN (defined as ULN for total bilirubin minus ULN for direct 
bilirubin) 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression.  
Study drug administration must be discontinued, if either of the following criteria is met: 
• Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, 
or alcohol ingestion) is identified, regardless of whether transaminase levels have improved 
• Indirect bilirubin >2 × ULN (defined as ULN for total bilirubin minus ULN for direct 
bilirubin), in association with decreased haptoglobin 
If an alternative, reversible cause of transaminase elevation and/or increased bilirubin or clinical 
jaundice has been identified, study drug administration may be resumed once transaminases or 
bilirubin return to baseline or are ≤2 × ULN, whichever is higher. Approval of the medical 
monitor is required before resumption of study drug. Upon resumption of study drug, 
transaminases and bilirubin should be assessed weekly for 4 weeks. If a protocol-defined 
transaminase or bilirubin elevation interruption threshold recurs within 4 weeks of rechallenge 
with the study drug (with confirmation of the initial elevation by repeat testing within 48 to 
72 hours), then the study drug must be permanently discontinued, regardless of the presumed 
etiology. 
All subjects in whom treatment is discontinued for elevated transaminases and/or bilirubin 
should have these levels monitored closely until levels normalize or return to baseline. 
10.5 
Packaging and Labeling 
Study drug tablets will be supplied in blister cards by Vertex. Study drug labeling will be in 
compliance with applicable local and national regulations. Additional details regarding 
packaging, labeling, and dispensing for study drug will be included in the Pharmacy Manual. 
10.6 
Study Drug Supply, Storage, and Handling 
VX-440 (200 mg) and matching placebo will be supplied as tablets of similar size and 
appearance containing 200 mg VX-440 and 0 mg VX-440, respectively. 
TEZ/IVA (100 mg/150 mg) and matching placebo will be supplied as light yellow film-coated 
tablets of similar size and appearance containing 100 mg TEZ/150 mg IVA and 0 mg TEZ/0 mg 
IVA, respectively.  
TEZ (50 mg) and matching placebo will be supplied as white tablets of similar size and 
appearance containing 50 mg TEZ and 0 mg TEZ, respectively. 
IVA (150 mg) and matching placebo will be supplied as light blue film-coated tablets of similar 
size and appearance containing 150 mg IVA and 0 mg IVA, respectively. 
Blister cards must be stored under conditions noted in Table 10-1 and in the Pharmacy Manual. 
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 


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accordance with applicable regulatory requirements. To ensure adequate records, all study drugs 
will be accounted for via the drug accountability forms as instructed by Vertex. 
Table 10-1 
Study Drug  
Drug Name 
Strength/Formulation/ 
Route 
Dosage 
Storage Condition 
VX-440 
200-mg tablet, oral 
200 mg q12h 
600 mg q12h 
(planned) 
≤25°C (77°F) with 
excursions to 30°C (86°F) 
VX-440-matching placebo 
0-mg tablet, oral 
0 mg q12h 
≤25°C (77°F) with 
excursions to 30°C (86°F) 
TEZ/IVA fixed-dose 
100-mg/150-mg tablet; 
oral 
100 mg/150 mg qd 
(morning dose) 
≤25°C (77°F) with 
excursions to 30°C (86°F) 
TEZ/IVA-matching placebo 
0-mg/0-mg tablet; oral 
0 mg/0 mg qd 
(morning dose) 
≤25°C (77°F) with 
excursions to 30°C (86°F) 
TEZ 
50-mg tablet, oral 
50 mg q12h 
≤25°C (77°F) with 
excursions to 30°C (86°F). 
TEZ-matching placebo 
0-mg tablet, oral 
0 mg q12h 
≤25°C (77°F) with 
excursions to 30°C (86°F) 
IVA 
150-mg tablet, oral 
150 mg qd  
(evening dose) 
150 mg q12h 
≤25°C (77°F) with 
excursions to 30°C (86°F) 
IVA-matching placebo 
0-mg tablet, oral 
0 mg qd  
(evening dose) 
0 mg q12h  
≤25°C (77°F) with 
excursions to 30°C (86°F) 
IVA: ivacaftor; q12h: every 12 hours; qd: daily; TBD: to be determined 
10.7 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of study drug received; study drug dispensed to the subjects; and study drug returned by 
the subjects. Subjects will be instructed to return all used and unused materials associated with 
the study drug to the site. These materials will be retained at the site according to instructions 
provided by Vertex or its designee until inventoried by the study monitor. The study monitor will 
review study drug records and inventory throughout the study. 
10.8 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. At the end of the study, the study monitor 
will provide instructions as to the disposition of any unused investigational product. If the study 
monitor authorizes destruction at the study site, the investigator will ensure that the materials are 
destroyed in compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Vertex. Destruction will be adequately documented. 


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10.9 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel will review that the subject is compliant with 
study drug dosing and remind the subject of study drug dosing requirements. Compliance will 
also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator will contact the medical monitor to discuss discontinuing the subject 
from the study.  
10.10 
Blinding and Unblinding 
This will be a double-blind study. 
 
Blinding  
10.10.1
All subjects, site personnel (including the investigator, the site monitor, and the study team), and 
the Vertex study team will be blinded to the treatment codes with the exception of the following:  
• Any site personnel for whom this information is important to ensure the safety of the subject 
in the event of a life-threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of the subject 
and her fetus in the event of a pregnancy 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy serious 
adverse event (SAE) processing and reporting regulations 
• Unblinded statistician preparing the final (production) randomization list who is not part of 
the study team 
• Vertex IWRS Manager 
• Vertex Clinical Supply Chain 
• IDMC 
• Vendor preparing the unblinded analysis for the ongoing reviews of efficacy and safety data, 
and the IDMC  
• Vendor analyzing PK samples 
• Vertex Modeling and Simulation personnel or vendor conducting the population PK and 
PK/PD analyses 
• Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time 
Vertex Drug Metabolism and Pharmacokinetics laboratory personnel will not be involved in the 
conduct of the study and will be unblinded to the bioanalysis results but will remain blinded to 
subject number and treatment assignment. 
Spirometry and Sweat Chloride Data Blinding: During the conduct of the study, the Vertex study 
team will not have access to the spirometry or sweat chloride results after the morning dose on 
Day 1. Furthermore, sites, subjects, and their parents/caregivers/companions should not be 


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informed of their study-related spirometry and sweat chloride results during the Treatment 
Period regardless of whether the subject has prematurely discontinued treatment. 
A limited Vertex team will be unblinded and have access to safety, efficacy, and PD data for the 
purpose of conducting ongoing reviews of safety and efficacy data for planning and enabling 
clinical development, regulatory, and chemistry, manufacturing, and controls (CMC) decisions. 
Members of the limited unblinded Vertex team will not be part of the Vertex study team and will 
not be involved in or influence the conduct of the study.   
The Vertex study team and lead investigator(s) will conduct a blinded review of all available 
safety and PK data after all Cohort 1A subjects complete the Day 15 Visit. The Vertex study 
team will not have access to unblinded data from ongoing reviews by the limited Vertex team.  
After all subjects within Parts 1 and 2 have completed the Safety Follow-up Visit, results from 
each part will be unblinded for full review by the Vertex study team (Section 12.3.6.1). 
 
Unblinding 
10.10.2
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process.  
Unblinding of the individual subject
's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject
's study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the medical monitor, they will use their best 
judgment, based on the nature and urgency of the clinical situation, and may proceed with 
unblinding without having successfully reached and discussed the situation with the medical 
monitor. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center (
) will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If a subject
's treatment assignment has been unblinded for a medical emergency or urgent clinical 
situation, the medical monitor will be notified within 24 hours of the unblinding event. The 
reason and the date of the unblinding will be documented clearly in the subject
's study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with the sponsor (Vertex), contract 
research organization (CRO), or any site personnel (other than the physician treating the subject). 
In addition, the investigator will consider whether the clinical event that prompted unblinding 
will be considered an SAE, according to the regulatory definitions or criteria for SAEs, and if so, 
submit an SAE report to Vertex GPS or designee, per Section 13.1.2. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, unblind 
individual subjects at any time. 




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Processing and Handling of Pharmacokinetic Samples 
11.3.2
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be provided in the PK Sample Handling 
Guidelines. The shipment address and assay laboratory contact information will be provided to 
the investigational site before initiation of the study. 
 
Bioanalysis 
11.3.3
Samples will be analyzed using 1 or more validated analytical methods in compliance with 
Vertex or designee standard operating procedures. A description of the assay and validation data 
will be provided in separate reports. 
11.4 
Pharmacodynamics 
 
Sweat Chloride 
11.4.1
The sweat chloride test is a standard diagnostic tool for CF, serving as a biomarker of CFTR 
activity. Collection of sweat samples will be performed at visits specified in Table 3-1 (Part 1 
Cohort 1A), Table 3-2 (Part 1 Cohort 1B), Table 3-3 (Part 2), 
, using an 
approved collection device. At each time point, 2 samples will be collected, 1 from each arm 
(left and right). Sweat samples will be sent to a central laboratory for testing and interpretation of 
results. Individual sweat chloride test results will not be disclosed to the study sites with the 
exception of the screening values. Specific instructions for collection, handling, processing, and 
shipping of sweat chloride samples to the central laboratory will be provided separately. 
Subjects and their parents/caregivers/companions should not be informed of their study-related 
sweat chloride results during the Treatment Period, regardless of whether the subject prematurely 
discontinues treatment.  
11.6 
Efficacy 
 
Spirometry 
11.6.1
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines10 at the time points noted in Table 3-1 (Part 1 Cohort 1A), 
Table 3-2 (Part 1 Cohort 1B), Table 3-3 (Part 2), 
 and according to the 
additional guidelines that follow. 


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Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
• withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent
®]) for more than 4 hours before the spirometry 
assessment; 
• withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the 
spirometry assessment; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilators. At all other visits, all spirometry assessments should be performed 
"pre-bronchodilator". During the Treatment Period, spirometry assessments must be performed 
before the morning dose of study drugs at approximately the same time at each visit. Postdose 
spirometry assessments will be performed as noted in Table 3-1, Table 3-2, Table 3-3,   
 
In the event that a subject forgets to withhold bronchodilator(s), spirometry should be performed 
according to the following: 
• If a subject
's Day 1 spirometry assessment is pre-bronchodilator, but, on a subsequent visit, 
the subject forgets to withhold bronchodilator use, a post-bronchodilator spirometry 
assessment will be obtained for that visit only, and the visit will not be rescheduled. 
• If, on Day 1, the subject forgets to withhold his/her dose of bronchodilator, spirometry 
should be performed post-bronchodilator, and all subsequent spirometric measurements 
(according to the schedule of assessments detailed in Table 3-1, Table 3-2, Table 3-3,   
 should be performed post-bronchodilator. 
• Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator. 
If more than 1 spirometry assessment is required at a visit, bronchodilators will be withheld until 
completion of the last scheduled spirometry assessment. 
All sites will be provided with spirometers to be used for all study assessments. Spirometry data 
will be transmitted to a centralized spirometry service for quality review. 
Subjects and their parents/caregivers/companions should not be informed of their study-related 
spirometry results during the Treatment Period, regardless of whether the subject prematurely 
discontinues treatment. 
The measured spirometric values listed below will be converted to percent predicted values using 
the standards of GLI.
13  
• FEV1 (L) 
 
 
 
 
 
 




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11.7 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, ECGs, clinical evaluation 
of vital signs, pulse oximetry, PEs, and ophthalmologic examinations. 
 
Adverse Events 
11.7.1
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE case report form 
(CRF) completion guidelines for investigators as well as training will be provided. 
 
Clinical Laboratory Assessments 
11.7.2
Blood and urine samples will be analyzed at a central laboratory, with the exception of the urine 
pregnancy tests which will be performed and analyzed at the site. Fasting is not required. On 
Day 1, blood samples will be collected before the first dose of the study drug. 
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table 3-1 (Part 1 Cohort 1A), Table 3-2 (Part 1 Cohort 1B), Table 3-3 (Part 2), 
 
 Laboratory test results that are abnormal and considered clinically significant will be 
reported as AEs. 
The safety laboratory test panels are shown in Table 11-2. 


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Table 11-2  Safety Laboratory Test Panels 
Serum Chemistry 
Hematologya 
Urinalysisb 
Glucose 
Blood urea nitrogen 
Creatinine 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate 
Inorganic phosphate  
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase  
Alanine aminotransferase 
Lactate dehydrogenase 
Gamma-glutamyl transpeptidase 
Total protein 
Albumin 
Amylase 
Lipase 
Haptoglobinc 
Hemoglobin 
Erythrocytes 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration  
Mean corpuscular volume 
Reticulocytes 
Platelets 
Leukocytes 
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes  
Monocytes 
Coagulation Studies 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio 
Leukocyte esterase 
Nitrite 
Urobilinogen  
Urine protein  
pH 
Urine blood 
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose  
a Blood smears will be saved for future evaluation, if needed. 
b If urine is positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of urine will be 
performed for leukocytes, erythrocytes, crystals, bacteria, and casts. 
c 
Haptoglobin will be analyzed only if there is evidence of possible hemolysis. 
Pregnancy (β-human chorionic gonadotropin) Tests for Females of Childbearing Potential: 
Serum samples will be obtained as specified in Table 3-1, Table 3-2, Table 3-3, 
 
and analyzed at the central laboratory. Urine pregnancy tests will be performed at the site as 
specified in Table 3-1, Table 3-2, Table 3-3, 
 The urine pregnancy test on Day 1 
must be negative before the first dose of study drug. Additional urine pregnancy tests may be 
required according to local regulations and/or requirements. 
Follicle-stimulating Hormone (Screening Period only): Blood sample for FSH will be measured 
for any suspected postmenopausal female with at least 12 months of continuous spontaneous 
amenorrhea. Serum FSH levels must be within the postmenopausal reference range of the 
performing laboratory to be considered postmenopausal. 
CFTR genotype (Screening Period only): CFTR genotyping will be performed for all subjects. If 
the screening CFTR genotype result is not received before randomization, a previous CFTR 
genotype laboratory report may be used to establish eligibility. Subjects who have been 
randomized and whose screening genotype does not confirm study eligibility must be 
discontinued from the study (Section 9.5). 
G6PD Activity Test (Screening Period only): A single blood sample will be collected for the 
G6PD activity test, which will be performed in an established laboratory that runs the assay 
routinely. 


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Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 
becomes aware of the abnormal result. If it is not possible to send a timely specimen to the 
central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base the 
assessment of an AE on the local laboratory value. 
 
Physical Examinations and Vital Signs 
11.7.3
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits (see Table 3-1, Table 3-2, Table 3-3, 
 At other visits, 
symptom-directed PEs and symptom-directed vital sign assessments can be performed at the 
discretion of the investigator or healthcare provider. 
A complete 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. Breast, anorectal, and genital examinations will be performed 
when medically indicated. After screening, any clinically significant abnormal findings in PEs 
will be reported as AEs.  
The abbreviated PE will include an assessment of the following body systems: EENT, 
cardiovascular system, respiratory system, abdomen, and skin. 
Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse rate, and 
respiration rate. These will be assessed following at least a 5-minute rest in the seated position.  
 
