Clinical trial NCT02951195
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2016-11-01; Completion date: 2018-01-01
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, randomized, double blind, placebo and active-controlled, parallel group, multicenter study designed to evaluate the safety and tolerability of VX-152 in Triple Combination (TC) with tezacaftor (TEZ; VX-661) and ivacaftor (IVA; VX-770) in subjects with cystic fibrosis (CF) 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), or who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F508del/F508del).

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None
Interventions: intervention 1: VX-152 intervention 2: TEZ/IVA intervention 3: IVA intervention 4: Placebo intervention 5: Placebo
Intervention descriptions: intervention 1: Tablet for oral administration. intervention 2: Fixed-dose combination tablet for oral administration. intervention 3: Tablet for oral administration. intervention 4: Placebo matched to VX-152. intervention 5: Placebo matched to VX-152/TEZ/IVA triple combination (TC).

Protocol documents:
Prot_000.pdf: 




Protocol VX16-152-102, Version 3.0 
Page 3 of 81 
Vertex Pharmaceuticals Incorporated 
 
2 
PROTOCOL SYNOPSIS 
Title 
A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety of 
VX-152 Combination Therapy in Adults With Cystic Fibrosis 
Brief Title 
A Study Evaluating the Safety of VX-152 Combination Therapy in Adults With Cystic 
Fibrosis 
 
 
Clinical Phase 
and Clinical 
Study Type  
Phase 2 safety 
 
 
Objectives 
Primary Objectives 
 To evaluate the safety and tolerability of VX-152 in triple combination (TC) with 
VX-661 and ivacaftor (IVA) in adults with cystic fibrosis (CF) 
Secondary Objectives 
 To evaluate the pharmacodynamic (PD) effect of VX-152 in TC with VX-661 and IVA 
on CFTR function 
 To evaluate the efficacy of VX-152 in TC with VX-661 and IVA 
 To evaluate the pharmacokinetics (PK) of VX-152 when administered in TC with 
VX-661 and IVA 
 To evaluate the PK of VX-661, IVA, and their respective metabolites when 
administered with VX-152 
 
 
Endpoints 
Primary Endpoints 
 Safety and tolerability assessments based on adverse events (AEs), clinical laboratory 
values, standard 12-lead electrocardiograms (ECGs), vital signs, and pulse oximetry 
Secondary Endpoints 
 Absolute change in sweat chloride concentrations from baseline at Day 15 (Parts 1 
and 2) and through Day 29 (Part 2, Cohort 2B only) 
 Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
from baseline at Day 15 (Parts 1 and 2) and through Day 29 (Part 2, Cohort 2B only)  
 Relative change in ppFEV1 from baseline at Day 15 (Parts 1 and 2) and through Day 29 
(Part 2, Cohort 2B only) 
 Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain 
score from baseline at Day 15 (Parts 1 and 2) and at Day 29 (Part 2, Cohort 2B only) 
 PK parameters of VX-152, VX-661, M1-661, IVA, and M1-IVA 
 
 
 
 
 
Number of 
Subjects 
Up to approximately 72 subjects will be randomized: up to approximately 36 subjects in 
each of Part 1 and Part 2 
 
 
Study 
Population 
Male and female subjects with CF, 18 years of age or older 
Part 1: F508del/minimal function (MF) genotype 
Part 2: F508del/F508del genotype 
 
 


Protocol VX16-152-102, Version 3.0 
Page 4 of 81 
Vertex Pharmaceuticals Incorporated 
 
Investigational 
Drug 
Active substance: VX-152 
Activity: CF transmembrane conductance regulatory (CFTR) corrector (increased 
chloride ion [Cl−] secretion) 
Strength and route of administration: 100-mg tablet for oral administration 
 
 
 
Active substance: VX-661 and IVA 
 
Activity: CFTR corrector and potentiator (increased Cl− secretion) 
 
Strength and route of administration: 100-mg VX-661/150-mg IVA fixed-dose 
combination (light yellow) film-coated tablet for oral administration 
 
 
 
Active substance: IVA 
 
Activity: CFTR potentiator (increased Cl− secretion) 
 
Strength and route of administration: 150-mg IVA (light blue) film-coated tablet for 
oral administration 
 
 
 
Active substance: not applicable 
 
Activity: VX-152-matching placebo, VX-661/IVA-matching placebo, IVA-matching 
placebo 
 
Strength and route of administration: 0-mg film-coated matching placebo tablets for 
oral administration 
 
 
Study Duration 
Part 1 
The total study duration is approximately 10 weeks. Subjects will receive study drug for 
approximately 2 weeks. 
Part 2  
The total study duration is approximately 16 weeks for subjects in Cohort 2A and 
18 weeks for subjects in Cohort 2B.  
Study drug will be administered for approximately 8 weeks in Cohort 2A and 
approximately 10 weeks in Cohort 2B. 
 
 
Study Design 
This is a Phase 2, 2-part (Parts 1 and 2), randomized, double-blind, placebo- and 
VX-661/IVA-controlled, parallel-group, multicenter study designed to evaluate the safety 
of VX-152 in TC with VX-661 and IVA.  
Parts 1 and 2 will enroll multiple cohorts, with each cohort evaluating 1 dose level of 
VX-152 as part of TC with VX-661/IVA (100 mg daily [qd]/150 mg every 12 hours 
[q12h]). Each cohort will enroll up to approximately 12 subjects in Part 1 and Part 2 
Cohort 2A and up to approximately 24 subjects in Part 2 Cohort 2B. Subjects in all 
cohorts will be randomized 3:1 (active TC:comparator). Triple placebo will be the 
comparator in Part 1, and VX-661/IVA will be the comparator in Part 2. 
Up to 3 cohorts are planned for Part 1 (Cohorts 1A, 1B, and 1C). Up to 2 cohorts are 
planned for Part 2 (Cohorts 2A and 2B). The doses of VX-152 planned for evaluation are 
100 mg q12h in Cohort 1A, 200 mg q12h in Cohorts 1B and 2A, and 300 mg q12h in 
Cohorts 1C and 2B. The dose of VX-152 may be adjusted to be lower or the same as the 
dose level evaluated in the previous cohort. 
The actual number of cohorts enrolled in each part may be modified based on emerging 
safety and PK data. Blinded reviews of safety and available PK data will be conducted by 
the Vertex study team and lead investigator(s) on an ongoing basis. 
 
 


Protocol VX16-152-102, Version 3.0 
Page 5 of 81 
Vertex Pharmaceuticals Incorporated 
 
Cohorts will initiate dosing as follows: 
 Cohort 1A will initiate dosing first.  
 Cohorts 1B and 2A may initiate dosing if supported by blinded review of safety and 
available PK data after all subjects in Cohort 1A complete the Day 15 Visit. 
 Cohorts 1C and 2B may initiate dosing if supported by blinded review of safety and 
available PK data after any of the following has occurred: 
o 
All subjects in Cohort 1B complete the Day 15 Visit. 
o 
All subjects in Cohort 2A complete the Day 15 Visit. 
o 
At least 12 subjects across Cohorts 1B and 2A complete the Day 15 Visit. 
A schematic of the study design is shown below. 
 
 
 


Protocol VX16-152-102, Version 3.0 
Page 6 of 81 
Vertex Pharmaceuticals Incorporated 
 
Assessments 
Safety: AEs, clinical laboratory assessments, ECGs, vital signs, pulse oximetry, physical 
examinations (PEs), and ophthalmologic examinations 
PD: sweat chloride 
Efficacy: spirometry, CFQ-R 
PK: Plasma concentrations of VX-152, VX-661, M1-661, IVA, M1-IVA 
 
 
 
Statistical 
Analyses 
Primary Objective:  
The primary objective of the study is the evaluation of safety and tolerability of VX-152 in 
TC with VX-661/IVA. 
The safety endpoints include AEs, clinical laboratory values, 12-lead ECGs, vital signs, 
and pulse oximetry through the Safety Follow-up Visit. The safety analysis for all 
treatment groups in both parts will be descriptive only. 
Secondary Objectives: 
The secondary objectives of the study include the evaluation of the PD effect of VX-152 
in TC with VX-661/IVA, and the evaluation of the efficacy of VX-152 in TC with 
VX-661/IVA.  
The PD endpoint is the absolute change in sweat chloride from baseline at Day 15 of a 
non-decreasing dose-response trend in the mean absolute change from baseline at Day 15 
for sweat chloride, between placebo and the TC dose groups will be tested using a 
multiple comparisons procedure based on the 1-sided maximum t-statistic. In both parts, 
the null within-group hypothesis of no decrease in the mean absolute change from baseline 
at Day 15, for sweat chloride in the TC treatment groups, will be tested using a 1-sided 
1-sample t-test within the mixed-effects model for repeated measures (MMRM) 
framework at a 5% alpha level, with baseline value as a covariate. The adjusted means and 
2-sided 95% confidence intervals of the treatment effect at Day 15, for all within-group 
and between-group comparisons will be estimated within MMRM. 
The efficacy endpoint is the absolute change from baseline at Day 15 for ppFEV1. In both 
parts, the null within-group hypothesis of no increase in the mean absolute from baseline 
at Day 15, for ppFEV1 in the TC treatment groups, will be tested using a 1-sided 1-sample 
t-test within MMRM at a 5% alpha level. The adjusted means and 2-sided 95% confidence 
intervals of the treatment effect at Day 15, for all within-group and between-group 
comparisons will be estimated within MMRM. 
 
 
Interim 
Analyses 
Interim analyses for each cohort may be performed after all subjects in the cohort have 
completed the Day 15 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 VX16-152-102, Version 3.0 
Page 7 of 81 
Vertex Pharmaceuticals Incorporated 
 
3 
SCHEDULE OF ASSESSMENTS 
The schedule of assessments from the Screening Period through the Safety Follow-up Visit is 
provided in Table 3-1 for Part 1, and Table 3-2 and Table 3-3 for Part 2. 
All visits will be scheduled relative to the Day 1 Visit (first dose of VX-152 or placebo). 
Assessments will be performed in the order presented, unless specified otherwise.


Protocol VX16-152-102, Version 3.0 
Page 8 of 81 
Vertex Pharmaceuticals Incorporated 
 
Table 3-1 
Study VX16-152-102: Schedule of Assessments for Part 1 
Event/Assessmenta 
Screening 
Treatment Periodb 
 
ETT 
Visitc 
Safety 
Follow-up 
28 ( 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Days 3 and 5e 
(or Days 4/6 
or Days 3/6)f 
Day 8 
( 1 day) 
Day 11e 
( 1 day) 
Day 15 
( 1 day) 
Informed consent 
X 
 
 
 
 
 
 
 
Randomizationg 
 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Ophthalmological history 
X 
 
 
 
 
 
 
 
CFQ-Rh,i 
 
X 
 
 
 
X 
Xj  
X 
Weightk 
X 
X 
 
X 
 
X 
X 
X 
Heightk 
X 
 
 
 
 
 
 
 
Vital signsl 
X 
X 
 
X 
 
X 
X 
X 
 
a  
Assessments will be performed in the order presented, unless noted otherwise. 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., premature 
discontinuation of 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 before randomization, unless noted otherwise. 
e  
Days 3, 5, and 11 assessments may be collected at the clinic, at a local laboratory, or during a visit by a qualified individual (e.g., home nurse). 
f  
Day 3 and Day 5 assessments will be performed at least 2 days apart, with the first day of assessments occurring no earlier than Day 3 and the second day of 
assessments occurring no later than Day 6. (i.e., Assessments will be performed on Days 3 and 5, Days 4 and 6, or Days 3 and 6.) 
g  
Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria 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. 


Protocol VX16-152-102, Version 3.0 
Page 9 of 81 
Vertex Pharmaceuticals Incorporated 
 
Table 3-1 
Study VX16-152-102: Schedule of Assessments for Part 1 
Event/Assessmenta 
Screening 
Treatment Periodb 
 
ETT 
Visitc 
Safety 
Follow-up 
28 ( 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Days 3 and 5e 
(or Days 4/6 
or Days 3/6)f 
Day 8 
( 1 day) 
Day 11e 
( 1 day) 
Day 15 
( 1 day) 
Pulse oximetryl 
X 
X 
 
X 
 
X 
X 
X 
Physical examinationm 
Complete 
Abbreviated 
 
Abbreviated 
 
Abbreviated 
Abbreviated 
Complete 
Ophthalmologic 
examinationn 
X 
 
 
 
 
 
 
 
Standard 12-lead ECGo 
X 
X 
 
X 
 
X 
X 
X 
Sweat chloridei,p 
X 
X 
 
X 
 
X 
X 
X 
Spirometryq 
X 
X 
 
X 
 
X 
X 
X 
Urinalysisi 
X 
X 
 
X 
 
X 
X 
X 
Pregnancy test (all 
females of childbearing 
potential) 
Serum 
Urine 
 
 
 
 
Serum  
Serum 
CFTR genotyper 
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. 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. ECGs will be collected before procedures that may 
affect heart rate (e.g., blood sampling). 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.  


Protocol VX16-152-102, Version 3.0 
Page 10 of 81 
Vertex Pharmaceuticals Incorporated 
 
Table 3-1 
Study VX16-152-102: Schedule of Assessments for Part 1 
Event/Assessmenta 
Screening 
Treatment Periodb 
 
ETT 
Visitc 
Safety 
Follow-up 
28 ( 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Days 3 and 5e 
(or Days 4/6 
or Days 3/6)f 
Day 8 
( 1 day) 
Day 11e 
( 1 day) 
Day 15 
( 1 day) 
FSHs 
X 
 
 
 
 
 
 
 
G6PD activity testt 
X 
 
 
 
 
 
 
 
Serum chemistry and 
hematologyi 
X 
X 
Xe,v 
X 
Xe,v 
X 
X 
X 
Coagulationi 
X 
X 
 
X 
 
X 
 
X 
PK samplingw 
 
X 
 
X 
 
X 
X 
  
Study drug dosingx 
 
Day 1 through Day 15 
 
 
AEs, medicationsy, 
treatments, and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
 
 
r  
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. 
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  
On Days 3, 5, and 11, the following parameters will be measured: lactate dehydrogenase, total and direct bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, and gamma glutamyl transferase. 
w  
Blood samples will be collected for PK analysis of VX-152, VX-661, M1-661, 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 8, a predose sample will be collected before the morning dose of 
study drug (0 hours). On Day 15, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 8 hours after dosing. At the ETT Visits, a single 
blood sample for PK analysis will be collected. 
x  
The last dose of study drug will be the morning dose on Day 15. 
y  
Refer to Section 9.4 for details. 


Protocol VX16-152-102, Version 3.0 
Page 11 of 81 
Vertex Pharmaceuticals Incorporated 
 
Table 3-2 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2A 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
( 1 day) 
Day 29 
( 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Randomizationi 
 
 
 
X 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Ophthalmological 
history 
X 
 
 
 
 
 
 
 
 
 
 
CFQ-Rj,k 
 
 
 
X 
 
X 
 
X 
X 
Xl  
X 
Weightm 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
a  
Assessments will be performed in the order presented, unless noted otherwise. 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., premature 
discontinuation of 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  
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 before the subject receives VX-661/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 VX-661/IVA treatment. 
g  
Days 3, 5, and 11 assessments may be collected at the clinic, at a local laboratory, or during a visit by a qualified individual (e.g., home nurse). 
h  
Day 3 and Day 5 assessments will be performed at least 2 days apart, with the first day of assessments occurring no earlier than Day 3 and the second day of 
assessments occurring no later than Day 6. (i.e., Assessments will be performed on Days 3 and 5, Days 4 and 6, or Days 3 and 6.) 
i  
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. 
j  
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
k  
The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred. 
l  
Subjects will complete the CFQ-R at the ETT Visit only if it has been 2 weeks or more since their last visit. 


Protocol VX16-152-102, Version 3.0 
Page 12 of 81 
Vertex Pharmaceuticals Incorporated 
 
Table 3-2 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2A 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
( 1 day) 
Day 29 
( 3 days) 
Heightm 
X 
 
 
 
 
 
 
 
 
 
 
Vital signsn 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pulse oximetryn 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Physical 
examinationo 
Complete 
Abbrev-
iated 
 
Abbreviated 
 
Abbreviated 
 
Abbreviated Abbreviated Abbreviated Complete 
Ophthalmologic 
examinationp 
X 
 
 
 
 
 
 
 
 
 
 
Standard 12-lead 
ECGq 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Sweat chloridek,r 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Spirometrys 
X 
  
X 
X 
 
X 
 
X 
X 
X 
X 
Urinalysisk 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
m  
Weight and height will be measured with shoes off. 
n  
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 
o  
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. 
p  
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. 
q  
All standard 12-lead ECGs will be performed after the subject has been seated for at least 5 minutes. ECGs will be collected before procedures that may 
affect heart rate (e.g., blood sampling). 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.  
r  
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.  
s  
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.  


Protocol VX16-152-102, Version 3.0 
Page 13 of 81 
Vertex Pharmaceuticals Incorporated 
 
Table 3-2 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2A 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
( 1 day) 
Day 29 
( 3 days) 
Pregnancy test (all 
females of 
childbearing 
potential) 
Serum 
Urine 
 
Urine 
 
 
 
Urine 
 
Serum  
Serum 
CFTR genotypet 
X 
 
 
 
 
 
 
 
 
 
 
FSHu 
X 
 
 
 
 
 
 
 
 
 
 
G6PD activity testv 
X 
 
 
 
 
 
 
 
 
 
 
Serum chemistry 
and hematologyk 
X 
X 
 
X 
Xg,x 
X 
Xg,x 
X 
X 
X 
X 
Coagulationk 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
PK samplingy 
 
 
 
X 
 
X 
 
X 
 
Xy 
  
VX-661/IVA 
dosingz 
 
Day -28 through Day 29 
 
 
 
t  
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. 
u  
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
v  
A single blood sample will be collected for the G6PD activity test. 
  
 
x  
On Days 3, 5, and 11, the following parameters will be measured: lactate dehydrogenase, total and direct bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, and gamma glutamyl transferase. 
y 
Blood samples will be collected for PK analysis of VX-152, VX-661, M1-661, 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 8, a predose sample will be collected before the morning dose of study 
drug (0 hours). On Day 15, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 8 hours after dosing. At ETT Visits, a single blood sample 
for PK analysis will only be collected from subjects who discontinued study drug after Day 1, but before Day 15 PK was collected. 
z  
The last dose of VX-661/IVA will be the morning dose on Day 29. 


Protocol VX16-152-102, Version 3.0 
Page 14 of 81 
Vertex Pharmaceuticals Incorporated 
 
Table 3-2 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2A 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
( 1 day) 
Day 29 
( 3 days) 
VX-152 or placebo 
dosingaa 
 
 
 
Day 1 through Day 15 
 
 
 
AEs, medicationsbb, 
treatments and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
 
aa  The last dose of VX-152 or placebo will be the morning dose on Day 15. 
bb  Refer to Section 9.4 for details. 


