Clinical trial NCT03227471
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2017-01-23; Completion date: 2018-03-27
Enrollment: 225 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a first-in-human and proof-of-concept study of VX-445. The study includes 6 parts. Parts A, B, and C were conducted in healthy subjects. Parts D, E, and F were conducted in subjects with Cystic Fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F/F genotype), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ, IVA, or TEZ/IVA (F/MF genotypes).

Detailed description:

Arms: arm 1: Participants without CF who received single dose of placebo matched to VX-445 in Cohort A1 to A5. arm 2: Participants without CF who received single ascending dose of VX-445 tablet starting from 20 milligrams (mg) to 360 mg in Cohort A1 to A5. arm 3: Participants without CF who received single dose of VX-445 100 mg tablet on Day 1 in fasted state and on Day 7 in fed state, followed by VX-445 20 mg intravenous (IV) injection on Day 13 in fed state in Cohort A7. arm 4: Participants without CF who received multiple doses of placebo matched to VX-445 once daily (qd) for 10 days in Cohort B1 to B4. arm 5: Participants without CF who received VX-445 tablet qd for 10 days in Cohort B1 (60 mg), B2 (120 mg), B3 (240 mg) and B4 (340 mg). arm 6: Participants without CF who received placebo matched to VX-445/TEZ/IVA triple combination (TC) qd in the morning and placebo matched to IVA in the evening for 14 days. arm 7: Participants without CF who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C1; VX-445 280 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C2 and VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C3 for 14 days. arm 8: Participants with CF, F/MF genotype who received placebo matched to VX-445/TEZ/IVA TC qd in the morning and placebo matched to IVA qd in the evening for 4 weeks in the TC treatment period. arm 9: Participants with CF, F/MF genotype who received VX-445 50 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. arm 10: Participants with CF, F/MF genotype who received VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. arm 11: Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. arm 12: Following run-in period of 4 weeks with TEZ/IVA, participants with CF, F/F genotype who received TEZ 100 mg qd/IVA 150 mg q12h and placebo matched to VX-445 for 4 weeks in the TC treatment period. arm 13: Following run-in period of 4 weeks with TEZ/IVA, participants with CF, F/F genotype who received VX-445 200 mg qd/TEZ 100 mg qd /IVA 150 mg q12h for 4 weeks in the TC treatment period. arm 14: Participants with CF, F/MF genotype who received placebo matched to VX-445/TEZ/VX-561 for 4 weeks in the TC treatment period. arm 15: Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/VX-561 150 mg qd for 4 weeks in the TC treatment period.
Interventions: intervention 1: IVA intervention 2: TEZ/IVA intervention 3: VX-445 intervention 4: Matched Placebo intervention 5: TEZ intervention 6: VX-561 intervention 7: VX-445
Intervention descriptions: intervention 1: IVA tablet for oral administration intervention 2: TEZ/IVA fixed-dose combination for oral administration. intervention 3: VX-445 tablet for oral administration. intervention 4: Matched placebo. intervention 5: Tablet for oral administration. intervention 6: Tablet for oral administration. intervention 7: VX-445 IV injection

Protocol documents:
Prot_000.pdf: 






Protocol VX16-445-001, Version 7.0 
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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 1/2 Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis 
Brief Title 
A Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 1; safety, tolerability, and pharmacokinetics (PK) 
Phase 2; safety and efficacy 
 
 
Objectives 
Parts A and B 
Primary Objectives 
Part A: To evaluate the safety and tolerability of single ascending doses of VX-445 
in healthy subjects 
Part B: To evaluate the safety and tolerability of multiple ascending doses of VX-445 
administered in healthy subjects 
Secondary Objectives 
Part A 
 
To evaluate the PK of VX-445 after administration of single ascending doses 
of VX-445 in healthy subjects 
 
To evaluate the effect of food on VX-445 PK in healthy subjects 
 
To evaluate the absolute bioavailability (BA) of VX-445 when administered 
orally relative to intravenous (IV) administration in healthy subjects 
Part B: To evaluate the PK of VX-445 after multiple ascending doses of VX-445 in 
healthy subjects 
Part C 
Primary Objective: To evaluate the safety and tolerability of multiple doses of 
VX-445 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) for 
14 days in healthy subjects 
Secondary Objectives: 
 
To evaluate the PK of VX-445 after multiple ascending doses of VX-445 in 
TC with TEZ and IVA for 14 days in healthy subjects 
 
To evaluate the PK of TEZ and metabolites (M1-TEZ and M2-TEZ), and 
IVA and metabolites (M1-IVA and M6-IVA) after administration in TC with 
VX-445 for 14 days in healthy subjects 
Parts D and E: 
Primary Objectives: 
 
To evaluate the safety and tolerability of VX-445 in TC with TEZ and IVA 
in subjects with cystic fibrosis (CF) 
 
To evaluate the efficacy of VX-445 in TC with TEZ and IVA in subjects 
with CF 
Secondary Objectives 
 
To evaluate the pharmacodynamic (PD) effect of VX-445 in TC with TEZ 
and IVA on CFTR function in subjects with CF 
 
To evaluate the PK of VX-445 when administered in TC with TEZ and IVA 
in subjects with CF 


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 
To evaluate the PK of TEZ, IVA, and their respective metabolites (M1-TEZ 
and M1-IVA) when administered in TC with VX-445 in subjects with CF 
Part F (Optional): 
Primary Objectives: 
 
To evaluate the safety and tolerability of VX-445 in TC with TEZ and 
VX-561 (deuterated IVA, also known as CTP-656) in subjects with CF 
 
To evaluate the efficacy of VX-445 in TC with TEZ and VX-561 in subjects 
with CF 
Secondary Objectives 
 
To evaluate the PD effect of VX-445 in TC with TEZ and VX-561 on CFTR 
function in subjects with CF 
 
To evaluate the PK of VX-445 when administered in TC with TEZ and 
VX-561 in subjects with CF 
 
To evaluate the PK of TEZ and metabolite (M1-TEZ), and VX-561 when 
administered in TC with VX-445 in subjects with CF 
 
 
Endpoints 
Primary Endpoints 
Parts A, B, and C: Safety and tolerability, based on the assessment of adverse events 
(AEs), clinically significant laboratory test results, standard 12-lead 
electrocardiograms (ECGs), vital signs, and spirometry (Parts B and C only) 
Parts D, E, and F:  
 
Safety and tolerability assessments of AEs, clinical laboratory values, 
standard 12-lead ECGs, vital signs, pulse oximetry, and spirometry 
 
Absolute change in percent predicted forced expiratory volume in 1 second 
(ppFEV1) from baseline through Day 29 
Secondary Endpoints 
Parts A and B: PK parameter estimates of VX-445 derived from plasma 
concentration-time data 
Part C:  
 
PK parameter estimates of VX-445 derived from plasma concentration-time 
data 
 
PK parameter estimates for TEZ and metabolites (M1-TEZ and M2-TEZ), 
and IVA and metabolites (M1-IVA and M6-IVA) derived from plasma 
concentration-time data 
Parts D and E:  
 
Absolute change in sweat chloride concentrations from baseline through 
Day 29 
 
Relative change in ppFEV1 from baseline through Day 29 
 
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
respiratory domain score from baseline at Day 29 
 
PK parameters of VX-445, TEZ, M1-TEZ, IVA, and M1-IVA 
Part F: 
 
Absolute change in sweat chloride concentrations from baseline through 


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Day 29 
 
Relative change in ppFEV1 from baseline through Day 29 
 
Absolute change in CFQ-R respiratory domain score from baseline at 
Day 29 
 
PK parameters of VX-445, TEZ, M1-TEZ, and VX-561 
 
 
Number of Subjects 
Approximately 224 subjects: approximately 56 in Part A, approximately 48 in Part B, 
approximately 16 in Part C, approximately 56 in Part D (8 in D1 and 48 in D2), 
approximately 24 in Part E, and approximately 24 in Part F (if conducted) 
 
 
Study Population 
Parts A, B, and C: Healthy female subjects of non-childbearing potential and male 
subjects between the ages of 18 and 55 years, inclusive 
Parts D, E, and F: Female and male subjects aged 18 years or older with CF 
 
Parts D and F: F508del/minimal function (F/MF) genotypes (an MF 
mutation is a minimal CFTR function mutation that is not expected to 
respond to TEZ, IVA, or TEZ/IVA) 
 
Part E: F508del/F508del (F/F) genotype 
 
 
Investigational Drug 
Active substance: VX-445 (Parts A, B, C, D, E, and F) 
 
Activity: CFTR Corrector (increased Cl− secretion) 
 
Strength and route of administration: 
Tablet: 20-mg, 50-mg, and 100-mg tablets for oral administration 
IV dose: 0.1 mg/mL for IV administration (Cohort A7 only) 
   Oral dose:  
Parts A, B, and C: Doses starting at 20 mg. No dose will be predicted to result in an 
exposure that exceeds the nonclinical no-observed-adverse-effect level (NOAEL) 
exposure in the male rat (i.e., NOAEL exposure at the 50-mg/kg/day dose in male rats 
in the 28-day GLP toxicity study) 
Parts D, E, and F: 50 mg qd (Part D only), 100 mg qd (Part D only), or 200 mg qd 
 
 
 
Active substance: TEZ (tezacaftor; VX-661) and IVA (ivacaftor; VX-770) 
(Parts C, D, and E) 
 
Activity: CFTR corrector and potentiator (increased Cl− secretion) 
 
Strength and route of administration:  
100-mg TEZ/150-mg IVA fixed-dose combination (FDC) (light yellow) film-coated 
tablet for oral administration 
Dose administered: TEZ 100 mg/IVA 150 mg in the morning 
 
 
 
Active substance: IVA (Parts C, D, and E) 
 
Activity: CFTR potentiator (increased Cl− secretion) 
 
Strength and route of administration:  
150-mg IVA (light blue) film-coated tablet for oral administration 
Dose administered: 150 mg in the evening  


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Active substance: VX-561 (deuterated IVA, or CTP-656) (Part F) 
 
Activity: CFTR potentiator 
 
Strength and route of administration:  
50-mg VX-561 tablet for oral administration 
 
Dose administered: 150 mg qd 
 
 
 
Active substance: TEZ (Part F) 
 
Activity: CFTR corrector (increased Cl− secretion) 
 
Strength and route of administration:  
50-mg TEZ (white) tablet for oral administration 
Dose administered: 100 mg qd 
 
 
Study Duration 
Excluding the Screening Period, the study duration for each subject is as follows: 
Part A, Cohorts A1 through A6: 9 to 12 days 
Part A, Cohort A7: up to 21 to 24 days 
Part B: 18 to 21 days 
Part C: 22 to 25 days 
Parts D1 and D2: approximately 9 weeks (5 weeks for the Treatment Period 
[consisting of Dosing Periods 1 and 2] and 4 weeks for the Safety Follow-up Period) 
Part E: approximately 16 weeks (4 weeks for the Run-in Period, 4 weeks for the 
Treatment Period [Period 1], 4 weeks for the Washout Period, and 4 weeks for the 
Safety Follow-up Period) 
Part F: approximately 8 weeks (4 weeks for the Treatment Period [Period 1] and 
4 weeks for the Safety Follow-up Period) 
 
 
Study Design 
This is a first-in-human study of VX-445. The study includes 6 parts. Parts A, B, and 
C will be conducted in healthy subjects. Parts D, E, and F will be conducted in 
subjects with CF. Part F is an optional part of the study that may be conducted at the 
sponsor’s discretion. 
Parts A, B, and C (Healthy Subjects) 
Parts A, B, and C are randomized, double-blind, placebo-controlled, single- and 
multiple-dose parts in healthy subjects of this first-in-human study of VX-445. Part A 
also includes an evaluation of the effect of food on VX-445 PK and an evaluation of 
absolute BA. Part C doses VX-445 in TC with TEZ/IVA. 
Approximately 8 subjects in each cohort of Part A (except Cohort A7) and Part B will 
be randomized 3:1 to receive VX-445 or placebo. Cohort A7 will enroll 
approximately 8 subjects who will receive open-label VX-445 to evaluate the food 
effect on the tablet and the absolute BA. 
The decision to initiate successive cohorts and dose selection will be based on safety, 
tolerability, and available PK data from preceding cohort(s). In Parts A and B, 6 dose 
escalation cohorts are planned, although fewer than 6 or up to 2 additional cohorts 
each may be enrolled in each part, based on data from previous cohorts. In Part C, 
2 cohorts are planned, while fewer or up to 2 additional cohorts each may be enrolled 
based on data from previous cohorts. 
Part A includes Cohorts A1 through A6, which are single-dose escalation cohorts, 
and Cohort A7, a single cohort evaluating the food effect and absolute BA. 


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Cohorts A1 through A6: VX-445 or placebo will be administered in the morning of 
Day 1. Dosing will be staggered in Cohort A1 so that 2 subjects are dosed (1 with 
VX-445 and 1 with placebo) at least 24 hours before the remaining 6 subjects. Dosing 
may be staggered in subsequent cohorts if deemed necessary based on review of 
emerging safety data. The planned doses for Cohorts A1 through A6 are 20 mg, 
60 mg, 120 mg, 240 mg, 480 mg, and 800 mg. Doses may be modified upward or 
downward based on emerging data.  
Cohort A7 has an open-label, single sequence design in which subjects will receive a 
single dose of VX-445 on up to 3 dosing occasions with at least 6-day washouts 
between dosing occasions. VX-445 doses include 2 single oral doses of tablet (dose to 
be determined [TBD], pending PK data from previous Part A cohorts, but will not 
exceed the highest dose that was safe and well tolerated) and a single IV dose (the 
planned dose is 20 mg, which may be adjusted pending data from previous Part A 
cohorts, but will not be predicted to exceed the highest exposure that was safe and 
well tolerated). If the IV formulation or the data supporting the use of the IV 
formulation are not available, then the third dosing period, in which subjects receive 
the IV dose, will not be conducted. 
Part B may be initiated while Part A is ongoing after review of safety, tolerability, 
and PK data. The total daily dose in the starting cohort (Cohort B1) will be at least 
1 dose level below the highest Part A dose for which safety, tolerability, and PK 
results are available and that is safe and well tolerated. 
Part C may be initiated while Parts A and B are ongoing after review of safety, 
tolerability, and PK data. The VX-445 starting dose (Cohort C1) will be at least 
1 dose level below the highest Part B dose for which safety and tolerability results are 
available and supportive. The dosage of TEZ/IVA in the TC will be TEZ 100 mg 
once per day (qd)/IVA 150 mg every 12 hours (q12h). 
Dosing will be staggered in Cohort C1, with 2 subjects dosed (1 with VX-445 in TC 
with TEZ/IVA and 1 with triple placebo) at least 24 hours before the remaining 
6 subjects. Staggering at higher doses may be conducted if deemed necessary based 
on review of emerging safety data. 
Parts D, E, and F (Subjects With CF) 
Part D, which is comprised of Parts D1 and D2, is randomized, double-blind, 
placebo-controlled, and evaluates VX-445 in TC with TEZ/IVA in subjects with CF 
(F/MF genotypes).  
Part E is randomized, double-blind, TEZ/IVA-controlled, and evaluates VX-445 in 
TC with TEZ/IVA in subjects with CF (F/F genotype).  
Part F, an optional part of the study which will be conducted at the sponsor’s 
discretion, is randomized, double-blind, placebo-controlled, and evaluates VX-445 in 
TC with TEZ and VX-561 in subjects with CF (F/MF genotypes). 
Part D may be initiated while Parts A, B, and C are ongoing after review of safety, 
tolerability, and PK data. After all Part D1 subjects complete the Day 15 Visit, a 
blinded review of all available safety and PK data will be conducted by the Vertex 
study team and lead investigator(s). Dosing in Parts D2, E, and F will start after this 
review, if supported by safety and PK data. 
VX-445 will be dosed qd. 
Part D1 has 1 VX-445 dose level (mid: 100 mg qd). Part D2 has 3 VX-445 dose 
levels (low: 50 mg qd; mid: 100 mg qd; high: 200 mg qd). The TC-high dose of 
VX-445 in Part D2 does not exceed the highest dose that was safe and well tolerated 
in healthy subjects dosed with TC in Part C. Parts E and F will use the highest dose 
used in Part D2 (200 mg qd). 
Randomization will be stratified by ppFEV1 in Parts D2, E, and F. Randomization 
will not be stratified in Part D1 because of the small number of subjects in that Part 






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2-sided 95% confidence intervals of the average treatment effects through Day 29, for 
all within-group and between-group comparisons will be estimated within MMRM.  
The safety analysis will be descriptive only. 
 
 
Interim Analyses 
Parts A, B, and C: An interim analysis (IA) may be performed after the Safety 
Follow-up Visit for all Part C subjects has been completed.  
Parts D, E, and F: IAs for each part (D1, D2, E, and F) may be performed after at 
least 50% of subjects in the part have completed the Day 15 Visit.  
 
 
IDMC Reviews 
Parts D, E, and F: An independent monitoring committee (IDMC) will conduct safety 
reviews of study data. The IDMC Chair will review available safety and PK data from 
Parts A, B, and C of the study prior to commencement of dosing in Part D1 to 
determine if it is appropriate to proceed with the study. 


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3 
SCHEDULE OF ASSESSMENTS 
Parts A, B, and C: Schedules of Assessments are shown in Table 3-1 (Screening, Parts A though C), 
Table 3-2 (Part A, Cohorts A1 through A6), Table 3-3 (Part A, Cohort A7), Table 3-4 (Part B), and 
Table 3-5 (Part C). 
Parts D, E, and F: Schedules of assessments are provided in Table 3-6 (Screening through 
Follow-up, Part D), Table 3-7 (Screening through Follow-up, Part E), and Table 3-8 (Screening 
through Follow-up, Part F). All visits will be scheduled relative to the Day 1 Visit (first dose of 
VX-445 or VX-445 matched placebo). 
Assessments may be performed in any order when more than 1 assessment is required at a 
particular time point except for informed consent, which must be completed before any 
assessments are done at the Screening Visit, and the CFQ-R assessment in Parts D, E, and F, 
which must be completed before any other assessment at the clinic visit when it is required. All 
assessments will be performed before dosing, unless noted otherwise. 
 


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Table 3-1 
Study VX16-445-001: Parts A, B, and C, Screening 
Event/Assessment 
Screening Visit 
Day -28 to Day -2 
Informed consent  
X 
Demographics 
X 
Medical history 
X 
Medications reviewa 
X 
Height, weight, BMI, and vital signsb 
X 
Full PE 
X 
Standard 12-lead ECGc 
X 
Serum FSH (suspected postmenopausal female 
subjects only) 
X 
Serum β-hCG (all female subjects) 
X 
Serology (HBsAg, HCV, HIV-1 and HIV-2 Abs, and 
p24 antigen) 
X 
G6PD activity testd 
X 
Serum chemistrye 
X 
Hematologye 
X 
Coagulatione 
X 
Drug test (urine or blood), including cotinine  
X 
Alcohol test (urine, blood, or breath) 
X 
Urinalysis 
X 
Spirometry (Parts B and C only) 
X 
AEs 
Continuous from signing of ICF through Safety Follow-up 
Visit 
AE: adverse event; β-hCG: beta-human chorionic gonadotropin; BMI: body mass index; ECG: electrocardiogram; 
FSH: follicle-stimulating hormone; G6PD: glucose-6-phosphate dehydrogenase; HBsAg: hepatitis B surface 
antigen; HCV: hepatitis C virus; HIV-1/HIV-2 Abs: antibodies against human immunodeficiency viruses 1 
and 2; ICF: informed consent form; PE: physical examination 
 a  
All medications taken within 28 days before the first dose of study drug through the end of the study will be 
recorded. 
b  
Weight and height will be measured with shoes off. Vital signs will be performed after the subject has been 
seated for at least 5 minutes. 
c  
A standard 12-lead ECG will be performed after the subject has been seated or supine for at least 5 minutes 
(Section 11.7.5.1). 
d 
A single blood sample will be collected from all subjects for the G6PD activity test. 
e 
Following at least a 4-hour fast  blood samples will be collected for clinical laboratory assessments. 


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Table 3-2 
Study VX16-445-001: Part A, Cohorts A1 Through A6, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety Follow-up Visit 
(7 to 10 days After Last 
Dose of Study Drug) 
 -1 
 1 
 2 
 3 
 4 
 5 
Inpatient days 
X 
X 
X 
X 
X 
Xb 
 
Outpatient visit 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
Weightc 
X 
 
 
 
 
 
 
Continuous ECGsd 
 
X 
X 
 
 
 
 
Standard 12-lead ECGe 
X 
X 
 
 
 
 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
Full PE 
X 
 
 
 
 
 
X 
Serum chemistry 
X 
 
X 
 
 
 
X 
Hematology 
X 
 
X 
 
 
 
X 
Blood for PK analysisg 
 
X 
X 
X 
X 
X 
 
Drug test (urine or blood), including cotinine 
X 
 
 
 
 
 
 
Alcohol test (urine, blood, or breath) 
X 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
X 
Study drug administrationh 
 
X 
 
 
 
 
 
AEs 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications reviewi 
Continuous from signing of ICF through Safety Follow-up Visit 
AE: adverse event; CRU: clinical research unit; ECG: electrocardiogram; ICF: informed consent form; PE: physical examination; PK: pharmacokinetic 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise. 
b  
Subjects will be discharged from the CRU on Day 5 after completion of the study visit assessments. 
c 
Weight will be measured with shoes off. 
d  
Continuous ECGs will be extracted in up to 10 replicates on Day 1 before dosing (at -60, -50, and -40 minutes) and at 1, 2, 3, 4, 6, 8, 12 and 24 hours 
(Day 2) after dosing. Subjects should be supine or semi-recumbent for at least 15 minutes before these time points. 
e  
Standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On Day 1, ECGs will be collected before dosing 
and approximately 1, 3, 5, and 6 hours (± 15 min) after dosing.  
f  
Vital signs will be performed after the subject has been seated for at least 5 minutes. 
g  
Blood samples for PK assessments will be collected on Day 1 before dosing (0 hours) and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Day 2), 36 (Day 2), 
48 (Day 3), 72 (Day 4), and 96 (Day 5) hours after dosing. Acceptable PK sampling windows are provided in Table 11-1.  
h  
Study drug will be administered in the fed state. Details are provided in Section 9.6.1.1. 
i  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 


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Table 3-3 
Study VX16-445-001: Part A, Cohort A7, Treatment Period and Safety Follow-up Visit 
Event/ 
Assessmenta 
Study Day 
Safety Follow-up Visit 
(7 to 10 Days After Last Dose of 
Study Drug) 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14b 
15b 
16b 
17b 
Inpatient days X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
X 
X 
X 
Xd 
 
Outpatient 
visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weighte 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
12-lead ECGf 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full PE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum 
chemistry 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Hematology 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise. 
b 
If data to support use of the IV dose is not available, Dosing Period 3 will not be conducted and assessments on Days 14 to 17 will not be performed. 
c 
Subjects will be discharged from the CRU on Day 13 after completion of the study visit assessments if Dosing Period 3 is not conducted. 
d 
Subjects will be discharged from the CRU on Day 17 after completion of the study visit assessments. 
e 
Weight will be measured with shoes off. 
f  
Standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On Days 1, 7 and 13, ECGs will be collected 
before dosing and approximately 1, 3, 5, and 6 hours (± 15 min) after dosing. 
g  
Vital signs will be performed after the subject has been seated for at least 5 minutes. 


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Table 3-3 
Study VX16-445-001: Part A, Cohort A7, Treatment Period and Safety Follow-up Visit 
Event/ 
Assessmenta 
Study Day 
Safety Follow-up Visit 
(7 to 10 Days After Last Dose of 
Study Drug) 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14b 
15b 
16b 
17b 
Blood for PK 
analysish 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
X 
X 
X 
 
Drug test 
(urine or 
blood), 
including 
cotinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol test 
(urine, blood, 
or breath) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Study drug 
adminstrationj 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Xk 
 
 
 
 
 
AEs 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications 
reviewl 
Continuous from signing of ICF through Safety Follow-up Visit 
AE: adverse event; CRU: clinical research unit; ECG: electrocardiogram; ICF: informed consent form; IV: intravenous; PE: physical examination; 
PK: pharmacokinetic  
 h 
Blood samples for PK assessments will be collected on Days 1 and 7 before dosing (0 hours) and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Days 2, 8), 36 (Days 2, 
8), 48 (Days 3, 9), 72 (Days 4, 10), 96 (Days 5 and 11), and 120 (Days 6 and 12) hours postdose. Blood samples for PK assessments will be collected on 
Day 13 before dosing (0 hours, before the start of the IV infusion) and at 0.5 (after the end of the IV infusion), 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 
(Day 14), 36 (Day 14), 48 (Day 15), 72 (Day 16), and 96 hours (Day 17) after the start of the IV infusion. Acceptable PK sampling windows are provided in 
Table 11-1. 
i  
If Dosing Period 3 is not conducted, a blood sample for PK assessment will be collected on Day 13 (144 hours after dosing on Day 7). 
j  
Study drug will be administered as a tablet in the fasted state on Day 1 and in the fed state on Day 7. On Day 13, study drug will be administered in the fed 
state as a single IV dose infused over 30 minutes (See Section 9.6.1.1 for details). If the IV dose is not administered, subjects will be discharged on Day 13 
after completion of the study visit assessments. 
k 
If data to support use of the IV dose is not available, Dosing Period 3 will not be conducted and subjects will not receive the IV dose. 
l  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 


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Table 3-4 
Study VX16-445-001: Part B, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety Follow-up 
Visit 
(7 to 10 Days 
After Last Dose 
of Study Drug) 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Inpatient days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
 
Outpatient visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weightc 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Standard 12-lead ECGd 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full PE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum chemistry 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
Hematology 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
4β-hydroxycholesterol 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Blood for PK analysisf 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Drug test (urine or blood), 
including cotinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol test (urine, blood, 
or breath) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Spirometryg 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise. If Part B study drug is administered every q12h, assessments on 
dosing days will be performed relative to the morning dose only. 
b  
Subjects will be discharged from the CRU on Day 14 after completion of the study visit assessments. 
c 
Weight will be measured with shoes off. 
d  
Standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On Days 1 and 5, ECGs will be collected before 
dosing and at approximately 1, 3, 5, and 6 hours (± 15 min) after dosing. 
e  
Vital signs will be performed after the subject has been seated for at least 5 minutes. 
f  
Blood samples for PK assessments of VX-445 will be collected on Day 1 before dosing (0 hours), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours after dosing. If 
dosing is q12h, the 12-hour sample will be collected before the next administered dose. On Days 2, 3, and 4, a blood sample will be collected in the morning 
before dosing. On Day 10, blood samples for PK assessments will be collected before dosing (0 hours), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Day 11), 
36 (Day 11), 48 (Day 12), 72 (Day 13), and 96 (Day 14) hours after dosing. The acceptable PK sampling windows are provided in Table 11-1. 


Protocol VX16-445-001, Version 7.0 
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Table 3-4 
Study VX16-445-001: Part B, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety Follow-up 
Visit 
(7 to 10 Days 
After Last Dose 
of Study Drug) 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study drug administrationh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications reviewi 
Continuous from signing of ICF through Safety Follow-up Visit 
CRU: clinical research unit; ECG: electrocardiogram; ICF: informed consent form; PK: pharmacokinetic; q12h: every 12 hours 
 
 
g  
On Day 1, spirometry will be performed approximately 6 hours (± 1 hour) after dosing. On Day 9, spirometry will be performed before dosing and at 
approximately 6 hours (± 1 hour) after dosing. The assessment on Day -1 will be performed at approximately the same time of day (± 2 hours) as the 
nominal time of the 6-hour postdose assessments on Days 1 and 9.  
h  
Study drug will be administered in the fed state (see Section 9.6.1.2) If dosing is q12h, the last dose of study drug will be administered on the morning of 
Day 10.  
i  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 


Protocol VX16-445-001, Version 7.0 
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Table 3-5  
Study VX16-445-001: Part C, Treatment Period and Safety Follow-up Visit 
 
Study Day 
Safety 
Follow-up 
(7 to 10 Days 
After Last 
Dose of Study 
Drug) 
Event/Assessmenta 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Inpatient days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
 
Outpatient visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Standard 12-lead ECGc 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full PE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum chemistry 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Hematology 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Blood for VX-445 PK 
analysise 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Blood for TEZ/IVA PK 
analysisf 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise, and will be performed relative to the morning dose only.   
b  
Subjects will be discharged from the CRU on Day 18 after completion of the study visit assessments. 
c  
Standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On Days 1 and 7, ECGs will be collected before 
dosing and approximately 1, 3, 5, and 6 hours (± 15 min) after dosing. 
d  
Vital signs will be performed after the subject has been seated for at least 5 minutes. 
e  
Blood samples for PK assessments of VX-445 will be collected on Day 1 and Day 7 before dosing (0 hours) and at 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours after 
dosing. The 12-hour sample will be collected before the next administered dose if dosing is q12h. On Days 2, 3, 4, 5, and 8, blood samples will be collected 
before (morning) dosing. On Day 14, blood samples will be collected before dosing (0 hours), and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 (Day 15), 36 (Day 15), 48 
(Day 16), 72 (Day 17), and 96 (Day 18) hours after dosing. Acceptable PK sampling windows are provided in Table 11-1. 
f  
Blood samples for PK assessments of TEZ and metabolites, and IVA and metabolites will be collected on Day 1 and Day 7 before dosing (0 hours) and at 
0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours after dosing. The 12-hour sample will be collected before the next administered IVA dose. On Days 2, 3, 4, 5, and 8, 
blood samples will be collected before (morning) dosing. On Day 14, blood samples will be collected before dosing (0 hours), and at 0.5, 1, 2, 3, 4, 5, 6, 8, 
12, 24 (Day 15), 36 (Day 15), 48 (Day 16), 72 (Day 17), and 96 (Day 18) hours after dosing. Acceptable PK sampling windows are provided in Table 11-1. 


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Table 3-5  
Study VX16-445-001: Part C, Treatment Period and Safety Follow-up Visit 
 
Study Day 
Safety 
Follow-up 
(7 to 10 Days 
After Last 
Dose of Study 
Drug) 
Event/Assessmenta 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Drug test (urine or blood), 
including cotinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol test (urine, blood, or 
breath) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
Spirometryg 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug administrationi: 
VX-445 or placebo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Study drug administrationi: 
TEZ/IVA or placebo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications reviewj 
Continuous from signing of ICF through Safety Follow-up Visit 
CRU: clinical research unit; 
; ECG: electrocardiogram; ICF: informed consent form; IVA: ivacaftor; PE: physical examination; 
PK: pharmacokinetic; q12h: every 12 hours; TEZ: tezacaftor 
 g  
On Day 1, spirometry will be performed approximately 6 hours (± 1 hour) after dosing. On Day 9, spirometry will be performed before dosing and at 
approximately 6 hours (± 1 hour) after dosing. The assessment on Day -1 will be performed at approximately the same time of day (± 2 hours) as the 
nominal time of the 6-hour postdose assessments on Days 1 and 9  
i  
Study drug will be administered in the fed state (see Section 9.6.1.3). The last dose of study drug will be administered on the morning of Day 14. 
j  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 


Protocol VX16-445-001, Version 7.0 
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Vertex Pharmaceuticals Incorporated 
 
Table 3-6 
Study VX16-445-001: Schedule of Assessments for Parts D1 and D2 
Event/Assessmenta 
Screening 
Treatment Period  
ETT 
Visitb 
Safety Follow-up 
28 ( 7) Days After 
Last Dose 
Period 1 
Period 2 
Days -28 
to -1 
Day 1c  
Day 8 for 
Part D1 only 
( 1 day) 
Day 15 
( 2 days) 
Day 29 
( 2 days) 
Period 2 Visitd 
Informed consent 
X 
 
 
 
 
 
 
 
Randomizatione 
 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
CFQ-Rf,g 
 
X 
 
X 
X 
 
 
 
Weighth 
X 
X 
X 
X 
X 
 
X 
X 
Heighth 
X 
 
 
 
 
 
 
 
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryi 
X 
X 
X 
X 
X 
X 
X 
X 
 a 
All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once 
if study drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b 
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug 
treatment. Subjects who prematurely discontinue treatment will be required to complete the Safety Follow-up Visit. If the ETT Visit occurs 3 or more weeks 
after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be required. 
c  
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 9.1.2.4. 
d  
The Period 2 Visit will occur 6 to 10 days after the actual date of the Day 29 Visit. 
e 
Randomization may occur on the previous day (Day -1 Visit) after all inclusion and exclusion criteria have been confirmed. 
f 
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
g 
The predose assessment on the Day 1 Visit may be performed on the previous day (Day -1 Visit) if randomization has occurred. 
h 
Weight and height will be measured with shoes off. 
i 
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 


Protocol VX16-445-001, Version 7.0 
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Table 3-6 
Study VX16-445-001: Schedule of Assessments for Parts D1 and D2 
Event/Assessmenta 
Screening 
Treatment Period  
ETT 
Visitb 
Safety Follow-up 
28 ( 7) Days After 
Last Dose 
Period 1 
Period 2 
Days -28 
to -1 
Day 1c  
Day 8 for 
Part D1 only 
( 1 day) 
Day 15 
( 2 days) 
Day 29 
( 2 days) 
Period 2 Visitd 
Physical examinationj 
Complete 
Abbrev. 
 
Abbrev. 
Abbrev. 
 
Abbrev. 
Complete 
Standard 12-lead ECGk 
X 
X 
X 
X 
X 
 
X 
X 
Sweat chlorideg,l  
X 
X 
X 
X 
X 
Xm 
X 
X 
Spirometryn 
Xo 
X 
X 
X 
X 
Xm 
X 
X 
Urinalysisg 
X 
X 
X 
X 
X 
 
X 
X 
Pregnancy test (all 
females of childbearing 
potential)  
Serum 
Urine 
 
 
Urine 
 
Serum 
Serum 
CFTR genotypep 
X 
 
 
 
 
 
 
 
FSHq 
X 
 
 
 
 
 
 
 
G6PD activity testr 
X 
 
 
 
 
 
 
 
 j 
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. 
k 
All standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On the Day 1 and 15 Visits, ECGs will be 
collected before dosing and 5 hours (± 1 hour) after dosing. At all other visits, ECGs will be collected before dosing (as applicable). ECGs collected on the 
Day 1 Visit before dosing will be performed in triplicate.  
l 
Sweat chloride will be measured in all subjects as described in Section 11.4.1. If the value cannot be determined from the screening test, a sweat chloride 
value documented in a laboratory report may be used to establish eligibility. See Section 8.2.1 (Inclusion Criterion #5) for additional detail. 
m 
At the Period 2 Visit, sweat chloride and ppFEV1 assessments should be done within 2 hours before TEZ/IVA dosing in the morning.  
n 
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 visit. On the Day 1 and Day 15 Visits, spirometry will also be performed 
5 hours (± 1 hour) after study drug administration (pre-bronchodilator).  
o 
For Part D2 subjects only: The ppFEV1 assessment that will be used for stratification of randomization can be done any time during the Screening Period. 
See Section 9.1.2.2. 
p 
CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before randomization, a previous CFTR genotype 
laboratory report may be used to establish eligibility. However, as outlined in Section 9.9, 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. 
q 
FSH will be measured for any potential postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 


Protocol VX16-445-001, Version 7.0 
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Table 3-6 
Study VX16-445-001: Schedule of Assessments for Parts D1 and D2 
Event/Assessmenta 
Screening 
Treatment Period  
ETT 
Visitb 
Safety Follow-up 
28 ( 7) Days After 
Last Dose 
Period 1 
Period 2 
Days -28 
to -1 
Day 1c  
Day 8 for 
Part D1 only 
( 1 day) 
Day 15 
( 2 days) 
Day 29 
( 2 days) 
Period 2 Visitd 
Serum chemistry and 
hematologyg 
X 
X 
X 
X 
X 
 
X 
X 
Coagulationg 
X 
X 
 
X 
X 
 
X 
X 
PK samplingt 
 
X 
 
X 
X 
X 
X 
 
TEZ/IVA or placebo 
dosingu  
 
Day 1 through Period 2 Visit 
 
 
 
VX-445 or placebo 
dosingv 
 
Day 1 through Day 29 
 
 
 
AEs, medicationsw, 
treatments, and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
AE: adverse event; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; CFTR: CF transmembrane conductance regulator gene; 
; ECG: electrocardiogram; ETT: early termination of treatment; FSH: follicle-stimulating hormone; G6PD: glucose-6-phosphate 
dehydrogenase; ICF: informed consent form; IVA: ivacaftor; PE: physical examination; PK: pharmacokinetic; ppFEV1: percent predicted forced expiratory 
volume in 1 second ; TEZ: tezacaftor 
 r 
Blood samples will be collected for the G6PD activity test. 
 
Blood samples will be collected for PK analysis of VX-445, TEZ, M1-TEZ, IVA, and M1-IVA. On the Day 1 Visit, samples will be collected before dosing 
(0 hours) and at 1, 2, 4, and 6 hours after dosing (relative to the morning dose). On the Day 15 Visit, samples will be collected before dosing (0 hours) and at 
1, 2, 4, 6, and 8 hours after dosing. On the Day 29 Visit, a predose sample will be collected before the morning dose of study drug. At the Period 2 Visit, a 
single predose sample will be collected before TEZ/IVA dosing in the morning. At the ETT Visit, a single blood sample for PK analysis will be collected. 
u 
On days of scheduled visits, the in-clinic dose of study drugs will be given in the morning, at least 6 hours apart from any other scheduled dose and after all 
predose assessments are complete. The last dose of TEZ/IVA or placebo in Period 2 will be the morning dose of the Period 2 Visit. See Section 9.6.2 for 
additional information about study drug administration. 
v     On days of scheduled visits, the in-clinic dose of study drugs will be given in the morning, at least 6 hours apart from any other scheduled dose and after all 
predose assessments are complete. The last dose of VX-445 or placebo in Period 1 will be the morning dose on the Day 29 Visit. See Section 9.6.2 for 
additional information about study drug administration. 
w 
Refer to Section 9.5.2 for details. 


Protocol VX16-445-001, Version 7.0 
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Vertex Pharmaceuticals Incorporated 
 
Table 3-7 
Study VX16-445-001: Schedule of Assessments for Part E 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Period: Period 1 
Washout Period 
ETT 
Visitb 
Safety 
Follow-up 
28 ( 7) Days 
After Last 
Dosec 
Days -56 
to -29 
Day -28 
( 1 day) 
Day -14d 
(+ 13 days) 
Day 1e  
Day 15 
( 2 days) 
Day 29 
( 2 days) 
Day 43 
( 3 days) 
Day 57 
( 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Randomizationf 
 
 
 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
CFQ-Rg,h 
 
 
 
X 
X 
X 
 
X 
  
 
Weighti 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Heighti 
X 
 
 
 
 
 
 
 
 
 
Vital signsj 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryj 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical 
examinationk 
Complete 
Abbreviated 
 
Abbreviated Abbreviated Abbreviated 
 
Abbreviated Abbreviated 
Complete 
 a  
All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once 
if study drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b  
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, the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be required. 
c  
Part E subjects who meet criteria specified in Section 9.1.2.6 will not have a Safety Follow-up Visit.  
d  
The Day -14 Visit is only required for subjects who are not transitioning directly from at least 14 days of uninterrupted TEZ/IVA treatment. Assessments at 
this visit may be performed postdose. 
e  
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 9.1.2.4. 
f  
Randomization may occur on the previous day (Day -1 Visit) after all inclusion and exclusion criteria and criteria for entry into the Treatment Period have 
been confirmed. See Section 9.1.2.2.2. 
g  
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
h  
The predose assessment on the Day 1 Visit may be performed on the previous day (Day -1 Visit) if randomization has occurred. 
i  
Weight and height will be measured with shoes off. 
j  
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 
k  
Complete and abbreviated PEs are described in Section 11.7.3. Symptom-targeted PEs will occur at any time during the study if triggered by AEs or if 
deemed necessary by the investigator or healthcare provider. 