Pulse Oximetry 
11.7.4
Arterial oxygen saturation by pulse oximetry will be measured at visits specified in Table 3-1 
(Part 1 Cohort 1A), Table 3-2 (Part 1 Cohort 1B), Table 3-3 (Part 2), 
. This 
will be assessed following at least a 5-minute rest (seated) and before study drug dosing. At 
visits when study drug is taken at the site, pulse oximetry will be collected before the morning 
dose. This is a noninvasive measure of oxygen delivery to the tissues and has been correlated 
with clinical status and lung function. 
 
Electrocardiograms 
11.7.5
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Schedule of Assessments (Table 3-1 [Part 1 Cohort 1A], Table 3-2 [Part 1 Cohort 1B], Table 3-3 
[Part 2], 
. Additional standard 12-lead ECGs will be performed at any 
other time if clinically indicated.  
The subject will be instructed to rest in the seated position for at least 5 minutes before having an 
ECG performed. 
The ECG traces will be manually read at the study site at the Screening Visit and Safety 
Follow-up Visit. A printout of the ECG traces will be made for safety review by the investigator 
and maintained with source documentation. Clinically significant ECG abnormalities occurring 
during the study through the Safety Follow-up Visit will be recorded as AEs.  


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To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >45 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>45 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. Further details 
pertaining to ECGs will be provided to sites in a separate document (ECG Manual). 
 
Ophthalmologic Examination 
11.7.6
Subjects will undergo an ophthalmologic examination performed by a licensed ophthalmologist 
or optometrist as noted in Table 3-1, Table 3-2, Table 3-3, 
 which includes 
• measurement of best corrected distance visual acuity of each eye; and 
• pharmacologically dilated examination of the lens with a slit lamp. 
The screening ophthalmologic examination must be completed and the results reviewed before 
randomization. This examination does not have to be performed if there is documentation of an 
examination that met protocol criteria and was within 3 months before the date of informed 
consent (or assent, when applicable) or if there is documentation of bilateral lens removal for the 
subject. 
If a cataract or lens opacity is identified and determined to be clinically significant by the 
ophthalmologist or optometrist at the screening examination, the subject must not be 
randomized. If a cataract or lens opacity is identified and determined to be clinically significant 
by the ophthalmologist or optometrist after dosing, the subject will be notified. After discussion 
with the principal investigator and in collaboration with the medical monitor, the subject may 
elect to continue or discontinue study drug treatment. If the subject discontinues study drug 
treatment, the subject should complete the ETT and Safety Follow-up Visit. If the subject 
continues study drug treatment, more frequent ophthalmologic monitoring should be considered. 
Additional ophthalmologic examinations may be conducted at the discretion of the investigator. 
The medical monitor should be notified of any additional ophthalmologic examinations and their 
results. 
In addition, at screening, the following history will be obtained and documented for all subjects: 
• history of steroid use 
• history of trauma to the eye 
• any family history of glaucoma, congenital cataracts, or cataracts arising later in life 
 
Contraception and Pregnancy 
11.7.7
The effects of VX-440 monotherapy or in dual or triple combination with TEZ and IVA on 
conception, pregnancy, and lactation in humans are not known. VX-440, TEZ, and IVA did not 
show genotoxic potential in a standard battery of in vitro (Ames test, Chinese hamster ovary cell 
chromosomal aberration) and in vivo (mouse micronucleus) studies. TEZ and IVA were each 
found to be nonteratogenic in embryo-fetal developmental toxicity studies in rats and rabbits.
11,12 


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In the embryo-fetal developmental toxicity studies, VX-440 was found to be nonteratogenic in 
rats; however, it demonstrated teratogenicity in rabbits.
9,23  
Based on these findings and following the recommendations outlined by the Heads of Medicines 
Agencies Clinical Trial Facilitation Group,
24 male subjects with female partners of childbearing 
potential must use a condom to avoid exposure of a potential embryo or fetus to study drug via 
the seminal fluid. Female subjects who are of childbearing potential will be required to use 
highly effective methods of contraception with low user dependency. Based on the potential for 
CYP induction by VX-440, hormonal methods of contraception will not be considered 
acceptable methods for female subjects of childbearing potential. Pregnancy testing will be 
performed at monthly intervals. 
11.7.7.1 
Contraception 
Study participation requires compliance with the contraceptive requirements outlined in Table 
11-3.  
Table 11-3 Contraceptive Requirements  
Male subjectsa 
• A male subject with a female partner of childbearing potential
b must use a condom 
to avoid exposure of a potential embryo or fetus to study drug via the seminal 
fluid. This is required during the period starting from the first dose of study drug 
until 7 days after the last dose of study drug.  
Female subjectsc 
At least 1 of the following methods must be used: 
• Continuous use of a non-hormone-releasing intrauterine device for at least 90 days 
before the first dose of study drug, and until 7 days after the last dose of study drug 
• Bilateral tubal occlusion (e.g., ligation) in place at least 6 months before the first 
dose of study drug 
• Postmenopausal state (defined as amenorrheic for at least 12 consecutive months 
and a serum FSH level within the laboratory
's reference range for postmenopausal 
females) 
• Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
• Male partner is infertile (e.g., bilateral orchiectomy) 
• Male partner has vasectomy at least 6 months before the first dose of study drug, 
with a documented negative postvasectomy semen analysis for sperm 
a 
In addition to the male condom, other methods of contraception may be used by male subjects and their female 
partners of childbearing potential, with the exception of female condom due to risk of tearing. 
b 
Female partners of nonchildbearing potential must either be postmenopausal (defined as amenorrheic for at least 
12 consecutive months) or have had a hysterectomy or bilateral oophorectomy/salpino-oophorectomy. 
c 
Hormonal contraceptives are not considered an acceptable method for female study subjects because of the 
potential for a drug-drug interaction with VX-440 resulting in reduced exposure and contraception failure;  
however, female subjects are not required to discontinue their use of hormonal contraceptives as long as they 
agree to use at least 1 of the methods listed above. 
 
Additional notes: 
• During the course of the study, if a change in a female subject’s sexual partner leads to 
inability to comply with the requirements outlined in Table 11-3, the subject must 
immediately discontinue study drug and not engage in sexual intercourse with the new 
partner until 7 days after the last dose of study drug. 


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• Male subjects must not donate sperm during the period starting from the first dose of study 
drug until 7 days after the last dose of study drug. 
• Female subjects should not nurse a child during the period starting from the first dose of 
study drug until 7 days after the last dose of study drug. 
11.7.7.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a female subject or the female partner of a male subject becomes pregnant while participating 
in the study, study drug will be permanently discontinued immediately. The investigator will 
notify the medical monitor and Vertex GPS within 24 hours of the site
's knowledge of the 
subject
's (or partner
's) pregnancy using the Pregnancy Information Collection Form. 
If confirmed to be on active drug, the subject or partner will be followed until the end of the 
pregnancy and the infant will be followed for 1 year after the birth, provided informed consent is 
obtained. A separate ICF will be provided to explain these follow-up activities. Pregnancy itself 
does not constitute an AE. 
12 
STATISTICAL AND ANALYTICAL PLANS 
12.1 
Sample Size and Power 
 
Primary Objectives  
12.1.1
The primary objectives of the study are the evaluation of safety and tolerability, and efficacy of 
 VX-440 in TC with TEZ/IVA (all 
parts). The sample size calculations described below are deemed adequate to evaluate the 
objectives of the study, based on clinical and statistical considerations. 
12.1.1.1 
Safety and Tolerability 
The primary safety endpoint is the incidence of AEs. Approximately 198 subjects will be 
enrolled in the study with approximately 160 subjects receiving VX-440  
 or triple 
combination with IVA and/or TEZ. The sample size for each treatment group will provide 
sufficient data for a descriptive analysis of AEs. Table 12-1 provides the probability of observing 
an AE in at least 1 subject based on sample sizes ranging from 10 to 50 subjects per treatment 
group and AE incidences ranging from 5% to 15%. The probability calculations are based on a 
binomial model using the probability calculator in the PASS software package (Version 11.0). 
Table 12-1  Probability of Observing an Adverse Event 
AE Incidencesa 
Number of Subjects per Treatment Groupb 
10 
20 
30 
40 
50 
5% 
40% 
64% 
79% 
87% 
92% 
10%  
65% 
88% 
96% 
98% 
>99% 
15% 
80% 
96% 
>99% 
>99% 
>99% 
AE: adverse event 
a 
AE incidences are based on 4 weeks of treatment in Parts 1 and 2, 
 
b Applies to Parts 1 
 


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12.1.1.2 
Efficacy 
The primary efficacy endpoint is the absolute change from baseline in ppFEV1 through Day 29 
in Parts 1 and 2, 
 Table 12-2 provides the power to reject the null 
within-group hypothesis of no difference in the mean absolute change from baseline for ppFEV
1 
through Day 29 or Week 12, as applicable, for any treatment group in Parts 1, 2,  
 with a 
sample size ranging from 8 to 44 subjects per treatment group. The power calculations are based 
on a 2-sided 1-sample t-test at alpha = 5% using the PASS software package (Version 11.0), 
assuming an absolute mean change of 3 to 7 percentage points and an SD of 8 percentage points 
in the absolute change from baseline for ppFEV
1. Sample sizes of 16 to 44 subjects per treatment 
group provide adequate power for mean changes of 5 to 7 percentage points as expected in Parts 
1, 2,  
 
Table 12-2 Power for Within-group Difference for Mean Absolute Change From 
Baseline in ppFEV1 
Mean Absolute 
Change From 
Baseline in ppFEV1 
Number of Subjects per Treatment Groupa 
8 
16 
20 
22 
24 
40 
42 
44 
3% 
15% 
29% 
36% 
39% 
42% 
64% 
66% 
68% 
4%  
23% 
46% 
56% 
61% 
65% 
87% 
89% 
90% 
5% 
33% 
65% 
76% 
80% 
83% 
97% 
98% 
98% 
6% 
45% 
80% 
89% 
92% 
94% 
>99% 
>99% 
>99% 
7% 
57% 
90% 
96% 
97% 
98% 
>99% 
>99% 
>99% 
ppFEV1: forced expiratory volume in 1 second; SD: standard deviation 
Note: An SD of 8 percentage points for the absolute change from baseline in ppFEV1 was used for power 
calculations. 
a Applies to Parts 1 
 
 
Secondary Objectives  
12.1.2
A secondary objective of the study is the evaluation of the PD effect of VX-440 in TC with 
TEZ/IVA (all parts) 
  
12.1.2.1 
Pharmacodynamic Effect (Part 1) 
The absolute change from baseline through Day 29 in sweat chloride is a secondary endpoint 
used to evaluate the PD objective of the study. In Part 1, a test for a decreasing dose-response 
trend between placebo and the TC dose groups will be performed using a multiple comparisons 
procedure (MCP). The procedure consists of testing the null hypothesis of the lack of a 
decreasing dose-response trend versus a decreasing trend using the 1-sided maximum t-statistic 
that controls the type I error at alpha = 5%. The procedure requires a family of candidate dose-
response models to be prespecified, that covers the range of plausible and diverse dose-response 
profiles.  
The candidate models that best describe the expected decreasing dose-response profile of the TC 
groups compared to placebo include a linear model, a maximum effect (Emax) model, and a 
sigmoid E
max model. The contrasts (i.e., linear combinations of the treatment group means 
through Day 29) selected to perform the MCP and that capture the shape of these candidate 
models are described in Table 12-3 below.  


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Table 12-3 Contrast Coefficients for the Multiple Comparisons Procedure in Part 1, 
Cohort 1B 
Candidate Model 
Placebo 
TC-1B-low 
TC-1B-high 
Linear 
1.0 
0.0 
-1.0 
Emax 
1.0 
-0.5 
-0.5 
Sigmoid Emax 
0.5 
0.5 
-1.0 
Emax: maximum effect; TC: triple combination 
 
Table 12-4 provides the power to detect a dose-response trend with the MCP procedure for 
3 different expected dose-response profiles with a total sample size of 32 subjects in Cohort 1B 
assigned to TC-1B-high, TC-1B-low, and placebo in the ratio 2:1:1, based on 5000 simulations 
for each profile using the MCPMod R software package [Version 1.0-8]. 
Table 12-4 Power to Detect a Dose-response Trend Based on Change From Baseline in 
Sweat Chloride in Part 1, Cohort 1B 
 
Mean Change From Baseline in Sweat Chloride 
 
Candidate Model 
Placebo 
TC-1B-low 
TC-1B-high 
Power 
Linear 
0 
-15 
-20 
95% 
Sigmoid Emax 
0 
0 
-20 
99% 
Emax 
0 
-20 
-20 
96% 
Emax: maximum effect; TC: triple combination 
Note: A 1-sided maximum t-statistic with a sample size of 32 subjects in Cohort 1B assigned to TC-1B-high, TC-
1B-low, and placebo at a ratio 2:1:1 was used for power calculations. An SD change from baseline in sweat 
chloride of 13 mmol/L was used for power calculations. 
Table 12-5 provides the power to reject the null within-group hypothesis of no difference in the 
mean absolute change from baseline for sweat chloride through Day 29 (Parts 1 and 2)  
 
 for any treatment group with a sample size ranging from 8 to 44 subjects per 
treatment group. The power calculations are based on a 2-sided 1-sample t-test at alpha = 5% 
using the PASS software package (Version 11.0), assuming a mean change of -10 to -20
 mol/L 
and an SD of 13 mmol/L in the absolute change from baseline for sweat chloride.  
Table 12-5 Power for Within-group Difference for Mean Absolute Change From 
Baseline in Sweat Chloride 
Mean Absolute Change 
From Baseline in Sweat 
Chloride (mmol/L) 
Number of Subjects per Treatment Groupa 
8 
16 
20 
22 
24 
40 
42 
44 
-10 
47% 
82% 
90% 
93% 
95% 
>99% 
>99% 
>99% 
-12  
61% 
93% 
97% 
98% 
99% 
>99% 
>99% 
>99% 
-15 
80% 
99% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
-18 
92% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
-20 
96% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
SD: standard deviation 
Note: An SD of 13 mmol/L for the absolute change from baseline in sweat chloride was used for power calculations. 
a Applies to Parts 1 
 
 


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12.2 
Analysis Sets 
The following analysis sets are defined: All Subjects Set, Full Analysis Set, and Safety Set. 
Additional analysis sets related to the Run-in Period in Part 2 will be defined in the statistical 
analysis plan, as appropriate. 
The All Subjects Set will include all subjects who were randomized or received 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.  
The Full Analysis Set (FAS) will include all randomized subjects who have received at least 
1 dose of study drug in the Treatment Period. The FAS will be used to summarize subject 
demographics and baseline characteristics, and for all PD and efficacy analyses, unless otherwise 
specified. 
The Safety Set will include all subjects who received at least 1 dose of study drug in the 
Treatment Period. The Safety Set will be used for all safety analyses, unless otherwise specified. 
12.3 
Statistical Analysis 
This section presents a summary of the planned statistical analyses of the primary PD and 
efficacy endpoints of the study. Statistical analysis details will be provided in the statistical 
analysis plan (SAP) and clinical pharmacologic analysis details will be provided in the clinical 
pharmacology analysis plan (CPAP). Both plans will be finalized before the clinical data lock 
and unblinding of the study.  
 