Protocol VX16-152-102, Version 3.0 
Page 15 of 81 
Vertex Pharmaceuticals Incorporated 
 
Table 3-3 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2B 
Event/Assessment
a 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
and 
Day 29 
( 1 day) 
Day 43 
( 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Randomizationi 
 
 
 
X 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Ophthalmological 
history 
X 
 
 
 
 
 
 
 
 
 
 
CFQ-Rj,k 
 
 
 
X 
 
X 
 
X 
X 
Xl  
X 
 
a  
Assessments will be performed in the order presented, unless noted otherwise. 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., 
premature discontinuation of 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  
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 before the subject receives VX-661/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 VX-661/IVA treatment. 
g  
Days 3, 5, and 11 assessments may be collected at the clinic, at a local laboratory, or during a visit by a qualified individual (e.g., home nurse). 
h  
Day 3 and Day 5 assessments will be performed at least 2 days apart, with the first day of assessments occurring no earlier than Day 3 and the second 
day of assessments occurring no later than Day 6. (i.e., Assessments will be performed on Days 3 and 5, Days 4 and 6, or Days 3 and 6.) 
i  
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. 
j  
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
k  
The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred. 
l  
Subjects will complete the CFQ-R at the ETT Visit only if it has been 2 weeks or more since their last visit. 


Protocol VX16-152-102, Version 3.0 
Page 16 of 81 
Vertex Pharmaceuticals Incorporated 
 
Table 3-3 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2B 
Event/Assessment
a 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
and 
Day 29 
( 1 day) 
Day 43 
( 3 days) 
Weightm 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Heightm 
X 
 
 
 
 
 
 
 
 
 
 
Vital signsn 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pulse oximetryn 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Physical 
examinationo 
Complete 
Abbrev-
iated 
 
Abbrev-
iated 
 
Abbrev-
iated 
 
Abbrev-
iated 
Abbreviated Abbreviated Complete 
Ophthalmologic 
examinationp 
X 
 
 
 
 
 
 
 
 
 
 
Standard 12-lead 
ECGq 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Sweat chloridek,r 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Spirometrys 
X 
  
X 
X 
 
X 
 
X 
X 
X 
X 
 
m  
Weight and height will be measured with shoes off. 
n  
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 
o  
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. 
p  
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. 
q  
Standard 12-lead ECGs will be performed after the subject has been seated for at least 5 minutes. ECGs will be collected before procedures that may 
affect heart rate (e.g., blood sampling). On Days 1, 15, and 29, 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.  
r  
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.  


Protocol VX16-152-102, Version 3.0 
Page 17 of 81 
Vertex Pharmaceuticals Incorporated 
 
Table 3-3 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2B 
Event/Assessment
a 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
and 
Day 29 
( 1 day) 
Day 43 
( 3 days) 
Urinalysisk 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pregnancy test (all 
females of 
childbearing 
potential) 
Serum 
Urine 
 
Urine 
 
 
 
Urine 
 
Serum  
Serum 
CFTR genotypet 
X 
 
 
 
 
 
 
 
 
 
 
FSHu 
X 
 
 
 
 
 
 
 
 
 
 
G6PD activity testv 
X 
 
 
 
 
 
 
 
 
 
 
Serum chemistry 
and hematologyk 
X 
X 
 
X 
Xg,x 
X 
Xg,x 
X 
X 
X 
X 
Coagulationk 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
PK samplingy 
 
 
 
X 
 
X 
 
X 
 
Xy 
  
 
s  
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, 15, and 29, spirometry will be 
performed pre-bronchodilator 5 hours (± 1 hour) after study drug administration.  
t  
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. 
u  
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
v  
A single blood sample will be collected for the G6PD activity test. 
  
 
x  
On Days 3, 5, and 11, the following parameters will be measured: lactate dehydrogenase, total and direct bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, and gamma glutamyl transferase. 
y 
Blood samples will be collected for PK analysis of VX-152, VX-661, M1-661, 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 8, a predose sample will be collected before the morning dose of 
 


Protocol VX16-152-102, Version 3.0 
Page 18 of 81 
Vertex Pharmaceuticals Incorporated 
 
Table 3-3 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2B 
Event/Assessment
a 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
and 
Day 29 
( 1 day) 
Day 43 
( 3 days) 
VX-661/IVA 
dosingz 
 
Day -28 through Day 43 
 
 
VX-152 or placebo 
dosingaa 
 
 
 
Day 1 through Day 29 
 
 
 
AEs, 
medicationsbb, 
treatments and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
 
study drug (0 hours). 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 sample will 
be collected before the morning dose (0 hours). At ETT Visits, a single blood sample for PK analysis will only be collected from subjects who 
discontinued study drug after Day 1, but before Day 29. 
z  
The last dose of VX-661/IVA will be the morning dose on Day 43. 
aa  The last dose of VX-152 or placebo will be the morning dose on Day 29. 
bb  Refer to Section 9.4 for details. 


Protocol VX16-152-102, Version 3.0 
Page 19 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
4 
TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
 
2 
Protocol Synopsis ............................................................................................................. 3 
3 
Schedule of Assessments .................................................................................................. 7 
4 
Table of Contents ........................................................................................................... 19 
List of Tables ..................................................................................................................... 23 
List of Figures .................................................................................................................... 23 
List of Abbreviations ......................................................................................................... 24 
5 
Introduction .................................................................................................................... 26 
5.1 
Background ............................................................................................................... 26 
5.2 
Rationale for the Present Study ................................................................................ 27 
6 
Study Objectives ............................................................................................................ 28 
6.1 
Primary Objectives ................................................................................................... 28 
6.2 
Secondary Objectives ............................................................................................... 28 
7 
Study Endpoints ............................................................................................................. 28 
7.1 
Primary Endpoints .................................................................................................... 28 
7.2 
Secondary Endpoints ................................................................................................ 28 
 
 
8 
Study Design ................................................................................................................... 29 
8.1 
Overview of Study Design ....................................................................................... 29 
8.1.1 
Screening .......................................................................................................... 31 
8.1.1.1 
Repetition of Screening Assessment(s) ...................................................... 31 
8.1.1.2 
Rescreening ................................................................................................ 31 
8.1.1.3 
Extension of Screening Period Window .................................................... 32 
8.1.2 
Run-in Period (Part 2) ....................................................................................... 32 
8.1.3 
Treatment Period .............................................................................................. 32 
8.1.4 
Washout Period (Part 2) ................................................................................... 33 
8.1.5 
Follow-up .......................................................................................................... 33 
8.1.6 
Early Termination of Treatment ....................................................................... 33 
8.1.7 
Independent Data Monitoring Committee ........................................................ 34 
8.2 
Rationale for Study Design and Study Drug Regimens ........................................... 34 
8.2.1 
Study Design ..................................................................................................... 34 
8.2.2 
Study Drug Dose and Duration ........................................................................ 34 
8.2.3 
Rationale for Study Assessments ..................................................................... 35 
9 
Study Population ............................................................................................................ 36 
9.1 
Inclusion Criteria ...................................................................................................... 36 
9.2 
Exclusion Criteria ..................................................................................................... 36 
9.3 
Prohibited Medications ............................................................................................. 39 
9.4 
Prior and Concomitant Medications ......................................................................... 40 
9.5 
Removal of Subjects ................................................................................................. 40 
9.6 
Replacement of Subjects .......................................................................................... 41 
10  Study Drug Administration and Management ........................................................... 41 
10.1  Preparation and Dispensing ...................................................................................... 41 


Protocol VX16-152-102, Version 3.0 
Page 20 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
10.2 Administration .......................................................................................................... 41 
10.2.1 
Missed Doses .................................................................................................... 42 
10.3 Method of Assigning Subjects to Treatment Groups ............................................... 42 
10.4 Study Drug Interruption and Stopping Rules ........................................................... 42 
10.5 Packaging and Labeling ........................................................................................... 43 
10.6 Study Drug Supply, Storage, and Handling ............................................................. 43 
10.7 Drug Accountability ................................................................................................. 44 
10.8 Disposal, Return, or Retention of Unused Drug ....................................................... 44 
10.9 Compliance ............................................................................................................... 45 
10.10 Blinding and Unblinding .......................................................................................... 45 
10.10.1 Blinding ............................................................................................................ 45 
10.10.2 Unblinding ........................................................................................................ 46 
11 Assessments .................................................................................................................... 47 
11.1 Timing of Assessments ............................................................................................. 47 
11.2 Subject and Disease Characteristics ......................................................................... 47 
11.3 Pharmacokinetics ...................................................................................................... 47 
11.3.1 
Blood Sampling ................................................................................................ 47 
11.3.2 
Processing and Handling of Pharmacokinetic Samples ................................... 48 
11.3.3 
Bioanalysis........................................................................................................ 48 
11.4 Pharmacodynamics ................................................................................................... 48 
11.4.1 
Sweat Chloride ................................................................................................. 48 
 
11.6 Efficacy ..................................................................................................................... 49 
11.6.1 
Spirometry ........................................................................................................ 49 
11.6.2 
Height and Weight ............................................................................................ 50 
11.6.3 
Cystic Fibrosis Questionnaire-Revised ............................................................ 50 
11.7 Safety ........................................................................................................................ 50 
11.7.1 
Adverse Events ................................................................................................. 50 
11.7.2 
Clinical Laboratory Assessments ..................................................................... 51 
11.7.3 
Physical Examinations and Vital Signs ............................................................ 52 
11.7.4 
Pulse Oximetry ................................................................................................. 53 
11.7.5 
Electrocardiograms ........................................................................................... 53 
11.7.6 
Ophthalmologic Examination ........................................................................... 53 
11.7.7 
Contraception and Pregnancy ........................................................................... 54 
11.7.7.1 Contraception ............................................................................................. 54 
11.7.7.2 Pregnancy ................................................................................................... 56 
12 Statistical and Analytical Plans .................................................................................... 56 
12.1 Sample Size and Power ............................................................................................ 56 
12.1.1 
Primary Objectives ........................................................................................... 56 
12.1.1.1 Safety and Tolerability ............................................................................... 57 
12.1.2 
Secondary Objectives ....................................................................................... 57 
12.1.2.1 Pharmacodynamic Effect ........................................................................... 57 
12.1.2.2 Efficacy ...................................................................................................... 59 
12.2 Analysis Sets ............................................................................................................ 59 
12.3 Statistical Analysis ................................................................................................... 59 


Protocol VX16-152-102, Version 3.0 
Page 21 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
12.3.1 
General Considerations ..................................................................................... 60 
12.3.2 
Background Characteristics .............................................................................. 60 
12.3.2.1 Subject Disposition .................................................................................... 60 
12.3.2.2 Demographics and Baseline Characteristics .............................................. 61 
12.3.2.3 Prior and Concomitant Medications........................................................... 61 
12.3.2.4 Study Drug Exposure and Compliance ...................................................... 61 
12.3.2.5 Important Protocol Deviations ................................................................... 62 
12.3.3 
Efficacy Analysis .............................................................................................. 62 
12.3.3.1 Analysis of Primary Efficacy Variables ..................................................... 62 
12.3.3.2 Analysis of Secondary Efficacy Variables ................................................. 62 
 
 
12.3.4 
Pharmacodynamic Analysis ............................................................................. 63 
12.3.4.1 Pharmacodynamic Effect at Day 15 ........................................................... 63 
12.3.4.2 Pharmacodynamic Effect through Day 29 (Part 2, Cohort 2B only) ......... 63 
12.3.5 
Safety Analysis ................................................................................................. 63 
12.3.5.1 Adverse Events........................................................................................... 64 
12.3.5.2 Clinical Laboratory Assessments ............................................................... 65 
12.3.5.3 Electrocardiogram ...................................................................................... 65 
12.3.5.4 Vital Signs .................................................................................................. 65 
12.3.5.5 Pulse Oximetry ........................................................................................... 66 
12.3.5.6 Physical Examination ................................................................................. 66 
12.3.5.7 Other Safety Analysis ................................................................................ 66 
12.3.6 
Interim and IDMC Analyses ............................................................................. 66 
12.3.6.1 Interim Analysis ......................................................................................... 66 
12.3.6.2 IDMC Analysis .......................................................................................... 66 
12.4 Clinical Pharmacology Analysis .............................................................................. 66 
12.4.1 
Pharmacokinetic Analysis ................................................................................ 66 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses ................................................. 66 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ..................... 67 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting .................................................................................................................. 67 
13.1.1 
Adverse Events ................................................................................................. 67 
13.1.1.1 Definition of an Adverse Event.................................................................. 67 
13.1.1.2 Clinically Significant Assessments ............................................................ 67 
13.1.1.3 Documentation of Adverse Events............................................................. 68 
13.1.1.4 Adverse Event Severity .............................................................................. 68 
13.1.1.5 Adverse Event Causality ............................................................................ 69 
13.1.1.6 Study Drug Action Taken .......................................................................... 69 
13.1.1.7 Adverse Event Outcome ............................................................................ 70 
13.1.1.8 Treatment Given......................................................................................... 70 
13.1.2 
Serious Adverse Events .................................................................................... 70 
13.1.2.1 Definition of a Serious Adverse Event....................................................... 70 
13.1.2.2 Documentation of Serious Adverse Events................................................ 71 
13.1.2.3 Reporting Serious Adverse Events............................................................. 71 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ................................ 72 


Protocol VX16-152-102, Version 3.0 
Page 22 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
13.2 Administrative Requirements ................................................................................... 72 
13.2.1 
Ethical Considerations ...................................................................................... 72 
13.2.2 
Subject Information and Informed Consent ..................................................... 72 
13.2.3 
Investigator Compliance ................................................................................... 72 
13.2.4 
Access to Records ............................................................................................. 73 
13.2.5 
Subject Privacy ................................................................................................. 73 
13.2.6 
Record Retention .............................................................................................. 73 
13.2.7 
Study Termination ............................................................................................ 73 
13.3 Data Quality Assurance ............................................................................................ 74 
13.4 Monitoring ................................................................................................................ 74 
13.5 Electronic Data Capture ........................................................................................... 74 
13.6 Publications and Clinical Study Report .................................................................... 75 
 
 
13.6.2 
Clinical Study Report ....................................................................................... 75 
14 References ....................................................................................................................... 76 
APPENDIX A  CFTR Mutations That Are Predicted to Result in a CFTR Protein With 
Minimal Function (Part 1) ........................................................................................ 78 
15 Protocol Signature Pages .............................................................................................. 80 
15.1 Sponsor Signature Page ............................................................................................ 80 
15.2 Investigator Signature Page ...................................................................................... 81 
 


Protocol VX16-152-102, Version 3.0 
Page 23 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
List of Tables 
Table 3-1 
Study VX16-152-102: Schedule of Assessments for Part 1 ............................. 8 
Table 3-2 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2A ........ 11 
Table 3-3 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2B ........ 15 
Table 9-1 
Study Restrictions ........................................................................................... 39 
Table 10-1 
Study Drug ...................................................................................................... 44 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows .......................................... 48 
Table 11-2 
Safety Laboratory Test Panels ........................................................................ 51 
Table 11-3 
Acceptable Methods of Contraception............................................................ 55 
Table 12-1 
Probability of Observing an Adverse Event ................................................... 57 
Table 12-2 
Contrast Coefficients for the Multiple Comparisons Procedure in Part 1 ...... 58 
Table 12-3 
Power to Detect a Decreasing Dose-response Trend Based on Change From 
Baseline in Sweat Chloride in Part 1 .............................................................. 58 
Table 12-4 
Power for Within-group Decrease for Mean Absolute Change From Baseline 
in Sweat Chloride ............................................................................................ 58 
Table 12-5 
Power for Within-group Increase for Mean Absolute Change From Baseline in 
ppFEV1 ............................................................................................................ 59 
Table 13-1 
Grading of AE Severity .................................................................................. 69 
Table 13-2 
Classifications for AE Causality ..................................................................... 69 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE ............ 69 
Table 13-4 
Classifications for Outcome of an AE ............................................................ 70 
 
List of Figures 
Figure 8-1 
Schematic of the Study Design ....................................................................... 30 


Protocol VX16-152-102, Version 3.0 
Page 24 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransaminase 
AUC0-12h 
area under the concentration versus time curve from time of dosing to 12 hours. 
BMI 
body mass index 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator protein 
Cmax 
maximum observed concentration 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
 
 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes/ears/nose/throat 
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 
FEF 
forced expiratory flow 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
 
 
G6PD 
glucose-6-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
HBE 
human bronchial epithelial 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IPD 
important protocol deviation 
IRB 
institutional review board 
IVA 
ivacaftor 


Protocol VX16-152-102, Version 3.0 
Page 25 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
Abbreviation 
Term 
IWRS 
interactive web response system 
LFT 
liver function test 
LLN 
lower limit of normal 
LUM 
lumacaftor 
max 
maximum value 
MCP 
multiple comparisons procedure 
MF 
minimal function 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
N 
total sample size (e.g., number of subjects treated) 
OATP1B1 
organic anion transporting polypeptide 1B1 
OATP1B3 
organic anion transporting polypeptide 1B3 
P 
probability 
PCS 
potentially clinically significant 
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 
TC 
triple combination 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
Vertex 
Vertex Pharmaceuticals Incorporated 
 


Protocol VX16-152-102, Version 3.0 
Page 26 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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 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 pathology3, beginning at birth. Despite progress in the 
treatment of CF with antibiotics and mucolytics, the median predicted survival age for a 
person with CF is approximately 40 years.2,4 More effective treatments are needed for CF. 
To address this medical need, Vertex Pharmaceuticals Incorporated is developing treatment 
regimens that include CFTR modulators to target the underlying cause of CF: the defective 
CFTR protein. Two types of CFTR modulators have been developed: potentiators, which 
increase the channel gating activity of the CFTR protein, and correctors, which increase the 
quantity of CFTR at the cell surface. 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 depending on the country.5 
Lumacaftor (LUM) and 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 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 
VX-661/IVA combination therapy are ongoing in populations that are homozygous or 
heterozygous for F508del. 
VX-152 is a second-generation CFTR corrector that acts through a different site of the CFTR 
protein than LUM and VX-661. In vitro, VX-152 improves the processing and trafficking of 
F508del-CFTR, thereby increasing the quantity of functional F508del-CFTR protein at the 
cell surface. Consistent with different mechanisms of action, the effects of VX-152 and 
VX-661 are additive. The activity of the CFTR protein delivered to the cell surface by 
VX-152, alone or in combination with VX-661, is potentiated by IVA. In human bronchial 
epithelial (HBE) cells derived from CF patients homozygous for F508del, the triple 
combination (TC) of VX-152, VX-661, and IVA increased CFTR-mediated chloride 
transport more than the dual combinations (VX-152 and VX-661; VX-152 and IVA; VX-661 
and IVA) or individual agents (VX-152; VX-661; IVA). These data, as well as the 


Protocol VX16-152-102, Version 3.0 
Page 27 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
nonclinical pharmacokinetic (PK) and safety profile, support the development of VX-152 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-152 in subjects with CF and is designed to 
evaluate the safety, tolerability, pharmacodynamic (PD) effect, PK, and efficacy of VX-152 
in TC with VX-661 and IVA. 
VX-152 has been studied in vitro and in vivo, and the safety profile in the nonclinical 
toxicology studies supports clinical development of VX-152. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Based on in vitro results and modeling of in vitro and in vivo data, there is the potential for 
clinical efficacy at a safe dose, providing the rational for the present study. 


