Clinical trial NCT04340362
Conditions: Glomerulosclerosis, Focal Segmental
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2020-06-08; Completion date: 2021-12-09
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the efficacy, safety and pharmacokinetics (PK) of VX-147 in participants with apolipoprotein L1 (APOL1)-mediated focal segmental glomerulosclerosis (FSGS).

Detailed description:

Arms: arm 1: All participants received VX-147 at a dosage of 15 mg once daily (qd) for 2 weeks and VX-147 at a dosage of 45 mg qd for 11 weeks. Part A was enrolled in 2 cohorts: Cohort 1 and Cohort 2. Cohort 1 included participants with urine protein to creatinine ratio (UPCR) approximately greater than or equal to (≥) 3 g/g (± 10%) and less than (\<) 10 g/g and estimated glomerular filtration rate (eGFR) approximately ≥30 mL/min/1.73 m2 (± 10%). Cohort 2 included participants with UPCR approximately ≥0.8 g/g (± 10%) and \<2.7 g/g and eGFR approximately ≥30 mL/min/1.73 m2.
Interventions: intervention 1: VX-147
Intervention descriptions: intervention 1: Tablets for oral administration.

Protocol documents:
Prot_000.pdf: 


Protocol VX19-147-101, Version 2.0 
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Summary of Changes to the Protocol 
The previous version of this protocol (Version 1.0, dated 10 October 2019) was amended to 
create the current version (Version 2.0, dated 05 March 2020). 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 10 October 2019 
Original version 
Version 2.0, 05 March 2020 
Current version 
 
Key changes in the current version of the protocol are summarized below.  
Change and Rationale 
Affected Sections  
Modified the upper threshold of the inclusion criterion for estimated glomerular 
filtration rate from ≥30 mL/min/1.73 m2 to ≥45 mL/min/1.73 m2 to include 
subjects with less severe kidney disease. 
Sections 2 and 8.1 
Removed the requirement for kidney biopsy to be done within 18 months before 
screening. This timeframe was intended to ensure preserved renal function, which 
is no longer needed because the eligible eGFR was increased to 
≥45 mL/min/1.73 m2. 
Section 8.1 
Specified the doses to be used are 15 mg once daily (qd) (Treatment Period 1) and 
45 mg qd (Treatment Period 2). 
Sections 2, 9.1, 9.1.2.1, 
9.3.1, 9.3.3, 9.6, and 10.3 
Added an optional cohort of subjects (Cohort 2) who represent a broader 
population of FSGS patients than the population in version 1.0. Enrollment of 
Cohort 1 will be prioritized over enrollment of Cohort 2. 
Sections 2, 3, 8, 9.1, 
9.1.2.1, and 12 
The FSGS Patient-reported Outcome (PRO) assessment and endpoint were 
removed because the PRO form is not available to the sponsor. 
Sections 2, 7, 9.3, 9.3.4, 
11.5, and 12.3.5; Table 3-2  
The visit names for Part B were modified to reflect the time of the visit relative to 
the last dose of study drug. 
Table 3-3 
The Part B requirement to collect a confirmatory UPCR sample after the level 
returns to baseline was removed because Part B is optional and the requirement is 
an unnecessary burden for subjects. 
Table 3-3 
The blood pharmacokinetic (PK) sample was removed from the Safety Follow-up 
Visit (28 days after the last dose of study drug) because it is not needed for 
analysis. 
Table 3-3 
Clarified that the Postdose PK Sampling Visit is not required for subjects who 
complete an ETT Visit. 
Table 3-3 
The visit window for the Part A Week 13 Visit was changed from ± 2 days 
to -2 days to ensure that the efficacy samples for the primary endpoint are 
collected while the subject is on treatment. 
Table 3-2 
Added 1 additional UPCR sample during Week 9 (for a total of 2 samples) to 
provide a more accurate measurement at this timepoint. 
Table 3-2; Sections 11.3 
and 11.6.2 
Clarified the timing of visit windows. 
Table 3-2 and Table 3-3 
Clarified in several sections that Part B is optional. 
Sections 2 and 9.1 
Short form-36 (SF-36) was added at the Safety Follow-up Visit and as an 
exploratory endpoint for Part B to assess the sensitivity of this tool to changes in 
treatment (i.e., baseline, during treatment, and off treatment). 
Table 3-3; Sections 2 and 
7.2 
Added a visit window for the Treatment Period Day 15 Visit of ±2 days to allow 
flexibility in visit scheduling. 
Table 3-2 


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Change and Rationale 
Affected Sections  
Modified the requirement for the 3 urine samples collected during screening and 
Week 13 to be collected on separate days within a 7-day period, instead of 
requiring at least 1 day between 3 separate collections. This will allow additional 
operational flexibility without changing the intent of the assessment. The 
corresponding eligibility criteria were also updated.  
Table 3-1 and Table 3-2; 
Sections 8.1, 9.3.4.1, 11.3, 
11.6.2, and 12.3.3 
Urine PK was removed from the secondary endpoints because urine PK will not be 
collected. 
Sections 2 and 7 
Added rationale for the study duration and dose based on clinical and nonclinical 
data. 
Sections 5 and 9.3 
Added an additional exclusion criterion: “Hypersensitivity to investigational 
medicinal product or to any of its excipients”. 
Section 8.2 
Added exclusion of hemoglobin <10 g/dL to exclude subjects with clinically 
significant anemia. 
Section 8.2 
Lowered the eligible blood pressure threshold from 180/110 to 160/100. Requiring 
subjects to have better controlled blood pressure reduces the likelihood of changes 
to blood pressure medications during the study that could confound the study 
results. 
Section 8.2 
Revised the heading of “Eligibility Adjudication” to “Eligibility Review” to more 
accurately reflect the process. 
Sections 8.1 and 9.3.6 
Specified that subjects who discontinue study drug before completing Part A will 
not complete further Part A Visits. These subjects will not continue to Part B. 
Table 3-2; Sections 2 and 
9.1.2.3 
Removed the option to participate in Part B for subjects who have proteinuria 
levels in Part A that are at or greater than baseline before the end of Part A. These 
subjects cannot be followed for return to baseline Part B, because they have 
already reached that status.  
Section 9.1.3 
Added neprilysin inhibitor, sodium-glucose co-transporter-2 inhibitor, and 
corticosteroids (applies to Cohort 2 only) as additional medications that are 
commonly used in this population and that should not be planned for stopping, 
starting, or having dosing changes during study participation. 
Sections 8.1 and 9.4 
Based on Institutional Review Board feedback, guidance was added for 
concomitant medication use if it becomes clinically necessary to alter a subject’s 
antihypertensive regimen during the study. Changes to an antihypertensive 
medication dose or addition of a new antihypertensive medication are 
recommended before changes are made to any angiotensin converting enzyme 
inhibitor, angiotensin receptor blocker, neprilysin inhibitor, or renin inhibitor. 
Section 9.4 
Removed the study restriction for concomitant use of sensitive CYP3A substrates, 
based on Study VX18-147-001 data showing that VX-147 45 mg q24h does not 
result in clinically meaningful CYP3A inhibition or induction. 
Section 9.5 
Reduced the restriction for corticosteroid use before the first dose of 
investigational product from 12 weeks to 4 weeks, because this is a sufficient 
washout period for corticosteroid effects on proteinuria. 
Section 9.5 
Specified that, if local regulations or site practice do not allow telemedicine, all 
visits will be conducted at the site.  
Section 9.3.5 
Added rituximab to the list of restricted medications because this medication is 
used for FSGS treatment and concomitant or recent use could affect interpretation 
of the results of this study. 
Section 9.5 
Removed the requirement to fast before and after dosing, based on data from 
Study VX18-147-001 showing no food effect. 
Section 9.6 
Added blood smears to the safety laboratory panel to more completely assess 
hematology. 
Table 11-2 


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Change and Rationale 
Affected Sections  
Added instructions for the investigator to deliver the APOL1 genotype result to the 
subject. Vertex will ensure the subject can obtain the services of a genetic 
counselor, if desired. Sites will be responsible for managing the corresponding 
logistics. 
Section 11.4 
Removed electronic consent as an option, because this method will not be used. 
Section 8.1, 11.6.5.2, and 
13.1.1.1; Table 3-1, 
Table 3-2, and Table 3-3 
Streamlined statistical analysis section as details will be included in a separate 
statistical analysis plan. 
Section 12 
Added the option for interim analysis to support program planning. 
Section 12.3.6 
Updated the table for reporting of AE severity to match the table in Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
Section 13.1.1.4 
Specified that the lipid profile will only be measured at the Day 1, Week 3, 
Week 13, ETT, and Safety Follow-up Visits because these are visits that require 
overnight fasting before the serum chemistry blood draw and will provide a more 
robust assessment of safety compared to non-fasted samples. 
Table 11-2 
Specified that the baseline value used to determine when a subject in Part B has 
returned to baseline will be the average of the 2 screening values used to 
determine eligibility.  
Section 9.1.3; Table 3-3 
 
Typographical and administrative changes were also made to improve the clarity of the 
document. 


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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 2a, Open-label, Single-arm, 2-Part Study to Evaluate the Efficacy, Safety, and 
Pharmacokinetics of VX‑147 in Adults With APOL1-mediated Focal Segmental 
Glomerulosclerosis 
  
Brief Title 
Phase 2a Study of VX-147 in Adults With APOL1-mediated Focal Segmental 
Glomerulosclerosis 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 2a pharmacodynamics (PD), safety, and pharmacokinetics (PK) 
 
 
Objectives 
Part A (Treatment Period) 
Primary 
• 
To evaluate the ability of VX-147 to reduce proteinuria 
Secondary 
• 
To evaluate the safety and tolerability of VX-147 
• 
To characterize the PK of VX-147 
Part B (Optional Off-treatment Follow-up Period) 
Exploratory  
• To evaluate the change in proteinuria after stopping administration of VX-147 
 
 
Endpoints 
Part A (Treatment Period) 
Primary 
• 
Percent change from baseline in urine protein to creatinine ratio (UPCR) at 
Week 13 
Secondary 
• 
Safety and tolerability based on adverse events (AEs), clinical laboratory values 
(i.e., hematology, serum chemistry, urinalysis, coagulation studies), standard 
12-lead ECGs, and vital signs 
• 
Plasma PK of VX-147 
Exploratory  
• 
Percent change from baseline in UPCR over time during the Treatment Period  
• 
Percent change from baseline in urine albumin-to-creatinine ratio (UACR) at 
Week 13 
• 
Percent change from baseline in UACR over time during the Treatment Period 
• 
Change from baseline in patient-reported outcome (PRO) Short Form Health 
Survey 36 (SF-36) over time during the Treatment Period  
Part B (Optional Off-treatment Follow-up Period) 
Exploratory  
• Percent change from baseline in UPCR at the end of the Off-treatment Follow-up 
Period 
• Change from baseline in SF-36 over time during the Off-treatment Follow-up 
Period 
 
 


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Number of Subjects 
Approximately 10 subjects in Cohort 1 and approximately 10 subjects in optional 
Cohort 2 
 
 
Study Population 
Male and female subjects 18 to 60 years old with 2 apolipoprotein L1 (APOL1) risk 
alleles (G1/G1, G1/G2, or G2/G2 genotype) who have APOL1-mediated focal 
segmental glomerulosclerosis (FSGS), UPCR ≥3 g/g and < 10 g/g (Cohort 1) or ≥ 2 g/g 
and < 10 g/g (Cohort 2), and estimated glomerular filtration rate 
(eGFR) ≥45 mL/min/1.73 m2 
 
 
Investigational Drug 
Active substance: VX-147 
 
Activity: APOL1-inhibitor 
 
Strength and route of administration: 15 mg tablets for oral administration 
 
 
Study Duration 
Excluding the Screening Period, each subject will participate in the study for 
approximately 13 weeks of treatment in Part A. Subjects may choose to participate in 
an off-treatment observation for up to 12 weeks in Part B (optional). All subjects will 
complete a Safety Follow-up Visit (SFUV) at 28 (± 7) days after the last dose of study 
drug. 
 
 
Study Design 
This is a single-arm, open-label, 2-part study. In Part A, subjects will receive VX-147 
at a dosage of 15 mg qd for 2 weeks and VX-147 at a dosage of 45 mg qd for 
11 weeks. Part A will be enrolled in 2 cohorts: Cohort 1 and an optional Cohort 2. 
Cohort 1 includes approximately 10 subjects with UPCR ≥3 g/g and <10 g/g who are 
not taking systemic corticosteroid or other immunosuppressants. Cohort 2 includes 
approximately 10 subjects with UPCR ≥2 g/g and <10 g/g, and these subjects are 
permitted to take a stable low dose of systemic corticosteroid.  
Enrollment of Cohort 1 will be prioritized over enrollment of Cohort 2; this will be 
managed through the interactive web response system (IWRS). Each site will be 
required to enroll a subject in Cohort 1 before the same site can enroll in Cohort 2. 
After completing Part A, subjects will be followed for up to 12 weeks in Part B 
(optional) for evaluation of proteinuria off treatment if they consent to do so. If a 
subject prematurely discontinues study drug in Part A, an Early Treatment Termination 
(ETT) Visit should be scheduled as soon as possible after the decision to terminate 
study drug treatment. After completing the ETT Visit, subjects will not complete 
further Part A Visits; these subjects will come in for a SFUV and will not continue to 
Part B. 
All subjects are required to complete a SFUV at 28 (± 7) days after the last dose of 
study drug. The SFUV may occur while a subject is participating in Part B. 


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Figure 2-1 
VX19-147-101 Study Design 
 
 
D: Day; PK: pharmacokinetics; qd: once daily; UPCR: urine protein to creatinine ratio; 
W: Week 
Notes: The figure is not drawn to scale. After completing Part A, subjects will be followed 
monthly for up to 12 weeks or until UPCR returns to baseline, whichever occurs first. All 
subjects will be required to complete a SFUV at 28 (± 7) days after the last dose of study 
drug. 
a 
Proteinuria will be assessed at multiple timepoints throughout the Treatment Period and 
Off-treatment Follow-up. Triangles represent timepoints for the primary analysis. 
 
 
Assessments 
Efficacy: UPCR 
Safety: AEs; clinical laboratory assessments; ECGs; vital signs; and physical 
examinations 
PK: VX-147 plasma concentrations 
Exploratory: UACR, SF-36, biomarker blood and urine samples 
 
 
Statistical Analyses 
Efficacy 
Analyses will be done separately for Cohort 1 and Cohort 2. The primary endpoint is 
percent change from baseline in UPCR at Week 13. In all analyses of UPCR related 
data, the Week 13 UPCR value will be calculated as the average of the available UPCR 
measurements (maximum 3) taken during Week 13, and the baseline value will be the 
average of the 3 UPCR values from the urine samples collected for this purpose during 
screening. 
The percent change from baseline in UPCR at Week 13 will be analyzed by first 
log-transforming the UPCR data before analyses to reduce skewness, and calculating 
the change from baseline in log-transformed values. The geometric mean percent 
change (GMPC) from baseline in UPCR will be estimated along with the 
corresponding 2-sided 80% CI. The GMPC from baseline and associated confidence 
limits will be calculated by back-transforming the estimated simple mean of change 
from baseline in log-transformed data. 
Safety 
The safety analyses will be descriptive only.  
Pharmacokinetics 
Noncompartmental analyses will be performed, and summary statistics will be 
provided for VX-147 PK parameters. Additional analysis including population PK 
modeling will be performed to further characterize the PK and exposure-response 
relationships. 


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3 
SCHEDULE OF ASSESSMENTS  
Schedules of assessments for Cohort 1 and Cohort 2 are in Table 3-1 through Table 3-3. All 
visits will be scheduled relative to the Day 1 Visit.  
Subjects may choose to complete all screening assessments within the 28-day Screening Period 
or they may choose a 2-step screening process and first complete only the APOL1 genotype 
assessment at any time before Day -1 (including before Day -28), followed by the rest of the 
screening assessments during the 28-day Screening Period. The informed consent form (ICF) 
will outline the screening options. Additional information is provided in Section 9.1.1. Informed 
consent must be completed before any assessments are done at the Screening Visit. The SF-36 
must be completed before any other assessment when they are required. Other assessments may 
be performed in any order when more than 1 assessment is required at a particular time point, 
unless noted otherwise. All assessments will be performed before dosing, unless noted otherwise. 
Table 3-1 
Study VX19-147-101: Screening  
Event/Assessment 
Optional 
Genotype 
Screening Visit 
(Before Day -1) 
Screening 
Period 
(Day -28 to 
Day -1) 
Comments 
Subject visit 
 
X 
Activities may be performed by a home health 
visit or in the clinic, unless otherwise noted 
(Section 9.3.5). The complete physical exam 
must be done in a clinic (Section 11.6.3). 
Informed consent 
X 
X 
 
Demographics 
 
X 
 
Medical history 
 
X 
 
Medications review 
 
X 
Section 9.4 
Standard 12-lead ECG 
 
X 
To be performed in triplicate after the subject 
has been supine for at least 5 minutes. When 
ECGs, vital signs, and blood draws coincide, 
they should be performed in said order. 
(Section 11.6.4). 
Vital signs 
 
X 
Vital signs will be collected after the subject 
has rested for at least 5 minutes. Blood pressure 
must be collected in triplicate. (Section 11.6.3).  
Height and weight 
 
X 
Weight and height will be measured with shoes 
off with light weight clothing (no outerwear). 
BMI will be calculated using height and weight 
(Section 11.1). 
Complete physical 
examination 
 
X 
Cannot be done by home health nurse and must 
be done in a clinic (Section 11.6.3). 
Serum FSH 
(suspected 
postmenopausal 
female subjects only) 
 
X 
A blood sample will be collected 
(Section 11.6.2).  
Serum β-hCG (all 
female subjects) 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
Serum chemistry 
 
X 
A blood sample will be collected 
(Section 11.6.2). 