General Considerations 
12.3.1
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, standard error (SE), median, minimum value (min), and 
maximum value (max). The precision of the measurement for each continuous variable will be 
specified in the SAP. Unless otherwise specified, minimum and maximum values will be 
reported with the same precision as the units of the raw data. The mean, median, SD, and SE will 
be reported to 1 additional decimal place. Any values that require a transformation to standard 
units (metric or International System [SI]) will be converted with the appropriate precision. 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
The baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug in the 
Treatment Period (i.e., Day 1). For ECG, baseline will be defined as the average of the most 
recent triplicate pretreatment measurements before the first dose of study drug in the Treatment 
Period (i.e., Day 1). 
Absolute change from baseline will be calculated as postbaseline value – baseline value. 
Relative change from baseline will be calculated as (postbaseline value – baseline 
value)/baseline value. 
The Treatment-emergent (TE) Period will include the time from the first dose in the Treatment 
Period to the Safety Follow-up Visit or 28 days after the last dose of the study drug for subjects 
who do not complete the Safety Follow-up Visit. Additional TE periods related to the Run-in 
Period for Part 2 will be defined in the SAP, as appropriate. 


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There will be no multiplicity adjustment for performing multiple hypothesis tests.  
The rules for handling missing data due to treatment or study discontinuation will be described in 
the SAP. 
All data will be summarized for Parts 1, 2,  
 separately, unless specified otherwise. 
 
Background Characteristics 
12.3.2
12.3.2.1 
Subject Disposition 
The number and percentage of subjects in each disposition category (e.g., randomized, included 
in the FAS, included in the Safety Set, completed Treatment Period, completed study/Safety 
Follow-up Visit, and discontinued treatment or study with a breakdown of the reasons for 
discontinuation) will be summarized overall and by treatment group. 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized using descriptive summary statistics. 
The following demographics and baseline characteristics will be summarized overall and by 
treatment group for the FAS and will include (but are not limited to): sex, race, age, baseline 
weight, baseline height, baseline BMI, baseline ppFEV1, and baseline sweat chloride.  
No statistical tests will be performed to evaluate baseline imbalance between treatment groups. 
12.3.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded using the World Health Organization Drug 
Dictionary Enhanced and categorized as the following: 
• Prior medication: any medication that started before initial dosing of study drug, regardless 
of when it ended 
• Concomitant medication: medication continued or newly received during the TE Period 
• Post-treatment medication: medication continued or newly received after the TE Period 
A given medication may be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; or 
prior, concomitant, and post-treatment. If a medication has a missing or partially missing 
start/end date or time and if it cannot be determined whether it was taken before the first dose of 
study drug, concomitantly during the TE Period, or after the TE Period, it will be considered in 
all 3 categories of prior, concomitant, and post-treatment medication. 
Prior medications and concomitant medications will be summarized descriptively by Preferred 
Name based on the FAS. Post-treatment medications will be provided separately in an individual 
subject data listing. 
Additional classifications of concomitant medications related to the Run-in Period will be 
defined in the SAP, as appropriate. 
12.3.2.4 
Study Drug Exposure and Compliance 
Exposure to study drug 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. 






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comparisons in all parts will be estimated within MMRM, with appropriate adjustment for 
covariates. 
Additional details of the analysis will be provided in the SAP. 
 
Safety Analysis 
12.3.5
A coprimary objective of the study is the evaluation of safety and tolerability. All safety analyses 
will be based on data from the TE Period for all subjects in the Safety Set. 
The overall safety profile of study drug will be assessed based on the following safety and 
tolerability endpoints: 
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis) 
• ECGs 
• Vital signs 
• Pulse oximetry 
All safety data will be summarized by treatment group and overall, for each Part. 
All safety data will be presented in individual subject data listings. 
12.3.5.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
• Pretreatment AE: any AE that started before the first dose of study drug 
• TEAE: any AE that increased in severity or that was newly developed at or after the first 
dose of study drug through the end of the TE Period 
• Post-treatment AE: any AE that increased in severity or that was newly developed beyond 
the TE Period 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study drug treatment, then the AEs will be classified as TEAEs. 
AE summary tables will be presented for TEAEs only, overall and by treatment group for each 
Part, 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 
• Frequently reported TEAEs 


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Summaries will be presented by MedDRA system organ class and preferred term using 
frequency counts and percentages (i.e., number and percentage of subjects with an event). When 
summarizing the number and percentage of subjects with an event, subjects with multiple 
occurrences of the same AE or a continuing AE will be counted once, only the maximum 
severity level will be presented in the severity summaries, and the strongest relationship level in 
the relationship summaries. In addition, a listing containing individual subject level AE data for 
all deaths and other serious and significant AEs will be provided separately. All AEs, including 
pre- and post-treatment AEs, will be presented in individual subject data listings. 
12.3.5.2 
Clinical Laboratory Assessments 
For the treatment-emergent laboratory measurements, the observed values and change from 
baseline values of the continuous hematology, chemistry, and coagulation results will be 
summarized in SI units overall and by treatment group at each scheduled visit. 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized overall and by treatment group for each part. The threshold analysis 
criterion shift from baseline will also be summarized for selected laboratory parameters. The 
threshold analysis criteria and the parameter selection criteria will be provided in the SAP. 
Results of urinalysis and the serum pregnancy test will be listed in individual subject data listings 
only. In addition, a listing containing individual subject hematology, chemistry, and coagulation 
values outside the reference ranges will be provided. This listing will include data from 
scheduled and unscheduled visits. 
12.3.5.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided overall and by treatment group for each Part, at each scheduled 
visit and time point, as applicable, for the following ECG interval measurements (in ms): RR, 
PR, QT, and QT corrected for HR (QTcF), QRS duration, and HR (beats per minute). 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized overall and by treatment group. The threshold analysis criteria will be 
provided in the SAP. 
Additional ECG analyses will be described in the SAP. 
12.3.5.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized overall and by treatment group at each scheduled visit. The 
following vital signs parameters will be summarized: systolic and diastolic blood pressure 
(mm Hg), body temperature (°C), HR (beats per minute), and respiratory rate (breaths per 
minute). 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized overall and by treatment group for each part. The threshold analysis 
criteria will be provided in the SAP. 
Additional vital signs analyses will be described in the SAP. 


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12.3.5.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided overall and by treatment group for each Part, at 
each scheduled visit for the percent of oxygen saturation by pulse oximetry. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
Period will be summarized overall and by treatment group. 
12.3.5.6 
Physical Examination 
PE findings will be presented in an individual subject data listing only. 
12.3.5.7 
Other Safety Analysis 
Not applicable. 
 
Interim and IDMC Analyses 
12.3.6
12.3.6.1 
Interim Analysis 
Separate interim analyses will be performed after: 
• all subjects in Part 1 have completed the Safety Follow-up Visit 
• all subjects in Part 2 have completed the Safety Follow-up Visit 
The interim results of Parts 1 and 2 will be unblinded for full review by the Vertex study team. 
12.3.6.2 
IDMC Analysis 
The safety of the TC will be monitored by an external, IDMC to ensure the safety of the subjects 
in the study. 
An IDMC will be formed before study initiation. The IDMC’s objectives, responsibilities, and 
operational details will be defined in a separate document (IDMC Charter), which will be 
finalized before the first subject is randomized in the study. The IDMC will conduct planned 
safety reviews of study data from all parts of the study as outlined in the IDMC Charter. 
12.4 
Clinical Pharmacology Analysis 
 
Pharmacokinetic Analysis 
12.4.1
The PK analysis of VX-440, TEZ and metabolite M1-TEZ, and IVA and metabolite M1-IVA 
will be performed using nonlinear mixed effects modeling. Standard noncompartmental analysis 
may also be performed as data allow. Descriptive statistics will be used to summarize PK 
parameter values for all analytes. 
A detailed description of the planned PK analysis will be presented in the CPAP.  
 
Pharmacokinetic/Pharmacodynamic Analyses 
12.4.2
PD assessments to be included in PK/PD analyses may include sweat chloride, ppFEV
1, as well 
as other secondary endpoints such as 
 CFQ-R. Comparison between 
postdose and predose values will be performed and expressed as a change from baseline.  
A sequential approach will be used to perform the population PK/PD analysis. The Bayesian 
estimates of individual PK parameters from the final population PK model will be used to 


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simulate PK profiles for each subject. The simulated VX-440, TEZ, IVA, or metabolite plasma 
concentrations will be used in the potential pharmacological response models to describe 
changes in each endpoint from baseline. Fixed- and random-effect parameter estimates and the 
associated asymptotic SEs will be estimated. Descriptive statistics will be used to summarize 
Bayesian estimates of individual PK/PD parameters obtained from the population PK/PD model. 
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
 
Adverse Events 
13.1.1
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically-significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time 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) 


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• 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 28 days after the last dose of study drug, or 
o the ETT Visit, if that visit is 3 weeks or later following the last dose of study drug 
(see Section 8.1.6). 
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled in the study 
will be recorded only in the subject
's source documents. The following data will be documented 
for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity 
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.03, 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.   
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  
 


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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. 
AE: adverse event 
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 


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Table 13-4  Classifications for Outcome of an AE 
Classification 
Definition 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
AE: adverse event 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, hospitalization, 
surgery, or physical therapy. “No” indicates the absence of any kind of treatment for an AE. 
 
Serious Adverse Events 
13.1.2
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation in the study and is suspected of being a delayed toxicity due to administration of 
the study drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person
's ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 


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“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: 
  
Contact Telephone: 
 
13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities 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 independent ethics committees (IECs).  
It is the responsibility of the investigator or designee to promptly notify the local institutional 
review board (IRB)/local IEC of all unexpected serious adverse drug reactions involving risk to 
human subjects. 
13.2 
Administrative Requirements 
 
Ethical Considerations 
13.2.1
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 


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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. 
 
Subject Information and Informed Consent 
13.2.2
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
ICH GCP and all applicable laws and regulations and will be subject to approval by Vertex or its 
designee. 
 
Investigator Compliance 
13.2.3
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
 
Access to Records 
13.2.4
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
 
Subject Privacy 
13.2.5
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers and access to subject names linked to such 
numbers shall be limited to the site and the study physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 


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For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act and associated regulations (“HIPAA”) an executed HIPAA 
authorization shall be obtained by the site from each subject (or the legal representative of the 
subject) before research activities may begin. Each HIPAA authorization shall comply with all 
HIPAA requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
 
Record Retention 
13.2.6
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
 
Study Termination 
13.2.7
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated, web-based electronic data capture (EDC) application. Vertex 
will have read-only access to site-entered clinical data in the EDC application.  


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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.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a CD or other electronic media will be placed in the investigator
's study file. 
13.6 
Publications and Clinical Study Report 


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Clinical Study Report  
13.6.2
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in 
accordance with local regulations.  


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14 
REFERENCES 
1  
Cystic Fibrosis Foundation. About CF. Available at: http://www.cff.org/AboutCF/. 
Accessed 30 June 2015. 
2 
Kreindler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125(2):219-29. 
3  
Development FOoOP. Developing Products for Rare Diseases & Conditions [Internet]. 
Available from: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.
htm. . Accessed  
4  
Agency EM. Committee for Orphan Medicinal Products (COMP) [Internet]. Available 
from: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_
000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30. 
Accessed  
5  
Sheppard MN, Nicholson AG. The pathology of cystic fibrosis. Curr Diagn Pathol. 
2002;8(1):50-9. 
6  
Cystic Fibrosis Foundation. Patient Registry: 2014 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2015. 
7 
Vertex Pharmaceuticals Incorporated. Ivacaftor (VX-770) Investigator
's Brochure, 
Version 12.0. Report date: 08 May 2015. 
8 
Vertex Pharmaceuticals Incorporated. VX-440 Investigator
's Brochure, Version 1.0. 
Report date: 30 September 2015. 
10  
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
11 
Vertex Pharmaceuticals Incorporated. VX-661 Investigator
's Brochure, Version 7.0. 
Report date: 08 May 2015. 
12 
Vertex Pharmaceuticals Incorporated. Ivacaftor Investigator
's Brochure, Version 12.0. 
Report date: 8 May 2015. 
13  
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
14  
Levey AS, Bosch JP, Lewis JB, Green T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann 
Intern Med. 1999;130(6):461-70. 
15  
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-54. 
16  
Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt T. Estimation of 
glomerular filtration rate from plasma creatinine concentration in children. Arch Dis 
Child. 1976;51(11):875-8. 


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17  
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of 
the Cystic Fibrosis Questionnaire in the United States: a health-related quality-of-life 
measure for cystic fibrosis. Chest. 2005;128(4):2347-54. 
18  
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 
19  
Wenninger K, Aussage P, Wahn U, Staab D. German Cystic Fibrosis Questionnaire study 
group. The revised German Cystic Fibrosis Questionnaire: validation of a disease-
specific health-related quality of life instrument. Qual Life Res. 2003;12(1):77-85. 
20  
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life 
Res. 2003;12(1):63-76. 
21  
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR 
potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 
2011;365(18):1663-72. 
22  
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 
Effect of aerosolized recombinant human DNase on exacerbations of respiratory 
symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 
24  
Heads of Medicines Agencies CTFG. Recommendations related to contraception and 
pregnancy testing in clinical trials. [Internet]. Available from: Accessed 15 September 
2014. 


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APPENDIX A  CFTR Mutations That Are Predicted to Result in a CFTR 
Protein With Minimal Function (Part 1 
 
Per the study eligibility criteria, heterozygous F508del-CFTR subjects in Parts 1  
 must 
have a second CFTR allele containing a mutation that is predicted to result in a CFTR protein 
with minimal function and not likely to respond to TEZ and/or ivacaftor (IVA) therapy. 
These CFTR mutations were defined using 3 major sources:  
• biological plausibility for the mutation to respond (i.e., mutation class) 
• evidence of clinical severity on a population basis (per CFTR2 patient registry; 
accessed on 15 February 2016) 
o average sweat chloride >86 mmol/L, and 
o prevalence of pancreatic insufficiency (PI) >50% 
• in vitro testing 
o mutations resulting in baseline chloride transport <10% of wild-type CFTR 
were considered minimal function 
o mutations resulting in chloride transport <10% of wild-type CFTR following 
the addition of TEZ and/or IVA were considered nonresponsive  
The clinical severity criteria (average sweat chloride >86 mmol/L and %PI >50%) do not 
apply to the individual subjects to be enrolled in this study, but were used to classify the 
mutation status on a population level. 
The list below represents acceptable mutations, which are detectable by an FDA-cleared 
genotyping assay; however, this list may not include every eligible mutation, and 
investigators should contact the medical monitor regarding other mutations that may also 
meet study eligibility criteria. 