Protocol VX16-152-102, Version 3.0 
Page 28 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
 To evaluate the safety and tolerability of VX-152 in TC with VX-661 and IVA in adults 
with CF 
6.2 
Secondary Objectives 
 To evaluate the PD effect of VX-152 in TC with VX-661 and IVA on CFTR function 
 To evaluate the efficacy of VX-152 in TC with VX-661 and IVA 
 To evaluate the PK of VX-152 when administered in TC with VX-661 and IVA 
 To evaluate the PK of VX-661, IVA, and their respective metabolites when administered 
with VX-152 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoints 
 Safety and tolerability assessments based on AEs, clinical laboratory values, standard 
12-lead electrocardiograms (ECGs), vital signs, and pulse oximetry 
7.2 
Secondary Endpoints 
 Absolute change in sweat chloride concentrations from baseline at Day 15 (Parts 1 
and 2), and through Day 29 (Part 2, Cohort 2B only) 
 Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
from baseline at Day 15 (Parts 1 and 2), and through Day 29 (Part 2, Cohort 2B only) 
 Relative change in ppFEV1 from baseline at Day 15 (Parts 1 and 2), and through Day 29 
(Part 2, Cohort 2B only) 
 Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain 
score from baseline at Day 15 (Parts 1 and 2), and at Day 29 (Part 2, Cohort 2B only) 
 PK parameters of VX-152, VX-661, M1-661, IVA, and M1-IVA 
 
 
 
 


Protocol VX16-152-102, Version 3.0 
Page 29 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
8 
STUDY DESIGN 
8.1 
Overview of Study Design 
This is a Phase 2, 2-part, randomized, double-blind, placebo- and VX-661/IVA-controlled, 
parallel-group, multicenter study designed to evaluate the safety of VX-152 in TC with 
VX-661/IVA.  
Up to approximately 72 subjects with CF are planned for enrollment: up to approximately 
36 subjects in each of Part 1 (F508del/MF genotype) and in Part 2 (F508del/F508del 
genotype).  
Parts 1 and 2 will enroll multiple cohorts, with each cohort evaluating 1 dose level of 
VX-152 as part of TC with VX-661/IVA (100 mg qd/150 mg q12h). Each cohort will enroll 
up to approximately 12 subjects in Part 1 and Part 2 Cohort 2A and up to approximately 
24 subjects in Part 2 Cohort 2B. Subjects in all cohorts will be randomized 3:1 (active 
TC:comparator). Triple placebo will be the comparator in Part 1, and VX-661/IVA will be 
the comparator in Part 2. 
Up to 3 cohorts are planned for Part 1 (Cohorts 1A, 1B, and 1C). Up to 2 cohorts are planned 
for Part 2 (Cohorts 2A and 2B). The doses of VX-152 planned for evaluation are 100 mg 
q12h in Cohort 1A, 200 mg q12h in Cohorts 1B and 2A, and 300 mg q12h in Cohorts 1C and 
2B. The dose of VX-152 may be adjusted to be lower or the same as the dose level evaluated 
in the previous cohort. 
The actual number of cohorts enrolled in each part may be modified based on emerging 
safety and PK data. Blinded reviews of safety and available PK data will be conducted by the 
Vertex study team and lead investigator(s) on an ongoing basis. 
Cohorts will initiate dosing as follows: 
 Cohort 1A will initiate dosing first.  
 Cohorts 1B and 2A may initiate dosing if supported by blinded review of safety and 
available PK data after all subjects in Cohort 1A complete the Day 15 Visit. 
 Cohorts 1C and 2B may initiate dosing if supported by blinded review of safety and 
available PK data after any of the following has occurred: 
o All subjects in Cohort 1B complete the Day 15 Visit. 
o All subjects in Cohort 2A complete the Day 15 Visit. 
o At least 12 subjects across Cohorts 1B and 2A complete the Day 15 Visit. 
A schematic of the study design (including the doses of VX-152, VX-661, and IVA to be 
evaluated) is shown in Figure 8-1. 




Protocol VX16-152-102, Version 3.0 
Page 31 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
8.1.1 
Screening 
For Part 1, the Screening Period will occur within 28 days before the first dose of study drug 
in the Treatment Period. For Part 2, the Screening Period will occur within 28 days before the 
first dose of VX-661/IVA in the Run-in Period.  
The assessments to be conducted are shown in Table 3-1, Table 3-2, and Table 3-3 and will 
be used to confirm that subjects meet the eligibility criteria for the study. The investigator (or 
an appropriate authorized designee) will obtain informed consent from each subject before 
any study procedure takes place.  
The screening ophthalmologic 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 (Section 11.7.6) or if there is documentation of bilateral lens 
removal for the subject.  
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,6 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. 


Protocol VX16-152-102, Version 3.0 
Page 32 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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) 
 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 Part 1 subjects, washout of VX-661/IVA if enrolling from Study VX14-661-110 
(Study 661-110) 
 Operational or logistic delays 
8.1.2 
Run-in Period (Part 2) 
The Run-in Period will have a total duration of 4 weeks and is designed to establish a reliable 
on-treatment (VX-661/IVA) baseline for the Treatment Period. The first dose of 
VX-661/IVA will be administered at the Day -28 Visit. The last dose of VX-661/IVA within 
the Run-in Period will be administered in the evening of Day -1 (1 day before the Day 1 
Visit).  
Study eligibility for Part 2 subjects will be confirmed before the first dose of VX-661/IVA in 
the Run-in Period (on Day -28). 
Study visits during the Run-in Period will occur as shown in Table 3-2 and Table 3-3. All 
visits will occur within the windows specified. 
8.1.3 
Treatment Period 
For Part 1, the Treatment Period will last approximately 2 weeks. For Part 2, the Treatment 
Period will last approximately 2 weeks for subjects in Cohort 2A and approximately 4 weeks 
for subjects in Cohort 2B. 
Study visits during the Treatment Period will occur as shown in Table 3-1, Table 3-2, and 
Table 3-3. All visits should occur within the windows specified. Study drug administration 
details are provided in Section 10.2. 
Subjects must meet both of the following criteria to continue into the Treatment Period: 
 Must have stable CF disease (as judged by the investigator) and have remained on a 
stable CF medication regimen during the 28 days before the Day 1 Visit. (For example, 
subjects cannot have an acute upper or lower respiratory infection, pulmonary 
exacerbation, or changes in therapy [including antibiotics] for pulmonary disease within 
28 days before the Day 1 Visit.)  
 Must not have had an acute non-CF illness (e.g., gastroenteritis) within the 14 days 
before the Day 1 Visit. 


Protocol VX16-152-102, Version 3.0 
Page 33 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
If these criteria are not met, subjects may not be randomized and enter into the Treatment 
Period. 
Randomization will occur before the first dose of study drug during the Treatment Period and 
will occur on Day 1 (or Day -1) after all criteria for entry into the Treatment Period have 
been confirmed. Study eligibility for Part 1 subjects will be confirmed before randomization. 
For Part 2, subjects who prematurely discontinue VX-661/IVA during the Run-in Period will 
not be randomized or participate in the Treatment Period.  
8.1.4 
Washout Period (Part 2) 
The Washout Period will last approximately 2 weeks and is designed to allow for the 
measurement of off-treatment effects. Subjects will continue to receive VX-661/IVA during 
the Washout Period. 
Study visits during the Washout Period will occur as shown in Table 3-2 and Table 3-3. All 
visits should occur within the windows specified. 
8.1.5 
Follow-up 
The Safety Follow-up Visit assessments are listed in Table 3-1, Table 3-2, and Table 3-3. 
There will be an outpatient Safety Follow-up Visit occurring approximately 28 days after the 
last dose of study drug for subjects who complete study drug dosing and for subjects who 
prematurely discontinue study drug dosing. 
The following subjects will not have a Safety Follow-up Visit: 
 Part 2 subjects who do not meet the criteria to enter the Treatment Period (Section 8.1.3), 
and re-enter Study 661-110 
 Part 2 subjects in Cohort 2A who complete the Day 29 Visit and re-enter Study 661-110  
 Part 2 subjects in Cohort 2B who complete the Day 43 Visit and re-enter Study 661-110 
All other subjects will have a Safety Follow-up Visit. 
8.1.6 
Early Termination of Treatment  
If a subject prematurely discontinues treatment, an Early Termination of Treatment (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, approximately 28 days after their last dose of study drug. The 
assessments performed at the Safety Follow-up Visit are listed in Table 3-1, Table 3-2, and 
Table 3-3. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT 
Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not 
be required.  
If a subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. Vertex may retain and continue to use any data collected before such withdrawal 
of consent. 


Protocol VX16-152-102, Version 3.0 
Page 34 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
8.1.7 
Independent Data Monitoring Committee 
This study will be monitored by an external independent data monitoring committee (IDMC), 
which will conduct periodic reviews of safety data from all parts of the study 
(Section 12.3.6.2). Procedural details of the IDMC structure and function, frequency of 
meetings, and data planned for review will be included in the IDMC Charter. The IDMC 
Charter will be finalized before the first subject is screened.  
8.2 
Rationale for Study Design and Study Drug Regimens 
8.2.1 
Study Design 
This Phase 2 study is the first clinical study of VX-152 in subjects with CF. It is designed to 
evaluate the safety of VX-152 in TC with VX-661/IVA and to establish proof-of-concept in 
2 populations of subjects defined by CFTR genotype: subjects heterozygous for the 
F508del-CFTR mutation with a second CFTR mutation not expected to respond to 
VX-661/IVA (F508del/minimal function [MF]) (Part 1) and subjects homozygous for 
F508del (F508del/F508del) (Part 2). 
Based on in vitro data, TC is predicted to provide clinically relevant improvements in 
chloride transport in both populations, though the magnitude of response may not be the 
same in these populations. The subjects will be evaluated by genotype in separate cohorts in 
Parts 1 and 2, based on the potential for differences in the magnitude of treatment response 
among these genotype categories. PD will be evaluated through the assessment of sweat 
chloride, and efficacy will be evaluated through the assessment of spirometry and patient 
reported outcomes. Part 1 of the study will also obtain information regarding the 
exposure-response relationship (Section 12.1.2.1). 
Placebo is the comparator in Part 1, as efficacy has not been established for a corrector, 
potentiator, or corrector/potentiator combination in subjects with F508del/MF genotypes. 
VX-661/IVA is the comparator in Part 2, based on the potential for benefit demonstrated for 
VX-661/IVA in subjects with the F508del/F508del genotype in Study VX11-661-101.7 
Part 2 will have a 4-week run-in period to establish a reliable on-treatment (VX-661/IVA) 
baseline for comparison to the Treatment Period, when subjects will additionally receive 
VX-152 or placebo. Off-treatment effects will also be measured at the Safety Follow-up Visit 
in Part 1 and at the end of the Washout Period in Part 2. 
8.2.2 
Study Drug Dose and Duration 
Part 1 will evaluate up to 3 dose levels of VX-152 (100, 200, and 300 mg q12h) in TC with 
VX-661/IVA in subjects with the F508del/MF genotype. 
 
 
  
The dose escalation of VX-152 is no more than 2-fold. 
 
 
 
 
 
 
 
 


Protocol VX16-152-102, Version 3.0 
Page 35 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
Up to 3 dose levels of VX-152 will be evaluated as part of the TC in Part 1 to provide a range 
of doses and exposures that will enable dose-response and exposure-response analyses for 
PD (Section 12.1.2.1). Dose- and exposure-response information obtained from Part 1 
(F508del/MF genotype) is expected to be applicable to other populations with an F508del 
mutation, including F508del/F508del genotypes, based on similar in vitro potency for the TC 
in HBE cells with 1 or 2 copies of F508del.8  
The dose of VX-661 and IVA (100 mg qd and 150 mg q12h) in the TC are the same doses 
currently under evaluation in Phase 3 studies of VX-661/IVA. These doses of VX-661 and 
IVA are appropriate for evaluation in the TC based on in vitro experiments with VX-152 
which evaluated similar levels of VX-661 and IVA exposure after correction for protein-
binding. 
 
 
In 
Studies VX06-770-101 and VX11-661-101, improvements in sweat chloride and ppFEV1 
were observed as rapidly as 3 to 7 days after the start of dosing, with most of the effect 
observed within 14 days. Given the increased in vitro response of the TC relative to 
VX-661/IVA, it is expected that the 2-week treatment duration will be sufficient to observe 
differences between treatment arms with respect to efficacy and PD endpoints. In addition, 
based on previous clinical experience, 2 weeks is sufficient for VX-152, VX-661, and IVA to 
reach steady-state levels of exposure. The 4-week treatment duration in Part 2 Cohort 2B will 
provide additional safety data for the TC. 
8.2.3 
Rationale for Study Assessments 
 
 
 
 
 
 
 
 
The PD and efficacy assessments are widely accepted and generally recognized as reliable, 
accurate, and relevant to the study of patients in CF. All assessments were routinely 
measured in the registration studies of IVA (Kalydeco) or LUM/IVA combination therapy 
(Orkambi).  


Protocol VX16-152-102, Version 3.0 
Page 36 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
9 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are randomized (Part 1) or receive VX-661/IVA in the 
Run-in Period on Day -28 (Part 2). 
9.1 
Inclusion Criteria 
1. Subject will sign and date an informed consent form (ICF). 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Subjects will be aged 18 years or older on the date of informed consent. 
4. Body weight ≥35 kg. 
5. Sweat chloride value 60 mmol/L from test results obtained during screening. 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. (It is acceptable to use a 
sweat chloride value that was obtained before previous treatment with IVA, LUM/IVA, 
or an investigational CFTR modulator). 
6. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR 
genotype result is not received before randomization (Part 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). 
 Part 1: Heterozygous for F508del with a second CFTR allele carrying an MF 
mutation that is not likely to respond to VX-661 and/or IVA therapy (Appendix A) 
 Part 2: Homozygous for F508del 
7. Subjects must have an FEV1 ≥40% and ≤90% of predicted normal for age, sex, and 
height (equations of the Global Lung Function Initiative [GLI])9 at the Screening Visit. 
Spirometry measurements must meet American Thoracic Society/European Respiratory 
Society criteria6 for acceptability and repeatability. 
8. Stable CF disease as judged by the investigator. 
9. Willing to remain on a stable CF medication regimen through the planned end of 
treatment or, if applicable, the Safety Follow-up Visit. 
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. 


Protocol VX16-152-102, Version 3.0 
Page 37 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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 
 AST, 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)10,11 for 
subjects ≥18 years of age 
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 Part 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 Part 1, Day -28 for Part 2). 
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. 


Protocol VX16-152-102, Version 3.0 
Page 38 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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 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 VX-661/IVA, IVA, 
LUM/IVA, or other CFTR modulator. For Part 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 VX-661/IVA Run-in Period 
providing that they meet eligibility criteria. For both 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 (Part 1 only).  
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 Part 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 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. 


Protocol VX16-152-102, Version 3.0 
Page 39 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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-152, VX-661, and IVA are metabolized extensively via 
cytochrome P450 (CYP) 3A4. VX-152 is also metabolized by CYP2C9. 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-152, VX-661, or IVA, will be 
restricted in this study. VX-152 was shown in vitro to be an inhibitor of the hepatic 
transporters organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). 
Therefore, sensitive substrates of OATP1B1/1B3, such as HMG Co-A Reductase Inhibitors 
(i.e., “statins”), are also restricted during the study.  
A non-exhaustive list of study prohibitions and cautions for medication will be provided in 
the Study Reference Manual. 
Table 9-1 
Study Restrictions 
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 (Part 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 (Part 1) or Day -28 (Part 2) 
None allowed through the Safety 
Follow-up Visit 
Sensitive OATP1B1/1B3 
substrates 
None allowed within 14 days before 
the first dose of VX-152 or placebo 
on Day 1 
None allowed until after last dose of 
VX-152 or placebo 
Commercially available CFTR 
modulators (e.g., Kalydeco, 
Orkambi)  
Part 1: None allowed within 14 days 
before screening 
Part 2: None allowed from the start 
of the Run-in Period 
Part 1: None allowed through the 
Safety Follow-up Visit 
Part 2: None allowed through the 
end of the Washout Period 
Note: The use of restricted medication by subjects with medical needs will be addressed on a case-by-case basis 
with the medical monitor. 


Protocol VX16-152-102, Version 3.0 
Page 40 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
9.4 
Prior and Concomitant Medications 
Information regarding all prior and concomitant medications, including the subject's CF 
medications, other medications, and herbal and naturopathic remedies administered from 
28 days before the Screening Period through the Safety Follow-up Visit, if applicable, will be 
recorded in each subject's source documents. For subjects who are screened but are not 
subsequently randomized in the study, details of prior medication will only be documented in 
the subjects' source documents. 
 Subjects must remain on a stable medication (and supplement) regimen for their CF from 
28 days before Day 1 through the Safety Follow-up Visit. Stable medication regimen is 
defined as the current medication regimen for CF that subjects have been following for at 
least 28 days before Day 1. Subjects must not initiate long-term treatment with new 
medication from 28 days before Day 1 through the Safety Follow-up Visit unless 
discussed and approved by the medical monitor. Guidelines for stable medication 
regimens for CF are as follows: 
o Subjects who are taking daily inhaled tobramycin or other chronically inhaled 
antibiotics should remain on that regimen throughout the study. 
o Subjects who cycle onto and off an inhaled antibiotic should continue on their prior 
schedule. The timing of the first dose of study drug on Day 1 should be synchronized 
as closely as possible (and not more than ± 3 days) to the first day in the cycle onto 
the inhaled antibiotic. 
o Subjects who alternate between 2 different inhaled antibiotics should remain on the 
same cycling schedule during the study. The timing of the first dose of study drug on 
Day 1 should be synchronized as closely as possible (and not more than ± 3 days) to 
the first day in the cycle onto 1 of the inhaled antibiotics. 
 Subjects may receive doses of prednisone of up to 10 mg/day or equivalent (chronically) 
or prednisone 60 mg qd for up to 5 days without prior approval of the medical monitor. 
 Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments 
performed according to the guidelines provided in Section 11.6.1. 
9.5 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or 
Vertex for safety, behavior, noncompliance with study procedures, or administrative reasons. 
If a subject has been withdrawn from study drug treatment, the subject will continue to be 
followed, provided the subject has not withdrawn consent. 
Subjects who have been randomized and whose screening CFTR genotype does not confirm 
study eligibility must be discontinued from the study, even if a previous CFTR genotype 
laboratory report was used to establish eligibility. 
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. 


Protocol VX16-152-102, Version 3.0 
Page 41 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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-152, VX-661/IVA, 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.  


Protocol VX16-152-102, Version 3.0 
Page 42 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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. For visits after the Day 1 Visit, 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. 
10.2.1 
Missed Doses 
If a subject misses a dose and recalls the missed dose within 6 hours, the subject should take 
his/her dose with food. If more than 6 hours have elapsed after his/her usual dosing time, the 
subject should skip that dose and resume his/her normal schedule for the following dose. For 
example, 
 if the morning dose of study drug should have been taken at approximately 08:00, and the 
subject remembers at 12:00 that he/she forgot to take his/her dose, he/she should take the 
dose with food as soon as possible. 
 if the morning dose of study drug should have been taken at approximately 08:00, and 
more than 6 hours have elapsed beyond the scheduled dosing time (i.e., the time is past 
14:00), the subject would resume dosing with the evening dose at approximately 20:00. 
10.3 
Method of Assigning Subjects to Treatment Groups 
Approximately 12 subjects (Part 1 and Part 2, Cohort 1A) and approximately 24 subjects 
(Part 2, Cohort 2B) will be randomized in the ratio 3:1 to TC versus comparator in each 
cohort. 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. 
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). 