Protocol VX16-445-001, Version 7.0 
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Vertex Pharmaceuticals Incorporated 
 
Table 3-7 
Study VX16-445-001: Schedule of Assessments for Part E 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Period: Period 1 
Washout Period 
ETT 
Visitb 
Safety 
Follow-up 
28 ( 7) Days 
After Last 
Dosec 
Days -56 
to -29 
Day -28 
( 1 day) 
Day -14d 
(+ 13 days) 
Day 1e  
Day 15 
( 2 days) 
Day 29 
( 2 days) 
Day 43 
( 3 days) 
Day 57 
( 3 days) 
Standard 12-lead 
ECGl 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Sweat chlorideh,m 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Spirometryn 
Xo 
  
Xo 
X 
X 
X 
X 
X 
X 
X 
Urinalysish 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (all 
females of 
childbearing 
potential) 
Serum 
Urine 
 
Urine 
 
Urine 
 
Urine 
Serum 
Serum 
CFTR genotypep 
X 
 
 
 
 
 
 
 
 
 
FSHq 
X 
 
 
 
 
 
 
 
 
 
G6PD activity testr 
X 
 
 
 
 
 
 
 
 
 
 l  
All standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On the Days 1 and 15 Visits, ECGs will be 
collected before dosing and 5 hours (± 1 hour) after dosing. At all other visits, ECGs will be collected before dosing (as applicable). ECGs collected on the 
Day 1 Visit before dosing will be performed in triplicate.  
m  
Sweat chloride will be measured in all subjects as described in Section 11.4.1. If the value cannot be determined from the screening test (e.g. due to 
laboratory error), a sweat chloride value documented in a previous laboratory report may be used to establish eligibility. See Section 8.2.1 (Inclusion 
Criterion #5) for additional detail.  
n  
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 (except at the Day -14 Visit when spirometry may be performed postdose), and should be performed at approximately the same time at every 
visit. On the Day 1 and Day 15 Visits, spirometry will also be performed 5 hours (± 1 hour) after study drug administration (pre-bronchodilator).  
o  
The ppFEV1 assessment for stratification of randomization will be done at the Screening Visit for subjects transitioning directly from at least 14 days of 
uninterrupted TEZ/IVA treatment. For all other subjects, this assessment will be done at the Day -14 Visit. See Section 9.1.2.2 
p  
CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before the Day -28 Visit, a previous CFTR 
genotype laboratory report may be used to establish eligibility. However, as outlined in Section 9.9, 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. 
q  
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
r  
Blood samples will be collected for the G6PD activity test. 


Protocol VX16-445-001, Version 7.0 
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Vertex Pharmaceuticals Incorporated 
 
Table 3-7 
Study VX16-445-001: Schedule of Assessments for Part E 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Period: Period 1 
Washout Period 
ETT 
Visitb 
Safety 
Follow-up 
28 ( 7) Days 
After Last 
Dosec 
Days -56 
to -29 
Day -28 
( 1 day) 
Day -14d 
(+ 13 days) 
Day 1e  
Day 15 
( 2 days) 
Day 29 
( 2 days) 
Day 43 
( 3 days) 
Day 57 
( 3 days) 
Serum chemistry 
and hematologyh 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Coagulationh 
X 
X 
 
X 
X 
X 
 
 
X 
X 
PK samplingt 
 
 
 
X 
X 
X 
X 
 
X 
  
TEZ/IVA dosingu 
 
Day -28 through Day 57 
 
 
VX-445 or placebo 
dosingv 
 
 
 
Day 1 through Day 29 
 
 
 
 
AEs, medicationsw, 
treatments and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
AE: adverse event; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; CFTR: CF transmembrane conductance regulator gene; 
; ECG: electrocardiogram; ETT: early termination of treatment; FSH: follicle-stimulating hormone; G6PD: glucose-6-phosphate 
dehydrogenase; ICF: informed consent form; IVA: ivacaftor; PE: physical examination; PK: pharmacokinetic; ppFEV1: percent predicted forced expiratory 
volume in 1 second ; TEZ: tezacaftor 
t  
Blood samples will be collected for PK analysis of VX-445, TEZ, M1-TEZ, IVA, and M1-IVA. On the Day 1 Visit, samples will be collected before dosing 
(0 hours) and at 1, 2, 4, and 6 hours after dosing (relative to morning dose). On the Day 15 Visit, samples will be collected before dosing (0 hours) and at 1, 
2, 4, 6, and 8 hours after dosing. On the Day 29 Visit, a predose sample will be collected before the morning dose of study drug. At the Day 43 Visit, a single 
blood sample for PK analysis will be collected before the morning dose of TEZ/IVA. At the ETT Visit, a single blood sample for PK analysis will be 
collected. 
u 
The last dose of TEZ/IVA will be the morning dose on the Day 57 Visit. See Section 9.6.2 for additional information about study drug administration. 
v  
The last dose of VX-445 or placebo will be the morning dose on the Day 29 Visit. See Section 9.6.2 for additional information about study drug 
administration. 
w  
Refer to Section 9.5.2 for details. 


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Table 3-8 
Study VX16-445-001: Schedule of Assessments for Part F (if Conducted) 
Event/Assessmenta 
Screening 
Treatment Period: Period 1 
ETT 
Visitb 
Safety Follow-up 
28 ( 7) Days After 
Last Dose 
Days -28 
to -1 
Day 1c  
Day 8d 
( 1 day) 
Day 15 
( 2 days) 
Day 29 
( 2 days) 
Informed consent 
X 
 
 
 
 
 
 
Randomizatione 
 
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
CFQ-Rf,g 
 
X 
 
X 
X 
 
 
Weighth 
X 
X 
 
X 
X 
X 
X 
Heighth 
X 
 
 
 
 
 
 
Vital signsi 
X 
X 
 
X 
X 
X 
X 
Pulse oximetryi 
X 
X 
 
X 
X 
X 
X 
 a 
All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once 
if study drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b 
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug 
treatment. Subjects who prematurely discontinue treatment will be required to complete the Safety Follow-up Visit. If the ETT Visit occurs 3 or more weeks 
after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be required. 
c  
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 9.1.2.4. 
d  
The laboratory assessment may be collected at the clinic, at a local laboratory, or during a visit by a qualified individual (e.g., home nurse). If the laboratory 
assessment is not collected at the clinic, a telephone call to the clinic is required for the collection of AEs. When the laboratory assessment is done in the 
clinic, the AE collection will also occur in the clinic. 
e 
Randomization may occur on the previous day (Day -1 Visit) after all inclusion and exclusion criteria have been confirmed. 
f 
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
g 
The predose assessment on the Day 1 Visit may be performed on the previous day (Day -1 Visit) if randomization has occurred. 
h 
Weight and height will be measured with shoes off. 
i 
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 


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Table 3-8 
Study VX16-445-001: Schedule of Assessments for Part F (if Conducted) 
Event/Assessmenta 
Screening 
Treatment Period: Period 1 
ETT 
Visitb 
Safety Follow-up 
28 ( 7) Days After 
Last Dose 
Days -28 
to -1 
Day 1c  
Day 8d 
( 1 day) 
Day 15 
( 2 days) 
Day 29 
( 2 days) 
Physical examinationj 
Complete 
Abbrev. 
 
Abbrev. 
Abbrev. 
Abbrev. 
Complete 
Standard 12-lead ECGk 
X 
X 
 
X 
X 
X 
X 
Sweat chlorideg,l,  
X 
X 
 
X 
X 
X 
X 
Spirometrym 
Xn 
X 
 
X 
X 
X 
X 
Urinalysisg 
X 
X 
 
X 
X 
X 
X 
Pregnancy test (all females of childbearing 
potential)  
Serum 
Urine 
 
 
Urine 
Serum 
Serum 
CFTR genotypeo 
X 
 
 
 
 
 
 
FSHp 
X 
 
 
 
 
 
 
G6PD activity testq 
X 
 
 
 
 
 
 
Serum chemistry and hematologyg 
X 
X 
X 
X 
X 
X 
X 
 j 
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. 
k 
All standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On the Day 1 and 15 Visits, ECGs will be 
collected before dosing and 5 hours (± 1 hour) after dosing. At all other visits, ECGs will be collected before dosing (as applicable). ECGs collected on the 
Day 1 Visit before dosing will be performed in triplicate.  
l 
Sweat chloride will be measured in all subjects as described in Section 11.4.1. If the value cannot be determined from the screening test, a sweat chloride 
value documented in a previous laboratory report may be used to establish eligibility. See Section 8.2.1 (Inclusion Criterion #5) for additional detail. 
m 
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 visit. On the Day 1 and 15 Visits, spirometry will also be performed 
pre-bronchodilator, 5 hours (± 1 hour) after study drug administration.  
n 
The ppFEV1 assessment that will be used for stratification of randomization can be done any time during the Screening Period. See Section 9.1.2.2. 
o 
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. However, as outlined in Section 9.9, 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. 
p 
FSH will be measured for any potential postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
q 
Blood samples will be collected for the G6PD activity test. 


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Table 3-8 
Study VX16-445-001: Schedule of Assessments for Part F (if Conducted) 
Event/Assessmenta 
Screening 
Treatment Period: Period 1 
ETT 
Visitb 
Safety Follow-up 
28 ( 7) Days After 
Last Dose 
Days -28 
to -1 
Day 1c  
Day 8d 
( 1 day) 
Day 15 
( 2 days) 
Day 29 
( 2 days) 
Coagulationg 
X 
X 
 
X 
X 
X 
X 
PK samplings 
 
X 
 
X 
X 
X 
 
VX-445/TEZ/VX-561 or placebo dosingt  
 
Day 1 through Day 29 
 
 
 
AEs, medicationsu, treatments, and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
AE: adverse event; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; CFTR: CF transmembrane conductance regulator gene; 
 ECG: electrocardiogram; ETT: early termination of treatment; FSH: follicle-stimulating hormone; G6PD: glucose-6-phosphate 
dehydrogenase; ICF: informed consent form; IVA: ivacaftor; PE: physical examination; PK: pharmacokinetic; ppFEV1: percent predicted forced expiratory 
volume in 1 second ; TEZ: tezacaftor 
 s 
Blood samples will be collected for PK analysis of VX-445, TEZ, M1-TEZ, and VX-561. On the Day 1 Visit, samples will be collected before dosing 
(0 hours) and at 1, 2, 4, and 6 hours after dosing (relative to the morning dose). On the Day 15 Visit, samples will be collected before dosing (0 hours) and at 
1, 2, 4, 6, and 8 hours after dosing. On the Day 29 Visit, a predose sample will be collected before the morning dose of study drug. At the ETT visit, a single 
blood sample for PK analysis will be collected. 
t 
On days of scheduled visits, the in-clinic dose of study drugs will be given in the morning, at least 6 hours apart from any other scheduled dose and after all 
predose assessments are complete. The last dose of VX-445/TEZ/VX-561 or placebo will be the morning dose on the Day 29 Visit. See Section 9.6.2 for 
additional information about study drug administration. 
u 
Refer to Section 9.5.2 for details. 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 4 
3 
Schedule of Assessments...................................................................................................... 12 
4 
Table of Contents ................................................................................................................. 30 
List of Tables............................................................................................................................ 35 
List of Figures .......................................................................................................................... 35 
List of Abbreviations................................................................................................................ 36 
5 
Introduction.......................................................................................................................... 39 
5.1 
Background ..................................................................................................................... 39 
5.2 
Rationale for the Present Study ...................................................................................... 40 
6 
Study Objectives .................................................................................................................. 40 
6.1 
Primary Objectives ......................................................................................................... 40 
6.2 
Secondary Objectives ..................................................................................................... 41 
7 
Study Endpoints ................................................................................................................... 42 
7.1 
Primary Endpoints .......................................................................................................... 42 
7.2 
Secondary Endpoints ...................................................................................................... 42 
 
 
8 
Study Population .................................................................................................................. 43 
8.1 
Parts A, B, and C ............................................................................................................ 43 
8.1.1 
Inclusion Criteria: Parts A, B, and C ...................................................................... 43 
8.1.2 
Exclusion Criteria: Parts A, B, and C ..................................................................... 43 
8.2 
Parts D, E, and F ............................................................................................................. 45 
8.2.1 
Inclusion Criteria: Parts D, E, and F ....................................................................... 45 
8.2.2 
Exclusion Criteria: Parts D, E, and F ...................................................................... 45 
9 
Study Implementation ......................................................................................................... 47 
9.1 
Study Design .................................................................................................................. 47 
9.1.1 
Parts A, B, and C .................................................................................................... 47 
9.1.1.1 
Screening (Parts A, B, and C) .......................................................................... 49 
9.1.1.2 
Treatment Period (Parts A, B, and C) .............................................................. 50 
9.1.1.3 
Follow-up (Parts A, B, and C) ......................................................................... 50 
9.1.1.4 
Early Discontinuation (Parts A, B, and C) ....................................................... 51 
9.1.2 
Parts D, E, and F ..................................................................................................... 51 
9.1.2.1 
Screening (Parts D, E, and F) ........................................................................... 54 
9.1.2.2 
Stratification and Randomization (Parts D, E, and F) ...................................... 55 
9.1.2.3 
Run-in Period (Part E) ...................................................................................... 56 
9.1.2.4 
Treatment Period (Parts D, E, and F) ............................................................... 56 
9.1.2.5 
Washout Period (Part E)................................................................................... 56 
9.1.2.6 
Follow-up (Parts D, E, and F) .......................................................................... 56 
9.1.2.7 
Early Termination of Treatment (Parts D, E, and F)........................................ 56 
9.1.2.8 
Independent Data Monitoring Committee (Parts D, E, and F) ........................ 57 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 57 
9.3 
Rationale for Study Design and Study Drug Regimens ................................................. 57 
9.3.1 
Study Design........................................................................................................... 57 
9.3.1.1 
Parts A, B, and C .............................................................................................. 57 


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9.3.1.2 
Parts D, E, and F .............................................................................................. 58 
9.3.2 
Study Drug Dose and Duration .............................................................................. 59 
9.3.2.1 
Parts A, B, and C .............................................................................................. 59 
9.3.2.2 
Parts D, E, and F .............................................................................................. 60 
9.3.3 
Study Population (Parts D, E, and F)...................................................................... 62 
9.3.4 
Study Assessments ................................................................................................. 62 
9.3.4.1 
Parts A, B, and C .............................................................................................. 62 
9.3.4.2 
Parts D, E, and F .............................................................................................. 63 
9.4 
Study Restrictions ........................................................................................................... 63 
9.4.1 
Parts A, B, and C .................................................................................................... 63 
9.4.2 
Parts D, E, and F ..................................................................................................... 65 
9.4.2.1 
Prohibited Medications .................................................................................... 65 
9.5 
Prior and Concomitant Medications ............................................................................... 65 
9.5.1 
Parts A, B, and C .................................................................................................... 65 
9.5.2 
Parts D, E, and F ..................................................................................................... 66 
9.6 
Study Drug Administration ............................................................................................ 66 
9.6.1 
Parts A, B, and C .................................................................................................... 66 
9.6.1.1 
Part A ............................................................................................................... 67 
9.6.1.2 
Part B ................................................................................................................ 68 
9.6.1.3 
Part C ................................................................................................................ 68 
9.6.2 
Parts D, E, and F ..................................................................................................... 68 
Missed Doses ........................................................................................................................ 69 
9.7 
Dose Escalation Criteria ................................................................................................. 69 
9.7.1 
Parts A, B, and C .................................................................................................... 69 
9.7.1.1 
Part A ............................................................................................................... 70 
9.7.1.2 
Part B ................................................................................................................ 70 
9.7.1.3 
Part C ................................................................................................................ 70 
9.7.2 
Parts D, E, and F ..................................................................................................... 70 
9.8 
Stopping Criteria ............................................................................................................ 70 
9.8.1 
Parts A, B, and C .................................................................................................... 70 
9.8.2 
Parts D, E, and F ..................................................................................................... 71 
9.9 
Removal of Subjects ....................................................................................................... 72 
9.10 Replacement of Subjects ................................................................................................ 72 
10 Study Drug Information and Management ....................................................................... 73 
10.1 Preparation and Dispensing ............................................................................................ 73 
10.2 Packaging and Labeling ................................................................................................. 73 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 73 
10.4 Drug Accountability ....................................................................................................... 74 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 74 
10.6 Compliance ..................................................................................................................... 75 
10.6.1 
Parts A, B, and C .................................................................................................... 75 
10.6.2 
Parts D, E, and F ..................................................................................................... 75 
10.7 Blinding and Unblinding ................................................................................................ 75 
10.7.1 
Blinding .................................................................................................................. 75 
10.7.1.1 Parts A, B, and C .............................................................................................. 75 
10.7.1.2 Parts D, E, and F .............................................................................................. 76 


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10.7.2 
Unblinding .............................................................................................................. 77 
11 Assessments .......................................................................................................................... 78 
11.1 Timing of Assessments ................................................................................................... 78 
11.2 Subject and Disease Characteristics ............................................................................... 78 
11.3 Pharmacokinetics ............................................................................................................ 78 
11.3.1 
Blood Sampling ...................................................................................................... 78 
11.3.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 79 
11.3.3 
Bioanalysis.............................................................................................................. 79 
11.4 Pharmacodynamics ......................................................................................................... 79 
11.4.1 
Sweat Chloride (Parts 
D, E, and F) .................................................................... 79 
 
11.6 Efficacy (Parts D, E, and F) ............................................................................................ 80 
11.6.1 
Spirometry .............................................................................................................. 80 
11.6.2 
Cystic Fibrosis Questionnaire-Revised .................................................................. 81 
11.7 Safety .............................................................................................................................. 81 
11.7.1 
Adverse Events ....................................................................................................... 82 
11.7.2 
Clinical Laboratory Assessments ........................................................................... 82 
11.7.3 
Physical Examinations and Vital Signs .................................................................. 84 
11.7.4 
Pulse Oximetry (Parts D, E, and F) ........................................................................ 85 
11.7.5 
Electrocardiograms ................................................................................................. 85 
11.7.5.1 Safety ECGs ..................................................................................................... 85 
11.7.5.2 Continuous ECGs for Cardiodynamic Assessment (Part A, With the 
Exception of Cohort A7) .................................................................................. 85 
11.7.6 
Spirometry (Parts B, C, D, E, and F) ...................................................................... 86 
11.7.7 
Contraception and Pregnancy ................................................................................. 86 
11.7.7.1 Contraception ................................................................................................... 86 
11.7.7.2 Pregnancy ......................................................................................................... 87 
12 Statistical and Analytical Plans .......................................................................................... 88 
12.1 Sample Size and Power .................................................................................................. 88 
12.1.1 
Parts A, B, and C .................................................................................................... 88 
12.1.2 
Parts D, E, and F ..................................................................................................... 88 
12.1.2.1 Primary Objectives ........................................................................................... 88 
12.1.2.2 Secondary Objectives ....................................................................................... 88 
12.2 Analysis Sets .................................................................................................................. 89 
12.2.1 
Parts A, B, and C .................................................................................................... 89 
12.2.2 
Parts D, E, and F ..................................................................................................... 89 
12.3 Statistical Analysis ......................................................................................................... 90 
12.3.1 
General Considerations ........................................................................................... 90 
12.3.2 
Background Characteristics .................................................................................... 91 
12.3.2.1 Subject Disposition .......................................................................................... 91 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 91 
12.3.2.3 Prior and Concomitant Medications................................................................. 91 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 92 
12.3.2.5 Important Protocol Deviations (Parts D, E, and F Only) ................................. 93 
12.3.3 
Efficacy Analysis (Parts D, E, and F Only) ............................................................ 93 
12.3.3.1 Analysis of Primary Variables ......................................................................... 93 


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12.3.3.2 Analysis of Secondary Efficacy Variables ....................................................... 93 
12.3.4 
Pharmacodynamic Analysis ................................................................................... 93 
Dose-response Analysis .................................................................................................... 93 
Estimation of Treatment Effects ....................................................................................... 94 
12.3.5 
Safety Analysis ....................................................................................................... 94 
Parts A, B, and C............................................................................................................... 94 
Parts D, E, and F ............................................................................................................... 94 
12.3.5.1 Adverse Events................................................................................................. 95 
12.3.5.2 Clinical Laboratory Assessments ..................................................................... 96 
12.3.5.3 Electrocardiogram ............................................................................................ 96 
12.3.5.4 Vital Signs ........................................................................................................ 97 
12.3.5.5 Pulse Oximetry (Parts D, E, and F) .................................................................. 97 
12.3.5.6 Physical Examination ....................................................................................... 97 
12.3.5.7 Spirometry (Parts B, C, D, E, and F) ............................................................... 97 
12.3.6 
Interim and IDMC Analyses ................................................................................... 98 
12.3.6.1 Interim Analysis ............................................................................................... 98 
12.3.6.2 IDMC Analysis (Parts D, E, and F) ................................................................. 98 
12.4 Clinical Pharmacology Analysis .................................................................................... 98 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 98 
12.4.1.1 Parts A, B, and C .............................................................................................. 98 
12.4.1.2 Parts D, E, and F .............................................................................................. 98 
 
 
12.4.3 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 99 
 
12.4.3.2 Parts D, E, and F .............................................................................................. 99 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 99 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 99 
13.1.1 
Adverse Events ....................................................................................................... 99 
13.1.1.1 Definition of an Adverse Event........................................................................ 99 
13.1.1.2 Clinically Significant Assessments .................................................................. 99 
13.1.1.3 Documentation of Adverse Events................................................................. 100 
13.1.1.4 Adverse Event Severity .................................................................................. 100 
13.1.1.5 Adverse Event Causality ................................................................................ 101 
13.1.1.6 Study Drug Action Taken .............................................................................. 101 
13.1.1.7 Adverse Event Outcome ................................................................................ 102 
13.1.1.8 Treatment Given............................................................................................. 102 
13.1.2 
Serious Adverse Events ........................................................................................ 102 
13.1.2.1 Definition of a Serious Adverse Event........................................................... 102 
13.1.2.2 Documentation of Serious Adverse Events.................................................... 103 
13.1.2.3 Reporting Serious Adverse Events................................................................. 103 
13.1.2.4 Expedited Reporting and Investigator Safety Letters .................................... 104 
13.2 Administrative Requirements ....................................................................................... 104 
13.2.1 
Ethical Considerations .......................................................................................... 104 
13.2.2 
Subject Information and Informed Consent ......................................................... 104 
13.2.3 
Investigator Compliance ....................................................................................... 104 


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13.2.4 
Access to Records ................................................................................................. 105 
13.2.5 
Subject Privacy ..................................................................................................... 105 
13.2.6 
Record Retention .................................................................................................. 105 
13.2.7 
Study Termination ................................................................................................ 105 
13.3 Data Quality Assurance ................................................................................................ 106 
13.3.1 
Parts A, B, and C .................................................................................................. 106 
13.3.2 
Parts D, E, and F ................................................................................................... 106 
13.4 Monitoring .................................................................................................................... 106 
13.5 Data Capture (Parts A, B, and C) ................................................................................. 106 
13.6 Electronic Data Capture (Parts D, E, and F) ................................................................ 107 
13.7 Publications and Clinical Study Report ........................................................................ 107 
 
 
13.7.2 
Clinical Study Report ........................................................................................... 107 
14 References ........................................................................................................................... 108 
APPENDIX A  CFTR Mutations That Are Predicted to Result in a CFTR Protein With 
Minimal Function (Parts D and F) ................................................................................ 110 
15 Protocol Signature Pages .................................................................................................. 113 
15.1 Sponsor Signature Page ................................................................................................ 113 
15.2 Investigator Signature Page .......................................................................................... 114 
 


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List of Tables 
Table 3-1 
Study VX16-445-001: Parts A, B, and C, Screening ............................................ 13 
Table 3-2 
Study VX16-445-001: Part A, Cohorts A1 Through A6, Treatment Period and 
Safety Follow-up Visit .......................................................................................... 14 
Table 3-3 
Study VX16-445-001: Part A, Cohort A7, Treatment Period and Safety Follow-up 
Visit ....................................................................................................................... 15 
Table 3-4 
Study VX16-445-001: Part B, Treatment Period and Safety Follow-up Visit ..... 17 
Table 3-5  
Study VX16-445-001: Part C, Treatment Period and Safety Follow-up Visit ..... 19 
Table 3-6 
Study VX16-445-001: Schedule of Assessments for Parts D1 and D2 ................ 21 
Table 3-7 
Study VX16-445-001: Schedule of Assessments for Part E ................................. 24 
Table 3-8 
Study VX16-445-001: Schedule of Assessments for Part F (if Conducted) ........ 27 
Table 9-1 
Study Design for Parts A, B, and C ...................................................................... 48 
Table 9-2 
Parts D, E, and F: Key Study Elements ................................................................ 51 
Table 9-3 
Treatment Arms and Planned Doses by Part in the Treatment Period (Period 1) 52 
Table 9-4 
Parts A, B, and C: Study Restrictions ................................................................... 64 
Table 9-5 
Parts D, E, and F: Prohibited Medications ............................................................ 65 
Table 10-1 
Study Drug ............................................................................................................ 74 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 79 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 83 
Table 11-3 
Acceptable Methods of Contraception.................................................................. 87 
Table 12-1 
Contrast Coefficients for the Multiple Comparisons Procedure in Part D ........... 89 
Table 13-1 
Grading of AE Severity ...................................................................................... 101 
Table 13-2 
Classifications for AE Causality ......................................................................... 101 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE ................ 102 
Table 13-4 
Classifications for Outcome of an AE ................................................................ 102 
List of Figures 
Figure 9-1 
Parts D and E: Schematic of Study Design ........................................................... 53 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
AUC 
area under the concentration versus time curve 
AUC0-24h 
AUC from the time of dosing to 24 hours 
AUC0-∞ 
AUC from the time of dosing extrapolated to infinity 
β-hCG 
beta-human chorionic gonadotropin 
BA 
bioavailability 
BMI 
body mass index 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
CF transmembrane conductance regulator gene 
CFTR 
CF transmembrane conductance regulator protein 
Cmax 
maximum observed concentration 
Ctrough 
predose concentration 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRO 
clinical research organization 
CRU 
clinical research unit 
CSR 
clinical study report 
CYP 
cytochrome P450 
 
 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
Emax 
maximum effect 
E-R 
exposure-response 
ETT 
early termination of treatment 
EU 
European Union 
F508del 
CFTR gene mutation with an in-frame deletion of a phenylalanine codon 
corresponding to position 508 of the wild-type protein 
F508del 
CFTR protein lacking the phenylalanine normally found at position 508 of the 
wild-type protein 
F/F 
F508del/F508del genotype 
F/MF 
F508del/minimal function genotypes 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FDC 
fixed-dose combination 
FEF25%-75% 
forced expiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 


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Abbreviation 
Definition 
FVC 
forced vital capacity 
G6PD 
glucose-6-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
GLI 
Global Lung Function Initiative 
GLP 
Good Laboratory Practice 
GPS 
Global Patient Safety (Vertex) 
HBE 
human bronchial epithelial 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HED 
human equivalent dose 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV-1/HIV-2 Abs 
antibodies against human immunodeficiency viruses 1 and 2 
HR 
heart rate 
IA 
interim analysis 
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 
IV 
intravenous 
IVA 
ivacaftor 
IWRS 
interactive web response system 
LLN 
lower limit of normal 
LUM 
lumacaftor 
max 
maximum 
MCP 
multiple comparisons procedure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
minimal function 
min 
minimum 
MMRM 
mixed-effects model for repeated measures 
n 
number of subjects 
NOAEL 
no-observed-adverse-effect level 
NOEL 
no-observed-effect level 
OATP1B1 
organic anion transporting polypeptide 1B1 
P 
probability 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PK 
pharmacokinetic, pharmacokinetics 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
PR 
PR interval 
q12h 
every 12 hours 


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Abbreviation 
Definition 
QC 
quality control 
qd 
once daily 
QRS 
portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QTc 
QT interval corrected 
QTcB 
QT interval corrected by Bazett’s formula 
QTcF 
QT interval corrected by Fridericia’s formula 
RR 
interval from the onset of 1 QRS complex to the next 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SET 
study execution team 
SI 
International System 
SUSAR 
suspected, unexpected, serious adverse reaction 
TBD 
to be determined 
TC 
triple combination 
TC2 
triple combination 2 (VX-445/TEZ/VX-561) 
TEAE 
treatment-emergent adverse event 
TEZ 
tezacaftor 
ULN 
upper limit of normal 
US 
United States 
UV 
ultraviolet 
Vertex 
Vertex Pharmaceuticals Incorporated 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) is an autosomal recessive chronic disease with serious morbidities and 
frequent premature mortality. At present, there is no cure. CF affects approximately 
70,000 individuals worldwide1 (approximately 30,000 in the US1,2 and 32,000 in the EU).3 Based 
on its prevalence, CF qualifies as an orphan disease.4,5  
CF is caused by reduced quantity and/or function of the CFTR (CF transmembrane conductance 
regulator) protein due to mutations in the CFTR gene. The CFTR protein is an epithelial chloride 
channel that aids in regulating salt and water absorption, and secretion and pH balance in sweat 
glands and multiple organs, including the lungs, pancreas, and other gastrointestinal organs. 
Despite progress in the treatment of CF with antibiotics and mucolytics, the predicted median 
age of survival for a person with CF is approximately 40 years.2,6,7 Progressive loss of lung 
function is the leading cause of mortality.8 More effective treatments are needed for CF. 
More than 2000 mutations of the CFTR gene have been identified.9 Most of these mutations are 
not associated with CF disease or are very rare. Currently, the CFTR2 database contains 
information on only 322 of these identified mutations, with sufficient evidence to define 
281 mutations as disease-causing.10 The most common disease-causing CFTR mutation, 
F508del-CFTR, accounts for 70% of the identified alleles in patients with CF; nearly half of all 
people with CF are homozygous for F508del. 
Based on the understanding of the molecular defects caused by CFTR mutations, 
2 complementary approaches have been developed to address the decreased quantity and/or 
function of CFTR in order to enhance chloride transport in patients with CF. Correctors facilitate 
cellular processing and trafficking to increase the quantity of functional CFTR at the cell surface. 
Potentiators increase the channel open probability of the CFTR protein delivered to the cell 
surface to enhance ion transport. Depending on the amount of residual CFTR channel activity in 
the membrane and the pathophysiology of that activity (reflecting the CFTR genotype of the 
patient and possibly other factors), both approaches may be required to ameliorate lung disease 
in patients with CF.  
The therapeutic activity of CFTR correctors and potentiators has been established with products 
that were developed by Vertex Pharmaceuticals Incorporated (Vertex) and approved for the 
treatment of CF: ivacaftor (IVA) monotherapy (Kalydeco®) and lumacaftor (LUM) in 
combination with IVA (Orkambi®). Kalydeco and Orkambi are approved to treat CF in patients 
with specific CFTR genotypes. Tezacaftor (TEZ; VX-661), like LUM, is a first-generation CFTR 
corrector that improves the processing and trafficking of the F508del-CFTR protein, resulting in 
an increase in the quantity of F508del-CFTR protein at the cell surface. IVA increases the 
open-channel probability of the F508del-CFTR protein that has been delivered to the cell surface 
by TEZ, thereby enhancing total chloride transport. The combined effect of TEZ and IVA is 
increased quantity and function of F508del-CFTR at the cell surface. 
VX-445 is a next-generation CFTR corrector. In vitro, VX-445 improves the processing and 
trafficking of F508del-CFTR, thereby increasing the quantity of functional F508del-CFTR 
protein at the cell surface. 11 The effect of VX-445 was additive to the effect of TEZ. The CFTR 
protein delivered to the cell surface by VX-445 alone or in combination with TEZ 


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(VX-445/TEZ) was potentiated by IVA.11 In human bronchial epithelial (HBE) cells studied in 
vitro, the triple combination (TC) of VX-445, TEZ, and IVA (VX-445/TEZ/IVA) increased 
CFTR chloride transport more than any of the dual combinations (VX-445/TEZ, VX-445/IVA, 
and TEZ/IVA) or individual (VX-445, TEZ, and IVA) regimens.11  
VX-561 (also known as CTP-656 or C-10355) is a deuterated isotope of IVA with a specific 
pattern of 9 substituted deuteriums. In vitro data indicate similar potency of VX-561 in HBE 
cells relative to IVA. Safety pharmacology and nonclinical toxicology studies of VX-561 
demonstrate a similar safety profile relative to IVA. Phase 1 clinical studies in healthy subjects 
have shown that VX-561 had a reduced rate of clearance, increased exposure, greater plasma 
levels at 24 hours, and a longer half-life compared to IVA, thereby supporting once daily 
dosing.12 
5.2 
Rationale for the Present Study 
Results from nonclinical pharmacology, pharmacokinetic (PK), and toxicology studies of 
VX-445 alone and in combination with TEZ/IVA, and the unmet medical need for new 
treatments for CF, support the clinical development of VX-445 for the treatment of CF. 
This is the first clinical study of VX-445 and is designed to evaluate the safety, tolerability, and 
PK of VX-445 as monotherapy and in TC with TEZ/IVA in healthy subjects (Parts A, B, and C), 
as well as the safety and efficacy of VX-445 in TC with TEZ/IVA in subjects with CF who have 
F/MF (F508del/minimal function) or F/F genotypes (Parts D and E, respectively). Additionally, 
the safety and efficacy of VX-445 in TC with TEZ/VX-561 will be evaluated in subjects with 
F/MF genotypes in Part F, if the sponsor chooses to conduct this optional part of the study.  
6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
Part A: To evaluate the safety and tolerability of single ascending doses of VX-445 in healthy 
subjects 
Part B: To evaluate the safety and tolerability of multiple ascending doses of VX-445 
administered in healthy subjects 
Part C: To evaluate the safety and tolerability of multiple doses of VX-445 in TC with TEZ and 
IVA for 14 days in healthy subjects 
Parts D and E 
 To evaluate the safety and tolerability of VX-445 in TC with TEZ and IVA in subjects 
with CF 
 To evaluate the efficacy of VX-445 in TC with TEZ and IVA in subjects with CF 
Part F  
 To evaluate the safety and tolerability of VX-445 in TC with TEZ and VX-561 
(deuterated IVA) in subjects with CF 
 To evaluate the efficacy of VX-445 in TC with TEZ and VX-561 in subjects with CF 


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6.2 
Secondary Objectives 
Part A 
 To evaluate the PK of VX-445 after administration of single ascending doses of VX-445 
in healthy subjects 
 To evaluate the effect of food on VX-445 PK in healthy subjects 
 To evaluate the absolute bioavailability (BA) of VX-445 when administered orally 
relative to intravenous (IV) administration in healthy subjects 
Part B: To evaluate the PK of VX-445 after multiple ascending doses of VX-445 administered 
to healthy subjects 
Part C 
 To evaluate the PK of VX-445 after multiple ascending doses of VX-445 in TC with TEZ 
and IVA for 14 days in healthy subjects 
 To evaluate the PK of TEZ and metabolites (M1-TEZ and M2-TEZ), and IVA and 
metabolites (M1-IVA and M6-IVA) after administration in TC with VX-445 for 14 days in 
healthy subjects 
Parts D and E 
 To evaluate the PD effect of VX-445 in TC with TEZ and IVA on CFTR function in 
subjects with CF 
 To evaluate the PK of VX-445 when administered in TC with TEZ and IVA in subjects 
with CF 
 To evaluate the PK of TEZ, IVA, and their respective metabolites (M1-TEZ and 
M1-IVA) when administered in TC with VX-445 in subjects with CF 
Part F  
 To evaluate the PD effect of VX-445 in TC with TEZ and VX-561 on CFTR function in 
subjects with CF 
 To evaluate the PK of VX-445 when administered in TC with TEZ and VX-561 in 
subjects with CF 
 To evaluate the PK of TEZ and metabolite (M1-TEZ) and VX-561 when administered in 
TC with VX-445 in subjects with CF 


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7 
STUDY ENDPOINTS 
7.1 
Primary Endpoints 
Parts A, B, and C: Safety and tolerability, based on the assessment of adverse events (AEs), 
clinically significant laboratory test results, standard 12-lead electrocardiograms (ECGs), vital 
signs, and spirometry (Parts B and C only) 
Parts D, E, and F: 
 Safety and tolerability assessments of AEs, clinical laboratory values, standard 12-lead 
ECGs, vital signs, pulse oximetry, and spirometry 
 Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
from baseline through Day 29 
7.2 
Secondary Endpoints 
Parts A and B: PK parameter estimates of VX-445 derived from plasma concentration-time data 
Part C:  
 PK parameter estimates of VX-445 derived from plasma concentration-time data 
 PK parameter estimates for TEZ and metabolites (M1-TEZ and M2-TEZ), and IVA and 
metabolites (M1-IVA and M6-IVA) derived from plasma concentration-time data 
Parts D and E: 
 Absolute change in sweat chloride concentrations from baseline through Day 29 
 Relative change in ppFEV1 from baseline through Day 29 
 Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain 
score from baseline at Day 29 
 PK parameters of VX-445, TEZ, M1-TEZ, IVA, and M1-IVA 
Part F: 
 Absolute change in sweat chloride concentrations from baseline through Day 29 
 Relative change in ppFEV1 from baseline through Day 29 
 Absolute change in CFQ-R respiratory domain score from baseline at Day 29 
 PK parameters of VX-445, TEZ, M1-TEZ, and VX-561  


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8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are randomized (Parts A, B, C, D, and F) or receive TEZ/IVA 
in the Run-in Period (Part E). 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible 
for the study. 
8.1 
Parts A, B, and C 
8.1.1 
Inclusion Criteria: Parts A, B, and C 
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. Female subjects must be of non-childbearing potential. To be considered of non-childbearing 
potential, female subjects must meet at least 1 of the following criteria: 
a. Postmenopausal: spontaneous amenorrhea for at least 12 consecutive months with a 
serum follicle-stimulating hormone (FSH) level within the laboratory's reference range 
for postmenopausal females 
b. Documented bilateral oophorectomy or hysterectomy 
Note: All other female subjects (including subjects with tubal ligations and subjects who do 
not have a documented bilateral oophorectomy or hysterectomy) will be considered to be of 
childbearing potential and are not eligible for this study. 
4. Between the ages of 18 and 55 years, inclusive, and healthy, as defined by no clinically 
relevant abnormalities identified by a detailed medical history, full physical examination 
(PE), including blood pressure and pulse rate measurement, standard 12-lead ECG, and 
clinical laboratory tests. 
5. Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, and a total body weight >50 kg 
8.1.2 
Exclusion Criteria: Parts A, B, and C 
1. History of any illness or any clinical condition that, in the opinion of the investigator or the 
subject’s general practitioner, might confound the results of the study or pose an additional 
risk in administering study drug to the subject. This may include, but is not limited to, history 
of relevant drug or food allergies; history of cardiovascular or central nervous system 
disease; history or presence of clinically significant pathology; history of mental disease; and 
history of cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 
cervical carcinoma in situ (all 3 with no recurrence for the last 5 years). 
2. History of febrile illness within 14 days before the first study drug dose 
3. Any condition possibly affecting drug absorption (e.g., gastrectomy, cholecystectomy, or 
other gastrointestinal tract surgery, except appendectomy) 
4. Standard 12-lead ECG demonstrating QTc >450 msec at screening. If QTc exceeds 
450 msec, the ECG will be repeated 2 more times, and the average of the 3 QTc values will 


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be used to determine the subject’s eligibility. As stated in Section 11.7.5.1, study sites should 
use QTcF unless they receive approval in advance from the medical monitor to use QTcB. 
5. For female subjects: Pregnant or nursing subjects 
For male subjects: Male subjects with a female partner who is pregnant, nursing, or planning 
to become pregnant during the study or within 90 days after the last study drug dose 
6. Blood donation (of approximately 1 pint [500 mL] or more) within 56 days before the first 
study drug dose or any significant loss of blood, as determined by the investigator, within 
56 days before first study drug dose 
7. Use of the following substances, activities, or devices during the time periods indicated in 
Table 9-4 
 Medications: hormonal methods of contraception, hormone-replacement therapies, other 
prescription medications, or nonprescription medications 
 Foods and supplements: herbal supplements, vitamins, or other dietary supplements 
(e.g., grapefruit juice, etc., as applicable) 
 Caffeine 
 Alcohol 
 Tobacco- or nicotine-containing products 
 Strenuous exercise 
 Other investigational drugs or devices 
8. A screen positive for alcohol or drugs listed in Section 11.7.2 
9. A screen positive for p24 antigen, hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, or antibodies against human immunodeficiency virus 1 or 2  (HIV-1 and 
HIV-2 Abs) 
10. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, defined as G6PD activity less than 
the lower limit of normal (LLN) or 70% of the mean of the LLN and the upper limit of 
normal (ULN), whichever is greater 
11. History of hemolysis 
12. Total bilirubin level >2 × ULN at screening 
13. Forced expiratory volume in 1 second (FEV1) (L) or forced vital capacity (FVC) (L) 
<80 percent predicted (Parts B and C only) 
14. Subject, or close relative of the subject, is the investigator or a sub-investigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study at that site. 