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CFTR Mutations Eligible for VX15-440-101, Parts 1 
 
Criteria 
Mutation 
 
 
 
 
Truncation mutations  
• %PI >50% and/or 
SwCl- >86 mmol/L 
• no full-length protein  
S4X 
C276X 
G542X 
R792X 
E1104X 
G27X 
Q290X 
G550X 
E822X 
R1158X 
Q39X 
G330X 
Q552X 
W846X 
R1162X 
W57X 
W401X 
R553X 
Y849X 
S1196X 
E60X 
Q414X 
E585X 
R851X 
W1204X 
R75X 
S434X 
G673X 
Q890X 
L1254X 
E92X 
S466X 
Q685X 
S912X 
S1255X 
Q98X 
S489X 
R709X 
Y913X 
W1282X 
Y122X 
Q493X 
K710X 
W1089X 
Q1313X 
E193X 
W496X 
L732X 
Y1092X 
E1371X 
 
L218X 
C524X 
R764X 
W1098X 
Q1382X 
 
Q220X 
Q525X 
R785X 
R1102X 
Q1411X 
Splice mutations  
• %PI >50% and/or 
SwCl- >86 mmol/L 
• no or little mature 
mRNA   
 
185+1G→T 711+5G→A 1717-8G→A 
2622+1G→A 
3121-1G→A 
296+1G→A 712-1G→T 
1717-1G→A 
2790-1G→C 
3500-2A→G 
405+1G→A 1248+1G→A 1811+1G→C 
3040G→C 
 (G970R) 
3600+2insT 
405+3A→C 1249-1G→A 1811+1.6kbA→G 
3850-1G→A 
406-1G→A 1341+1G→A 1812-1G→A 
3120G→A 
4005+1G→A 
621+1G→T 1525-2A→G 1898+1G→A 
3120+1G→A 
4374+1G→T 
711+1G→T 1525-1G→A 1898+1G→C 
3121-2A→G 
 
Small (≤3 nucleotide) 
insertion/deletion (ins/del) 
frameshift mutations 
• %PI >50% and/or 
SwCl- >86 mmol/L 
• garbled and/or 
truncated protein 
182delT 
1119delA 
1782delA 
2732insA 
3876delA 
306insA 
1138insG 
1824delA 
2869insG 
3878delG 
365-366insT 1154insTC 
2043delG 
2896insAG 
3905insT 
394delTT 
1161delC 
2143delT 
2942insT 
4016insT 
442delA 
1213delT 
2183AA→G a 
2957delT 
4021dupT 
444delA 
1259insA 
2184delA 
3007delG 
4040delA 
457TAT→G 1288insTA 
2184insA 
3028delA 
4279insA 
 
541delC 
1471delA 
2307insA 
3171delC 
4326delTC 
 
574delA 
1497delGG 
2347delG 
3659delC 
 
 
663delT 
1548delG 
2585delT 
3737delA 
 
 
935delA 
1609del CA 2594delGT 
3791delC 
 
 
1078delT 
1677delTA 
2711delT 
3821delT 
 
Non-small (>3 nucleotide) 
insertion/deletion (ins/del) 
frameshift mutations 
• %PI >50% and/or 
SwCl- >86 mmol/L 
• garbled and/or 
truncated protein 
CFTRdele2,3 
1461ins4 
2991del32 
CFTRdele22,23 
1924del7 
3667ins4 
124del23bp 
2055del9→A 
4010del4 
852del22 
2105-
2117del13insAGAAA 
4209TGTT→AA 
991del5 
2721del11 
 
 
 
 


Protocol VX15-440-101, Version 2.0 
Page 86 of 88 
Vertex Pharmaceuticals Incorporated 
 
CFTR Mutations Eligible for VX15-440-101, Parts 1 
 
Criteria 
Mutation 
 
 
 
 
Class II, III, IV mutations 
not responsive to IVA 
alone or in combination 
with TEZ or LUM  
• %PI>50% and/or 
SwCl- >86 mmol/L 
AND 
• Not responsive in 
vitro to IVA alone or 
in combination with 
TEZ or LUM 
A46Db 
V520F 
Y569Db 
N1303K 
  
G85E 
A559Tb 
L1065P 
 
 
R347P 
R560T 
R1066C 
 
 
L467Pb 
R560S 
L1077Pb 
 
 
I507del 
A561E 
M1101K 
 
 
 
 
 
 
 
CFTR: cystic fibrosis transmembrane conductance regulator; IVA: ivacaftor; LUM: lumacaftor; PI: pancreatic 
insufficiency; SwCl-: sweat chloride; TEZ: tezacaftor  
Source: CFTR2.org [Internet]. Baltimore (MD): Clinical and functional translation of CFTR. The Clinical and 
Functional Translation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins University, the 
Hospital for Sick Children. Available at: http://www.cftr2.org/. Accessed 15 February 2016. 
%PI: percentage of F508del-CFTR heterozygous patients in the CFTR2 patient registry who are pancreatic 
insufficient; SwCl
-: mean sweat chloride of F508del-CFTR heterozygous patients in the CFTR2 patient registry 
a Also known as 2183delAA→G.  
b Unpublished data. 




Protocol VX15-440-101, Version 2.0 
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Vertex Pharmaceuticals Incorporated 
 
15.2 
Investigator Signature Page 
Protocol #: VX15-440-101 
Version #: 2.0 Version Date: 16 September 2016 
Study Title: A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety 
and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With 
Cystic Fibrosis 
 
 
I have read Protocol VX15-440-101, Version 2.0, and agree to conduct the study according 
to its terms. I understand that all information concerning VX-440, tezacaftor, and ivacaftor 
and this protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is 
confidential. 
 
 
Printed Name 
  
Signature 
 Date 
 
 

SAP_000.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX15-440-101 Version 2.0 
(Final Analysis) 
 
A Phase 2, Randomized, Double blind, Controlled Study to Evaluate 
the Safety and Efficacy of VX 440 Combination Therapy in Subjects 
Aged 12 Years and Older With Cystic Fibrosis 
 
 
Authors of SAP: 
 
 
Version: Version 1.0 
Version Date of SAP: 12 June 2017 
 
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) 
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Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
 
8.4.3 
Electrocardiogram ............................................................................................ 39 
8.4.4 
Vital Signs ........................................................................................................ 39 
8.4.5 
Pulse Oximetry ................................................................................................. 40 
8.4.6 
Physical Examination ....................................................................................... 40 
 
 
9 
Interim and IDMC Analyses ......................................................................................... 40 
9.1 
Interim Analysis ....................................................................................................... 40 
9.2 
IDMC Analysis ......................................................................................................... 40 
10 References ....................................................................................................................... 41 
11 List of Appendices.......................................................................................................... 42 
Appendix A: Schedule of Assessments.............................................................................. 42 
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments ................... 56 
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates ........... 60 
Appendix D: Important Protocol Deviation Programming Rules (Based on the Clinical 
Database) .................................................................................................................. 61 
Appendix E: Details of GLI Equations for Calculating ppFEV1 ....................................... 63 
 
Appendix G: Calculation of BMI z-score for subjects <20 years old at screening ........... 66 
Appendix H: Imputation Rules for Missing AE dates ....................................................... 67 
Appendix I: Criteria for Threshold Analysis ..................................................................... 70 
 
 




Statistical Analysis Plan (Methods) 
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Vertex Pharmaceuticals Incorporated 
 
3 
INTRODUCTION 
This statistical analysis plan (SAP) for the final analysis is based on the approved clinical 
study protocol (CSP), Version 2.0, dated 16 SEP 2016, approved electronic case report form 
(eCRF), Version 1.0, dated 13 Jul 2016, and approved eCRF completion guidelines, Version 
1.0, dated 18 Oct 2016. This SAP will also be used to perform two separate interim analyses 
(IAs), after all subjects participating in Part 1 have completed the safety follow-up, and 
correspondingly, after all subjects participating in Part 2 have completed the safety follow-
up.  
This is a Phase 2, randomized, double-blind, placebo- and TEZ/IVA-controlled, parallel 
group, multicenter study to evaluate the safety and efficacy of VX-440 combination therapy 
in subjects aged 12 years and older with cystic fibrosis. 
This SAP (Methods) documents the planned statistical analyses of efficacy endpoints and 
safety endpoints. 
Vertex Biometrics will perform the statistical analysis for each IA, and the final analysis. 
SAS® Version 9.2 or higher software (SAS Institute, Cary, North Carolina, USA) will be 
used to generate all statistical outputs (tables, figures, listings, and datasets).  
The SAP (Methods) will be finalized and approved prior to the data cut for the first IA. 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 evaluate the safety and tolerability of VX-440 in 
 triple combination with 
TEZ and IVA 
• To evaluate the efficacy of VX-440 in 
 triple combination with TEZ and IVA 
4.2 
Secondary Objectives  
• To evaluate the pharmacodynamic (PD) effect of VX-440 in 
 triple combination 
with TEZ and IVA on sweat chloride concentrations 
• To evaluate the PK of VX-440 when administered in 
 triple combination with 
TEZ and IVA 
• To evaluate the PK of TEZ, IVA, and their respective metabolites when administered 
with VX-440 


Statistical Analysis Plan (Methods) 
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Vertex Pharmaceuticals Incorporated 
 
5 
STUDY ENDPOINTS 
5.1 
Efficacy Endpoint 
5.1.1 
Primary Efficacy Endpoint 
• Absolute change in percent predicted forced expiratory volume in 1 second1 (ppFEV1) 
from baseline through Day 29 (Parts 1 and 2) 
 
5.1.2 
Secondary Efficacy Endpoints 
• Absolute change in sweat chloride concentrations from baseline through Day 29 (Parts 1 
and 2) 
 
• Relative change in ppFEV1 from baseline through Day 29 (Parts 1 and 2) 
 
 
 
 
 
 
 
 
 
 
 
 
• Absolute change in Cystic Fibrosis Questionnaire-Revised2, 3, 4 (CFQ-R) respiratory 
domain score from baseline at Day 29 (Parts 1 and 2) 
 
• PK parameters of VX-440, TEZ, M1-TEZ, IVA, and M1-IVA 
5.2 
Safety Endpoints 
The safety and tolerability is evaluated via the following endpoints: 
• adverse events (AEs) 
• clinical laboratory values 
• standard 12-lead electrocardiograms (ECGs) 
• vital signs 
• pulse oximetry 
 




Statistical Analysis Plan (Methods) 
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Vertex Pharmaceuticals Incorporated 
 
Table 6-1 
Key Study Elements by Part 
Part 1a 
Part 2 
Genotype 
F508del/MF 
F508del/F508del 
Age 
≥18 years 
≥18 years 
ppFEV1 criteria 
≥40 to ≤90  
≥40 to ≤90 
Number of subjects Approximately 42a 
Approximately 24 
Stratification c 
ppFEV1
d 
• ≥70  
• <70 
ppFEV1  
• ≥70 
• <70 
Study design 
Parallel 
Parallel 
Comparator 
Placebo 
TEZ/IVA 
VX-440 treatment 
duration 
4 weeks 
4 weeks 
IVA: ivacaftor; MF: minimal function; ppFEV1: percent predicted forced expiratory volume in 1 second; q12h: 
every 12 hours; TC: triple combination; TEZ: tezacaftor 
a 
Part 1 consists of Cohort 1A and Cohort 1B. Approximately 10 subjects will be in Cohort 1A and 
approximately 32 subjects will be in Cohort 1B. 
c 
Additional stratification information is provided in Section 8.1.3 of protocol. 
d 
Stratification will be conducted for Cohort 1B subjects only. 


Statistical Analysis Plan (Methods) 
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Vertex Pharmaceuticals Incorporated 
 
 
Table 6-2 
Treatment Arms and Planned Doses by Part 
Part 
Randomization ratio 
 
Treatment Arm 
VX-440 Dosage 
TEZ 
Dosage 
IVA 
Dosage 
Part 1 Cohort 1A 
TC-1A 
200 mg q12h 
100 mg qd 
150 mg q12h 
4:1 
Triple placebo 
Placebo 
Placebo 
Placebo 
Part 1 Cohort 1B 
TC-1B-high 
600 mg q12ha 
50 mg q12h 
300 mg q12ha 
2:1:1 
TC-1B-low 
200 mg q12h 
50 mg q12h 
150 mg q12h 
 
Triple placebo 
Placebo 
Placebo 
Placebo 
Part 2b 
TC-2 
 600 mg q12ha 
50 mg q12h 
300 mg q12ha  
3:1 
TEZ/IVA 
Placebo 
100 mg qd 
150 mg q12h 
a 
In the “TC-1B-high” and “TC-2” treatment arms, the dosage of VX-440 will be determined based on safety 
and PK data from Cohort 1A. The planned dose is shown, but may be reduced to 400 mg q12h.  
b 
In Part 2, all subjects will also receive TEZ 100 mg qd/IVA 150 mg q12h during the Run-in Period and the 
Washout Period. 
 






Statistical Analysis Plan (Methods) 
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Vertex Pharmaceuticals Incorporated 
 
Table 6-3 
Probability of Observing an Adverse Event 
AE Incidencesa 
Number of Subjects per Treatment Groupb 
10 
20 
30 
40 
50 
5% 
40% 
64% 
79% 
87% 
92% 
10%  
65% 
88% 
96% 
98% 
>99% 
15% 
80% 
96% 
>99% 
>99% 
>99% 
AE: adverse event 
a 
AE incidences are based on 4 weeks of treatment in Parts 1 and 2, 
 
b 
Applies to Parts 1 
 
6.2.1.2 
Efficacy 
The primary efficacy endpoint is the absolute change from baseline in ppFEV1 through 
Day 29 in Parts 1 and 2, 
 Table 6-4 provides the power to 
reject the null within-group hypothesis of no difference in the mean absolute change from 
baseline for ppFEV1 through Day 29 or Week 12, as applicable, for any treatment group in 
Parts 1, 2, 
 with a sample size ranging from 8 to 44 subjects per treatment group. The 
power calculations are based on a 2-sided 1-sample t-test at alpha = 5% using the PASS 
software package (Version 11.0), assuming an absolute mean change of 3 to 7 percentage 
points and an SD of 8 percentage points in the absolute change from baseline for ppFEV1. 
Sample sizes of 16 to 44 subjects per treatment group provide adequate power for mean 
changes of 5 to 7 percentage points as expected in Parts 1, 2,
. 
Table 6-4 
Power for Within-group Difference for Mean Absolute Change From 
Baseline in ppFEV1 
Mean Absolute 
Change From 
Baseline in ppFEV1 
Number of Subjects per Treatment Groupa 
8 
16 
20 
22 
24 
40 
42 
44 
3% 
15% 
29% 
36% 
39% 
42% 
64% 
66% 
68% 
4%  
23% 
46% 
56% 
61% 
65% 
87% 
89% 
90% 
5% 
33% 
65% 
76% 
80% 
83% 
97% 
98% 
98% 
6% 
45% 
80% 
89% 
92% 
94% 
>99% 
>99% 
>99% 
7% 
57% 
90% 
96% 
97% 
98% 
>99% 
>99% 
>99% 
ppFEV1: forced expiratory volume in 1 second; SD: standard deviation 
Note: An SD of 8 percentage points for the absolute change from baseline in ppFEV1 was used for power 
calculations. 
a 
Applies to Parts 1 
 
6.2.2 
Secondary Objectives  
A secondary objective of the study is the evaluation of the PD effect of VX-440 in TC with 
TEZ/IVA (all parts) 
  
6.2.2.1 
Pharmacodynamic Effect (Part 1) 
The absolute change from baseline through Day 29 in sweat chloride is a secondary endpoint 
used to evaluate the PD objective of the study. In Part 1, a test for a decreasing dose-response 
trend between placebo and the TC dose groups will be performed using a multiple 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
 
comparisons procedure (MCP). The procedure consists of testing the null hypothesis of the 
lack of a decreasing dose-response trend versus a decreasing trend using the 1-sided 
maximum t-statistic that controls the type I error at alpha = 5%. The procedure requires a 
family of candidate dose-response models to be prespecified, the range of plausible and 
diverse dose-response profiles.  
The candidate models that best describe the expected decreasing dose-response profile of the 
TC groups compared to placebo include a linear model, a maximum effect (Emax) model, and 
a sigmoid Emax model. The contrasts (i.e., linear combinations of the treatment group means 
through Day 29) selected to perform the MCP that captures the shape of these candidate 
models are described in Table 6-5 below.  
Table 6-5 
Contrast Coefficients for the Multiple Comparisons Procedure in Part 1, 
Cohort 1B 
Candidate Model 
Placebo 
TC-1B-low 
TC-1B-high 
Linear 
1.0 
0.0 
-1.0 
Emax 
1.0 
-0.5 
-0.5 
Sigmoid Emax 
0.5 
0.5 
-1.0 
Emax: maximum effect; TC: triple combination 
 
Table 6-6 provides the power to detect a dose-response trend with the MCP procedure for 
3 different expected dose-response profiles with a total sample size of 32 subjects in 
Cohort 1B assigned to TC-1B-high, TC-1B-low, and placebo in the ratio 2:1:1, based on 
5000 simulations for each profile using the MCPMod R software package [Version 1.0-8]. 
Table 6-6 
Power to Detect a Dose-response Trend Based on Change From Baseline 
in Sweat Chloride in Part 1, Cohort 1B 
 
Mean Change From Baseline in Sweat Chloride 
 
Candidate Model 
Placebo 
TC-1B-low 
TC-1B-high 
Power 
Linear 
0 
-15 
-20 
95% 
Sigmoid Emax 
0 
0 
-20 
99% 
Emax 
0 
-20 
-20 
96% 
Emax: maximum effect; TC: triple combination 
Note: A 1-sided maximum t-statistic with a sample size of 32 subjects in Cohort 1B assigned to TC-1B-high, 
TC-1B-low, and placebo at a ratio 2:1:1 was used for power calculations. An SD change from baseline in 
sweat chloride of 13 mmol/L was used for power calculations. 
Table 6-7 provides the power to reject the null within-group hypothesis of no difference in 
the mean absolute change from baseline for sweat chloride through Day 29 (Parts 1 and 2) 
 
for any treatment group with a sample size ranging from 8 to 44 subjects 
per treatment group. The power calculations are based on a 2-sided 1-sample t-test at 
alpha = 5% using the PASS software package (Version 11.0), assuming a mean change 
of -10 to -20 mol/L and an SD of 13 mmol/L in the absolute change from baseline for sweat 
chloride.  