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Table 3-1 
Study VX19-147-101: Screening  
Event/Assessment 
Optional 
Genotype 
Screening Visit 
(Before Day -1) 
Screening 
Period 
(Day -28 to 
Day -1) 
Comments 
Hematology 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
Coagulation 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
Serology (HIV-1 and 
HIV-2 Antibodies) 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
Hepatitis B surface 
antigen 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
HCV nucleic acid test 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
Confirmation of 
APOL1 genotype 
X 
X 
A genotyping sample will be collected if a 
result is not available using a Vertex-approved 
clinical study assay (Section 9.1.1).  
Urine sample 
 
X 
(3 samples) 
Collected after signing the informed consent for 
use in efficacy, biomarker, and safety analyses 
(Sections 11.3 and 11.6.2). The first morning 
void will be collected for 3 independent 
samples, which are collected on 3 separate days 
within a 7-day period. The third sample must be 
collected by Day -5 to allow confirmation that 
UPCR values meet eligibility criteria 
(Section 8.1). 
Adverse events 
 
Continuous from 
signing of ICF 
through SFUV 
For subjects undergoing a 2-step screening 
process, AEs will not be collected during the 
time between a subject undergoing genotype 
screening and the start of the Screening Visit. 
Additional information about AE reporting is 
provided in Section 11.6.1. 
 


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Table 3-2 
Study VX19-147-101: Part A Treatment Period 1, Treatment Period 2, and Early Termination of Treatment Visit 
Event/ 
Assessmenta 
Treatment Period 1 
Treatment Period 2 
Early 
Termination 
of 
Treatment 
Visitb 
Comments 
Day 1 
Visit 
Week 1 
Visit 
Day 15 
Visit 
Week 3 
Visit 
Week 5 
Visit 
Week 9 
Visit 
Week 13 
Visit 
Window: 
Day 1  
(±0 days) 
Window:  
Day 8 
(±1 day) 
Window: 
Day 15  
(±2 days) 
Window: 
Day 22 
(±2 days) 
Window: 
Day 36 
(±2 days) 
Window: 
Day 64 
(±2 days) 
Window: 
Day 92 
(-2 days) 
Subject visit  
X 
X 
X 
X 
X 
X 
X 
X 
All visits may be performed by a home health 
visit or in the clinic at the discretion of the 
investigator (Section 9.3.5). All visits must 
have a consultation between the subject and 
investigator (i.e., in person, phone, or 
telemedicine video conference) within 
1 business day after the home health visit, 
which can be outside the visit window. 
SF-36 
X 
 
 
 
X 
 
X 
X 
To be completed before all other study 
assessments (Section 11.5.4).  
Standard 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
Complete predose after SF-36 and before other 
assessments. The subject should be supine for 
at least 5 minutes before the start of ECG. 
When ECGs, vital signs, and blood draws 
coincide, they should be performed in said 
order. On Day 1 and Day 15, an ECG 
(Section 11.6.4) will also be collected 
2 (± 1) hours postdose. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Complete before the assessments listed in rows 
below. The subject should rest for at least 
5 minutes before the start of vital sign 
collection and they should be seated during the 
assessment (Section 11.6.3). 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Weight will be measured with shoes off and 
light weight clothing (no outerwear) 
(Section 11.1). 
 
a 
All assessments will be performed before dosing unless noted otherwise. 
b 
If the subject prematurely discontinues study treatment during the Treatment Period, an ETT Visit should be scheduled as soon as possible after the subject decides to terminate study treatment. If the 
ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit will replace the SFUV, and a separate SFUV will not be required. After the ETT Visit, subjects will not 
complete further Part A Visits; these subjects will not continue to Part B (Table 3-3).  


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Table 3-2 
Study VX19-147-101: Part A Treatment Period 1, Treatment Period 2, and Early Termination of Treatment Visit 
Event/ 
Assessmenta 
Treatment Period 1 
Treatment Period 2 
Early 
Termination 
of 
Treatment 
Visitb 
Comments 
Day 1 
Visit 
Week 1 
Visit 
Day 15 
Visit 
Week 3 
Visit 
Week 5 
Visit 
Week 9 
Visit 
Week 13 
Visit 
Window: 
Day 1  
(±0 days) 
Window:  
Day 8 
(±1 day) 
Window: 
Day 15  
(±2 days) 
Window: 
Day 22 
(±2 days) 
Window: 
Day 36 
(±2 days) 
Window: 
Day 64 
(±2 days) 
Window: 
Day 92 
(-2 days) 
Abbreviated 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
In addition to the scheduled visits, 
symptom-targeted physical examinations will 
occur at any time during the study if triggered 
by AEs or if deemed necessary by the 
investigator (Section 11.6.3). 
Serum 
chemistry 
X 
Fasted 
X 
X 
X 
Fasted 
X 
X 
X 
Fasted 
X 
Fasted 
A blood sample will be collected predose after 
an overnight fast on indicated days. All other 
days do not require fasting. (Section 11.6.2). 
Hematology  
X 
X 
X 
X 
X 
X 
X 
X 
A blood sample will be collected 
(Section 11.6.2). 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
A blood sample will be collected 
(Section 11.6.2). 
RNA sample 
X 
X 
X 
X 
X 
X 
X 
X 
A blood sample will be collected for use in 
exploratory biomarker analysis 
(Section 11.5.3). 
Optional DNA 
sample 
X 
 
 
 
 
 
 
 
This optional sample will be collected for use 
in exploratory biomarker analysis 
(Section 11.5.3). 
Biomarker 
blood sample 
X 
X 
X 
X 
X 
X 
X 
X 
Section 11.5.1. 
VX-147 PK 
blood sample  
intensive 
predose 
intensive 
predose 
intensive 
predose 
X 
X 
A blood sample will be collected 
(Section 11.2.1). 
Intensive PK sampling  
Day 1, Day 15, Week 5: predose (within 
60 min before dosing) and 0.25, 0.5, 1, 2, 4 and 
12 hours postdose  
 
Post treatment samples (Week 13 and ETT):  
A single sample collected anytime during the 
Visit. 


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Table 3-2 
Study VX19-147-101: Part A Treatment Period 1, Treatment Period 2, and Early Termination of Treatment Visit 
Event/ 
Assessmenta 
Treatment Period 1 
Treatment Period 2 
Early 
Termination 
of 
Treatment 
Visitb 
Comments 
Day 1 
Visit 
Week 1 
Visit 
Day 15 
Visit 
Week 3 
Visit 
Week 5 
Visit 
Week 9 
Visit 
Week 13 
Visit 
Window: 
Day 1  
(±0 days) 
Window:  
Day 8 
(±1 day) 
Window: 
Day 15  
(±2 days) 
Window: 
Day 22 
(±2 days) 
Window: 
Day 36 
(±2 days) 
Window: 
Day 64 
(±2 days) 
Window: 
Day 92 
(-2 days) 
Urine sample  
Xc 
X 
X 
X 
X 
X 
(3 samples) 
X 
(3 samples) 
X 
The first morning urine void (predose) will be 
collected and used for efficacy, safety, and 
biomarker analyses (Sections 11.3 and 11.6.2). 
During Week 9 and Week 13, 3 samples will 
be collected on 3 separate days within a 7-day 
period. If the subject forgets to collect the first 
morning void on the day of the visit, they may 
provide this sample predose on a different day 
within the visit window. 
β-hCG (urine) 
X 
 
 
 
X 
X 
X 
X 
All female subjects of childbearing potential 
(Sections 11.6.2 and 11.6.5). This can be 
collected in the same sample as the urine 
sample for efficacy, safety, and biomarker 
analysis. 
VX-147 
dosing  
X 
 
The last dose of Treatment Period 1 will be 
Day 14. The first dose of Treatment Period 2 
will be on Day 15 after all predose assessments 
are completed. The last day of dosing will 
occur the day before the Week 13 visit. 
The first dose in each period must be 
administered under the supervision of site 
medical staff or a home health nurse. Subjects 
will be monitored for 4 hours after receiving 
the first dose of each Treatment Period. 
(Section 9.6). 
Adverse 
events 
Continuous from signing of ICF through SFUV 
Section 11.6.1. 
Medications 
review 
Continuous from signing of ICF through SFUV 
Section 9.4 
 
 
c Day 1 urinalysis will be for safety and biomarker assessments. Efficacy assessments will not be done. 


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Table 3-3 
Study VX19-147-101: Postdose PK Sampling, Safety Follow-up Visit, and Part B 
Off-treatment Follow-up Period 
Event/Assessment 
Postdose PK 
Sampling 
(Approximately 
48 hours after 
the last dose of 
study drug)a 
SFUV 
28 (± 7) Days 
After Last Dose of 
Study Drugb 
Part B: Optional 
Off-treatment Follow-up 
Visits c 
(Part B Week 4b, 8, and 
12)  
Comments 
Subject visit 
X 
X 
X 
(until UPCR returns to the 
baseline level)d 
The visit may be 
performed by a home 
health visit or in the clinic 
at the discretion of the 
investigator 
(Section 9.3.5). For each 
visit, at least 1 interaction 
with the subject and 
investigator will occur by 
phone, video, or in the 
clinic (i.e., in person, 
phone, or telemedicine 
video conference) within 
1 business day after the 
home health visit, which 
can be outside the visit 
window. 
SF-36 
 
X 
 
To be completed before 
all other study 
assessments 
(Section 11.5.4). 
Standard 12-lead ECG 
 
X 
 
Complete after SF-36 and 
before other assessments 
after subject has been 
supine for at least 5 
minutes. ECGs 
(Section 11.6.4), vital 
signs, and blood draws 
should be performed in 
said order. 
Vital signs 
 
X 
 
Complete before other 
assessments listed below 
after subject has been at 
rest for at least 5 minutes; 
they should be seated 
during the assessment 
(Section 11.6.3). 
 
a 
The postdose PK sampling visit is required for all subjects, with the exception of those who complete an ETT Visit. 
b 
The SFUV and Part B Week 4 Off-treatment Follow-up Visit may occur on the same day, provided the visit windows are met 
for both visits. 
c  
Visit windows for Part B are as follows: Week 4 Visit (Day 120 ± 2 weeks), Week 8 Visit (Day 148 ± 2 weeks), Week 12 Visit 
(Day 176 ± 2 weeks). 
d 
For the purpose of this assessment, baseline UPCR is defined as the average of the last 3 screening assessments ± 10%. If a 
subject has not achieved ≥90% of baseline UPCR by the Part B Week 12 Visit, the Part B Week 12 Visit will be the last study 
visit.  


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Table 3-3 
Study VX19-147-101: Postdose PK Sampling, Safety Follow-up Visit, and Part B 
Off-treatment Follow-up Period 
Event/Assessment 
Postdose PK 
Sampling 
(Approximately 
48 hours after 
the last dose of 
study drug)a 
SFUV 
28 (± 7) Days 
After Last Dose of 
Study Drugb 
Part B: Optional 
Off-treatment Follow-up 
Visits c 
(Part B Week 4b, 8, and 
12)  
Comments 
Weight 
 
X 
 
Weight will be measured 
with shoes off and light 
weight closing (no 
outerwear). 
(Section 11.1). 
Abbreviated physical 
examination 
 
X 
 
In addition to the 
scheduled visits, 
symptom-targeted 
physical examinations 
will occur at any time 
during the study if 
triggered by AEs or if 
deemed necessary by the 
investigator 
(Section 11.6.3). 
Serum chemistry 
 
X 
Fasted 
 
A blood sample will be 
collected following an 
overnight fast 
(Section 11.6.2). 
Hematology  
 
X 
 
A blood sample will be 
collected (Section 11.6.2) 
Coagulation 
 
X 
 
A blood sample will be 
collected (Section 11.6.2) 
VX-147 PK Sampling 
X 
 
 
A blood sample will be 
collected (Section 11.2.1). 
Urine sample 
 
X 
X 
The first morning urine 
void will be collected and 
used for efficacy, safety, 
and biomarker analyses 
(Sections 11.3 and 
11.6.2). 
β-hCG (urine) 
 
X 
 
All female subjects of 
childbearing potential 
(Section 11.6.2). This can 
be collected in the same 
sample as the other urine 
sample. 
Adverse events 
Continuous from signing of ICF through 
SFUV 
NA 
Section 11.6.1 
Medications review 
Continuous from signing of ICF through 
SFUV 
NA 
Section 9.4 
 
 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
Summary of Changes to the Protocol......................................................................................... 2 
2 
Protocol Synopsis ................................................................................................................... 5 
3 
Schedule of Assessments ........................................................................................................ 8 
4 
Table of Contents ................................................................................................................. 15 
List of Tables ........................................................................................................................... 19 
List of Figures .......................................................................................................................... 19 
List of Abbreviations ............................................................................................................... 20 
5 
Introduction .......................................................................................................................... 22 
6 
Study Objectives .................................................................................................................. 23 
6.1 
Part A (Treatment Period) .............................................................................................. 23 
6.1.1 
Primary Objective ................................................................................................... 23 
6.1.2 
Secondary Objectives ............................................................................................. 23 
6.2 
Part B .............................................................................................................................. 23 
6.2.1 
Exploratory Objective ............................................................................................. 23 
7 
Study Endpoints ................................................................................................................... 23 
7.1 
Part A .............................................................................................................................. 23 
7.1.1 
Primary Endpoints .................................................................................................. 23 
7.1.2 
Secondary Endpoints .............................................................................................. 23 
7.1.3 
Exploratory Endpoints ............................................................................................ 23 
7.2 
Part B (Optional Off-treatment Follow-up Period) ........................................................ 23 
7.2.1 
Exploratory Endpoints ............................................................................................ 23 
8 
Study Population .................................................................................................................. 24 
8.1 
Inclusion Criteria ............................................................................................................ 24 
8.2 
Exclusion Criteria ........................................................................................................... 25 
9 
Study Implementation ......................................................................................................... 26 
9.1 
Study Design .................................................................................................................. 26 
9.1.1 
Screening ................................................................................................................ 27 
9.1.1.1 
Repetition of Screening Assessments .............................................................. 28 
9.1.1.2 
Extension of Screening Period Window .......................................................... 28 
9.1.1.3 
Rescreening ...................................................................................................... 28 
9.1.2 
Part A ...................................................................................................................... 28 
9.1.2.1 
Treatment Period .............................................................................................. 28 
9.1.2.2 
Safety Follow-up .............................................................................................. 28 
9.1.2.3 
Early Termination of Treatment or Early Discontinuation .............................. 28 
9.1.3 
Part B ...................................................................................................................... 29 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 29 
9.2.1 
Replacement Subjects ............................................................................................. 29 
9.3 
Rationale for Study Elements ......................................................................................... 29 
9.3.1 
Study Design ........................................................................................................... 29 
9.3.2 
Study Population..................................................................................................... 30 
9.3.3 
Study Drug Dose .................................................................................................... 30 
9.3.4 
Study Assessments ................................................................................................. 30 
9.3.4.1 
UPCR ............................................................................................................... 30 
9.3.4.2 
SF-36 ................................................................................................................ 30 


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9.3.5 
Use of Telemedicine for Study Visits ..................................................................... 31 
9.3.6 
Eligibility Review ................................................................................................... 31 
9.4 
Prior and Concomitant Medications ............................................................................... 31 
9.5 
Study Restrictions ........................................................................................................... 32 
9.6 
Administration ................................................................................................................ 32 
9.7 
Dose Modification .......................................................................................................... 33 
9.8 
Study Drug Interruption ................................................................................................. 33 
9.9 
Removal of Subjects ....................................................................................................... 33 
9.10 Replacement of Subjects ................................................................................................ 34 
10 Study Drug Information and Management ....................................................................... 34 
10.1 Preparation and Dispensing ............................................................................................ 34 
10.2 Packaging and Labeling ................................................................................................. 34 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 34 
10.4 Drug Accountability ....................................................................................................... 34 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 35 
10.6 Compliance ..................................................................................................................... 35 
10.7 Blinding and Unblinding ................................................................................................ 35 
11 Assessments .......................................................................................................................... 35 
11.1 Subject and Disease Characteristics ............................................................................... 35 
11.2 Pharmacokinetics ............................................................................................................ 35 
11.2.1 
Blood Sampling ...................................................................................................... 35 
11.2.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 36 
11.2.3 
Bioanalysis .............................................................................................................. 36 
11.3 Urine Sampling for UPCR, UACR, and Safety Laboratory Panel ................................. 36 
11.4 APOL1 Genotyping ........................................................................................................ 37 
11.5 Exploratory Assessments ................................................................................................ 37 
11.5.1 
Blood Biomarker Samples ...................................................................................... 37 
11.5.2 
Urine Biomarker Samples ...................................................................................... 37 
11.5.3 
Pharmacogenomic Samples .................................................................................... 37 
11.5.4 
SF-36 ...................................................................................................................... 37 
11.6 Safety .............................................................................................................................. 37 
11.6.1 
Adverse Events ....................................................................................................... 37 
11.6.2 
Clinical Laboratory Assessments ........................................................................... 38 
11.6.3 
Physical Examinations and Vital Signs .................................................................. 40 
11.6.4 
Electrocardiograms ................................................................................................. 40 
11.6.5 
Contraception and Pregnancy ................................................................................. 41 
11.6.5.1 Contraception ................................................................................................... 41 
11.6.5.2 Pregnancy ......................................................................................................... 42 
12 Statistical and Analytical Plans .......................................................................................... 43 
12.1 Sample Size and Power .................................................................................................. 43 
12.2 Analysis Sets .................................................................................................................. 43 
12.3 Statistical Analysis ......................................................................................................... 44 
12.3.1 
General Considerations ........................................................................................... 44 
12.3.2 
Background Characteristics .................................................................................... 45 
12.3.2.1 Subject Disposition .......................................................................................... 45 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 45 