Protocol VX16-152-102, Version 3.0 
Page 43 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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 
 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 confirmatory testing results obtained 
after study drug interruption meet any of the following criteria: 
 ALT or AST >8 × ULN 
 ALT or AST >5 × ULN for more than 2 weeks 
 ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical 
jaundice 
 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. 
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-152 (100 mg) and matching placebo will be supplied as tablets of similar size and 
appearance containing 100 mg VX-152 and 0 mg VX-152, respectively. 
VX-661/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 VX-661/150 mg IVA 
and 0 mg VX-661/0 mg IVA, 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. 


Protocol VX16-152-102, Version 3.0 
Page 44 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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 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-152 
100-mg tablet, oral  
100, 200, or 300 mg 
q12h (planned) 
≤25°C (77°F) with 
excursions to 30°C (86°F) 
VX-152-matching placebo 
0-mg tablet, oral 
0 mg q12h 
≤25°C (77°F) with 
excursions to 30°C (86°F) 
VX-661/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) 
VX-661/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) 
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) 
 
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. 


Protocol VX16-152-102, Version 3.0 
Page 45 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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. 
10.10.1 
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 performing the interim analyses and preparing the unblinded analysis for the 
ongoing reviews of efficacy and safety data, and a limited Vertex team not involved in 
the conduct of the study 
 Vendor analyzing PK samples and Vertex Bioanalytical staff (non-study team) reviewing 
raw data from vendor  
 Vertex Modeling and Simulations 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 


Protocol VX16-152-102, Version 3.0 
Page 46 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
Sweat Chloride and Spirometry Blinding: During the conduct of the study, the Vertex study 
team will not have access to the spirometry results after the morning dose on Day 1. 
Furthermore, sites, subjects, and their parents/caregivers/companions should not be informed 
of their study-related sweat chloride and spirometry results during the Treatment Period 
regardless of whether the subject has prematurely discontinued treatment. 
A limited Vertex team not involved in the conduct of the study will be unblinded to results of 
the interim analyses and will 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.  
The Vertex study team and lead investigator(s) will also conduct blinded reviews of all 
available safety and PK data after all subjects within a cohort complete the Day 15 Visit to 
make decisions about dose selection for potential subsequent cohorts. 
When an interim analysis is performed after all subjects in 1 part have completed the Safety 
Follow-up Visit, results from that part will be unblinded for full review by the Vertex study 
team. 
10.10.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process.  
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment 
is necessary for clinical management. In such cases, investigators will use their best 
judgment as to whether to unblind without first attempting to contact the medical monitor to 
discuss and agree to the need for unblinding. If investigators deem it not necessary to unblind 
immediately, they will first attempt to contact the medical monitor to discuss and agree to the 
need for unblinding. If investigators have tried but are unable to reach the medical monitor, 
they will use their best judgment, based on the nature and urgency of the clinical situation, 
and may proceed with unblinding without having successfully reached and discussed the 
situation with the medical monitor. 
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 


Protocol VX16-152-102, Version 3.0 
Page 47 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
definitions or criteria for SAEs, and if so, submit an SAE report to Vertex GPS or designee, 
per Section 13.1.2. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, 
unblind individual subjects at any time. 
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments is shown in Table 3-1, Table 3-2, and Table 3-3.  
The CFQ-R assessment must be completed before any other assessment at the clinic visits 
when it is required. For the remaining assessments, the following assessments must be 
performed in the following order when more than 1 assessment is required at a particular 
time point: 
1. Vital signs and pulse oximetry 
2. Standard 12-lead ECG recordings  
3. Sweat chloride, spirometry 
4. Safety laboratory assessments (including all blood draws) 
5. PK sampling 
11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, 
height, and weight. 
Medical history will be elicited from each subject and extracted from medical records during 
screening. Based on the medical history, the subject will be assessed for any disqualifying 
medical conditions as specified in the inclusion and exclusion criteria. The medical history 
shall include a complete review of systems, past medical and surgical histories, and any 
allergies. 
11.3 
Pharmacokinetics 
11.3.1 
Blood Sampling 
Blood samples will be collected as shown in Table 3-1, Table 3-2, and Table 3-3 for the 
determination of plasma concentrations of VX-152, VX-661, M1-661, IVA, and M1-IVA. 
 
 
 
 
All efforts will be made to obtain the PK samples at the exact nominal time relative to 
dosing. Acceptable windows for sampling times are shown in Table 11-1. Samples collected 
outside of these acceptable windows will be considered protocol deviations.   


Protocol VX16-152-102, Version 3.0 
Page 48 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Sampling Time 
Time From Scheduled Sampling Allowed 
Predose 
-60 minutes 
From 0.25 up to ≤8 hours after study drug dosing 
± 15 minutes 
 
For each visit with a PK blood draw, a record of study drug administration will be collected 
as described in Section 10.2. The collection date and exact time that each PK blood sample is 
drawn will also be recorded. 
Samples from the PK sampling will be kept frozen by Vertex or its designee until all analyses 
have been completed and then disposed of according to Vertex or designee standard 
operating procedures. 
Plasma concentration samples collected from subjects treated with placebo will not be 
routinely analyzed. 
11.3.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be provided in the PK Sample Handling 
Guidelines. The shipment address and assay laboratory contact information will be provided 
to the investigational site before initiation of the study. 
11.3.3 
Bioanalysis 
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 
11.4.1 
Sweat Chloride 
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, 
Table 3-2, and Table 3-3, 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.  


Protocol VX16-152-102, Version 3.0 
Page 49 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
 
 
 
 
 
 
 
 
 
  
11.6 
Efficacy 
11.6.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society 
Guidelines/European Respiratory Society Guidelines6 at the time points noted in Table 3-1, 
Table 3-2, and Table 3-3 and according to the additional guidelines that follow. 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who 
have 
 withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 
 withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before 
the spirometry assessment; and 
 withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide 
[Spiriva®]) for more than 24 hours before the spirometry assessment. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilator. At all other visits, all spirometry assessments should be performed 
"pre-bronchodilator". During the Treatment Period, spirometry assessments must be 
performed before 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, 
and 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, and Table 3-3) 
should be performed post-bronchodilator. 


Protocol VX16-152-102, Version 3.0 
Page 50 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
 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.9  
 FEV1 (L) 
 
 
 
 
 
 
 
11.6.2 
Height and Weight 
Height and weight will be measured with shoes off at time points noted in Table 3-1, 
Table 3-2, and Table 3-3. 
11.6.3 
Cystic Fibrosis Questionnaire-Revised 
Subjects will be asked to complete the CFQ-R in their native language, if validated 
translations are available.12,13 The CFQ-R will be completed before any other study 
assessments are performed at the visits noted in Table 3-1 (Part 1) , Table 3-2 (Part 2, 
Cohort 2A), and Table 3-3 (Part 2, Cohort 2B). Subjects will complete the Adolescent/Adult 
version of the questionnaire themselves at all visits. The questionnaires provide information 
about demographics; general quality of life, school, work, or daily activities; and symptom 
difficulties (pertaining to CF). Copies of the CFQ-R used in this study will be provided in the 
Study Reference Manual. Validated translations of the CFQ-R, if available, will be provided 
for participating centers in non-English-speaking countries.14,15 
11.7 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, ECGs, clinical 
evaluation of vital signs, pulse oximetry, PEs, and ophthalmologic examinations. 
11.7.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE case report 
form (CRF) completion guidelines for investigators as well as training will be provided. 


Protocol VX16-152-102, Version 3.0 
Page 51 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
11.7.2 
Clinical Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table 3-1, Table 3-2, and Table 3-3. Fasting is not required. 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. 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. 
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, and 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, and 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. 


Protocol VX16-152-102, Version 3.0 
Page 52 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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. The use of a local laboratory that routinely runs quantitative G6PD activity assays 
is acceptable as an alternative to the central laboratory. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, the central laboratory must be used for all laboratory tests 
with the exception of the G6PD activity test. Local laboratories may be used at the discretion 
of the local investigator for management of urgent medical issues. If a local laboratory test 
value is found to be abnormal and clinically significant, it will be verified by the central 
laboratory as soon as possible after the investigator becomes aware of the abnormal result. If 
it is not possible to send a timely specimen to the central laboratory (e.g., the subject was 
hospitalized elsewhere), the investigator may base the assessment of an AE on the local 
laboratory value. 
11.7.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening and 
select study visits (Table 3-1, Table 3-2, and Table 3-3). At other visits, symptom-directed 
PEs and symptom-directed vital sign assessments can be performed at the discretion of the 
investigator or healthcare provider. 
A 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 a 5-minute rest in the seated position.  


Protocol VX16-152-102, Version 3.0 
Page 53 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
11.7.4 
Pulse Oximetry 
Arterial oxygen saturation by pulse oximetry will be measured at visits specified in 
Table 3-1, Table 3-2, and Table 3-3. This will be assessed following 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. 
11.7.5 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Schedule of Assessments (Table 3-1, Table 3-2, and Table 3-3). Additional standard 12-lead 
ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines: 
 The subject will be instructed to rest in the seated position for at least 5 minutes before 
having an ECG performed. 
 The ECG will be performed before any other procedures that may affect heart rate (HR), 
such as blood draws. 
The ECG traces will be manually read at the study site at the Screening Visit and Safety 
Follow-up Visit. A printout of the ECG traces will be made for safety review by the 
investigator and maintained with source documentation. Clinically significant ECG 
abnormalities occurring during the study through the Safety Follow-up Visit will be recorded 
as AEs.  
To ensure safety of the subjects, a qualified individual at the study site will make 
comparisons to baseline measurements. If the QTcF is increased by >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). 
11.7.6 
Ophthalmologic Examination 
Subjects will undergo an ophthalmologic examination performed by a licensed 
ophthalmologist or optometrist as noted in Table 3-1, Table 3-2, and Table 3-3, which 
includes 
 measurement of best corrected distance visual acuity of each eye; 
 pharmacologically-dilated examination of the lens with a slit lamp. 
The screening ophthalmologic examination must be completed 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 if there is documentation of bilateral lens removal for the 
subject. 


Protocol VX16-152-102, Version 3.0 
Page 54 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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 
11.7.7 
Contraception and Pregnancy 
The effects of VX-152 monotherapy or in dual or triple combination with VX-661 and IVA 
on conception, pregnancy, and lactation in humans are not known. VX-152, VX-661, and 
IVA did not show any genotoxic potential in a standard battery of in vitro (Ames test, 
chromosomal aberration or micronucleus in cultured mammalian cells) and in vivo (rodent 
micronucleus) studies. VX-152, VX-661, and IVA were each found to be nonteratogenic in 
reproductive toxicology studies in rats and rabbits.5,7,16,17,18,19,20 
11.7.7.1 
Contraception 
Study participation requires compliance with the contraception guidelines outlined below. 
Contraception requirement for the couple is waived for the following: 
 True abstinence for the subject, when this is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
True abstinence must be practiced from the Screening Visit through 90 days after the last 
dose of study drug. 
 If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the 
first dose of study drug (e.g., examination of a semen specimen or by demonstration of 
the absence of the vas deferens by ultrasound). 


Protocol VX16-152-102, Version 3.0 
Page 55 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
 If the female is of non-childbearing potential. To be considered of non-childbearing 
potential, the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH 
level within the laboratory's reference range for postmenopausal females. 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy. 
Note: All other females (including females with tubal ligations and females who do not 
have a documented bilateral oophorectomy) will be considered to be of childbearing 
potential. 
 Same sex relationships 
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used as a couple. Acceptable methods of contraception are listed in Table 11-3.  
Table 11-3 
Acceptable Methods of Contraception 
 
Male Subjects and 
Their Female 
(Non-study) Partners 
Female Subjects and 
Their Male 
(Non-study) Partners 
Vasectomy 6 months or more previously, with a 
documented negative postvasectomy semen analysis for 
sperm 
Yes 
Yes 
Bilateral tubal ligation performed at least 6 months 
previously. 
Yes 
Yes 
Male or female condom with or without spermicidea 
Yes 
Yes 
Female barrier contraception (such as diaphragm, cervical 
cap, or sponge) with spermicide 
Yes 
Yes 
Continuous use of an intrauterine device for at least 90 days 
before the first dose of study drug. 
 
 
 Hormone-releasing 
Yes 
Nob 
 Non-hormone releasing 
Yes 
Yes 
Hormonal contraceptives, if successfully used for at least 
60 days before the first dose of study drug. 
Yes 
Nob 
Note: At least 1 acceptable method of contraception must be used by couples not exempt from the contraception 
requirement. Methods of contraception must be in successful use from signing of consent, approximately 
28 days before the first dose of study drug (unless otherwise noted), and until 90 days following the last 
dose of study drug. Additional contraception requirements may need to be followed according to local 
regulations and/or requirements. 
a 
A female condom cannot be used with a male condom due to risk of tearing. 
b 
Hormone-releasing intrauterine devices and hormonal contraceptives are not considered an acceptable 
method in female study subjects; however, female subjects are not required to discontinue their use of 
hormone-releasing intrauterine devices or hormonal contraceptives. 


Protocol VX16-152-102, Version 3.0 
Page 56 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
Additional notes: 
 Male subjects must not donate sperm after the first dose of study drug, throughout the 
study, and for 90 days following the last dose of study drug. 
 Female subjects and female partners of male subjects should not plan to become pregnant 
during the study through 90 days following the last dose of study drug. 
 Male subjects whose female partner becomes pregnant through well-documented in vitro 
fertilization (donated sperm) or banked sperm (collected before the subject received study 
drug), or is otherwise already pregnant before the male subject’s first dose of study drug, 
must be compliant with the contraception requirements. In this scenario, the male subject 
and his female partner must commit to using a male condom (to ensure there is no 
exposure of the fetus to study drug) for the duration of the study and until 90 days after 
the last dose of study drug. 
 Female subjects should not nurse a child from the start of study drug dosing through 
90 days following the last dose of study drug. 
 Unique situations that may not fall within the above specifications should be discussed 
with the medical monitor. 
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 
12.1.1 
Primary Objectives  
The primary objective of the study is the evaluation of safety and tolerability of VX-152 in 
TC with VX-661/IVA. The sample size calculations described below are deemed adequate to 
evaluate the safety objective of the study, based on clinical and statistical considerations. 


Protocol VX16-152-102, Version 3.0 
Page 57 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
12.1.1.1 
Safety and Tolerability 
The primary safety endpoint is the incidence of AEs. Up to approximately 72 subjects are 
planned to be enrolled in the study with up to 36 subjects receiving VX-152 in TC with 
VX-661/IVA for 2 weeks (Part 1 and Part 2, Cohort 2A), and 18 subjects receiving VX-152 
in TC with VX-661/IVA for 4 weeks (Part 1 and Part 2, Cohort 2B). The sample size for 
each treatment group in Parts 1 and 2 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 a 
sample size of 9 or 18 subjects subjects per TC 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 in TC Treatment Group a 
9 
18 
 
 
 
5% 
37% 
60% 
 
 
 
10%  
61% 
85% 
 
 
 
15% 
77% 
95% 
 
 
 
a 
AE incidences are based on 2 weeks of treatment in 9 subjects for Part 1 and Part 2 (Cohort 
1A), and 4 weeks of treatment in 18 subjects for Part 2, Cohort 2B. 
 
12.1.2 
Secondary Objectives  
The secondary objectives of the study include the evaluation of the PD effect of VX-152 in 
TC with VX-661/IVA on sweat chloride concentrations, and the evaluation of the efficacy of 
VX-152 in TC with VX-661/IVA.  
12.1.2.1 
Pharmacodynamic Effect 
The absolute change from baseline at Day 15 in sweat chloride concentrations 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 a non-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 Emax model. The contrasts (i.e., linear combinations of the treatment group means 
at Day 15) selected to perform the MCP and that capture the shape of these candidate models 
are described in Table 12-2 below.  


Protocol VX16-152-102, Version 3.0 
Page 58 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
Table 12-2 
Contrast Coefficients for the Multiple Comparisons 
Procedure in Part 1  
 
Candidate Model 
Placebo 
Cohort 1A Dose 
Cohort 1B Dose 
Cohort 1C Dose 
Linear 
3.0 
1.0 
-1.0 
-3.0 
Emax 
3.0 
-1.0 
-1.0 
-1.0 
Sigmoid Emax 
1.0 
1.0 
-1.0 
-1.0 
Note: Contrast coefficients are presented for 2 TC dose groups and placebo. 
 
Table 12-3 provides the power to detect a dose-response trend with the MCP procedure for 
3 different expected dose-response profiles with 9 subjects assigned to placebo, 9 subjects 
assigned to TC in Cohort 1A, 9 subjects assigned to TC in Cohort 1B, and 9 subjects 
assigned to TC in Cohort 1C for a total sample size of 36 subjects in Part 1 (based on 
5000 simulations for each profile using the R software package MCPMod [Version 1.0-8]). 
Table 12-3 
Power to Detect a Decreasing Dose-response Trend Based on Change 
From Baseline in Sweat Chloride in Part 1 
 
 
Mean Change From Baseline in Sweat Chloride 
Candidate Model 
Placebo 
Cohort 1A 
Dose 
Cohort 1B 
Dose 
Cohort 1C 
Dose 
Power  
Linear 
0 
-12 
-16 
-20 
94% 
Emax 
0 
-20 
-20 
-20 
98% 
Sigmoid Emax 
0 
0 
-20 
-20 
>99% 
 
 
 
 
 
 
Note: A 1-sided maximum t-statistic with a sample size of 36 subjects in Part 1 assigned to TC in Cohort 1C, 
TC in Cohort 1B, TC in Cohort 1A, and placebo at a ratio 1:1:1:1 was used for power calculations. An SD 
change from baseline in sweat chloride of 13 mmol/L was used for power calculations. 
Table 12-4 provides the power to reject the null within-group hypothesis of no decrease in 
the mean absolute change from baseline for sweat chloride at Day 15 for the TC treatment 
groups in Parts 1 and 2 with a sample size of 9 or 18 subjects per treatment group. The power 
calculations are based on a 1-sided 1-sample t-test at alpha = 5% using the software package 
PASS (Version 11.0), assuming a mean change of -10 to -20 mmol/L and an SD of 13 
mmol/L in the absolute change from baseline for sweat chloride.  
Table 12-4 
Power for Within-group Decrease 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 
9 
18 
-10 
68% 
93% 
-15 
93% 
>99% 
-20 
>99% 
>99% 
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 and 2. 
 