Statistical Analysis Plan (Methods) 
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Vertex Pharmaceuticals Incorporated 
 
Table 6-7 
Power for Within-group Difference for Mean Absolute Change From 
Baseline in Sweat Chloride 
Mean Absolute Change 
From Baseline in Sweat 
Chloride (mmol/L) 
Number of Subjects per Treatment Groupa 
8 
16 
20 
22 
24 
40 
42 
44 
-10 
47% 
82% 
90% 
93% 
95% 
>99% 
>99% 
>99% 
-12  
61% 
93% 
97% 
98% 
99% 
>99% 
>99% 
>99% 
-15 
80% 
99% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
-18 
92% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
-20 
96% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
SD: standard deviation 
Note: An SD of 13 mmol/L for the absolute change from baseline in sweat chloride was used for power 
calculations. 
a 
Applies to Parts 1 
 
 
6.3 
Randomization 
Treatment arms, randomization ratios, and stratification factors for each part are described in 
Table 6-1. An interactive web response system (IWRS) will be used to assign subjects to 
treatment. The randomization code list will be produced by Vertex Biostatistics or a qualified 
randomization vendor. 
6.4 
Blinding and Unblinding 
6.4.1 
Blinding  
All subjects, site personnel (including the investigator, the site monitor, and the study team), 
and the Vertex study team will be blinded to the treatment codes with the exception of the 
following:  
• Any site personnel for whom this information is important to ensure the safety of the 
subject in the event of a life-threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of the 
subject and her fetus in the event of a pregnancy 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy serious 
adverse event (SAE) processing and reporting regulations 
• Unblinded statistician preparing the final (production) randomization list who is not part 
of the study team 
• Vertex IWRS Manager 
• Vertex Clinical Supply Chain 
• IDMC 
• Vendor preparing the unblinded analysis for the ongoing reviews of efficacy and safety 
data, and the IDMC  
• Vendor analyzing PK samples 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
 
• Vertex Modeling and Simulation personnel or vendor conducting the population PK and 
PK/PD analyses 
• Vertex medical monitor (or contract medical monitor) may, for matters relating to safety 
concerns, unblind individual subjects at any time 
Vertex Drug Metabolism and Pharmacokinetics laboratory personnel will not be involved in 
the conduct of the study and will be unblinded to the bioanalysis results but will remain 
blinded to subject number and treatment assignment. 
Spirometry and Sweat Chloride Data Blinding: During the conduct of the study, the Vertex 
study team will not have access to the spirometry results or sweat chloride concentration 
values after the morning dose on Day 1. Furthermore, sites, subjects, and their 
parents/caregivers/companions should not be informed of their study-related spirometry and 
sweat chloride results during the Treatment Period regardless of whether the subject has 
prematurely discontinued treatment. 
A limited Vertex team will be unblinded and have access to safety, efficacy, and PD data for 
the purpose of conducting ongoing reviews of safety and efficacy data for planning and 
enabling clinical development, regulatory, and chemistry, manufacturing, and controls 
(CMC) decisions. Members of the limited unblinded Vertex team will not be part of the 
Vertex study team and will not be involved in or influence the conduct of the study.   
The Vertex study team and lead investigator(s) will conduct a blinded review of all available 
safety and PK data after all Cohort 1A subjects complete the Day 15 Visit. The Vertex study 
team will not have access to unblinded data from ongoing reviews by the limited Vertex 
team.  
After all subjects within Parts 1 and 2 have completed the Safety Follow-up Visit, results 
from each part will be unblinded for full review by the Vertex study team (Section 12.3.6.1 
of protocol). 
6.4.2 
Unblinding 
At the initiation of the study, each study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process.  
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment 
is necessary for clinical management. In such cases, investigators will use their best 
judgment as to whether to unblind without first attempting to contact the medical monitor to 
discuss and agree to the need for unblinding. If investigators deem it not necessary to unblind 
immediately, they will first attempt to contact the medical monitor to discuss and agree to the 
need for unblinding. If investigators have tried but are unable to reach the medical monitor, 
they will use their best judgment, based on the nature and urgency of the clinical situation, 
and may proceed with unblinding without having successfully reached and discussed the 
situation with the medical monitor. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 




Statistical Analysis Plan (Methods) 
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7.3.2 
Part 2  
The Safety Set for the Run-in Period will include all subjects who received at least 1 dose 
of study drug TEZ/IVA in the Run-in Period. This Safety Set will be used for individual 
subject data listings for the Run-in Period, unless specified otherwise.  
The Safety Set for the Treatment Period will include all subjects who received at least 1 
dose of study drug in the Treatment Period. This Safety Set will be used for all safety 
analyses for the Treatment Period, unless specified otherwise. 
If a subject received at least 1 dose of the higher TC treatment group in the increasing 
priority order: placebo + TEZ/IVA, TC-2 (VX-440 + TEZ/IVA), the subject will be analyzed 
in the higher treatment group.  
Note: The safety analysis will focus on the Safety Set for the Treatment Period only, unless 
otherwise specified.  
8 
STATISTICAL ANALYSIS 
8.1 
General Considerations 
The analysis will be performed for each part, and presented by treatment group and overall, 
for the Treatment Period, unless specified otherwise. The treatment groups are defined as 
follows:  
• Part 1: F508del/MF genotype group 
o TC-1B-high, TC-1B-low, TC-1A, and placebo, with the TEZ component in the 
TC-1B-low and TC-1B-high groups administered as 50 mg q12h, and that in the 
TC-1A group administered as 100 mg qd. More specifically, Part 1 includes 
cohorts 1A and 1B; Cohort 1A includes TC-1A while Cohort 1B includes TC-1B-
low and TC-1B-high. The placebo group is randomized in  both cohorts. 
• Part 2: F508del/F508del genotype group  
o TC-2, and TEZ/IVA, with the TEZ component in the TC group administered as 
50 mg q12h 
The Schedule of Assessments is provided in Appendix A. The precision standards for 
reporting safety and efficacy variables are provided in an internal Biometrics document that 
specifies the programming rules including the precision for derived variables.  
All individual subject data for those randomized or dosed with any amount of study drug will 
be presented in data listings. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, SD, standard error (SE), median, minimum value 
(min), and maximum value (max). SE may not be reported for safety summary tables.  


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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 first dose of study drug on Day 
1 of the Treatment Period. For ECG, baseline will be defined as the most recent non-missing 
measurement (the average of triplicate measurements, if the most recent non-missing 
measurement is obtained in triplicate), before the first dose of study drug on Day 1 of the 
Treatment Period. 
Absolute change from baseline will be calculated as postbaseline value – baseline value. 
Relative change from baseline will be calculated as (postbaseline value – baseline 
value)/baseline value. 
Treatment-emergent (TE) period for Parts 1 
 will include the time from the first dose 
of study drug in the Treatment Period to the Safety Follow-up (SFU) Visit, or 28 Days after 
the last dose of study drug for subjects who do not complete the SFU Visit.  
For Part 2, the TE period will be defined separately for the Run-In Period, and the Treatment 
Period: 
• The TE period for the Run-in Period will include the time from  the first dose of study 
drug in the Run-in Period to: (1) the  last day prior to the first dose of study drug in the 
Treatment Period for subjects who complete the Run-in Period and continue to the 
Treatment Period, or  (2) the SFU Visit for subjects who do not continue to the Treatment 
Period and have an SFU Visit, or (3) 28 days after the last dose of study drug in the Run-
in Period for subjects who do not have an SFU Visit (e.g., subjects who do not meet the 
criteria to enter the Treatment Period and re-enter Study 661-110).  
• The TE period for the Treatment Period will include the first dose of study drug in the 
Treatment Period to: (1) the SFU Visit, or (2) 28 days after the last dose of study drug for 
subjects who do not have an SFU Visit (e.g. subjects whose Early Treatment Termination 
(ETT) Visit occurs 3 weeks or later following the last dose of study drug and the ETT 
visit replaces the SFU visit, or who leave the Treatment Period early and re-enter Study 
661-110).  
Note: only data collected up to the end of study for a subject will be included in analysis. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
• In scheduled visit windows per specified visit windowing rules 
• In the derivation of baseline and last on-treatment measurements 
• In the derivation of maximum and minimum on-treatment values, and maximum and 
minimum change from baseline values for safety analyses 
• In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided 
in Appendix B.  


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Incomplete/missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence 
of statistical outliers, unless specified otherwise. 
Multiplicity: There will be no multiplicity adjustment for performing multiple hypothesis 
tests, unless specified otherwise. 
8.2 
Background Characteristics  
8.2.1 
Subject Disposition 
For the Treatment Period in Part 1, Part 2, 
, subject disposition will be summarized 
as described below. 
The number of subjects in the following categories will be summarized by treatment group 
and overall, for each part:  
• All Subjects Set (randomized or dosed  in the Treatment Period) 
• Randomized 
• Full Analysis Set (FAS) 
• Safety Set (for Part 2, this is the Safety Set for the Treatment Period) 
The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized by treatment group and overall: 
• Completed study drug treatment  
• Prematurely discontinued treatment and the reason for discontinuation (i.e., discontinued 
all study drugs)  
• Completed study (i.e., completed Safety Follow-up Visit or completed all study drugs 
and re-entered Study 661-110 without Safety Follow-up per protocol) 
• Prematurely discontinued the study and the reason for discontinuation  
For the Run-in Period in Part 2, a separate disposition table will be provided with the 
following categories:  
• All Subjects Set (enrolled or dosed in the Run-in Period) 
• Completed treatment in the Run-in Period (i.e., completed randomization) 
• Prematurely discontinued  treatment during the Run-in Period and the reason for 
treatment discontinuation (i.e., discontinued all study drugs in the Run-in Period) 
• Prematurely discontinued the study during the Run-in Period and the reason for study 
discontinuation 
A listing will be provided by part, for subjects who discontinued treatment (including the 
Run-in Period in Part 2) or who discontinued study with reasons for discontinuation. A 
randomization listing of subjects will also be provided, by part. 


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8.2.2 
Demographics and Baseline Characteristics 
Demographics, medical history and baseline characteristics will be summarized based on the 
FAS, and presented by treatment group and overall, for each part and cohort, as applicable. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and Other) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
Stratification categories will include the following: 
• ppFEV1 at stratification (< 70 and ≥ 70) 
For subjects who are naïve to TEZ/IVA treatment in Part 2, ppFEV1 at Day -14 will be used 
for stratification; otherwise, ppFEV1 at screening will be used for stratification.  
Disease characteristics will include the following: 
• ppFEV1 at baseline (<40, ≥ 40 to <70, ≥70 to ≤90, >90) 
• ppFEV1 at baseline (continuous)  
• Sweat Chloride at baseline (continuous) 
• FEV1 (L) at baseline (continuous) 
• CFQ-R Respiratory Symptoms domain at baseline (continuous) 
• Prior use of dornase alfa before first dose of study drug (Yes, No) 
• Prior use of inhaled antibiotic before first dose of study drug (Yes, No) 
• Prior use of any bronchodilator before first dose of study drug (Yes, No)  
• Prior use of any inhaled bronchodilator before first dose of study drug (Yes, No)  
• Prior use of any inhaled hypertonic saline before first dose of study drug (Yes, No) 
• Prior use of any inhaled corticosteroids before first dose of study drug (Yes, No) 


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• Colonization with Pseudomonas aeruginosa at baseline (Positive, Negative) 
A summary of medical history will be provided by MedDRA system organ class (SOC) and 
preferred term (PT) for the FAS. In addition, the number of subjects reported to have had 
positive cultures for respiratory pathogens in 2 years prior to screening will be summarized 
for the FAS. Further, the CFTR genotype for each subject will be provided in an individual 
subject data listing.   
8.2.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHODDE) and categorized as follows: 
For Parts 1 
  
Prior medication: any medication that started before the first dose date of study drug, 
regardless of when the medication ended. 
Concomitant medication: medication continued or newly received on or after the first dose 
date of study drug through the end of the TE period. 
Post-treatment medication: medication continued or newly received after the TE period. 
For Part 2:  
Prior medication: any medication that started before the first dose date of study drug in the 
Run-in Period, regardless of when the medication ended. 
Concomitant medication during the Run-in Period: medication continued or newly 
received on or after the first dose date of study drug during the Run-in Period through the end 
of the TE period for the Run-in Period. 
Concomitant medication during the Treatment Period: medication continued or newly 
received on or after the first dose date of study drug during the Treatment Period through the 
end of the TE period for the Treatment Period. 
Post-treatment medication: medication continued or newly received after the TE period. 
A given medication may be classified as follows: prior, concomitant, post-treatment, both 
prior and concomitant, both concomitant and post-treatment, or prior, concomitant, and 
post-treatment. In Part 2, concomitant may be concomitant during the Run-in Period, or 
concomitant during the Treatment Period, or both.  
If a medication has a completely missing or partially missing start/stop date and it cannot be 
determined whether it was taken before the first dose date of study drug, concomitantly, or 
after the TE period, it will be classified as prior, concomitant, and post-treatment. 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by preferred name.  
Summaries of medications will be based on the FAS, and presented by treatment group and 
overall for each part.  
Post-treatment medications will be listed by subject.  