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12.3.2.3 Prior and Concomitant Medications ................................................................ 45 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 46 
12.3.2.5 Important Protocol Deviations ......................................................................... 46 
12.3.3 
Efficacy Analysis .................................................................................................... 46 
12.3.3.1 Analysis of Primary Variables ......................................................................... 46 
12.3.3.2 Analysis of Other Variables ............................................................................. 46 
12.3.4 
Safety Analysis ....................................................................................................... 47 
12.3.4.1 Adverse Events ................................................................................................ 47 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 48 
12.3.4.3 Electrocardiogram ............................................................................................ 48 
12.3.4.4 Vital Signs ........................................................................................................ 48 
12.3.4.5 Physical Examination ....................................................................................... 48 
12.3.4.6 Other Safety Analysis ...................................................................................... 49 
12.3.5 
Other Analyses ....................................................................................................... 49 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses ........................... 49 
12.4 Clinical Pharmacology Analysis .................................................................................... 49 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 49 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 49 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 50 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 50 
13.1.1 
Adverse Events ....................................................................................................... 50 
13.1.1.1 Definition of an Adverse Event........................................................................ 50 
13.1.1.2 Clinically Significant Assessments .................................................................. 50 
13.1.1.3 Documentation of Adverse Events................................................................... 50 
13.1.1.4 Adverse Event Severity .................................................................................... 51 
13.1.1.5 Adverse Event Causality .................................................................................. 52 
13.1.1.6 Study Drug Action Taken ................................................................................ 52 
13.1.1.7 Adverse Event Outcome .................................................................................. 52 
13.1.1.8 Treatment Given............................................................................................... 53 
13.1.2 
Serious Adverse Events .......................................................................................... 53 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 53 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 54 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 54 
13.2 Administrative Requirements ......................................................................................... 54 
13.2.1 
Ethical Considerations ............................................................................................ 54 
13.2.2 
Subject Information and Informed Consent ........................................................... 55 
13.2.3 
Investigator Compliance ......................................................................................... 55 
13.2.4 
Access to Records ................................................................................................... 55 
13.2.5 
Subject Privacy ....................................................................................................... 55 
13.2.6 
Record Retention .................................................................................................... 56 
13.2.7 
Study Termination .................................................................................................. 56 
13.2.8 
End of Study ........................................................................................................... 56 
13.3 Data Quality Assurance .................................................................................................. 56 
13.4 Monitoring ...................................................................................................................... 57 
13.5 Electronic Data Capture ................................................................................................. 57 


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13.6 Confidentiality and Disclosure ....................................................................................... 57 
13.7 Publications and Clinical Study Report .......................................................................... 58 
13.7.1 
Publication of Study Results................................................................................... 58 
13.7.2 
Clinical Study Report ............................................................................................. 58 
14 References ............................................................................................................................. 59 
15 Protocol Signature Pages .................................................................................................... 61 
15.1 Sponsor Signature Page .................................................................................................. 61 
15.2 Investigator Signature Page ............................................................................................ 62 
 


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List of Tables 
Table 3-1 
Study VX19-147-101: Screening ............................................................................ 8 
Table 3-2 
Study VX19-147-101: Part A Treatment Period 1, Treatment Period 2, and Early 
Termination of Treatment Visit ............................................................................ 10 
Table 3-3 
Study VX19-147-101: Postdose PK Sampling, Safety Follow-up Visit, and Part B 
Off-treatment Follow-up Period ........................................................................... 13 
Table 9-1 
Study Restrictions ................................................................................................. 32 
Table 10-1 
Study Drug ............................................................................................................ 34 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 36 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 39 
Table 11-3 
Allowed Methods of Contraception ...................................................................... 42 
Table 12-1 
Two-sided 80% Confidence Interval for GMPC from Baseline in UPCR ........... 43 
Table 13-1 
Grading of AE Severity ........................................................................................ 51 
Table 13-2 
Classifications for AE Causality ........................................................................... 52 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 52 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 52 
List of Figures 
Figure 2-1 
VX19-147-101 Study Design ................................................................................. 7 
Figure 9-1 
VX19-147-101 Study Design ............................................................................... 27 
 


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List of Abbreviations 
Abbreviation 
Definition 
ACE 
angiotensin converting enzyme 
ADL 
activities of daily living 
AE 
adverse event 
AKI 
acute kidney injury 
ALT 
alanine transaminase 
APOL1 
apolipoprotein L1 
ARB 
angiotensin receptor blocker 
AST 
aspartate transaminase 
AUCτ 
AUC during a dosing interval 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
bpm 
beats per minute 
CAKUT 
congenital anomaly of the kidney or urinary tract 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL/F 
apparent clearance 
Cmax 
maximum observed concentration 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
predose concentration 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
eGFR 
estimated glomerular filtration rate 
ESKD 
end-stage kidney disease 
ETT 
Early Termination of Treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FSGS 
focal segmental glomerulosclerosis 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMPC 
Geometric Mean Percent Change 
GPS 
Global Patient Safety 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV-1 
human immunodeficiency virus-1 
HIV-2 
human immunodeficiency virus-2 
HR 
heart rate 


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Abbreviation 
Definition 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IPD 
important protocol deviation 
IRB 
institutional review board 
IWRS 
interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
not applicable 
PC 
publication committee 
PD 
pharmacodynamics 
PE 
physical examination 
PK 
pharmacokinetic, pharmacokinetics 
PR 
PR interval, segment 
PRO 
patient-reported outcome 
PT 
Preferred Term 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization  
QT 
QT interval 
QTcF 
QT interval corrected by Fridericia’s formula 
RNA 
ribonucleic acid 
RR 
interval from the onset of 1 QRS complex to the next 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
steering committee 
SD 
standard deviation 
SF-36 
Short Form Health Survey 36 
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SRA 
serum resistant associated-protein 
SUSARs 
suspected, unexpected, serious adverse reactions 
TE 
Treatment-emergent 
TEAE 
treatment-emergent adverse event 
UACR 
urine albumin to creatinine ratio 
ULN 
upper limit of normal 
UPCR 
urine protein to creatinine ratio 
Vss/F 
apparent volume of distribution at steady-state 
WHO-DD 
World Health Organization-Drug Dictionary 
 


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5 
INTRODUCTION 
Focal segmental glomerulosclerosis (FSGS) is a rare kidney disease with an estimated global 
incidence of 0.2 to 1.1/100,000/year.1 FSGS is caused by damage to podocytes, which are part of 
the glomerular filtration barrier, resulting in proteinuria.2 Patients with nephrotic-range 
proteinuria (i.e., protein to creatinine ratio >3 g/g) are at a higher risk of developing end-stage 
kidney disease (ESKD) and developing proteinuria-related complications, such as infections or 
thromboembolic events. There is no well-standardized treatment regimen for FSGS. Current 
therapeutic options for patients with FSGS who have nephrotic-range proteinuria include 
high-dose corticosteroids, which induce remission of proteinuria in a minority of patients.2 
FSGS can be divided into different subgroups based on the underlying etiology. One 
homogeneous subgroup of FSGS is characterized by the presence of 2 independent common 
sequence variants in the apolipoprotein L1 (APOL1) gene termed G1 and G2, which are referred 
to as the “APOL1 risk alleles.” G1 encodes a correlated pair of non-synonymous amino acid 
changes (S342G and I384M), G2 encodes a 2 amino acid deletion (N388del:Y389del) near the 
C-terminus of the protein, and G0 is the ancestral (low risk) allele.3,4  
The APOL1 gene is expressed in multiple organs in humans, including the liver and kidney.5,6 
The biologic function of APOL1 is to protect against parasitic infection (Trypanosoma brucei 
brucei [T. b. brucei]).7 APOL1 is endocytosed by T. b. brucei and transported to lysosomes, 
where it inserts into the lysosomal membrane and forms pores that lead to parasite swelling and 
death.8 While the ability to lyse T. b. brucei is shared by all 3 APOL1 variants (G0, G1, and G2), 
APOL1 G1 and G2 variants confer additional protection against parasite species that have 
evolved a serum resistant associated-protein (SRA) which inhibits APOL1 G0; these species 
cause sleeping sickness. G1 and G2 variants evade inhibition by SRA and G1 confers additional 
protection against T. b. gambiense (which causes West African sleeping sickness), 
and G2 confers additional protection against T. b. rhodesiense (which causes East African 
sleeping sickness).9 
In the kidney, APOL1 is expressed in podocytes, endothelial cells (including glomerular 
endothelial cells), and some tubular cells.6, 10 Podocyte-specific expression of APOL1 G1 or G2 
(but not G0) in transgenic mice induces structural and functional changes, including albuminuria, 
decreased kidney function, podocyte abnormalities, and glomerulosclerosis.11 Consistent with 
these data, G1 and G2 variants of APOL1 play a causative role in inducing FSGS and 
accelerating its progression in humans. Individuals with 2 APOL1 risk alleles (i.e., homozygous 
or compound heterozygous for the APOL1 G1 or APOL1 G2 alleles) have increased risk of 
developing FSGS with an odds ratio of 10 to 17, and they are at risk for rapid decline in kidney 
function if they develop FSGS.3, 4, 12 Thus, inhibition of APOL1 could have a positive impact in 
individuals who harbor 2 APOL1 risk alleles. 
VX-147 is a small molecule that inhibits APOL1-induced cell death and inhibits the biological 
function of APOL1, i.e., APOL1-induced lysis of T. b. brucei. These nonclinical data suggest 
that VX-147 has the potential to reduce proteinuria and reverse APOL1-induced podocyte 
lesions in patients with APOL1-mediated FSGS. Therefore, VX-147 is being developed to treat 
individuals with FSGS who also have 2 APOL1 risk alleles and nephrotic-range proteinuria.  
This study is a Phase 2a proof-of-concept study designed to assess the efficacy effects, safety, 
and pharmacokinetics (PK) of VX-147 in subjects with APOL1-mediated FSGS.  


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Additional information about the first-in-human (FIH) study (VX18-147-001; Study 001) and 
nonclinical studies is available in the Investigator’s Brochure.  
6 
STUDY OBJECTIVES 
6.1 
Part A (Treatment Period) 
6.1.1 
Primary Objective 
• To evaluate the ability of VX-147 to reduce proteinuria 
6.1.2 
Secondary Objectives 
• To evaluate the safety and tolerability of VX-147 
• To characterize the PK of VX-147  
6.2 
Part B 
6.2.1 
Exploratory Objective 
• To evaluate the change proteinuria after stopping administration of VX-147 
7 
STUDY ENDPOINTS 
7.1 
Part A 
7.1.1 
Primary Endpoints 
• Percent change from baseline in urine protein to creatinine ratio (UPCR) at Week 13 
7.1.2 
Secondary Endpoints 
• Safety and tolerability based on adverse events (AEs), clinical laboratory values 
(i.e., hematology, serum chemistry, urinalysis, coagulation studies), standard 12-lead 
ECGs, and vital signs 
• Plasma PK of VX-147  
7.1.3 
Exploratory Endpoints 
• Percent change from baseline in UPCR over time during the Treatment Period  
• Percent change from baseline in urine albumin to creatinine ratio (UACR) at Week 13 
• Percent change from baseline in UACR over time during the Treatment Period 
• Change from baseline in patient-reported outcome (PRO) Short Form Health Survey 36 
(SF-36) over time during the treatment period  
7.2 
Part B (Optional Off-treatment Follow-up Period) 
7.2.1 
Exploratory Endpoints 
• Percent change from baseline in UPCR at the end of the Off-treatment Follow-up Period  
• Change from baseline in SF-36 over time during the Off-treatment Follow-up Period   


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8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
8.1 
Inclusion Criteria 
The following criteria are applicable for Cohort 1 and Cohort 2: 
1. Willing to sign and date an informed consent form (ICF).  
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions 
(Section 9.5), laboratory tests, contraceptive guidelines (Section 11.6.5), and other study 
procedures. 
3.  An APOL1 genotype of G1/G1, G2/G2, or G1/G2 obtained with a Vertex-approved clinical 
study assay. 
4. Between the ages of 18 and 60 years, inclusive. 
5. Body mass index (BMI) of 18.0 to 40.0 kg/m2, inclusive, and a total body weight >50 kg. 
6. FSGS diagnosed by kidney biopsy, with the exception of the tip variant, as confirmed 
through the eligibility review process.  
7. Estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 based on the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.13, 14 
The following criteria are applicable for Cohort 1: 
8. A UPCR ratio of ≥3 g/g and <10 g/g in the first morning void on 3 measurements collected 
on at least 3 separate days within a 7-day period, during the Screening Period. All 
3 measurements must meet this criterion. 
9. There should be no plan to start, stop, or modify dosing for an angiotensin converting 
enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), neprilysin inhibitor, 
sodium-glucose co-transporter-2 inhibitor, or renin inhibitor during the Treatment Period or 
Follow-up Period. 
The following criteria are applicable for Cohort 2: 
10. A UPCR ratio of ≥ 2 g/g and <10 g/g in the first morning void on 3 measurements collected 
on at least 3 separate days within a 7-day period, during the Screening Period. All 
3 measurements must meet this criterion. 
11. There should be no plan to start, stop, or modify dosing for an ACE inhibitor, ARB, 
neprilysin inhibitor, sodium-glucose co-transporter-2 inhibitor, renin inhibitor, or systemic 
corticosteroids during the Treatment Period or Follow-up Period. 
 


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8.2 
Exclusion Criteria 
The following criteria are applicable for Cohort 1 and Cohort 2: 
1. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study drug(s) to 
the subject. This includes, but is not limited to, the following: 
• Solid organ or bone marrow transplantation 
• Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical 
carcinoma in situ (each being disease-free for the last 5 years) 
• Clinically significant and active bacterial, viral, fungal, or parasitic infection as 
determined by the investigator 
• Clinically significant liver disease 
• Ongoing alcohol or drug abuse as determined by the investigator 
• Any condition possibly affecting drug absorption (e.g., gastrectomy, gastrointestinal tract 
surgery except appendectomy and cholecystectomy) 
• Stroke or myocardial infarction within 6 months before Day 1  
2. Evidence of non-APOL1-mediated FSGS. This includes but is not limited to the following: 
• FSGS occurring concomitantly to administration of drugs known to induce FSGS, 
including but not limited to lithium, interferon, and bisphosphonates (e.g., pamidronate), 
or FSGS occurring in a subject using intravenous illicit drugs at the time of diagnosis. 
• Evidence of another underlying kidney disease that can cause FSGS, including evidence 
of congenital anomaly of the kidney or urinary tract (CAKUT) on renal ultrasound, 
history of CAKUT, history of nephrectomy. 
• FSGS occurring in a subject with known sickle cell disease. 
• Known genetic mutation other than APOL1 G1 or G2 that is associated with FSGS. 
• Positive serology for human immunodeficiency virus-1 (HIV-1) or human 
immunodeficiency virus-2 (HIV-2). 
3. Evidence of kidney disease other than FSGS on kidney biopsy, as assessed by the eligibility 
review process. 
4. Kidney biopsy showing the tip variant of FSGS, as assessed by the eligibility review process. 
5. Any of the following abnormal laboratory values at screening: 
• Serum albumin <1 g/dL 
• Total bilirubin ≥1.5 × upper limit of normal (ULN) 
• Aspartate transaminase (AST) or alanine transaminase (ALT) ≥2 × ULN  
• Potassium above the ULN 
• Hemoglobin <10 g/dL. 


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6. Positive for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody during 
screening.  
7. Risk factors for Torsade de Pointes (e.g., familial long QT syndrome, chronic hypokalemia, 
heart failure) or concomitant medications that prolong the QT/QTc interval or any history of 
cardiac disorders that, in the opinion of the investigator, might put the subject at risk or may 
confound the results of the study.  
8. Any clinically significant ECG abnormality (as determined by the investigator) or median 
QTcF of triplicate standard 12 ECGs >450 msec at screening. 
9. Screening blood pressure ≥160 mm Hg (systolic) or ≥100 mm Hg (diastolic), based on the 
average of 3 measurements.  
10. Pregnant or nursing female subjects. 
11. Subjects of reproductive potential who are not willing to follow the contraception 
requirements outlined in Section 11.6.5.1. 
12. Plan to travel to countries where sleeping sickness is endemic, from the Screening Visit 
through 1 week after the last dose of study drug. 
13. Subject, or 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 at that site. 
14. Hypersensitivity to investigational medicinal product or to any of its excipients. 
The following criterion is applicable for Cohort 1  
15. Use of the substances or activities as indicated in Section 9.5 during the specified times, 
including but not limited to ongoing treatment with corticosteroids (any dose level) or 
another immunosuppressive drug.  
The following criterion is applicable for Cohort 2  
16. Use of the substances or activities as indicated in Section 9.5 during the specified times, 
including but not limited to ongoing treatment with high doses of corticosteroids 
(>10 mg/day of prednisone or prednisone equivalent) or another immunosuppressive drug.  
 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a single-arm, open-label, 2-part study. In Part A, all subjects will receive VX-147 at a 
dosage of 15 mg qd for 2 weeks and VX-147 at a dosage of 45 mg qd for 11 weeks. Part A will 
be enrolled in 2 cohorts: Cohort 1 and an optional Cohort 2. Cohort 1 includes approximately 
10 subjects with UPCR ≥ 3 g/g and < 10 g/g who are not taking systemic corticosteroids or other 
immunosuppressants. The optional Cohort 2 includes approximately 10 subjects with UPCR 
≥ 2 g/g and < 10 g/g, and these subjects are permitted to have a stable low dose of systemic 
corticosteroid.  