Protocol VX16-152-102, Version 3.0 
Page 59 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
12.1.2.2 
Efficacy 
The absolute change from baseline in ppFEV1 at Day 15 is a secondary endpoint used to 
evaluate the efficacy objective of the study. Table 12-5 provides the power to reject the null 
within-group hypothesis of no increase in the mean absolute change from baseline for 
ppFEV1 at Day 15, for the TC treatment groups in Parts 1 and 2 with a sample size of 9 or 18 
subjects per treatment group. The power calculations are based on a 1-sided 1-sample t-test at 
alpha = 5% using the software package PASS (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.  
Table 12-5 
Power for Within-group Increase for Mean Absolute Change 
From Baseline in ppFEV1 
Mean Absolute Change From 
Baseline in ppFEV1 
Number of Subjects per Treatment Groupa 
9 
18 
3% 
27% 
45% 
5% 
53% 
82% 
7% 
77% 
97% 
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 and 2. 
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 will be defined in the statistical analysis 
plan (SAP), 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 carry the intended 
CFTR allele mutation and 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 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.  


Protocol VX16-152-102, Version 3.0 
Page 60 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
12.3.1 
General Considerations 
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 will be defined in the SAP, as appropriate.  
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 and 2, separately, unless specified otherwise. 
12.3.2 
Background Characteristics 
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. 


Protocol VX16-152-102, Version 3.0 
Page 61 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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 body mass index (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. 
Dosing compliance based on number of tablets taken, will be summarized for the FAS, and 
will be derived 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). 
Dosing compliance based on study drug exposure, will be derived as 100 × [1 - (total number 
of days of study drug interruption) / (duration of study drug exposure in days)].   


Protocol VX16-152-102, Version 3.0 
Page 62 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
12.3.2.5 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a 
subject’s rights, safety, or well-being. The rules for identifying an IPD will be described in 
the SAP. 
All IPDs will be provided in an individual subject data listing. 
12.3.3 
Efficacy Analysis 
A secondary objective of the study is the evaluation of the efficacy of VX-152 in TC with 
VX-661/IVA in Parts 1 and 2. 
12.3.3.1 
Analysis of Primary Efficacy Variables 
The primary efficacy variable is the absolute change from baseline for ppFEV1 at Day 15. 
The analysis will be performed using a mixed-effects model for repeated measures (MMRM) 
with change from baseline for ppFEV1 as the dependent variable. The model will include 
treatment group, visit, and treatment-by-visit interaction as fixed effects, with the baseline 
ppFEV1 value as a covariate. The model will be estimated using restricted maximum 
likelihood. Denominator degrees of freedom for the F test for fixed effects will be estimated 
using the Kenward-Roger approximation. A compound symmetry covariance structure will 
be used to model the within-subject errors. Conditional on the fixed effects, missing data due 
to treatment or study discontinuation will be assumed to be missing at random.  
Descriptive analyses of the change from baseline will be performed for all treatment groups. 
Adjusted means and 2-sided 95% confidence intervals of the treatment effect at Day 15, with 
1-sided P values for all within-group and between-group comparisons, will be estimated 
within MMRM using LSMeans via PROC MIXED in SAS in both parts.  
 
  
 
 
There will be no multiplicity adjustment for performing multiple hypothesis tests. 
12.3.3.2 
Analysis of Secondary Efficacy Variables 
The secondary efficacy variables include: 
 Absolute change from baseline for ppFEV1 through Day 29 (Part 2, Cohort 2B only).  
 Relative change in ppFEV1 from baseline at Day 15 (Part 1 and Part 2), and through Day 
29 (Part 2, Cohort 2B only) 
 Absolute change in the CFQ-R respiratory domain score from baseline at Day 15 (Part 1 
and Part 2), and at Day 29 (Part 2, Cohort 2B only) 
Details of the analysis will be provided in the SAP. 


Protocol VX16-152-102, Version 3.0 
Page 63 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
 
 
 
 
 
 
 
12.3.4 
Pharmacodynamic Analysis 
A secondary objective of the study is the evaluation of the PD effect of VX-152 in TC with 
VX-661/IVA on sweat chloride concentrations. 
12.3.4.1 
Pharmacodynamic Effect at Day 15 
The absolute change in sweat chloride from baseline at Day 15 is a secondary endpoint used 
to evaluate the PD objective of the study. In Part 1, the test to detect a decreasing 
dose-response trend between placebo and the TC dose groups will be performed using the 
MCP procedure with the prespecified comparisons (contrasts) of the treatment group means 
within a linear MMRM framework. The model will include the absolute change from 
baseline for sweat chloride as the dependent variable, with treatment group, visit, and 
treatment-by-visit interaction as fixed effects, and the baseline sweat chloride value as a 
covariate. The test will be performed using the 1-sided maximum t-statistic of the individual 
t-statistics for the multiple prespecified contrasts at alpha = 5%, based on the treatment group 
means at Day 15.  
Further, adjusted means and 2-sided 95% confidence intervals of the treatment effect at 
Day 15, with 1-sided P values for all within-group and between-group comparisons, will be 
estimated within MMRM, in both parts.  
Additional details of the analysis will be provided in the SAP. 
12.3.4.2 
Pharmacodynamic Effect through Day 29 (Part 2, Cohort 2B only) 
The absolute change in sweat chloride from baseline through Day 29 (Part 2, Cohort 2B 
only) is also a secondary endpoint used to evaluate the PD objective of the study. The 
adjusted mean and 2-sided 95% confidence interval of the average treatment effect through 
Day 29 for the within-group and between-group comparisons in Part 2, Cohort 2B will be 
estimated within MMRM. 
12.3.5 
Safety Analysis 
The primary 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. 


Protocol VX16-152-102, Version 3.0 
Page 64 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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. In addition, 
safety data will also be summarized separately for Part 2, Cohort 2B. 
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 
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 


Protocol VX16-152-102, Version 3.0 
Page 65 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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 at least 1 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 at least 1 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 at least 1 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. 


Protocol VX16-152-102, Version 3.0 
Page 66 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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. 
12.3.6 
Interim and IDMC Analyses 
12.3.6.1 
Interim Analysis 
Interim analyses for each cohort may be performed after all subjects in the cohort have 
completed the Day 15 Visit. The results of these analyses will be reviewed by a limited 
Vertex team. When an interim analysis is performed after all subjects in 1 part have 
completed the Safety Follow-up Visit, results from that part 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 
12.4.1 
Pharmacokinetic Analysis 
The PK analysis of VX-152, VX-661 and metabolite M1-661, 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.  
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses 
PD assessments to be included in PK/PD analyses may include sweat chloride, ppFEV1, 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.  


Protocol VX16-152-102, Version 3.0 
Page 67 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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 
simulate PK profiles for each subject. The simulated VX-152, VX-661, 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 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the 
event does not necessarily have a causal relationship with the treatment. This includes any 
newly occurring event or worsening of a pre-existing condition (e.g., increase in its severity 
or frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically-significant worsening from baseline will be documented as 
an AE. When possible, a clinical diagnosis for the study assessment will be provided, rather 
than the abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a 
diagnosis, the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine 
or decreased hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more 
of the following: 
 Concomitant signs or symptoms related to the abnormal study assessment 
 Further diagnostic testing or medical/surgical intervention 
 A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of 
whether the study assessment results are clinically significant will be made by the 
investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory 
value will be an SAE if the subject’s clinical status indicates a life-threatening AE. 


Protocol VX16-152-102, Version 3.0 
Page 68 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF is signed until the following time points: 
 For subjects who do not enroll: until time of screen failure (e.g., screen failure, 
withdrawal of consent) 
 For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up 
Visit 
 For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of 
o 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.   


Protocol VX16-152-102, Version 3.0 
Page 69 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
Table 13-1 
Grading of AE Severity 
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening 
(Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to 
the study drug(s). Causality will be classified using the categories presented in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled 
out, and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to 
be related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject's medical record). 
 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action 
taken will be classified according to the categories shown in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
AE: adverse event 


Protocol VX16-152-102, Version 3.0 
Page 70 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/Resolved 
With Sequelae 
Resolution of an AE with residual signs or symptoms 
Not Recovered/Not 
Resolved (Continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
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. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
 Fatal (death, regardless of cause, that occurs during participation in the study or occurs 
after participation in the study and is suspected of being a delayed toxicity due to 
administration of the study drug) 
 Life-threatening, such that the subject was at immediate risk of death from the reaction as 
it occurred  
 Inpatient hospitalization or prolongation of hospitalization 
 Persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person's ability to conduct normal life functions) 
 Congenital anomaly or birth defect 
 Important medical event that, based upon appropriate medical judgment, may jeopardize 
the subject or may require medical or surgical intervention to prevent 1 of the outcomes 
listed above (e.g., an allergic bronchospasm requiring intensive treatment in an 
emergency room or at home)  


Protocol VX16-152-102, Version 3.0 
Page 71 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled 
sooner or to be prolonged relative to what was planned. In addition, hospitalizations clearly 
not associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may 
be of relatively minor medical significance, such as a severe headache. This is not the same 
as “serious,” which is based on subject/event outcome or action described above, and is 
usually associated with events that pose a threat to a subject's life or functioning. 
Seriousness, not severity, serves as a guide for defining expedited regulatory reporting 
obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent 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: 
 


Protocol VX16-152-102, Version 3.0 
Page 72 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in 
accordance with local applicable laws and regulations. The IRB/IEC will review all 
appropriate study documentation to safeguard the rights, safety, and well-being of the 
subjects. The study will only be conducted at sites where IRB/IEC approval has been 
obtained. The protocol, Investigator's Brochure, sample ICF, advertisements (if applicable), 
written information given to the subjects (including diary cards), safety updates, annual 
progress reports, and any revisions to these documents will be provided to the IRB/IEC by 
the investigator or Vertex, as allowable by local applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject before study participation. The method of obtaining and documenting the informed 
consent and the contents of the consent will comply with ICH GCP and all applicable laws 
and regulations and will be subject to approval by Vertex or its designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator 
and Vertex. Changes that significantly affect the safety of the subjects, the scope of the 
investigation, or the scientific quality of the study (i.e., efficacy assessments) will require 
IRB/IEC notification before implementation, except where the modification is necessary to 
eliminate an apparent immediate hazard to human subjects. Vertex will submit all protocol 
modifications to the required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the 
protocol, the investigator will contact Vertex to discuss the planned course of action. If 
possible, contact 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.  


Protocol VX16-152-102, Version 3.0 
Page 73 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit 
and for audits. The records will also be available for direct inspection, verification, and 
copying, as required by applicable laws and regulations, by officials of the regulatory health 
authorities (FDA and others). The investigator will comply with applicable privacy and 
security laws for use and disclosure of information related to the research set forth in this 
protocol.  
13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and 
privacy laws and regulations, all CRFs, study reports, and communications relating to the 
study will identify subjects by assigned subject numbers and access to subject names linked 
to such numbers shall be limited to the site and the study physician and shall not be disclosed 
to Vertex. As required by applicable laws and regulations in the countries in which the study 
is being conducted, the investigator will allow Vertex and/or its representatives access to all 
pertinent medical records to allow for the verification of data gathered in the CRFs/SAE 
forms and the review of the data collection process. The FDA and regulatory authorities in 
other jurisdictions, including the IRB/IEC, may also request access to all study records, 
including source documentation, for inspection. 
For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act and associated regulations (“HIPAA”) an executed 
HIPAA authorization shall be obtained by the site from each subject (or the legal 
representative of the subject) before research activities may begin. Each HIPAA 
authorization shall comply with all HIPAA requirements including authorization allowing the 
site access to and use of the subject’s personally identifiable health information, 
authorization for the site to disclose such information to Vertex, the FDA, and other parties 
requiring access under the protocol, and statements as to the purpose for which such 
information may be used and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and 
Vertex will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs 
may terminate the study at their center. 


Protocol VX16-152-102, Version 3.0 
Page 74 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
Conditions that may lead to reasonable cause and warrant termination include, but are not 
limited to: 
 Subject or investigator noncompliance 
 Unsatisfactory subject enrollment 
 Lack of adherence to protocol procedures 
 Lack of evaluable and/or complete data 
 Potentially unacceptable risk to study subjects 
 Decision to modify drug development plan 
 Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the 
qualifications of each investigator, inspect clinical study site facilities, and inform the 
investigator of responsibilities and procedures for ensuring adequate and correct study 
documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated, web-based electronic data capture (EDC) application. 
Vertex will have read-only access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator 
for resolution. Any changes to study data will be made to the CRF and documented in an 
audit trail, which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness 
and clarity, cross-checking with source documents, and clarification of administrative matters 
will be performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
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.  


Protocol VX16-152-102, Version 3.0 
Page 75 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.6.2 
Clinical Study Report  
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted 
in accordance with local regulations.  


Protocol VX16-152-102, Version 3.0 
Page 76 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
14 
REFERENCES 
1 
Cystic Fibrosis Foundation. 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 
Sheppard MN, Nicholson AG. The pathology of cystic fibrosis. Curr Diagn Pathol. 
2002;8(1):50-59. 
4 
Cystic Fibrosis Foundation. Patient Registry: 2014 Annual Data Report. Bethesda, 
MD: Cystic Fibrosis Foundation; 2015. 
5 
Vertex Pharmaceuticals Incorporated. Ivacaftor Investigator's Brochure, Version 12.0. 
Report date: 8 May 2015. 
6 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
7 
Vertex Pharmaceuticals Incorporated. VX-661 Investigator's Brochure, Version 7.0. 
Report date: 08 May 2015. 
8 
Vertex Pharmaceuticals Incorporated. VX-152 Investigator's Brochure, Version 1.0. 
Report date: 17 September 2015. 
9 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 
2012 equations. Eur Respir J. 2012;40(6):1324-43. 
10 
Levey AS, Bosch J, Lewis J, Greene 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. 
11 
Levey AS, Coresh J, Greene T, Stevens L, Zhang Y, 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. 
12 
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. 
13 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 
14 
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. 
15 
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing the quality of life in pediatric and adult patients. 
Qual Life Res. 2003;12(1):63-76. 
16 
Charles River Laboratories Inc. Report WIL-395107. Vertex Report Number 
VX-152-TX-005. An Oral (Gavage) Dose Range-Finding Study of the Effects of 
VX-152 on Embryo/Fetal Development in Rats. Audited Draft Report date: 
19 September 2016. 


Protocol VX16-152-102, Version 3.0 
Page 77 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
17 
Charles River Laboratories Inc. Report WIL-395109. Vertex Report Number 
VX-152-TX-007. VX-152: An Oral (Gavage) Study of the Effects on Embryo/Fetal 
Development in Rats. Audited Draft Report date: 20 May 2016. 
18 
Charles River Laboratories Inc. Report WIL-395106. Vertex Report Number 
VX-152-TX-004. An Oral (Gavage) 7-Day Tolerability Study of VX-152 in 
Nonpregnant New Zealand White Rabbits. Unaudited Draft Report date: 
9 March 2016. 
19 
Charles River Laboratories Inc. Report WIL-395108. Vertex Report Number 
VX-152-TX-006. VX-152: An Oral (Gavage) Dose Range-Finding Study of the 
Effects on Embryo/Fetal Development in Rabbits. Audited Draft Report date: 
10 May 2016. 
20 
Charles River Laboratories Inc. Report WIL-395110. Vertex Report Number 
VX-152-TX-008. VX-152: An Oral (Gavage) Study of the Effects on Embryo/Fetal 
Development in Rabbits. Audited Draft Report date: 15 July 2016. 
 


Protocol VX16-152-102, Version 3.0 
Page 78 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
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 Part 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 VX-661 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 VX-661 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; 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. 
 
CFTR Mutations Eligible for VX15-152-101, Part 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 


Protocol VX16-152-102, Version 3.0 
Page 79 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
CFTR Mutations Eligible for VX15-152-101, Part 1 
Criteria 
Mutation 
 
 
 
 
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 
 
Class II, III, IV mutations 
not responsive to IVA 
alone or in combination 
with VX-661 or LUM  
 
%PI >50% and/or 
SwCl- >86 mmol/L 
AND 
 
Not responsive 
in vitro to IVA alone 
or in combination 
with VX-661 or 
LUM 
A46Db 
V520F 
Y569Db 
 
 
G85E 
A559Tb 
L1065P 
 
R347P 
R560T 
R1066C 
 
L467Pb 
R560S 
M1101K 
 
I507del 
A561E 
N1303K 
 
 
 
 
CFTR: cystic fibrosis transmembrane conductance regulator; IVA: ivacaftor; LUM: lumacaftor; SwCl-: sweat 
chloride; PI: pancreatic insufficiency 
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.  
 
 




Protocol VX16-152-102, Version 3.0 
Page 81 of 81 
Vertex Pharmaceuticals Incorporated                                                                               
 
15.2 
Investigator Signature Page 
Protocol #: 
VX16-152-102 
Version #: 
3.0 
Version Date: 
14 April 2017 
Study Title: A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety 
of VX-152 Combination Therapy in Adults With Cystic Fibrosis 
 
 
I have read Protocol VX16-152-102, Version 3.0, and agree to conduct the study according 
to its terms. I understand that all information concerning VX-152, VX-661, and ivacaftor, 
and this protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is 
confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 68 
Protocol Number: VX16-152-102 Version 3.0 
 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX16-152-102 Version 3.0 
(Final Analysis) 
 
A Phase 2, Randomized, Double blind, Controlled Study to Evaluate 
the Safety of VX-152 Combination Therapy in Adults With Cystic 
Fibrosis 
 
 
Author of SAP: 
 
 
Version: 1.0 
Version Date of SAP: 27 July 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) 
Page 2 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
1 
TABLE OF CONTENTS 
1 
Table of Contents ............................................................................................................. 2 
 
 
 
 
 
 
 
 
3 
Introduction...................................................................................................................... 5 
4 
Study Objectives .............................................................................................................. 5 
4.1 
Primary Objective ....................................................................................................... 5 
4.2 
Secondary Objectives ................................................................................................. 5 
5 
Study Endpoints ............................................................................................................... 6 
5.1 
Efficacy Endpoint ....................................................................................................... 6 
5.1.1 
Primary Efficacy Endpoint ................................................................................. 6 
5.1.2 
Secondary Efficacy Endpoints ............................................................................ 6 
 
 
5.2 
Safety Endpoints ......................................................................................................... 6 
6 
Study Design ..................................................................................................................... 6 
6.1 
Overall Design ............................................................................................................ 6 
6.2 
Sample Size and Power .............................................................................................. 9 
6.2.1 
Primary Objectives ............................................................................................. 9 
6.2.2 
Secondary Objectives ......................................................................................... 9 
6.3 
Randomization .......................................................................................................... 11 
6.4 
Blinding and Unblinding .......................................................................................... 11 
6.4.1 
Blinding ............................................................................................................ 11 
6.4.2 
Unblinding ........................................................................................................ 12 
7 
Analysis Sets ................................................................................................................... 13 
7.1 
All Subjects Set ........................................................................................................ 13 
7.2 
Full Analysis Set ....................................................................................................... 13 
7.3 
Safety Set .................................................................................................................. 13 
8 
Statistical Analysis ......................................................................................................... 14 
8.1 
General Considerations ............................................................................................ 14 
8.2 
Background Characteristics ...................................................................................... 16 
8.2.1 
Subject Disposition ........................................................................................... 16 
8.2.2 
Demographics and Baseline Characteristics ..................................................... 17 
8.2.3 
Prior and Concomitant Medications ................................................................. 18 
8.2.4 
Study Drug Exposure........................................................................................ 18 
8.2.5 
Study Drug Compliance ................................................................................... 19 
8.2.6 
Important Protocol Deviations .......................................................................... 19 
8.3 
Efficacy Analysis ...................................................................................................... 20 
8.3.1 
Primary Efficacy Variable ................................................................................ 20 
8.3.2 
Analysis of Secondary Efficacy Variables ....................................................... 22 
 