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Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix C. 
8.2.4 
Study Drug Exposure  
Study drug exposure (in days) will be calculated as: last dose date of study drug – first dose 
date of study drug + 1 day, regardless of study drug interruption, and will be summarized 
descriptively. Study drug exposure will be summarized for the overall study drug period, 
which includes the Run-in Period, Treatment Period and Washout Period for Part 2, and the 
Treatment Period for Parts 1 
 Further, study drug exposure for the combined Treatment 
Period and Washout Period in Part 2 will also be summarized descriptively.  
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects 
(n), mean, SD, SE, median, min, and max. It will also be summarized in categories: ≤2 
weeks, >2- ≤4 weeks, and >4 weeks (for Parts 1 and 2); and ≤2 weeks, >2- ≤4 weeks, >4 - ≤8 
weeks, >8 - ≤12 weeks, and >12 weeks (for Part 4), using counts and percentages. 
Additionally, the total study drug exposure, defined as the sum total of the study drug 
exposure across all subjects (in patient-weeks), will be provided. 
Exposure summaries will be based on the Safety Set, and presented by treatment group and 
overall, for each part. For Part 2, exposure summaries will be based on the Safety Set for the 
Treatment Period.  
8.2.5 
Study Drug Compliance 
Percentage of tablets taken will be calculated as: 100 × [(total number of tablets dispensed) – 
(total number of tablets returned)]/( total number of tablets planned to be taken per 
day × duration of study drug exposure in days). The maximum percentage of tablets taken 
will be 100%.  
Study drug compliance will be calculated as: 100 × [1 - (total number of days of study drug 
interruption) / (duration of study drug exposure in days)].  A study drug interruption on a 
given day will be determined by an interruption of all drugs on that day. 
Percentage of tablets taken and study drug compliance will be summarized descriptively by 
the number of subjects (n), mean, SD, SE, median, min, and max. It will also be summarized 
in categories: <80% and ≥80% using frequency tables.  
For all parts, study drug compliance will be summarized for the Treatment Period only.  
Similarly, for all parts, percentage of tablets taken will be summarized for the Treatment 
Period only. 
Percentage of tablets taken and study drug compliance summaries will be based on the FAS, 
and presented by treatment group and overall, for each part. 
8.2.6 
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 lock. 




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8.3.1.1 
Primary Analysis of the Primary Efficacy Variable 
8.3.1.1.1 
Parts 1 and 2 
The null hypothesis to be tested is that the mean absolute within-group change from baseline 
in percent predicted FEV1 (ppFEV1) through Day 29 is zero for VX-440 in triple 
combination (TC) with TEZ/IVA, for each part, separately. A 2-sided p-value of 0.05 or less 
will be interpreted as sufficient evidence to reject the null hypothesis.  
The primary analysis will be performed using a mixed-effects model for repeated measures 
(MMRM) with change from baseline in ppFEV1 as the dependent variable for each part, 
separately. This MMRM analysis will include all treatment groups within a part. For Part 1, 
the analysis will include 3 treatment groups: placebo, pooled TC-1A and TC-1B-low, and 
TC-1B-high. For Part 2, the analysis will include 2 treatment groups: placebo + TEZ/IVA, 
and TC-2 (VX-440 + TEZ/IVA). The model will include treatment group, visit, and 
treatment-by-visit interaction as fixed effects, with the continuous baseline ppFEV1 as a 
covariate, and will include all data from each treatment group and visit in the analysis. The 
model will be estimated using restricted maximum likelihood. Denominator degrees of 
freedom for the F test for fixed effects will be estimated using the Kenward-Roger 
approximation. An unstructured covariance structure will be used to model the within-subject 
errors. If the model estimation does not converge, a reduced compound symmetry covariance 
structure will be used instead. Conditional on the observed data and covariates, missing 
ppFEV1 data due to treatment or study discontinuation will be assumed to be missing at 
random; consequently, no imputation of missing data will be performed.  
The adjusted means and 95% confidence intervals (CI) of the average treatment effect 
through Day 29 (Day 15 and Day 29 only) for each triple combination, with a 2-sided p-
value will be estimated within MMRM using PROC MIXED in SAS, for all within-treatment 
and between-treatment comparisons, for each part, separately. Contrasts based on the fixed 
effects in the model, defined at the baseline covariate mean for the combined treatment 
groups using unique subjects in the FAS who have at least one post-baseline measurement 
through Day 29, will be used to estimate the average treatment effect across post-baseline 
visits through Day 29.  
Further, the adjusted mean and 95% CI of the treatment difference between each triple 
combination and placebo at each post-baseline visit through Day 29 will be provided along 
with the corresponding p-value, for each part. In addition, the adjusted mean and 95% CI of 
the within-treatment difference at each post-baseline visit through Day 29 for each treatment 
group will be provided along with the p-value, for each part.   
The adjusted mean (with 95% CI) obtained from the MMRM analysis at each post-baseline 
visit through Day 29 will be plotted by treatment group, for each part. In addition, a waterfall 
plot showing the subject-level absolute change in ppFEV1 at Day 29 will be presented, by 
treatment group. The plots will be based on the pooled treatment groups for Part 1. 
In addition, for each part, descriptive analyses of the change from baseline will be performed 
for all treatment groups by post-baseline visit through the safety follow-up visit. Treatment 
groups in Part 1 will be presented both with TC-1A and TC-1B-low pooled, and separately 
for descriptive analysis.  


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8.3.2 
Analysis of Secondary Efficacy Variables 
The secondary efficacy variables include: 
• Relative change in ppFEV1 from baseline through Day 29 (Parts 1 and 2) 
 
 








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8.3.2.9 
Multiplicity adjustment 
There will be no multiplicity adjustment to control the overall type 1 error rate for secondary 
efficacy variables. 








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8.3.5.3 
Absolute Change in Sweat Chloride from Baseline through Day 29 
(Parts 1 and 2) 
 
8.3.5.3.1 
Parts 1 and 2 
The analysis of the absolute change in sweat chloride from baseline through Day 29 will be 
based on an MMRM model similar to the analysis of the primary efficacy variable in Part 1, 
with the continuous baseline sweat chloride as a covariate. The presentation of results will 
also be similar. 
The adjusted mean (with 95% CI) obtained from the MMRM analysis at each post-baseline 
visit through Day 29 in the Treatment Period will be plotted by treatment group, for each 
part.  
A waterfall plot showing the subject-level absolute change in sweat chloride at Day 29 will 
be presented, by treatment group. The plots will be based on the pooled treatment groups for 
Part 1. 
In addition, for each part, descriptive analyses of the change from baseline will be performed 
for all treatment groups by post-baseline visit. Treatment groups TC-1A and TC-1B-low in 
Part 1 will be presented both pooled and separately, for descriptive analysis. 


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8.4 
Safety Analysis 
For Parts 1 
 all safety analyses will be based on data from the TE Period for all subjects 
in the Safety Set. For Part 2, all safety analyses will be based on the TE Period for the 
Treatment Period for all subjects in the corresponding Safety Set for the Treatment Period. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and 
urinalysis) 
• ECGs 
• Vital signs 
• Pulse oximetry 
All safety data will be summarized by treatment group and overall, for each part. 
All safety data will be presented in individual subject data listings. 
8.4.1 
Adverse Events  
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  


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For Parts 1 
  
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  
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed beyond the TE period 
For Part 2:  
Pretreatment AE: any AE that started before the first dose date of study drug 
TEAE during the Run-in 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 through the end of 
the TE period for the Run-in Period 
TEAE during the Treatment 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 through 
the end of the TE period for the Treatment Period  
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed beyond the TE period 
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of adverse events are described in 
Appendix H. 
AE summary tables will be presented for TEAEs only, for the TE period, or accordingly, the 
TE Period for Treatment Period in Part 2, by treatment group and overall, for each part and 
cohort, as applicable, for the following:  
• Number of TEAEs (total number of TEAEs only) 
• Subjects with any TEAEs  
• Subjects with TEAEs by Strongest Relationship 
• Subjects with TEAEs by Maximum Severity 
• Subjects with TEAEs Leading to Study Drug Discontinuation (Discontinuation of all 
study drug) 
• Subjects with TEAEs Leading to Study Drug Interruption (Interruption of all study drug) 
• Subjects with Serious TEAEs 
• Subjects with TEAE 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 percentages of subjects, subjects with multiple 
occurrences of the same adverse event or a continuing adverse event will be counted once, 




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and cohort, as applicable. The following vital signs parameters will be summarized: systolic 
and diastolic blood pressure (mm Hg), body temperature (°C), HR (beats per minute), and 
respiratory rate (breaths per minute). 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during 
the TE period, or TE period for the Treatment Period in Part 2, will be summarized by 
treatment group and overall, for each part. The threshold analysis criteria are provided in 
Appendix I. 
8.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each scheduled visit, for the percent of 
oxygen saturation, by treatment group, for each part. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the 
TE Period, or accordingly, the TE period for the Treatment Period in Part 2, will be 
summarized by treatment group and overall, for each part. 
8.4.6 
Physical Examination  
PE findings will be presented as an individual subject data listing only. 
9 
INTERIM AND IDMC ANALYSES 
9.1 
Interim Analysis 
The first interim analysis will be performed after all subjects in Part 1 have completed the 
Safety Follow-up Visit. All Data from Part 1 will be unblinded after the data from Part 1 are 
cleaned for analysis and a data cut is performed. The Vertex Study Team will be unblinded to 
the interim analysis results from Part 1. 
The second interim analysis will be performed after all subjects in Part 2 have completed the 
Safety Follow-up Visit. The Vertex Study Team will be unblinded to the interim analysis 
results from Part 2, following a process similar to Part 1. 
9.2 
IDMC Analysis  
An independent data monitoring committee (IDMC) was formed before study initiation. The 
IDMC’s objectives and operational details were defined in a separate document (IDMC 
Charter) which was finalized before the first subject was screened in the study. The IDMC’s 
planned safety reviews of study data are outlined in the IDMC Charter and IDMC Statistical 
Analysis Plan. Further, planned ongoing reviews of key study data by the limited Vertex 
team are also described in the IDMC Statistical Analysis Plan.  


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10 
REFERENCES 
1Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 
2Quittner 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. 
3Goss C, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc. 
2007;4:1-9. 
4Modi 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. 


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11 
LIST OF APPENDICES 
Appendix A: Schedule of Assessments 
Table 11-1 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1A) 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Day 8 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Informed consent 
X 
 
 
 
 
 
 
 
Randomizatione 
 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Ophthalmological history 
X 
 
 
 
 
 
 
 
CFQ-Rf,g 
 
X 
 
X 
X 
X 
Xh  
X 
Weighti 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
                                                 
a  
All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once 
if study drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b  
To be eligible to continue into the Treatment Period, subjects must have stable CF disease and have remained on stable CF medication regimen during the 
28 days before the Day 1 Visit AND must not have had an acute non-CF illness within 14 days before the Day 1 Visit. See Section 8.1.3 of the protocol. 
c  
If the subject prematurely discontinues study treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug 
treatment. Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit. If the ETT Visit occurs 3 weeks or 
later following the last dose of study drug, then the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
d  
All screening results must be reviewed by an appropriately qualified member of the investigator’s team before randomization, unless noted otherwise. 
e  
Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria have been confirmed. 
f  
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
g  
The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred. 
h  
Subjects will complete the CFQ-R at the ETT Visit only if it has been 2 weeks or more since their last visit. 
i  
Weight and height will be measured with shoes off. 


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Table 11-1 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1A) 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Day 8 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Vital signsj 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
                                                 
j  
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 


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Table 11-1 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1A) 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Day 8 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Physical examinationk 
Complete 
Abbreviated 
 
Abbreviated 
Abbreviated 
 
Abbreviated 
Complete 
Ophthalmologic 
examinationl 
X 
 
 
 
 
 
 
 
Standard 12-lead ECGm 
X 
X 
X 
X 
X 
X 
X 
X 
Sweat chlorideg,n 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometryo 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (all females 
of childbearing potential) 
Serum 
Urine 
 
 
Urine 
 
Serum  
Serum 
CFTR genotypep 
X 
 
 
 
 
 
 
 
FSHq 
X 
 
 
 
 
 
 
 
                                                 
k  
Complete and abbreviated PEs are described in Section 11.7.3 of the protocol. Symptom-targeted PEs will occur at any time during the study if triggered by 
AEs or if deemed necessary by the investigator or healthcare provider. 
l  
The ophthalmological examination can be performed at any time during the Screening Period through the Day 1 Visit (before the first dose of study drug). 
The screening ophthalmological examination does not have to be performed if there is documentation of an examination that met protocol criteria and was 
within 3 months before the date of informed consent, or if there is documentation of bilateral lens removal for the subject. 
m  
All standard 12-lead ECGs will be performed after the subject has been seated for at least 5 minutes. On Days 1 and 15, ECGs will be collected before 
dosing and 4 hours (± 1 hour) after dosing. At all other visits, ECGs will be collected before dosing (as applicable). ECGs collected on Day 1 before dosing 
will be performed in triplicate.  
n  
Sweat chloride will be measured in all subjects. If the value cannot be determined from the screening test, a sweat chloride value documented in the subject’s 
medical record may be used to establish eligibility. 
o  
Spirometry may be performed pre- or post-bronchodilator at the Screening Visit. Spirometry will be performed pre-bronchodilator, before the morning dose 
of study drugs, and should be performed at approximately the same time at every other study visit. On Days 1 and 15, spirometry will also be performed 
pre-bronchodilator 5 hours (± 1 hour) after study drug administration.  
p  
CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before randomization, a previous CFTR genotype 
laboratory report may be used to establish eligibility. 
q  
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 


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Table 11-1 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1A) 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Day 8 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
G6PD activity testr
X
 
Serum chemistry and 
hematology 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
X 
X 
 
 
X 
PK samplingt 
 
X 
X 
X 
X 
X 
X 
  
Study drug dosingu 
 
Day 1 through Day 29 
 
 
 
AEs, medicationsv, 
treatments, and procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
 
                                                 
r  
A single blood sample will be collected for the G6PD activity test  
  
Blood samples will be collected for PK analysis of VX-440, TEZ, M1-TEZ, IVA, and M1-IVA. On Day 1, samples will be collected before dosing (0 hours) 
and at 1, 2, 4, and 6 hours after dosing (relative to the morning dose). On Days 8 and 29, a predose sample will be collected before the morning dose of study 
drug. On Day 15, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 8 hours after dosing. At the Day 43 and the ETT Visits, a single 
blood sample for PK analysis will be collected. 
u  
The last dose of study drug will be the morning dose on Day 29. 
v  
Refer to Section 9.4 of the protocol for details. 