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9.1.1.1 
Repetition of Screening Assessments 
Repetition of any individual screening assessment that did not meet eligibility criteria is not 
permitted, unless there is clear evidence of a laboratory error (e.g., hemolysis of sample) or 
equipment failure, or if the investigator believes the result is not consistent with the subject’s 
current status. 
9.1.1.2 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 2 weeks for the following 
reasons: 
• Repetition of the Screening Period assessments (Section 9.1.1.1), 
• Unexpected operational or logistic delays, or 
If more than 42 days have elapsed from screening before first dose of study drug, all screening 
assessments need to be repeated. 
9.1.1.3 
Rescreening 
Individuals who do not meet the eligibility criteria for participation upon initial screening can be 
rescreened up to 3 times. All screening tests should be repeated to determine eligibility except 
for APOL1 genotyping, confirmation of biopsy-proven APOL1-mediated FSGS by the eligibility 
review process (Section 9.3.6), and follicle-stimulating hormone (FSH).  
Rescreened participants will keep the same subject identification number assigned during the 
initial screening process. The rescreening period will start from the date of the first assessment of 
the rescreen. 
9.1.2 
Part A 
9.1.2.1 
Treatment Period  
Subjects will be enrolled in Cohort 1 and optional Cohort 2. Treatment Period assessments are 
listed in Table 3-2. During Treatment Period 1, subjects will receive VX-147 at a dosage 
of 15 mg qd for 2 weeks. During Treatment Period 2, subjects will receive VX-147 at a dosage 
of 45 mg qd for 11 weeks. Dosing details are in Section 9.6. 
9.1.2.2 
Safety Follow-up 
Subjects will have a SFUV 28 (± 7) days after the last dose of study drug. SFUV assessments are 
listed in Table 3-3.  
9.1.2.3 
Early Termination of Treatment or Early Discontinuation 
If a subject prematurely discontinues study treatment, an Early Termination of Treatment (ETT) 
Visit should be scheduled as soon as possible after the subject decides to terminate study 
treatment. Subjects who prematurely discontinue treatment will also be required to complete the 
SFUV, approximately 28 (± 7) days after their last dose of study drug. The assessments 
performed at the SFUV are listed in Table 3-3. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the SFUV, and a separate SFUV will not be required.  
After the ETT Visit, subjects will not complete further Part A Visits; these subjects will not 
continue to Part B.  


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If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue to use any data and samples collected before such withdrawal of 
consent. 
9.1.3 
Part B 
Participation in Part B is optional. After the last Part A Visit, subjects will be followed 
off-treatment at a visit scheduled every 4 weeks (± 2 weeks) to assess the change in proteinuria 
after stopping administration of VX-147 (Table 3-3). Part B visits will continue until the UPCR 
level reaches baseline levels or 3 months after the last dose of study drug, whichever occurs first. 
For the purpose of this assessment, baseline UPCR is defined as the average of the last 
3 screening assessments ± 10%. If a subject has not achieved ≥90% of baseline UPCR by the 
Part B Week 12 Visit, the Part B Week 12 Visit will be the last study visit.  
Subjects will not be allowed to participate in Part B if (1) their UPCR level during Part A 
remained ≥ baseline or (2) their UPCR level reached baseline (as defined above) before the 
Part A Week 13 Visit and remained at that level through the Week 13 Visit. 
The SFUV and Part B Week 4 Off-treatment Follow-up Visit may occur on the same day, 
provided the visit windows for both visits are met.  
9.2 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study. All subjects will receive VX-147. 
9.2.1 
Replacement Subjects 
Subjects may be replaced at the discretion of Vertex. 
9.3 
Rationale for Study Elements 
9.3.1 
Study Design  
The study will be single-arm and open-label. All subjects will receive VX-147 for a total of 
13 weeks. A placebo arm was not included because FSGS is a rare, severe disease with a very 
low likelihood of spontaneous remission.15-17 This is the first study targeting the APOL1 pathway 
in patients with FSGS, so the duration required for proteinuria levels to reach nadir is unknown. 
Clinical practice guidelines18 for other therapies indicate that ≥4 months of therapy may be 
required for patients with nephrotic-range proteinuria to achieve complete remission (defined as 
UPCR <0.3 g/g). The duration of 13 weeks for this study was selected to allow the maximum 
treatment time supported by nonclinical data.  
This is the first study in patients with FSGS, therefore subjects will receive 2 dose levels of 
VX-147 to characterize PK of VX-147 at 2 dose levels in this population. As shown in 
Figure 9-1, the 15 mg qd dose will be administered for 2 weeks and the 45 mg qd dose will be 
administered for 11 weeks. The 2-week duration for the 15 mg qd dose was selected based on an 
exposure-response model suggesting that a measurable decrease in proteinuria may be observed 
after 2 weeks of dosing. The 11-week additional duration for the 45 mg qd dose, provides a total 
of 13 weeks continuous dosing, which is the longest observation period supported by available 
nonclinical data. 


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9.3.2 
Study Population 
The study will enroll male and female subjects, aged 18 to 60 years old, with biopsy proven 
FSGS, 2 APOL1-risk alleles, and nephrotic-range proteinuria. These patients have need for new 
treatments, because patients with FSGS and nephrotic-range proteinuria have rapid progression 
to kidney failure, with mean renal survival less than 10 years.15, 16, 19-21 The presence of FSGS on 
biopsy will be confirmed by an independent, external expert (Section 9.3.6) to determine 
eligibility.  
9.3.3 
Study Drug Dose 
The administration of once daily doses of 15 mg and 45 mg were selected on the totality of 
clinical safety, tolerability, and PK from the FIH study (Study 001); as well as toxicology and 
non-clinical pharmacodynamic (PD) data. 
In Study 001, single ascending oral doses of VX-147 up to 50 mg and multiple ascending doses 
of VX-147 up to 45 mg once daily for 14 days were evaluated. The doses were well-tolerated 
and no clinically significant safety concerns were identified. In this study, a low dose of 15 mg 
once daily is selected to characterize the PK in FSGS patients and to assess any measurable 
decrease in proteinuria. Based on an exposure-response model, the exposures from the 15 mg 
dose are expected to result in approximately 90% inhibition in the in vitro ion flux model. This 
level of inhibition may result in a measurable decrease in proteinuria after 2 weeks of dosing.  
A high dose of 45 mg once daily is selected to maximize the probability of reduction in 
proteinuria over the 11-week dosing period. Based on the exposure-response model referenced 
above, exposures from this dose are expected to result in over 96% inhibition in the in vitro ion 
flux model. VX-147 exposure from the 2 doses are expected to be well differentiated based on 
data from the FIH healthy subject study (Study 001). Thus, the doses selected will provide an 
adequate assessment of the dose-response relationship and safety profile of VX-147 in the 
exposure range of interest.  
Additional information about FIH and nonclinical data are available in the Investigator’s 
Brochure.  
9.3.4 
Study Assessments 
All efficacy, safety, and PK assessments are common assessments for clinical studies, with the 
exception of those described below.  
9.3.4.1 
UPCR  
Percent change from baseline in UPCR at Week 13 was chosen as the primary endpoint because 
proteinuria is a characteristic feature of FSGS and 1 of its main prognostic factors. Urine samples 
will be collected for UPCR using the first morning void, which is standardly used in clinical 
practice to determine accurate urine protein levels. As UPCR is variable within an individual, 
3 samples will be taken during screening, Week 9, and Week 13; and the average of the 3 values 
will be used to determine baseline, Week 9, and end-of-treatment UPCR values.  
9.3.4.2 
SF-36 
Change in SF-36 from baseline over the study treatment period will be assessed as an 
exploratory outcome. SF-36 is a patient-reported generic measure of health status. It has been 


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previously used to evaluate health-related quality of life in patients with chronic kidney disease, 
including FSGS.22,23 
9.3.5 
Use of Telemedicine for Study Visits  
Telemedicine may be used for a number of study visits as detailed in Table 3-2 and Table 3-3. 
These visits will include home health nurse visits to the subject’s home to complete assessments. 
All visits must have a consultation between the subject and investigator (i.e., in person, phone, or 
telemedicine video conference) within 1 business day after the home health visit, in order to 
check-in and collect AEs. Subjects and investigators may choose to conduct individual visits in 
the clinic or through use of home health. Periodic phone or telemedicine video visits may also be 
done to allow the investigator and subject to communicate directly; these visits may be done 
face-to-face in the clinic at the discretion of the investigator. 
If local regulations or site practice do not allow telemedicine, all visits will be conducted at the 
site.  
9.3.6 
Eligibility Review 
An independent, external expert with appropriate clinical and scientific background will evaluate 
the histopathological eligibility criteria to ensure that the subjects meet the study’s definition of 
FSGS. Details of the process will be included in a separate procedure manual. 
9.4 
Prior and Concomitant Medications 
Information about all prior and concomitant medications, including the subject’s FSGS 
medications, other medications, and herbal and naturopathic remedies administered from 28 days 
before the Screening Visit through the SFUV, 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 in Cohort 1 and Cohort 2 who are taking ACE inhibitors, ARB, neprilysin inhibitor, 
sodium-glucose co-transporter-2 inhibitor, or a renin inhibitor must remain on a stable 
medication regimen at least 28 days before the Screening Visit through the Week 13 or ETT (if 
applicable) Visit. Subjects in Cohort 2 who are taking systemic corticosteroids must remain on a 
stable low dose (i.e., ≤ 10 mg/day of prednisone or prednisone equivalent) from at least 28 days 
before the Screening Visit through the Week 13 or ETT (if applicable) Visit. During the 
Off-Treatment Period, every effort should be made to avoid starting, stopping, or modifying 
doses of these medications. If it becomes clinically necessary to alter a subject’s antihypertensive 
regimen during the study, changes to an antihypertensive medication dose or addition of a new 
antihypertensive medication are recommended before changes are made to any ACE inhibitor, 
ARB, neprilysin inhibitor, or renin inhibitor. 


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9.5 
Study Restrictions 
Study restrictions are summarized in Table 9-1. A nonexhaustive list of medications is provided 
in the Study Reference Manual. 
Table 9-1 
Study Restrictions  
Restricted 
Medication/Food/Activitya 
Timing of Restriction 
Start 
Stop 
Moderate and strong CYP3A4 
inhibitors or inducers, including 
consumption of herbal medications 
(e.g., St. John’s Wort) 
None allowed within 14 days 
before the first dose of the 
study drug 
Completion of Safety Follow-up 
Visit assessments 
Systemic corticosteroids (applicable to 
Cohort 1 only) 
None allowed within 4 weeks 
before the first dose of the 
study drug 
Completion of the last study 
assessment 
Immunosuppressants 
None allowed within 12 weeks 
before the first dose of study 
drug 
Completion of the last study 
assessment 
Rituximab 
None allowed within 6 months 
before the first dose of study 
drug 
Completion of the last study 
assessment 
Other investigational drugs or devices 
28 days before first dose of 
study drug, 5 half-lives before 
first dose of study drug dose, or 
time determined by local 
requirements (whichever is 
longer) 
Completion of the last study 
assessment 
Creatine or creatine-containing dietary 
supplements  
7 days before first dose of 
study drug  
Completion of Safety Follow-up 
Visit assessments  
Grapefruit, grapefruit juice, pomelos, 
orange marmalade, Seville/blood 
oranges 
7 days before first dose of 
study drug  
Until last PK sample is taken 
a 
See Section 9.4 for guidance on concomitant medications. 
9.6 
Administration  
VX-147 will be administered as 15 mg tablets, orally, as shown in Table 3-2.  
Study drug will be administered according to the following guidelines: 
• The first dose in each period must be administered under the supervision of site medical 
staff or a home health nurse. Subjects will be monitored for 4 hours after receiving the 
first dose of each Treatment Period 
• On days of scheduled visits, the dose of study drug will be administered after predose 
assessments have been completed. 
• Study drug will be taken at approximately the same time on each dosing occasion. For 
example, subjects that administer VX-147 dose at 8AM on Day 1 should administer all 
subsequent doses at 08:00AM ± 2 hours. 
• Study drug may be taken with or without food. 


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• Subjects will swallow the study drug whole, with a full glass of water and will not chew 
it before swallowing. 
• On days of intensive PK sampling, the date, dose taken, and time of study drug 
administration will be recorded for the 2 doses before PK sample collection and on the 
morning of PK sample collection. 
•  Subjects will be instructed to bring all used and unused materials associated with the 
study drug to the site or the nurse will take these materials at each study visit; 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, the subject should take 
his/her dose according to the guidance above. If more than 6 hours have elapsed after his/her 
usual dosing time, the subject should skip that dose and resume his/her normal schedule for the 
following dose. An example is provided below: 
• If the morning dose of study drug should have been taken at approximately 08:00AM, 
and the subject remembers at 12:00PM that he/she forgot to take his/her dose, he/she 
should take the dose as soon as possible. If they remember after 2:00PM that they forgot 
to take the morning dose, they should skip that dose and resume the normal schedule the 
next day. 
Additional information is provided in the Pharmacy Manual. 
9.7 
Dose Modification 
No dose modifications are allowed. Treatment may be interrupted as outlined in Section 9.8. If 
any unacceptable toxicity arises in the opinion of the investigator, individual subjects may 
discontinue dosing. The Vertex medical monitor must be notified immediately.  
9.8 
Study Drug Interruption 
Study drug may be interrupted for safety concerns by the investigator. The Vertex medical 
monitor should be notified of an interruption of study drug and of the resumption of study drug 
after such interruption. 
9.9 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons. A subject 
who withdraws from study drug treatment will continue to be followed unless the subject 
withdraws consent.  
Subjects who discontinue study treatment early should complete the ETT and SFUV, as noted in 
Sections 9.1.2.2 and 9.1.2.3.  
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a SFUV, if applicable (see 
Section 9.1.2.3), and follow up with the subject regarding any unresolved AEs. 


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If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a 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. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period(s) may be replaced at Vertex’s discretion. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
10.2 
Packaging and Labeling 
Vertex will supply the 15-mg VX-147 tablets. Study drug labeling will be in compliance with 
applicable local and national regulations. Additional details about packaging, labeling, and 
dispensing for VX-147 will be in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
The investigator, or an authorized designee (e.g., a licensed pharmacist), will ensure that all 
investigational product is stored in a secured area, under recommended storage conditions, and in 
accordance with applicable regulatory requirements. To ensure adequate records, all study drugs 
will be accounted for in the drug accountability forms as instructed by Vertex. 
Detailed instructions regarding the storage, handling, and dispensation of the study drug will be 
provided in the Pharmacy Manual. 
Table 10-1 
Study Drug  
Drug Name 
Dosing Form/ 
Route 
Dosage 
How Supplied 
VX-147 
Tablet/ 
oral 
15-mg  
Supplied as 15-mg tablets  
VX-147 
Tablet/ 
oral 
45-mg  
Supplied as 3 × 15-mg 
tablets 
 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information about the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. A central pharmacy will be used for subjects opting to have home 
health visits. Subjects will be instructed to return all used and unused materials associated with 


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the study drug to the home health nurse or site. These materials will be retained at the site or 
central pharmacy according to instructions provided by Vertex or its designee. The study monitor 
will review study drug records and inventory throughout the study. If a site or central pharmacy 
uses a site-specific drug accountability system and/or process, including processes associated 
with the destruction of returned materials, the process must be documented and approved by 
Vertex. The study monitor must review the drug accountability documentation on a regular basis. 
The study monitor will promptly communicate to Vertex any discrepancies he/she is unable to 
resolve with the site. 
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. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site or in the subject’s home at required study visits. At each visit, site 
personnel/home health care nurses 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 should consider discontinuing the subject from the study  
10.7 
Blinding and Unblinding 
This is an open-label study.  
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1 through Table 3-3. 
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 
Medical history will be elicited from each subject and extracted from medical records during 
screening. Based on the medical history, the subject will be assessed for any disqualifying 
medical conditions as specified in the inclusion and exclusion criteria. The medical history will 
include a complete review of systems, past medical and surgical histories, and any allergies. 
Height and weight will be measured with shoes off with light weight clothing (no outerwear). 
BMI will be calculated from weight and height. 
11.2 
Pharmacokinetics 
11.2.1 
Blood Sampling  
Blood samples will be collected to determine plasma concentrations of VX-147. Metabolites of 
VX-147 may be analyzed, if necessary. These samples may also be used for further evaluation of 


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the bioanalytical method, evaluation of unbound concentration of VX‑147, and for exploratory 
analyses that provide information on the metabolic pathways used by or affected by VX-147; 
these results may not be included in the clinical study report. 
All efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
Acceptable windows for sampling times are shown in Table 11-1. Samples collected outside of 
these acceptable windows will be considered protocol deviations.  
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Sampling Time 
Time From Scheduled Sampling Allowed 
Predose 
Up to 60 minutes before dose 
From 0.25 up to ≤4 hours after study drug dosing 
± 15 minutes 
> 4 hours after study drug dosing 
± 120 minutes 
48 hours after study drug dosing 
± 180 minutes 
 
For each visit with a PK blood draw, a record of study drug administration will be collected. 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. 
11.2.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of samples and further procedures for processing and 
handling of samples for PK analysis will be in a separate document.  
11.2.3 
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. 
11.3 
Urine Sampling for UPCR, UACR, and Safety Laboratory Panel 
Urine will be collected from the first morning void (predose) for use in efficacy and safety 
analyses. Efficacy analyses will include UPCR and UACR, as calculated from protein, albumin, 
and creatinine measured in the urine lab panel (Table 11-2). Safety assessments will include the 
urine laboratory parameters in Section 11.6.2. During the Week 9 and Week 13 Visits, when 
3 samples are collected on 3 separate days within a 7-day period, the third sample collected will 
be used for the safety lab and biomarker assessments; all 3 samples will be used for UPCR and 
UACR.  
If the subject does not remember to collect their first morning void on the scheduled visit day, 
the subject may provide the sample on another day within the visit window.  
Details about the collection and processing of urine samples will be provided in the Laboratory 
Manual.  