 
 
 


Statistical Analysis Plan (Methods) 
Page 3 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
8.4 
Pharmacodynamic Analysis ..................................................................................... 24 
8.5 
Safety Analysis ......................................................................................................... 25 
8.5.1 
Adverse Events ................................................................................................. 25 
8.5.2 
Clinical Laboratory ........................................................................................... 27 
8.5.3 
Electrocardiogram ............................................................................................ 27 
8.5.4 
Vital Signs ........................................................................................................ 27 
8.5.5 
Pulse Oximetry ................................................................................................. 28 
8.5.6 
Physical Examination ....................................................................................... 28 
8.5.7 
Other Safety Analysis ....................................................................................... 28 
9 
Interim and IDMC Analysis ......................................................................................... 28 
9.1 
Interim Analysis ....................................................................................................... 28 
9.1.1 
Summary of the Flow of Data for Interim Analyses by a Limited Vertex 
Team ................................................................................................................. 28 
9.2 
IDMC Analysis ......................................................................................................... 29 
10 References ....................................................................................................................... 30 
11 List of Appendices.......................................................................................................... 31 
Appendix A: Schedule of Assessments.............................................................................. 31 
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments ................... 43 
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates ........... 48 
Appendix D: Important Protocol Deviation Programming Rules ...................................... 49 
Appendix E: Details of GLI Equations for Calculating ppFEV1 ....................................... 51 
 
Appendix G: Imputation Rules for Missing AE dates ....................................................... 54 
Appendix H: Criteria for Threshold Analysis .................................................................... 57 
 
 




Statistical Analysis Plan (Methods) 
Page 5 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
3 
INTRODUCTION 
This statistical analysis plan (SAP) for the final analysis is based on the approved clinical 
study protocol (CSP), Version 3.0, dated 14 Apr 2017, approved electronic case report form 
(eCRF), Version 1.0, dated 28 Oct 2016, and approved eCRF completion guidelines, Version 
1.0, dated 24 Nov 2016. This SAP will also be used to perform interim analyses (IAs) that 
may be performed for each cohort after 50% or 100% subjects in the cohort have completed 
the Day 15 Visit or Day 29 Visit. 
This is a Phase 2, 2-part, randomized, double blind, placebo and VX-661/ivacaftor (IVA) 
controlled, parallel group, multicenter study designed to evaluate the safety of VX-152 in TC 
with VX-661 and IVA. 
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 9.4 (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 unblinding of the data for the 
first IA that involves model-based analyses. 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-152 in triple combination (TC) with 
VX-661 and IVA in adults with cystic fibrosis (CF) 
4.2 
Secondary Objectives  
 To evaluate the pharmacodynamic (PD) effect of VX-152 in TC with VX-661 and 
IVA on CFTR function 
 To evaluate the efficacy of VX-152 in TC with VX-661 and IVA 
 To evaluate the pharmacokinetics (PK) of VX-152 when administered in TC with 
VX-661 and IVA 
 To evaluate the PK of VX-661, IVA, and their respective metabolites when 
administered with VX-152 


Statistical Analysis Plan (Methods) 
Page 6 of 68 
Protocol Number: VX16-152-102 Version 3.0 
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 second (ppFEV1) 
from baseline at Day 15 (Parts 1 and 2) and through Day 29 (Part 2, Cohort 2B only)  
5.1.2 
Secondary Efficacy Endpoints 
 Absolute change in sweat chloride concentrations from baseline at Day 15 (Parts 1 and 2) 
and through Day 29 (Part 2, Cohort 2B only) 
 Relative change in ppFEV1 from baseline at Day 15 (Parts 1 and 2) and through Day 29 
(Part 2, Cohort 2B only) 
 Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain 
score from baseline at Day 15 (Parts 1 and 2) and at Day 29 (Part 2, Cohort 2B only) 
 
 
 
 
 
5.2 
Safety Endpoints 
Safety and tolerability assessments are evaluated via the following: 
 adverse events (AEs) 
 clinical laboratory values 
 standard 12-lead electrocardiograms (ECGs) 
 vital signs 
 pulse oximetry 
6 
STUDY DESIGN  
6.1 
Overall Design  
This is a Phase 2, 2-part, randomized, double blind, placebo and VX-661/IVA controlled, 
parallel group, multicenter study designed to evaluate the safety of VX-152 in TC with VX-
661/IVA.  
Up to approximately 72 subjects with CF are planned for enrollment: up to approximately 36 
subjects in each of Part 1 (F508del/MF genotype) and in Part 2 (F508del/F508del genotype).  
Parts 1 and 2 will enroll multiple cohorts, with each cohort evaluating 1 dose level of VX-
152 as part of TC with VX-661/IVA (100 mg qd/150 mg q12h). Each cohort will enroll up to 
approximately 12 subjects in Part 1 and Part 2 Cohort 2A and up to approximately 24 
subjects in Part 2 Cohort 2B. Subjects in all cohorts will be randomized 3:1 (active TC: 


Statistical Analysis Plan (Methods) 
Page 7 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
comparator). Triple placebo will be the comparator in Part 1, and VX-661/IVA will be the 
comparator in Part 2. 
Up to 3 cohorts are planned for Part 1 (Cohorts 1A, 1B, and 1C). Up to 2 cohorts are planned 
for Part 2 (Cohorts 2A and 2B). The doses of VX-152 planned for evaluation are 100 mg 
q12h in Cohort 1A, 200 mg q12h in Cohorts 1B and 2A, and 300 mg q12h in Cohorts 1C and 
2B. The dose of VX-152 may be adjusted to be lower or the same as the dose level evaluated 
in the previous cohort. 
The actual number of cohorts enrolled in each part may be modified based on emerging 
safety and PK data. Blinded reviews of safety and available PK data will be conducted by the 
Vertex study team and lead investigator(s) on an ongoing basis. 
Cohorts will initiate dosing as follows: 
 Cohort 1A will initiate dosing first.  
 Cohorts 1B and 2A may initiate dosing if supported by blinded review of safety and 
available PK data after all subjects in Cohort 1A complete the Day 15 Visit. 
 Cohorts 1C and 2B may initiate dosing if supported by blinded review of safety and 
available PK data after any of the following has occurred: 
o All subjects in Cohort 1B complete the Day 15 Visit. 
o All subjects in Cohort 2A complete the Day 15 Visit. 
o At least 12 subjects across Cohorts 1B and 2A complete the Day 15 Visit. 
A schematic of the study design (including the doses of VX-152, VX-661, and IVA to be 
evaluated) is shown in Figure 6-1.  


Statistical Analysis Plan (Methods) 
Page 8 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
Figure 6-1 
Schematic of the Study Design 
 
Notes: Schematic is not drawn to scale. The actual number of cohorts enrolled in each part may be modified 
based on emerging safety and PK data. The planned doses of VX-152 are shown in the figure but may be 
adjusted to be lower or the same as the dose level evaluated in the previous cohort. VX-661 will be 
administered 100 mg qd. IVA will be administered 150 mg q12h. 
Part 1: F508del/MF (up to ~12 subjects per cohort; randomized 3:1) 
Part 2: F508del/F508del (up to ~12 subjects in Cohort 2A, up to ~24 subjects in 
Cohort 2b; randomized 3:1) 
VX-152 100 mg q12h + 
VX-661/IVA 
N = 9
Triple Placebo 
Cohort 1A 
N = 3 
Treatment Period 
2 weeks 
N = 9 
N = 3 
VX-661/IVA 
Washout Period 
2 weeks 
VX-152 200 mg q12h + 
VX-661/IVA 
Placebo + VX-661/IVA 
Cohort 2A 
 
VX-661/IVA 
Run-in Period 
4 weeks 
Screening 
Treatment Period 
2 weeks 
Screening 
Safety Follow-up  
Cohort 1B 
 
VX-152 200 mg q12h + 
VX-661/IVA 
N = 9
Triple Placebo 
N = 3 
Cohort 1C 
 
VX-152 300 mg q12h + 
VX-661/IVA 
N = 9 
N = 3
Triple Placebo 
Cohort 2B 
 
VX-661/IVA 
VX-152 300 mg q12h + VX-661/IVA 
Placebo + VX-661/IVA 
VX-661/IVA 
N = 6 
N = 18 
Run-in Period 
4 weeks 
Treatment Period 
4 weeks 
Washout Period 
2 weeks 
Screening 
Safety 
Follow-up 
Safety 
Follow-up 


Statistical Analysis Plan (Methods) 
Page 9 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
6.2 
Sample Size and Power 
6.2.1 
Primary Objectives  
The primary objective of the study is the evaluation of safety and tolerability of VX-152 in 
TC with VX-661/IVA. The sample size calculations described below are deemed adequate to 
evaluate the safety objective of the study, based on clinical and statistical considerations. 
6.2.1.1 
Safety and Tolerability 
The primary safety endpoint is the incidence of AEs. Up to approximately 72 subjects are 
planned to be enrolled in the study with up to 36 subjects receiving VX-152 in TC with 
VX-661/IVA for 2 weeks (Part 1 and Part 2, Cohort 2A), and 18 subjects receiving VX-152 
in TC with VX-661/IVA for 4 weeks (Part 1 and Part 2, Cohort 2B). The sample size for 
each treatment group in Parts 1 and 2 will provide sufficient data for a descriptive analysis of 
AEs. Table 6-1 provides the probability of observing an AE in at least 1 subject based on a 
sample size of 9 or 18 subjects per TC 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 6-1 
Probability of Observing an Adverse Event 
AE Incidencesa 
Number of Subjects in TC Treatment Group a 
9 
18 
5% 
37% 
60% 
10%  
61% 
85% 
15% 
77% 
95% 
a 
AE incidences are based on 2 weeks of treatment in 9 subjects for Part 1 and Part 2 (Cohort 
1A), and 4 weeks of treatment in 18 subjects for Part 2, Cohort 2B. 
 
6.2.2 
Secondary Objectives  
The secondary objectives of the study include the evaluation of the PD effect of VX-152 in 
TC with VX-661/IVA on sweat chloride concentrations, and the evaluation of the efficacy of 
VX-152 in TC with VX-661/IVA.  
6.2.2.1 
Pharmacodynamic Effect  
The absolute change from baseline at Day 15 in sweat chloride concentrations 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 a non-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 Emax model. The contrasts (i.e., linear combinations of the treatment group means 


Statistical Analysis Plan (Methods) 
Page 10 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
at Day 15) selected to perform the MCP and that capture the shape of these candidate models 
are described in Table 6-2 below.  
Table 6-2 
Contrast Coefficients for the Multiple Comparisons 
Procedure in Part 1  
 
Candidate Model 
Placebo 
Cohort 1A Dose 
Cohort 1B Dose 
Cohort 1C Dose 
Linear 
3.0 
1.0 
-1.0 
-3.0 
Emax 
3.0 
-1.0 
-1.0 
-1.0 
Sigmoid Emax 
1.0 
1.0 
-1.0 
-1.0 
Note: Contrast coefficients are presented for 2 TC dose groups and placebo. 
 
Table 6-3 provides the power to detect a dose-response trend with the MCP procedure for 
3 different expected dose-response profiles with 9 subjects assigned to placebo, 9 subjects 
assigned to TC in Cohort 1A, 9 subjects assigned to TC in Cohort 1B, and 9 subjects 
assigned to TC in Cohort 1C for a total sample size of 36 subjects in Part 1 (based on 
5000 simulations for each profile using the R software package MCPMod [Version 1.0-8]). 
Table 6-3 
Power to Detect a Decreasing Dose-response Trend Based on Change 
From Baseline in Sweat Chloride in Part 1 
 
 
Mean Change From Baseline in Sweat Chloride 
Candidate Model 
Placebo 
Cohort 1A 
Dose 
Cohort 1B 
Dose 
Cohort 1C 
Dose 
Power  
Linear 
0 
-12 
-16 
-20 
94% 
Emax 
0 
-20 
-20 
-20 
98% 
Sigmoid Emax 
0 
0 
-20 
-20 
>99% 
Note: A 1-sided maximum t-statistic with a sample size of 36 subjects in Part 1 assigned to TC in Cohort 1C, TC in Cohort 
1B, TC in Cohort 1A, and placebo at a ratio 1:1:1:1 was used for power calculations. An SD change from baseline in 
sweat chloride of 13 mmol/L was used for power calculations. 
Table 6-4 provides the power to reject the null within-group hypothesis of no decrease in the 
mean absolute change from baseline for sweat chloride at Day 15 for the TC treatment 
groups in Parts 1 and 2 with a sample size of 9 or 18 subjects per treatment group. The power 
calculations are based on a 1-sided 1-sample t-test at alpha = 5% using the software package 
PASS (Version 11.0), assuming a mean change of -10 to -20 mmol/L and an SD of 13 
mmol/L in the absolute change from baseline for sweat chloride.  
Table 6-4 
Power for Within-group Decrease 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 
9 
18 
-10 
68% 
93% 
-15 
93% 
>99% 
-20 
>99% 
>99% 
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 and 2. 
 


Statistical Analysis Plan (Methods) 
Page 11 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
6.2.2.2 
Efficacy 
The absolute change from baseline in ppFEV1 at Day 15 is a secondary endpoint used to 
evaluate the efficacy objective of the study. Table 6-5 provides the power to reject the null 
within-group hypothesis of no increase in the mean absolute change from baseline for 
ppFEV1 at Day 15, for the TC treatment groups in Parts 1 and 2 with a sample size of 9 or 18 
subjects per treatment group. The power calculations are based on a 1-sided 1-sample t-test at 
alpha = 5% using the software package PASS (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.  
Table 6-5 
Power for Within-group Increase for Mean Absolute Change 
From Baseline in ppFEV1 
Mean Absolute Change From 
Baseline in ppFEV1 
Number of Subjects per Treatment Groupa 
9 
18 
3% 
27% 
45% 
5% 
53% 
82% 
7% 
77% 
97% 
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 and 2. 
6.3 
Randomization 
Approximately 12 subjects or 24 subjects (Part 2, Cohort 2B) will be randomized in the ratio 
3:1 to TC versus comparator in each cohort. An interactive web response system (IWRS) will 
be used to assign subjects to treatment. The randomization code lists was produced by 
 
 
6.4 
Blinding and Unblinding 
This will be a double-blind study.  
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 


Statistical Analysis Plan (Methods) 
Page 12 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
 Vertex IWRS Manager 
 Vertex Clinical Supply Chain 
 IDMC 
 Vendor performing the interim analyses and preparing the unblinded analysis for the 
ongoing reviews of efficacy and safety data, and a limited Vertex team not involved 
in the conduct of the study 
 Vendor analyzing PK samples and Vertex Bioanalytical staff (non-study team) 
reviewing raw data from vendor 
 Vertex Modeling and Simulations 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 
Sweat Chloride and Spirometry Blinding: During the conduct of the study, the Vertex study 
team will not have access to the spirometry results after the morning dose on Day 1. 
Furthermore, sites, subjects, and their parents/caregivers/companions should not be informed 
of their study-related sweat chloride and spirometry results during the Treatment Period 
regardless of whether the subject has prematurely discontinued treatment. 
A limited Vertex team not involved in the conduct of the study will be unblinded to results of 
the interim analyses and will 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.  
The Vertex study team and lead investigator(s) will also conduct blinded reviews of all 
available safety and PK data after all subjects within a cohort complete the Day 15 Visit to 
make decisions about dose selection for potential subsequent cohorts. 
When an interim analysis is performed after all subjects in 1 part have completed the Safety 
Follow-up Visit, results from that part will be unblinded for full review by the Vertex study 
team. 
6.4.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process.  
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment 
is necessary for clinical management. In such cases, investigators will use their best 
judgment as to whether to unblind without first attempting to contact the medical monitor to 
discuss and agree to the need for unblinding. If investigators deem it not necessary to unblind 
immediately, they will first attempt to contact the medical monitor to discuss and agree to the 
need for unblinding. If investigators have tried but are unable to reach the medical monitor, 
they will use their best judgment, based on the nature and urgency of the clinical situation, 


Statistical Analysis Plan (Methods) 
Page 13 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
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 of the protocol. 
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. 
7 
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set, Full Analysis Set and Safety Set.  
7.1 
All Subjects Set 
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.  
7.2 
Full Analysis Set  
The Full Analysis Set (FAS) will be defined as all randomized subjects who carry the 
intended CFTR allele mutation and 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 specified otherwise. 
7.3 
Safety Set 
Part 1: 
The Safety Set will include all subjects who received at least 1 dose of study drug. The 
Safety Set will be used for all safety analyses, unless otherwise specified. 
If a subject received at least 1 dose of the higher VX-152 dose, then the subject will be 
analyzed in the treatment group with the highest VX-152 dose in the order of triple placebo, 


Statistical Analysis Plan (Methods) 
Page 14 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
VX-152 100mg + VX-661/IVA, VX-152 200mg + VX-661/IVA, and VX-152 300mg + VX-
661/IVA.   
Part 2:  
The Safety Set for the Run-in Period will include all subjects who received at least 1 dose 
of study drug 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 VX-152 dose, then the subject will be 
analyzed in the treatment group with the highest VX-152 dose in the order of placebo + 
TEZ/IVA, VX-152 200mg + VX-661/IVA, and VX-152 300mg + VX-661/IVA.   
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, unless 
specified otherwise. The treatment groups are defined as follows:   
 Part 1: F508del/MF genotype group 
o VX-152 100mg q12h + VX-661/IVA, VX-152 200mg q12h + VX-661/IVA, VX-
152 300mg q12h + VX-661/IVA, and placebo, with VX-661 component 
administered as 100 mg qd and IVA component administered as 150 mg q12h.  
 Part 2: F508del/F508del genotype group  
o VX-152 200mg q12h + VX-661/IVA, VX-152 300mg q12h + VX-661/IVA, VX-
661/IVA, VX-661/IVA from Cohort 2A and VX-661/IVA from Cohort 2B, with 
VX-661 component administered as 100 mg qd and IVA component administered 
as 150 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.  
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 


Statistical Analysis Plan (Methods) 
Page 15 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
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 (or 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 Part 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 did 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). Only data 
collected up to the end of study for a subject will be included in analysis. 
 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 study early and re-enter Study 661-110). 
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/last on-treatment measurements. 
 In the derivation of maximum/minimum on-treatment values and maximum/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. 
Spirometry (ppFEV1) will be used for both efficacy and safety purposes. For efficacy 
analysis, the assessments will follow the visit windowing rules for efficacy. For safety 
analysis, the assessments at 5 hours post-dose on nominal days 1 and 15 will be used. 


Statistical Analysis Plan (Methods) 
Page 16 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
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 Parts 1 and 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, as applicable:  
 All Subjects Set  
 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 drug 
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:  
 Safety Set for the Run-in Period 
 Enrolled but not 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. 


Statistical Analysis Plan (Methods) 
Page 17 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
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, 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) 
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) 
 Infection with Pseudomonas aeruginosa at baseline (Positive, Negative) 
Medical history will be summarized by MedDRA system organ class (SOC) and preferred 
term (PT) based 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. 