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8.2 
Parts D, E, and F 
8.2.1 
Inclusion Criteria: Parts D, E, and F 
1. Subject will sign and date an 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. Subjects must be able to produce a valid (quantity-sufficient) sweat sample at screening, in 
addition to having a sweat chloride value ≥60 mmol/L documented at screening or in a 
previous laboratory report. If the initial screening collection results in insufficient sweat 
volume, then the sweat chloride collection may be repeated once, after approval by the 
medical monitor. For the laboratory report requirement, it is acceptable to use a sweat 
chloride value that was obtained before previous treatment with IVA, LUM/IVA, or an 
investigational CFTR modulator, if applicable. 
6. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR 
genotype result is not received before randomization, 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 9.9). 
 Parts D and F: Heterozygous for F508del with a second CFTR allele carrying a MF 
mutation that is not expected to respond to TEZ, IVA, and TEZ/IVA (Appendix A) 
 Part E: 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])13 at the Screening Visit. Spirometry 
measurements must meet American Thoracic Society/European Respiratory Society criteria14 
for acceptability and repeatability. 
8. Stable CF disease as judged by the investigator. 
9. Willing to remain on a stable CF treatment regimen through the planned end of treatment or, 
if applicable, the Safety Follow-up Visit. 
8.2.2 
Exclusion Criteria: Parts D, E, and F 
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 clinically significant cirrhosis with or without portal hypertension. 
3. Risk factors for Torsade de Pointes, including but not limited to, history of any of the 
following: familial long QT syndrome, chronic hypokalemia, heart failure, left ventricular 
hypertrophy, chronic bradycardia, myocardial infarction, cardiomyopathy, history of 
arrhythmia (ventricular or atrial fibrillation), obesity, acute neurologic events (subarachnoid 
hemorrhage, intracranial hemorrhage, cerebrovascular accident, or intracranial trauma), or 
autonomic neuropathy. 


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4. History of hemolysis. 
5. G6PD deficiency, defined as G6PD activity less than the LLN or 70% of the mean of the 
LLN and the ULN, whichever is greater. 
6. Any of the following abnormal laboratory values at screening: 
 Hemoglobin <10 g/dL 
 Total bilirubin ≥2 × ULN 
 Aspartate transaminase (AST), alanine transaminase (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)15, 16   
7. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in 
therapy (including antibiotics) for sino-pulmonary disease within 28 days before the first 
dose of study drug. 
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. 
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. As stated in Section 11.7.5.1, study sites should use QTcF unless they receive 
approval in advance from the medical monitor to use QTcB. 
11. History of solid organ or hematological transplantation. 
12. History of alcohol or drug abuse in the past year, including but not limited to, cannabis, 
cocaine, and opiates, as deemed by the investigator. 
13. Ongoing or prior participation in a study of an investigational treatment other than a CFTR 
modulator within 28 days or 5 terminal half-lives (whichever is longer) before screening. 
The duration of the elapsed time may be longer if required by local regulations.  
14. Use of prohibited medications as defined in Table 9-5, within the specified window before 
the first dose of study drug. 
15. For female subjects: Pregnant or nursing females. Females of childbearing potential must 
have a negative pregnancy test at screening, Day -28 (Part E only), and Day 1. 


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For male subjects: Male subjects with a female partner who is pregnant, nursing, or planning 
to become pregnant during the study or within 90 days after the last study drug dose. 
16. 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. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a first-in-human study of VX-445. Approximately 224 subjects will be enrolled: 
120 healthy subjects (Parts A, B, and C) and 104 subjects with CF (Parts D, E, and F). Part F is 
an optional part of the study, which will be conducted at the sponsor’s discretion.  
No subject will be allowed to randomize to more than 1 dose cohort. 
9.1.1 
Parts A, B, and C 
Parts A, B, and C are randomized, double-blind, placebo-controlled, single- and multiple-dose 
parts in healthy subjects of this first-in-human study of VX-445. Part A also includes an 
evaluation of the effect of food on VX-445 PK and an evaluation of absolute BA. Part C doses 
VX-445 in TC with TEZ/IVA. 
There is no pre-specified ratio of males to females, but reasonable effort will be made to enroll 
females of non-childbearing potential in all dosing cohorts.  
Parts A, B, and C (Healthy Subjects) 
A schematic of the study design for Parts A, B, and C is shown in Table 9-1.  
Number of Cohorts 
In Parts A and B, 6 dose escalation cohorts are planned, although fewer than 6 or up to 
2 additional cohorts may be enrolled in each part, based on data from previous cohorts. The 
additional cohorts will follow the corresponding schedule of assessments. In Part C, 2 cohorts are 
planned, while fewer or up to 2 additional cohorts each may be enrolled based on data from 
previous cohorts. The decision to initiate successive cohorts and dose selection will be based on 
safety, tolerability, and available PK data from preceding cohort(s). Refer to Section 9.7.1 for 
dose escalation criteria and Section 9.8.1 for stopping criteria. 
Staggering of Dosing 
In Cohort A1 (first single dose cohort) and in Cohort C1 (first TC cohort), dosing will be 
staggered so that 2 subjects are dosed (Cohort A1: 1 with VX-445 and 1 with placebo; 
Cohort C1: 1 with TC and 1 with triple placebo) at least 24 hours before the remaining 6 subjects 
in each cohort. Doses may be staggered in other cohorts if deemed necessary based on review of 
emerging safety data. 




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Table 9-1 
Study Design for Parts A, B, and C 
Part B: Multiple-dose escalation of VX-445  
8 subjects per cohort, randomized 3:1 (VX-445:placebo) 
The total daily dose in Cohort B1 will be at least 1 dose level below the highest Part A dose for which safety, 
tolerability, and PK results are available and that is safe and well tolerated. 
 
Planned Dosage (qd or q12h, 10 days) 
Cohort B1 
TBD 
 
 
 
 
 
Cohort B2  
 
TBD 
 
 
 
 
Cohort B3 
 
 
TBD 
 
 
 
Cohort B4 
 
 
 
TBD 
 
 
Cohort B5 
 
 
 
 
TBD 
 
Cohort B6 
 
 
 
 
 
TBD 
 
 
 
 
 
 
 
Part C: Multiple-dose escalation of VX-445 in TC with TEZ/IVAb 
8 subjects per cohort, randomized 3:1 (VX-445/TEZ/IVA:triple placebo) 
The starting dose for Part C (Cohort C1) will be at least 1 dose level below the highest Part B dose for which 
safety and tolerability results are available and supportive. 
 
Planned Dosage (qd or q12h, 14 days) 
Cohort C1 
TBD 
 
 
 
 
 
Cohort C2 
 
TBD 
 
 
 
 
 
 
 
 
 
 
 
CRU: clinical research unit; IV: intravenous; IVA: ivacaftor; PK: pharmacokinetic; q12h: every 12 hours; qd: once 
daily; TBD: to be determined; TC: triple combination (VX-445/TEZ/IVA); TEZ: tezacaftor 
Note: Dose escalation criteria are described in Section 9.7.1, and dose escalation will be stopped when the 
predefined stopping criteria is met (see Section 9.8.1). 
a 
The Washout Period is a minimum of 6 days and may be increased as needed based on emerging data from 
earlier cohorts (Cohorts A1 through A6). Subjects in Cohort A7 will receive a single dose of VX-445 on up to 
3 dosing occasions. VX-445 doses include 2 single oral doses of tablet (dose TBD, pending PK data from 
previous Part A cohorts, but will not exceed the highest dose that was safe and well tolerated) and a single IV 
dose (the planned dose is 20 mg, but may be adjusted pending data from previous Part A cohorts; however, the 
final selected dose will not be predicted to exceed the highest exposure that was safe and well tolerated). If the 
IV formulation or the data supporting the use of the IV formulation are not available, then the third dosing 
period, in which subjects receive the IV dose, will not be conducted. If the IV dose is not administered, subjects 
will be discharged from the CRU on Day 13 after completing all study visit assessments and will return for a 
Safety Follow-up Visit (Table 3-3). 
b 
The dosage of TEZ/IVA will be TEZ 100 mg qd/IVA 150 mg q12h which will be administered as TEZ 
100-mg/IVA 150-mg FDC in the morning and IVA 150 mg in the evening. 
9.1.1.1 
Screening (Parts A, B, and C) 
Screening Visit assessments are listed in Table 3-1. 
Screening will occur within 28 days before administration of study drug. If the time between 
screening and dosing exceeds 28 days as a result of unexpected operational delays (e.g., delayed 
drug shipment), then subjects do not require rescreening if the Day -1 laboratory results meet the 
eligibility criteria. 
Subjects will be instructed on the study restrictions (Section 9.4.1). 


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A subject who qualified but did not enroll for an earlier cohort may enroll in a subsequent cohort 
with no required rescreening if the Day -1 laboratory results meet the eligibility criteria and if all 
other screening data were obtained within 28 days before administration of study drug. No 
subject will be allowed to participate in more than 1 dose cohort or in more than 1 study part. 
Subjects who do not meet the eligibility criteria may not be rescreened with the following 
exceptions, all of which require principal investigator approval: 
 Subjects who met all eligibility criteria but had an intercurrent illness (e.g., upper respiratory 
infection with fever) in the 14 days before the first study drug dose that was properly 
evaluated and which resolved fully 
 Subjects who met all eligibility criteria but were not able to obtain required documentation 
within the allotted screening window 
 Subjects who met all eligibility criteria but transiently (for personal reasons) are unable to 
commit to all study procedures 
 Subjects who met all eligibility criteria but are not randomized for administrative reasons 
(e.g., study drug is not available at the study site) 
 Subjects who were screened under a prior version of the protocol and did not meet any 
exclusion criterion, with the exception of a criterion that was updated in a subsequent version 
of the protocol 
Repetition of any screening assessment that did not meet eligibility criteria is not permitted, 
unless there is clear evidence of a damaged sample, laboratory error, or equipment malfunction. 
In all cases, the principal investigator must authorize retesting. 
The medical monitor must be notified of any decisions made regarding rescreening or retesting. 
9.1.1.2 
Treatment Period (Parts A, B, and C) 
Subjects will be admitted on Day -1 and will remain in the Clinical Research Unit (CRU) for the 
duration of the Treatment Period. 
Treatment Period assessments are listed in Table 3-2 (Cohorts A1 through A6), Table 3-3 
(Cohort A7), Table 3-4 (Part B), and Table 3-5 (Part C). 
The treatment periods will be conducted as described in Section 9.1. Dosing details are given in 
Section 9.6.1. 
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the medical monitor (or authorized designee) will be 
notified, and the subject will be asked to remain in the CRU until such abnormalities resolve. If 
the subject is unable or unwilling to remain in the CRU, the medical monitor (or authorized 
designee) will be notified, and the investigator will make every effort to arrange follow-up 
evaluations at appropriate intervals to document the course of the abnormalities. 
9.1.1.3 
Follow-up (Parts A, B, and C) 
Subjects will have a Safety Follow-up Visit 7 to 10 days after the last study drug dose. Safety 
Follow-up Visit assessments are listed in Table 3-2 (Cohorts A1 through A6), Table 3-3 
(Cohort A7), Table 3-4 (Part B), and Table 3-5 (Part C). 


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9.1.1.4 
Early Discontinuation (Parts A, B, and C) 
Subjects who prematurely discontinue study drug dosing will be asked to return to the CRU for a 
Safety Follow-up Visit. Safety Follow-up Visit assessments are listed in Table 3-2 (Cohorts A1 
through A6), Table 3-3 (Cohort A7), Table 3-4 (Part B), and Table 3-5 (Part C). 
9.1.2 
Parts D, E, and F 
Part D, which is comprised of Parts D1 and D2, is randomized, double-blind, placebo-controlled 
and evaluates VX-445 in TC with TEZ/IVA in subjects with CF (F/MF genotypes). Part E is 
randomized, double-blind, TEZ/IVA-controlled and evaluates VX-445 in TC with TEZ/IVA in 
subjects with CF (F/F genotype). Part F is randomized, double-blind, placebo-controlled, and 
evaluates VX-445 in TC with TEZ/VX-561 in subjects with CF (F/MF genotypes). Part F is an 
optional part of the study, which will be conducted at the sponsor’s discretion. All parts are 
multicenter and designed to evaluate the safety and efficacy of VX-445 in TC. 
Approximately 104 subjects with CF will be enrolled. Part D may be initiated while Parts A, B, 
and C are ongoing after review of safety, tolerability, and PK data. Enrollment of Parts D1 and 
D2 will be sequential, while enrollment of Parts E and F will be in parallel with Part D2.  
After all Part D1 subjects complete the Day 15 Visit, a blinded review of all available safety and 
PK data will be conducted by the Vertex study team and lead investigator(s). Dosing in Parts D2, 
E, and F will start after this review, if supported by safety and PK data.  
Part E subjects who are participating in Study VX11-661-110 (Study 661-110), an open-label 
study of TEZ/IVA combination therapy, will not need to washout TEZ/IVA treatment; these 
subjects will transition directly from their prior treatment to the TEZ/IVA Run-in Period 
providing that they meet all eligibility criteria. These subjects can have screening assessments for 
this study done while they are continuing to participate in Study 661-110.  
Key study elements are summarized in Table 9-2. The treatment arms and randomization ratios 
for each part are summarized in Table 9-3. A schematic of the study design is shown in 
Figure 9-1. Study visits and assessments are shown in Table 3-6 (Parts D1 and D2), Table 3-7 
(Part E), and Table 3-8 (Part F). 
Table 9-2 
Parts D, E, and F: Key Study Elements 
Element 
Part D1 
Part D2 
Part E 
Part F 
Study population 
 
 
 
Genotype(s) 
F/MF 
F/MF 
F/F 
F/MF 
Age 
≥18 years 
≥18 years 
≥18 years 
≥18 years 
ppFEV1 criteria 
≥40 to ≤90  
≥40 to ≤90  
≥40 to ≤90 
≥40 to ≤90  
Number of subjects Approximately 8 
Approximately 48 
Approximately 24 
Approximately 24 
Study design 
Parallel group 
Parallel group 
Parallel group 
Parallel group 
Control 
Placebo 
Placebo 
TEZ/IVA 
Placebo 
IVA: ivacaftor; MF: minimal function; ppFEV1: percent predicted forced expiratory volume in 1 second; TEZ: 
tezacaftor 


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Table 9-3 
Treatment Arms and Planned Doses by Part in the Treatment Period 
(Period 1) 
Part 
Randomization 
ratio 
 
Treatment Arm 
VX-445 Dosage 
TEZ 
Dosage 
IVA 
Dosage 
VX-561 
Dosage 
Part D1a 
TC-mid 
100 mg qd 
100 mg qd 
150 mg q12h 
N/A 
3:1 
Triple placebo 
Placebo 
Placebo 
Placebo 
N/A 
Part D2a 
TC-high 
200 mg qd 
100 mg qd 
150 mg q12h 
N/A 
6:4:3:3 
TC-mid 
100 mg qd 
100 mg qd 
150 mg q12h 
N/A 
 
TC-low 
50 mg qd 
100 mg qd 
150 mg q12h 
N/A 
 
Triple placebo 
Placebo 
Placebo 
Placebo 
N/A 
Part Eb 
TC-high 
 200 mg qd 
100 mg qd 
150 mg q12h 
N/A 
3:1 
TEZ/IVA 
Placebo 
100 mg qd 
150 mg q12h 
N/A 
Part F 
TC2-high 
 200 mg qd 
100 mg qd 
N/A 
150 mg qdc 
3:1 
Triple placebo 
Placebo 
Placebo 
N/A 
Placebo 
TC2: triple combination 2 (VX-445/TEZ/VX-561); IVA: ivacaftor; N/A: not applicable; q12h: every 12 hour; 
qd: once daily; TC: triple combination (VX-445/TEZ/IVA); TEZ: tezacaftor 
a 
In Parts D1 and D2, all subjects will also receive TEZ 100 mg qd/IVA 150 mg q12h or dual placebo 
during Period 2. 
b 
In Part E, all subjects will also receive TEZ 100 mg qd/IVA 150 mg q12h during the Run-in Period and 
the Washout Period, which is the dosage evaluated in Phase 3 studies of TEZ/IVA. 
c 
See Section 9.3.2.2 for information relating to the selection of the VX-561 dose. 






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9.1.2.1.2 
Rescreening (Parts D, E, and F) 
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, FSH level 
(if serum FSH level was ≥40 mIU/mL during prior screening), G6PD activity test, and the sweat 
chloride concentration. If a subject is rescreened, the new screening window will begin once the 
first rescreening assessment has been initiated. 
9.1.2.1.3 
Extension of Screening Period Window (Parts D, E, and F) 
A subject may have the Screening Period window extended without medical monitor approval by 
2 weeks for the following reasons: 
 Repetition of the Screening Period assessments (Section 9.1.2.1.1) 
 Unexpected operational or logistic delays, or to meet the eligibility criteria 
 Repetition of spirometry assessment if results are of poor quality 
A subject may have the Screening Period window extended for an additional 2 weeks (total of 
4 weeks) with medical monitor approval. 
9.1.2.2 
Stratification and Randomization (Parts D, E, and F) 
All subjects will have a spirometry assessment done at the Screening Visit. Subjects in Part E 
may have an additional spirometry assessment done for stratification purposes before 
randomization based on prior CFTR modulator treatment.  
9.1.2.2.1 
Stratification (Parts D, E, and F) 
Part D1 
No ppFEV1 stratification will be performed. 
Part D2 
ppFEV1 stratification (<70 versus ≥70) will be performed using the screening (Days -28 to -1) 
ppFEV1 value.  
Part E 
ppFEV1 stratification (<70 versus ≥70) will be performed using a value obtained at the following 
visit: 
 Screening Visit (Days -56 to -29) for subjects transitioning directly from at least 14 days 
of uninterrupted TEZ/IVA treatment 
 Day -14 Visit (+ 13 days) for all other subjects 
Part F 
ppFEV1 stratification (<70 versus ≥70) will be performed using the screening (Days -28 to -1) 
ppFEV1 value.  
 


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9.1.2.2.2 
Randomization (Parts D, E, and F) 
Randomization will occur before the first dose of study drug and may be done on either Day -1 
or Day 1, after all inclusion and exclusion criteria have been satisfied and the criteria for entry 
into the Treatment Period have been confirmed (see Section 9.1.2.4). 
9.1.2.3 
Run-in Period (Part E) 
The Run-in Period of Part E is 4 weeks and is designed to establish a reliable on-treatment 
(TEZ/IVA) baseline for the Treatment Period (Period 1). Subjects will receive TEZ 100 mg 
qd/IVA 150 mg q12h during the Run-in Period. The first dose of TEZ/IVA will be administered 
at the Day -28 Visit. The last dose of TEZ/IVA within the Run-in Period will be administered on 
Day -1 (1 day before the Day 1 Visit).  
Study eligibility for Part E subjects will be confirmed before the first dose of TEZ/IVA in the 
Run-in Period (on the Day -28 Visit). Subjects who prematurely discontinue TEZ/IVA during the 
Run-in Period will not be randomized or participate in the Treatment Period (Period 1), unless 
they rescreen and complete a 4-week Run-in Period (Section 9.1.2.1.2). 
Study visits during the Run-in Period will occur as shown in Table 3-7.  
9.1.2.4 
Treatment Period (Parts D, E, and F) 
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. 
The VX-445 treatment duration is 4 weeks. The Treatment Period duration is approximately 
5 weeks for Parts D1 and D2 (Period 1 + Period 2), 4 weeks for Part E (Period 1), and 4 weeks 
for Part F (Period 1). All study periods will be conducted as described in Section 9.1. Study drug 
administration details are provided in Section 9.6.2. 
9.1.2.5 
Washout Period (Part E) 
The Washout Period of Part E will last approximately 4 weeks and is designed to evaluate the 
effect on PD and efficacy endpoints as subjects step down from TC to TEZ/IVA. Subjects will 
receive TEZ 100 mg qd/ IVA 150 mg q12h during the Washout Period. 
9.1.2.6 
Follow-up (Parts D, E, and F) 
There will be a 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. 
A subject who was enrolled in Study 661-110 and then enrolled in Part E of this study can 
re-enroll in Study 661-110 after completing the Washout Period of this study. If the subject 
completes the Day 57 Visit of this study and then re-enters Study 661-110, the subject will not 
have a Safety Follow-up Visit in this study. 
9.1.2.7 
Early Termination of Treatment (Parts D, E, and F) 
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. All 
subjects who prematurely discontinue treatment (other than those who re-enroll in 


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Study 661-110, as described in Section 9.1.2.6) will also be required to complete the Safety 
Follow-up Visit, approximately 28 days after their last dose of study drug.  
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, 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 and samples collected before such 
withdrawal of consent. 
9.1.2.8 
Independent Data Monitoring Committee (Parts D, E, and F) 
This study will be monitored by an independent data monitoring committee (IDMC), which will 
conduct reviews of safety data from all parts of the study. The IDMC Charter, which will be 
finalized before the first subject is screened, will include procedural details of the IDMC 
structure and function, triggers for meetings, and plans for data to be reviewed. The IDMC Chair 
will review available safety and PK data from Parts A, B, and C of the study prior to 
commencement of dosing in Part D1 to determine if it is appropriate to proceed with the study. 
9.2 
Method of Assigning Subjects to Treatment Groups 
A randomization list for each part will be produced by Vertex Biostatistics or a qualified 
randomization vendor. The Vertex study biostatistician will review and approve the dummy 
randomization list. The final randomization list will be reviewed and approved by a designated 
unblinded biostatistician who is not a member of the study execution team (SET).  
Only subjects who have completed screening assessments and are eligible for participation in the 
study will be randomized to receive active study drug or placebo. Randomized subjects will be 
assigned a unique subject number.  
For Parts A, B, and C, a list identifying subjects by their subject number will be maintained in 
the study file at the CRU. 
For Parts D, E, and F, an interactive web response system (IWRS) will be used to assign subjects 
to treatment.  
9.3 
Rationale for Study Design and Study Drug Regimens 
9.3.1 
Study Design 
9.3.1.1 
Parts A, B, and C 
Parts A (except Cohort A7) and B have a parallel-group, dose-escalation design, with each 
subject participating in only 1 cohort to avoid PK and/or PD carryover effects. 
VX-445 is being developed in TC with TEZ/IVA for the treatment of CF, and subjects with CF 
will be dosed with the TC in Parts D and E of this study (see Section 9.3.1.2). Part C of this 
study is included to evaluate the safety, tolerability, and PK of the TC in healthy subjects before 
subjects with CF are dosed with the TC. 
Parts A (except Cohort A7), B, and C will be randomized, double-blind, and placebo-controlled 
in order to avoid bias in the collection and evaluation of safety and tolerability data during study 
conduct. Placebo was chosen as the control treatment to assess whether any observed effects are 
treatment-related or simply related to the study conditions. 


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Staggered Dosing in Cohorts A1 and C1 
In Cohorts A1 and C1, after the first 2 subjects are dosed (1 active, 1 placebo), there will be at 
least a 24-hour observation period before the remaining subjects in Cohorts A1 and C1 are 
dosed. Staggered dosing will be used in Cohort A1 because this is the first time VX-445 will be 
administered to humans. In addition, staggered dosing is proposed for Part C as it is the first time 
VX-445 will be administered in TC with TEZ/IVA in humans. Staggered dosing for Part B is not 
considered necessary because the total daily dose in the first cohort (Cohort B1) will be at least 
1 dose level below the highest Part A dose for which safety, tolerability and PK results are 
available and that is safe and well tolerated. Therefore, the relative risk to subjects dosed in 
Cohort B1 is considered to be less than that of subjects in Cohorts A1 and C1. 
Cohort A7 
Cohort A7 will not be initiated until all data required to support administration of the VX-445 
tablet and IV formulations are available. Subjects in Cohort A7 will receive up to 3 single doses 
of VX-445: 2 single oral doses of tablet (dose to be determined [TBD] pending PK data from 
previous Part A cohorts, but not to exceed the highest dose that was safe and well tolerated) and 
a single IV dose (the planned dose is 20 mg, but may be adjusted pending data from previous 
Part A cohorts; however, the final selected dose will not be predicted to exceed the highest 
exposure that was safe and well tolerated). Each dosing occasion will be separated by at least 
6 days. Based on nonclinical data, the interval between dosing occasions is considered adequate 
to minimize any potential for carryover. However, the washout interval of 6 days may be 
increased if needed based on emerging PK data from earlier Part A cohorts. 
9.3.1.2 
Parts D, E, and F 
This is the first time that VX-445 will be administered to subjects with CF. The TC regimen of 
VX-445/TEZ/IVA will be evaluated in Parts D and E because in vitro, the TC has shown high 
levels of efficacy and has shown to provide a greater increase in chloride transport than any of 
the dual combinations or individual compounds.11 The safety of VX-445 monotherapy will be 
evaluated in Parts A and B in healthy subjects, and the safety of VX-445 in TC with TEZ/IVA 
will be evaluated in Part C in healthy subjects. A Phase 3 program for TEZ/IVA is ongoing. 
Parts D and E are designed to evaluate the safety and efficacy of VX-445 in TC with TEZ/IVA 
and to establish proof-of-concept in 2 populations of subjects defined by CFTR genotype (F/MF 
and F/F). Additionally, Part F will evaluate the safety and efficacy of VX-445 in TC with TEZ 
and VX-561 (a deuterated form of IVA) in subjects with F/MF genotypes, if conducted at the 
sponsor’s discretion. 
Efficacy has not been demonstrated for a corrector, potentiator, or any corrector/potentiator 
combination in subjects with F/MF genotypes. A Phase 3 study of TEZ/IVA in subjects with 
F/MF genotypes (Study VX14-661-107) was terminated following a planned interim futility 
analysis which showed that the combination of TEZ/IVA did not result in a pre-specified 
improvement in lung function. Because there is no effective treatment for this population, 
placebo is the control in Parts D1, D2, and F.  
A potential for benefit was demonstrated for TEZ/IVA in subjects with the F/F genotype in 
Study VX11-661-10117, and a Phase 3 study of TEZ/IVA in subjects with the F/F genotype 
(Study VX14-661-106) demonstrated a clinically meaningful benefit across multiple endpoints.18 
Therefore, TEZ/IVA is the active control in Part E. 




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Part B VX-445 Starting Dose and Dose Escalation 
The starting dose in Part B will be selected based on safety, tolerability, and PK data in Part A. 
The total daily dose in Cohort B1 will be at least 1 dose level below the highest Part A dose for 
which safety, tolerability, and PK results are available and that is safe and well tolerated. 
Initiation of successive cohorts and dose selection will be based on safety and PK data as 
described in Section 9.7.1.2.  
Part C VX-445 Starting Dose and Dose Escalation 
Part C may be initiated while Parts A and B are ongoing after review of safety, tolerability, and 
PK data.  
The starting dose (Cohort C1) will be at least 1 dose level below the highest Part B dose for 
which safety and tolerability results are available and supportive. Dosing will be staggered in 
Cohort C1, with 2 subjects dosed (1 with VX-445 in TC with TEZ/IVA and 1 with triple 
placebo) at least 24 hours before the remaining 6 subjects. Staggering at higher doses may be 
conducted if deemed necessary based on review of emerging safety data. 
Parts B and C Treatment Duration 
The duration of dosing in Part B (10 days) and Part C (14 days) is a standard duration for 
multiple-dosing in first-in-human studies and is of sufficient length for an early assessment of 
safety and tolerability and for assessment of steady-state PK.  
TEZ and IVA Doses (Part C) 
The doses of TEZ and IVA are the same as those being evaluated in Phase 3 studies of TEZ/IVA 
combination therapy (TEZ: 100 mg qd; IVA: 150 mg q12h). These doses of TEZ and IVA are 
appropriate for evaluation in the TC based on in vitro experiments with VX-445 that evaluated 
similar levels of TEZ and IVA exposure after correction for protein-binding. 
Administration of VX-445 with Food 
Doses of VX-445 will be administered under fed conditions in all cohorts except Cohort A7, 
which includes a dosing period where VX-445 is also administered under fasting conditions to 
evaluate the food effect. Only a mild food effect is predicted for VX-445 oral absorption. 
However, given the ultimate intent to administer VX-445 in combination with TEZ/IVA, which 
are administered with fat-containing food, this early assessment of safety and PK will be 
conducted under fed conditions.  
9.3.2.2 
Parts D, E, and F 
VX-445 Dosage 
VX-445 will be given qd. 
Part D may be initiated while Parts A, B, and C are ongoing after review of safety, tolerability, 
and PK data. Single doses of VX-445 up to 360 mg were safe and well tolerated in Part A, and 
multiple doses of VX-445 up to 340 mg qd for 10 days were safe and well tolerated in Part B. In 
Part C, multiple doses of VX-445 up to 280 mg qd in TC with TEZ 100 mg qd and IVA 150 mg 
q12h were safe and well tolerated after 14 days of dosing. 
Part D1 will evaluate 1 dose level (mid-dose: 100 mg qd) of VX-445 in TC with TEZ/IVA to 
assess safety, tolerability, and PK in a smaller subset of subjects before enrolling a larger number 


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of subjects and evaluating a higher VX-445 dose. The mid-dose of VX-445 100 mg qd was 
selected to ensure a sufficient safety margin relative to nonclinical data and the clinical 
experience in Parts A, B, and C in healthy subjects, and is at least 1 dose level below the highest 
Part C dose for which safety and tolerability results are available and supportive. 
Part D2 will evaluate 3 dose levels of VX-445 (low: 50 mg qd; mid: 100 mg qd; and 
high: 200 mg qd) in TC with TEZ/IVA. The TC-high dose of VX-445 does not exceed the 
highest dose shown to be safe and well tolerated in Parts A, B, and C. 
The dose levels evaluated in Part D2 will be expected to provide clinical benefit (based on 
in vitro data) and will be selected to provide a range of exposure for exposure-response analyses 
of safety and efficacy.  
The highest TC dose of 200 mg qd VX-445 used in Part D2 will also be used in Parts E and F. 
Dose- and exposure-response information obtained for the TC in Part D (subjects with F/MF 
genotypes) is expected to be applicable to other populations with an F508del mutation, including 
F/F, based on similar potency of the TC in HBE cells that have 1 copy or 2 copies of F508del.11  
TEZ Dosage 
In all study parts, the TEZ dosage will be 100 mg qd, which is the same dose being evaluated in 
Phase 3 studies of TEZ/IVA.  
IVA Dosage 
In Parts D and E, the IVA dosage will be 150 mg q12h. This dosage is being used in Phase 3 
studies of TEZ/IVA and is also the approved IVA monotherapy dosage for patients aged 
12 years and older.  
VX-561 Dosage 
A VX-561 dose of 150 mg qd was selected for evaluation in Part F based on preliminary PK 
results from a relative bioavailability study (Study VX16-770-018) evaluating the 50-mg tablet 
formulation of VX-561. 150-mg qd is predicted to result in similar PK parameters as IVA when 
administered alone at a dose of 150 mg q12h, including AUC0-24h and Ctrough. The VX-561 dose 
selection accounts for differences in the PK profile relative to IVA. VX-561 has been dosed up 
to 225 mg qd for 7 days in a Phase 1 study.  
Treatment Duration 
The 4-week treatment duration for the TC is based on previous experience with CF correctors 
and potentiators in clinical studies of subjects with CF. In previous studies of TEZ and IVA, PD 
effects were observed within 4 weeks of treatment. In Study VX06-770-101, treatment with IVA 
for 4 weeks resulted in statistically significant within-group changes from baseline in ppFEV1 as 
well as a trend toward clinically meaningful improvements in the respiratory domain of the 
CFQ-R; differences in biomarkers of CFTR activity (sweat chloride) between IVA and placebo 
groups were also demonstrated. Furthermore, in Study VX11-661-101 dose-dependent 
improvements in lung function were observed for TEZ/IVA after 4 weeks of treatment, with the 
2 highest dose groups showing statistically significant improvement in lung function versus 
placebo.17 In both studies, improvements in sweat chloride and ppFEV1 were observed during 
the first week of dosing, with most of the effect observed within 14 days. Given the increased 
in vitro response of the TC relative to TEZ/IVA, it is expected that the 4-week treatment duration 


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of VX-445 will be sufficient to observe differences between treatment arms with respect to 
efficacy and PD endpoints. 
Administration of VX-445, TEZ, IVA, and VX-561 With Food 
Oral doses of VX-445, TEZ, IVA, and VX-561 will be administered under fed conditions. This 
is consistent with how VX-445, TEZ, IVA, and VX-561 were administered in nonclinical 
studies, including the GLP toxicity studies. Only a mild food effect is predicted for VX-445 oral 
absorption. 
9.3.3 
Study Population (Parts D, E, and F) 
The study will include subjects with F/MF and F/F genotypes. The inclusion of subjects with 
F/MF and F/F genotypes is based on in vitro data that indicate the potential for significant 
improvements in chloride transport for CF patients with 1 or 2 copies of F508del in response to 
treatment with TC.11 Subjects homozygous and heterozygous for F508del will be evaluated in 
different parts of the study because of the potential for differences in the magnitude of treatment 
response across the 2 genotype categories, and also because of the differences in current standard 
of care (See Section 9.3.1.2). 
9.3.4 
Study Assessments 
9.3.4.1 
Parts A, B, and C 
The majority of safety and PK assessments are standard parameters for Phase 1 clinical studies.  
Rationales for other safety, PK, and PD assessments are listed below: 
4β-hydroxycholesterol (Part B) 
4β-hydroxycholesterol is an endogenous marker for cytochrome P450 (CYP) 3A activity.20 
Evaluation of 4β-hydroxycholesterol is increasingly being used to assess potential clinical 
CYP3A induction. In Part B, comparison of 4β-hydroxycholesterol on Day 10 (predose) relative 
to baseline (Day 1 predose) will be used to evaluate potential induction of CYP3A by VX-445. 
Based on in vitro data, VX-445 is not expected to be an inducer of CYP3A.11 
Spirometry (Parts B and C) 
Transient declines in lung function have been observed at initiation of treatment with another 
CFTR corrector that is not included in the current study (LUM).21 Although nonclinical toxicity 
results do not indicate a risk of lung function decline for VX-445, lung function, as assessed by 
spirometry, will be included in Parts B and C as a precautionary safety measure. 




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Subjects should also take appropriate measures to minimize exposure to UV-radiation 
(e.g., prolonged sunlight, tanning booths) from the Day 1 Visit through the Safety Follow-up 
Visit. 
Other study restrictions are summarized in Table 9-4. 
Table 9-4 
Parts A, B, and C: Study Restrictions 
Restricted 
Medication/Food/Activitya 
Timing of Restriction 
From (minimum) 
To 
Depo-Provera®  
6 months before first study drug dose  
Completion of Safety Follow-up Visit 
assessments 
Tobacco- or nicotine-containing 
product 
45 days before first study drug dose 
Completion of Safety Follow-up Visit 
assessments 
Other investigational drugs or 
devices 
30 days or 5 half-lives before first 
study drug dose, or time determined 
by local requirements (whichever is 
longest)  
Completion of Safety Follow-up Visit 
assessments 
Hormonal methods of 
contraception (oral or patch) or 
hormonal replacement therapies 
28 days before first study drug dose 
Completion of Safety Follow-up Visit 
assessments 
Prescription medications 
14 days or 5 half-lives (whichever is 
longer) before first study drug dose 
Completion of Safety Follow-up Visit 
assessments 
Nonprescription medications 
14 days or 5 half-lives (whichever is 
longer) before first study drug dose. 
Occasional, limited ibuprofen 
(≤800 mg/day) and acetaminophen 
(≤2 g/day) is allowed for pain. 
Completion of Safety Follow-up Visit 
assessments 
Herbal supplements, vitamins, or 
other dietary supplements 
14 days before first study drug dose 
Completion of Safety Follow-up Visit 
assessments 
Grapefruit; grapefruit, apple, or 
orange juice; vegetables from the 
mustard green family (e.g., kale, 
broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts, 
mustard); and charbroiled meats 
72 hours before first study drug dose  
Until last PK sample is taken 
Alcohol 
Not more than 14 drinks/week for 
female subjects or 21 drinks/week for 
male subjects, where 1 drink equals 
5 oz (150 mL) of wine, 12 oz 
(360 mL) of beer, or 1.5 oz (45 mL) 
of hard liquor, within 6 months before 
the Screening Visit and none from 
48 hours before admission to the CRU 
Completion of Safety Follow-up Visit 
assessments 
Caffeine 
24 hours before first study drug dose 
Until last PK sample is taken 
Strenuous exercise (e.g., heavy 
lifting, weight training, and 
aerobics) 
96 hours before first clinical 
laboratory testing 
Completion of Safety Follow-up 
assessments 
CRU: clinical research unit; PK: pharmacokinetic. 
a 
See Section 9.5.1 for guidance on concomitant medications. 


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9.4.2 
Parts D, E, and F 
Subjects should take appropriate measures to minimize exposure to UV-radiation 
(e.g., prolonged sunlight, tanning booths) from the Day 1 Visit through the Safety Follow-up 
Visit. 
9.4.2.1 
Prohibited Medications 
Table 9-5 lists prohibited medications. TEZ, IVA, and VX-561 are metabolized extensively via 
cytochrome P450 (CYP) 3A4. VX-445 has a low potential to be an inhibitor or inducer of CYP 
enzymes based on in vitro data but is metabolized by CYP3A4/5. Therefore, use of moderate and 
strong inducers and inhibitors of CYP3A, which have the potential to alter the exposure of 
VX-445, TEZ, IVA, and VX-561 will be prohibited. VX-445 is a potential inhibitor of the 
hepatic transporter organic anion transporting polypeptide 1B1 (OATP1B1). Therefore, sensitive 
substrates of OATP1B1, such as HMG-Co-A Reductase Inhibitors (“statins”) are prohibited 
during treatment. Commercially available CFTR modulators are also prohibited. 
A non-exhaustive list of study prohibitions and cautions for medication will be provided in the 
Study Reference Manual. 
Table 9-5 
Parts D, E, and F: Prohibited Medications 
Medication 
Timing of Restriction 
Start of Restriction 
End of Restriction 
Moderate and strong CYP3A 
inducers 
None allowed within 14 days before 
the first dose of the study drug on 
Day 1  
None allowed through 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 
None allowed through the Safety 
Follow-up Visit 
Sensitive OATP1B1 substrates 
None allowed within 14 days before 
the first dose of the study drug on 
Day 1 
None allowed through the Safety 
Follow-up Visit 
CFTR modulators (investigational 
or approved, except for study 
drug) 
Parts D and F: None allowed within 
28 days before Screening 
 
Part E: None allowed beginning on 
Day -28 Visit 
Parts D and F: None allowed through 
the Safety Follow-up Visit 
 
Part E: None allowed through Day 57 
Note: The use of prohibited medication by subjects with medical needs will be addressed on a case-by-case basis 
with the medical monitor. 
 
9.5 
Prior and Concomitant Medications 
9.5.1 
Parts A, B, and C 
 Subjects will abstain from medication as described in Table 9-4. 
 All medications taken from 28 days before the first dose of study drug through the end of 
the study will be recorded with indication, route of administration, and start and stop 
dates of administration. All subjects will be questioned about medications at each clinic 
visit. 


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9.5.2 
Parts D, E, and F 
Information regarding all prior and concomitant medications, including the subject’s CF 
medications, other medications, and herbal and naturopathic remedies administered from 28 days 
before the Screening Visit through the Safety Follow-up Visit, if applicable, will be recorded in 
each subject's source documents. For subjects who are screened but not subsequently 
randomized, 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 of 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. 
9.6 
Study Drug Administration 
9.6.1 
Parts A, B, and C 
For all dosing occasions, study drug will be administered under supervision of the investigator or 
authorized designee. VX-445 and matching placebo will be administered as a tablet, and VX-445 
will be administered as an IV solution for infusion if Dosing Period 3 of Cohort A7 is conducted. 
TEZ and IVA and their matching placebos will be administered as tablets (Part C). 
Study drug will be administered according to the following guidelines: 
 Study drug will be administered after baseline vital signs and ECGs are performed. 
 Study drug should be given to subjects within each treatment period at approximately the 
same time (± 30 minutes) on each dosing occasion. 