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11.4 
APOL1 Genotyping 
A blood sample will be collected for determining APOL1 genotype during screening. This 
sample is not required if a genotype result is available from a previous Vertex study using a 
Vertex-approved clinical study assay.  
The results of the genotyping test will be provided to the investigator. The investigator will 
inform the subject of the APOL1 genotype. Vertex will ensure that subjects can obtain the 
services of a genetic counselor, if desired. The site will be responsible for managing the 
corresponding logistics. 
11.5 
Exploratory Assessments 
These data will be used for internal exploratory purposes. Detailed procedures for the collection 
of blood, urine, and pharmacogenomic samples, as well as additional procedures for processing 
and handling samples will be provided in a separate document. 
11.5.1 
Blood Biomarker Samples 
Blood samples will be collected for potential exploratory evaluation of correlations between 
blood markers (e.g., proteins, peptides, lipids, endogenous metabolites, etc.) with PK and AEs 
observed in the study. The samples may also be used for the evaluation of safety biomarkers.  
11.5.2 
Urine Biomarker Samples 
Urine samples will be collected from the first morning void for potential exploratory evaluation 
of correlations between urine markers with PK, treatment response, and AEs observed in the 
study. At the Week 13 Visit, only the last on-treatment urine sample will be used for urine 
biomarker analysis. Additional details will be provided in the Laboratory Manual. 
11.5.3 
Pharmacogenomic Samples 
RNA and optional DNA samples will be collected for potential exploratory evaluation of 
correlations between DNA and RNA markers with PK, treatment response, and AEs observed in 
the study. The RNA sample may be considered optional if so required by an IRB/IEC reviewing 
this study on behalf of a participating institution. 
11.5.4 
SF-36 
Subjects will complete the SF-36 ePRO (if available) in their native language (if validated 
translations are available) before all other study assessments at each scheduled time point. If 
there is no validated translation available in the subject’s native language, the subject will not 
complete the questionnaire. The questionnaire provides information about functional health and 
wellbeing, as well as 2 psychometrically based physical and mental health summary measures. 
11.6 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, and physical examinations (PEs). 
11.6.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP Guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF completion 
guidelines for investigators as well as training will be provided. 


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11.6.2 
Clinical Laboratory Assessments 
The safety laboratory test panels are shown in Table 11-2. For purposes of study conduct, blood 
and urine samples will be analyzed at a central laboratory, with the exception of urine pregnancy 
tests, as described below.  
Urine samples for safety laboratory assessments may be collected at the same time as the urine 
samples for efficacy and biomarker assessments (See Section 11.3). At the Week 9 and Week 13 
Visit, only the third urine sample will be used for urinalysis and biomarker assessments, with the 
exception of urine protein, creatinine, and albumin, which will be assessed for all 3 samples 
collected during this visit. 
On days when overnight fasts are required (see Table 3-2 and Table 3-3), subjects will abstain 
from food and beverages for 8 hours before the start of the visit. During this period, water may 
be consumed up to 1 hour before study drug administration.  
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. Laboratory test results that are abnormal and 
considered clinically significant will be reported as AEs (see Section 13.1).  


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Table 11-2 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Creatine kinase 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Total bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate transaminase 
Alanine transaminase 
Amylase  
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Cholesterold  
Triglyceridesd 
Low-density lipoprotein-directd  
High-density lipoproteind  
Hemoglobin  
Hematocrit 
Erythrocytes 
Mean corpuscular volume 
Platelets  
Reticulocytes  
Leukocytes  
Differential (absolute and percent): 
Eosinophils 
Basophils  
Neutrophils 
Lymphocytes 
Monocytes  
Blood smeare 
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
Leukocyte esterase  
Nitrite  
Urine proteinc  
Urine creatininec 
Urine albuminc 
Urine blood 
  
  
Urine ketones 
Urine glucose 
Urobilinogen 
Urine pH 
Specific gravity 
 
 
a 
For the Day 1 predose sample, microscopic examination of urine will be done, and results will be provided 
for leukocytes, erythrocytes, crystals, bacteria, and casts. 
b 
If blood urea nitrogen cannot be measured, urea may be substituted. 
c 
eGFR will be calculated using the CKD-EPI equation, and AKI will be determined using KDIGO criteria.24 
Urine protein, creatinine, and albumin measurements will be used for PD and safety. 
d 
Lipid profile will only be measured at the visits with fasting: Day 1, Week 3, Week 13, ETT, and SFUV. 
e 
A blood smear will be collected on Day 1, Week 13, and the ETT Visit. 
Additional Tests at Screening: The following additional tests will be performed during screening 
to assess eligibility: 
• Serum beta-human chorionic gonadotropin (β-hCG) for all subjects: Serum samples will 
be analyzed for β-hCG at the central laboratory.  
• Follicle-stimulating Hormone (Screening Period only): Blood sample for FSH will be 
measured for any suspected postmenopausal female with at least 12 months of continuous 
spontaneous amenorrhea. Serum FSH levels must be within the postmenopausal 
reference range of the performing laboratory to be considered postmenopausal. 
• APOL1: A blood sample will be collected to determine APOL1 genotype, if required per 
Table 3-1. 
• HIV-1 and HIV-2 antibodies: A blood sample will be collected for serology. 
• Hepatitis B surface antigen: A blood sample will be collected for serology. 


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• Hepatitis C nucleic acid test: A blood sample will be collected for nucleic acid testing.  
Pregnancy Testing for Female Subjects of Childbearing Potential (Section 11.6.5): 
• Urine pregnancy tests will either be performed and analyzed at the site or, when there is 
no clinic visit scheduled, at home using a home kit provided by the site/home health 
nurse. The urine pregnancy test on Day 1 must be negative before the first dose of study 
drug. Additional pregnancy tests may be required according to local regulations and/or 
requirements. 
If a urine pregnancy test is positive, all study drug dosing will stop and the pregnancy will be 
confirmed with a serum β-hCG test. If pregnancy is confirmed, the procedures outlined in 
Section 11.6.5.2 will be followed. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate. 
11.6.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits. At other visits, symptom-directed PEs and symptom-directed vital signs assessments 
can be performed at the discretion of the investigator or healthcare provider. 
A PE includes a review of the following systems: head, neck, and 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. 
The abbreviated PE will include an assessment of the following body systems: cardiovascular 
system; respiratory system; skin; and abdomen. 
Vital signs include blood pressure (systolic and diastolic), oral temperature, pulse rate, and 
respiration rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed.  
11.6.4 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines: 
• The ECG will be done before any other procedures that may affect heart rate, such as 
blood draws. 
• The subject will be instructed to rest for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position 
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 SFUV will be recorded as AEs.  
If study sites cannot use QTcF they should discuss alternatives with the medical monitor. 


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To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >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. A subject with a 
confirmed QTcF value above the threshold value will discontinue dosing. 
11.6.5 
Contraception and Pregnancy 
The effects of VX-147 on conception, pregnancy, and lactation in humans are not known. Refer 
to the VX-147 Investigator’s Brochure for additional details. 
11.6.5.1 
Contraception 
Study participation requires compliance with the contraception guidelines outlined below: 
Contraception for the couple is waived for the following: 
• True abstinence for the subject, when this is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and 
post-ovulation 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 the female is of non-childbearing potential. To be considered of non-childbearing 
potential, the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH 
level within the laboratory’s reference range for postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
Note: All other females (including females with tubal ligations and females who do 
not have a documented hysterectomy or bilateral oophorectomy/salpingo-
oophorectomy) will be considered to be of childbearing potential. 
• Same sex relationships. 
For subjects for whom the contraception requirement is not waived: 
For male subjects with female partners of childbearing potential, in addition to wearing a 
condom, study participation requires a commitment from the subject that at least 1 allowed 
method of contraception (in addition to a condom) will be used as a couple. Refer to Table 11-3 
for allowed methods of contraception. 
For female subjects with childbearing potential, study participation requires a commitment 
from the subject that at least 1 allowed method of contraception is used as a couple. Allowed 
methods of contraception are listed in Table 11-3. 
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.  


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Table 11-3 
Allowed Methods of Contraception 
Method 
Male Subjects and 
Their Female 
(Non-study) Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy 6 months or more previously, with a 
documented negative postvasectomy semen 
analysis for sperm 
Yes 
Yes 
Documented tubal ligation 4 weeks or more 
previously 
Yes 
Yes 
Continuous use of an intrauterine device for at 
least 90 days before the first dose of study drug  
Yes 
Yes a 
Oral, patch, implanted, or injected hormonal 
contraceptives, if used consistently and correctly 
for at least 60 days before the first dose of study 
drug 
Yes b 
No c 
a 
Non-hormonal releasing IUD only  
b 
Female (Non-study) Partners only 
c 
The effects of VX-147 on the PK of hormonal contraceptives are not known. Thus, hormonal contraception 
is NOT an acceptable method of contraception for female subjects. 
Additional notes: 
• Male subjects must use a condom to avoid exposing a potential fetus to study drug via the 
seminal fluid. The female condom is not an acceptable method due to the increased risk 
of tearing when the female and male condoms are used at the same time. 
• Male and female subjects who are not sexually active at the time of screening must agree 
to follow the contraceptive requirements of this study if they become sexually active with 
a partner of the opposite sex.  
• Male subjects must not donate sperm from the first study drug dose until 90 days after the 
last dose of study drug. 
• Female subjects of childbearing potential should not plan to become pregnant during the 
study or within 90 days after the last dose of study drug. For male subjects with a female 
partner of childbearing potential, the couple should not plan to become pregnant during 
the study or within 90 days after the last dose of study drug.  
• If applicable, additional contraception requirements may need to be followed according 
to local regulations and/or requirements. 
• Unique situations that may not fall within the above specifications may be discussed with 
the Vertex medical monitor or designee on an individual basis. 
11.6.5.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a female subject, or the female partner of a male subject, becomes pregnant while participating 
in the study, the study drug will be permanently discontinued immediately. The investigator will 
notify the medical monitor and Vertex Global Patient Safety (GPS) within 24 hours of the site’s 


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knowledge of the subject’s (or partner’s) pregnancy, and send the Pregnancy Information 
Collection Form to Vertex GPS. 
A subject (or their partner, if relevant) who becomes pregnant while on study will be followed 
until the end of the pregnancy. The infant will be followed for 1 year after birth, provided 
informed consent is obtained. A separate ICF will be provided to explain these follow-up 
activities. Pregnancy itself is not an AE.  
12 
STATISTICAL AND ANALYTICAL PLANS 
This section presents a summary of the planned final analyses for efficacy, safety, and clinical 
pharmacology. Efficacy and 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 last 
subject last visit for the treatment period (Part A). 
The primary endpoint analysis will occur after all subjects in Cohort 1 have completed the 
SFUV, and all related data have been locked. 
An additional analysis for Part A will occur after all subjects in Cohort 2 have completed the 
SFUV and the related data have been locked. 
The final analysis for the study will occur after all subjects have completed their last required 
visit of the study (Part A or Part B, as applicable) and the database has been locked. 
12.1 
Sample Size and Power 
The sample size was not calculated based on power assumptions, because this is an estimation 
study. The primary endpoint is percent change from baseline in UPCR at Week 13. Assuming an 
SD of 0.672 (in log scale),25 a sample size of 10 subjects will provide a precision of 0.294 (in log 
scale) for the estimation of the Geometric Mean Percent Change (GMPC) from baseline in 
UPCR. The precision of the estimate corresponds to the half width of its 80% CI, in log scale. 
Table 12-1 displays the expected size of the 80% CIs for the GMPC at various values of the 
observed GMPC.  
Table 12-1 
Two-sided 80% Confidence Interval for GMPC from Baseline in UPCR 
Number of 
Subjects 
Completing 
Assumption for 
SD in Log Scale 
Observed GMPC (corresponding percent reduction from baseline) 
0.5 (-50%) 
0.6 (-40%) 
0.7 (-30%) 
0.8 (-20%) 
10 
0.672 
0.37, 0.67  
(-63%, -33%) 
0.45, 0.81  
(-55%, -19%) 
0.52, 0.94  
(-48%, -6%) 
0.60, 1.07  
(-40%, 7%) 
 
12.2 
Analysis Sets 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), Safety Set, 
and Follow-up Set. 
The All Subjects Set will include all subjects who were enrolled in the study. This analysis set 
will be used for all individual subject data listings and disposition summary tables, unless 
otherwise specified.  


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The FAS will include all subjects who received at least 1 dose of study drug in the Treatment 
Period and at least 1 post-baseline efficacy assessment. The FAS will be used for all efficacy 
analyses in the Treatment Period, unless otherwise specified. 
The Follow-up Set will include all subjects who entered the Off-treatment Follow-up Period 
(Part B) and have at least 1 efficacy assessment in that period. The Follow-up Set will be used 
for all efficacy analyses in the Follow-up Period, unless otherwise specified.  
The Safety Set will include all subjects who received at least 1 dose of study drug. The Safety 
Set will be to summarize subject demographics and baseline characteristics, and used for all 
safety analyses, unless otherwise specified. 
12.3 
Statistical Analysis 
This section presents a summary of the planned statistical analyses of efficacy, safety and PK 
endpoints of the study. Statistical analysis details will be provided in the SAP. 
12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). 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, and SD 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. 
Baseline value, unless specified otherwise, 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., the Day 1 Visit). For ECGs, 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., the Day 1 visit). For UPCR (and UACR) data baseline value will be the 
average of UPCR (UACR) values from the 3 urine samples collected during screening for the 
purpose of assessing eligibility. 
Change (absolute change) from baseline will be calculated as Post-baseline value − Baseline 
value. 
Treatment-emergent (TE) Period will include the time from the first dose of study drug in the 
Treatment Period to either (1) the SFUV, (2) ETT Visit if it replaces the SFUV, or (3) the date of 
the last dose + 28 days for subjects who do not have a SFUV. The TE Period will be used for 
safety analyses unless specified otherwise. 
The analysis visit windows for protocol-defined visits will be described in the SAP. 
The rules for handling missing data due to treatment or study discontinuation will be described in 
the SAP.  
Data will be analyzed separately for the Treatment Period (Part A) and the Off-treatment 
Follow-up Period (Part B), unless specified otherwise. 


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12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
The number and percentage of subjects in each disposition category in the Treatment Period 
(e.g., included in the All Subjects Set, included in the Safety Set, completed Treatment Period, 
completed SFUV, and discontinued treatment or study with a breakdown of the reasons for 
discontinuation) will be summarized. 
The number and percentage of subjects in each disposition category in the Off-treatment 
Follow-up Period (e.g., included in the Follow-up Set, completed Follow-up Period, and 
discontinued study/Follow-up Period with a breakdown of the reasons for discontinuation) will 
be summarized. 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographics, background (e.g. medical history), and baseline characteristics will be 
summarized using descriptive summary statistics. 
The following demographics and baseline characteristics will be summarized based on the Safety 
Set and will include (but not limited to): sex, race, age, weight, height, BMI, UPCR, UACR, and 
eGFR. 
12.3.2.3 
Prior and Concomitant Medications 
Medications used will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) and categorized as the following: 
Prior medication: any medication that started before the date of the first dose of study drug, 
regardless of when the medication ended 
Concomitant medication: medication continued or newly received on or after the date of the 
first dose of study drug through the end of the TE Period 
A given medication may be classified as prior, concomitant, or both prior and concomitant.  
If a medication start date is on or after the first dose date of study drug, then the medication will 
be categorized as concomitant medication regardless of whether the medication end date is 
missing or not. If a medication end date is before the first dose date of study drug, then the 
medication will be categorized as prior medication regardless of whether the medication start 
date is missing or not. Note that medication that started before the first dose of study drug and 
continued after the first dose will be categorized as prior medication and separately as 
concomitant medication.  
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, or concomitantly, it will be 
considered in both categories of prior and concomitant medication. 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by Preferred Name based on the Safety Set.  
Details for imputing missing or partial start and/or stop dates of medication will be in the SAP. 


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12.3.2.4 
Study Drug Exposure and Compliance 
Exposure to study drug will be summarized for the Safety Set in terms of duration of treatment a 
subject received (in days), defined as: last dose date – first dose date + 1 day, regardless of study 
drug interruption. 
Study drug compliance based on study drug exposure, will be summarized for the Safety Set, and 
will be calculated as: 100 × [1 – (total number of days of any study drug interruption)/(duration 
of study drug exposure in days)].  
12.3.2.5 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. The rules for identifying an IPD will be described in the SAP. 
IPDs will be provided in an individual subject data listing. 
12.3.3 
Efficacy Analysis 
Analyses will be done separately for Cohort 1 and Cohort 2. 
12.3.3.1 
Analysis of Primary Variables 
The primary efficacy endpoint is percent change from baseline in UPCR at Week 13. The 
Week 13 UPCR value will be calculated as the average of the available UPCR measurements 
(maximum 3) taken during Week 13. The baseline value will be the average of the 3 UPCR 
values from the urine samples collected during screening. 
The percent change from baseline in UPCR at Week 13 will be analyzed by first 
log-transforming the UPCR data before analyses to reduce skewness, and calculating the change 
from baseline in log-transformed values. The GMPC from baseline in UPCR will be estimated 
along with the corresponding 2-sided 80% CI. The GMPC from baseline and associated 
confidence limits will be calculated by back-transforming the estimated simple mean of change 
from baseline in log-transformed data. 
Sensitivity analyses for handling missing data due to treatment or study discontinuation will be 
described in the SAP. 
12.3.3.2 
Analysis of Other Variables 
In all exploratory analyses of UPCR and UACR related data, the Week 9 and Week 13 
UPCR/UACR value will be calculated as the average of the available UPCR/UACR 
measurements (maximum 3) taken during Week 9 or Week 13, and the baseline value will be the 
average of the 3 UPCR/UACR values from the urine samples collected for this purpose during 
screening. 
The percent change from baseline in UPCR over time during the Treatment period is an 
exploratory efficacy endpoint. Similar to the primary endpoint analysis, UPCR data will be 
log-transformed and change from baseline at each planned visit, up to Week 13, will be analyzed 
using the log-transformed UPCR values. The GMPC from baseline and associated 2-sided 
80% CI at each planned visit will be calculated by back-transforming the corresponding 
estimated simple mean and CI from the log-transformed data. 