Statistical Analysis Plan (Methods) 
Page 18 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
8.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced (WHO-DDE) and categorized as the following: 
For Part 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 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 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. Concomitant for Part 2 can be concomitant during the Run-in Period, 
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 only.  
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, 


Statistical Analysis Plan (Methods) 
Page 19 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
which includes the Run-in Period, Treatment Period and Washout Period for Part 2, and the 
Treatment Period for Part 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, >4- ≤6 weeks and >6 weeks, 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. 
The protocol deviations that should be considered as potential IPDs include, but are not 
limited to: 
 Subject was enrolled in the study despite the violation of inclusion/exclusion criteria 
 Subject was less than 80% compliant with study drug  
 Subject received prohibited concomitant medications 
 Subject received the wrong treatment or incorrect doses  


Statistical Analysis Plan (Methods) 
Page 20 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
 Subject remained in the study despite meeting withdrawal criteria 
Occurrence of any of these events should be considered as potential IPDs, but a blinded team 
should categorize them as IPDs only if they have the potential to significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a 
subject’s rights, safety, or well-being.  
IPDs will be provided in an individual subject data listing. Details of the IPD rules are 
provided in Appendix D. 
8.3 
Efficacy Analysis  
All efficacy analyses described in this section will be based on the FAS, unless otherwise 
specified. The placebo groups will be pooled across all cohorts in Part 1. The TEZ/IVA 
groups of varying durations during the Treatment Period (2 weeks and 4 weeks) will be kept 
separate in Part 2, unless specified otherwise.  The analysis will include all available 
measurements through the last scheduled on-treatment visit including measurements after 
treatment discontinuation, per the visit windowing rules described in Appendix B. The post-
dose measurements on the same day will not be used for any model-based analyses. 
8.3.1 
Primary Efficacy Variable 
The primary efficacy variable is the absolute change from baseline for percent predicted 
FEV1 at Day 15 in Part 1 and Part 2 Cohort 2A, and through Day 29 in Part 2 Cohort 2B.  
The percent predicted FEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), expressed as a 
percentage. The predicted FEV1 will be calculated using the Quanjer GLI-2012 Regression 
Equations and Lookup Tables, adjusting for age, height, sex and geographic region. Details 
are provided in Appendix E. 
8.3.1.1 
Primary Analysis of the Primary Efficacy Variable 
The null hypothesis to be tested is that the mean absolute change from baseline in percent 
predicted FEV1 (ppFEV1) is not greater than zero for VX-152 in triple combination (TC) 
with VX-661/IVA at Day 15 in Part 1 and Part 2 Cohort 2A and through Day 29 in Part 2 
Cohort 2B.  
Part 1:  
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. This MMRM 
analysis will include all treatment groups within Part 1, including placebo, VX-152 100mg, 
VX-152 200mg and VX-152 300mg. 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 up to Day 15. 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. A compound symmetry covariance structure will be used to model the 
within-subject errors. 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.  


Statistical Analysis Plan (Methods) 
Page 21 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
The adjusted means and 95% confidence intervals (CI) of the treatment effect for each triple 
combination at Day 15, with a 1-sided P value, will be estimated within MMRM using 
PROC MIXED in SAS, for all within-treatment and between-treatment comparisons. 
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 15, will be used to estimate the treatment effect at Day 
15, with the corresponding 1-sided P value for the 1-sided hypothesis test.  
Further, the adjusted mean and the 2-sided 95% CI of the treatment difference for within-
group and between-group comparisons at each post-baseline visit up to Day 15 will be 
provided.  
In addition, descriptive analyses of the change from baseline will be performed for all 
treatment groups by post-baseline visit.  
The adjusted mean (with 95% CI) obtained from the MMRM analysis at each post-baseline 
visit through Day 15 will also be plotted by treatment group. In addition, a waterfall plot 
showing the subject-level absolute change in ppFEV1 at Day 15 will be presented, by 
treatment group.  
Part 2:  
A similar MMRM with change from baseline in ppFEV1 as the dependent variable will be 
performed separately for each cohort in Part 2. The MMRM analysis will include VX-
661/IVA and VX-152 200mg for Cohort 2A, and VX-661/IVA and VX-152 300mg for 
Cohort 2B.  
The adjusted means and 95% CI of the treatment effect for each triple combination at Day 15 
in Cohort 2A and through Day 29 in Cohort 2B, with a 1-sided P value, will be estimated for 
all within-treatment and between-treatment comparisons. 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 15 
for Cohort 2A and through Day 29 for Cohort 2B, will be used to estimate the treatment 
effect at Day 15 in Cohort 2A and the average treatment effect through Day 29 (Day 15 and 
Day 29 only) in Part 2 Cohort 2B, with the corresponding 1-sided P value for the 1-sided 
hypothesis test. 
In addition, descriptive analyses of the change from baseline will be performed for all 
treatment groups by post-baseline visit.  
The adjusted mean (with 95% CI) obtained from the MMRM analysis at each post-baseline 
visit will also be plotted separately for each cohort. In addition, a waterfall plot showing 
subject-level absolute change in ppFEV1 at Day 15 for Cohort 2A and at Day 29 for Cohort 
2B will be presented, by treatment group.   
 
 
 
 
 


Statistical Analysis Plan (Methods) 
Page 22 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
 
 
 
 
 
   
 
 
  
 
 
 
   
8.3.2 
Analysis of Secondary Efficacy Variables 
The secondary efficacy variables include: 
 Relative change in ppFEV1 from baseline at Day 15 (Part 1 and Part 2 Cohort 2A) and 
through Day 29 (Part 2 Cohort 2B) 
 Absolute change in the CFQ-R respiratory domain score from baseline at Day 15 (Part 1 
and Part 2 Cohort 2A) and at Day 29 (Part 2 Cohort 2B) 
8.3.2.1 
Relative change in ppFEV1 from baseline at Day 15 (Part 1 and 
Part 2 Cohort 2A) and through Day 29 (Part 2 Cohort 2B) 
The relative change in ppFEV1 from baseline is defined in Section 8.1. Analysis of this 
variable will be based on an MMRM model, similar to the primary analysis of the primary 
efficacy variable. The presentation of results will also be similar. 
8.3.2.2 
Absolute change in the CFQ-R respiratory domain score from 
baseline at Day 15 (Part 1 and Part 2 Cohort 2A) and at Day 29 
(Part 2 Cohort 2B) 
The absolute change in the CFQ-R respiratory domain score from baseline at Day 15 (Part 1 
and Part 2 Cohort 2A) and at Day 29 (Part 2 Cohort 2B) will use the 'Adolescents and Adults' 
Version for ages 14 and above at baseline, and will be based on the CFQ-R scaled scores,
 
 For Part 1, the analysis of this variable will be based on an 
ANCOVA model with treatment as a fixed effect. For Part 2, the analysis of this variable will 
be based on an MMRM model, similar to the analysis of the primary efficacy variable.  The 
continuous baseline CFQ-R respiratory domain score will be used as a covariate in Parts 1 
and 2. The presentation of results will also be similar. 
 
 
 
 
 
 


Statistical Analysis Plan (Methods) 
Page 23 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan (Methods) 
Page 24 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
 
  
8.4 
Pharmacodynamic Analysis  
The sweat chloride measurement for a given visit will be calculated as the mean of the non-
missing sweat chloride measurements obtained on the left and right arms at that visit. If one 
of the two arm measurements at a time point is missing, the other will be used as the mean. A 
volume ≥15 μL is required for an accurate determination of sweat chloride. Any results 
reported as having volume <15 μL will be considered missing. Any sweat chloride values 
reported as <10 mmol/L or >160 mmol/L will be considered missing. 
The analysis of the pharmacodynamic (PD) effect of VX-152 in TC with VX-661/IVA (all 
parts) on sweat chloride concentrations will be described in this section. 
8.4.1.1 
Primary Analysis of the Dose Response trend of absolute change 
in sweat chloride from baseline at Day 15 in Part 1 
The null hypothesis to be tested is that the dose response of the mean absolute change from 
baseline at Day 15 for sweat chloride is not decreasing between placebo and the TC dose 
groups. The test will be performed using the MCP procedure with the pre-specified contrasts 
provided in Section 6.2.2.1, within a linear MMRM framework using PROC GLIMMIX in 
SAS. The model will include treatment group, visit, and treatment-by-visit interaction as 
fixed effects, with continuous baseline sweat chloride as a covariate. The dose response test 
will be based on the 1-sided maximum t-statistic of the individual t-statistics for the multiple 
pre-specified contrasts at alpha = 5%, based on the treatment group means at Day 15, using a 
compound symmetry covariance structure for the within-subject errors 
The presentation of results for the treatment effect at Day 15, and the treatment effect by visit 
will be similar to the primary analysis of the primary efficacy variable. The corresponding P 
value for the decreasing dose response trend will be provided. In addition, descriptive 
analyses of the change from baseline will be performed for all treatment groups at each post-
baseline visit. A waterfall plot showing the subject-level absolute change from baseline in 
sweat chloride at Day 15 will be presented, by treatment group. 
8.4.1.2 
Absolute change in sweat chloride from baseline at Day 15 (Part 2 
Cohort 2A) and through Day 29 (Part 2 Cohort 2B) 
The analysis of the absolute change in sweat chloride from baseline at Day 15 (Part 2 Cohort 
2A) and through Day 29 (Part 2 Cohort 2B) using the average of Day 15 and Day 29, will be 
based on an MMRM model fitted to each cohort, separately, similar to the analysis of the 
primary efficacy variable, 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 in the Treatment Period will also be plotted by treatment group, for each cohort, 
separately.  
In addition, descriptive analyses of the change from baseline will be performed for all 
treatment groups at each post-baseline visit.  


Statistical Analysis Plan (Methods) 
Page 25 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
A waterfall plot showing the subject-level absolute change in sweat chloride at Day 15 and 
Day 29, as applicable, will be presented, by treatment group.  
 
  
 
 
 
 
 
     
 
 
  
 
 
 
   
8.5 
Safety Analysis 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
 Adverse events 
 Clinical laboratory values (hematology, chemistry, coagulation, and urinalysis) 
 Standard 12-lead electrocardiograms 
 Vital signs  
 Pulse oximetry 
Safety endpoints will be analyzed based on the Safety Set. Only a descriptive analysis of 
safety will be performed. Safety results for treatment groups in Part 2 Cohort 2A and Part 2 
Cohort 2B will be presented separately, and overall.   
For Part 2, the Safety Set refers to the Safety Set for the Treatment Period.  
8.5.1 
Adverse Events  
AEs will be classified as pretreatment AEs, TEAEs, or post-treatment AEs, defined as 
follows:  
For Part 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 


Statistical Analysis Plan (Methods) 
Page 26 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
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 G. 
An adverse event overview table will be provided for the TE period (TE period for the 
Treatment Period for Part 2) by treatment group, 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 Treatment Discontinuation  
 Subjects with TEAEs Leading to Drug Interruption  
 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, 
and only the maximum severity level will be presented in the severity summaries, and the 
strongest relationship level in the relationship summaries.   
All AEs, including pre-treatment AEs, TEAEs for all applicable periods, and post-treatment 
AEs, will be presented in an individual subject data listing based on the All Subjects Set. 
Subjects who enrolled from Study 661-110 will be identified in the listing based on the 
subject ID.  


Statistical Analysis Plan (Methods) 
Page 27 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
8.5.2 
Clinical Laboratory 
For the treatment-emergent laboratory assessments, the observed values and change from 
baseline values of the continuous hematology, chemistry, and coagulation results will be 
summarized in SI units at each scheduled visit, by treatment group and part.  
The number and percentage of subjects meeting at least 1 threshold analysis criterion event 
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. The threshold analysis criterion 
shift from baseline will also be summarized for selected laboratory parameters.  The 
threshold analysis criteria are provided in Appendix H.  
For select LFT laboratory test (alanine aminotransferase [ALT], aspartate aminotransferase 
[AST], alkaline phosphatase [ALP], and total bilirubin), a scatter plot of the maximum 
treatment-emergent value versus the baseline value corresponding to xULN will be 
presented. Further, a scatter plot of the maximum treatment-emergent value of ALT and 
AST, separately, versus the maximum treatment-emergent value of total bilirubin 
corresponding to xULN will also be presented by treatment group, for each part.   
Results of abnormal urinalysis and positive urine/serum pregnancy test will be listed in 
individual subject data listings only.  
In addition, a listing containing individual subject hematology, chemistry, urinalysis, and 
coagulation values outside the normal reference ranges will be provided. This listing will 
include data from both scheduled and unscheduled visits.  
8.5.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change 
from baseline values will be provided at each scheduled visit and time point, by treatment 
group, for each part, 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 at least 1 threshold analysis criterion 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. The threshold analysis criteria are 
provided in Appendix H. 
8.5.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized by treatment group, at each scheduled visit, for each part 
and cohort, as applicable. The following vital signs parameters will be summarized: systolic 
and diastolic blood pressure (mm Hg), body temperature (C), pulse rate (beats per minute), 
and respiratory rate (breaths per minute). 
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 H. 


Statistical Analysis Plan (Methods) 
Page 28 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
In addition, a listing containing all individual subjects will be provided. This listing will 
include data from both scheduled and unscheduled visits.  
8.5.5 
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. 
8.5.6 
Physical Examination  
PE findings will be presented as an individual subject data listing only. 
8.5.7 
Other Safety Analysis 
Not applicable.  
9 
Interim and IDMC Analysis 
9.1 
Interim Analysis 
Interim analyses may be performed for each cohort after 50% or 100% of subjects in the 
cohort have completed the Day 15 or Day 29 Visit. The results of these analyses will be 
reviewed by a limited Vertex team. When an interim analysis is performed after all subjects 
in 1 part have completed the Safety Follow-up Visit, results from that part will be unblinded 
for full review by the Vertex study team. 
9.1.1 Summary of the Flow of Data for Interim Analyses by a Limited Vertex 
Team 
To protect the integrity of the treatment assignment and study data, the following steps for 
the flow of data will be executed for interim analysis: 
1. The Vertex Biometrics group will prepare the SAS codes, SDTM/ADaM data sets,  
and blinded outputs (tables, figures and listings) using dummy treatment codes, 
dummy spirometry data, and dummy sweat chloride data; 
2. The IWRS vendor, 
 will provide the unblinded treatment codes to an 
independent unblinded Vertex Biometrics group 
 
3. Biomedical Systems (BMS) will provide the unblinded spirometry data directly to an 
independent unblinded Vertex Biometrics group 
 
will provide the unblinded sweat chloride data directly to an independent unblinded 
Vertex Biometrics group 
  


Statistical Analysis Plan (Methods) 
Page 29 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
4. The independent unblinded Vertex Biometrics group that is not involved with the 
conduct of the study will generate the unblinded outputs and provide them directly to 
the limited Vertex team for their review.  
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. 


Statistical Analysis Plan (Methods) 
Page 30 of 68 
Protocol Number: VX16-152-102 Version 3.0 
Vertex Pharmaceuticals Incorporated 
 
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. 


Protocol VX16-152-102, Version 3.0 
Page 31 of 68 
Vertex Pharmaceuticals Incorporated 
 
11 
LIST OF APPENDICES 
Appendix A: Schedule of Assessments 
 
Table 11-1 
Study VX16-152-102: Schedule of Assessments for Part 1 
Event/Assessmenta 
Screening 
Treatment Periodb 
 
ETT 
Visitc 
Safety 
Follow-up 
28 ( 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Days 3 and 5e 
(or Days 4/6 
or Days 3/6)f 
Day 8 
( 1 day) 
Day 11e 
( 1 day) 
Day 15 
( 1 day) 
Informed consent 
X 
 
 
 
 
 
 
 
Randomizationg 
 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Ophthalmological history 
X 
 
 
 
 
 
 
 
CFQ-Rh,i 
 
X 
 
 
 
X 
Xj  
X 
                                                 
a  
Assessments will be performed in the order presented, unless noted otherwise. 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., premature 
discontinuation of 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 before randomization, unless noted otherwise. 
e  
Days 3, 5, and 11 assessments may be collected at the clinic, at a local laboratory, or during a visit by a qualified individual (e.g., home nurse). 
f  
Day 3 and Day 5 assessments will be performed at least 2 days apart, with the first day of assessments occurring no earlier than Day 3 and the second day of 
assessments occurring no later than Day 6. (i.e., Assessments will be performed on Days 3 and 5, Days 4 and 6, or Days 3 and 6.) 
g  
Randomization may occur on the previous day (Day -1) after all inclusion and exclusion criteria 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. 


Protocol VX16-152-102, Version 3.0 
Page 32 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 11-1 
Study VX16-152-102: Schedule of Assessments for Part 1 
Event/Assessmenta 
Screening 
Treatment Periodb 
 
ETT 
Visitc 
Safety 
Follow-up 
28 ( 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Days 3 and 5e 
(or Days 4/6 
or Days 3/6)f 
Day 8 
( 1 day) 
Day 11e 
( 1 day) 
Day 15 
( 1 day) 
Weightk 
X 
X 
 
X 
 
X 
X 
X 
Heightk 
X 
 
 
 
 
 
 
 
Vital signsl 
X 
X 
 
X 
 
X 
X 
X 
Pulse oximetryl 
X 
X 
 
X 
 
X 
X 
X 
Physical examinationm 
Complete 
Abbreviated 
 
Abbreviated 
 
Abbreviated 
Abbreviated 
Complete 
Ophthalmologic 
examinationn 
X 
 
 
 
 
 
 
 
Standard 12-lead ECGo 
X 
X 
 
X 
 
X 
X 
X 
Sweat chloridei,p 
X 
X 
 
X 
 
X 
X 
X 
Spirometryq 
X 
X 
 
X 
 
X 
X 
X 
                                                                                                                                                                                                                         
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. 
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. ECGs will be collected before procedures that may 
affect heart rate (e.g., blood sampling). 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.  


Protocol VX16-152-102, Version 3.0 
Page 33 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 11-1 
Study VX16-152-102: Schedule of Assessments for Part 1 
Event/Assessmenta 
Screening 
Treatment Periodb 
 
ETT 
Visitc 
Safety 
Follow-up 
28 ( 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Days 3 and 5e 
(or Days 4/6 
or Days 3/6)f 
Day 8 
( 1 day) 
Day 11e 
( 1 day) 
Day 15 
( 1 day) 
Urinalysisi 
X 
X 
 
X 
 
X 
X 
X 
Pregnancy test (all 
females of childbearing 
potential) 
Serum 
Urine 
 
 
 
 
Serum  
Serum 
CFTR genotyper 
X 
 
 
 
 
 
 
 
                                                 
r  
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. 