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 When study drug is administered as a tablet, subjects will swallow the tablet(s) whole 
with 240 mL of water. Subjects may take additional water, as needed, to swallow tablets. 
 Subjects will be supine if VX-445 is administered intravenously 
 To standardize the conditions on PK sampling days, all subjects will be required to 
refrain from lying down (except when required for PK sampling, continuous ECG 
measurements, and IV dosing), eating, and drinking beverages other than water during 
the first 4 hours after dosing. 
9.6.1.1 
Part A 
Part A, Cohorts A1 Through A6: Single-ascending Dose Escalation 
Cohorts A1 though A6 will be dosed under fed conditions. 
Subjects must abstain from all food and drink (except water) at least 8 hours before the start of 
the standard breakfast. A standard breakfast, containing approximately 20 g of fat, will be served 
to subjects 30 minutes before dosing. Subjects must complete the entire meal in 30 minutes or 
less; study drug will be administered 30 minutes after the start of the meal. Food will not be 
permitted for at least 4 hours after dosing. Water (including clear liquids) may be consumed 
without restriction beginning 1 hour after dosing. 
Lunch will be provided 4 to 6 hours after dosing. Dinner will be provided 8 to 11 hours after 
dosing. 
An evening snack will be permitted. 
Part A, Cohort A7: Food Effect and Absolute Bioavailability 
Day 1 (Fasted State) 
Subjects will receive VX-445 tablets on Day 1. 
On Day 1 (fasted state), subjects must abstain from all food and drink (except water) at least 
8 hours before and 4 hours after study drug dosing. Water is permitted until 1 hour before the 
dose of study drug and beginning 1 hour after dosing.  
Lunch will be provided 4 to 6 hours after dosing. Dinner will be provided 8 to 11 hours after 
dosing. 
An evening snack will be permitted. 
Days 7 and 13 (Fed State) 
Subjects will receive VX-445 tablets on Day 7. If Dosing Period 3 is conducted (Section 9.1), 
subjects will receive a single IV dose of VX-445 infused over 30 minutes on Day 13. 
On Days 7 and 13 (fed state), subjects must abstain from all food and drink (except water) at 
least 8 hours before the start of the standard breakfast. A standard breakfast, containing 
approximately 20 g of fat, will be served to subjects 30 minutes before dosing. Subjects must 
complete the entire meal in 30 minutes or less; study drug will be administered 30 minutes after 
the start of the meal. Food will not be permitted for at least 4 hours after dosing. Water 
(including clear liquids) may be consumed without restriction beginning 1 hour after dosing. 


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Lunch will be provided 4 to 6 hours after dosing. Dinner will be provided 8 to 11 hours after 
dosing. 
An evening snack will be permitted. 
9.6.1.2 
Part B 
All cohorts in Part B will be dosed under fed conditions.  
On all days of study drug administration, a standard breakfast, containing approximately 20 g of 
fat, will be served 30 minutes before morning dosing. Additionally, if dosing is every 12 hours, a 
standard dinner, containing approximately 40 g of fat, will be served 45 minutes before evening 
dosing. Subjects must complete the entire meal in 30 minutes or less (for breakfast) or 
45 minutes or less (for dinner); study drug will be administered 30 minutes (for breakfast) or 
45 minutes (for dinner) after the start of the meal. 
On days of intensive PK sampling, subjects must abstain from all food and drink (except water) 
at least 8 hours before the start of the standard breakfast. Food will not be permitted for at least 
4 hours after the morning dose, but water and other clear liquids may be consumed without 
restriction beginning 1 hour after the morning dose. 
9.6.1.3 
Part C 
All doses of VX-445, TEZ, and IVA will be administered under fed conditions, consistent with 
the dosing recommendations for TEZ/IVA. 
On all days of study drug administration, a standard breakfast, containing approximately 20 g of 
fat, will be served 30 minutes before morning dosing. Additionally, if dosing is every 12 hours, a 
standard dinner, containing approximately 40 g of fat, will be served 45 minutes before evening 
dosing. Subjects must complete the entire meal in 30 minutes or less (for breakfast) or 
45 minutes or less (for dinner); study drug will be administered 30 minutes (for breakfast) or 
45 minutes (for dinner) after the start of the meal.  
On days of intensive PK sampling, subjects must abstain from all food and drink (except water) 
at least 8 hours before the start of the standard breakfast. Food will not be permitted for at least 
4 hours after the morning doses but water and clear liquids may be consumed without restriction 
beginning 1 hour after the morning doses. 
9.6.2 
Parts D, E, and F 
Study drug will be administered orally. In each part, subjects in all groups will receive the same 
number of tablets at each dosing occasion 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" 
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 qd (± 2 hours) or q12h (± 2 hours). For each subject, doses 
of study drugs will be taken at approximately the same time each day. For example, if dosing 
is q12h, 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. 


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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 all predose assessments are complete. A meal or snack will be provided by the site for 
the morning dose of study drug. For subjects in Part E requiring a Day -14 Visit, study drug 
does not need to be administered at the site for that visit only. 
5. Subjects will be instructed to return all used and unused materials associated with the study 
drug to the site; study drug will be dispensed at each visit, as appropriate. 
Missed Doses 
If a subject misses a dose and recalls the missed dose within 6 hours (q12h dosing) or within 12 
hours (qd dosing), the subject should take his/her dose with food. If more than 6 hours (q12h 
dosing) or 12 hours (qd dosing) have elapsed after his/her usual dosing time, the subject should 
skip that dose and resume his/her normal schedule for the following dose. Examples are provided 
below: 
If study drug is administered q12h: 
 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. 
If study drug is administered qd: 
 if the 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 dose of study drug should have been taken at approximately 08:00, and more than 
12 hours have elapsed beyond the scheduled dosing time (i.e., the time is past 20:00), the 
subject would resume dosing the following day at approximately 08:00. 
9.7 
Dose Escalation Criteria 
9.7.1 
Parts A, B, and C 
The decision to initiate successive cohorts and dose selection will be based on safety, tolerability, 
and available PK data from preceding cohort(s), as indicated in Sections 9.7.1.1, 9.7.1.2, 
and 9.7.1.3. The investigator, Vertex medical monitor, and Vertex Global Patient Safety (GPS) 
physician will conduct a blinded evaluation of all safety data on an ongoing basis, and all 
Grade 3 or higher laboratory abnormalities or AEs (Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials) will be evaluated to 
determine if dosing/dose escalation should be continued. A safety report, which includes 
available PK data and justification for selection of the dose, will be prepared by the investigator 
for the proposed dose escalation. 


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9.7.1.1 
Part A 
The planned dose escalation scheme for Part A is shown in Table 9-1. Doses may be adjusted 
upward or downward based on safety, tolerability, and PK data from preceding dose group(s). 
No dose increment will be expected to yield greater than a 3-fold increase (Cohorts A1 
through A3) or a 2-fold increase (all other Part A cohorts except Cohort A7) in exposure from 
the preceding dose level. Dose escalation will be stopped when the predefined stopping criteria 
are met (see Section 9.8). 
The decision to initiate successive cohorts and dose selection will be based on safety, tolerability, 
and available PK data from all subjects in each preceding cohort. 
9.7.1.2 
Part B 
Part B may be initiated while Part A is ongoing after review of safety, tolerability, and PK data. 
The starting daily dose (Cohort B1) will be at least 1 dose level below the highest Part A dose for 
which safety, tolerability, and PK results are available and that is safe and well tolerated. 
The decision to initiate successive cohorts and dose selection will be based on safety, tolerability, 
and available PK data through Day 10 from previous cohorts. Doses may be adjusted upward or 
downward based on safety, tolerability, and PK data from preceding dose group(s). The highest 
daily dose of VX-445 in Part B will not exceed the highest Part A dose for which safety and 
tolerability results are supportive. Stopping criteria are presented in Section 9.8.1. 
9.7.1.3 
Part C 
Part C may be initiated while Parts A and B are ongoing after review of safety, tolerability, and 
PK data. The starting dose (Cohort C1) will be at least 1 dose level below the highest Part B dose 
for which safety and tolerability results are available and supportive. The highest dose of 
VX-445 in Part C will not exceed the highest Part B dose for which safety and tolerability results 
are available and supportive. 
9.7.2 
Parts D, E, and F 
If any unacceptable toxicity arises, individual subjects will discontinue dosing (Section 9.1.2.7). 
No dose modifications for toxicity are allowed. 
9.8 
Stopping Criteria 
9.8.1 
Parts A, B, and C 
Dose escalation will be stopped if the mean AUC0-∞ (single-dose escalation) or AUC0-24h 
(multiple-dose escalation) of the next dose is predicted to exceed an AUC of 290 μg·h/mL or the 
Cmax is predicted to exceed 19.5 μg/mL (NOAEL exposure at the 50 mg/kg/day dose in male rats 
in the 28-day GLP toxicity study). 
An individual subject will discontinue study drug dosing if the subject has a serious adverse 
event (SAE) or an AE that jeopardizes the subject’s safety. The investigator must immediately 
notify the Vertex medical monitor if either an SAE or a severe (or greater) AE occurs that is 
considered related or possibly related to study drug. All SAEs, regardless of the presumed 
relationship to study drug, must also be reported to Vertex GPS within 24 hours 
(Section 13.1.2.3). 


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If an SAE occurs that is considered related or possibly related to study drug, or if 2 severe (or 
greater) AEs occur that are considered related or possibly related to study drug, then the study 
will be halted (i.e., dosing of study drug in all study subjects will be halted). Occurrence of such 
events will trigger an internal safety review, including discussion between the investigator and 
medical monitor. The study may be restarted if the sponsor and the investigator decide that this is 
appropriate.  
9.8.2 
Parts D, E, and F 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, or total bilirubin 
>2 × ULN, must be followed closely, including confirmatory testing performed by the central 
laboratory within 48 to 72 hours of the initial finding and subsequent close monitoring of ALT, 
AST, and bilirubin levels, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results must be reported immediately to the medical monitor, and the subject 
must have the tests repeated and sent to the central laboratory as soon as possible (ideally within 
48 to 72 hours). 
Study drug administration must be interrupted immediately (prior to confirmatory testing), and 
the medical monitor must be notified, if any of the following criteria are met: 
 ALT or AST >8 × ULN 
 ALT or AST >5 × ULN for more than 2 weeks 
 ALT or AST >3 × ULN, in association with total bilirubin >2 × ULN and/or clinical 
jaundice 
 Indirect bilirubin >2 × ULN (defined as ULN for total bilirubin minus ULN for direct 
bilirubin) 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression.  
Study drug administration must be discontinued, if either of the following criteria is met: 
 Subsequent ALT or AST values confirm the initial elevation that satisfied the interruption 
rule (above), and no convincing alternative etiology (e.g., acetaminophen use, viral 
hepatitis, or alcohol ingestion) is identified, regardless of whether transaminase levels 
have improved 
 Subsequent indirect bilirubin values confirm the initial value as >2 × ULN (defined as 
ULN for total bilirubin minus ULN for direct bilirubin), in association with decreased 
haptoglobin 
If an alternative, reversible cause of transaminase elevation and/or increased bilirubin or clinical 
jaundice has been identified, study drug administration may be resumed once transaminases or 
bilirubin return to baseline or are ≤2 × ULN, whichever is higher. Approval of the medical 
monitor is required before resumption of study drug. Upon resumption of study drug, 
transaminases and bilirubin should be assessed weekly for 4 weeks. If a protocol-defined 
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(with confirmation of the initial elevation by repeat testing within 48 to 72 hours), then the study 
drug must be permanently discontinued, regardless of the presumed etiology. 
All subjects in whom treatment is discontinued for elevated transaminases and/or bilirubin 
should have these levels monitored closely until levels normalize or return to baseline. 
9.9 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety reasons, behavior, noncompliance with study drug dosing or study procedures, 
ineligibility, or administrative reasons. 
Whenever possible, subjects who have been withdrawn from study drug treatment will continue 
on study; however, Vertex retains the right to remove a subject from the study. 
In Parts D, E, and F, 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. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational products (Parts D, E, and F), request that the subject return for a Safety 
Follow-up Visit, if applicable (see Section 9.1.1.3 for Parts A, B, and C and Section 9.1.2.7 for 
Parts D, E, and F), 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 the study data and 
samples collected. The study data and the samples may be used for the development of the study 
compound, other drugs, or diagnostics, in publications and presentations, or for education 
purposes. If the subject withdraws from the study, the study data and samples collected will 
remain part of the study. A subject will not be able to request the withdrawal of his/her 
information from the study data. A subject may request destruction of the samples collected from 
him/her during the study as long as those samples can be identified as his/her samples. Any 
information that already has been obtained from the samples will continue to be used. 
Stopping criteria are presented in Section 9.8. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn before the first dose of study drug (Day 1 for Parts A, 
B, C, D, and F; Day -28 for Part E) may be replaced.  
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
periods may be replaced at Vertex's discretion. 


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10 
STUDY DRUG INFORMATION AND MANAGEMENT 
Study drug refers to VX-445, TEZ/IVA, TEZ, IVA, VX-561, and their matching placebos. 
10.1 
Preparation and Dispensing 
Parts A, B, and C 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
Tablets will be dispensed at the CRU to individual dosing containers by 2 operators, 1 of whom 
is a qualified pharmacist, following national and local laws and regulations. 
The Formulation Preparation Instructions will provide details of the preparation of the VX-445 
IV infusion solution, if used in the study. 
Parts D, E, and F 
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 
Packaging and Labeling 
Vertex will supply the VX-445 tablets and matching placebos and IV solution (if used), as well 
as TEZ/IVA FDC tablets, TEZ tablets, IVA tablets, VX-561 tablets, and all matching placebos. 
Study drug tablets will be supplied in blister cards by Vertex for Parts D, E, and F. Study drug 
labeling will be in compliance with applicable local and national regulations. Additional details 
regarding packaging, labeling, and dispensing for study drug will be included in the Pharmacy 
Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
VX-445 and matching placebo will be supplied as tablets of similar size and appearance 
containing 20 mg, 50 mg, or 100 mg VX-445 and 0 mg VX-445, respectively. 
VX-445 will be supplied as a sterile solution for IV administration, if used in the study. 
TEZ/IVA (100 mg/150 mg) and matching placebo will be supplied as light yellow film-coated 
tablets of similar size and appearance containing 100 mg TEZ/150 mg IVA and 0 mg TEZ/0 mg 
IVA, respectively.  
TEZ (50 mg) and matching placebo will be supplied as white tablets of similar size and 
appearance containing 50 mg TEZ and 0 mg TEZ, respectively, if Part F is conducted. 
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.  
VX-561 (50 mg) and matching placebo will be supplied as tablets of similar size and appearance 
containing 50 mg VX-561 and 0 mg VX-561, respectively, if Part F is conducted. 
Study drug and 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 


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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 
Storage Condition 
Part 
VX-445 
20-mg, 50-mg, and 100-mg tablets, 
oral 
≤ 25°C (77°F) with excursions to 
30°C (86°F) 
All 
VX-445-matching 
placebo 
0-mg tablet, oral 
≤ 25°C (77°F) with excursions to 
30°C (86°F) 
All 
TEZ/IVA fixed-dose 
100-mg/150-mg tablet; oral 
≤25°C (77°F) with excursions to 
30°C (86°F) 
C, D, and E 
TEZ/IVA-matching 
placebo 
0-mg/0-mg tablet; oral 
≤25°C (77°F) with excursions to 
30°C (86°F) 
C, D, and E 
TEZ 
50-mg tablet, oral 
≤25°C (77°F) with excursions to 
30°C (86°F) 
F 
TEZ-matching 
placebo 
0-mg tablet, oral 
≤25°C (77°F) with excursions to 
30°C (86°F) 
F 
IVA 
150-mg tablet, oral 
≤25°C (77°F) with excursions to 
30°C (86°F) 
C, D, and E 
IVA-matching 
placebo 
0-mg tablet, oral 
≤25°C (77°F) with excursions to 
30°C (86°F) 
C, D, and E 
VX-561 
50-mg tablet, oral 
Refer to Pharmacy Manual 
F 
VX-561-matching 
placebo 
0-mg tablet, oral 
Refer to Pharmacy Manual 
F 
IVA: ivacaftor; TEZ: tezacaftor 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received, (2) study drug dispensed to the subjects, and (3) study drug 
returned by the subjects (Parts D, E, and F only). Subjects in Parts D, E, and F 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. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. At the end of the study, the study monitor 
will provide instructions as to the disposition of any unused investigational product. If the study 
monitor authorizes destruction at the study site, the investigator will ensure that the materials are 
destroyed in compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Vertex. Destruction will be adequately documented. 


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10.6 
Compliance  
10.6.1 
Parts A, B, and C 
All doses will be administered under the direct supervision of the investigator or designee. A 
hand-and-mouth check will be done after each dose administration of the tablet in the CRU to 
ensure 100% study treatment compliance. 
10.6.2 
Parts D, E, and F 
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.  
10.7 
Blinding and Unblinding 
This will be a double-blind study with the exception of Cohort A7, which will be open-label. 
10.7.1 
Blinding  
10.7.1.1 
Parts A, B, and C 
Blinding of subject treatment assignments will be maintained until database lock. The packaging 
and labeling of study drug will be done to ensure that treatment assignments are blinded within 
each cohort in all parts of the study. 
During the conduct of the study, all study personnel will be blinded to subject treatment 
assignments except for 
 the unblinded site monitor; 
 Bioanalytical CRO analyzing PK samples and Vertex Bioanalytical personnel who is not 
a member of the SET but reviews raw data from Bioanalytical CRO. The Vertex 
Bioanalytical SET member will continue to be blinded; 
 vendor preparing the unblinded statistical and PK/PD analysis of continuous ECG data 
collected in Part A (with the exception of Cohort A7); 
 the unblinded biostatistician preparing the randomization list as well as an unblinded 
quality control (QC) biostatistician; 
 the dispensing contracted pharmacist;  
 the pharmacy QC/quality assurance personnel, as applicable; and 
 Vertex GPS and Regulatory Affairs when required to satisfy regulatory reporting 
requirements. 
The Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time. 


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A limited Vertex team, which may include members of the Vertex SET, may be unblinded to 
individual subject treatment assignments for the purposes of review of PD, PK/PD, and/or safety 
data. No unblinded data or results of unblinded analyses will be shared with the CRU or with 
blinded Vertex personnel. All instances of unblinding by Vertex personnel will be documented. 
Bioanalytical results (i.e., concentrations of VX-445) will be reported by the bioanalytical CRO 
using masked identification numbers for PK analysis. 
10.7.1.2 
Parts D, E, and F 
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 GPS and Regulatory Affairs personnel to satisfy 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 (IAs) 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 
 Bioanalytical CRO analyzing PK samples and the Vertex Bioanalytical personnel who is 
not a member of the SET but reviews raw data from Bioanalytical CRO. The Vertex 
Bioanalytical SET member will continue to be blinded. 
 Vertex Modeling and Simulation personnel or vendor conducting the population PK and 
PK/PD analyses 
 Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time 
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 29 Visit to make decisions 
about dose selection for potential subsequent cohorts. 
Blinding of Sweat Chloride and Spirometry Results: 
 The Vertex study team will not have access to the spirometry or sweat chloride results 
after the first dose of study drug until after the data are unblinded for full review per 
Section 12.3.6.1.2. 


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 Sites, subjects, and their parents/caregivers/companions should not be informed of a 
subject’s study-related sweat chloride results until after the subject’s last study visit, even 
if the subject prematurely discontinues treatment. 
 Subjects and their parents/caregivers/companions should not be informed of a subject’s 
study-related spirometry results until after the subject’s last study visit, even if the subject 
prematurely discontinues treatment. 
10.7.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of Individual Subject Treatment Assignments by Investigator for Medical 
Emergencies or Urgent Clinical Situations 
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the medical monitor, they will use their best 
judgment, based on the nature and urgency of the clinical situation, and may proceed with 
unblinding without having successfully reached and discussed the situation with the medical 
monitor. In case of emergency, the investigator will have the final decision and unilateral right 
for unblinding. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center (
) will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If a subject's treatment assignment has been unblinded for a medical emergency or urgent clinical 
situation, the medical monitor will be notified within 24 hours of the unblinding event. The 
reason and the date of the unblinding will be documented clearly in the subject's study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with the sponsor (Vertex), CRO, or 
any site personnel (other than the physician treating the subject). In addition, the investigator will 
consider whether the clinical event that prompted unblinding will be considered an SAE, 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to 
GPS or designee, per Section 13.1.2. 
Unblinding of Individual Subject Treatment Assignments by Vertex GPS or Designee for 
SAEs or Safety Concerns 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, unblind 
individual subjects at any time.  




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Based on emergent data, the number of sampling points for VX-445 plasma may be reduced, 
and/or time points may be modified. Actual sampling times may change upon agreement of the 
clinical pharmacologist and investigator. 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. 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Part 
Sampling Time 
Time From Scheduled Sampling 
Allowed 
Parts A, B, and C 
Predose 
Within 30 minutes before dosing  
 
From 0.25 up to ≤12 hours after study drug dosing 
± 5 minutes 
 
From >12 up to ≤24 hours after study drug dosing 
± 10 minutes 
 
From >24 up to ≤48 hours after study drug dosing 
± 20 minutes 
 
From >48 up to ≤120 hours after study drug dosing 
± 30 minutes 
Parts D, E, and F 
Predose 
From 1 up to ≤8 hours after study drug dosing 
-60 minutes 
± 15 minutes 
 
Samples collected outside of these acceptable windows will be considered protocol deviations.  
In Parts A, B, and C, the date and time of administration of the dose before the PK dose and date 
and time of the last meal before the PK dose will be recorded accurately in the source document. 
For each visit in Parts D, E, and F with a PK blood draw, a record of study drug administration 
will be collected as described in Section 9.6.2. For all parts, 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. 
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. 
11.3.3 
Bioanalysis 
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee standard operating procedures. A description of the assay and validation data will be 
provided in separate reports. 
In addition to the analysis using validated methods, PK samples may be used to assess potential 
metabolites of VX-445 by exploratory or validated methods. 
11.4 
Pharmacodynamics 
11.4.1 
Sweat Chloride (Parts 
 D, E, and F) 
Collection of sweat samples will be performed in Parts 
 D, E, and F using an approved 
collection device. 


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 In Parts D, E, and F, there are 
no fasting requirements. 
At each time point, 2 samples will be collected, 1 from each arm (left and right). Additionally, 
sweat collections will be performed on any single day during screening. Collection of sweat 
chloride will not overlap with any other study assessments. 
Sweat collection should occur at approximately the same time at every visit. 
Sweat samples will be sent to a central laboratory for analysis of sweat chloride concentrations. 
Sweat chloride results for individual subjects will not be disclosed to the study sites, with the 
exception of the screening values in Parts D, E, and F. 
Specific instructions for collection, handling, processing, and shipping of sweat chloride samples 
to the central laboratory will be provided separately. See Section 10.7.1.2 for information about 
blinding of sweat chloride results in Parts D, E, and F. 
11.6 
Efficacy (Parts D, E, and F) 
11.6.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines14 and the following additional guidelines: 
Pre-bronchodilator spirometry is defined as spirometry testing performed for subjects who have 
 withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic 
(e.g., ipratropium bromide [Atrovent®]) for more than 4 hours before the spirometry 
assessment; 
 withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before 
the spirometry assessment; and 
 withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide 
[Spiriva®]) for more than 24 hours before the spirometry assessment. 
During the Screening Period, spirometry assessments may be performed pre- or 
post-bronchodilators. At all other visits, all spirometry assessments should be performed 


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"pre-bronchodilator." During the Treatment Period, spirometry assessments must be performed 
before the in-clinic dose of study drug, at approximately the same time at each visit. For subjects 
in Part E requiring a Day -14 Visit, spirometry may be performed postdose. An additional 
spirometry assessment will be performed 5 hours (± 1 hour) after study drug administration on 
the Day 1 and Day 15 Visits.  
If 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 
should be performed post-bronchodilator. 
 Each spirometry assessment will be recorded in the source documents as pre- or 
post-bronchodilator. 
If more than 1 spirometry assessment is required at a visit, bronchodilators will be withheld until 
completion of the last scheduled spirometry assessment. 
All sites will be provided with spirometers to be used for all study assessments. Spirometry data 
will be transmitted to a centralized spirometry service for quality review. 
See Section 10.7.1.2 for information about blinding of spirometry results. 
The measured spirometric values listed below will be converted to percent predicted values using 
the GLI standards.13  
 FEV1 (L) 
 FVC (L) 
 FEV1/FVC (ratio) 
 Forced expiratory flow (FEF25%-75%) (L/s) 
11.6.2 
Cystic Fibrosis Questionnaire-Revised 
Subjects will be asked to complete the CFQ-R in their native language, if validated translations 
are available.23,24 The CFQ-R will be completed before any other study assessments are 
performed at the study visit. 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 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.25, 26 
11.7 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, PEs, spirometry (Parts B, C, D, E, and F), and pulse oximetry (Parts D, E, and F). 


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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. 
11.7.2 
Clinical Laboratory Assessments 
Parts A, B, and C: Blood and urine samples will be analyzed at a local laboratory. At the 
Screening Visit, blood specimens will be collected for safety laboratory tests following at least a 
4-hour fast. Fasting is not required at other time points. 
Parts D, E, and F: Blood and urine samples will be analyzed at a central laboratory, with the 
exceptions noted below. Fasting is not required. 
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Section 3. Laboratory test results that are abnormal and considered clinically significant will be 
reported as AEs (see Section 13.1). 
The safety laboratory test panels are shown in Table 11-2. 


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Table 11-2 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematologya 
Urinalysisb 
Glucose 
Blood urea nitrogenc 
Creatinine 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Bicarbonate (TCO2) 
Phosphate 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Aspartate transaminase 
Alanine transaminase 
Amylase 
Lipase 
Gamma-glutamyl transferase 
Protein 
Albumin 
Creatine kinase 
Cholesterol 
Triglycerides 
Low-density lipoprotein-direct 
High-density lipoprotein 
Lactate dehydrogenase 
Haptoglobind 
Hemoglobin 
Erythrocytes 
Mean corpuscular volume 
Platelets  
Reticulocytes (absolute) 
Leukocytes  
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes 
Monocytes 
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
Leukocyte esterase 
Nitrite  
Urobilinogen 
Urine protein 
pH 
Urine blood 
Specific gravity 
Urine ketones 
Urine bilirubin 
Urine glucose  
Note: Screening Visit blood draws for Parts A, B, and C will be done after a minimum 4-hour fast. All subsequent 
blood draws do not require fasting. Fasting is not required for Parts D, E, and F.  
a 
Blood smears will be saved for future evaluation, if needed. 
b 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be performed and results provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
c 
If blood urea nitrogen cannot be collected, urea may be substituted. 
d 
Haptoglobin will be analyzed only if there is evidence of possible hemolysis as determined by the site. 
Pregnancy (β-human chorionic gonadotropin) tests 
Parts A, B, and C: serum samples will be analyzed at the local laboratory for all female 
subjects. 
Parts D, E, and F: serum samples will be analyzed at the central laboratory for all females of 
childbearing potential. Urine pregnancy tests will be performed at the site. The urine pregnancy 
test must be negative before the first dose of study drug (Day 1 for Parts D1, D2, and F; Day -28 
for Part E). Additional pregnancy tests may be required according to local regulations and/or 
requirements.  
Follicle-stimulating Hormone, Screening Period only (All Parts): Blood sample for FSH will be 
measured for any suspected postmenopausal female with at least 12 months of continuous 


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spontaneous amenorrhea. Serum FSH levels must be within the postmenopausal reference range 
of the performing laboratory to be considered postmenopausal. 
G6PD Activity Test, Screening Period only (All Parts): Blood samples will be collected for the 
G6PD activity test, which will be performed in an established laboratory that runs the assay 
routinely. For Parts D, E, and F, the use of a local laboratory that routinely runs quantitative 
G6PD activity assays is acceptable as an alternative to the central laboratory. 
Serology (Parts A, B, and C): HBsAg, HCV antibody, HIV-1 and HIV-2 Abs, and p24 antigen 
will be tested for. 
Drug and Alcohol Testing (Parts A, B, and C): Opiates, methadone, cannabinoids, cocaine, 
amphetamines/methamphetamines, barbiturates, benzodiazepines, cotinine, and alcohol levels 
will be assessed by a blood or urine test; alcohol breath tests are acceptable alternatives for 
alcohol testing. Subjects may undergo random urine drug screen and alcohol testing if deemed 
appropriate by the investigator. Drug screen result must be negative for all subjects to receive 
study drug. 
CFTR genotype, Screening Period only (Parts D, E, and F): 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 9.9). 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
In Parts D, E, and F, for purposes of study conduct, the central laboratory must be used for all 
laboratory tests with the exceptions noted above. 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 (Section 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, 
and throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; 
and neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs. 
Parts D, E, and F only: The abbreviated PE will include an assessment of the following body 
systems: EENT, cardiovascular system, respiratory system, skin, and abdomen. 
Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse rate, and 
respiration rate. These will be assessed following at least a 5-minute rest in the seated position. 


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11.7.4 
Pulse Oximetry (Parts D, E, and F) 
Arterial oxygen saturation by pulse oximetry will be measured after at least a 5-minute rest 
(seated) and before study drug dosing. At visits when study drug is taken at the site, pulse 
oximetry will be collected before the morning dose. This is a noninvasive measure of oxygen 
delivery to the tissues and has been correlated with clinical status and lung function. 
11.7.5 
Electrocardiograms 
11.7.5.1 
Safety ECGs 
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Schedule of Assessments (Section 3). Additional standard 12-lead ECGs will be performed at 
any other time if clinically indicated.  
The subject will be instructed to rest in the seated or supine position for at least 5 minutes before 
having an ECG performed. 
The ECG traces will be manually read at the study site, as shown in Section 3. 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.  
Study sites should use QTcF unless they receive approval in advance from the medical monitor 
to use QTcB. 
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. Further details 
pertaining to ECGs will be provided to sites in a separate document (ECG Manual). 
11.7.5.2 
Continuous ECGs for Cardiodynamic Assessment (Part A, With the 
Exception of Cohort A7) 
In Part A, continuous ECGs will be obtained per Table 3-2 using a continuous 12-lead digital 
recorder. The continuous 12-lead digital ECG data will be stored onto Secure Digital memory 
cards. ECGs to be used in the analyses will be selected by predetermined time points as defined 
in Table 3-2 and will be read centrally. At each protocol-specified time point, 10 ECG replicates 
will be extracted from a 5-minute “ECG window” (typically, the last 5 minutes of the 15-minute 
period when the subject is maintained in a supine or semi-recumbent quiet position). 
The following principles will be followed in the laboratory: 
 ECG analysts are blinded to the subject, visit, and treatment allocation. 
 Baseline and on-treatment ECGs for a particular subject will be over-read on the same 
lead and will be analyzed by the same reader. 
 The primary analysis lead is lead II. If lead II is not analyzable, then the primary lead of 
analysis will be changed to another lead for the entire subject data set. 


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The ECG data collected by continuous monitoring may or may not be analyzed, or the analysis 
may be restricted initially to 1 or more cohorts. The decision to analyze the ECG data will be 
based on future development decisions for VX-445. If it is determined that the continuous ECG 
data will be analyzed, a separate analysis plan will be created for the evaluation of the ECG data, 
including the Cardiodynamic ECG Assessment and Concentration-QTc Analysis. 
11.7.6 
Spirometry (Parts B, C, D, E, and F) 
Spirometry will be performed according to the American Thoracic Society Guidelines/European 
Respiratory Society Guidelines.14 
11.7.7 
Contraception and Pregnancy 
The effects of VX-445, TEZ, IVA, and VX-561 on conception, pregnancy, and lactation in 
humans are not known. VX-445, TEZ, IVA, and VX-561 did not show genotoxic potential in a 
standard battery of in vitro (Ames test, chromosomal aberration, or micronucleus in cultured 
mammalian cells) and in vivo (rodent micronucleus) studies.11, 12, 17, 27 Reproductive studies of 
VX-445, TEZ, and IVA have not shown teratogenicity in rats and rabbits.11, 17, 27 
11.7.7.1 
Contraception 
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). 
 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: 
• 
Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH level 
within the laboratory's reference range for postmenopausal females. 
• 
Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy. 
Note: All other females (including females with tubal ligations and females who do not have 
a documented bilateral oophorectomy or hysterectomy) will be considered to be of 
childbearing potential. 
 Same sex relationships 


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 For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception is 
used as a couple. Methods of contraception must be in successful use from signing of 
consent, approximately 28 days before the first dose of study drug (unless otherwise noted), 
and until 90 days following the last dose of study drug. Additional contraception 
requirements may need to be followed according to local regulations and/or requirements. 
Acceptable methods of contraception are listed in Table 11-3.  
Table 11-3 
Acceptable Methods of Contraception 
 
All Study Subjects and Their 
Non-study Partners 
Vasectomy 6 months or more previously, with a documented negative 
postvasectomy semen analysis for sperm 
Yes 
Bilateral tubal occlusion (e.g., ligation) performed at least 6 months previously. 
Yes 
Male or female condom with or without spermicidea 
Yes 
Female barrier contraception (such as diaphragm, cervical cap, or sponge) with 
spermicide 
Yes 
Continuous use of an intrauterine device for at least 90 days before the first dose 
of study drug. 
Yes 
Oral, implanted, injected, or vaginal hormonal contraceptives, if successfully 
used for at least 60 days before the first dose of study drug. 
Yes 
a 
A female condom cannot be used with a male condom due to risk of tearing.  
 
Additional notes: 
 Male subjects must not donate sperm during the period starting from the first dose of study 
drug until 90 days after the last dose of study drug. 
 Female subjects should not nurse a child during the period starting from the first dose of 
study drug until 90 days after the last dose of study drug. 
 For male subjects with a female partner of childbearing potential, the couple must not plan to 
become pregnant during the study or within 90 days after the last study drug dose. 
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 during study 
participation, other than a female partner as the result of artificial insemination using sperm 
banked by the male subject before the first dose of study drug, 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 


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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 
This section presents a summary of the planned safety analyses and clinical pharmacology for 
this study. Safety statistical analysis details will be provided in the statistical analysis plan (SAP) 
for this study, and clinical pharmacologic analysis details will be provided in the clinical 
pharmacology analysis plan (CPAP), both of which will be finalized before clinical database 
lock. 
Final analyses will take place after all subjects have completed the study, all data have been 
entered in the clinical study database, and the database has been locked. 
12.1 
Sample Size and Power 
12.1.1 
Parts A, B, and C 
No formal sample size calculations have been performed. The number of subjects participating in 
each cohort is common in early clinical pharmacology studies and is considered sufficient to 
achieve the objectives of the study. 
12.1.2 
Parts D, E, and F 
12.1.2.1 
Primary Objectives  
The primary objectives of Parts D, E, and F are the evaluation of safety and tolerability, and 
efficacy of VX-445 in TC with TEZ/IVA (Parts D and E) and in TC with TEZ/VX-561 (Part F) 
in subjects with CF. The sample size calculations described below are deemed adequate to 
evaluate the primary objectives, based on clinical and statistical considerations. 
Safety and Tolerability 
The primary safety endpoint is the incidence of AEs. Approximately 104 subjects with CF will 
be enrolled in the study with approximately 81 subjects receiving VX-445 in TC with either 
TEZ/IVA or TEZ/VX-561. The sample size for each treatment group will provide sufficient data 
for a descriptive analysis of AEs.  
Efficacy 
The primary efficacy endpoint is the absolute change from baseline in ppFEV1 through Day 29 
in Parts D, E, and F. A sample size of 18 subjects per treatment group provides at least 90% 
power to detect a mean change of 7 percentage points. 
12.1.2.2 
Secondary Objectives  
A secondary objective of Parts D, E, and F is the evaluation of the PD effect of VX-445 in TC 
with TEZ/IVA (Parts D and E) and in TC with TEZ/VX-561 (Part F) in subjects with CF. 
The absolute change from baseline through Day 29 in sweat chloride is a secondary endpoint 
used to evaluate the PD objective of the study. In Part D, a test for a decreasing dose-response 
trend between placebo and the TC dose groups will be performed using a multiple comparisons 
procedure (MCP). The procedure consists of testing the null hypothesis of the lack of a 
decreasing dose-response trend versus a decreasing trend using the 1-sided maximum t-statistic 
that controls the type I error at alpha = 5%. The procedure requires a family of candidate 




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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. Subjects will be analyzed 
according to the treatment they received. If a subject received at least 1 dose of a higher dose TC 
treatment, the subject will be analyzed in the higher dose TC treatment group. For the purpose of 
analysis, the priority order of increasing study drug treatment will be defined as placebo, TC-
low, TC-mid, and TC-high. 
12.3 
Statistical Analysis 
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 of Treatment Period for Parts A, B, and C or Day 1 of Period 1 for 
Parts D, E, and F). For ECG, baseline will be defined as the most recent pretreatment 
measurement (or the average of triplicate measurements, if the most recent pretreatment 
measurement is obtained in triplicate) before the first dose of study drug in the Treatment Period 
(i.e., Day 1, as described above). 
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. 
Parts D, E, and F Only 
The Treatment-emergent (TE) Period will include the time from the first dose in Period 1 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. An additional TE period related to the Run-in Period in 
Part E will be defined in the SAP, as appropriate. Only data collected through the end of the 
study will be included for analysis. 
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 D, E, and F separately, unless specified otherwise. 


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12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
Parts A, B, and C 
The number and percentage of subjects in each disposition category (e.g., randomized, included 
in Safety Set, included in PK Set, PD Set, completed Treatment Period, completed the Safety 
Follow-up Visit, and discontinued study with a breakdown of the reasons for discontinuation) 
will be summarized for the All Subjects Set. 
Parts D, E, and F 
The number and percentage of subjects in each disposition category (e.g., randomized, included 
in the FAS, included in the Safety Set, completed Treatment Period, completed study/Safety 
Follow-up Visit, and discontinued treatment or study with a breakdown of the reasons for 
discontinuation) will be summarized overall and by treatment group. 
12.3.2.2 
Demographics and Baseline Characteristics 
Parts A, B, and C 
Demographic and other baseline characteristics will include, but are not limited to, age, sex, race, 
weight, height, BMI, medical history, baseline safety parameters, 
 
 These characteristics will be summarized for the Safety Set. No statistical tests will be 
done to evaluate baseline imbalances between groups. 
Parts D, E, and F 
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized using descriptive summary statistics. 
The following demographics and baseline characteristics will be summarized overall and by 
treatment group for the FAS and will include (but are not limited to): sex, race, age, baseline 
weight, baseline height, baseline BMI, baseline ppFEV1, and baseline sweat chloride.  
No statistical tests will be performed to evaluate baseline imbalance between treatment groups. 
12.3.2.3 
Prior and Concomitant Medications 
Parts A, B, and C 
Medications will be coded using the World Health Organization-Drug Dictionary Enhanced 
(WHO-DDE) and categorized as the following for the purpose of analysis: 
1. Prior medication: Medication that started before the first dose of study drug, regardless of 
when dosing of the medication ended 
2. Concomitant medication: Medication received at or after the first dose of study drug, 
medication that was received before initial dosing and continued after initial dosing of study 
drug, or medication with missing stop date 
If a medication start date is on or after the date of initial dosing of the study drug, then the 
medication will be summarized as concomitant medication regardless of whether the medication 
end date is missing or not. If a medication end date is before the date of initial dosing of the 
study drug, then the medication will be summarized as prior medication regardless of whether 
the medication start date is missing or not. Note that medication that started before initial dosing 


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of the study drug and continued after initial dosing will be summarized as prior medication and 
separately as concomitant medication. 
Prior medications will be listed only. Concomitant medications will be summarized using 
Preferred Name. 
Parts D, E, and F 
Medications used in this study will be coded using the WHO-DDE and categorized as the 
following for the purpose of analysis: 
 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. 
An additional classification of concomitant medications related to the Run-in Period in Part E 
will be defined in the SAP, as appropriate. 
12.3.2.4 
Study Drug Exposure and Compliance 
Parts A, B, and C 
Exposure to study drug in Parts B and C (i.e., duration of treatment) will be summarized for the 
Safety Set 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. 
Duration of treatment will be summarized by means of descriptive summary statistics for Parts B 
and C only. 
Dosing administration will be presented in an individual subject data listing for all parts. 
Parts D, E, and F 
Exposure to study drug will be summarized for the Safety Set 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 pills taken, will be summarized for the FAS, and will be 
derived as 100  [(total number of pills dispensed) – (total number of pills returned)]/ (total 
number of pills 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)]. 