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Other exploratory efficacy endpoints include percent change from baseline in urinary 
albumin-to-creatinine ratio (UACR) at Week 13, and percent change from baseline in UACR 
over time during the Treatment period. Analysis of these 2 endpoints will be similar to that 
performed for the corresponding UPCR endpoints. 
Off-treatment Follow-up Period (Part B): The exploratory endpoint of percent change from 
baseline in UPCR at the end of the Off-treatment Follow-up Period will be analyzed similarly to 
the primary efficacy endpoint. 
Additional details of these analyses will be provided in the SAP. 
12.3.4 
Safety Analysis 
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 in terms of the following safety and 
tolerability endpoints:  
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (hematology, serum chemistry, coagulation studies, and 
urinalysis) 
• Standard 12-lead ECG outcomes 
• Vital signs  
Only a descriptive analysis of safety will be performed. 
All safety data will be presented in individual subject data listings. 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs or TEAEs, defined as follows:  
Pretreatment AE: any AE that started before the first dose date of study drug 
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed on 
or after the first dose date of study drug through the end of the TE Period  
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs. 
AE summary tables will be presented for TEAEs only and will include the following: 
• All TEAEs 
• TEAEs by strongest relationship  
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• Serious TEAEs 
• TEAEs leading to death 
Summaries will be presented by MedDRA System Organ Class (SOC) and Preferred Term (PT) 
using frequency counts and percentages (i.e., number and percentage of subjects with an event). 


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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 
will be presented in the relationship summaries.  
In addition, a listing of individual subject level AE data for TEAEs leading to treatment 
discontinuation, serious adverse events (SAEs), and deaths will be provided separately. All AEs, 
including pretreatment AEs, will be in individual subject data listings. 
12.3.4.2 
Clinical Laboratory Assessments 
For 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 by visit.  
The number and percentage of subjects with at least 1 laboratory event outside threshold criteria 
for the event during the TE Period will be summarized, including a shift of the event from 
baseline to post-baseline. The threshold criteria will be in the SAP. 
Results of urinalysis and the urine/serum pregnancy test will be in individual subject data listings 
only.  
In addition, a listing of 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. 
12.3.4.3 
Electrocardiogram 
For treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided by visit and time point, as applicable, for the following ECG 
measurements: RR (msec), heart rate (HR; beats per minute [bpm]), PR (msec), QRS duration 
(msec), QT (msec), and QT corrected for HR intervals (QTcF [msec]).  
The number and percentage of subjects meeting a threshold analysis criterion during the 
TE Period will be summarized. The threshold analysis criteria will be provided in the SAP. 
Clinically significant abnormal findings will be reported as AEs. 
Additional ECG analyses may be described in the SAP. 
12.3.4.4 
Vital Signs 
For treatment-emergent vital signs measurements, the observed values and change from baseline 
values will be summarized by visit: systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), pulse rate (bpm), and respiratory rate (breaths per minute). 
The number and percentage of subjects with at least 1 event outside the threshold criteria for a 
vital sign during the TE Period will be summarized. The threshold analysis criteria will be 
provided in the SAP. 
Clinically significant abnormal findings in vital signs will be reported as AEs. 
Additional vital signs analyses may be described in the SAP. 
12.3.4.5 
Physical Examination 
PE findings will be presented in individual subject data listings only. 


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12.3.4.6 
Other Safety Analysis 
Change from baseline in weight will be summarized by visit. 
12.3.5 
Other Analyses 
Analysis of the exploratory endpoints for SF-36 will be provided in the SAP. 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses 
Interim analyses may be done at the discretion of the sponsor to allow for regulatory interactions 
and clinical development planning. There is no independent Data Monitoring Committee for this 
study.  
12.4 
Clinical Pharmacology Analysis 
The following systemic exposure parameters will be estimated using noncompartmental and 
population PK analysis: AUCτ during a dosing interval, Cmax and Ctrough will be estimated for all 
subjects who provide adequate number of PK samples: 
• on Day 1 after single administration of the lower dose;  
• at Week 2 after the first administration of the higher dose; 
• at Week 5 after multiple administrations of the higher dose. 
In addition, observed Ctrough will be reported at Weeks 1, 3, 9, and 13. Based on availability of 
data after the last administration of the higher dose, half-life will be reported after multiple 
administrations of the higher dose.  
12.4.1 
Pharmacokinetic Analysis 
Mean and/or median plasma concentrations versus time will be plotted on log and linear scales. 
The PK parameters (Cmax, Ctrough, AUCτ, and other parameters as needed) of VX-147 estimated 
by noncompartmental analysis will be listed and summarized using summary statistics. Ongoing 
analyses of plasma concentrations of VX-147 may be conducted before database lock. 
Details of the analyses will be in the CPAP. 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses 
A population PK analysis of plasma concentration versus time data of VX-147 will be performed 
using the nonlinear mixed-effects modeling approach. Population and individual PK parameters: 
clearance after oral administration (CL/F) and apparent volume of distribution at steady state 
(Vss/F) will be estimated and the influence of various covariates (such as age, gender, and body 
weight) on these parameters will be investigated in an exploratory way. If deemed necessary, 
data may be pooled with data from other studies with VX-147 in order to improve the parameter 
estimates from the model.  
Plasma concentration − response relationship (PD markers and AEs, if any) will be explored. A 
more detailed description of the methodology to be followed will be in either the CPAP or the 
population PK/PD analysis plan. Listings of VX-147 plasma concentration data will be in the 
bioanalytical report. The population PK analysis will be in a stand-alone report.  


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13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the following times: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, 
withdrawal of consent) 
• For enrolled subjects who have a SFUV: through the SFUV 
• For enrolled subjects who do not have a SFUV, 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 9.1.2.3) 


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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 will be 
recorded only in the subject’s source documents. The following data will be documented for 
each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
February 2020). The severity of an AE described by a term that does not appear in the CTCAE 
will be determined according to the definitions in Table 13-1. 
Table 13-1 
Grading of AE Severity  
Classification 
Description 
Mild (Grade 1) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Moderate (Grade 2) 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADLa 
Severe (Grade 3) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADLb 
Life-threatening (Grade 4) 
Life-threatening consequences, urgent intervention indicated  
Death (Grade 5) 
Death related to AE 
Source: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
ADL: activities of daily living; AE: adverse event 
Note: A semi-colon indicates ‘or’ within the description of the grade. 
a 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 


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13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories 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 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 in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories 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 


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


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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 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
SFUV, regardless of causality, will be reported by the investigator to Vertex GPS within 
24 hours of identification. In addition, all SAEs that occur after the SFUV and are considered 
related to study drug(s) will be reported to Vertex GPS within 24 hours of identification.  
For SAEs that occur after obtaining informed consent and assent (where applicable) through the 
SFUV, 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: 
 
  
For technical issues related to submitting the form, contact telephone: 
 
SAEs that occur after the SFUV and are considered related to study drug(s) will be recorded on 
the Vertex Clinical Trial 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 the outcome to Vertex using the SAE Form. 
13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IECs, and 
participating investigators in accordance with ICH Guidelines and/or local regulatory 
requirements, as applicable. In addition, Vertex, or authorized designee, will be responsible for 
the submission of safety letters to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/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 


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with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will be 
conducted only 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.  
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 will be limited to the site and the study physician and will not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE Forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 


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For sites participating in the US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will 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 
• 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. 
13.2.8 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
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 subject. Study 
data for each enrolled subject will be entered into a CRF by study site personnel using a secure, 


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validated, web-based electronic data capture (EDC) application. Vertex will have read-only 
access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP Guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application is 
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 them, 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 compact disc (CD) or other electronic media will be placed in the investigator’s 
study file. 
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator's employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 


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The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 
13.7.1 
Publication of Study Results 
Vertex is committed to reporting the design and results of all clinical studies in a complete, 
accurate, balanced, transparent, and timely manner, consistent with Good Publication Practices 
(GPP3).26  
Publication Planning: Vertex staff along with the lead principal investigators (PIs), the steering 
committee (SC), and/or the publication committee (PC) will work together to develop a 
publication plan.  
Authorship: Authorship of publications will be determined based on the Recommendations for 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, which 
states that authorship should be based on the following 4 criteria27: 
1. Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data;  
2. Drafting of the article or revising it critically for important intellectual content;  
3. Final approval of the version to be published; and 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved. 
All authors must meet conditions 1, 2, 3, and 4. All persons designated as authors should qualify 
for authorship, and all those who qualify should be listed. Contributions such as medical writing, 
enrollment of subjects, acquisition of funding, collection of data, or general supervision of the 
research group, alone, do not justify authorship.  
Contributors: Contributors who meet fewer than all 4 of International Committee of Medical 
Journal Editors (ICMJE) criteria for authorship will not be listed as authors, but their 
contribution will be acknowledged and specified either as a group (e.g., “study investigators”) or 
individually (e.g., “served as scientific advisor”).  
Publication Review: As required by a separate clinical study agreement, Vertex must have the 
opportunity to review all publications, including any manuscripts, abstracts, oral/slide 
presentations, and book chapters regarding this study before submission to congresses or journals 
for consideration.  
13.7.2 
Clinical Study Report  
A clinical study report (CSR), written in accordance with the ICH E3 Guideline, will be 
submitted in accordance with local regulations. 


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14 
REFERENCES 
1 
McGrogan A, Franssen C, de Vries C. The incidence of primary glomerulonephritis 
worldwide: a systematic review of the literature. Nephrology Dialysis Transplantation. 
2011;26(2):414-30. 
2 
D'Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 
2011;365(25):2398-411. 
3 
Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, et al. APOL1 genetic 
variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am 
Soc Nephrol. 2011;22(11):2129-37. 
4 
Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et al. 
Association of trypanolytic ApoL1 variants with kidney disease in African Americans. 
Science. 2010;329(5993):841-5. 
5 
Shukha K, Mueller JL, Chung RT, Curry MP, Friedman DJ, Pollak MR, et al. Most 
ApoL1 is secreted by the liver. J Am Soc Nephrol. 2017;28(4):1079-83. 
6 
Madhavan SM, O'Toole JF, Konieczkowski M, Ganesan S, Bruggeman LA, Sedor JR. 
APOL1 localization in normal kidney and nondiabetic kidney disease. J Am Soc Nephrol. 
2011;22(11):2119-28. 
7 
Vanhamme L, Paturiaux-Hanocq F, Poelvoorde P, Nolan DP, Lins L, Van Den Abbeele 
J, et al. Apolipoprotein L-I is the trypanosome lytic factor of human serum. Nature. 
2003;422(6927):83-7. 
8 
Perez-Morga D. Apolipoprotein L-I promotes trypanosome lysis by forming pores in 
lysosomal membranes. Science. 2005;309(5733):469-72. 
9 
Cooper A, Ilboudo H, Alibu VP, Ravel S, Enyaru J, Weir W, et al. APOL1 renal risk 
variants have contrasting resistance and susceptibility associations with African 
trypanosomiasis. Elife. 2017;6:e25461. 
10 
Ma L, Chou JW, Snipes JA, Bharadwaj MS, Craddock AL, Cheng D, et al. APOL1 renal-
risk variants induce mitochondrial dysfunction. J Am Soc Nephrol. 2017;28(4):1093-105. 
11 
Beckerman P, Bi-Karchin J, Park ASD, Qiu C, Dummer PD, Soomro I, et al. Transgenic 
expression of human APOL1 risk variants in podocytes induces kidney disease in mice. 
Nat Med. 2017;23(4):429-38. 
12 
Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, et al. Missense 
mutations in the APOL1 gene are highly associated with end stage kidney disease risk 
previously attributed to the MYH9 gene. Hum Genet. 2010;128(3):345-50. 
13 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A 
new equation to estimate glomerular filtration rate. Annals of internal medicine. 
2009;150(9):604-12. 
14 
Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. 
Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C. New 
England Journal of Medicine. 2012;367(1):20-29. 
15 
Chun MJ, Korbet SM, Schwartz MM, Lewis EJ. Focal segmental glomerulosclerosis in 
nephrotic adults: presentation, prognosis, and response to therapy of the histologic 
variants. J Am Soc Nephrol. 2004;15(8):2169-77. 
16 
Stirling CM, Mathieson P, Boulton-Jones JM, Feehally J, Jayne D, Murray HM, et al. 
Treatment and outcome of adult patients with primary focal segmental glomerulosclerosis 
in five UK renal units. QJM. 2005;98(6):443-9. 


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17 
Cattran DC, Rao P. Long-term outcome in children and adults with classic focal 
segmental glomerulosclerosis. Am J Kidney Dis. 1998;32(1):72-9. 
18 
(KDIGO) KDIGO. 2012 Clinical Practice Guideline for the Evaluation and Management 
of Glomerulonephritis. Kidney Int. 2012;2(2):15-16. 
19 
Korbet SM, Schwartz MM, Lewis EJ. Primary focal segmental glomerulosclerosis: 
clinical course and response to therapy. Am J Kidney Dis. 1994;23(6):773-83. 
20 
Troyanov S, Wall CA, Miller JA, Scholey JW, Cattran DC, Toronto Glomerulonephritis 
Registry G. Focal and segmental glomerulosclerosis: definition and relevance of a partial 
remission. J Am Soc Nephrol. 2005;16(4):1061-8. 
21 
Rydel JJ, Korbet SM, Borok RZ, Schwartz MM. Focal segmental glomerular sclerosis in 
adults: presentation, course, and response to treatment. Am J Kidney Dis. 
1995;25(4):534-42. 
22 
Gipson DS, Trachtman H, Kaskel FJ, Radeva MK, Gassman J, Greene TH, et al. Clinical 
trials treating focal segmental glomerulosclerosis should measure patient quality of life. 
Kidney International. 2011;79(6):678-85. 
23 
Komers R, Gipson DS, Nelson P, Adler S, Srivastava T, Derebail VK, et al. Efficacy and 
Safety of Sparsentan Compared With Irbesartan in Patients With Primary Focal 
Segmental Glomerulosclerosis: Randomized, Controlled Trial Design (DUET). Kidney 
International Reports. 2017;2(4):654-64. 
24 
Kidney Disease: Improving Global Outcomes (KDIGO) Working Group. KDIGO 
Clinical Practice Guideline for Acute Kidney Injury. Kidney International Supplement. 
2012;2(1)  
25 
Trachtman H, Nelson P, Adler S, Campbell KN, Chaudhuri A, Derebail VK, et al. 
DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients 
with FSGS. Journal of the American Society of Nephrology. 2018;29(11):2745-54. 
26 
Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
Publication Practice for Communicating Company-Sponsored Medical Research: GPP3. 
Ann Intern Med. 2015;163(6):461-4. 
27 
(ICMJE) ICoMJE. International Committee of Medical Journal Editors (ICMJE). 
Recommendations for conduct, reporting, editing, and publication of scholarly work in 
medical journals. [Internet]. Available from: http://www.icmje.org/recommendations. 
Accessed 06 September. 
 