Statistical Analysis Plan (Methods) 
Page 46 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
 
Table 11-2 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1B) 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dose 
Days -28 
to -1d 
Day 1  
Day 15 
(± 2 day) 
Day 29 
(± 2 day) 
Informed consent 
X 
 
 
 
 
 
 
Randomizatione 
 
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Ophthalmological history 
X 
 
 
 
 
 
 
CFQ-Rf,g 
 
X 
X 
X 
X 
Xh  
X 
Weighti 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Vital signsj 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetry 
X 
X 
X 
X 
X 
X 
X 
                                                 
a  
All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once 
if study drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b  
To be eligible to continue into the Treatment Period, subjects must have stable CF disease and have remained on stable CF medication regimen during the 
28 days before the Day 1 Visit AND must not have had an acute non-CF illness within 14 days before the Day 1 Visit. See Section 8.1.3 of the protocol. 
c  
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug 
treatment. Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit. If the ETT Visit occurs 3 weeks or 
later following the last dose of study drug, then the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
d  
All screening results must be reviewed by an appropriately qualified member of the investigator’s team before randomization, unless noted otherwise. 
e  
Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria have been confirmed. 
f  
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
g  
The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred. 
h  
Subjects will complete the CFQ-R at the ETT Visit only if it has been 2 weeks or more since their last visit. 
i  
Weight and height will be measured with shoes off. 
j  
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 


Statistical Analysis Plan (Methods) 
Page 47 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
 
Table 11-2 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1B) 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dose 
Days -28 
to -1d 
Day 1  
Day 15 
(± 2 day) 
Day 29 
(± 2 day) 
Physical examinationk 
Complete 
Abbreviated 
Abbreviated 
Abbreviated 
 
Abbreviated 
Complete 
Ophthalmologic 
examinationl 
X 
 
 
 
 
 
 
Standard 12-lead ECGm 
X 
X 
X 
X 
X 
X 
X 
Sweat chlorideg,n 
X 
X 
X 
X 
X 
X 
X 
Spirometryo 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (all females 
of childbearing potential) 
Serum 
Urine 
 
Urine 
 
Serum 
Serum 
CFTR genotypep 
X 
 
 
 
 
 
 
FSHq 
X 
 
 
 
 
 
 
                                                 
k  
Complete and abbreviated PEs are described in Section 11.7.3 of the protocol. Symptom-targeted PEs will occur at any time during the study if triggered by 
AEs or if deemed necessary by the investigator or healthcare provider. 
l  
The ophthalmological examination can be performed at any time during the Screening Period through the Day 1 Visit (before the first dose of study drug). 
The screening ophthalmological examination does not have to be performed if there is documentation of an examination that met protocol criteria and was 
within 3 months before the date of informed consent, or if there is documentation of bilateral lens removal for the subject. 
m  
All standard 12-lead ECGs will be performed after the subject has been seated for at least 5 minutes. On Days 1 and 15, ECGs will be collected before 
dosing and 4 hours (± 1 hour) after dosing. At all other visits, ECGs will be collected before dosing (as applicable). ECGs collected on Day 1 before dosing 
will be performed in triplicate.  
n  
Sweat chloride will be measured in all subjects. If the value cannot be determined from the screening test, a sweat chloride value documented in the subject’s 
medical record may be used to establish eligibility. 
o  
Spirometry may be performed pre- or post-bronchodilator at the Screening Visit. Spirometry will be performed pre-bronchodilator, before the morning dose 
of study drugs, and should be performed at approximately the same time at every other study visit. On Days 1 and 15, spirometry will also be performed 
pre-bronchodilator, 5 hours (± 1 hour) after study drug administration.  
p  
CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before randomization, a previous CFTR genotype 
laboratory report may be used to establish eligibility. 
q  
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 


Statistical Analysis Plan (Methods) 
Page 48 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
 
Table 11-2 
Study VX15-440-101: Schedule of Assessments for Part 1 (Cohort 1B) 
Event/Assessmenta 
Screening 
Treatment Periodb 
Day 43 
(± 3 days) 
 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last Dose 
Days -28 
to -1d 
Day 1  
Day 15 
(± 2 day) 
Day 29 
(± 2 day) 
G6PD activity testr 
X 
 
 
 
 
 
 
Serum chemistry and 
hematology 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
X 
X 
 
 
X 
PK samplingt 
 
X 
X 
X 
X 
X 
  
Study drug dosingu 
 
Day 1 through Day 29 
 
 
 
AEs, medicationsv, 
treatments and procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
 
                                                 
r  
A single blood sample will be collected for the G6PD activity test. 
  
Blood samples will be collected for PK analysis of VX-440, TEZ, M1-TEZ, IVA, and M1-IVA. On Day 1, samples will be collected before dosing (0 hours) 
and at 1, 2, 4, and 6 hours after dosing (relative to the morning dose). On Day 15, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 8 
hours after dosing. On Day 29, a predose sample will be collected before the morning dose of study drug. At the Day 43 and the ETT Visits, a single blood 
sample for PK analysis will be collected. 
u  
The last dose of study drug will be the morning dose on Day 29. 
v  
Refer to Section 9.4 of the protocol for details. 


Statistical Analysis Plan (Methods) 
Page 49 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
 
Table 11-3 
Study VX15-440-101: Schedule of Assessments for Part 2 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Periodb 
Washout Period 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dosed 
Days -56 
to -29e 
Day -28 
(± 1 day) 
Day -14f 
(± 1 day) 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Randomizationg 
 
 
 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Ophthalmological 
history 
X 
 
 
 
 
 
 
 
 
 
CFQ-Rh,i 
 
 
 
X 
X 
X 
X 
X 
Xj  
X 
Weightk 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
                                                 
a  
All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once 
if study drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b  
To be eligible to continue into the Treatment Period, subjects must have stable CF disease and have remained on stable CF medication regimen during the 
28 days before the Day 1 Visit AND must not have had an acute non-CF illness within 14 days before the Day 1 Visit. See Section 8.1.3 of the protocol. 
c  
If the subject prematurely discontinues study treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug 
treatment. Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit. If the ETT Visit occurs 3 weeks or 
later following the last dose of study drug, then the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be 
required. 
d  
Part 2 subjects who meet criteria specified in Section 8.1.5 of the protocol will not have a Safety Follow-up Visit. 
e  
All screening results must be reviewed by an appropriately qualified member of the investigator’s team before the subject receives the first dose of TEZ/IVA 
in the Run-in Period on Day -28, unless noted otherwise.  
f  
The Day -14 Visit is only required for subjects who are naïve to TEZ/IVA treatment. 
g  
Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria and criteria for entry into the Treatment Period have been 
confirmed. See Section 8.1.3 of the protocol. 
h  
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
i  
The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred. 
j  
Subjects will complete the CFQ-R at the ETT Visit only if it has been 2 weeks or more since their last visit. 
k  
Weight and height will be measured with shoes off. 


Statistical Analysis Plan (Methods) 
Page 50 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
 
Table 11-3 
Study VX15-440-101: Schedule of Assessments for Part 2 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Periodb 
Washout Period 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dosed 
Days -56 
to -29e 
Day -28 
(± 1 day) 
Day -14f 
(± 1 day) 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
Vital signsl 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetry 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical 
examinationm 
Complete 
Abbreviated 
 
Abbreviated Abbreviated Abbreviated 
 
Abbreviated Abbreviated 
Complete 
Ophthalmologic 
examinationn 
X 
 
 
 
 
 
 
 
 
 
Standard 12-lead 
ECGo 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Sweat chloridei,p 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Spirometryq 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
                                                 
l  
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 
m  
Complete and abbreviated PEs are described in Section 11.7.3 of the protocol. Symptom-targeted PEs will occur at any time during the study if triggered by 
AEs or if deemed necessary by the investigator or healthcare provider. 
n  
The ophthalmological examination can be performed at any time during the Screening Period through the Day 1 Visit (before the first dose of study drug). 
The screening ophthalmological examination does not have to be performed if there is documentation of an examination that met protocol criteria and was 
within 3 months before the date of informed consent, or if there is documentation of bilateral lens removal for the subject. 
o  
All standard 12-lead ECGs will be performed after the subject has been seated for at least 5 minutes. On Days 1 and 15, ECGs will be collected before 
dosing and 4 hours (± 1 hour) after dosing. At all other visits, ECGs will be collected before dosing (as applicable). ECGs collected on Day 1 before dosing 
will be performed in triplicate.  
p  
Sweat chloride will be measured in all subjects. If the value cannot be determined from the screening test, a sweat chloride value documented in the subject’s 
medical record may be used to establish eligibility.  
q  
Spirometry may be performed pre- or post-bronchodilator at the Screening Visit. Spirometry will be performed pre-bronchodilator, before the morning dose 
of study drugs, and should be performed at approximately the same time at every other study visit. On Days 1 and 15, spirometry will also be performed 
pre-bronchodilator, 5 hours (± 1 hour) after study drug administration.  


Statistical Analysis Plan (Methods) 
Page 51 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
 
Table 11-3 
Study VX15-440-101: Schedule of Assessments for Part 2 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Periodb 
Washout Period 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dosed 
Days -56 
to -29e 
Day -28 
(± 1 day) 
Day -14f 
(± 1 day) 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
Pregnancy test (all 
females of 
childbearing 
potential) 
Serum 
Urine 
 
Urine 
 
Urine 
 
Urine 
Serum 
Serum 
CFTR genotyper 
X 
 
 
 
 
 
 
 
 
 
FSHs 
X 
 
 
 
 
 
 
 
 
 
G6PD activity testt 
X 
 
 
 
 
 
 
 
 
 
Serum chemistry 
and hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
X 
X 
X 
 
 
 
X 
PK samplingv 
 
 
 
X 
X 
X 
X 
 
X 
  
TEZ/IVA dosingw 
 
Day -28 through Day 57 
 
 
VX-440 or placebo 
dosingx 
 
 
 
Day 1 through Day 29 
 
 
 
 
                                                 
r  
CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before Day -28, a previous CFTR genotype 
laboratory report may be used to establish eligibility. 
s  
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
t  
A single blood sample will be collected for the G6PD activity test. 
  
Blood samples will be collected for PK analysis of VX-440, TEZ, M1-TEZ, IVA, and M1-IVA. On Day 1, samples will be collected before dosing (0 hours) 
and at 1, 2, 4, and 6 hours after dosing (relative to morning dose). On Day 15, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 8 hours 
after dosing. On Day 29, a predose sample will be collected before the morning dose of study drug. At the Day 43 Visit, a single blood sample for PK 
analysis will be collected before the morning dose of TEZ/IVA. At the ETT Visit, a single blood sample for PK analysis will be collected. 
w  
The last dose of TEZ/ivacaftor will be the morning dose on Day 57. 
x  
The last dose of VX-440 or placebo will be the morning dose on Day 29. 


Statistical Analysis Plan (Methods) 
Page 52 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
 
Table 11-3 
Study VX15-440-101: Schedule of Assessments for Part 2 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Periodb 
Washout Period 
ETT 
Visitc 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dosed 
Days -56 
to -29e 
Day -28 
(± 1 day) 
Day -14f 
(± 1 day) 
Day 1  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
AEs, medicationsy, 
treatments and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
                                                 
y  
Refer to Section 9.4 of the protocol for details. 








Statistical Analysis Plan (Methods) 
Page 56 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 11-5 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
Safety Assessment (Part 1, Cohort 1A) 
Serum Chemistry 
Hematology 
Urinalysis 
Vital Signs (including 
Weight) 
 
Day 1 (Baseline)  
Day 8 
Day 15 
Day 29 
Day 43 
Safety Follow-up 
1 
8 
15 
29 
43 
57 
≤1 Pre-dose 
[1, 12] 
(12,22] 
(22, 36] 
(36, 50] 
Use nominal visit 
Coagulation 
Day 1 (Baseline)  
Day 15 
Day 29 
Safety Follow-up 
1 
15 
29 
57 
≤1 Pre-dose 
[1, 22] 
(22, 43] 
Use nominal visit 
Standard 12-Lead ECG 
Day 1 (Baseline; before dosing) 
Day 1 (4 hours after dosing)  
Day 8 
Day 15 (before dosing and 4 
hours after dosing) 
Day 29 
Day 43 
Safety Follow-up 
1 
1 
8 
15 
 
29 
43 
57 
Use nominal visit for all 
visits 
Safety Assessment (Part 1, Cohort 1B) 
Serum Chemistry 
Hematology 
Urinalysis 
Vital Signs (including 
Weight) 
Day 1 (Baseline)  
Day 15 
Day 29 
Day 43 
Safety Follow-up 
1 
15 
29 
43 
57 
≤1 Pre-dose 
[1,22] 
(22, 36] 
(36, 50] 
Use nominal visit 
Coagulation 
Day 1 (Baseline)  
Day 15 
Day 29 
Safety Follow-up 
1 
15 
29 
57 
≤1 Pre-dose 
[1,22] 
(22, 43] 
Use nominal visit 
Standard 12-Lead ECG 
Day 1 (Baseline; before dosing) 
Day 1 (4 hours after dosing)  
Day 15 (before dosing and 4 
hours after dosing) 
Day 29 
Day 43 
Safety Follow-up 
1 
1 
15 
 
29 
43 
57 
Use nominal visit for all 
visits 
Safety Assessment (Part 2) 
                                                 
a  Visit name is used to report data in tables, listings and figures. 
 
b  Target day time point per protocol is predose, except for ECG measurements. 


Statistical Analysis Plan (Methods) 
Page 57 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-5 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
Serum Chemistry 
Hematology 
Urinalysis 
Vital Signs (including 
Weight) 
Day 1 (Baseline)  
Day 15 
Day 29 
Day 43 
Day 57 
Safety Follow-up 
1 
15 
29 
43 
57 
85 
≤1 Pre-dose 
[1,22] 
(22, 36] 
(36, 50] 
(50, 71] 
Use nominal visit 
Coagulation 
 
Day 1 (Baseline)  
Day 15 
Day 29 
Safety Follow-up 
1 
15 
29 
85 
≤1 Pre-dose 
[1,22] 
(22, 57] 
Use nominal visit 
Standard 12-Lead ECG  
Day 1 (Baseline; before dosing) 
Day 1 (4 hours after dosing)  
Day 15 (before dosing and 4 
hours after dosing) 
Day 29 
Day 43 
Day 57 
Safety Follow-up 
1 
1 
15 
 
29 
43 
57 
85 
Use nominal visit for all 
visits 
Efficacy Assessment (Part 1, Cohort 1A) 


Statistical Analysis Plan (Methods) 
Page 58 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-5 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
Spirometry  
Sweat Chloride 
Day 1 (Baseline)  
Day 1 (5 hours after dosing for 
Spirometry) 
Day 8 
Day 15  
 
Day 29 
Day 43 
Safety Follow-up 
1 
1 
 
8 
15 
 
29 
43 
57 
≤1 Pre-dose 
1 Post-dose for Spirometry 
 
(1, 12] 
(12,22] (Pre and Post for 
Spirometry) 
(22, 36] 
(36, 50] 
Use nominal visit 
CFQ-R 
Day 1 (Baseline)  
Day 15 
Day 29 
Day 43 
Safety Follow-up 
1 
15 
29 
43 
57 
≤1 
(1,22] 
(22, 36] 
(36, 50] 
Use nominal visit 
Efficacy Assessment (Part 1, Cohort 1B) 
Spirometry  
Sweat Chloride 
CFQ-R 
Day 1 (Baseline)  
Day 1 (5 hours after dosing for 
Spirometry) 
Day 15 
 
Day 29 
Day 43 
Safety Follow-up 
1 
1 
 
15 
 
29 
43 
57 
≤1 
1 
 
(1,22] (Pre and Post for 
Spirometry) 
(22, 36] 
(36, 50] 
Use nominal visit 
Efficacy Assessment (Part 2) 
Spirometry  
Sweat Chloride 
CFQ-R 
Day 1 (Baseline) 
Day 1 (5 hours after dosing for 
Spirometry)   
Day 15 
 
Day 29 
Day 43 
Day 57 
Safety Follow-up 
1 
1 
 
15 
 
29 
43 
57 
85 
≤1 
1 
 
(1,22] (Pre and Post for 
Spirometry) 
(22, 36] 
(36, 50] 
(50, 71] 
Use nominal visit 
aVisit name is used to report data in tables, listings and figures.  
bTarget day time point is predose. 