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12.3.2.5 
Important Protocol Deviations (Parts D, E, and F Only) 
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 (Parts D, E, and F Only) 
12.3.3.1 
Analysis of Primary Variables 
The primary efficacy variable is the absolute change from baseline for ppFEV1 through Day 29 
in Parts D, E, and F. The analysis will be performed using a mixed-effects model for repeated 
measures (MMRM) with change from baseline as the dependent variable. The model will include 
treatment group, visit, and treatment-by-visit interaction as fixed effects, subject as random 
effect, and the continuous baseline ppFEV1 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. An unstructured covariance structure 
will be used to model the within-subject errors. If the model estimation does not converge, a 
compound symmetry covariance structure will be used. Conditional on observed data and 
covariates, missing data due to treatment or study discontinuation will be assumed to be missing 
at random. 
Adjusted means and 95% confidence intervals of the average treatment effects through Day 29, 
as applicable, with 2-sided P values, will be estimated within MMRM using LSMeans via PROC 
MIXED in SAS, for all within-group and between-group comparisons in both parts. 
Sensitivity analyses for handling missing data due to treatment or study discontinuation will be 
described in the SAP.  
Additional supportive analyses utilizing the Washout Period in Part E to compare treatment 
groups will be described in the SAP. Subgroup analyses will also be described in the SAP. 
There will be no multiplicity adjustment for performing multiple hypothesis tests. 
12.3.3.2 
Analysis of Secondary Efficacy Variables 
The secondary efficacy variables are relative change in ppFEV1 from baseline through Day 29 
and absolute change in the CFQ-R respiratory domain score from baseline at Day 29. Analysis of 
secondary efficacy variables will be similar to that performed for the primary efficacy variable. 
Additional details of these analyses will be provided in the SAP. 
12.3.4 
Pharmacodynamic Analysis 
Dose-response Analysis 
The absolute change in sweat chloride from baseline through Day 29 is a secondary endpoint 
used to evaluate the PD objective of the study. The test to detect a decreasing dose-response 
trend (in Part D) of VX-445 at 3 doses in TC with TEZ/IVA relative to placebo based on sweat 
chloride, will be performed using the MCP procedure with the pre-specified comparisons 
(contrasts) of the treatment group means within an MMRM framework. The model will include 
treatment group, visit, and treatment-by-visit interaction as fixed effects, with the continuous 
baseline sweat chloride as a covariate. The test will be performed using the 1-sided maximum 


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t-statistic of the individual t-statistics for the multiple pre-specified contrasts at alpha = 5%, 
based on the treatment group means through Day 29 in Part D.  
Estimation of Treatment Effects 
In a separate MMRM model, adjusted means and 95% confidence intervals of the average 
treatment effects through Day 29, with 2-sided P values, for all within-group and between-group 
comparisons for each part, separately, will be estimated within MMRM, with appropriate 
adjustment for covariates. 
Additional details of the analysis will be provided in the SAP. 
12.3.5 
Safety Analysis 
Parts A, B, and C 
The overall safety profile of VX-445 will be assessed in terms of the following primary (safety) 
endpoints:  
 Incidence of treatment-emergent adverse events (TEAEs) 
 Clinical laboratory values (including coagulation studies) 
 ECG outcomes 
 Vital signs 
 Spirometry (Parts B and C) 
Safety analyses will be based on the Safety Set. No statistical hypothesis testing will be 
conducted. 
For safety variables, the baseline value will be defined as the most recent non-missing 
measurement collected before the initial administration of study drug. 
All safety data will be presented in individual subject data listings. 
Parts D, E, and F 
All safety analyses will be based on data from the TE Period for all subjects in the Safety Set. 
The overall safety profile of study drug will be assessed based on the following safety and 
tolerability endpoints: 
 TEAEs 
 Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and 
urinalysis) 
 ECGs 
 Vital signs 
 Pulse oximetry 
 Spirometry 
All safety data will be summarized by treatment group and overall, for each Part. 
All safety data will be presented in individual subject data listings. 


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12.3.5.1 
Adverse Events 
12.3.5.1.1 
Parts A, B, and C 
AEs will be coded according to MedDRA. The number and percentage of subjects experiencing 
an AE will be summarized by the MedDRA System Organ Class and Preferred Term. AEs will 
be classified as pretreatment or treatment-emergent. 
Pretreatment AEs are defined as AEs that were reported or worsened after signing the ICF up 
to the start of study drug dosing. 
Treatment-emergent AEs are defined as AEs that were reported or worsened on or after the 
start of study drug dosing through the Safety Follow-up Visit. 
Only TEAEs will be summarized in tables. All summaries of TEAEs will be presented by the 
severity of the AE and relationship to the study drug. Some rules that will apply to the 
summarization of AEs are (1) a subject with multiple occurrences of the same AE or a 
continuing AE will be counted only once; (2) only the maximum severity level will be presented 
in the severity summary; and (3) only the worst relationship level will be presented in the 
relationship summary. 
AEs leading to death, SAEs, dose interruption, and permanent discontinuation will be listed 
separately. All AEs through the Safety Follow-up Visit will be listed in an individual subject data 
listing, including pretreatment AEs. 
12.3.5.1.2 
Parts D, E, and F 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
 Pretreatment AE: any AE that started before the first dose of study drug 
 TEAE: any AE that increased in severity or that was newly developed at or after the first 
dose of study drug through the end of the TE Period 
 Post-treatment AE: any AE that increased in severity or that was newly developed 
beyond the TE Period 
For AEs with missing or partial start dates, if there is no clear evidence that the AEs started 
before or after study drug treatment, then the AEs will be classified as TEAEs. 
AE summary tables will be presented for TEAEs only, overall and by treatment group for each 
Part, and will include the following: 
 All TEAEs 
 TEAEs by strongest relationship  
 TEAEs by maximum severity 
 TEAEs leading to treatment discontinuation 
 Serious TEAEs 
 TEAEs leading to death 
 Frequently reported TEAEs 


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Summaries will be presented by MedDRA System Organ Class and Preferred Term using 
frequency counts and percentages (i.e., number and percentage of subjects with an event). When 
summarizing the number and percentage of subjects with an event, subjects with multiple 
occurrences of the same AE or a continuing AE will be counted once, only the maximum 
severity level will be presented in the severity summaries, and the strongest relationship level in 
the relationship summaries. In addition, a listing containing individual subject level AE data for 
all deaths and other serious and significant AEs will be provided separately. All AEs, including 
pre- and post-treatment AEs, will be presented in individual subject data listings. 
12.3.5.2 
Clinical Laboratory Assessments 
12.3.5.2.1 
Parts A, B, and C 
All statistical analyses of laboratory values will be performed using SI units. Observed and 
change from baseline values for hematology and clinical chemistry results will be summarized at 
each scheduled time point. A listing of abnormal individual subject hematology and clinical 
chemistry values from scheduled and unscheduled time points will be provided. Urinalysis 
results will be listed only in individual subject data listings. These results will not be 
summarized. Clinically significant abnormal laboratory findings will be reported as AEs.  
12.3.5.2.2 
Parts D, E, and F 
For the treatment-emergent laboratory measurements, the observed values and change from 
baseline values of the continuous hematology, chemistry, and coagulation results will be 
summarized in SI units overall and by treatment group at each scheduled visit. 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized overall and by treatment group for each part. The threshold analysis 
criterion shift from baseline will also be summarized for selected laboratory parameters. The 
threshold analysis criteria and the parameter selection criteria will be provided in the SAP. 
Results of urinalysis and the serum pregnancy test will be listed in individual subject data listings 
only. In addition, a listing containing individual subject hematology, chemistry, and coagulation 
values outside the reference ranges will be provided. This listing will include data from 
scheduled and unscheduled visits. 
12.3.5.3 
Electrocardiogram 
12.3.5.3.1 
Parts A, B, and C 
A summary of raw values and change from baseline values will be provided at each scheduled 
visit for the following ECG measurements: PR, QT, QRS, and QTc intervals and heart rate (HR). 
In addition, the number and percentage of subjects by maximum on-treatment value of QT/QTc 
intervals, categorized as ≤450 msec, >450 msec and ≤480 msec, >480 msec and ≤500 msec, and 
>500 msec, as well as maximum on-treatment change from baseline value of QT/QTc intervals, 
categorized as ≤0 msec, >0 and ≤30 msec, >30 and ≤60 msec, and >60 msec, will be provided. 
Clinically significant abnormal findings will be reported as AEs.  
Cardiodynamic ECG Assessment (Part A Only, With the Exception of Cohort A7) 
If it is determined that the continuous ECG data will be analyzed, a separate analysis plan will be 
created for the evaluation of the continuous ECG data, including the Cardiodynamic ECG 
Assessment and Concentration-QTc Analysis. 


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12.3.5.3.2 
Parts D, E, and F 
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 msec): RR, 
PR, QT, and QT corrected for HR (QTcF), QRS duration, and HR (beats per minute). 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized overall and by treatment group. The threshold analysis criteria will be 
provided in the SAP. 
Additional ECG analyses will be described in the SAP. 
12.3.5.4 
Vital Signs 
12.3.5.4.1 
Parts A, B, and C 
The following vital signs will be summarized at each scheduled time point: systolic and diastolic 
blood pressure (mm Hg), body temperature, pulse rate (beats per minute), and respiratory rate 
(breaths per minute). Clinically significant abnormal findings in vital signs will be reported as 
AEs. 
12.3.5.4.2 
Parts D, E, and F 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized overall and by treatment group at each scheduled visit. The 
following vital signs parameters will be summarized: systolic and diastolic blood pressure 
(mm Hg), body temperature (C), HR (beats per minute), and respiratory rate (breaths per 
minute). 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized overall and by treatment group for each part. The threshold analysis 
criteria will be provided in the SAP. 
Additional vital signs analyses will be described in the SAP. 
12.3.5.5 
Pulse Oximetry (Parts D, E, and F) 
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 results will be presented in individual subject data listings only.  
12.3.5.7 
Spirometry (Parts B, C, D, E, and F) 
The spirometry assessment will be administered in Parts B, C, D, E, and F. The following 
parameters of FEV1 (L), FVC (L), FEV1/FVC (ratio), FEF25%-75% (L/s), and the corresponding 
percent predicted values based on the GLI equations will be summarized using descriptive 
statistics. 


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12.3.6 
Interim and IDMC Analyses 
12.3.6.1 
Interim Analysis 
12.3.6.1.1 
Parts A, B, and C 
An IA of the continuous ECG data may be performed after all subjects in Part A (with the 
exception of Cohort A7) have completed the Safety Follow-up Visit. See Section 12.3.5.3.1. 
These interim results will be reviewed by a small unblinded Vertex team. 
An IA for Parts A, B, and C may be performed after all subjects in Part C have completed the 
Safety Follow-up Visit. The results of this analysis will be unblinded for full review by the 
Vertex study team. 
12.3.6.1.2 
Parts D, E, and F 
IAs for each part (D1, D2, E, and F) may be performed after at least 50% of subjects in the part 
have completed the Day 15 Visit. The results of these analyses will be reviewed by a limited 
Vertex team. When an IA is performed after all subjects in a 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 (Parts D, E, and F) 
Details of the safety reviews will be described in the IDMC Charter. The IDMC Chair will 
review available safety and PK data from Parts A, B, and C of the study prior to commencement 
of dosing in Part D1 to determine if it is appropriate to proceed with the study. 
12.4 
Clinical Pharmacology Analysis 
A detailed analysis plan that addresses the PK objectives of the study will be presented in the 
CPAP. 
12.4.1 
Pharmacokinetic Analysis 
12.4.1.1 
Parts A, B, and C 
The PK parameters of VX-445 (all parts), TEZ and metabolites (Part C only), and IVA and 
metabolites (Part C only) will be estimated using standard noncompartmental analysis methods. 
The analysis of PK results for all analytes will be based on the PK Set and will be described 
using descriptive statistics. Further details of the PK analyses will be provided in the CPAP. 
12.4.1.2 
Parts D, E, and F 
The PK analysis of VX-445, TEZ and metabolite M1-TEZ, IVA and metabolite M1-IVA, and 
VX-561 and metabolites, if assessed, 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. 


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12.4.3 
Pharmacokinetic/Pharmacodynamic Analyses  
12.4.3.2 
Parts D, E, and F 
PD assessments to be included in PK/PD analyses may include sweat chloride, ppFEV1, as well 
as other secondary endpoints such as BMI, BMI z-score, or CFQ-R. Comparison between 
postdose and predose values will be performed and expressed as a change from baseline.  
A sequential approach will be used to perform the population PK/PD analysis. The Bayesian 
estimates of individual PK parameters from the final population PK model will be used to 
simulate PK profiles for each subject. The simulated VX-445, TEZ, IVA, VX-561, 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. 
A detailed description of the planned PK/PD analysis will be presented in the CPAP. 
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 


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Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF is signed until the following time points: 
 For subjects who do not enroll: until time of screen failure (e.g., screen failure, 
withdrawal of consent) 
 For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up 
Visit 
 For enrolled subjects in Parts A, B, and C who do not have a Safety Follow-up Visit, 
10 days after the last dose of study drug 
 For enrolled subjects in Parts D, E, and F 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 9.1.2.7) 
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 
13.1.1.4.1 
Parts A, B, and C 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 


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September 2007, Center for Biologics Evaluation and Research, 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidance
s/Vaccines/ucm074775.htm (Accessed October 2016). The severity of an AE that does not appear 
in this scale will be determined according to the definitions in Table 13-1.  
Table 13-1 
Grading of AE Severity  
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
13.1.1.4.2 
Parts D, E, and F 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed August 
2015). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” The severity of 
an AE that does not appear in the CTCAE will be determined according to the definitions in 
Table 13-1.  
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.  


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Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/Resolved With 
Sequelae 
Resolution of an AE with residual signs or symptoms 
Not Recovered/Not 
Resolved (Continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
 
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 


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 Persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person's ability to conduct normal life functions) 
 Congenital anomaly or birth defect 
 Important medical event that, based upon appropriate medical judgment, may jeopardize 
the subject or may require medical or surgical intervention to prevent 1 of the outcomes 
listed above (e.g., an allergic bronchospasm requiring intensive treatment in an 
emergency room or at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject's life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up 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: 


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Email:
 
Fax: 
  
Contact Telephone: 
 
13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IECs, and 
participating investigators in accordance with ICH Guidelines and/or local regulatory 
requirements, as applicable. In addition, Vertex, or authorized designee, will be responsible for 
the submission of safety letters to central 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 assent (if applicable) and the contents of the consent will comply with ICH GCP and 
all applicable laws and regulations and will be subject to approval by Vertex or its designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  


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13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers and access to subject names linked to such 
numbers shall be limited to the site and the study physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 
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. 
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 


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 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.  
13.3.1 
Parts A, B, and C 
Data collected during the study, including results from screening, will be recorded in the enrolled 
subject’s CRF. Each CRF book, once completed, will be signed and dated by the investigator. 
13.3.2 
Parts D, E, and F 
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 
Data Capture (Parts A, B, and C) 
A CRF book will be provided for each subject. All appropriate subject data gathered during the 
study will be recorded on these forms. The forms will be filled out with either a black or blue 
ballpoint pen. All corrections will be made by drawing a single line through the error and writing 
the correct information next to the change. All corrections will be initialed and dated. Correction 
fluid will not be used to correct an error. CRFs will be completed for each randomized 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 reporting the CRF data will 


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indicate the subject's participation in the study and will document the dates and details of study 
procedures, AEs, other observations, and subject status. 
13.6 
Electronic Data Capture (Parts D, E, and F) 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator's responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject's 
CRF. Source documentation supporting the CRF data will indicate the subject's participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user's identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a CD or other electronic media will be placed in the investigator's study file. 
13.7 
Publications and Clinical Study Report 
13.7.2 
Clinical Study Report  
A CSR, written in accordance with the ICH E3 Guideline, will be submitted in accordance with 
local regulations. 


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14 
REFERENCES 
 1 
Cystic Fibrosis Foundation. What is cystic fibrosis? Available at: 
http://www.cff.org/AboutCF. Accessed 17 June 2016. 
2 
Cystic Fibrosis Foundation Patient Registry. 2013 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2014. 
3 
European Cystic Fibrosis Society. ECFS Patient Registry: 2010 Annual Report. Karup, 
Denmark: 2014. 
4 
United States Department of Health and Human Services. Food and Drug Administration. 
Office of Orphan Products Development. Developing Products for Rare Diseases & 
Conditions. Available at: 
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.
htm. Accessed 17 June 2016. 
5 
European Medicines Agency [Internet]. Committee for Orphan Medicinal Products 
(COMP). Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_
000263.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e30. 
Accessed 17 June 2016. 
6 
Stern M, Wiedemann B, Wenzlaff P. From registry to quality management: The German 
Cystic Fibrosis Quality Assessment Project 1995-2006. Eur Respir J. 2008;31(1):29-35. 
7 
Cystic Fibrosis Trust. UK Cystic Fibrosis Trust Annual Review 2010. Bromley, Kent, 
UK: Cystic Fibrosis Trust; 2012. 
8  
Flume PA, Van Devanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Med. 2012;10(1):88. 
9  
Cystic Fibrosis Centre at the Hospital for Sick Children in Toronto [Internet]. Cystic 
Fibrosis Mutation Database (CFTR1). Available at: 
http://www.genet.sickkids.on.ca/cftr/StatisticsPage.html. Accessed: 17 June 2016. 
10  
US Cystic Fibrosis Foundation JHU, the Hospital for Sick Children. The Clinical and 
Functional Translation of CFTR (CFTR2). Available at: http://cftr2.org/. Accessed 
24 May 2017. 
13  
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
14  
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. 
 


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 15  
Levey AS, Bosch JP, Lewis JB, Green T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann 
Intern Med. 1999;130(6):461-70. 
16  
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-54. 
19  
US Department of Health and Human Services, Center for Drug Evaluation and Research 
(CDER). FDA guidance for industry: estimating the maximum safe starting dose in initial 
clinical trials for therapeutics in adult healthy volunteers. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ 
Guidances/UCM078932.pdf. Updated 2005. 
20  
Kasichayahula S, Boulton DW, Luo W-L, Rodrigues DA, Yang Z, Goodenough A, et al. 
Validation of 4β-hydroxycholesterol and evaluation of other endogenous biomarkers for 
the assessment of CYP3A activity in healthy subjects. Br J Clin Pharmacol. 
2014;78(5):1122-1134.  
22  
Darpo B, Benson C, Dota C, Ferber G, Garnett C, Green CL, et al. Results from the 
IQ-CSRC prospective study support replacement of the thorough QT study by QT 
assessment in the early clinical phase. Clin Pharmacol Ther. 2015;97(4):326-35. 
23  
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. 
24  
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac 
Soc. 2007;4(4):378-86. 
25  
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. 
26  
Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life 
Res. 2003;12(1):63-76. 


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


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CFTR Mutations Eligible for VX16-445-001, Parts D and F 
Criteria 
Mutation 
 
 
 
 
Truncation mutations  
 %PI >50% and/or 
SwCl- >86 mmol/L 
 no full-length protein  
S4X 
C276X 
G542X 
R792X 
E1104X 
G27X 
Q290X 
G550X 
E822X 
R1158X 
Q39X 
G330X 
Q552X 
W846X 
R1162X 
W57X 
W401X 
R553X 
Y849X 
S1196X 
E60X 
Q414X 
E585X 
R851X 
W1204X 
R75X 
S434X 
G673X 
Q890X 
L1254X 
E92X 
S466X 
Q685X 
S912X 
S1255X 
Q98X 
S489X 
R709X 
Y913X 
W1282X 
Y122X 
Q493X 
K710X 
W1089X 
Q1313X 
E193X 
W496X 
L732X 
Y1092X 
E1371X 
 
L218X 
C524X 
R764X 
W1098X 
Q1382X 
 
Q220X 
Q525X 
R785X 
R1102X 
Q1411X 
Splice mutations  
 %PI >50% and/or 
SwCl- >86 mmol/L 
 no or little mature 
mRNA   
 
185+1G→T 
711+5G→A 
1717-8G→A 
2622+1G→A 
3121-1G→A 
296+1G→A 
712-1G→T 
1717-1G→A 
2790-1G→C 
3500-2A→G 
405+1G→A 
1248+1G→A 
1811+1G→C 
3040G→C 
 (G970R) 
3600+2insT 
405+3A→C 
1249-1G→A 
1811+1.6kbA→G 
3850-1G→A 
406-1G→A 
1341+1G→A 
1812-1G→A 
3120G→A 
4005+1G→A 
621+1G→T 
1525-2A→G 
1898+1G→A 
3120+1G→A 
4374+1G→T 
711+1G→T 
1525-1G→A 
1898+1G→C 
3121-2A→G 
Small (≤3 nucleotide) 
insertion/deletion (ins/del) 
frameshift mutations 
 %PI >50% and/or 
SwCl- >86 mmol/L 
 garbled and/or 
truncated protein 
182delT 
1119delA 
1782delA 
2732insA 
3876delA 
306insA 
1138insG 
1824delA 
2869insG 
3878delG 
365-366insT 
1154insTC 
2043delG 
2896insAG 
3905insT 
394delTT 
1161delC 
2143delT 
2942insT 
4016insT 
442delA 
1213delT 
2183AA→G a 
2957delT 
4021dupT 
444delA 
1259insA 
2184delA 
3007delG 
4040delA 
457TAT→G 
1288insTA 
2184insA 
3028delA 
4279insA 
 
541delC 
1471delA 
2307insA 
3171delC 
4326delTC 
 
574delA 
1497delGG 
2347delG 
3659delC 
 
663delT 
1548delG 
2585delT 
3737delA 
 
 
935delA 
1609del CA 
2594delGT 
3791delC 
 
1078delT 
1677delTA 
2711delT 
3821delT 
Non-small (>3 nucleotide) 
insertion/deletion (ins/del) 
frameshift mutations 
 %PI >50% and/or 
SwCl- >86 mmol/L 
 garbled and/or 
truncated protein 
CFTRdele2,3 
1461ins4 
2991del32 
CFTRdele22,23 
1924del7 
3667ins4 
124del23bp 
2055del9→A 
4010del4 
852del22 
2105-
2117del13insAGAAA 
4209TGTT→AA 
991del5 
2721del11 
 
 
 


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CFTR Mutations Eligible for VX16-445-001, Parts D and F 
Criteria 
Mutation 
 
 
 
 
Class II, III, IV mutations 
not responsive to IVA 
alone or in combination 
with TEZ or LUM  
 
%PI>50% and/or 
SwCl- >86 mmol/L 
AND 
 
Not responsive in vitro 
to IVA alone or in 
combination with TEZ 
or LUM 
A46Db 
V520F 
Y569Db 
N1303K 
 
G85E 
A559Tb 
L1065P 
 
R347P 
R560T 
R1066C 
 
L467Pb 
R560S 
L1077Pb 
 
I507del 
A561E 
M1101K 
 
 
 
 
CFTR: cystic fibrosis transmembrane conductance regulator; IVA: ivacaftor; LUM: lumacaftor; PI: pancreatic 
insufficiency; SwCl-: sweat chloride; TEZ: tezacaftor  
Source: CFTR2.org [Internet]. Baltimore (MD): Clinical and functional translation of CFTR. The Clinical and Functional 
Translation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins University, the Hospital for Sick 
Children. Available at: http://www.cftr2.org/. Accessed 15 February 2016. 
%PI: percentage of F508del-CFTR heterozygous patients in the CFTR2 patient registry who are pancreatic insufficient; 
SwCl-: mean sweat chloride of F508del-CFTR heterozygous patients in the CFTR2 patient registry 
a 
Also known as 2183delAA→G.  
b 
Unpublished data. 
 




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15.2 
Investigator Signature Page 
Protocol #:  VX16-445-001 Version #: 7.0 
Version Date: 
8 August 2017 
Study Title: A Phase 1/2 Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis 
 
 
I have read Protocol VX16-445-001, Version 7.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-445, tezacaftor, ivacaftor, and VX-561 
(CTP-656) and this protocol supplied to me by Vertex Pharmaceuticals Incorporated (Vertex) is 
confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 

SAP_001.pdf: 
 
Statistical Analysis Plan Methods, Version 1.0 06Oct2017 
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Vertex Pharmaceuticals Incorporated 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
 
Statistical Analysis Plan 
 
Methods for Parts A, B and C  
 
 
Protocol Number: VX16-445-001 
A Phase 1/2 Study of VX-445 in Healthy Subjects and 
Subjects With Cystic Fibrosis 
 
Author of SAP: 
 
 
 
Version: 1.0 
Version Date of SAP: Oct 06, 2017 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, MA 02210, USA 
CONFIDENTIAL   
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 


 
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2 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Table of contents .................................................................................................................... 2 
List of Tables.............................................................................................................................. 4 
3 
Introduction............................................................................................................................ 5 
4 
Study Objectives .................................................................................................................... 5 
4.1 
Primary Objectives ........................................................................................................... 5 
4.2 
Secondary Objectives ....................................................................................................... 5 
5 
Study Endpoints ..................................................................................................................... 6 
5.1 
Primary Endpoints ............................................................................................................ 6 
5.2 
Secondary Endpoints ........................................................................................................ 6 
 
 
6 
Study Design ........................................................................................................................... 6 
6.1 
Overall Design .................................................................................................................. 6 
6.2 
Sample Size and Power .................................................................................................... 9 
6.3 
Randomization .................................................................................................................. 9 
6.4 
Replacement ..................................................................................................................... 9 
6.5 
Blinding and Unblinding .................................................................................................. 9 
6.5.1 
Blinding .................................................................................................................... 9 
6.5.2 
Unblinding .............................................................................................................. 10 
8 
Analysis Sets ......................................................................................................................... 11 
8.1 
All Subjects Set .............................................................................................................. 11 
8.2 
Safety Set ........................................................................................................................ 11 
 
 
9 
Statistical Analysis ............................................................................................................... 11 
9.1 
General Considerations .................................................................................................. 11 
9.2 
Background Characteristics ............................................................................................ 13 
9.2.1 
Subject Disposition ................................................................................................. 13 
9.2.2 
Demographics and Baseline Characteristics ........................................................... 13 
9.2.3 
Prior and Concomitant Medications ....................................................................... 14 
9.2.4 
Study Drug Exposure and Compliance .................................................................. 15 
9.3 
Safety Analysis ............................................................................................................... 15 
9.3.1 
Adverse Events ....................................................................................................... 16 
9.3.2 
Clinical Laboratory ................................................................................................. 16 
9.3.3 
Electrocardiogram .................................................................................................. 17 
9.3.4 
Vital Signs .............................................................................................................. 17 
9.3.5 
Physical Examination ............................................................................................. 17 
9.3.6 
Spirometry (Parts B 
) ........................................................................... 17 
9.3.7 
Other Safety Analyses ............................................................................................ 17 
 
 
9.5 
Other Analysis ................................................................................................................ 18 


 
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10 Summary of Interim and IDMC Analyses ........................................................................ 18 
10.1 Summary of Flow of Data for Interim Analysis of Safety Data ..................................... 18 
10.2 Summary of Flow of Data for Continuous ECG Interim Analysis ................................ 18 
10.3 IDMC Analysis ............................................................................................................... 19 
11 References ............................................................................................................................. 19 
12 Appendices............................................................................................................................ 19 
Appendix A 
Schedule of Assessments ................................................................................. 19 
Appendix B:  Details of GLI Equations for Calculating ppFEV1 ......................................... 28 
 
 
 
 
 


 
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List of Tables 
Table 9-1 
Summaries Planned for Safety Data ..................................................................... 16 
Table 12-1 
Study VX16-445-001: Parts A, B, and C, Screening ............................................ 20 
Table 12-2 
Study VX16-445-001: Part A, Cohorts A1 Through A6, Treatment Period and 
Safety Follow-up Visit .......................................................................................... 21 
Table 12-3 
Study VX16-445-001: Part A, Cohort A7, Treatment Period and Safety Follow-up 
Visit ....................................................................................................................... 22 
Table 12-4 
Study VX16-445-001: Part B, Treatment Period and Safety Follow-up Visit ..... 24 
Table 12-5  
Study VX16-445-001: Part C, Treatment Period and Safety Follow-up Visit ..... 26 
 
 
 


 
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3 
INTRODUCTION 
The statistical analysis plan (SAP) describes the statistical methods to be used for the interim 
analyses of safety data to support the preparation of regulatory submissions, and the final 
analysis and reporting of data collected under the approved clinical study protocol VX16-445-
001 (Version 7.0 dated 08Aug2017), and approved case report forms (CRFs) (Version 1.0 dated 
18Jan2017 for Part A (Cohort A1-A6, A8 and A9), Version 2.0 dated 03Apr2017 for Part A 
(Cohort A7), Version 3.0 dated 13Feb2017 for Part B, Version 1.0 dated 10Apr2017 for Part C). 
This SAP addresses the safety objectives of the study and describes the planned safety statistical 
analyses and data presentations only for Parts A, B and C. All analyses and data presentations 
will be generated by Tigermed Clinical Research Limited, Biometrics group, using SAS® 
Version 9.4 software (SAS Institute, Cary, North Carolina, USA). This SAP will be finalized and 
approved before the data cut for the interim analyses. Any changes made to the SAP for the final 
analysis will be finalized and approved before the clinical database lock, and any changes made 
to the SAP after the clinical database lock will be documented and discussed in the clinical study 
report for this study. 
4 
STUDY OBJECTIVES 
4.1 
Primary Objectives 
Part A 
To evaluate the safety and tolerability of single ascending doses of VX-445 in healthy subjects 
Part B 
To evaluate the safety and tolerability of multiple ascending doses of VX-445 administered in 
healthy subjects 
Part C 
To evaluate the safety and tolerability of multiple doses of VX-445 in triple combination (TC) 
with tezacaftor (TEZ) and ivacaftor (IVA) for 14 days in healthy subjects 
4.2 
Secondary Objectives 
Part A 
 
To evaluate the PK of VX-445 after administration of single ascending doses of VX-445 
in healthy subjects 
 To evaluate the effect of food on VX-445 PK in healthy subjects 
 To evaluate the absolute bioavailability (BA) of VX-445 when administered orally 
relative to intravenous (IV) administration in healthy subjects 
Part B  
To evaluate the PK of VX-445 after multiple ascending doses of VX-445 administered to healthy 
subjects 
Part C  


 
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 To evaluate the PK of VX-445 after multiple ascending doses of VX-445 in TC with TEZ 
and IVA for 14 days in healthy subjects 
 To evaluate the PK of TEZ and metabolites (M1-TEZ and M2-TEZ), and IVA and 
metabolites (M1-IVA and M6-IVA) after administration in TC with VX-445 for 14 days in 
healthy subjects 
5 
STUDY ENDPOINTS 
5.1 
Primary Endpoints 
Safety and tolerability based on the assessment of adverse events (AEs), clinically significant 
laboratory test results, standard 12-lead electrocardiograms (ECGs), vital signs, and spirometry 
(Parts B and C only). 
5.2 
Secondary Endpoints 
Parts A and B:  
PK parameter estimates of VX-445 derived from plasma concentration-time data 
Part C: 
 PK parameter estimates of VX-445 derived from plasma concentration-time data 
 PK parameter estimates for TEZ and metabolites (M1-TEZ and M2-TEZ), and IVA and 
metabolites (M1-IVA and M6-IVA) derived from plasma concentration-time data 
6 
STUDY DESIGN 
6.1 
Overall Design 
This is a first-in-human study of VX-445. Approximately 120 healthy subjects will be enrolled 
for Parts A, B, and C.  
No subject will be allowed to randomize to more than 1 dose cohort. 
Parts A, B, and C are randomized, double-blind, placebo-controlled, single- and multiple-dose 
parts in healthy subjects of this first-in-human study of VX-445. Part A also includes an 
evaluation of the effect of food on VX-445 PK and an evaluation of absolute BA. Part C doses 
VX-445 in TC with TEZ/IVA. 
There is no pre-specified ratio of males to females, but reasonable effort will be made to enroll 
females of non-childbearing potential in all dosing cohorts.  
A schematic of the study design for Parts A, B, and C is shown in Table 6-1.  
Number of Cohorts 
In Parts A and B, 6 dose escalation cohorts are planned, although fewer than 6 or up to 
2 additional cohorts may be enrolled in each part, based on data from previous cohorts. The 
additional cohorts will follow the corresponding schedule of assessments. In Part C, 2 cohorts are 


 
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planned, while fewer or up to 2 additional cohorts each may be enrolled based on data from 
previous cohorts. The decision to initiate successive cohorts and dose selection will be based on 
safety, tolerability, and available PK data from preceding cohort(s). Refer to Section 9.7.1 of the 
protocol for dose escalation criteria and Section 9.8.1 of the protocol for stopping criteria. 
Staggering of Dosing 
In Cohort A1 (first single dose cohort) and in Cohort C1 (first TC cohort), dosing will be 
staggered so that 2 subjects are dosed (Cohort A1: 1 with VX-445 and 1 with placebo; 
Cohort C1: 1 with TC and 1 with triple placebo) at least 24 hours before the remaining 6 subjects 
in each cohort. Doses may be staggered in other cohorts if deemed necessary based on review of 
emerging safety data. 
Timing of Part B and C Initiation 
Part B may be initiated while Part A is ongoing after review of safety, tolerability, and PK data. 
Part C may be initiated while Parts A and B are ongoing after review of safety, tolerability, and 
PK data.  
Starting Dose in Parts B and C 
Information about the starting doses of Cohorts B1 and C1 can be found in Table 6-1 and Section 
9.3.2.1 of the protocol. 
Table 6-1 
Study Design for Parts A, B, and C 
Part A: Single-dose escalation of VX-445  
Cohorts A1 to A6: 8 subjects per cohort, randomized 3:1 (VX-445:placebo). Planned doses are shown; doses may be 
modified upward or downward based on emerging data.  
Cohort A7: 8 subjects. VX-445 tablet dose is TBD, pending PK data from previous Part A cohorts, but will not 
exceed the highest dose that was safe and well tolerated. The planned IV dose is 20 mg. 
No dose increment will be predicted to yield greater than a 3-fold increase (Cohorts A1 through A3) or a 2-fold 
increase (all other Part A cohorts except Cohort A7) in exposure from the preceding dose level. 
 
Planned Dose 
Cohort A1 
20 mg  
 
 
 
 
 
Cohort A2 
 
60 mg 
 
 
 
 
Cohort A3 
 
 
120 mg 
 
 
 
Cohort A4 
 
 
 
240 mg 
 
 
Cohort A5 
 
 
 
 
480 mg 
 
Cohort A6 
 
 
 
 
 
800 mg 
 
 
 
 
 
 
 
Cohort A7 (open label VX-445, single sequence)a 
 
 
≥6-day  
Washout 
Day 7: 
Tablet, fed 
(TBD) 
Dosing Period 1 
Dosing Period 2 
Day 1: 
Tablet, fasted 
(TBD)  
Dosing Period 3 
Day 13: 
IV, fed 
(20 mg) 
≥6-day  
Washout 


 
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Table 6-1 
Study Design for Parts A, B, and C 
Part B: Multiple-dose escalation of VX-445  
8 subjects per cohort, randomized 3:1 (VX-445:placebo) 
The total daily dose in Cohort B1 will be at least 1 dose level below the highest Part A dose for which safety, 
tolerability, and PK results are available and that is safe and well tolerated. 
 
Planned Dosage (qd or q12h, 10 days) 
Cohort B1 
TBD 
 
 
 
 
 
Cohort B2  
 
TBD 
 
 
 
 
Cohort B3 
 
 
TBD 
 
 
 
Cohort B4 
 
 
 
TBD 
 
 
Cohort B5 
 
 
 
 
TBD 
 
Cohort B6 
 
 
 
 
 
TBD 
 
 
 
 
 
 
 
Part C: Multiple-dose escalation of VX-445 in TC with TEZ/IVAb 
8 subjects per cohort, randomized 3:1 (VX-445/TEZ/IVA:triple placebo) 
The starting dose for Part C (Cohort C1) will be at least 1 dose level below the highest Part B dose for which 
safety and tolerability results are available and supportive. 
 
Planned Dosage (qd or q12h, 14 days) 
Cohort C1 
TBD 
 
 
 
 
 
Cohort C2 
 
TBD 
 
 
 
 
 
 
 
 
 
 
 
CRU: clinical research unit; IV: intravenous; IVA: ivacaftor; PK: pharmacokinetic; q12h: every 12 hours; qd: once 
daily; TBD: to be determined; TC: triple combination (VX-445/TEZ/IVA); TEZ: tezacaftor 
Note: Dose escalation criteria are described in Section 9.7.1 of the protocol, and dose escalation will be stopped 
when the predefined stopping criteria is met (see Section 9.8.1of the protocol). 
a 
The Washout Period is a minimum of 6 days and may be increased as needed based on emerging data from 
earlier cohorts (Cohorts A1 through A6). Subjects in Cohort A7 will receive a single dose of VX-445 on up to 
3 dosing occasions. VX-445 doses include 2 single oral doses of tablet (dose TBD, pending PK data from 
previous Part A cohorts, but will not exceed the highest dose that was safe and well tolerated) and a single IV 
dose (the planned dose is 20 mg, but may be adjusted pending data from previous Part A cohorts; however, the 
final selected dose will not be predicted to exceed the highest exposure that was safe and well tolerated). If the 
IV formulation or the data supporting the use of the IV formulation are not available, then the third dosing 
period, in which subjects receive the IV dose, will not be conducted. If the IV dose is not administered, subjects 
will be discharged from the CRU on Day 13 after completing all study visit assessments and will return for a 
Safety Follow-up Visit (Table 12-3). 
b 
The dosage of TEZ/IVA will be TEZ 100 mg qd/IVA 150 mg q12h which will be administered as TEZ 
100-mg/IVA 150-mg FDC in the morning and IVA 150 mg in the evening. 
 
 


 
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6.2 
Sample Size and Power 
No formal sample size calculations have been performed. The number of subjects participating in 
each cohort is common in early clinical pharmacology studies and is considered sufficient to 
achieve the objectives of the study. 
6.3 
Randomization 
A randomization list for each part will be produced by Vertex Biostatistics or a qualified 
randomization vendor. The Vertex study biostatistician will review and approve the dummy 
randomization list. The final randomization list will be reviewed and approved by a designated 
unblinded biostatistician who is not a member of the study execution team (SET).  
Only subjects who have completed screening assessments and are eligible for participation in the 
study will be randomized to receive active study drug or placebo. Randomized subjects will be 
assigned a unique subject number. A list identifying subjects by their subject number will be 
maintained in the study file at the CRU. 
6.4 
Replacement 
Subjects who withdraw or are withdrawn before the first dose of study drug on Day 1 for each 
part may be replaced. 
Subjects who withdraw or are withdrawn for non-safety reasons during the study drug treatment 
periods may be replaced at Vertex’s discretion. 
6.5 
Blinding and Unblinding 
This will be a double-blind study with the exception of Cohort A7, which will be open-label. 
6.5.1 
Blinding 
Blinding of subject treatment assignments will be maintained until database lock. The packaging 
and labeling of study drug will be done to ensure that treatment assignments are blinded within 
each cohort in all parts of the study. 
During the conduct of the study, all study personnel will be blinded to subject treatment 
assignments except for 
 the unblinded site monitor; 
 Bioanalytical CRO analyzing PK samples and Vertex Bioanalytical personnel who is not a 
member of the SET but reviews raw data from Bioanalytical CRO. The Vertex Bioanalytical 
SET member will continue to be blinded; 
 vendor preparing the unblinded statistical and PK/PD analysis of continuous ECG data 
collected in Part A(with the exception of Cohort A7); 
 the unblinded biostatistician preparing the randomization list as well as an unblinded quality 
control (QC) biostatistician; 
 the dispensing contracted pharmacist; 
 the pharmacy QC/quality assurance  personnel, as applicable; and 
 Vertex GPS and Regulatory Affairs, when required to satisfy regulatory reporting 
requirements. 