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15.2 
Investigator Signature Page 
Protocol #:  
VX19-147-101 Version #: 
2.0 
Version Date: 05 March 2020 
Study Title: A Phase 2a, Open-label, Single-arm, 2-Part Study to Evaluate the Efficacy, 
Safety, and Pharmacokinetics of VX‑147 in Adults With APOL1-mediated Focal Segmental 
Glomerulosclerosis 
 
 
I have read Protocol VX19-147-101, Version 2.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-147 and this protocol supplied to me by 
Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 




Protocol VX19-147-101, Version 6.0  
 
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Summary of Changes to the Protocol 
The previous version of this protocol (Version 5.0, dated 09 April 2021) was amended to create 
the current version (Version 6.0, 26 July 2021). 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 10 October 2019 
Original version 
Version 2.0, 05 March 2020 
Specified the doses to be used; added optional Cohort 2; modified the 
schedule of assessments and eligibility criteria. 
Version 3.0, 23 September 2020 
Added an option for telemedicine and home health nurse visits to be used 
during to the Screening Visit; amended the eligibility criteria; several 
administrative and minor changes. 
Version 4.0, 11 December 2020 
Amended the eligibility criteria; specified that both cohorts will be 
analyzed for the primary endpoint; several administrative and minor 
changes. 
Version 5.0, 09 April 2021 
Modified the eligibility criteria for estimated glomerulofiltration rate 
(eGFR) and UPCR; updated the study restrictions to allow concomitant 
use of cyclosporine. 
Version 6.0, 26 July 2021 
Current version 
 
Key changes in the current version of the protocol are summarized below.  
Change and Rationale 
Affected Sections  
Specified that Cohort 1 will enroll “up to 10 subjects” and not “approximately 
10 subjects.” This change clarifies that enrollment may be stopped before 
10 subjects are enrolled.  
Sections 2, 9.1, and 12.1 
 


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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 2a, Open-label, Single-arm, 2-Part Study to Evaluate the Efficacy, Safety, and 
Pharmacokinetics of VX‑147 in Adults With APOL1-mediated Focal Segmental 
Glomerulosclerosis 
  
Brief Title 
Phase 2a Study of VX-147 in Adults With APOL1-mediated Focal Segmental 
Glomerulosclerosis 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 2a pharmacodynamics (PD), safety, and pharmacokinetics (PK) 
 
 
Objectives 
Part A (Treatment Period) 
Primary 
• 
To evaluate the ability of VX-147 to reduce proteinuria 
Secondary 
• 
To evaluate the safety and tolerability of VX-147 
• 
To characterize the PK of VX-147 
Part B (Optional Off-treatment Follow-up Period) 
Exploratory  
• To evaluate the change in proteinuria after stopping administration of VX-147 
 
 
Endpoints 
Part A (Treatment Period) 
Primary 
• 
Percent change from baseline in urine protein to creatinine ratio (UPCR) at 
Week 13 
Secondary 
• 
Safety and tolerability based on adverse events (AEs), clinical laboratory values 
(i.e., hematology, serum chemistry, urinalysis, coagulation studies), standard 
12-lead ECGs, and vital signs 
• 
Plasma PK of VX-147 
Exploratory  
• 
Percent change from baseline in UPCR over time during the Treatment Period  
• 
Percent change from baseline in urine albumin-to-creatinine ratio (UACR) at 
Week 13 
• 
Percent change from baseline in UACR over time during the Treatment Period 
• 
Change from baseline in patient-reported outcome (PRO) Short Form Health 
Survey 36 (SF-36) over time during the Treatment Period  
• 
Change from baseline in SF-36 at 4 weeks after the last dose (Safety Follow-up 
Visit [SFUV]) 
Part B (Optional Off-treatment Follow-up Period) 
Exploratory  
• Percent change from baseline in UPCR at the end of the Off-treatment Follow-up 
Period 
 
 
 


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Number of Subjects 
Up to 10 subjects in Cohort 1 and approximately 10 subjects in optional Cohort 2 
 
 
Study Population 
Male and female subjects 18 to 65 years old with 2 apolipoprotein L1 (APOL1) risk 
alleles (G1/G1, G1/G2, or G2/G2 genotype) who have APOL1-mediated focal 
segmental glomerulosclerosis (FSGS), UPCR ≥3 g/g and < 10 g/g (Cohort 1) or 
≥ 0.8 g/g and < 2.7 g/g (Cohort 2), and estimated glomerular filtration rate 
(eGFR)  ≥30 mL/min/1.73 m2 (Cohort 1 and Cohort 2) 
 
 
Investigational Drug 
Active substance: VX-147 
 
Activity: APOL1-inhibitor 
 
Strength and route of administration: 15 mg tablets for oral administration 
 
 
Study Duration 
Excluding the Screening Period, each subject will participate in the study for 
approximately 13 weeks of treatment in Part A. Subjects may choose to participate in 
an off-treatment observation for up to 12 weeks in Part B (optional). All subjects will 
complete a SFUV at 28 (± 7) days after the last dose of study drug. 
 
 
Study Design 
This is a single-arm, open-label, 2-part study. In Part A, subjects will receive VX-147 
at a dosage of 15 mg once daily (qd) for 2 weeks and VX-147 at a dosage of 45 mg qd 
for 11 weeks. Part A will be enrolled in 2 cohorts: Cohort 1 and optional Cohort 2. 
Cohort 1 includes up to 10 subjects with UPCR approximately ≥3 g/g and <10 g/g and 
eGFR approximately ≥30 mL/min/1.73 m2. Optional Cohort 2 includes approximately 
10 subjects with UPCR approximately ≥0.8 g/g and <2.7 g/g and eGFR approximately 
≥30 mL/min/1.73 m2.   
Subjects in Cohort 1 and Cohort 2 are permitted to take a stable low dose of systemic 
corticosteroid (prednisone ≤ 10 mg per day or prednisone equivalent) and/or an 
allowed immunosuppressant (i.e., tacrolimus, mycophenolate, or cyclosporine). 
Enrollment of Cohort 1 and Cohort 2 will be managed through the interactive web 
response system (IWRS).  
After completing Part A, subjects will be followed for up to 12 weeks in Part B 
(optional) for evaluation of proteinuria off treatment if they consent to do so. If a 
subject prematurely discontinues study drug in Part A, an Early Treatment Termination 
(ETT) Visit should be scheduled as soon as possible after the decision to terminate 
study drug treatment. After completing the ETT Visit, subjects will not complete 
further Part A Visits; these subjects will come in for a SFUV and will not continue to 
Part B. 
All subjects are required to complete a SFUV at 28 (± 7) days after the last dose of 
study drug. The SFUV may occur while a subject is participating in Part B. 


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Figure 2-1 
VX19-147-101 Study Design 
 
 
D: Day; PK: pharmacokinetics; qd: once daily; UPCR: urine protein to creatinine ratio; 
W: Week 
Notes: The figure is not drawn to scale. After completing Part A, subjects will be followed 
monthly for up to 12 weeks or until UPCR returns to baseline, whichever occurs first. All 
subjects will be required to complete a SFUV at 28 (± 7) days after the last dose of study 
drug. 
a 
Proteinuria will be assessed at multiple timepoints throughout the Treatment Period and 
Off-treatment Follow-up. Triangles represent timepoints for the primary analysis. 
 
 
Assessments 
Efficacy: UPCR 
Safety: AEs; clinical laboratory assessments; ECGs; vital signs; and physical 
examinations 
PK: VX-147 plasma concentrations 
Exploratory: UACR, SF-36, biomarker blood and urine samples 
 
 
Statistical Analyses 
Efficacy 
Analyses will be done separately for Cohort 1 and Cohort 2, as well as combined. The 
primary endpoint is percent change from baseline in UPCR at Week 13. In all analyses 
of UPCR related data, the Week 13 UPCR value will be calculated as the average of 
the available UPCR measurements (maximum 3) taken during Week 13, and the 
baseline value will be the average of the 3 UPCR values from the urine samples 
collected for this purpose during screening. 
The percent change from baseline in UPCR at Week 13 will be analyzed by first 
log-transforming the UPCR data before analyses to reduce skewness and calculating 
the change from baseline in log-transformed values. The geometric mean percent 
change (GMPC) from baseline in UPCR will be estimated along with the 
corresponding 2-sided 80% CI. The GMPC from baseline and associated confidence 
limits will be calculated by back-transforming the estimated simple mean of change 
from baseline in log-transformed data. 
Safety 
The safety analyses will be descriptive only.  
Pharmacokinetics 
Noncompartmental analyses will be performed, and summary statistics will be 
provided for VX-147 PK parameters. Additional analysis including population PK 
modeling will be performed to further characterize the PK and exposure-response 
relationships. 


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3 
SCHEDULE OF ASSESSMENTS  
Schedules of assessments for Cohort 1 and Cohort 2 are in Table 3-1 through Table 3-3. All 
visits will be scheduled relative to the Day 1 Visit.  
Subjects may choose to complete all screening assessments within the 28-day Screening Period 
or they may choose a 2-step screening process and first complete only the APOL1 genotype 
assessment at any time before Day -1 (including before Day -28), followed by the rest of the 
screening assessments during the 28-day Screening Period. The informed consent form (ICF) 
will outline the screening options. Additional information is provided in Section 9.1.1. Informed 
consent must be completed before any assessments are done at the Screening Visit. The SF-36 
must be completed before any other assessment when they are required. Other assessments may 
be performed in any order when more than 1 assessment is required at a particular time point, 
unless noted otherwise. All assessments will be performed before dosing, unless noted otherwise. 
Table 3-1 
Study VX19-147-101: Screening  
Event/Assessment 
Optional 
Genotype 
Screening Visit 
(Before Day -1) 
Screening 
Period 
(Day -28 to 
Day -1) 
Comments 
Subject visit 
X 
X 
Activities may be performed by a home health 
visit or in the clinic, unless otherwise noted 
(Section 9.3.5). The complete physical exam 
must be done by the investigator 
(Section 11.6.3). The Screening Visit should 
occur in the clinic if possible, but home health 
may be used if extenuating circumstances 
prevent a clinic visit (Section 9.1.1). 
Informed consent 
X 
X 
Informed consent must be obtained before any 
study-related procedures. It may be obtained in 
person or remotely, and it may be collected 
before the first visit (Section 13.2.2). 
Demographics 
 
X 
 
Medical history 
 
X 
 
Medications review 
 
X 
Section 9.4 
Standard 12-lead ECG 
 
X 
To be performed in triplicate after the subject 
has been supine for at least 5 minutes. When 
ECGs, vital signs, and blood draws coincide, 
they should be performed in said order. 
(Section 11.6.4). 
Vital signs 
 
X 
Vital signs will be collected after the subject 
has rested for at least 5 minutes. Blood pressure 
must be collected in triplicate. (Section 11.6.3).  
Height and weight 
 
X 
Weight and height will be measured with shoes 
off with light weight clothing (no outerwear). 
BMI will be calculated using height and weight 
(Section 11.1). 
Physical examination 
 
X 
A complete exam will be done if the visit 
occurs in the clinic. If the visit occurs using a 
home health nurse, an abbreviated exam will be 
done (Section 11.6.3). 


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Table 3-1 
Study VX19-147-101: Screening  
Event/Assessment 
Optional 
Genotype 
Screening Visit 
(Before Day -1) 
Screening 
Period 
(Day -28 to 
Day -1) 
Comments 
Serum FSH 
(suspected 
postmenopausal 
female subjects only) 
 
X 
A blood sample will be collected 
(Section 11.6.2).  
Serum β-hCG (all 
female subjects) 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
Serum chemistry 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
Hematology 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
Coagulation 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
Serology (HIV-1 and 
HIV-2 Antibodies) 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
Hepatitis B surface 
antigen 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
HCV test 
 
X 
A blood sample will be collected 
(Section 11.6.2). 
Confirmation of 
APOL1 genotype 
X 
X 
A genotyping sample will be collected if a 
result is not available using a Vertex-approved 
clinical study assay (Section 9.1.1).  
Urine sample 
 
X 
(3 samples) 
Collected after signing the informed consent for 
use in efficacy, biomarker, and safety analyses 
(Sections 11.3 and 11.6.2). The first morning 
void will be collected for 3 independent 
samples, which are collected on 3 separate days 
within a 7-day period. The third sample must be 
collected by Day -5 to allow confirmation that 
UPCR values meet eligibility criteria 
(Section 8.1). Refer to sample handling 
guidelines to ensure samples are submitted 
appropriately for analysis. 
Adverse events 
Continuous from signing of ICF 
through SFUV 
For subjects undergoing a 2-step screening 
process, AEs related to phlebotomy will be 
collected for up to 24 hours after the blood 
collection; AEs will not be collected during the 
time between a subject undergoing genotype 
screening and the start of the Screening Visit. 
Additional information about AE reporting is 
provided in Section 11.6.1. 
 


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Table 3-2 
Study VX19-147-101: Part A Treatment Period 1, Treatment Period 2, and Early Termination of Treatment Visit 
Event/ 
Assessmenta 
Treatment Period 1 
Treatment Period 2 
Early 
Termination 
of Treatment 
Visitb 
Comments 
Day 1 
Visit 
Week 1 
Visit 
Day 15 
Visit 
Week 3 
Visit 
Week 5 
Visit 
Week 9 
Visit 
Week 13 
Visit 
Window: 
Day 1  
(±0 days) 
Window:  
Day 8 
(±1 day) 
Window: 
Day 15  
(±2 days) 
Window: 
Day 22 
(±2 days) 
Window: 
Day 36 
(±2 days) 
Window: 
Day 64 
(±2 days) 
Window: 
Day 92 
(-2 days) 
Subject visit  
X 
X 
X 
X 
X 
X 
X 
X 
All visits may be performed by a home health 
visit or in the clinic at the discretion of the 
investigator (Section 9.3.5). All visits must 
have a consultation between the subject and 
investigator (i.e., in person, phone, or 
telemedicine video conference) within 
1 business day after the home health visit, 
which can be outside the visit window. 
SF-36 
X 
 
 
 
X 
 
X 
X 
To be completed before all other study 
assessments (Section 11.5.3).  
Standard 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
Complete predose after SF-36 and before 
other assessments. The subject should be 
supine for at least 5 minutes before the start of 
ECG. When ECGs, vital signs, and blood 
draws coincide, they should be performed in 
said order. On Day 1 and Day 15, an ECG 
(Section 11.6.4) will also be collected 
2 (± 1) hours postdose. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Complete before the assessments listed in 
rows below. The subject should rest for at 
least 5 minutes before the start of vital sign 
collection and they should be seated during 
the assessment (Section 11.6.3). Blood 
pressure will be collected in triplicate. 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Weight will be measured with shoes off and 
light weight clothing (no outerwear) 
(Section 11.1). 
 
a 
All assessments will be performed before dosing unless noted otherwise. 
b 
If the subject prematurely discontinues study treatment during the Treatment Period, an ETT Visit should be scheduled as soon as possible after the subject decides to terminate study treatment. If the 
ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit will replace the SFUV, and a separate SFUV will not be required. After the ETT Visit, subjects will not 
complete further Part A Visits; these subjects will not continue to Part B (Table 3-3).  


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Table 3-2 
Study VX19-147-101: Part A Treatment Period 1, Treatment Period 2, and Early Termination of Treatment Visit 
Event/ 
Assessmenta 
Treatment Period 1 
Treatment Period 2 
Early 
Termination 
of Treatment 
Visitb 
Comments 
Day 1 
Visit 
Week 1 
Visit 
Day 15 
Visit 
Week 3 
Visit 
Week 5 
Visit 
Week 9 
Visit 
Week 13 
Visit 
Window: 
Day 1  
(±0 days) 
Window:  
Day 8 
(±1 day) 
Window: 
Day 15  
(±2 days) 
Window: 
Day 22 
(±2 days) 
Window: 
Day 36 
(±2 days) 
Window: 
Day 64 
(±2 days) 
Window: 
Day 92 
(-2 days) 
Abbreviated 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
In addition to the scheduled visits, 
symptom-directed physical examinations will 
occur at any time during the study if triggered 
by AEs or if deemed necessary by the 
investigator (Section 11.6.3). 
Serum 
chemistry 
X 
Fasted 
X 
X 
X 
Fasted 
X 
X 
X 
Fasted 
X 
Fasted 
A blood sample will be collected predose 
after an overnight fast on indicated days. All 
other days do not require fasting. 
(Section 11.6.2). 
Hematology  
X 
X 
X 
X 
X 
X 
X 
X 
A blood sample will be collected 
(Section 11.6.2). 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
A blood sample will be collected 
(Section 11.6.2). 
Biomarker 
blood sample 
X 
X 
X 
X 
X 
X 
X 
X 
Section 11.5.1. 
VX-147 PK 
blood sample  
intensive 
predose 
intensive 
predose 
intensive 
predose 
X 
X 
A blood sample will be collected 
(Section 11.2.1). 
Intensive PK sampling  
Day 1, Day 15, Week 5: predose (within 
60 min before dosing) and 0.25, 0.5, 1, 2, 4 
and 12 hours postdose  
 
Post treatment samples (Week 13 and 
ETT):  
A single sample collected anytime during the 
Visit. 


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Table 3-2 
Study VX19-147-101: Part A Treatment Period 1, Treatment Period 2, and Early Termination of Treatment Visit 
Event/ 
Assessmenta 
Treatment Period 1 
Treatment Period 2 
Early 
Termination 
of Treatment 
Visitb 
Comments 
Day 1 
Visit 
Week 1 
Visit 
Day 15 
Visit 
Week 3 
Visit 
Week 5 
Visit 
Week 9 
Visit 
Week 13 
Visit 
Window: 
Day 1  
(±0 days) 
Window:  
Day 8 
(±1 day) 
Window: 
Day 15  
(±2 days) 
Window: 
Day 22 
(±2 days) 
Window: 
Day 36 
(±2 days) 
Window: 
Day 64 
(±2 days) 
Window: 
Day 92 
(-2 days) 
Urine sample  
Xc 
X 
X 
X 
X 
(3 samples) 
X 
(3 samples) 
X 
(3 samples) 
X 
The first morning urine void (predose) will be 
collected and used for efficacy, safety, and 
biomarker analyses (Sections 11.3 and 
11.6.2). During Week 5, Week 9, and 
Week 13, 3 samples will be collected on 
3 separate days within a 7-day period. If the 
subject forgets to collect the first morning 
void on the day of the visit, they may provide 
this sample predose on a different day within 
the visit window. Refer to sample handling 
guidelines to ensure samples are submitted 
appropriately for analysis. 
β-hCG (urine) 
X 
 
 
 
X 
X 
X 
X 
All female subjects of childbearing potential 
(Sections 11.6.2 and 11.6.5). This can be 
collected in the same sample as the urine 
sample for efficacy, safety, and biomarker 
analysis. 
VX-147 
dosing  
X 
 
The last dose of Treatment Period 1 will be 
Day 14. The first dose of Treatment Period 2 
will be on Day 15 after all predose 
assessments are completed. The last day of 
dosing will occur the day before the Week 13 
visit. 
The first dose in each period must be 
administered under the supervision of site 
medical staff or a home health nurse. Subjects 
will be monitored for 4 hours after receiving 
the first dose of each Treatment Period. 
(Section 9.6). 
 
c Day 1 urinalysis will be for safety and biomarker assessments. Efficacy assessments will not be done. 