Statistical Analysis Plan (Methods) 
Page 59 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-5 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
 
Notes:  
The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
1. If no numerical measurement is available within a visit window, the measurement will be considered 
missing for the visit. 
2. If there is more than 1 numerical measurement available within the same visit window, use the 
following rules:  
a. 
For efficacy parameters: if there are multiple measurements within a visit window, the 
measurement at the scheduled visit will be used. Otherwise, 
i. If there are no measurements at the scheduled visit, then the measurement closest to the target 
day will be used; or 
ii. If there are multiple measurements with the same distance to the target day, the latest 
measurement will be used.   
b. For safety parameters: if there are multiple measurements within a visit window,   
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements within the same distance from the target day, the latest 
measurement will be used. 
iii. For tables of the extreme lab measurement based on ULN or LLN, convert the lab 
measurements into times of ULN or LLN first, and then select the extreme measurement. 
 
Derived Variables 
1. Age (in years) at first dose date  
Obtain age at screening (in days) in yy mm format (e.g., 24 years, 6 months) from screening vital signs page, 
and add 0.5 month to convert to days. 
Obtain screening date from Date of Visit (DOV) page. 
Then age (in years) at first dose date = integer part of {[(first dose date-screening date) in days + age at 
screening (in days)]/365.25}. 
Correspondingly, age (in months) at first dose date = integer part of 12*{[(first dose date-screening date) in 
days + age at screening (in days)]/365.25}. 
2. Age (in years) at post-baseline visit (for use in calculation of percent predicted spirometry variables) 
Age (in years) at post-baseline visit = integer part of {[(post-baseline visit date – screening date) in days + age 
at screening (in days)]/365.25} 
3. Missing First Dose Date or Last Dose Date 
If the first dose date is missing, use Day 1 visit date. 
If the last dose date is missing at final analysis, use maximum of Early Treatment Termination (ETT) visit date 
and last study drug administration date from EX SDTM domain (excluding PK dosing dates). When a subject is 
lost to follow up without ETT, impute the last dose date as the last on-treatment visit date. 
 
 


Statistical Analysis Plan (Methods) 
Page 60 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month.  
b. If DAY and Month are both missing, use the first day of the year.  
c. If DAY, Month and Year are all missing, use a date before the first dose date 
(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. 
Table 11-6 
Prior, Concomitant, and Post Categorization of a Medication in Parts 1 and  4 
Medication Start Date 
Medication Stop Date 
< First Dose Date of Study 
Drug 
≥ First Dose Date and ≤ 
End Date of TE Period 
> End Date of TE Period 
< First dose date of study drug 
P 
PC 
PCA 
≥ First dose date and  
≤ End date of TE period 
- 
C 
CA 
> End date of TE period 
- 
- 
A 
P: Prior; C: Concomitant; A: Post 
Table 11-7 
Prior, Concomitant, and Post Categorization of a Medication in Part 2 
Medication Start Date 
 
Medication Stop Date 
< First Dose 
Date of Run-in 
TE Period 
≥ First Dose Date and ≤ 
End Date of Run-in TE 
Period  
≥ First Dose Date and ≤ End 
Date of Treatment TE Period  
> End Date of 
Treatment TE 
Period  
< First dose date of Run-in 
TE period  
P 
PC1 
PC1C2 
PC1C2A 
≥ First dose date and  
≤ End date of Run-in  TE 
Period 
- 
C1 
C1C2 
C1C2A 
≥ First dose date and  
≤ End date of Treatment TE 
Period 
- 
- 
C2 
C2A 
> End date of Treatment TE 
Period 
- 
- 
- 
A 
P: Prior; C1: Concomitant during the Run-in Period; C2: Concomitant during the Treatment Period; A: Post 
 
 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX15-440-101 Version 2.0 
 
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Appendix D: Important Protocol Deviation Programming Rules (Based on the 
Clinical Database) 
Important protocol deviations before first dose 
1. Inclusion criteria: 
a) I1: Subject (or subject’s legally appointed and authorized representative) will sign 
and date an informed consent form (ICF), and, when appropriate, an assent form. 
b) I3: Subjects will be aged 18 years or older for Parts 1 and 2, 
 
 on the date of informed consent and, when appropriate, date of 
assent. 
c) I4: Body weight ≥35 kg. 
d) I6: Subjects must have an eligible CFTR genotype as noted below. If the screening 
CFTR genotype result is not received before randomization (Parts 1 
) or before 
Day -28 (Part 2), a previous CFTR genotype laboratory report may be used to 
establish eligibility. Note: Subjects who have been randomized and whose screening 
genotype does not confirm study eligibility must be discontinued from the 
study (Section 9.5). 
e) I7: Part 1 
 Heterozygous for F508del with a second CFTR allele carrying 
an MF mutation that is not likely to respond to TEZ and/or IVA therapy 
(Appendix A) 
Part 2: Homozygous for F508del 
Parts 1, 2, 
 subjects must have an FEV1 ≥40% and ≤90% of predicted normal 
for age, sex, and height (equations of the Global Lung Function Initiative [GLI])13 at 
the Screening Visit. Spirometry measurements must meet American Thoracic 
Society/European Respiratory Society criteria10 for acceptability and repeatability. 
2. Exclusion criteria: 
a) E4: History of hemolysis. 
b) E5: G6PD deficiency, defined as G6PD activity less than the lower limit of normal 
(LLN) or 70% of the mean of the LLN and the ULN, whichever is greater. 
c) E6: Any of the following abnormal laboratory values at screening: 
• Hemoglobin <10 g/dL 
• Total bilirubin ≥2 × ULN 
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-
glutamyl transpeptidase (GGT), or alkaline phosphatase (ALP) ≥3 × ULN 
• Abnormal renal function defined as glomerular filtration rate 
≤50 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease 
Study Equation)14, 15 for subjects ≥18 years of age and ≤45 mL/min/1.73 m2 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
(calculated by the Counahan-Barratt equation)16 for subjects aged 12 to 17 
years (inclusive) 
d) E10: A standard digital ECG demonstrating QTc >450 msec at screening. If QTc 
exceeds 450 msec for the screening ECG, the ECG should be repeated 2 more times 
during the Screening Period, and the subject will be excluded if the average of the 
3 QTc values is >450 msec. 
e) E11: History of solid organ or hematological transplantation. 
f) E16: Use of restricted medications as defined in the clinical study protocol, within the 
specified window before the first dose of study drug (Day 1 in Parts 1
, Day -28 
in Part 2). 
g) E17: Pregnant or nursing females: Females of childbearing potential must have a 
negative pregnancy test at screening and Day 1. 
3. Stratification error based on comparing the IWRS stratification with the clinical database:  
• Age at Screening Visit (<18, ≥18 years) from IWRS versus age at screening visit 
in the clinical database 
• % predicted FEV1 at Stratification (<70 , ≥70) from IWRS versus ppFEV1 at the 
screening visit or Day -14 (Part 2) of the Run-in Period from the clinical database 
Important protocol deviations during the Treatment Period 
1. Compliance < 80% based on the number of tablets taken 
2. Use of prohibited medications 
3. Actual treatment received is different from the randomized treatment  
 
 


Statistical Analysis Plan (Methods) 
Page 63 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Appendix E: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, 
 
 using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Quanjer GLI-2012 Regression Equations and Lookup Tables. Philip H. Quanjer, Sanja 
Stanojevic, Tim J. Cole, Janet Stocks. Version 7 April 2013. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/quanjer-gli-
2012-regression-equations-and-lookup-tables.aspx.  
Accessed March 13, 2017.  
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Implementing GLI-2012 regression equations. Philip H. Quanjer, Sanja Stanojevic, Tim J. 
Cole, Janet Stocks. Version 19 July 2015. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/gli-2012-
explained.aspx. 
Accessed March 13, 2017 .   
GLI-2012 - SAS Macro. Sanja Stanojevic. Version 2, 7 April 2013. Available at:  
http://www.ers-education.org/guidelines/global-lung-function-initiative/tools/sas-macro.aspx 
Accessed March 13, 2017. 
 
 






Statistical Analysis Plan (Methods) 
Page 66 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
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Appendix G: Calculation of BMI z-score for subjects <20 years old at screening 
BMI will be calculated from weight and height at baseline and post-baseline time points (Day 
15, Week 4, 8, and 12), as applicable for Parts 1, 2 
 
BMI, adjusted for age and sex, will be referred to as BMI-for-age z-score (BMI z-score). 
BMI z-score will be calculated by using Centers for Disease Control and Prevention (CDC) 
growth charts. The BMI z-score will be calculated as follows: 










=






≠
−






=
0
,
ln
0
,
1
L
S
M
X
L
LS
M
X
z
L
 
where X is the derived BMI value in kg/m2 based on the raw weight and raw height and L, M, 
and S are selected from the CDC BMI-for-age chart by subject sex and age. The BMIAGE 
file contains these parameters by sex (1=male, 2=female) and age; it is available at:  
http://www.cdc.gov/growthcharts/percentile_data_files.htm.  
Additionally, SAS code for calculating percentiles and z-scores is available at:    
http://www.cdc.gov/growthcharts/computer_programs.htm. 
NOTE: The CDC BMI-for-age charts are designed for use in pediatric populations (2 to 20 
years of age); in this analysis plan, BMI z-score will be calculated only for subjects between 
2 and <20 years. 


Statistical Analysis Plan (Methods) 
Page 67 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Appendix H: Imputation Rules for Missing AE dates  
H.1 Parts 1
 
Imputation rules for missing or partial AE start date for Parts 1 
 are defined below. 
• If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the 
Treatment Period or AE end date is missing, then  
 if AE start year and month are equal to the month and year of first dose 
date of the Treatment Period, then impute the AE start day as the day of 
first dose date of the Treatment Period;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the 
Treatment Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment 
Period, then impute the AE start month and day as the month and day of 
first dose date of the Treatment Period;  
 else impute the AE start month as January and day as 1.  
o else impute the AE start month as January and day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site 
with no imputation.  
o If the full (or partial) AE end date is NOT before the first dose date of the 
Treatment Period or AE end date is missing, then the AE will be considered as 
TEAE for the Treatment Period.  
o else the AE will be considered as a pretreatment AE. 
 
H.2 Part 2 
Imputation rules for missing or partial AE start date for Part 2 are defined below. 
• If only Day of AE start date is missing: 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
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 if AE start year and month are equal to the month and year of first 
dose date of the Run-in Period, then impute the AE start day as the day of 
first dose date of the Run-in Period;  
 else impute the AE start day as 1.  
o else if the full (or partial) AE end date is NOT before the first dose date of the 
Run-in Period, then impute the AE start day as the day of first dose date of the 
Run-in Period;  
 if AE start year and month are equal to the month and year of first dose 
date of the Run-in Period, then impute the AE start day as the day of first 
dose date of the Run-in Period;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the 
Treatment Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment 
Period, then impute the AE start month and day as the month and day of 
first dose date of the Treatment Period;  
 else if AE start year is equal to the year of first dose date of the Run-in 
Period, then impute the AE start month and day as the month and day of 
first dose date of the Run-in Period;  
 else impute the AE start month as January and day as 1.  
o else if the full (or partial) AE end date is NOT before the first dose date of the 
Run-in Period, then impute the AE start day as the day of first dose date of the 
Run-in Period;  
 if AE start year is equal to the year of first dose date of the Run-in Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Run-in 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.  


Statistical Analysis Plan (Methods) 
Page 69 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site 
with no imputation.  
o If the full (or partial) AE end date is NOT before the first dose date of the 
Treatment Period or AE end date is missing, then the AE will be considered as 
TEAE for the Treatment Period.  
o else if the full (or partial) AE end date is NOT before the first dose date of the 
Run-in Period, then the AE will be considered as TEAE for the Run-in Period. 
o else the AE will be considered as a pretreatment AE. 
 
Imputation rules for partial AE end date are defined below:  
If partial end date, then impute as min (the last day of the month, end of study) if day is 
missing, or min (Dec, end of study) if month is missing. 
 
 


Statistical Analysis Plan (Methods) 
Page 70 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Appendix I: Criteria for Threshold Analysis 
Table 11-10 Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤  3xULN) or (AST>ULN - ≤  
3xULN) 
(ALT>3x - ≤  5xULN) or  (AST>3x - ≤  
5xULN) 
(ALT>5x- ≤  8xULN) or  (AST>5x - ≤    
8xULN) 
(ALT>8x - ≤  20xULN) or (AST>8x - ≤ 
20xULN) 
ALT>20xULN or AST> 20 xULN 
FDA DILI Guidance 
Alkaline 
Phosphatase 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5 xULN 
>2.5 – ≤ 5.0 x ULN 
>5.0 – ≤ 20.0 x ULN 
>20.0 x ULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total 
Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
AST and Total 
Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and 
Total Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 


Statistical Analysis Plan (Methods) 
Page 71 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-10 Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
GGT 
>ULN - ≤ 2.5xULN 
>2.5 –  ≤ 5.0xULN 
>5.0 –  ≤ 20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>1x -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤ 1.5xULN 
>1.5 - ≤ 3.0xULN 
>3.0 - ≤ 6.0xULN 
>6.0xULN 
CTCAE grades 1-4 
Lipase 
>ULN -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L  
< 80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L  
<50.0 – ≥ 25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 
Reticulocytes 
 
<LLN 
>ULN 
No CTCAE 
 


Statistical Analysis Plan (Methods) 
Page 72 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-11 Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
 
Per HV grade 2, 3, plus shift change 
 
 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
QTc 
Borderline 
Prolonged* 
Additional 
 
 
>450 ms (Male) and <500ms; >470 ms and 
<500ms (Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
 
To be applied to any kind of QT correction 
formula.  
 
 
 
 
Note: Based on CPMP 1997 guideline. 
 


Statistical Analysis Plan (Methods) 
Page 73 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-12 Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
HR 
Same as above in ECG category 
 
 
SBP increased 
 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from 
baseline 
>140 mmHg & >20 mmHg increase from 
baseline 
>160 mmHg & >10 mmHg increase from 
baseline 
>160 mmHg & >20 mmHg increase from 
baseline 
 
809/770 analyses 
SBP decrease 
 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from 
baseline 
<90 mmHg and >20 mmHg decrease from 
baseline 
<80 mmHg and >10 mmHg decrease from 
baseline 
<80 mmHg and >20 mmHg decrease from 
baseline 
 
Per HV grade 1, 3, plus shift change 


Statistical Analysis Plan (Methods) 
Page 74 of 85 
Protocol Number: VX15-440-101 Version 2.0 
 
Vertex Pharmaceuticals Incorporated 
Table 11-12 Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
DBP increased 
 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from 
baseline 
>90 mmHg and >10 mmHg increase from 
baseline 
>100 mmHg and >5 mmHg increase from 
baseline 
>100 mmHg and >10 mmHg increase from 
baseline 
 
 
DBP decreased 
 
 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from 
baseline 
<60 mmHg and >10 mmHg decrease from 
baseline 
<45 mmHg and >5 mmHg decrease from 
baseline 
<45 mmHg and >10 mmHg decrease from 
baseline 
 
 
 
 
Weight   
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
 
CTCAE grade 1-3 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
 
CTCAE grade 1-3