 
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The Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time. 
A limited Vertex team, which may include members of the Vertex SET, may be unblinded to 
individual subject treatment assignments for the purposes of review of PD, PK/PD, and/or safety 
data. No unblinded data or results of unblinded analyses will be shared with the clinical research 
unit or with blinded Vertex personnel. All instances of unblinding by Vertex personnel will be 
documented. 
Bioanalytical results (i.e., concentrations of VX-445) will be reported by the bioanalytical CRO 
using masked identification numbers  for PK analysis. 
6.5.2 
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 Individual Subject Treatment Assignments by Investigator for Medical 
Emergencies or Urgent Clinical Situations 
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the medical monitor, they will use their best 
judgment, based on the nature and urgency of the clinical situation, and may proceed with 
unblinding without having successfully reached and discussed the situation with the medical 
monitor. In case of emergency, the investigator will have the final decision and unilateral right 
for unblinding. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center (
) will answer calls 24 
hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study medical 
monitor or appropriate backup. 
If a subject's treatment assignment has been unblinded for a medical emergency or urgent clinical 
situation, the medical monitor will be notified within 24 hours of the unblinding event. The 
reason and the date of the unblinding will be documented clearly in the subject's study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with the sponsor (Vertex), CRO, or 
any site personnel (other than the physician treating the subject). In addition, the investigator will 
consider whether the clinical event that prompted unblinding will be considered a serious 
adverse event (SAE), according to the regulatory definitions or criteria for SAEs, and if so, 
submit an SAE report to GPS or designee, per Section 13.1.2 of the protocol. 
Unblinding of Individual Subject Treatment Assignments by Vertex GPS or Designee for 
SAEs or Safety Concerns 


 
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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.  
Unblinding: Interim Analysis Results 
When an IA is performed after all subjects in Part C have completed the Safety Follow-up Visit, 
results from Parts A, B, and C will be unblinded for full review by the Vertex study team. 
8 
ANALYSIS SETS 
8.1 
All Subjects Set 
The All Subjects Set is defined as all subjects who were randomized or received at least 1 dose 
of study drug. The All Subjects Set will be used for individual subject data listings, and the 
disposition summary table, unless specified otherwise. 
8.2 
Safety Set 
The Safety Set will include all subjects who received at least 1 dose of study drug. All safety, 
demographics, baseline characteristics, study drug exposure, and concomitant medications will 
be summarized for the Safety Set. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Appendix A. 
The precision standards for reporting safety variables are provided in an internal Biometrics 
document that specifies the programming rules including the precision for derived variables. 
Continuous data will be summarized using the following descriptive summary statistics: the 
number of subjects (n), mean, standard deviation (SD), standard error (SE), median, minimum 
value (min), and maximum value (max). Unless otherwise specified, minimum and maximum 


 
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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 data will be summarized using frequency counts and percentages. Percentages will 
be presented to 1 decimal place. 
Treatment Emergent (TE) Periods:  
For subjects included in all cohorts in Parts A (except Cohort A7), B and C, One single TE 
period will begin from the initial administration of study drug through the Safety Follow-up 
Visit.  
Treatment Groups 
The Treatment Groups in Part A (excluding Cohort A7), Parts B and C will be defined as the 
corresponding dose groups. 
For subjects participating in Cohort A7 in Part A, 3 TE periods will be analyzed: 
 TE Period 1 (tablet [fasted]) will begin from the initial administration of study drug on 
Day 1 until the administration of study drug on Day 7.  
 TE Period 2 (tablet [fed]) will begin from the initial administration of study drug on 
Day 7 until the administration of study drug on Day 13.  
 TE Period 3 (IV [fed]) will begin from the initial administration of study drug on Day 13 
through the Safety Follow-up Visit.  
 The 3 Treatment Groups in Cohort A7 will correspond to tablet [fasted], tablet [fed] 
and IV [fed] respectively. 
Baseline value: 
The baseline value will be defined as the most recent non-missing measurement (scheduled or 
unscheduled) collected before the first administration of study drug on Day 1. If a pre-dose 
measurement is missing and no drug-free unscheduled assessments are performed before the first 
dose of the study, the baseline will be missing. 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. 
For Cohort A7   
The baseline value will be defined as the most recent non-missing measurement collected before 
the initial administration of study drug on Day 1.  If the pre-dose measurement is missing and no 
drug-free unscheduled assessments are performed before the first dose of study drug, the baseline 
value will be determined to be missing. 
Change from baseline value will be defined as change from baseline at each scheduled post-
baseline time point. The change from baseline value will be calculated as the post-baseline value 
minus the baseline value.  


 
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Visit Window: As the majority of assessments are predicted to be on schedule, visit windows 
will not add significant value to the analysis and will not be applied. 
Unscheduled visits: Subject data obtained during unscheduled visits will not be summarized but 
will be included in subject data listings only, except for the ECG analysis of the maximum 
values during TE period and maximum changes from baseline in QT/QTcF intervals during TE 
period (see Protocol Section 11.7.5). Unscheduled visit values will not be used to impute missing 
scheduled visit values, except for baseline calculation. 
Incomplete/missing data (e.g., dates, post-baseline values) will not be imputed, unless 
otherwise specified; i.e., all missing values and missing post-baseline values will remain as 
missing in all statistical analyses and listings, unless otherwise specified. 
Outliers: No formal statistical analyses will be performed to detect and/or remedy the presence 
of statistical outliers. 
Hypothesis testing: No statistical hypothesis testing will be performed.  
All subject level data, including those derived, will be presented in the individual subject data 
listings; listings will be based on the All Subjects Set. 
Unless otherwise specified, the analyses will be done by Treatment Group in all cohorts for Parts 
A, B and C. Separate summary tables will be produced for each part. 
- Part A (Cohorts A1 through A5): Placebo, VX-445 20 mg, VX-445 60 mg, VX-445 120 mg,  
VX-445 240 mg, VX-445 360 mg, and VX-445 Total. The dose levels are subject to change to 
reflect the real dose levels.  
- Part A (Cohort A7): tablet [fasted] 100 mg, tablet [fed] 100 mg and IV [fed] 20 mg. 
- Part B: Placebo, VX-445 60 mg QD, VX-445 120 mg QD, VX-445 240 mg QD, VX-445 340 
mg QD and VX-445 Total.  
- Part C: Triple Placebo, VX-445 200 mg QD + TEZ/IVA, VX-445 280 mg QD + TEZ/IVA, 
VX-445 100 mg QD + TEZ/IVA and VX-445 + TEZ/IVA Total. 
9.2 
Background Characteristics 
9.2.1 
Subject Disposition 
Disposition summary will be based on the All Subjects Set. 
The number and percentage of subjects in each disposition category (randomized; included in the 
Safety Set; PD set; completed dosing; completed study; discontinued treatment for Cohort A7 
and for all cohorts in Parts B and C, and discontinued study with a breakdown of the reasons for 
early discontinuation, when applicable) will be summarized overall and by Treatment Group for 
Parts A (Cohorts A1 through A6), B and C, and by treatment sequence for Cohort A7. 
9.2.2 
Demographics and Baseline Characteristics 
Demographics, medical history and baseline characteristics summary will be based on the Safety 
Set. 
Demographics and baseline characteristics (age, sex, race, ethnicity, weight, height, BMI, 
medical history, baseline spirometry [Parts B and C] 
 will 


 
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be summarized overall and by Treatment Group for Parts A (Cohorts A1 through A6),B and C, 
and by sequence for Cohort A7. 
No statistical tests will be done to evaluate baseline imbalances between groups. 
9.2.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization-Drug Dictionary Enhanced 
(WHO-DDE) 1st March 2016, Format B2 or higher. Medications used in the study will be 
categorized as prior and/or concomitant medications as follows: 
1. Prior medication: Medication that started before the first dose of study drug, regardless 
of when dosing of the medication ended 
2. Concomitant medication: Medication received at or after the first dose of study drug, 
medication that was received before initial dosing and continued after initial dosing of 
study drug, or medication with missing stop date 
If a medication start date is on or after the date of initial dosing of the study drug, then the 
medication will be summarized as concomitant medication regardless of whether the medication 
end date is missing or not. If a medication end date is before the date of initial dosing of the 
study drug, then the medication will be summarized as prior medication regardless of whether 
the medication start date is missing or not. Note that medication that started before initial dosing 
of the study drug and continued after initial dosing will be summarized as prior medication and 
separately as concomitant medication. 
Missing or partial dates will be imputed for medication. Algorithm for missing or partial start 
date is: 
Missing day: first day of the month is imputed; 
Missing month: January is imputed; 
Missing year: not imputed. 
Algorithm for missing or partial end date is: 
Missing day: last day of the month is imputed; 
Missing month: December is imputed (31 December if day is also missing); 
Missing year: not imputed. 
Missing data algorithms will be reviewed to ensure the algorithm works. For example, end date 
will not be before the start date after the imputation.  
For Cohort A7, concomitant medications will be assigned to each TE period based on the start 
date of the medication and the study drug administration dates (concomitant medications taken 
during the TE period will be assigned to the TE period, and so forth). 
Note that a concomitant medication may be assigned to multiple TE periods. 
Prior medications will not be summarized, but will only be listed. Concomitant medications will 
be summarized using preferred name by Treatment Group and overall for all cohorts in Parts A 
(except for Cohort A7), B and C, and by Treatment Group only for Cohort A7. Concomitant 
Medications summary will be based on the Safety Set. 


 
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9.2.4 
Study Drug Exposure and Compliance 
Study drug exposure (i.e., duration of treatment) will be summarized by Treatment Group and 
overall for all cohorts in Parts B and C for the Safety Set.  
Study drug exposure (in days) will be defined as (last date of dosing – first date of dosing) + 1. 
The study drug administration will be presented in an individual subject listing for Parts A, B 
and C. 
9.3 
Safety Analysis 
Safety is the primary objective of this study. The overall safety profile of VX-445 will be 
assessed in terms of the following primary (safety) endpoints: 
 Incidence of treatment-emergent adverse events (TEAEs) 
 Clinical laboratory values (including coagulation studies) 
 ECG outcomes 
 Vital signs 
 Spirometry (Parts B and C only) 
Safety analyses will be performed by Treatment Group and overall for all cohorts in Parts A 
(except for cohort A7), B and C, and by Treatment Group only for Cohort A7. Safety analysis 
will be conducted for the Safety Set. Safety data will be presented in the individual subject data 
listings based on the All Subjects Set. Only descriptive analysis of safety will be performed (i.e., 
no statistical hypothesis testing will be performed). 
Table 9-1 shows the safety summaries (e.g., raw value, change from baseline, incidence, and 
clinical abnormalities) that will be summarized for TEAEs, clinical laboratory values, 12-lead 
ECG, vital signs, spirometry (Parts B and C), and physical examination. Details are provided in 
the corresponding subsections.  
The incidence of TEAEs will be summarized. TEAE summaries will include the following: all 
TEAEs (regardless of severity or relationship to study drug), serious adverse events (SAEs), 
TEAE severity, TEAE relationship, and discontinuations of study drug treatment due to TEAEs. 
For the non-AE safety evaluations (clinical laboratory, spirometry, ECGs and vital signs), raw 
values, and changes from baseline will be summarized as indicated in Table 9-1. For example, an 
“X” under the raw value column (second column) means that the raw values for the safety 
evaluation will be summarized; an “X” under the Change column (third column) means that 
change will be summarized.  
Throughout this section, “change” refers to absolute change from baseline. 


 
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Table 9-1 
Summaries Planned for Safety Data 
Safety Assessment 
Incidence 
Raw Value 
Change 
Clinical Abnormalities 
TEAEs 
X 
 
 
Not applicable 
Hematology and 
chemistry  
 
X 
X 
Present in listing only 
Coagulation 
 
Present in listing only 
 
Present in listing only 
Urinalysis 
 
Present in listing only 
 
Present in listing only 
12-lead ECG 
 
X 
X 
Present in listing only 
Vital signs 
 
X 
X 
Not applicable 
Spirometry (Parts 
B and C) 
 
X 
X 
Not applicable 
Physical 
Examination 
 
Present in listing only 
 
Not applicable 
ECG: electrocardiogram; TEAEs: treatment-emergent adverse events; X: safety assessment will be summarized in 
tables. 
9.3.1 
Adverse Events 
AEs will be coded according to MedDRA (Version 19.1 or above). The number and percentage 
of subjects experiencing an AE will be summarized by the MedDRA System Organ Class (SOC) 
and Preferred Term (PT). AEs will be classified as pretreatment or treatment-emergent. 
Pretreatment AEs are defined as AEs that were reported or worsened after signing the ICF up 
to the start of study drug dosing. 
Treatment-emergent adverse events (TEAEs) for all cohorts except Cohort A7 are defined as 
AEs that started or worsened on or after the start of study drug dosing within the TE Period. 
For Cohort A7, TEAEs will be assigned to each Treatment Group based on the start date of the 
AE and the start of study drug administration dates within the corresponding TE Period.  
AE summary tables will be presented for TEAEs only and will include the following: (1) all 
TEAEs; (2) related (defined as possibly related, related, or unknown) TEAEs; (3) serious 
TEAEs; (4) TEAEs by severity; (5) TEAEs by relationship; and (6) TEAEs leading to treatment 
discontinuation. Summaries will be presented by MedDRA SOC and PT using frequency counts 
and percentages by Treatment Group and overall for each part. A subject with multiple 
occurrences of the same TEAE or a continuing TEAE will be counted only once under the 
highest reported severity and relationship. In addition, a listing containing individual subject AEs 
leading to death, SAEs, dose interruption, and permanent discontinuation will be listed 
separately. All AEs will be presented in individual subject data listings. 
9.3.2 
Clinical Laboratory 
All statistical analyses of laboratory values will be performed using SI units. Continuous 
hematology and chemistry results including baseline and change from baseline values will be 
summarized at each scheduled time point by Treatment Group and overall for Parts A (except 
Cohort A7), B and C, and by Treatment Group only for Cohort A7 using descriptive statistics. 
In addition, a listing containing individual subject hematology, coagulation and chemistry values 
outside the normal reference ranges will be provided. This listing will include data from 
scheduled and unscheduled time points.  


 
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Urinalysis results will only be listed in individual subject data listings and will not be 
summarized.  
Clinically significant abnormal findings will be reported as AEs.  
9.3.3 
Electrocardiogram 
A summary of raw values and change from baseline values will be provided for each scheduled 
time point by Treatment Group and overall for Parts A (except Cohort A7), B and C, and by 
Treatment Group only for Cohort A7 during the TE Period for the following 12-lead ECG 
measurements using descriptive statistics: PR, RR, QT, QRS, and QTc intervals and heart rate. 
In addition, the number and percentage of subjects by maximum value of QT/QTc intervals 
during the TE period, categorized as ≤450 msec, >450 msec and ≤480 msec, >480 msec and 
≤500 msec, and >500 msec, as well as maximum change from baseline value of QT/QTc 
intervals during the TE period, categorized as ≤0 msec, >0 msec and ≤30 msec, >30 msec and 
≤60 msec, and >60 msec will be tabulated based on scheduled and unscheduled 12-lead ECG 
measurements.  
Clinically significant abnormal findings will be reported as AEs. 
9.3.4 
Vital Signs 
A summary of raw values and change from baseline values will be provided for each scheduled 
time point by Treatment Group and overall for Parts A (Cohorts A1 through A6), B and C, and 
by Treatment Group only for Cohort A7 using descriptive statistics for the following vital signs 
measurements: systolic and diastolic blood pressure (mm Hg), body temperature (°C), pulse rate 
(beats per minute), and respiratory rate (breaths per minute). 
Clinically significant abnormal findings in vital signs will be reported as AEs. 
9.3.5 
Physical Examination 
PE results will be presented in individual subject data listings only. Clinically relevant changes 
identified after screening will be reported as AEs. 
9.3.6 
Spirometry (Parts B and C Only) 
The spirometry assessment will be administered in Part B and C only. A summary of raw values 
and change from baseline values will be provided for each scheduled time point by Treatment 
Group and overall for all cohorts in Parts B and C. The following spirometry parameters of FEV1 
(L) and ppFEV1, FVC (L) and ppFVC, FEV1/FVC (ratio) and ppFEV1/FVC as well as FEF25%-
75% (L/s) and ppFEF25%-75% will be summarized using descriptive statistics. 
In addition, a listing containing individual subject data with scheduled and unscheduled time 
points will be provided. 
9.3.7 
Other Safety Analyses 
Not applicable. 


 
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9.5 
Other Analysis 
Not applicable. 
10 
SUMMARY OF INTERIM AND IDMC ANALYSES 
Separate interim analyses of safety data may be performed after  
 all subjects in Cohort C1 have completed the Safety Follow-up Visit;  
 all subjects in Cohort C2 have completed the Safety Follow-up Visit;  
The interim analyses might be blinded or unblinded depending on the decision of VX-445 Study 
Team. If an unblinded interim analysis is decided,   the unblinded results will be reviewed by a 
limited unblinded Vertex group not involved in the conduct of the study.  
Continuous ECG  
An interim analysis of the continuous ECG data may be performed after all subjects in Part A 
(with the exception of Cohort A7) have completed the Safety Follow-up Visit. These results will 
be reviewed by a small unblinded Vertex team not involved in the conduct of the study. 
The analysis of the continuous ECG data will be performed 
 The 
analysis plan was documented in the SAP for the continuous ECG, version 1.0, dated 17 May 
2017. 
An interim analysis for Parts A, B, and C may be performed after all subjects in Part C have 
completed the Safety Follow-up Visit. The results of this analysis will be unblinded for full 
review by the Vertex study team. 
10.1 
Summary of Flow of Data for Interim Analysis of Safety Data 
To protect the integrity of the treatment assignment and study data, the following steps for the 
flow of data will be executed for the interim analyses: 
1. The unblinded Biometrics group 
, will download 
the treatment codes directly 
;  
2.
 will generate the unblinded outputs (tables, figures and listings) and upload 
 
 for retrieval by the limited unblinded Vertex team. 
10.2 
Summary of Flow of Data for Continuous ECG Interim Analysis  
To protect the scientific integrity of the treatment assignments, the following steps for the flow 
of continuous ECG data will be executed for the interim analysis: 


 
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1. 
 will access the password-protected production randomization 
data from a Vertex Biometrics 
; 
2. 
 with the 
password to open the production randomization data file; 
3. 
 will generate the unblinded outputs (tables and figures) for 
review by a limited unblinded Vertex group. 
10.3 
IDMC Analysis 
Not applicable. 
11 
REFERENCES 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. 
EurRespir J. 2012; 40 (6):1324-43. 
12 
APPENDICES 
Appendix A Schedule of Assessments 
Schedules of Assessments are shown in Table 12-1 (Screening, Parts A through C), Table 12-2 
(Part A, Cohorts A1 through A6), Table 12-3 (Part A, Cohort A7), Table 12-4 (Part B), and 
Table 12-5 (Part C). 
 


 
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Table 12-1 
Study VX16-445-001: Parts A, B, and C, Screening 
Event/Assessment 
Screening Visit 
Day -28 to Day -2 
Informed consent  
X 
Demographics 
X 
Medical history 
X 
Medications reviewa 
X 
Height, weight, BMI, and vital signsb 
X 
Full PE 
X 
Standard 12-lead ECGc 
X 
Serum FSH (suspected postmenopausal female 
subjects only) 
X 
Serum β-hCG (all female subjects) 
X 
Serology (HBsAg, HCV, HIV-1 and HIV-2 Abs, and 
p24 antigen) 
X 
G6PD activity testd 
X 
Serum chemistrye 
X 
Hematologye 
X 
Coagulatione 
X 
Drug test (urine or blood), including cotinine  
X 
Alcohol test (urine, blood, or breath) 
X 
Urinalysis 
X 
Spirometry (Parts B and C only) 
X 
AEs 
Continuous from signing of ICF through Safety Follow-up 
Visit 
AE: adverse event; β-hCG: beta-human chorionic gonadotropin; BMI: body mass index; ECG: electrocardiogram; 
FSH: follicle-stimulating hormone; G6PD: glucose-6-phosphate dehydrogenase; HBsAg: hepatitis B surface 
antigen; HCV: hepatitis C virus; HIV-1/HIV-2 Abs: antibodies against human immunodeficiency viruses 1 
and 2; ICF: informed consent form; PE: physical examination 
 a  
All medications taken within 28 days before the first dose of study drug through the end of the study will be 
recorded. 
b  
Weight and height will be measured with shoes off. Vital signs will be performed after the subject has been 
seated for at least 5 minutes. 
c  
A standard 12-lead ECG will be performed after the subject has been seated or supine for at least 5 minutes 
(Section 11.7.5.1 of the protocol). 
d 
A single blood sample will be collected from all subjects for the G6PD activity test. 
e 
Following at least a 4-hour fast, blood samples will be collected for clinical laboratory assessments. 


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Table 12-2 
Study VX16-445-001: Part A, Cohorts A1 Through A6, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety Follow-up Visit 
(7 to 10 days After Last 
Dose of Study Drug) 
 -1 
 1 
 2 
 3 
 4 
 5 
Inpatient days 
X 
X 
X 
X 
X 
Xb 
 
Outpatient visit 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
Weightc 
X 
 
 
 
 
 
 
Continuous ECGsd 
 
X 
X 
 
 
 
 
Standard 12-lead ECGe 
X 
X 
 
 
 
 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
Full PE 
X 
 
 
 
 
 
X 
Serum chemistry 
X 
 
X 
 
 
 
X 
Hematology 
X 
 
X 
 
 
 
X 
Blood for PK analysisg 
 
X 
X 
X 
X 
X 
 
Drug test (urine or blood), including cotinine 
X 
 
 
 
 
 
 
Alcohol test (urine, blood, or breath) 
X 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
X 
Study drug administrationh 
 
X 
 
 
 
 
 
AEs 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications reviewi 
Continuous from signing of ICF through Safety Follow-up Visit 
AE: adverse event; CRU: clinical research unit; ECG: electrocardiogram; ICF: informed consent form; PE: physical examination; PK: pharmacokinetic 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise. 
b  
Subjects will be discharged from the CRU on Day 5 after completion of the study visit assessments. 
c 
Weight will be measured with shoes off. 
d  
Continuous ECGs will be extracted in up to 10 replicates on Day 1 before dosing (at -60, -50, and -40 minutes) and at 1, 2, 3, 4, 6, 8, 12 and 24 hours 
(Day 2) after dosing. Subjects should be supine or semi-recumbent for at least 15 minutes before these time points. 
e  
Standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On Day 1, ECGs will be collected before dosing 
and approximately 1, 3, 5, and 6 hours (± 15 min) after dosing.  
f  
Vital signs will be performed after the subject has been seated for at least 5 minutes. 
g  
Blood samples for PK assessments will be collected on Day 1 before dosing (0 hours) and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Day 2), 36 (Day 2), 
48 (Day 3), 72 (Day 4), and 96 (Day 5) hours after dosing. Acceptable PK sampling windows are provided in Table 11-1 of the protocol.  
h  
Study drug will be administered in the fed state. Details are provided in Section 9.6.1.1 of the protocol. 
i  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 


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Table 12-3 
Study VX16-445-001: Part A, Cohort A7, Treatment Period and Safety Follow-up Visit 
Event/ 
Assessmenta 
Study Day 
Safety Follow-up Visit 
(7 to 10 Days After Last Dose of 
Study Drug) 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14b 
15b 
16b 
17b 
Inpatient days X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
X 
X 
X 
Xd 
 
Outpatient 
visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weighte 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
12-lead ECGf 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full PE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum 
chemistry 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Hematology 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise. 
b 
If data to support use of the IV dose is not available, Dosing Period 3 will not be conducted and assessments on Days 14 to 17 will not be performed. 
c 
Subjects will be discharged from the CRU on Day 13 after completion of the study visit assessments if Dosing Period 3 is not conducted. 
d 
Subjects will be discharged from the CRU on Day 17 after completion of the study visit assessments. 
e 
Weight will be measured with shoes off. 
f  
Standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On Days 1, 7 and 13, ECGs will be collected 
before dosing and approximately 1, 3, 5, and 6 hours (± 15 min) after dosing. 
g  
Vital signs will be performed after the subject has been seated for at least 5 minutes. 


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Table 12-3 
Study VX16-445-001: Part A, Cohort A7, Treatment Period and Safety Follow-up Visit 
Event/ 
Assessmenta 
Study Day 
Safety Follow-up Visit 
(7 to 10 Days After Last Dose of 
Study Drug) 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14b 
15b 
16b 
17b 
Blood for PK 
analysish 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
X 
X 
X 
 
Drug test 
(urine or 
blood), 
including 
cotinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol test 
(urine, blood, 
or breath) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Study drug 
adminstrationj 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Xk 
 
 
 
 
 
AEs 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications 
reviewl 
Continuous from signing of ICF through Safety Follow-up Visit 
AE: adverse event; CRU: clinical research unit; ECG: electrocardiogram; ICF: informed consent form; IV: intravenous; PE: physical examination; 
PK: pharmacokinetic  
 h 
Blood samples for PK assessments will be collected on Days 1 and 7 before dosing (0 hours) and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Days 2, 8), 36 (Days 2, 
8), 48 (Days 3, 9), 72 (Days 4, 10), 96 (Days 5 and 11), and 120 (Days 6 and 12) hours postdose. Blood samples for PK assessments will be collected on 
Day 13 before dosing (0 hours, before the start of the IV infusion) and at 0.5 (after the end of the IV infusion), 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 
(Day 14), 36 (Day 14), 48 (Day 15), 72 (Day 16), and 96 hours (Day 17) after the start of the IV infusion. Acceptable PK sampling windows are provided in 
Table 11-1 of the protocol. 
i  
If Dosing Period 3 is not conducted, a blood sample for PK assessment will be collected on Day 13 (144 hours after dosing on Day 7). 
j  
Study drug will be administered as a tablet in the fasted state on Day 1 and in the fed state on Day 7. On Day 13, study drug will be administered in the fed 
state as a single IV dose infused over 30 minutes (See Section 9.6.1.1 of the protocol for details). If the IV dose is not administered, subjects will be 
discharged on Day 13 after completion of the study visit assessments. 
k 
If data to support use of the IV dose is not available, Dosing Period 3 will not be conducted and subjects will not receive the IV dose. 
l  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 


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Table 12-4 
Study VX16-445-001: Part B, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety Follow-up 
Visit 
(7 to 10 Days 
After Last Dose 
of Study Drug) 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Inpatient days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
 
Outpatient visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weightc 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Standard 12-lead ECGd 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full PE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum chemistry 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
Hematology 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
4β-hydroxycholesterol 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Blood for PK analysisf 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Drug test (urine or blood), 
including cotinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol test (urine, blood, 
or breath) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise. If Part B study drug is administered every q12h, assessments on 
dosing days will be performed relative to the morning dose only. 
b  
Subjects will be discharged from the CRU on Day 14 after completion of the study visit assessments. 
c 
Weight will be measured with shoes off. 
d  
Standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On Days 1 and 5, ECGs will be collected before 
dosing and at approximately 1, 3, 5, and 6 hours (± 15 min) after dosing. 
e  
Vital signs will be performed after the subject has been seated for at least 5 minutes. 
f  
Blood samples for PK assessments of VX-445 will be collected on Day 1 before dosing (0 hours), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours after dosing. If 
dosing is q12h, the 12-hour sample will be collected before the next administered dose. On Days 2, 3, and 4, a blood sample will be collected in the morning 
before dosing. On Day 10, blood samples for PK assessments will be collected before dosing (0 hours), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 (Day 11), 
36 (Day 11), 48 (Day 12), 72 (Day 13), and 96 (Day 14) hours after dosing. The acceptable PK sampling windows are provided in Table 11-1 of the 
protocol. 


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Table 12-4 
Study VX16-445-001: Part B, Treatment Period and Safety Follow-up Visit 
Event/Assessmenta 
Study Day 
Safety Follow-up 
Visit 
(7 to 10 Days 
After Last Dose 
of Study Drug) 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Spirometryg 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Study drug administrationh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications reviewi 
Continuous from signing of ICF through Safety Follow-up Visit 
CRU: clinical research unit; ECG: electrocardiogram; ICF: informed consent form; PK: pharmacokinetic; q12h: every 12 hours 
 
 
g  
On Day 1, spirometry will be performed approximately 6 hours (± 1 hour) after dosing. On Day 9, spirometry will be performed before dosing and at 
approximately 6 hours (± 1 hour) after dosing. The assessment on Day -1 will be performed at approximately the same time of day (± 2 hours) as the 
nominal time of the 6-hour postdose assessments on Days 1 and 9.  
h  
Study drug will be administered in the fed state (see Section 9.6.1.2 of the protocol) If dosing is q12h, the last dose of study drug will be administered on the 
morning of Day 10.  
i  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 


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Table 12-5  
Study VX16-445-001: Part C, Treatment Period and Safety Follow-up Visit 
 
Study Day 
Safety 
Follow-up 
(7 to 10 Days 
After Last 
Dose of Study 
Drug) 
Event/Assessmenta 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Inpatient days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
 
Outpatient visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Standard 12-lead ECGc 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full PE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum chemistry 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Hematology 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Blood for VX-445 PK 
analysise 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Blood for TEZ/IVA PK 
analysisf 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 a  
On dosing days, assessments will be performed before dosing, unless noted otherwise, and will be performed relative to the morning dose only.   
b  
Subjects will be discharged from the CRU on Day 18 after completion of the study visit assessments. 
c  
Standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On Days 1 and 7, ECGs will be collected before 
dosing and approximately 1, 3, 5, and 6 hours (± 15 min) after dosing. 
d  
Vital signs will be performed after the subject has been seated for at least 5 minutes. 
e  
Blood samples for PK assessments of VX-445 will be collected on Day 1 and Day 7 before dosing (0 hours) and at 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours after 
dosing. The 12-hour sample will be collected before the next administered dose if dosing is q12h. On Days 2, 3, 4, 5, and 8, blood samples will be collected 
before (morning) dosing. On Day 14, blood samples will be collected before dosing (0 hours), and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 (Day 15), 36 (Day 15), 48 
(Day 16), 72 (Day 17), and 96 (Day 18) hours after dosing. Acceptable PK sampling windows are provided in Table 11-1 of the protocol. 
f  
Blood samples for PK assessments of TEZ and metabolites, and IVA and metabolites will be collected on Day 1 and Day 7 before dosing (0 hours) and at 
0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours after dosing. The 12-hour sample will be collected before the next administered IVA dose. On Days 2, 3, 4, 5, and 8, 
blood samples will be collected before (morning) dosing. On Day 14, blood samples will be collected before dosing (0 hours), and at 0.5, 1, 2, 3, 4, 5, 6, 8, 
12, 24 (Day 15), 36 (Day 15), 48 (Day 16), 72 (Day 17), and 96 (Day 18) hours after dosing. Acceptable PK sampling windows are provided in Table 11-1 
of the protocol. 


Statistical Analysis Plan Methods, Version 1.0 06Oct2017 
Protocol VX16-445-001, Version 7.0 
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Vertex Pharmaceuticals Incorporated 
 
Table 12-5  
Study VX16-445-001: Part C, Treatment Period and Safety Follow-up Visit 
 
Study Day 
Safety 
Follow-up 
(7 to 10 Days 
After Last 
Dose of Study 
Drug) 
Event/Assessmenta 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Drug test (urine or blood), 
including cotinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol test (urine, blood, or 
breath) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
Spirometryg 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug administrationi: 
VX-445 or placebo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Study drug administrationi: 
TEZ/IVA or placebo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Adverse events 
Continuous from signing of ICF through Safety Follow-up Visit 
Medications reviewj 
Continuous from signing of ICF through Safety Follow-up Visit 
CRU: clinical research unit; 
; ECG: electrocardiogram; ICF: informed consent form; IVA: ivacaftor; PE: physical examination; 
PK: pharmacokinetic; q12h: every 12 hours; TEZ: tezacaftor 
 g  
On Day 1, spirometry will be performed approximately 6 hours (± 1 hour) after dosing. On Day 9, spirometry will be performed before dosing and at 
approximately 6 hours (± 1 hour) after dosing. The assessment on Day -1 will be performed at approximately the same time of day (± 2 hours) as the 
nominal time of the 6-hour postdose assessments on Days 1 and 9. 
i  
Study drug will be administered in the fed state (see Section 9.6.1.3 of the protocol). The last dose of study drug will be administered on the morning of 
Day 14. 
j  
All medications taken from 28 days before the first dose of study drug through the end of the study will be recorded. 


Statistical Analysis Plan Methods, Version 1.0, 06Oct2017 
Page 28 of 28 
Protocol Number: VX16-445-001 (Version 7.0, dated 8Aug2017) 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Appendix B:  
Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
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 Sept 14, 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:  
ttp://www.ers-education.org/guidelines/global-lung-function-initiative/spirometry-tools/it-
engineers-and-manufacturers.aspx 
Accessed Sept 14, 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 Sept 14, 2017. 
 


 
 
Statistical Analysis Plan VX16-445-001 




























Statistical Analysis Plan (Methods) 
Page 1 of 62 
Protocol Number: VX16-445-001 Version 7.0 
 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX16-445-001 Version 7.0 
(Final Analysis Parts D, E and F) 
 
A Phase 1/2 Study of VX-445 in Healthy Subjects and Subjects With 
Cystic Fibrosis 
 
Authors of SAP: 
 
 
Version: Version 1.0 
Version Date of SAP: 15 September 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) 
Protocol VX16-445-001, Version 7.0 
Page 2 of 62 
Vertex Pharmaceuticals Incorporated 
 
1 
TABLE OF CONTENTS 
1 
Table of Contents ............................................................................................................................. 2 
2 
Modifications .................................................................................................................................... 4 
2.1 
Modifications to the Approved Clinical Study Protocol ............................................................ 4 
2.2 
Modifications to the Approved Statistical Analysis Plan ........................................................... 4 
2.3 
Modifications to the Approved DMC Charter ........................................................................... 4 
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 ..................................................................................................................................... 7 
6.1 
Overall Design ............................................................................................................................ 7 
6.2 
Sample Size and Power ............................................................................................................ 11 
6.2.1.1 
Primary Objectives..................................................................................................... 11 
6.2.1.2 
Secondary Objectives................................................................................................. 11 
6.3 
Randomization ......................................................................................................................... 12 
6.4 
Blinding and Unblinding .......................................................................................................... 12 
6.4.1 
Blinding ............................................................................................................................ 12 
6.4.2 
Unblinding ........................................................................................................................ 13 
7 
Analysis Sets ................................................................................................................................... 14 
7.1 
All Subjects Set ........................................................................................................................ 14 
7.2 
Full Analysis Set ...................................................................................................................... 14 
7.3 
Safety Set .................................................................................................................................. 14 
7.3.1 
Parts D and F .................................................................................................................... 14 
7.3.2 
Part E ................................................................................................................................ 15 
8 
Statistical Analysis ......................................................................................................................... 15 
8.1 
General Considerations ............................................................................................................ 15 
8.2 
Background Characteristics ...................................................................................................... 17 
8.2.1 
Subject Disposition ........................................................................................................... 17 
8.2.2 
Demographics and Baseline Characteristics .................................................................... 18 
8.2.3 
Prior and Concomitant Medications ................................................................................. 19 
8.2.4 
Study Drug Exposure ....................................................................................................... 20 
8.2.5 
Study Drug Compliance ................................................................................................... 20 
8.2.6 
Important Protocol Deviations ......................................................................................... 21 
8.3 
Efficacy Analysis ..................................................................................................................... 21 
8.3.1 
Primary Efficacy Variable ................................................................................................ 21 
8.3.1.1 
Primary Analysis of the Primary Efficacy Variable .................................................. 22 
8.3.1.2 
Sensitivity Analysis of the Primary Efficacy Variable .............................................. 23 
8.3.1.3 
Supportive Analysis for the Primary Efficacy Variable ............................................ 23 
8.3.2 
Analysis of Secondary Efficacy Variables ....................................................................... 24 
8.3.2.1 
Relative change in ppFEV1 from baseline through Day 29 (Parts D , E and F) ........ 24 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
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8.3.2.2 
Absolute change in the CFQ-R respiratory domain score from baseline at Day 29 
(Parts D, E and F)....................................................................................................... 24 
8.3.2.3 
Multiplicity adjustment .............................................................................................. 24 
8.3.3 
Analysis of Other Efficacy Variables (Parts D, E and F) ................................................. 24 
8.3.3.1 
Absolute change in CFQ-R non-respiratory domain scores from baseline at Day 29 
(Parts D, E and F)....................................................................................................... 25 
8.3.4 
Analysis of Additional Efficacy Variables (Parts D, E and F) ......................................... 25 
8.3.5 
Pharmacodynamic Analysis ............................................................................................. 25 
8.3.5.1 
Primary Analysis of the Dose Response trend of absolute change in sweat chloride 
from baseline through Day 29 (Part D) ...................................................................... 26 
8.3.5.2 
Absolute Change in Sweat Chloride from Baseline through Day 29 (Parts D, E and 
F) ................................................................................................................................ 26 
8.3.5.3 
Supportive Analysis for Absolute Change from Baseline in Sweat Chloride from 
Baseline through Day 29 ............................................................................................ 27 
8.4 
Safety Analysis ......................................................................................................................... 27 
8.4.1 
Adverse Events ................................................................................................................. 28 
8.4.2 
Clinical Laboratory ........................................................................................................... 29 
8.4.3 
Electrocardiogram ............................................................................................................ 29 
8.4.4 
Vital Signs ........................................................................................................................ 30 
8.4.5 
Pulse Oximetry ................................................................................................................. 30 
8.4.6 
Physical Examination ....................................................................................................... 30 
8.4.7 
Other Safety Analysis ....................................................................................................... 30 
8.4.7.1 
Post-dose Spirometry ................................................................................................. 30 
9 
Interim and IDMC Analyses ........................................................................................................ 30 
9.1 
Interim Analysis ....................................................................................................................... 30 
9.1.1 
Summary of the Flow of Data for Interim Analyses for each part (D1, D2 and E) at or 
after 50% of Subjects have Completed the Day 15 Visit ................................................. 31 
9.2 
IDMC Analysis ........................................................................................................................ 31 
10 References ...................................................................................................................................... 32 
List of Appendices................................................................................................................................. 33 
Appendix A: Schedule of Assessments ............................................................................................. 33 
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments ................................... 45 
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates ........................... 49 
Appendix D: Important Protocol Deviation Rules ............................................................................. 50 
Appendix E: Details of GLI Equations for Calculating ppFEV1 ....................................................... 51 
Appendix F: Details of CFQ-R Analysis and Scoring Manual.......................................................... 52 
Appendix G: Imputation Rules for Missing AE dates ....................................................................... 54 
Appendix H: Criteria for Threshold Analysis .................................................................................... 57 
 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
Page 4 of 62 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
2 
MODIFICATIONS  
2.1 
Modifications to the Approved Clinical Study Protocol 
•  Changed the definition of Treatment-emergent Period.   
• Added sensitivity analysis for ppFEV1. 
2.2 
Modifications to the Approved Statistical Analysis Plan 
This is the 1st version of Statistical Analysis Plan for the final analysis.   
2.3 
Modifications to the Approved DMC Charter 
Not Applicable. 
 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
Page 5 of 62 
Vertex Pharmaceuticals Incorporated 
 