Protocol VX16-152-102, Version 3.0 
Page 34 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 11-1 
Study VX16-152-102: Schedule of Assessments for Part 1 
Event/Assessmenta 
Screening 
Treatment Periodb 
 
ETT 
Visitc 
Safety 
Follow-up 
28 ( 7) Days 
After Last 
Dose  
Days -28 
to -1d 
Day 1  
Days 3 and 5e 
(or Days 4/6 
or Days 3/6)f 
Day 8 
( 1 day) 
Day 11e 
( 1 day) 
Day 15 
( 1 day) 
FSHs 
X 
 
 
 
 
 
 
 
G6PD activity testt 
X 
 
 
 
 
 
 
 
Serum chemistry and 
hematologyi 
X 
X 
Xe,v 
X 
Xe,v 
X 
X 
X 
Coagulationi 
X 
X 
 
X 
 
X 
 
X 
PK samplingw 
 
X 
 
X 
 
X 
X 
  
Study drug dosingx 
 
Day 1 through Day 15 
 
 
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  
On Days 3, 5, and 11, the following parameters will be measured: lactate dehydrogenase, total and direct bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, and gamma glutamyl transferase. 
w  
Blood samples will be collected for PK analysis of VX-152, VX-661, M1-661, 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 8, a predose sample will be collected before the morning dose of 
study drug (0 hours). On Day 15, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 8 hours after dosing. At the ETT Visits, a single 
blood sample for PK analysis will be collected. 
x  
The last dose of study drug will be the morning dose on Day 15. 
y  
Refer to Section 9.4 for details. 


Protocol VX16-152-102, Version 3.0 
Page 35 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 11-2 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2A 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
( 1 day) 
Day 29 
( 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Randomizationi 
 
 
 
X 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Ophthalmological 
history 
X 
 
 
 
 
 
 
 
 
 
 
CFQ-Rj,k 
 
 
 
X 
 
X 
 
X 
X 
Xl  
X 
                                                 
a  
Assessments will be performed in the order presented, unless noted otherwise. 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., premature 
discontinuation of 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  
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 before the subject receives VX-661/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 VX-661/IVA treatment. 
g  
Days 3, 5, and 11 assessments may be collected at the clinic, at a local laboratory, or during a visit by a qualified individual (e.g., home nurse). 
h  
Day 3 and Day 5 assessments will be performed at least 2 days apart, with the first day of assessments occurring no earlier than Day 3 and the second day of 
assessments occurring no later than Day 6. (i.e., Assessments will be performed on Days 3 and 5, Days 4 and 6, or Days 3 and 6.) 
i  
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. 
j  
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
k  
The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred. 
l  
Subjects will complete the CFQ-R at the ETT Visit only if it has been 2 weeks or more since their last visit. 


Protocol VX16-152-102, Version 3.0 
Page 36 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 11-2 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2A 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
( 1 day) 
Day 29 
( 3 days) 
Weightm 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Heightm 
X 
 
 
 
 
 
 
 
 
 
 
Vital signsn 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pulse oximetryn 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Physical 
examinationo 
Complete 
Abbrev-
iated 
 
Abbreviated 
 
Abbreviated 
 
Abbreviated Abbreviated Abbreviated Complete 
Ophthalmologic 
examinationp 
X 
 
 
 
 
 
 
 
 
 
 
Standard 12-lead 
ECGq 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Sweat chloridek,r 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Spirometrys 
X 
  
X 
X 
 
X 
 
X 
X 
X 
X 
                                                 
m  
Weight and height will be measured with shoes off. 
n  
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 
o  
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. 
p  
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. 
q  
All standard 12-lead ECGs will be performed after the subject has been seated for at least 5 minutes. ECGs will be collected before procedures that may 
affect heart rate (e.g., blood sampling). 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.  
r  
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.  
s  
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.  


Protocol VX16-152-102, Version 3.0 
Page 37 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 11-2 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2A 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
( 1 day) 
Day 29 
( 3 days) 
Urinalysisk 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pregnancy test (all 
females of 
childbearing 
potential) 
Serum 
Urine 
 
Urine 
 
 
 
Urine 
 
Serum  
Serum 
CFTR genotypet 
X 
 
 
 
 
 
 
 
 
 
 
FSHu 
X 
 
 
 
 
 
 
 
 
 
 
G6PD activity testv 
X 
 
 
 
 
 
 
 
 
 
 
Serum chemistry 
and hematologyk 
X 
X 
 
X 
Xg,x 
X 
Xg,x 
X 
X 
X 
X 
Coagulationk 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
PK samplingy 
 
 
 
X 
 
X 
 
X 
 
Xy 
  
VX-661/IVA 
dosingz 
 
Day -28 through Day 29 
 
 
                                                 
t  
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. 
u  
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
v  
A single blood sample will be collected for the G6PD activity test. 
  
 
x  
On Days 3, 5, and 11, the following parameters will be measured: lactate dehydrogenase, total and direct bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, and gamma glutamyl transferase. 
y 
Blood samples will be collected for PK analysis of VX-152, VX-661, M1-661, 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 8, a predose sample will be collected before the morning dose of study 
drug (0 hours). On Day 15, samples will be collected before dosing (0 hours) and at 1, 2, 4, 6, and 8 hours after dosing. At ETT Visits, a single blood sample 
for PK analysis will only be collected from subjects who discontinued study drug after Day 1, but before Day 15 PK was collected. 


Protocol VX16-152-102, Version 3.0 
Page 38 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 11-2 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2A 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
( 1 day) 
Day 29 
( 3 days) 
VX-152 or placebo 
dosingaa 
 
 
 
Day 1 through Day 15 
 
 
 
AEs, medicationsbb, 
treatments and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
                                                                                                                                                                                                                         
z  
The last dose of VX-661/IVA will be the morning dose on Day 29. 
aa  The last dose of VX-152 or placebo will be the morning dose on Day 15. 
bb  Refer to Section 9.4 for details. 


Protocol VX16-152-102, Version 3.0 
Page 39 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 11-3 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2B 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
and 
Day 29 
( 1 day) 
Day 43 
( 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Randomizationi 
 
 
 
X 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Ophthalmological 
history 
X 
 
 
 
 
 
 
 
 
 
 
CFQ-Rj,k 
 
 
 
X 
 
X 
 
X 
X 
Xl  
X 
                                                 
a  
Assessments will be performed in the order presented, unless noted otherwise. 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., premature 
discontinuation of 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  
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 before the subject receives VX-661/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 VX-661/IVA treatment. 
g  
Days 3, 5, and 11 assessments may be collected at the clinic, at a local laboratory, or during a visit by a qualified individual (e.g., home nurse). 
h  
Day 3 and Day 5 assessments will be performed at least 2 days apart, with the first day of assessments occurring no earlier than Day 3 and the second day of 
assessments occurring no later than Day 6. (i.e., Assessments will be performed on Days 3 and 5, Days 4 and 6, or Days 3 and 6.) 
i  
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. 
j  
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
k  
The predose assessment on Day 1 may be performed on the previous day (Day -1) if randomization has occurred. 


Protocol VX16-152-102, Version 3.0 
Page 40 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 11-3 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2B 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
and 
Day 29 
( 1 day) 
Day 43 
( 3 days) 
Weightm 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Heightm 
X 
 
 
 
 
 
 
 
 
 
 
Vital signsn 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pulse oximetryn 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Physical 
examinationo 
Complete 
Abbrev-
iated 
 
Abbrev-
iated 
 
Abbrev-
iated 
 
Abbrev-
iated 
Abbreviated Abbreviated Complete 
Ophthalmologic 
examinationp 
X 
 
 
 
 
 
 
 
 
 
 
Standard 12-lead 
ECGq 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Sweat chloridek,r 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Spirometrys 
X 
  
X 
X 
 
X 
 
X 
X 
X 
X 
                                                                                                                                                                                                                         
l  
Subjects will complete the CFQ-R at the ETT Visit only if it has been 2 weeks or more since their last visit. 
m  
Weight and height will be measured with shoes off. 
n  
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 
o  
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. 
p  
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. 
q  
Standard 12-lead ECGs will be performed after the subject has been seated for at least 5 minutes. ECGs will be collected before procedures that may affect 
heart rate (e.g., blood sampling). On Days 1, 15, and 29, 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.  
r  
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.  


Protocol VX16-152-102, Version 3.0 
Page 41 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 11-3 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2B 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
and 
Day 29 
( 1 day) 
Day 43 
( 3 days) 
Urinalysisk 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pregnancy test (all 
females of 
childbearing 
potential) 
Serum 
Urine 
 
Urine 
 
 
 
Urine 
 
Serum  
Serum 
CFTR genotypet 
X 
 
 
 
 
 
 
 
 
 
 
FSHu 
X 
 
 
 
 
 
 
 
 
 
 
G6PD activity testv 
X 
 
 
 
 
 
 
 
 
 
 
Serum chemistry 
and hematologyk 
X 
X 
 
X 
Xg,x 
X 
Xg,x 
X 
X 
X 
X 
Coagulationk 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
PK samplingy 
 
 
 
X 
 
X 
 
X 
 
Xy 
  
                                                                                                                                                                                                                         
s  
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, 15, and 29, spirometry will be performed 
pre-bronchodilator 5 hours (± 1 hour) after study drug administration.  
t  
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. 
u  
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
v  
A single blood sample will be collected for the G6PD activity test. 
  
 
x  
On Days 3, 5, and 11, the following parameters will be measured: lactate dehydrogenase, total and direct bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, and gamma glutamyl transferase. 
y 
Blood samples will be collected for PK analysis of VX-152, VX-661, M1-661, 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 8, a predose sample will be collected before the morning dose of study 
 


Protocol VX16-152-102, Version 3.0 
Page 42 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 11-3 
Study VX16-152-102: Schedule of Assessments for Part 2, Cohort 2B 
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  
Days 3 and 5g 
(or Days 4/6 
or Days 3/6)h 
Day 8 
( 1 day) 
Day 11g 
( 1 day) 
Day 15 
and 
Day 29 
( 1 day) 
Day 43 
( 3 days) 
VX-661/IVA 
dosingz 
 
Day -28 through Day 43 
 
 
VX-152 or placebo 
dosingaa 
 
 
 
Day 1 through Day 29 
 
 
 
AEs, medicationsbb, 
treatments and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
                                                                                                                                                                                                                         
drug (0 hours). 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 sample will be 
collected before the morning dose (0 hours). At ETT Visits, a single blood sample for PK analysis will only be collected from subjects who discontinued 
study drug after Day 1, but before Day 29. 
z  
The last dose of VX-661/IVA will be the morning dose on Day 43. 
aa  The last dose of VX-152 or placebo will be the morning dose on Day 29. 
bb  Refer to Section 9.4 for details. 


Protocol VX16-152-102, Version 3.0 
Vertex Pharmaceuticals Incorporated 
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 11-3 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target 
Study 
Dayb 
Analysis 
Visit 
Window 
(in study 
days) 
Safety Assessment (Part 1) 
Serum Chemistry I (lactate dehydrogenase, total and direct 
bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, and gamma 
glutamyl transferase)  
 
Day 1 (Baseline)  
Day 3  
Day 5 
Day 8 
Day 11 
Day 15 
Safety Follow-up 
1 
3 
5 
8 
11 
15 
43 
1 
[1, 4] 
(4, 6] 
(6, 9] 
(9, 13] 
(13, 29] 
Use nominal 
visit 
Serum Chemistry II (all others) 
Hematology 
Coagulation 
Vital Signs (including Weight) 
Urinalysis (nominal visit for all visits) 
Day 1 (Baseline)  
Day 8 
Day 15 
Safety Follow-up 
1 
8 
15 
43 
 
1 
[1, 12] 
(12, 29] 
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) 
Safety Follow-up 
1 
 
1 
 
8 
15 
 
 
43 
Use nominal 
visit for all 
visits 
Safety Assessment (Part 2 Cohort 2A) 
Serum Chemistry I (lactate dehydrogenase, total and direct 
bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, and gamma 
glutamyl transferase)  
 
Day 1 (Baseline)  
Day 3  
Day 5 
Day 8 
Day 11 
Day 15 
Day 29 
Safety Follow-up 
1 
3 
5 
8 
11 
15 
29 
57 
1 
[1, 4] 
(4, 6] 
(6, 9] 
(9, 13] 
(13, 22] 
(22, 43] 
Use nominal 
visit 
                                                 
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. 


Protocol VX16-152-102, Version 3.0 
Vertex Pharmaceuticals Incorporated 
Table 11-3 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target 
Study 
Dayb 
Analysis 
Visit 
Window 
(in study 
days) 
Serum Chemistry II (all others) 
Hematology 
Vital Signs (including Weight) 
Urinalysis (nominal visit for all visits) 
Day 1 (Baseline)  
Day 8 
Day 15 
Day 29 
Safety Follow-up 
1 
8 
15 
29 
57 
 
1 
[1, 12] 
(12, 22] 
(22, 43] 
Use nominal 
visit 
Coagulation 
 
Day 1 (Baseline)  
Day 8 
Day 15 
Safety Follow-up 
1 
8 
15 
57 
 
1 
[1, 12] 
(12, 36] 
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 
Safety Follow-up 
1 
 
1 
 
8 
15 
 
 
29 
57 
Use nominal 
visit for all 
visits 
Safety Assessment (Part 2 Cohort 2B) 
Serum Chemistry I (lactate dehydrogenase, total and direct 
bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, and gamma 
glutamyl transferase)  
 
Day 1 (Baseline)  
Day 3  
Day 5 
Day 8 
Day 11 
Day 15 
Day 29 
Day 43 
Safety Follow-up 
1 
3 
5 
8 
11 
15 
29 
43 
71 
1 
[1, 4] 
(4, 6] 
(6, 9] 
(9, 13] 
(13, 22] 
(22, 36] 
(36, 57] 
Use nominal 
visit 
Serum Chemistry II (all others) 
Hematology 
Vital Signs (including Weight) 
Urinalysis (nominal visit for all visits) 
Day 1 (Baseline)  
Day 8 
Day 15 
Day 29 
Day 43 
Safety Follow-up 
1 
8 
15 
29 
43 
71 
1 
[1, 12] 
(12, 22] 
(22, 36] 
(36, 57] 
Use nominal 
visit 


Protocol VX16-152-102, Version 3.0 
Vertex Pharmaceuticals Incorporated 
Table 11-3 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target 
Study 
Dayb 
Analysis 
Visit 
Window 
(in study 
days) 
Coagulation 
 
Day 1 (Baseline)  
Day 8 
Day 15 
Day 29 
Safety Follow-up 
1 
8 
15 
29 
71 
1 
[1, 12] 
(12, 22] 
(22, 50] 
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 
Safety Follow-up 
1 
 
1 
 
8 
15 
 
 
29 
71 
Use nominal 
visit for all 
visits 
Efficacy Assessment (Part 1) 
Spirometry  
 
Day 1 (Baseline; 
predose)  
Day 8 
Day 15 (predose) 
Safety Follow-up 
1 
 
8 
15 
43 
1 
 
(1, 12] 
(12, 29] 
Use nominal 
visit 
Sweat Chloride 
Day 1 
Day 8 
Day 15 
Safety Follow-up 
1 
8 
15 
43 
1 
(1, 12] 
(12, 29] 
Use nominal 
visit 
CFQ-R 
Day 1 
Day 15 
Safety Follow-up 
1 
15 
43 
1 
(1, 29] 
Use nominal 
visit 
Efficacy Assessment (Part 2 Cohort 2A) 
Spirometry  
 
Day 1 (Baseline; 
pedose)  
Day 8 
Day 15 (predose 
Day 29 
Safety Follow-up 
1 
 
8 
15 
29 
57 
1 
 
(1, 12] 
(12, 22] 
(22, 43] 
Use nominal 
visit 


Protocol VX16-152-102, Version 3.0 
Vertex Pharmaceuticals Incorporated 
Table 11-3 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target 
Study 
Dayb 
Analysis 
Visit 
Window 
(in study 
days) 
Sweat Chloride 
CFQ-R 
Day 1 
Day 8 
Day 15 
Day 29 
Safety Follow-up 
1 
8 
15 
29 
57 
1 
(1, 12] 
(12, 22] 
(22, 43] 
Use nominal 
visit 
Efficacy Assessment (Cohort 2B) 
Spirometry  
 
Day 1 (Baseline; 
predose)  
Day 8 
Day 15 (before 
dosing and 5 hours 
after dosing) 
Day 29 
Day 43 
Safety Follow-up 
1 
 
8 
15 
 
 
29 
43 
71 
1 
 
(1, 12] 
(12, 22] 
 
 
(22, 36] 
(36, 57] 
Use nominal 
visit 
Sweat Chloride 
CFQ-R 
Day 1 
Day 8 
Day 15 
Day 29 
Day 43 
Safety Follow-up 
1 
8 
15 
29 
43 
71 
1 
(1, 12] 
(12, 22] 
(22, 36] 
(36, 57] 
Use nominal 
visit 
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. 
 


Protocol VX16-152-102, Version 3.0 
Vertex Pharmaceuticals Incorporated 
Table 11-3 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target 
Study 
Dayb 
Analysis 
Visit 
Window 
(in study 
days) 
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. 
4. Missing Date for Drug Interruption 
If the dates for drug interruption are completely missing or partially missing and cannot determine which period 
the interruption occurred, then assume the interruption occurred during the treatment period for 1 day.  
 
 


Protocol VX16-152-102, Version 3.0 
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 11-4 
Prior, Concomitant, and Post Categorization of a Medication in Part 1  
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 11-5 
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 
 
 


Protocol VX16-152-102, Version 3.0 
Vertex Pharmaceuticals Incorporated 
Appendix D: Important Protocol Deviation Programming Rules   
Important protocol deviations before first dose 
1. Inclusion criteria: 
a) I1: Subject will sign and date an informed consent form (ICF). 
b) I3: Subjects will be aged 18 years or older on the date of informed consent. 
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 (Part 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). 
Part 1: Heterozygous for F508del with a second CFTR allele carrying an MF 
mutation that is not likely to respond to VX-661 and/or IVA therapy (Appendix A) 
Part 2: Homozygous for F508del 
e) I7: Subjects must have an FEV1 ≥40% and ≤90% of predicted normal for age, sex, 
and height (equations of the Global Lung Function Initiative [GLI])9 at the Screening 
Visit. Spirometry measurements must meet American Thoracic Society/European 
Respiratory Society criteria6 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)for subjects ≥18 years of age  


Protocol VX16-152-102, Version 3.0 
Vertex Pharmaceuticals Incorporated 
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) 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 Part 1, Day -28 in Part 
2). 
f) E17: Pregnant or nursing females: Females of childbearing potential must have a 
negative pregnancy test at screening and Day 1. 
Important protocol deviations during the Treatment Period 
1. Compliance < 80% based on percentage of tablets taken 
2. Use of prohibited medications 
3. Actual treatment received is different from the randomized treatment  
 
 


Protocol VX16-152-102, Version 3.0 
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. 
 
 






Protocol VX16-152-102, Version 3.0 
Vertex Pharmaceuticals Incorporated 
Appendix G: Imputation Rules for Missing AE dates  
G.1 Part 1  
Imputation rules for missing or partial AE start date for Part 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. 
 
G.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: 


Protocol VX16-152-102, Version 3.0 
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.  


Protocol VX16-152-102, Version 3.0 
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. 
 
 


Protocol VX16-152-102, Version 3.0 
Vertex Pharmaceuticals Incorporated 
Appendix H: 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. 


Protocol VX16-152-102, Version 3.0 
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 
 


Protocol VX16-152-102, Version 3.0 
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. 
 


Protocol VX16-152-102, Version 3.0 
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 


Protocol VX16-152-102, Version 3.0 
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