3 
INTRODUCTION 
This statistical analysis plan (SAP) for the final analysis is based on the approved clinical study 
protocol (CSP), Version 7.0, dated 08 Aug 2017, approved electronic case report form (eCRF) for 
Parts D and E, Version 1.0, dated 25 Jul 2016, and approved eCRF completion guidelines for Parts D 
and E, Version 1.0, dated 02 August 2017. The eCRF and eCRF completion guidelines for Part F are 
still in development at the time this version of SAP method is approved. This SAP will be used to 
perform interim analyses (IAs) for each part after 50% of subjects in the part have completed the Day 
15 Visit. This SAP will be used to perform 3 IAs for Parts D, E and F separately that will occur after 
all subjects in each part have completed the Safety Follow-Up Visit. This SAP will also be used to 
perform the analysis of key study data for ongoing review by an internal limited Vertex Team.  
This is a Phase 2, randomized, double-blind, placebo- and TEZ/IVA-controlled, parallel group, 
multicenter study to evaluate the safety and efficacy of VX-445 in triple combination with TEZ/IVA 
and in triple combination with TEZ/VX-561 in subjects aged 18 years and older with cystic fibrosis. 
This SAP (Methods) documents the planned statistical analyses of efficacy endpoints and safety 
endpoints. 
Vertex Biometrics will perform the statistical analysis for each IA, and the final analysis. SAS® 
Version 9.4 or higher software (SAS Institute, Cary, North Carolina, USA) will be used to generate all 
statistical outputs (tables, figures, listings, and datasets).  
The SAP (Methods) will be finalized and approved prior to the data cut for the first IA. Any revisions 
to the approved SAP will be documented and approved in an amendment to the SAP prior to the 
clinical database lock for the final analysis. Any changes made to the SAP Methods after the clinical 
database lock has occurred will be documented in the clinical study report for this study.  
4 
STUDY OBJECTIVES  
4.1 
Primary Objective 
Parts D and E 
• To evaluate the safety and tolerability of VX-445 in TC with TEZ and IVA in subjects with CF 
• To evaluate the efficacy of VX-445 in TC with TEZ and IVA in subjects with CF 
Part F  
• To evaluate the safety and tolerability of VX-445 in TC with TEZ and VX-561 (deuterated 
IVA) in subjects with CF 
• To evaluate the efficacy of VX-445 in TC with TEZ and VX-561 in subjects with CF 
4.2 
Secondary Objectives  
Parts D and E 
• To evaluate the PD effect of VX-445 in TC with TEZ and IVA on CFTR function in subjects 
with CF 
• To evaluate the PK of VX-445 when administered in TC with TEZ and IVA in subjects with 
CF 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
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Vertex Pharmaceuticals Incorporated 
 
• To evaluate the PK of TEZ, IVA, and their respective metabolites (M1-TEZ and M1-IVA) 
when administered in TC with VX-445 in subjects with CF 
Part F  
• To evaluate the PD effect of VX-445 in TC with TEZ and VX-561 on CFTR function in 
subjects with CF 
• To evaluate the PK of VX-445 when administered in TC with TEZ and VX-561 in subjects 
with CF 
• To evaluate the PK of TEZ and metabolite (M1-TEZ) and VX-561 when administered in TC 
with VX-445 in subjects with CF 
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 through Day 29 
5.1.2 
Secondary Efficacy Endpoints 
Parts D and E: 
• Absolute change in sweat chloride concentrations from baseline through Day 29 
• Relative change in ppFEV1 from baseline through Day 29 
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score 
from baseline at Day 29 
• PK parameters of VX-445, TEZ, M1-TEZ, IVA, and M1-IVA 
Part F: 
• Absolute change in sweat chloride concentrations from baseline through Day 29 
• Relative change in ppFEV1 from baseline through Day 29 
• Absolute change in CFQ-R respiratory domain score from baseline at Day 29 
• PK parameters of VX-445, TEZ, M1-TEZ, and VX-561  
5.2 
Safety Endpoints 
The safety and tolerability is evaluated via the following endpoints: 
• adverse events (AEs) 
• clinical laboratory values 
• standard 12-lead electrocardiograms (ECGs) 
• vital signs 
• pulse oximetry 
• spirometry 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
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6 
STUDY DESIGN  
6.1 
Overall Design  
Part D, which is comprised of Parts D1 and D2, is randomized, double-blind, placebo-controlled and 
evaluates VX-445 in TC with TEZ/IVA in subjects with CF (F/MF genotypes). Part E is randomized, 
double-blind, TEZ/IVA-controlled and evaluates VX-445 in TC with TEZ/IVA in subjects with CF 
(F/F genotype). Part F is randomized, double-blind, placebo-controlled, and evaluates VX-445 in TC 
with TEZ/VX-561 in subjects with CF (F/MF genotypes). Part F is an optional part of the study, which 
will be conducted at the sponsor’s discretion. All parts are multicenter and designed to evaluate the 
safety and efficacy of VX-445 in TC. 
Approximately 104 subjects with CF will be enrolled. Part D may be initiated while Parts A, B, and C 
are ongoing after review of safety, tolerability, and PK data. Enrollment of Parts D1 and D2 will be 
sequential, while enrollment of Parts E and F will be in parallel with Part D2.  
After all Part D1 subjects complete the Day 15 Visit, a blinded review of all available safety and PK 
data will be conducted by the Vertex study team and lead investigator(s). Dosing in Parts D2, E, and F 
will start after this review, if supported by safety and PK data.  
Part E subjects who are participating in Study VX11-661-110 (Study 661-110), an open-label study of 
TEZ/IVA combination therapy, will not need to washout TEZ/IVA treatment; these subjects will 
transition directly from their prior treatment to the TEZ/IVA Run-in Period providing that they meet 
all eligibility criteria. These subjects can have screening assessments for this study done while they are 
continuing to participate in Study 661-110.  
Key study elements are summarized in Table 6-1. The treatment arms and randomization ratios for 
each part are summarized in Table 6-2. A schematic of the study design is shown in Figure 6-1. Study 
visits and assessments are shown in Table 11-1 (Parts D1 and D2), Table 11-2 (Part E), and Table 11-3 
(Part F). 
Table 6-1 
Parts D, E, and F: Key Study Elements 
Element 
Part D1 
Part D2 
Part E 
Part F 
Study population 
 
 
 
Genotype(s) 
F/MF 
F/MF 
F/F 
F/MF 
Age 
≥18 years 
≥18 years 
≥18 years 
≥18 years 
ppFEV1 criteria 
≥40 to ≤90  
≥40 to ≤90  
≥40 to ≤90 
≥40 to ≤90  
Number of subjects 
Approximately 8 
Approximately 48 
Approximately 24 
Approximately 24 
Study design 
Parallel group 
Parallel group 
Parallel group 
Parallel group 
Control 
Placebo 
Placebo 
TEZ/IVA 
Placebo 
IVA: ivacaftor; MF: minimal function; ppFEV1: percent predicted forced expiratory volume in 1 second; TEZ: tezacaftor 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
Page 8 of 62 
Vertex Pharmaceuticals Incorporated 
 
Table 6-2 
Treatment Arms and Planned Doses by Part in the Treatment Period (Period 
1) 
Part 
Randomization 
ratio 
 
Treatment Arm 
VX-445 Dosage 
TEZ 
Dosage 
IVA 
Dosage 
VX-561 Dosage 
Part D1a 
TC-mid 
100 mg qd 
100 mg qd 
150 mg q12h 
N/A 
3:1 
Triple placebo 
Placebo 
Placebo 
Placebo 
N/A 
Part D2a 
TC-high 
200 mg qd 
100 mg qd 
150 mg q12h 
N/A 
6:4:3:3 
TC-mid 
100 mg qd 
100 mg qd 
150 mg q12h 
N/A 
 
TC-low 
50 mg qd 
100 mg qd 
150 mg q12h 
N/A 
 
Triple placebo 
Placebo 
Placebo 
Placebo 
N/A 
Part Eb 
TC-high 
 200 mg qd 
100 mg qd 
150 mg q12h 
N/A 
3:1 
TEZ/IVA 
Placebo 
100 mg qd 
150 mg q12h 
N/A 
Part F 
TC2-high 
 200 mg qd 
100 mg qd 
N/A 
150 mg qdc 
3:1 
Triple placebo 
Placebo 
Placebo 
N/A 
Placebo 
TC2: triple combination 2 (VX-445/TEZ/VX-561); IVA: ivacaftor; N/A: not applicable; q12h: every 12 hour; qd: 
once daily; TC: triple combination (VX-445/TEZ/IVA); TEZ: tezacaftor 
a 
In Parts D1 and D2, all subjects will also receive TEZ 100 mg qd/IVA 150 mg q12h or dual placebo during 
Period 2. 
b 
In Part E, all subjects will also receive TEZ 100 mg qd/IVA 150 mg q12h during the Run-in Period and the 
Washout Period, which is the dosage evaluated in Phase 3 studies of TEZ/IVA. 
c 
See Section 9.3.2.2 of the protocol for information relating to the selection of the VX-561 dose. 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
Page 9 of 62 
Vertex Pharmaceuticals Incorporated 
 
Figure 6-1 
Parts D, E, and F: Schematic of Study Design 
Part D1: F/MF 
N ~ 8 
Randomization: 3:1 
 
 
Part D2: F/MF 
N ~ 48 
Randomization: 6:4:3:3 
Stratification: ppFEV1: ≥70 versus <70 
 
 
 
 
Part E: F/F 
N ~ 24 
Randomization: 3:1 
Stratification: ppFEV1: ≥70 versus <70 
 
 
TC-mid 
(VX-445/TEZ/IVA) 
Triple Placebo 
N = 6
N = 2 
TEZ/IVA 
Dual Placebo 
Period 2  
(1 week) 
Period 1 
(4 weeks) 
Safety 
Follow-up 
Period 
(4 weeks) 
Screening 
Period 
(4 weeks) 
TC-high (VX-445/TEZ/IVA) 
TC-mid (VX-445/TEZ/IVA) 
TC-low (VX-445/TEZ/IVA) 
Triple Placebo 
N = 18 
N = 12 
N = 9 
N = 9 
TEZ/IVA 
Dual Placebo 
Period 2 
(1 week)  
Period 1 
(4 weeks) 
Safety 
Follow-up 
Period 
 (4 weeks) 
Screening 
Period 
(4 weeks) 
TEZ/IVA 
TC-high (VX-445/TEZ/IVA) 
Placebo + TEZ/IVA 
TEZ/IVA 
Run-in Period 
(4 weeks) 
Washout 
Period 
(4 weeks) 
Period 1 
(4 weeks) 
N = 6 
N = 18 
Safety 
Follow-up 
Period 
(4 weeks) 
Screening 
Period 
(4 weeks) 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
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Part F (if Conducted): F/MF 
N ~ 24 
Randomization: 3:1 
Stratification: ppFEV1: ≥70 versus <70 
 
 
 
TC2: triple combination 2 (VX-445/TEZ/VX-561); IVA: ivacaftor; MF: minimal function; N: number of subjects; 
ppFEV1: percent predicted forced expiratory volume in 1 second; TC: triple combination (VX-445/TEZ/IVA); 
TEZ: tezacaftor 
Note: to maintain the blind, matching placebo tablets will be administered, as applicable, so that all subjects receive the 
same number of tablets within a given dosing period.  
 
 
 
 
TC2-high 
(VX-445/TEZ/VX-561) 
Triple Placebo 
N = 18 
N = 6 
Period 1 
(4 weeks) 
Safety 
Follow-up 
Period 
(4 weeks) 
Screening 
Period 
(4 weeks) 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
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6.2 
Sample Size and Power 
6.2.1.1 
Primary Objectives  
The primary objectives of Parts D, E, and F are the evaluation of safety and tolerability, and 
efficacy of VX-445 in TC with TEZ/IVA (Parts D and E) and in TC with TEZ/VX-561 (Part F) 
in subjects with CF. The sample size calculations described below are deemed adequate to 
evaluate the primary objectives, based on clinical and statistical considerations. 
Safety and Tolerability 
The primary safety endpoint is the incidence of AEs. Approximately 104 subjects with CF will 
be enrolled in the study with approximately 81 subjects receiving VX-445 in TC with either 
TEZ/IVA or TEZ/VX-561. The sample size for each treatment group will provide sufficient data 
for a descriptive analysis of AEs.  
Efficacy 
The primary efficacy endpoint is the absolute change from baseline in ppFEV1 through Day 29 
in Parts D, E, and F. A sample size of 18 subjects per treatment group provides at least 90% 
power to detect a mean change of 7 percentage points. 
6.2.1.2 
Secondary Objectives  
A secondary objective of Parts D, E, and F is the evaluation of the PD effect of VX-445 in TC 
with TEZ/IVA (Parts D and E) and in TC with TEZ/VX-561 (Part F) in subjects with CF. 
The absolute change from baseline through Day 29 in sweat chloride is a secondary endpoint 
used to evaluate the PD objective of the study. In Part D, a test for a decreasing dose-response 
trend between placebo and the TC dose groups will be performed using a multiple comparisons 
procedure (MCP). The procedure consists of testing the null hypothesis of the lack of a 
decreasing dose-response trend versus a decreasing trend using the 1-sided maximum t-statistic 
that controls the type I error at alpha = 5%. The procedure requires a family of candidate 
dose-response models to be pre-specified 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 
through Day 29) selected to perform the MCP and that capture the shape of these candidate 
models are described in Table 6-3.  
Table 6-3 
Contrast Coefficients for the Multiple Comparisons Procedure in Part D 
Candidate Model 
Placebo 
TC-low 
TC-mid 
TC-high 
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 
Emax: maximum effect; TC: triple combination (VX-445/TEZ/IVA) 
 
A total sample size of 56 subjects in Part D will provide at least 90% power to detect a 
dose-response trend with MCP. 


Statistical Analysis Plan (Methods) 
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6.3 
Randomization 
A randomization list for each part will be produced by Vertex Biostatistics or a qualified 
randomization vendor. The Vertex study biostatistician will review and approve the dummy 
randomization list. The final randomization list will be reviewed and approved by a designated 
unblinded biostatistician who is not a member of the study execution team (SET).  
Only subjects who have completed screening assessments and are eligible for participation in the 
study will be randomized to receive active study drug or placebo. Randomized subjects will be 
assigned a unique subject number.  
For Parts D, E, and F, an interactive web response system (IWRS) will be used to assign subjects 
to treatment.  
6.4 
Blinding and Unblinding 
6.4.1 
Blinding  
All subjects, site personnel (including the investigator, the site monitor, and the study team), and 
the Vertex study team will be blinded to the treatment codes with the exception of the following:  
• Any site personnel for whom this information is important to ensure the safety of the 
subject in the event of a life-threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of the 
subject and her fetus in the event of a pregnancy 
• Vertex GPS and Regulatory Affairs personnel to satisfy 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 (IAs) 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 
• Bioanalytical CRO analyzing PK samples and the Vertex Bioanalytical personnel who is 
not a member of the SET but reviews raw data from Bioanalytical CRO. The Vertex 
Bioanalytical SET member will continue to be blinded. 
• Vertex Modeling and Simulation personnel or vendor conducting the population PK and 
PK/PD analyses 
• Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time 
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 29 Visit to make decisions 
about dose selection for potential subsequent cohorts. 
Blinding of Sweat Chloride and Spirometry Results: 


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• The Vertex study team will not have access to the spirometry or sweat chloride results 
after the first dose of study drug until after the data are unblinded for full review per 
Section 12.3.6.1.2 of the protocol. 
• Sites, subjects, and their parents/caregivers/companions should not be informed of a 
subject’s study-related sweat chloride results until after the subject’s last study visit, even 
if the subject prematurely discontinues treatment. 
• Subjects and their parents/caregivers/companions should not be informed of a subject’s 
study-related spirometry results until after the subject’s last study visit, even if the subject 
prematurely discontinues treatment. 
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 Individual Subject Treatment Assignments by Investigator for Medical 
Emergencies or Urgent Clinical Situations 
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the medical monitor, they will use their best 
judgment, based on the nature and urgency of the clinical situation, and may proceed with 
unblinding without having successfully reached and discussed the situation with the medical 
monitor. In case of emergency, the investigator will have the final decision and unilateral right 
for unblinding. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center (
) will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If a subject's treatment assignment has been unblinded for a medical emergency or urgent clinical 
situation, the medical monitor will be notified within 24 hours of the unblinding event. The 
reason and the date of the unblinding will be documented clearly in the subject's study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with the sponsor (Vertex), CRO, or 
any site personnel (other than the physician treating the subject). In addition, the investigator will 
consider whether the clinical event that prompted unblinding will be considered an SAE, 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to 
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Unblinding of Individual Subject Treatment Assignments by Vertex GPS or Designee for 
SAEs or Safety Concerns 
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.  
Parts D, E, and F Only: Unblinded Reviews of Data by Vertex for Administrative Purposes 
(Planning, Decision-making, and Regulatory Submission) 
A limited Vertex team not involved in the conduct of the study will be unblinded to results of the 
IAs 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. Members of 
the limited unblinded Vertex team will not be part of the Vertex study team and will not be 
involved in or influence the conduct of the study. 
Unblinding: Interim Analysis Results 
Parts D, E, and F: When an IA is performed after all subjects in a part have completed the Safety 
Follow-up Visit, results from that part will be unblinded for full review by the Vertex study team 
with approval of Data Dissemination Plan before the unblinding. 
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 Period 1 of 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. Subjects will be 
analyzed according to the treatment they were randomized to. 
7.3 
Safety Set 
7.3.1 
Parts D and F 
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. Subjects will be analyzed 
according to the treatment they received.  
If a subject received at least 1 dose of a higher TC treatment , the subject will be analyzed in the 
higher treatment group (in the increasing priority order: Triple placebo, TC-low, TC-mid, TC-
high/TC2-high).    


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7.3.2 
Part E  
The Safety Set for the Run-in Period will include all subjects who received at least 1 dose of 
study drug TEZ/IVA in the Run-in Period. This Safety Set will be used for individual subject 
data listings for the Run-in Period, unless specified otherwise.  
The Safety Set for Treatment Period will include all subjects who received at least 1 dose of 
study drug in Period 1 of 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 a higher TC treatment group, the subject will be analyzed 
in the higher dose TC treatment group (in increasing priority order of TEZ/IVA, TC-high).  
Note: The safety analysis will focus on the Safety Set for the Treatment  Period  only, thus 
Safety Set for Part E, implicitly, refers to Safety Set for Period 1, unless otherwise specified.   
8 
STATISTICAL ANALYSIS 
8.1 
General Considerations 
The analysis will be performed for each part, and presented by treatment group and overall, for 
the Treatment Period, unless specified otherwise. The treatment groups are defined as follows:  
• Part D: F508del/MF genotypes group 
o Placebo, TC-low, TC-mid, and TC-high.  The pooled TC-mid groups and the pooled 
placebo groups from Parts D1 and D2 will be used in all efficacy, pharmacodynamic 
(PD) and safety analyses for Part D.  
• Part E: F508del/F508del genotype group 
o TEZ/IVA and TC-high.  
• Part F: F508del/MF genotypes group 
Placebo and TC2-high.  
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. 
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 


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measurement is obtained in triplicate), before the first dose of study drug on Day 1 of the 
Treatment Period. 
Absolute change from baseline will be calculated as postbaseline value – baseline value. 
Relative change from baseline will be calculated as (postbaseline value – baseline 
value)/baseline value. 
Treatment-emergent (TE) period for Parts D and F will include the time from the first dose of 
study drug in the Treatment Period  until 28 days after the last dose of study drug or end of study 
date (based on end of follow-up visit in CRFs), whichever occurs first.   
For Part E, 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 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)  28 days after 
the last dose of study drug in the Run-in Period or end of study date (based on end of follow-
up visit in CRFs), whichever occurs first, for subjects who do not continue to the Treatment 
Period  (e.g., subjects who do not meet the criteria to enter the Treatment Period and re-enter 
Study 661-110).  
• The TE period for the Treatment Period will include the first dose of study drug in Period 1 
of the Treatment Period to 28 days after the last dose of study drug or end of study date 
(based on end of follow-up visit in CRFs), whichever occurs first. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
• In scheduled visit windows per specified visit windowing rules 
• In the derivation of baseline and last on-treatment measurements 
• In the derivation of maximum and minimum on-treatment values, and maximum and 
minimum change from baseline values for safety analyses 
• In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix B.  
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 both pre-dose and 5 hours postdose on nominal days 1 and 15 will be used.   
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. 


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8.2 
Background Characteristics  
8.2.1 
Subject Disposition 
For the Periods 1 and 2 in Part D, the Period 1 and Washout Period in Part E, and the Period 1 in 
Part F 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 Parts D and F:  
• All Subjects Set (randomized or dosed ) 
• Randomized  
• Safety Set 
• Randomized but not dosed in the Period 1 
• Full Analysis Set (FAS) 
The number of subjects in the following categories will be summarized by treatment group and 
overall for Part E:  
• All Subjects Set (randomized or dosed) 
• Randomized or dosed in the Period 1 
• Randomized 
• Safety Set for the Treatment Period 
• Randomized but not dosed in the Period 1 
• Full Analysis Set (FAS) 
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  (Separated by Periods 1 and 2 for Part D, and by Period 
1 and washout period for Part E) 
• Prematurely discontinued treatment and the reason for discontinuation (i.e., discontinued 
all study drugs)  (Separated by Periods 1 and 2 for Part D, and by Period 1 and washout 
period for Part E) 
• Completed study (i.e., completed Safety Follow-up Visit or completed all study drugs 
and re-entered Study 661-110 without Safety Follow-up per protocol) 
• Prematurely discontinued the study and the reason for discontinuation  
For the Run-in Period in Part E, 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) 


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• 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 E) or who discontinued study with reasons for discontinuation. A randomization 
listing of subjects will also be provided, by part. 
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. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and Other) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
Stratification categories will include the following: 
• ppFEV1 at stratification (< 70 and ≥ 70) 
For Part D1, no stratification will be performed. 
For Part D2, ppFEV1 stratification (<70 versus ≥70) will be performed using the 
screening (Days -28 to -1) ppFEV1 value.  
For Part E, ppFEV1 stratification (<70 versus ≥70) will be performed using a value 
obtained at the following visit: 
• Screening Visit (Days -56 to -29) for subjects transitioning directly from at least 
14 days of uninterrupted TEZ/IVA treatment 
• Day -14 Visit (+ 13 days) for all other subjects 
For Part F, ppFEV1 stratification (<70 versus ≥70) will be performed using the screening 
(Days -28 to -1) ppFEV1 value.  
Disease characteristics will include the following: 
• ppFEV1 at baseline (<40, ≥ 40 to <70, ≥70 to ≤90, >90) 


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• 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 in the Treatment Period (Yes, 
No) 
• Prior use of inhaled antibiotic before first dose of study drug in the Treatment Period 
(Yes, No) 
• Prior use of any bronchodilator before first dose of study drug in the Treatment Period (Yes, 
No)  
• Prior use of any inhaled bronchodilator before first dose of study drug in the Treatment 
Period (Yes, No)  
• Prior use of any inhaled hypertonic saline before first dose of study drug in the Treatment 
Period (Yes, No) 
• Prior use of any inhaled corticosteroids before first dose of study drug in the Treatment 
Period (Yes, No) 
• Infection with Pseudomonas aeruginosa at baseline (Positive, Negative) 
A summary of medical history will be provided by MedDRA System Organ Class (SOC) and 
Preferred Term (PT) for the FAS. In addition, the number of subjects reported to have had 
positive cultures for respiratory pathogens in 2 years prior to screening will be summarized for 
the FAS. Further, the CFTR genotype for each subject will be provided in an individual subject 
data listing.   
8.2.3 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHO-DDE) and categorized as follows: 
For Parts D and F:  
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 E:  
Prior medication: any medication that started before the first dose date of study drug in the 
Run-in Period, regardless of when the medication ended. 
Concomitant medication during the Run-in Period: medication continued or newly received 
on or after the first dose date of study drug during the Run-in Period through the end of the TE 
period for the Run-in Period. 


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Concomitant medication during the Treatment Period: medication continued or newly 
received on or after the first dose date of study drug during the Treatment Period through the end 
of the TE period for the Treatment Period. 
Post-treatment medication: medication continued or newly received after the TE period. 
A given medication may be classified as follows: prior, concomitant, post-treatment, both prior 
and concomitant, both concomitant and post-treatment, or prior, concomitant, and 
post-treatment. In Part E, concomitant may be concomitant during the Run-in Period, or 
concomitant during the Treatment Period, or both.  
If a medication has a completely missing or partially missing start/stop date and it cannot be 
determined whether it was taken before the first dose date of study drug, concomitantly, or after 
the TE period, it will be classified as prior, concomitant, and post-treatment. 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by preferred name.  
Summaries of medications will be based on the FAS, and presented by treatment group and 
overall for each part.  
Post-treatment medications will be listed by subject.  
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix C. 
8.2.4 
Study Drug Exposure  
Study drug exposure (in days) will be calculated as: last dose date of study drug – first dose 
date of study drug + 1 day, regardless of study drug interruption, and will be summarized 
descriptively. Study drug exposure will be summarized for the overall study drug period, which 
includes the Run-in Period, Period 1 of the Treatment Period and Washout Period for Part E, the 
Period 1 and Period 2 of the Treatment Period for Part D, and include the Period 1 for Part F. 
Further, study drug exposure for the combined Period 1 of the Treatment Period and Washout 
Period in Part E will also be summarized descriptively.  
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, SE, median, min, and max. It will also be summarized in categories: ≤2 weeks, >2- ≤4 
weeks, and > weeks (for Part D); and ≤2 weeks, >2- ≤4 weeks, >4 - ≤8 weeks, >8 weeks 
(Treatment and washout periods for Part E); ≤2 weeks, >2- ≤4 weeks (for Part F), 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 E, 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%.  


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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 and  percentage of tablets taken will be summarized for 
Period 1 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  
• 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 for each part. 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 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. Except the sensitivity analyses, the post-dose measurements on the 
same day (e.g. days when spirometry is repeated pre- and post-dose) will not be used for any 
model-based analyses, but only reported in descriptive safety analyses. 
8.3.1 
Primary Efficacy Variable 
The primary efficacy variable is the absolute change from baseline in pre-dose percent predicted 
FEV1 (ppFEV1 in percentage units) through Day 29 in Parts D, E and F.  


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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 ethnicity. Details are provided 
in Appendix E. 
8.3.1.1 
Primary Analysis of the Primary Efficacy Variable 
8.3.1.1.1 
Parts D, E and F 
The null hypothesis to be tested is that the mean absolute within-group change from baseline in 
percent predicted FEV1 (ppFEV1) through Day 29 is zero for VX-445 in triple combination (TC) 
with TEZ/IVA in Parts D and E, or with VX-561 in Part F, separately. A 2-sided p-value of 0.05 
or less will be interpreted as sufficient evidence to reject the null hypothesis.  
The primary analysis will be performed using a mixed-effects model for repeated measures 
(MMRM) with change from baseline in ppFEV1 as the dependent variable for each part, 
separately. For Part D, the analysis will include 4 treatment groups: placebo, TC-low, pooled 
TC-mid, and TC-high. For Part E, the analysis will include 2 treatment groups: placebo + 
TEZ/IVA, and TC-high (VX-445/TEZ/IVA). For Part F, the analysis will include 2 treatment 
groups: placebo and TC2-high (VX-445/TEZ/VX-561). The model will include treatment group, 
visit, and treatment-by-visit interaction as fixed effects and subject as a random effect, with the 
continuous baseline ppFEV1 as a covariate, and will include all data from each treatment group 
and visit during Period 1 in the analysis. The model will be estimated using restricted maximum 
likelihood. Denominator degrees of freedom for the F test for fixed effects will be estimated 
using the Kenward-Roger approximation. An unstructured covariance structure will be used to 
model the within-subject errors. If the model estimation does not converge, a reduced compound 
symmetry covariance structure will be used instead. Conditional on the observed data and 
covariates, missing ppFEV1 data due to treatment or study discontinuation will be assumed to be 
missing at random; consequently, no imputation of missing data will be performed.  
The adjusted means and 95% confidence intervals (CI) of the average treatment effect through 
Day 29 (Day 15 and Day 29 only) for each triple combination, with a 2-sided p-value will be 
estimated within MMRM using PROC MIXED in SAS, for all within-treatment and 
between-treatment comparisons, for each part, separately. Contrasts based on the fixed effects in 
the model, defined at the baseline covariate mean for the combined treatment groups using 
unique subjects in the FAS who have at least one post-baseline measurement through Day 29, 
will be used to estimate the average treatment effect across post-baseline visits through Day 29. 
Day 8 data will not be included in the model for the through Day 29 analysis for Part D. 
Further, the adjusted mean and 95% CI of the treatment difference between each triple 
combination and placebo or TEZ/IVA at each post-baseline visit through Day 29 will be 
provided along with the corresponding p-value, for each part. In addition, the adjusted mean and 
95% CI of the within-treatment difference at each post-baseline visit through Day 29 for each 
treatment group will be provided along with the p-value, for each part.   
The adjusted mean (with 95% CI) obtained from the MMRM analysis at each post-baseline visit 
through Day 29 will be plotted by treatment group, for each part. In addition, a waterfall plot 
showing the subject-level absolute change in ppFEV1 at Day 29 will be presented, by treatment 
group.  


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In addition, for each part, descriptive analyses of the change from baseline will be performed 
using pre-dose records for all treatment groups by post-baseline visit through the safety follow-
up visit.  
8.3.1.2 
Sensitivity Analysis of the Primary Efficacy Variable 
If pre-dose assessment is missing and the post-dose assessment is available on Day 15, the 
missing record will be imputed by post-dose assessment on the same day. The sensitivity 
analysis of the change from baseline in ppFEV1 is performed on the imputed data. The sensitivity 
analysis will be based on an MMRM model, similar to the primary analysis of the primary 
efficacy variable in Parts D, E and F. The tabular presentation of results will also be similar. The 
adjusted mean and 95% CI of the mean change from baseline of the average treatment effect 
through Day 29 will be provided along with p-value for all within-treatment and 
between-treatment comparisons, for each part, separately. 
8.3.1.3 
Supportive Analysis for the Primary Efficacy Variable 
8.3.1.3.1 
Part D: Period 2 
Period 2 in Part D (after Day 29 through the Period 2 visit) will be used to assess the washout 
effect of VX-445 on the primary efficacy variable during the 1-week Period 2. This analysis will 
be based on fitting an Analysis of Covariance (ANCOVA) model to the primary efficacy 
variable in the Period 2, using the group as a fixed effect, and continuous baseline ppFEV1 as a 
covariate in the ANCOVA model. Group will be assigned to placebo, TC-low, pooled TC-mid, 
and TC-high the 4 randomized groups in the Period 1.   
The adjusted mean and 95% CI of the mean change from baseline for placebo, TC-low, pooled 
TC-mid, and TC-high at the Period 2 visit will be provided along with the corresponding 95% CI 
and p-value. The adjusted mean (with 95% CI) obtained from the ANCOVA analysis at Period 2 
visit will be plotted by randomized group, and will be combined with the corresponding plot for 
the Period 1 from the primary efficacy analysis.  
8.3.1.3.2 
Part E: Washout Period 
The Washout Period in Part E after Day 29 through Day 57 will be used to assess the washout 
effect of VX-445 on the primary efficacy variable during the 4-week Washout Period. This 
analysis will be based on fitting a fully saturated model to the primary efficacy variable in the 
Washout Period, using group, visit and the group-by-visit interaction effect as a fixed effect, and 
continuous baseline ppFEV1 as a covariate in the MMRM model. Group (1 versus 2) will be 
assigned to the two randomized groups in the Period 1, and visit will be assigned the 
chronological visit within each subject.  The other aspects of the MMRM model will be similar 
to that of the primary analysis.  
The adjusted mean of the mean change from baseline for TC and TEZ/IVA at the Washout 
Period visits Day 43, and Day 57 will be provided along with the corresponding 95% CI and p-
value. 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 in the Washout Period, will be used to estimate the adjusted mean at each 
visit in the Washout Period.  
The adjusted mean (with 95% CI) obtained from the MMRM analysis at each post-baseline visit 
post Day 29 of the Period 1 through Day 57 of the Washout Period will be plotted by randomized 


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group, and combined with the corresponding plot for the Period 1 from the primary efficacy 
analysis.  
8.3.2 
Analysis of Secondary Efficacy Variables 
The secondary efficacy variables include: 
• Relative change in ppFEV1 from baseline through Day 29 
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain 
score from baseline at Day 29 
8.3.2.1 
Relative change in ppFEV1 from baseline through Day 29 (Parts D , E 
and F)  
The relative change in ppFEV1 from baseline through Day 29 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 in Parts D, E and F. The tabular presentation of results will also be similar. 
8.3.2.2 
Absolute change in the CFQ-R respiratory domain score from 
baseline at Day 29 (Parts D, E and F)  
The absolute change in the CFQ-R respiratory domain score from baseline at Day 29 will use the 
'Adolescents and Adults' Version for ages 14 and above at baseline, and will be based on the 
CFQ-R scaled scores, as described in Appendix F. Analysis of this variable will be based on an 
MMRM model, similar to the analysis of the primary efficacy variable in Parts D, E and F.  Sex, 
the continuous baseline ppFEV1, and the continuous baseline CFQ-R respiratory domain score 
will be used as covariates in Parts D, E and F. The presentation of results will also be similar.  
Part E: Washout Period  
In Part E, a supportive analysis will be based on fitting an ANCOVA model to the CFQ-R 
respiratory domain score Day 57 Visit during Washout Period, using the randomized group in 
Period 1, as a fixed effect. Sex, continuous baseline ppFEV1, and continuous baseline CFQ-R 
respiratory domain score will be used as covariates.  
The tabular presentation of results for the average treatment effect across visits will be similar to 
the primary analysis of the primary efficacy variable for all parts. The adjusted mean (with 95% 
CI) obtained from the model-based analysis at each post-baseline visit will be plotted by 
randomized group for each part.  
In addition, a waterfall plot showing the subject-level absolute change in CFQ-R at Day 29 will 
be presented, by treatment group, for each part. 
8.3.2.3 
Multiplicity adjustment 
There will be no multiplicity adjustment to control the overall type 1 error rate for secondary 
efficacy variables. 
8.3.3 
Analysis of Other Efficacy Variables (Parts D, E and F) 
Other efficacy variables include: 
• Absolute change in CFQ-R non-respiratory domain scores from baseline at Day 29  
Only descriptive analyses will be performed.  


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8.3.3.1 
Absolute change in CFQ-R non-respiratory domain scores from 
baseline at Day 29 (Parts D, E and F)  
The Adolescent/Adult  versions include the following non-respiratory domains: Body Image, 
Digestive Symptoms, Eating Problems, Emotional Functioning, Health Perceptions, Physical 
Functioning, Role Functioning, Social Functioning, Treatment Burden, Vitality, and Weight.  
The absolute change in CFQ-R non-respiratory domain scores from baseline at Day 29 will use 
the 'Adolescents and Adults' Version for ages 14 and above at baseline, and will be based on the 
CFQ-R scaled scores, as described in Appendix F. Descriptive analyses will be performed for all 
treatment groups by post-baseline visit.  
8.3.4 
Analysis of Additional Efficacy Variables (Parts D, E and F) 
Other spirometry efficacy variables in parts D, E and F include: 
• FEV1: 
o Absolute change from baseline in FEV1 (L)  
o Relative change from baseline in FEV1 (%) 
• FVC: 
o Absolute change from baseline in FVC (L) 
o Relative change from baseline in FVC (%) 
o Absolute change from baseline in percent predicted FVC (percentage points) 
o Relative change from baseline in percent predicted FVC (%) 
• FEF25-75%: 
o Absolute change from baseline in FEF25-75% (L/sec) 
o Relative change from baseline in FEF25-75% (%) 
o Absolute change from baseline in percent predicted FEF25-75% (percentage points) 
o Relative change from baseline in percent predicted FEF25-75% (%) 
• FEV1/FVC: 
o Absolute change from baseline in FEV1/FVC 
o Relative change from baseline in FEV1/FVC (%) 
o Absolute change from baseline in percent predicted FEV1/ percent predicted FVC 
o Relative change from baseline in percent predicted FEV1/ percent predicted FVC (%) 
Descriptive analyses of the change from baseline will be performed for all treatment groups by 
post-baseline visit. 
8.3.5 
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 


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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-445 in combination with TEZ/IVA 
(Parts D and E) and in combination with TEZ/VX-561 (Part F) on sweat chloride concentrations 
will be described in this section.  
Descriptive analyses of the change from baseline will also be performed for all treatment groups 
by post-baseline visit. 
8.3.5.1 
Primary Analysis of the Dose Response trend of absolute change in 
sweat chloride from baseline through Day 29 (Part D) 
The null hypothesis to be tested is that the dose response of the mean absolute change from 
baseline through Day 29 for sweat chloride is not decreasing between placebo and the 3 dose 
levels of VX-445 with TEZ/IVA in Part D. The test will be performed using the MCP procedure 
with the pre-specified contrasts provided in Section 6.2.1.2, 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 and subject as a random effect, with continuous 
baseline sweat chloride and continuous baseline ppFEV1 as covariates, and will include all data 
from all treatment groups and visits through Day 29 for analysis. 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 through Day 29 (Day 15 
and Day 29 only), using an unstructured covariance structure for the within-subject errors. If the 
model estimation does not converge, a reduced compound symmetry covariance structure will be 
used instead. 
The tabular presentation of results for the average treatment effect across visits, will be similar to 
the primary analysis of the primary efficacy variable for Parts D. 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 by post-baseline visit.  
8.3.5.2 
Absolute Change in Sweat Chloride from Baseline through Day 29 
(Parts D, E and F) 
8.3.5.2.1 
Parts D, E and F 
The analysis of the absolute change in sweat chloride from baseline through Day 29 will be 
based on an MMRM model similar to the analysis of the primary efficacy variable for Parts D, E, 
and F, with the continuous baseline sweat chloride and continuous baseline ppFEV1 as  
covariates. The presentation of results will also be similar. 
The adjusted mean (with 95% CI) obtained from the MMRM analysis at each post-baseline visit 
through Day 29 in the Period 1 will be plotted by treatment group, for each part.  
A waterfall plot showing the subject-level absolute change in sweat chloride at Day 29 will be 
presented, by treatment group for each part.  
In addition, for each part, descriptive analyses of the change from baseline will be performed for 
all treatment groups by post-baseline visit.  


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8.3.5.3 
Supportive Analysis for Absolute Change from Baseline in Sweat 
Chloride from Baseline through Day 29 
Part D: Period 2 
The Period 2 in Part D after Day 29 through Period 2 visit will be used to assess the washout 
effect of VX-445 on sweat chloride during the 1-week Period 2. This analysis will be based on 
fitting an Analysis of Covariance (ANCOVA) model to the absolute change from baseline in 
sweat chloride in the Period 2, using the group as a fixed effect, with the continuous baseline 
sweat chloride and baseline ppFEV1 as  covariates in the ANCOVA model. Groups will be 
assigned to placebo, TC-low, pooled TC-mid and TC-high the 4 randomized groups in the Period 
1, will be assigned within each subject.   
The adjusted mean of the change from baseline for placebo, TC-low, pooled TC-mid and TC-
high at the Period 2 visit will be provided along with the corresponding p-value.  
The adjusted mean (with 95% CI) obtained from the ANCOVA analysis at Period 2 visit will be 
plotted by randomized group, will be combined with the corresponding plot for the Period 1 from 
the primary analysis of sweat chloride. 
Part E: Washout Period 
The Washout Period in Part E after Day 29 through Day 57 will be used to assess the washout 
effect of VX-445 on sweat chloride during the 4-week Washout Period. This analysis will be 
based on fitting a fully saturated model to the absolute change from baseline in sweat chloride in 
the Washout Period, using the group, visit, and group-by-visit interaction effect as a fixed effect, 
with the continuous baseline sweat chloride and baseline ppFEV1 as covariates in the MMRM 
model. Group (1 versus 2) will be assigned to the two randomized groups in the Treatment 
Period, and visit will be assigned the chronological visit within each subject. The other aspects of 
the MMRM model will be similar to that of the primary analysis.   
The adjusted mean and 95% CI of the mean change from baseline for TC and TEZ/IVA at the 
Washout Period visits Day 43 and Day 57 will be provided along with the corresponding p-
value. Contrasts based on the fixed effects at the covariate mean of the continuous baseline sweat 
chloride and baseline ppFEV1 for the combined treatment groups based on unique subjects in the 
FAS who have at least one post-baseline measurement in the Washout Period, will be used to 
estimate the adjusted mean at each visit in the Washout Period.  
The adjusted mean (with 95% CI) obtained from the MMRM analysis at each post-baseline visit 
in the Washout Period will be plotted by group, combined with the corresponding plot for the 
Period 1 from the primary analysis of sweat chloride. 
8.4 
Safety Analysis 
For Parts D and F, all safety analyses will be based on data from the TE Period for all subjects in 
the Safety Set. For Part E, all safety analyses will be based on the TE Period for the Treatment 
Period for all subjects in the corresponding Safety Set for Treatment Period. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis) 


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• ECGs 
• Vital signs 
• Pulse oximetry 
• Spirometry 
All safety data will be summarized by treatment group and overall, for each part. 
8.4.1 
Adverse Events  
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
For Parts D and F:  
Pretreatment AE: any AE that started before the first dose date of study drug 
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed at 
or after the first dose date of study drug through the end of the TE period  
Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was newly 
developed beyond the TE period 
For Part E:  
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. 
AE summary tables will be presented for TEAEs only, for the TE period for Parts D and F, or the 
TE period for Treatment Period in Part E, by treatment group and overall, for each part 
respectively, as applicable, for the following:  
• Number of TEAEs (total number of TEAEs only) 
• Subjects with any TEAEs  
• Subjects with TEAEs by Strongest Relationship 
• Subjects with TEAEs by Maximum Severity 
• Subjects with TEAEs Leading to Study Drug Discontinuation (Discontinuation of all study 
drug) 


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• Subjects with TEAEs Leading to Study Drug Interruption (Interruption of all study drug) 
• Subjects with Serious TEAEs 
• Subjects with TEAE Leading to Death  
Summaries will be presented by MedDRA System Organ Class (SOC) and Preferred Term (PT) 
using frequency counts and percentages (i.e., number and percentage of subjects with an event). 
When summarizing the number and percentages of subjects, subjects with multiple occurrences 
of the same adverse event or a continuing adverse event will be counted once, 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. Further, 
subjects who enrolled from Study 661-110 will be identified from the subject ID in the listing. 
8.4.2 
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 for Parts D and F, or the TE period for Treatment Period for Part E, 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, and coagulation values 
outside the normal reference ranges will be provided. This listing will include data from both 
scheduled and unscheduled visits.  
8.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided at each 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 for Parts D and F, or the TE period for the Treatment Period in Part E, will be 
summarized by treatment group and overall, for each part. The threshold analysis criteria are 
provided in Appendix H. 


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8.4.4 
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 . 
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 for Parts D and F, or the TE period for the Treatment Period for Part E will be 
summarized by treatment group and overall, for each part. The threshold analysis criteria are 
provided in Appendix H. 
8.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements, a summary of observed values and 
change from baseline values will be provided at each scheduled visit, for the percent of oxygen 
saturation, by treatment group, for each part. 
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
Period for Parts D and F, or the TE period for the Treatment Period for Part E will be 
summarized by treatment group and overall, for each part. 
8.4.6 
Physical Examination  
PE findings will be presented as an individual subject data listing only. 
8.4.7 
Other Safety Analysis 
8.4.7.1 
Post-dose Spirometry 
A summary of the pre-dose values for percent predicted FEV1 and change from pre-dose value 
for the post-dose percent predicted FEV1 value at time point 5-hours post-dose will be presented 
on nominal visits Day 1 and Day 15, by treatment group, for each part.  Further, a box plot of 
differences (post-dose - pre-dose) will be presented by visit and treatment group, for each part.  
9 
INTERIM AND IDMC ANALYSES 
9.1 
Interim Analysis 
Interim analyses may be performed for each part (D1, D2, E and F) after at least 50% of subjects 
in the part have completed the Day 15 Visit. These results will be reviewed by a limited Vertex 
team. 
Interim analyses for Parts D, E and F separately will be performed after all subjects in each part 
have completed the Safety Follow-up Visit. All Data from the part will be unblinded after the 
data from that part are cleaned for analysis and a data cut is performed. The Vertex Study Team 
will be unblinded to the interim analysis results.  
The internal limited Vertex team data reviews will be conducted at a regular frequency during 
the conduct of the study. 


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9.1.1 Summary of the Flow of Data for Interim Analyses for each part (D1, D2 and 
E) at or after 50% of Subjects have Completed the Day 15 Visit 
To protect the integrity of the treatment assignment and study data, the following steps for the 
flow of data will be executed for each interim analysis that may be performed after at least 50% 
of the subjects have completed the Day 15 visit in each part (D1, D2, E and F) and for the 
internal limited Vertex team data review: 
1. The blinded Vertex Biometrics group will prepare the SAS codes, SDTM/ADaM data 
sets,  and blinded outputs (tables, figures and listings) of safety, efficacy and PD data 
using dummy treatment codes, dummy spirometry data, and dummy sweat chloride data; 
2. The IWRS vendor, 
t, will provide the unblinded treatment codes  to the unblinded 
Vertex Biometrics team, 
  
3. 
 provide the unblinded spirometry data to unblinded 
Vertex Biometrics team, 
 provide the unblinded 
sweat chloride data to  unblinded Vertex Biometrics team, 
;  
4. An unblinded Vertex Biometrics group  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 Chair reviewed available safety and PK data from Parts A, B, and C of the study prior to 
commencement of dosing in Part D1 to determine if it is appropriate to proceed with the study. 
Similarly the IDMC Chair will review available blinded safety and PK data from Part D1 prior to 
commencement of dosing in Part D2 to determine if it is appropriate to proceed with the rest 
parts of the study. 
The IDMC’s objectives and operational details were defined in a separate document (IDMC 
Charter) which was finalized before the first subject was screened in the study. The IDMC’s 
planned safety reviews of study data are outlined in the IDMC Charter and IDMC Statistical 
Analysis Plan. Further, planned ongoing reviews of key study data by the limited Vertex team 
are also described in the IDMC Statistical Analysis Plan. 
 


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10 
REFERENCES 
1Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference values for spirometry for the 3-95-yr age 
range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324-43. 
 
 


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LIST OF APPENDICES 
Appendix A: Schedule of Assessments 


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Table 11-1 
Study VX16-445-001: Schedule of Assessments for Parts D1 and D2 
Event/Assessmenta 
Screening 
Treatment Period  
ETT 
Visitb 
Safety Follow-up 
28 (± 7) Days After 
Last Dose 
Period 1 
Period 2 
Days -28 
to -1 
Day 1c  
Day 8 for 
Part D1 only 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Period 2 Visitd 
Informed consent 
X 
 
 
 
 
 
 
 
Randomizatione 
 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
CFQ-Rf,g 
 
X 
 
X 
X 
 
 
 
Weighth 
X 
X 
X 
X 
X 
 
X 
X 
Heighth 
X 
 
 
 
 
 
 
 
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryi 
X 
X 
X 
X 
X 
X 
X 
X 
                                                 
a 
All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once 
if study drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b 
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug 
treatment. Subjects who prematurely discontinue treatment will be required to complete the Safety Follow-up Visit. If the ETT Visit occurs 3 or more weeks 
after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be required. 
c  
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 9.1.2.4 of the protocol. 
d  
The Period 2 Visit will occur 6 to 10 days after the actual date of the Day 29 Visit. 
e 
Randomization may occur on the previous day (Day -1 Visit) after all inclusion and exclusion criteria have been confirmed. 
f 
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
g 
The predose assessment on the Day 1 Visit may be performed on the previous day (Day -1 Visit) if randomization has occurred. 
h 
Weight and height will be measured with shoes off. 
i 
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 


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Table 11-1 
Study VX16-445-001: Schedule of Assessments for Parts D1 and D2 
Event/Assessmenta 
Screening 
Treatment Period  
ETT 
Visitb 
Safety Follow-up 
28 (± 7) Days After 
Last Dose 
Period 1 
Period 2 
Days -28 
to -1 
Day 1c  
Day 8 for 
Part D1 only 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Period 2 Visitd 
Physical examinationj 
Complete 
Abbrev. 
 
Abbrev. 
Abbrev. 
 
Abbrev. 
Complete 
Standard 12-lead ECGk 
X 
X 
X 
X 
X 
 
X 
X 
Sweat chlorideg,l  
X 
X 
X 
X 
X 
Xm 
X 
X 
Spirometryn 
Xo 
X 
X 
X 
X 
Xm 
X 
X 
Urinalysisg 
X 
X 
X 
X 
X 
 
X 
X 
Pregnancy test (all 
females of childbearing 
potential)  
Serum 
Urine 
 
 
Urine 
 
Serum 
Serum 
CFTR genotypep 
X 
 
 
 
 
 
 
 
FSHq 
X 
 
 
 
 
 
 
 
                                                 
j 
Complete and abbreviated PEs are described in Section 11.7.3 of the protocol. Symptom-targeted PEs will occur at any time during the study if triggered by 
AEs or if deemed necessary by the investigator or healthcare provider. 
k 
All standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On the Day 1 and 15 Visits, ECGs will be 
collected before dosing and 5 hours (± 1 hour) after dosing. At all other visits, ECGs will be collected before dosing (as applicable). ECGs collected on the 
Day 1 Visit before dosing will be performed in triplicate.  
l 
Sweat chloride will be measured in all subjects as described in Section 11.4.1 of the protocol. If the value cannot be determined from the screening test, a 
sweat chloride value documented in a laboratory report may be used to establish eligibility. See Section 8.2.1 of the protocol (Inclusion Criterion #5) for 
additional detail. 
m 
At the Period 2 Visit, sweat chloride and ppFEV1 assessments should be done within 2 hours before TEZ/IVA dosing in the morning.  
n 
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 visit. On the Day 1 and Day 15 Visits, spirometry will also be performed 
5 hours (± 1 hour) after study drug administration (pre-bronchodilator).  
o 
For Part D2 subjects only: The ppFEV1 assessment that will be used for stratification of randomization can be done any time during the Screening Period. 
See Section 9.1.2.2 of the protocol. 
p 
CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before randomization, a previous CFTR genotype 
laboratory report may be used to establish eligibility. However, as outlined in Section 9.9 of the protocol 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. 


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Table 11-1 
Study VX16-445-001: Schedule of Assessments for Parts D1 and D2 
Event/Assessmenta 
Screening 
Treatment Period  
ETT 
Visitb 
Safety Follow-up 
28 (± 7) Days After 
Last Dose 
Period 1 
Period 2 
Days -28 
to -1 
Day 1c  
Day 8 for 
Part D1 only 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Period 2 Visitd 
G6PD activity testr 
X 
 
 
 
 
 
 
 
Serum chemistry and 
hematologyg 
X 
X 
X 
X 
X 
 
X 
X 
Coagulationg 
X 
X 
 
X 
X 
 
X 
X 
PK samplingt 
 
X 
 
X 
X 
X 
X 
 
TEZ/IVA or placebo 
dosingu  
 
Day 1 through Period 2 Visit 
 
 
 
VX-445 or placebo 
dosingv 
 
Day 1 through Day 29 
 
 
 
AEs, medicationsw, 
treatments, and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
                                                                                                                                                                                                                         
q 
FSH will be measured for any potential postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
r 
Blood samples will be collected for the G6PD activity test. 
 
t 
Blood samples will be collected for PK analysis of VX-445, TEZ, M1-TEZ, IVA, and M1-IVA. On the Day 1 Visit, samples will be collected before dosing 
(0 hours) and at 1, 2, 4, and 6 hours after dosing (relative to the morning dose). On the Day 15 Visit, samples will be collected before dosing (0 hours) and at 
1, 2, 4, 6, and 8 hours after dosing. On the Day 29 Visit, a predose sample will be collected before the morning dose of study drug. At the Period 2 Visit, a 
single predose sample will be collected before TEZ/IVA dosing in the morning. At the ETT Visit, a single blood sample for PK analysis will be collected. 
u 
On days of scheduled visits, the in-clinic dose of study drugs will be given in the morning, at least 6 hours apart from any other scheduled dose and after all 
predose assessments are complete. The last dose of TEZ/IVA or placebo in Period 2 will be the morning dose of the Period 2 Visit. See Section 9.6.2 of the 
protocol for additional information about study drug administration. 
v     On days of scheduled visits, the in-clinic dose of study drugs will be given in the morning, at least 6 hours apart from any other scheduled dose and after all 
predose assessments are complete. The last dose of VX-445 or placebo in Period 1 will be the morning dose on the Day 29 Visit. See Section 9.6.2 of the 
protocol for additional information about study drug administration. 
w 
Refer to Section 9.5.2 of the protocol for details. 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
Page 37 of 62 
Vertex Pharmaceuticals Incorporated 
 
Table 11-1 
Study VX16-445-001: Schedule of Assessments for Parts D1 and D2 
Event/Assessmenta 
Screening 
Treatment Period  
ETT 
Visitb 
Safety Follow-up 
28 (± 7) Days After 
Last Dose 
Period 1 
Period 2 
Days -28 
to -1 
Day 1c  
Day 8 for 
Part D1 only 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Period 2 Visitd 
AE: adverse event; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; CFTR: CF transmembrane conductance regulator gene; 
; ECG: electrocardiogram; ETT: early termination of treatment; FSH: follicle-stimulating hormone; G6PD: glucose-6-phosphate 
dehydrogenase; ICF: informed consent form; IVA: ivacaftor; PE: physical examination; PK: pharmacokinetic; ppFEV1: percent predicted forced expiratory 
volume in 1 second ; TEZ: tezacaftor 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
Page 38 of 62 
Vertex Pharmaceuticals Incorporated 
 
Table 11-2 
Study VX16-445-001: Schedule of Assessments for Part E 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Period: Period 1 
Washout Period 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dosec 
Days -56 
to -29 
Day -28 
(± 1 day) 
Day -14d 
(+ 13 days) 
Day 1e  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Randomizationf 
 
 
 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
CFQ-Rg,h 
 
 
 
X 
X 
X 
 
X 
  
 
Weighti 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Heighti 
X 
 
 
 
 
 
 
 
 
 
Vital signsj 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryj 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical 
examinationk 
Complete 
Abbreviated 
 
Abbreviated Abbreviated Abbreviated 
 
Abbreviated Abbreviated 
Complete 
                                                 
a  
All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once 
if study drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b  
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, the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be required. 
c  
Part E subjects who meet criteria specified in Section 9.1.2.6 of the protocol will not have a Safety Follow-up Visit.  
d  
The Day -14 Visit is only required for subjects who are not transitioning directly from at least 14 days of uninterrupted TEZ/IVA treatment. Assessments at 
this visit may be performed postdose. 
e  
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 9.1.2.4 of the protocol. 
f  
Randomization may occur on the previous day (Day -1 Visit) after all inclusion and exclusion criteria and criteria for entry into the Treatment Period have 
been confirmed. See Section 9.1.2.2.2 of the protocol. 
g  
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
h  
The predose assessment on the Day 1 Visit may be performed on the previous day (Day -1 Visit) if randomization has occurred. 
i  
Weight and height will be measured with shoes off. 
j  
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
Page 39 of 62 
Vertex Pharmaceuticals Incorporated 
 
Table 11-2 
Study VX16-445-001: Schedule of Assessments for Part E 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Period: Period 1 
Washout Period 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dosec 
Days -56 
to -29 
Day -28 
(± 1 day) 
Day -14d 
(+ 13 days) 
Day 1e  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
Standard 12-lead 
ECGl 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Sweat chlorideh,m 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Spirometryn 
Xo 
  
Xo 
X 
X 
X 
X 
X 
X 
X 
Urinalysish 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (all 
females of 
childbearing 
potential) 
Serum 
Urine 
 
Urine 
 
Urine 
 
Urine 
Serum 
Serum 
CFTR genotypep 
X 
 
 
 
 
 
 
 
 
 
FSHq 
X 
 
 
 
 
 
 
 
 
 
                                                                                                                                                                                                                         
k  
Complete and abbreviated PEs are described in Section 11.7.3 of the protocol. Symptom-targeted PEs will occur at any time during the study if triggered by 
AEs or if deemed necessary by the investigator or healthcare provider. 
l  
All standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On the Days 1 and 15 Visits, ECGs will be 
collected before dosing and 5 hours (± 1 hour) after dosing. At all other visits, ECGs will be collected before dosing (as applicable). ECGs collected on the 
Day 1 Visit before dosing will be performed in triplicate.  
m  
Sweat chloride will be measured in all subjects as described in Section 11.4.1 of the protocol. If the value cannot be determined from the screening test (e.g. 
due to laboratory error), a sweat chloride value documented in a previous laboratory report may be used to establish eligibility. See Section 8.2.1 of the 
protocol (Inclusion Criterion #5) for additional detail.  
n  
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 (except at the Day -14 Visit when spirometry may be performed postdose), and should be performed at approximately the same time at every 
visit. On the Day 1 and Day 15 Visits, spirometry will also be performed 5 hours (± 1 hour) after study drug administration (pre-bronchodilator).  
o  
The ppFEV1 assessment for stratification of randomization will be done at the Screening Visit for subjects transitioning directly from at least 14 days of 
uninterrupted TEZ/IVA treatment. For all other subjects, this assessment will be done at the Day -14 Visit. See Section 9.1.2.2 of the protocol.  
p  
CFTR genotyping will be performed for all subjects. If the screening CFTR genotype result is not received before the Day -28 Visit, a previous CFTR 
genotype laboratory report may be used to establish eligibility. However, as outlined in Section 9.9 of the protocol, 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. 
q  
FSH will be measured for any suspected postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
Page 40 of 62 
Vertex Pharmaceuticals Incorporated 
 
Table 11-2 
Study VX16-445-001: Schedule of Assessments for Part E 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Period: Period 1 
Washout Period 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dosec 
Days -56 
to -29 
Day -28 
(± 1 day) 
Day -14d 
(+ 13 days) 
Day 1e  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
G6PD activity testr 
X 
 
 
 
 
 
 
 
 
 
Serum chemistry 
and hematologyh 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Coagulationh 
X 
X 
 
X 
X 
X 
 
 
X 
X 
PK samplingt 
 
 
 
X 
X 
X 
X 
 
X 
  
TEZ/IVA dosingu 
 
Day -28 through Day 57 
 
 
VX-445 or placebo 
dosingv 
 
 
 
Day 1 through Day 29 
 
 
 
 
AEs, medicationsw, 
treatments and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
                                                 
r  
Blood samples will be collected for the G6PD activity test. 
  
Blood samples will be collected for PK analysis of VX-445, TEZ, M1-TEZ, IVA, and M1-IVA. On the Day 1 Visit, samples will be collected before dosing 
(0 hours) and at 1, 2, 4, and 6 hours after dosing (relative to morning dose). On the Day 15 Visit, samples will be collected before dosing (0 hours) and at 1, 
2, 4, 6, and 8 hours after dosing. On the Day 29 Visit, a predose sample will be collected before the morning dose of study drug. At the Day 43 Visit, a single 
blood sample for PK analysis will be collected before the morning dose of TEZ/IVA. At the ETT Visit, a single blood sample for PK analysis will be 
collected. 
u 
The last dose of TEZ/IVA will be the morning dose on the Day 57 Visit. See Section 9.6.2 of the protocol for additional information about study drug 
administration. 
v  
The last dose of VX-445 or placebo will be the morning dose on the Day 29 Visit. See Section 9.6.2 of the protocol for additional information about study 
drug administration. 
w  
Refer to Section 9.5.2 of the protocol for details. 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
Page 41 of 62 
Vertex Pharmaceuticals Incorporated 
 
Table 11-2 
Study VX16-445-001: Schedule of Assessments for Part E 
Event/Assessmenta 
Screening 
Run-in Period 
Treatment Period: Period 1 
Washout Period 
ETT 
Visitb 
Safety 
Follow-up 
28 (± 7) Days 
After Last 
Dosec 
Days -56 
to -29 
Day -28 
(± 1 day) 
Day -14d 
(+ 13 days) 
Day 1e  
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 43 
(± 3 days) 
Day 57 
(± 3 days) 
AE: adverse event; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; CFTR: CF transmembrane conductance regulator gene; 
; ECG: electrocardiogram; ETT: early termination of treatment; FSH: follicle-stimulating hormone; G6PD: glucose-6-phosphate 
dehydrogenase; ICF: informed consent form; IVA: ivacaftor; PE: physical examination; PK: pharmacokinetic; ppFEV1: percent predicted forced expiratory 
volume in 1 second ; TEZ: tezacaftor 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
Page 42 of 62 
Vertex Pharmaceuticals Incorporated 
 
Table 11-3 
Study VX16-445-001: Schedule of Assessments for Part F (if Conducted) 
Event/Assessmenta 
Screening 
Treatment Period: Period 1 
ETT 
Visitb 
Safety Follow-up 
28 (± 7) Days After 
Last Dose 
Days -28 
to -1 
Day 1c  
Day 8d 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Informed consent 
X 
 
 
 
 
 
 
Randomizatione 
 
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
CFQ-Rf,g 
 
X 
 
X 
X 
 
 
Weighth 
X 
X 
 
X 
X 
X 
X 
Heighth 
X 
 
 
 
 
 
 
Vital signsi 
X 
X 
 
X 
X 
X 
X 
Pulse oximetryi 
X 
X 
 
X 
X 
X 
X 
                                                 
a 
All assessments will be performed before dosing, unless noted otherwise. Assessments that are collected before and after dosing will only be collected once 
if study drug is not administered on the day of the visit (i.e., if subject prematurely discontinued study drug treatment). 
b 
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study drug 
treatment. Subjects who prematurely discontinue treatment will be required to complete the Safety Follow-up Visit. If the ETT Visit occurs 3 or more weeks 
after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be required. 
c  
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 9.1.2.4 of the protocol. 
d  
The laboratory assessment may be collected at the clinic, at a local laboratory, or during a visit by a qualified individual (e.g., home nurse). If the laboratory 
assessment is not collected at the clinic, a telephone call to the clinic is required for the collection of AEs. When the laboratory assessment is done in the 
clinic, the AE collection will also occur in the clinic. 
e 
Randomization may occur on the previous day (Day -1 Visit) after all inclusion and exclusion criteria have been confirmed. 
f 
CFQ-R must be completed before the start of any other assessments scheduled at that visit. 
g 
The predose assessment on the Day 1 Visit may be performed on the previous day (Day -1 Visit) if randomization has occurred. 
h 
Weight and height will be measured with shoes off. 
i 
Vital signs and pulse oximetry will be collected after the subject has been seated for at least 5 minutes. 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
Page 43 of 62 
Vertex Pharmaceuticals Incorporated 
 
Table 11-3 
Study VX16-445-001: Schedule of Assessments for Part F (if Conducted) 
Event/Assessmenta 
Screening 
Treatment Period: Period 1 
ETT 
Visitb 
Safety Follow-up 
28 (± 7) Days After 
Last Dose 
Days -28 
to -1 
Day 1c  
Day 8d 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Physical examinationj 
Complete 
Abbrev. 
 
Abbrev. 
Abbrev. 
Abbrev. 
Complete 
Standard 12-lead ECGk 
X 
X 
 
X 
X 
X 
X 
Sweat chlorideg,l,  
X 
X 
 
X 
X 
X 
X 
Spirometrym 
Xn 
X 
 
X 
X 
X 
X 
Urinalysisg 
X 
X 
 
X 
X 
X 
X 
Pregnancy test (all females of childbearing 
potential)  
Serum 
Urine 
 
 
Urine 
Serum 
Serum 
CFTR genotypeo 
X 
 
 
 
 
 
 
FSHp 
X 
 
 
 
 
 
 
G6PD activity testq 
X 
 
 
 
 
 
 
                                                 
j 
Complete and abbreviated PEs are described in Section 11.7.3 of the protocol. Symptom-targeted PEs will occur at any time during the study if triggered by 
AEs or if deemed necessary by the investigator or healthcare provider. 
k 
All standard 12-lead ECGs will be performed after the subject has been seated or supine for at least 5 minutes. On the Day 1 and 15 Visits, ECGs will be 
collected before dosing and 5 hours (± 1 hour) after dosing. At all other visits, ECGs will be collected before dosing (as applicable). ECGs collected on the 
Day 1 Visit before dosing will be performed in triplicate.  
l 
Sweat chloride will be measured in all subjects as described in Section 11.4.1 of the protocol. If the value cannot be determined from the screening test, a 
sweat chloride value documented in a previous laboratory report may be used to establish eligibility. See Section 8.2.1 of the protocol (Inclusion Criterion 
#5) for additional detail. 
m 
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 visit. On the Day 1 and 15 Visits, spirometry will also be performed 
pre-bronchodilator, 5 hours (± 1 hour) after study drug administration.  
n 
The ppFEV1 assessment that will be used for stratification of randomization can be done any time during the Screening Period. See Section 9.1.2.2 of the 
protocol. 
o 
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. However, as outlined in Section 9.9 of the protocol, 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. 
p 
FSH will be measured for any potential postmenopausal female subjects with at least 12 months of continuous spontaneous amenorrhea. 
q 
Blood samples will be collected for the G6PD activity test. 


Statistical Analysis Plan (Methods) 
Protocol VX16-445-001, Version 7.0 
Page 44 of 62 
Vertex Pharmaceuticals Incorporated 
 
Table 11-3 
Study VX16-445-001: Schedule of Assessments for Part F (if Conducted) 
Event/Assessmenta 
Screening 
Treatment Period: Period 1 
ETT 
Visitb 
Safety Follow-up 
28 (± 7) Days After 
Last Dose 
Days -28 
to -1 
Day 1c  
Day 8d 
(± 1 day) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Serum chemistry and hematologyg 
X 
X 
X 
X 
X 
X 
X 
Coagulationg 
X 
X 
 
X 
X 
X 
X 
PK samplings 
 
X 
 
X 
X 
X 
 
VX-445/TEZ/VX-561 or placebo dosingt  
 
Day 1 through Day 29 
 
 
 
AEs, medicationsu, treatments, and 
procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
AE: adverse event; CF: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; CFTR: CF transmembrane conductance regulator gene; 
; ECG: electrocardiogram; ETT: early termination of treatment; FSH: follicle-stimulating hormone; G6PD: glucose-6-phosphate 
dehydrogenase; ICF: informed consent form; IVA: ivacaftor; PE: physical examination; PK: pharmacokinetic; ppFEV1: percent predicted forced expiratory 
volume in 1 second ; TEZ: tezacaftor 
                                                 
 
Blood samples will be collected for PK analysis of VX-445, TEZ, M1-TEZ, and VX-561. On the Day 1 Visit, samples will be collected before dosing 
(0 hours) and at 1, 2, 4, and 6 hours after dosing (relative to the morning dose). On the Day 15 Visit, samples will be collected before dosing (0 hours) and at 
1, 2, 4, 6, and 8 hours after dosing. On the Day 29 Visit, a predose sample will be collected before the morning dose of study drug. At the ETT visit, a single 
blood sample for PK analysis will be collected. 
t 
On days of scheduled visits, the in-clinic dose of study drugs will be given in the morning, at least 6 hours apart from any other scheduled dose and after all 
predose assessments are complete. The last dose of VX-445/TEZ/VX-561 or placebo will be the morning dose on the Day 29 Visit. See Section 9.6.2 of the 
protocol for additional information about study drug administration. 
u 
Refer to Section 9.5.2 of the protocol for details. 


Statistical Analysis Plan (Methods) 
Page 45 of 62 
Protocol Number: VX16-445-001 Version 7.0 
 
Vertex Pharmaceuticals Incorporate                                                                                     
 
 
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 11-4 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
Safety Assessment (Parts D1 and D2) 
Serum Chemistry 
Hematology 
Weight 
 
Day 1 (Baseline)  
Day 8 (Part D1) 
Day 15(Part D1) 
Day 15(Part D2) 
Day 29 
Safety Follow-up 
1 
8 
15 
15 
29 
64 
≤1 Pre-dose 
[1, 12] Day 1 post dose 
(12, 22] 
[1,  22] Day 1 post dose 
(22, 47] 
Use nominal visit 
Coagulation 
 
Day 1 (Baseline)  
Day 15 
Day 29 
Safety Follow-up 
1 
15 
29 
64 
≤1 Pre-dose 
[1,  22] Day 1 post dose 
(22, 47] 
Use nominal visit 
Vital Signs  
Pulse Oximetry 
Day 1 (Baseline)  
Day 8 (Part D1) 
Day 15(Part D1) 
Day 15(Part D2) 
Day 29 
Period 2 visit 
 
Safety Follow-up 
1 
8 
15 
15 
29 
Period 2 visit 
(36) 
64 
≤1 Pre-dose 
[1, 12]  
(12,22] 
[1,  22]  
(22, 33] 
(33, 50] 
 
Use nominal visit 
Standard 12-Lead ECG 
Day 1 (Baseline; before dosing) 
Day 1 (5 hours after dosing)  
Day 8 (Part D1 only) 
Day 15 (before dosing and 5 hours 
after dosing) 
Day 29 
Safety Follow-up 
1 
1 
8 
15 
 
29 
64 
Use nominal visit for all 
visits 
Spirometry 
Day 1  (5 hours post dose) 
Day 15 ( 5 hours post dose) 
1 
15 
Use nominal visit 
Use nominal visit 
Safety Assessment (Part E) 
Serum Chemistry 
Hematology 
Vital Signs (including 
Weight) 
Pulse Oximetry 
Day 1 (Baseline)  
Day 15 
Day 29 
Day 43 
Day 57 
Safety Follow-up 
1 
15 
29 
43 
57 
85 
≤1 Pre-dose 
[1, 22] Day 1 post dose 
(22, 36] 
(36, 50] 
(50, 71] 
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 and Spirometry measurements. 


Statistical Analysis Plan (Methods) 
Page 46 of 62 
Protocol Number: VX16-445-001 Version 7.0 
 
Vertex Pharmaceuticals Incorporate                                                                                     
 
Table 11-4 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
Coagulation 
 
Day 1 (Baseline)  
Day 15 
Day 29 
Safety Follow-up 
1 
15 
29 
85 
≤1 Pre-dose 
[1,22] Day 1 post dose 
(22, 57] 
Use nominal visit 
Standard 12-Lead ECG  
Day 1 (Baseline; before dosing) 
Day 1 (5 hours after dosing)  
Day 15 (before dosing and 5 hours 
after dosing) 
Day 29 
Day 43 
Day 57 
Safety Follow-up 
1 
 
1 
15 
29 
43 
57 
85 
Use nominal visit for all 
visits 
Spirometry 
Day 1  (5 hours post dose) 
Day 15 ( 5 hours post dose) 
1 
15 
Use nominal visit 
Use nominal visit 
Safety Assessment (Part F) 
Serum Chemistry 
Hematology 
 
Day 1 (Baseline)  
Day 8 
Day 15 
Day 29 
Safety Follow-up 
1 
8 
15 
29 
57 
≤1 Pre-dose 
[1, 12] Day 1 post dose 
(12,22] 
(22, 43] 
Use nominal visit 
Coagulation 
Vital Signs (including 
Weight) 
Pulse oximetry 
Day 1 (Baseline)  
Day 15 
Day 29 
Safety Follow-up 
1 
15 
29 
57 
≤1 Pre-dose 
[1,22] 
(22, 43] 
Use nominal visit 
Standard 12-Lead ECG  
Day 1 (Baseline; before dosing) 
Day 1 (5 hours after dosing)  
Day 15 (before dosing and 5 hours 
after dosing) 
Day 29 
Safety Follow-up 
1 
1 
15 
 
29 
57 
Use nominal visit for all 
visits 
Spirometry 
Day 1  (5 hours post dose) 
Day 15 ( 5 hours post dose) 
1 
15 
Use nominal visit 
Use nominal visit 
Efficacy Assessment (Parts D1 and D2) 
Spirometry  
Sweat Chloride 
Day 1 (Baseline)  
Day 8 (Part D1) 
Day 15 (Part D1)  
Day 15 (Part D2)  
Day 29 
Period 2 visit 
 
Safety Follow-up  
1 
8 
15 
15 
29 
Period 2 visit 
(36) 
 
64 
≤1 Pre-dose 
(1, 12] 
(12, 22]  
(1, 22]  
(22, 33] 
(33, 50] 
 
Use nominal visit 
CFQR  
Day 1 (Baseline)  
Day 15 
Day 29 
1 
15 
29 
≤1 Pre-dose 
(1, 22]  
(22, 47] 
Efficacy Assessment (Part E) 


Statistical Analysis Plan (Methods) 
Page 47 of 62 
Protocol Number: VX16-445-001 Version 7.0 
 
Vertex Pharmaceuticals Incorporate                                                                                     
 
Table 11-4 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study days) 
Spirometry  
 
Day 1 (Baseline)  
Day 15 
Day 29 
Day 43 
Day 57 
Safety Follow-up 
1 
15 
29 
43 
57 
85 
≤1 Pre-dose 
(1,22]  
(22, 36] 
(36, 50] 
(50, 71] 
Use nominal visit 
Sweat Chloride 
Day 1 (Baseline)  
Day 15 
Day 29 
Day 43 
Day 57 
1 
15 
29 
43 
57 
≤1 Pre-dose 
(1,22]  
(22, 36] 
(36, 50] 
(50, 71] 
CFQR  
Day 1 (Baseline)  
Day 15 
Day 29 
Day 57 
1 
15 
29 
57 
≤1 Pre-dose 
(1,22]  
(22, 43] 
(43, 71] 
Efficacy Assessment (Part F) 
Spirometry  
Sweat Chloride 
Day 1 (Baseline)  
Day 15 
Day 29 
Safety Follow-up 
1 
15 
29 
57 
≤1 Pre-dose 
(1,22]  
(22, 43] 
Use nominal visit 
CFQR  
Day 1 (Baseline)  
Day 15 
Day 29 
1 
15 
29 
≤1 Pre-dose 
(1,22]  
(22, 43] 
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 extreme lab measurements based on ULN or LLN, convert the lab measurements into 
times of ULN or LLN first, and then select the extreme measurement. 
 
Derived Variables 
1. Age (in years) at first dose date  
Obtain age at screening (in days) in yy mm format (e.g., 24 years, 6 months) from screening vital signs page, and add 
0.5 month to convert to days. 


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Vertex Pharmaceuticals Incorporate                                                                                     
 
Table 11-4 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visita 
Target Study 
Dayb 
Analysis Visit Window 
(in study 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 = [(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 treatment period visit date. 
4. Missing Date for Drug Interruption 
If the dates for drug interruption are completely missing or partially missing and cannot be determine in which period 
the interruption occurred, then assume the interruption occurred during the Period 1 for 1 day. 
5. Sweat Chloride: 
The qualified left arm and right arm sweat chloride assessments on Day 1 with the end date/time for a given arm up 
to 30 minutes after first dose time will be considered for baseline. If Day 1 value is unavailable or invalid, screening 
value will qualify as baseline. 
 
 
 


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Vertex Pharmaceuticals Incorporate                                                                                     
 
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 11-5 
Prior, Concomitant, and Post Categorization of a Medication in Parts D and F 
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 11-6 
Prior, Concomitant, and Post Categorization of a Medication in Part E 
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 
 
 


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Vertex Pharmaceuticals Incorporate                                                                                     
 
Appendix D: Important Protocol Deviation Rules  
Important protocol deviations before first dose 
Stratification error based on comparing the IWRS stratification with the clinical database 
For Part D2, ppFEV1 stratification (<70 versus ≥70) will be performed using the 
screening (Days -28 to -1) ppFEV1 value.  
For Part E, ppFEV1 stratification (<70 versus ≥70) will be performed using a value 
obtained at the following visit: 
• Screening Visit (Days -56 to -29) for subjects transitioning directly from at least 
14 days of uninterrupted TEZ/IVA treatment 
• Day -14 Visit (+ 13 days) for all other subjects 
For Part F, ppFEV1 stratification (<70 versus ≥70) will be performed using the screening 
(Days -28 to -1) ppFEV­1 value. 
Important programmable protocol deviations during the Treatment Period 
1. Compliance < 80%  
2. Use of prohibited medications 
3. Actual treatment received is different from the randomized treatment  
 
 


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Vertex Pharmaceuticals Incorporate                                                                                     
 
Appendix E: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
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 Sept 14, 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:  
ttp://www.ers-education.org/guidelines/global-lung-function-initiative/spirometry-tools/it-
engineers-and-manufacturers.aspx 
Accessed Sept 14, 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 Sept 14, 2017. 
Data handling rule for spirometry is as follows:  
• Input age and height with at least 2 decimal places. 
•  Use height at screening regardless if height is collected at study visit. 
• For race, map CRF black or AA to black, all other races in CRF (except white) are 
mapped to 'other'; multiple checks for race in CRF are also mapped to 'other'; white is a 
reference race in the equations and assumes 0 values for all race coefficients in the       
GLI  equations. 
 
 


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Vertex Pharmaceuticals Incorporate                                                                                     
 
Appendix F: Details of CFQ-R Analysis and Scoring Manual 
The CFQ-R is a valid CF-specific instrument that measures quality-of-life domains. This study 
uses CFQ-R for Adolescents and Adult (subjects 14 years and older) in this study. CFQ-R for 
Adolescents and Adult (subjects 14 years and older) has a total of 50 questions to form 12 
domains. Question 43, which is scored 1, 2, 3, 4, or 5, is not used in calculating any domains; all 
the other 49 questions are scored 1, 2, 3, or 4. 
To calculate the score for each domain, the response scores on the negatively phrased questions 
are reversed (reversed scores = 5 – response scores) so that 1 always represents the worst 
condition and 4 always represents the best condition. In each domain, in cases where individual 
questions were skipped, the missing scores are imputed with the mean score of the non-missing 
questions for that domain.  
The scaled score for each domain ranges from 0 (worst condition) to 100 (best condition). It is 
calculated as follows: 
Scaled score for a domain = 100 × (mean(scores of all questions in that domain) - 1)/3 
The scaled score for a specific domain will not be calculated if more than half of the questions in 
the domain have missing scores. 
Table 11-7 provides the questions included in each domain, the questions with the reversed 
scores, as well as the CFQ-R for Adolescents and Adults. The CFQ-R scoring manual is also 
attached. 
Table 11-7 
CFQ-R for Adolescents and Adults (subjects 14 years and older)  
 
Domain 
Questions 
 
Reversed questions 
Maximum number of 
missing questions 
Total 
Individual 
Physical 
8 
1, 2, 3, 4, 5, 13, 19, 20 
13 
4 
Role 
4 
35, 36, 37, 38 
35 
2 
Vitality 
4 
6, 9, 10, 11 
6, 10 
2 
Emotion 
5 
7, 8, 12, 31, 33 
- 
2 
Social 
6 
22, 23, 27, 28, 29, 30 
23, 28, 30 
3 
Body 
3 
24, 25, 26 
- 
1 
Eat 
3 
14, 21, 50 
- 
1 
Treatment burden 
3 
15, 16, 17 
15, 17 
1 
Health perceptions 
3 
18, 32, 34 
18, 32, 34 
1 
Weight 
1 
39 
- 
0 
Respiration* 
6 
40, 41, 42, 44, 45, 46 
43 
3 
Digestion 
3 
47, 48, 49 
- 
1 
*: Question 43 not used to calculate a domain.  
 
The CFQ-R scoring manual is attached. 
 




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Vertex Pharmaceuticals Incorporate                                                                                     
 
Appendix G: Imputation Rules for Missing AE dates  
H.1 Parts D1, D2 and F 
Imputation rules for missing or partial AE start date for Parts D1, D2 and F are defined below. 
• If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year and month are equal to the month and year of first dose date 
of the Treatment Period, then impute the AE start day as the day of first dose 
date of the Treatment Period;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Treatment Period;  
 else impute the AE start month as January and day as 1.  
o else impute the AE start month as January and day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site with 
no imputation.  
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then the AE will be considered as TEAE for the 
Treatment Period.  
o else the AE will be considered as a pretreatment AE. 
 
H.2 Part E 
Imputation rules for missing or partial AE start date for Part E 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  


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Vertex Pharmaceuticals Incorporate                                                                                     
 
 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.  
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.  


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Vertex Pharmaceuticals Incorporate                                                                                     
 
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. 
 
 


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Vertex Pharmaceuticals Incorporate                                                                                     
 
Appendix H: Criteria for Threshold Analysis 
Table 11-8 
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. 


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Vertex Pharmaceuticals Incorporate                                                                                     
 
Table 11-8 
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 
CPK 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
CTCAE grades 1-4 
 
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 
 


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Vertex Pharmaceuticals Incorporate                                                                                     
 
Table 11-8 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Reticulocytes/Erythrocytes (%)    <LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated Partial thromboplastin 
time  (PPT) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
 
CTCAE grade 1-3 
 
Prothrombin time (PT) 
International Normalized Ratio 
(INR) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
 
 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX16-445-001 Version 7.0 
 
Vertex Pharmaceuticals Incorporate                                                                                     
 
Table 11-9 
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. 
 


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Vertex Pharmaceuticals Incorporate                                                                                     
 
Table 11-10 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 


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Vertex Pharmaceuticals Incorporate                                                                                     
 
Table 11-10 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