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Table 3-2 
Study VX19-147-101: Part A Treatment Period 1, Treatment Period 2, and Early Termination of Treatment Visit 
Event/ 
Assessmenta 
Treatment Period 1 
Treatment Period 2 
Early 
Termination 
of Treatment 
Visitb 
Comments 
Day 1 
Visit 
Week 1 
Visit 
Day 15 
Visit 
Week 3 
Visit 
Week 5 
Visit 
Week 9 
Visit 
Week 13 
Visit 
Window: 
Day 1  
(±0 days) 
Window:  
Day 8 
(±1 day) 
Window: 
Day 15  
(±2 days) 
Window: 
Day 22 
(±2 days) 
Window: 
Day 36 
(±2 days) 
Window: 
Day 64 
(±2 days) 
Window: 
Day 92 
(-2 days) 
Adverse 
events 
Continuous from signing of ICF through SFUV 
Section 11.6.1. 
Medications 
review 
Continuous from signing of ICF through SFUV 
Section 9.4. 
 


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Table 3-3 
Study VX19-147-101: Postdose PK Sampling, Safety Follow-up Visit, and Part B 
Off-treatment Follow-up Period 
Event/Assessment 
Postdose PK 
Sampling 
(Approximately 
48 hours after 
the last dose of 
study drug)a 
SFUV 
28 (± 7) Days 
After Last Dose of 
Study Drugb 
Part B: Optional 
Off-treatment Follow-up 
Visits c 
(Part B Week 4b, 8, and 
12)  
Comments 
Subject visit 
X 
X 
X 
(until UPCR returns to 
≥90% of baseline level) 
The visit may be 
performed by a home 
health visit or in the clinic 
at the discretion of the 
investigator 
(Section 9.3.5). For each 
visit, at least 1 interaction 
with the subject and 
investigator will occur by 
phone, video, or in the 
clinic (i.e., in person, 
phone, or telemedicine 
video conference) within 
1 business day after the 
home health visit, which 
can be outside the visit 
window. See Section 9.1.3 
for details about 
determining the last visit 
for Part B. 
SF-36 
 
X 
 
To be completed before 
all other study 
assessments 
(Section 11.5.3). 
Standard 12-lead ECG 
 
X 
 
Complete after SF-36 and 
before other assessments 
after subject has been 
supine for at least 5 
minutes. ECGs 
(Section 11.6.4), vital 
signs, and blood draws 
should be performed in 
said order. 
Vital signs 
 
X 
 
Complete before other 
assessments listed below 
after subject has been at 
rest for at least 5 minutes; 
they should be seated 
during the assessment 
(Section 11.6.3). Blood 
pressure will be collected 
in triplicate. 
 
a 
The postdose PK sampling visit is required for all subjects, with the exception of those who complete an ETT Visit. 
b 
The SFUV and Part B Week 4 Off-treatment Follow-up Visit may occur on the same day, provided the visit windows are met 
for both visits. 
c  
Visit windows for Part B are as follows: Week 4 Visit (Day 120 ± 2 weeks), Week 8 Visit (Day 148 ± 2 weeks), Week 12 Visit 
(Day 176 ± 2 weeks). 


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Table 3-3 
Study VX19-147-101: Postdose PK Sampling, Safety Follow-up Visit, and Part B 
Off-treatment Follow-up Period 
Event/Assessment 
Postdose PK 
Sampling 
(Approximately 
48 hours after 
the last dose of 
study drug)a 
SFUV 
28 (± 7) Days 
After Last Dose of 
Study Drugb 
Part B: Optional 
Off-treatment Follow-up 
Visits c 
(Part B Week 4b, 8, and 
12)  
Comments 
Weight 
 
X 
 
Weight will be measured 
with shoes off and light 
weight closing (no 
outerwear). 
(Section 11.1). 
Abbreviated physical 
examination 
 
X 
 
In addition to the 
scheduled visits, 
symptom-directed 
physical examinations 
will occur at any time 
during the study if 
triggered by AEs or if 
deemed necessary by the 
investigator 
(Section 11.6.3). 
Serum chemistry 
 
X 
Fasted 
 
A blood sample will be 
collected following an 
overnight fast 
(Section 11.6.2). 
Hematology  
 
X 
 
A blood sample will be 
collected (Section 11.6.2) 
Coagulation 
 
X 
 
A blood sample will be 
collected (Section 11.6.2) 
VX-147 PK Sampling 
X 
 
 
A blood sample will be 
collected (Section 11.2.1). 
Urine sample 
 
X 
X 
The first morning urine 
void will be collected and 
used for efficacy, safety, 
and biomarker analyses 
(Sections 11.3 and 
11.6.2). Refer to sample 
handling guidelines to 
ensure samples are 
collected and submitted 
appropriately for analysis. 
β-hCG (urine) 
 
X 
 
All female subjects of 
childbearing potential 
(Section 11.6.2). This can 
be collected in the same 
sample as the other urine 
sample. 
Adverse events 
Continuous from signing of ICF through 
SFUV 
NA 
Section 11.6.1 
Medications review 
Continuous from signing of ICF through SFUV or last off-treatment 
follow-up visit, whichever is later 
May be collected via 
telemedicine (Section 9.4) 
 
 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
Summary of Changes to the Protocol......................................................................................... 2 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 6 
4 
Table of Contents ................................................................................................................. 14 
List of Tables............................................................................................................................ 18 
List of Figures .......................................................................................................................... 18 
List of Abbreviations................................................................................................................ 19 
5 
Introduction.......................................................................................................................... 22 
5.1 
FSGS Background .......................................................................................................... 22 
5.2 
VX-147 Background ...................................................................................................... 22 
6 
Study Objectives .................................................................................................................. 24 
6.1 
Part A (Treatment Period) .............................................................................................. 24 
6.1.1 
Primary Objective ................................................................................................... 24 
6.1.2 
Secondary Objectives ............................................................................................. 24 
6.2 
Part B .............................................................................................................................. 24 
6.2.1 
Exploratory Objective ............................................................................................. 24 
7 
Study Endpoints ................................................................................................................... 24 
7.1 
Part A .............................................................................................................................. 24 
7.1.1 
Primary Endpoints .................................................................................................. 24 
7.1.2 
Secondary Endpoints .............................................................................................. 24 
7.1.3 
Exploratory Endpoints ............................................................................................ 24 
7.2 
Part B (Optional Off-treatment Follow-up Period) ........................................................ 25 
7.2.1 
Exploratory Endpoints ............................................................................................ 25 
8 
Study Population .................................................................................................................. 25 
8.1 
Inclusion Criteria ............................................................................................................ 25 
8.2 
Exclusion Criteria ........................................................................................................... 26 
9 
Study Implementation ......................................................................................................... 27 
9.1 
Study Design .................................................................................................................. 27 
9.1.1 
Screening ................................................................................................................ 28 
9.1.1.1 
Repetition of Screening Assessments .............................................................. 29 
9.1.1.2 
Extension of Screening Period Window .......................................................... 29 
9.1.1.3 
Rescreening ...................................................................................................... 29 
9.1.2 
Part A ...................................................................................................................... 29 
9.1.2.1 
Treatment Period .............................................................................................. 29 
9.1.2.2 
Safety Follow-up .............................................................................................. 30 
9.1.2.3 
Early Termination of Treatment or Early Discontinuation .............................. 30 
9.1.3 
Part B ...................................................................................................................... 30 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 30 
9.2.1 
Replacement Subjects ............................................................................................. 30 
9.3 
Rationale for Study Elements ......................................................................................... 30 
9.3.1 
Study Design........................................................................................................... 30 
9.3.2 
Study Population..................................................................................................... 31 
9.3.3 
Study Drug Dose .................................................................................................... 31 
9.3.4 
Study Assessments ................................................................................................. 32 


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9.3.4.1 
UPCR ............................................................................................................... 32 
9.3.4.2 
SF-36 ................................................................................................................ 32 
9.3.5 
Use of Telemedicine for Study Visits..................................................................... 32 
9.3.6 
Eligibility Review ................................................................................................... 32 
9.4 
Prior and Concomitant Medications ............................................................................... 32 
9.5 
Study Restrictions ........................................................................................................... 33 
9.6 
Administration ................................................................................................................ 33 
9.7 
Dose Modification .......................................................................................................... 34 
9.8 
Study Drug Interruption ................................................................................................. 34 
9.9 
Removal of Subjects ....................................................................................................... 34 
9.10 Replacement of Subjects ................................................................................................ 35 
10 Study Drug Information and Management ....................................................................... 35 
10.1 Preparation and Dispensing ............................................................................................ 35 
10.2 Packaging and Labeling ................................................................................................. 35 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 35 
10.4 Drug Accountability ....................................................................................................... 36 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 36 
10.6 Compliance ..................................................................................................................... 36 
10.7 Blinding and Unblinding ................................................................................................ 36 
11 Assessments .......................................................................................................................... 37 
11.1 Subject and Disease Characteristics ............................................................................... 37 
11.2 Pharmacokinetics ............................................................................................................ 37 
11.2.1 
Blood Sampling ...................................................................................................... 37 
11.2.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 37 
11.2.3 
Bioanalysis.............................................................................................................. 38 
11.3 Urine Sampling for UPCR, UACR, and Safety Laboratory Panel ................................. 38 
11.4 APOL1 Genotyping ........................................................................................................ 38 
11.5 Exploratory Assessments ................................................................................................ 38 
11.5.1 
Blood Biomarker Samples ...................................................................................... 38 
11.5.2 
Urine Biomarker Samples ...................................................................................... 38 
11.5.3 
SF-36 ...................................................................................................................... 39 
11.6 Safety .............................................................................................................................. 39 
11.6.1 
Adverse Events ....................................................................................................... 39 
11.6.2 
Clinical Laboratory Assessments ........................................................................... 39 
11.6.3 
Physical Examinations and Vital Signs .................................................................. 41 
11.6.4 
Electrocardiograms ................................................................................................. 42 
11.6.5 
Contraception and Pregnancy ................................................................................. 42 
11.6.5.1 Contraception ................................................................................................... 42 
11.6.5.2 Pregnancy ......................................................................................................... 44 
12 Statistical and Analytical Plans .......................................................................................... 44 
12.1 Sample Size and Power .................................................................................................. 44 
12.2 Analysis Sets .................................................................................................................. 45 
12.3 Statistical Analysis ......................................................................................................... 45 
12.3.1 
General Considerations ........................................................................................... 45 
12.3.2 
Background Characteristics .................................................................................... 46 
12.3.2.1 Subject Disposition .......................................................................................... 46 


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12.3.2.2 Demographics and Baseline Characteristics .................................................... 46 
12.3.2.3 Prior and Concomitant Medications................................................................. 46 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 47 
12.3.2.5 Important Protocol Deviations ......................................................................... 47 
12.3.3 
Efficacy Analysis .................................................................................................... 47 
12.3.3.1 Analysis of Primary Variables ......................................................................... 47 
12.3.3.2 Analysis of Other Variables ............................................................................. 47 
12.3.4 
Safety Analysis ....................................................................................................... 48 
12.3.4.1 Adverse Events................................................................................................. 48 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 49 
12.3.4.3 Electrocardiogram ............................................................................................ 49 
12.3.4.4 Vital Signs ........................................................................................................ 49 
12.3.4.5 Physical Examination ....................................................................................... 50 
12.3.4.6 Other Safety Analysis ...................................................................................... 50 
12.3.5 
Other Analyses ....................................................................................................... 50 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses ........................... 50 
12.4 Clinical Pharmacology Analysis .................................................................................... 50 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 50 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 50 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 51 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 51 
13.1.1 
Adverse Events ....................................................................................................... 51 
13.1.1.1 Definition of an Adverse Event........................................................................ 51 
13.1.1.2 Clinically Significant Assessments .................................................................. 51 
13.1.1.3 Documentation of Adverse Events................................................................... 51 
13.1.1.4 Adverse Event Severity .................................................................................... 52 
13.1.1.5 Adverse Event Causality .................................................................................. 53 
13.1.1.6 Study Drug Action Taken ................................................................................ 53 
13.1.1.7 Adverse Event Outcome .................................................................................. 54 
13.1.1.8 Treatment Given............................................................................................... 54 
13.1.2 
Serious Adverse Events .......................................................................................... 54 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 54 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 55 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 55 
13.2 Administrative Requirements ......................................................................................... 56 
13.2.1 
Ethical Considerations ............................................................................................ 56 
13.2.2 
Subject Information and Informed Consent ........................................................... 56 
13.2.3 
Investigator Compliance ......................................................................................... 56 
13.2.4 
Access to Records ................................................................................................... 56 
13.2.5 
Subject Privacy ....................................................................................................... 57 
13.2.6 
Record Retention .................................................................................................... 57 
13.2.7 
Study Termination .................................................................................................. 57 
13.2.8 
End of Study ........................................................................................................... 58 
13.3 Data Quality Assurance .................................................................................................. 58 
13.4 Monitoring ...................................................................................................................... 58 


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13.5 Electronic Data Capture ................................................................................................. 58 
13.6 Confidentiality and Disclosure ....................................................................................... 59 
13.7 Publications and Clinical Study Report .......................................................................... 59 
13.7.1 
Publication of Study Results ................................................................................... 59 
13.7.2 
Clinical Study Report ............................................................................................. 60 
14 References ............................................................................................................................. 61 
15 Protocol Signature Pages .................................................................................................... 63 
15.1 Sponsor Signature Page .................................................................................................. 63 
15.2 Investigator Signature Page ............................................................................................ 64 
 


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List of Tables 
Table 3-1 
Study VX19-147-101: Screening ............................................................................ 6 
Table 3-2 
Study VX19-147-101: Part A Treatment Period 1, Treatment Period 2, and Early 
Termination of Treatment Visit .............................................................................. 8 
Table 3-3 
Study VX19-147-101: Postdose PK Sampling, Safety Follow-up Visit, and Part B 
Off-treatment Follow-up Period ........................................................................... 12 
Table 9-1 
Study Restrictions ................................................................................................. 33 
Table 10-1 
Study Drug ............................................................................................................ 36 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 37 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 40 
Table 11-3 
Allowed Methods of Contraception ...................................................................... 43 
Table 12-1 
Two-sided 80% Confidence Interval for GMPC from Baseline in UPCR ........... 44 
Table 13-1 
Grading of AE Severity ........................................................................................ 52 
Table 13-2 
Classifications for AE Causality ........................................................................... 53 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 53 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 54 
List of Figures 
Figure 2-1 
VX19-147-101 Study Design ................................................................................. 5 
Figure 9-1 
VX19-147-101 Study Design ............................................................................... 28 
 


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List of Abbreviations 
Abbreviation 
Definition 
ACE 
angiotensin converting enzyme 
ADL 
activities of daily living 
AE 
adverse event 
AKI 
acute kidney injury 
ALT 
alanine transaminase 
APOL1 
apolipoprotein L1 
ARB 
angiotensin receptor blocker 
AST 
aspartate transaminase 
AUC0-∞ 
AUC from the time of dosing extrapolated to infinity 
AUCτ 
AUC during a dosing interval 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
bpm 
beats per minute 
CAKUT 
congenital anomaly of the kidney or urinary tract 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL/F 
apparent clearance 
Cmax 
maximum observed concentration 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
predose concentration 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
EE 
ethinyl estradiol 
EENT 
eyes, ears, nose, and throat 
eGFR 
estimated glomerular filtration rate 
ESKD 
end-stage kidney disease 
ETT 
Early Termination of Treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FSGS 
focal segmental glomerulosclerosis 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMPC 
Geometric Mean Percent Change 
GMR 
geometric mean ratio 
GPS 
Global Patient Safety 
HBsAg 
hepatitis B surface antigen 


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Abbreviation 
Definition 
HCV 
hepatitis C virus 
HIV-1 
human immunodeficiency virus-1 
HIV-2 
human immunodeficiency virus-2 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IPD 
important protocol deviation 
IRB 
institutional review board 
IWRS 
interactive web response system 
LN 
levonorgestrel 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
not applicable 
PC 
publication committee 
PD 
Pharmacodynamics 
PE 
physical examination 
P-gp 
P-glycoprotein 
PI 
principal investigator 
PK 
pharmacokinetic, pharmacokinetics 
PR 
PR interval, segment 
PRO 
patient-reported outcome 
PT 
Preferred Term 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization  
QT 
QT interval 
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 
SC 
steering committee 
SD 
standard deviation 
SF-36 
Short Form Health Survey 36 
SFUV 
Safety Follow-up Visit 
SGLT2 
sodium-glucose co-transporter-2  
SI 
SI units (International System of Units) 
SOC 
System Organ Class 
SRA 
serum resistant associated-protein 
SUSARs 
suspected, unexpected, serious adverse reactions 
TE 
Treatment-emergent 
TEAE 
treatment-emergent adverse event 
UACR 
urine albumin to creatinine ratio 
ULN 
upper limit of normal 


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Abbreviation 
Definition 
UPCR 
urine protein to creatinine ratio 
Vss/F 
apparent volume of distribution at steady-state 
WHO-DD 
World Health Organization-Drug Dictionary 
 


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5 
INTRODUCTION 
5.1 
FSGS Background  
Focal segmental glomerulosclerosis (FSGS) is a rare kidney disease with an estimated global 
incidence of 0.2 to 1.1/100,000/year.1 FSGS is caused by damage to podocytes, which are part of 
the glomerular filtration barrier, resulting in proteinuria.2 Patients with nephrotic-range 
proteinuria (i.e., protein to creatinine ratio >3 g/g) are at a higher risk of developing end-stage 
kidney disease (ESKD) and developing proteinuria-related complications, such as infections or 
thromboembolic events. There is no well-standardized treatment regimen for FSGS. Current 
therapeutic options for patients with FSGS who have nephrotic-range proteinuria include 
high-dose corticosteroids, which induce remission of proteinuria in a minority of patients.2 
FSGS can be divided into different subgroups based on the underlying etiology. One 
homogeneous subgroup of FSGS is characterized by the presence of 2 independent common 
sequence variants in the apolipoprotein L1 (APOL1) gene termed G1 and G2, which are referred 
to as the “APOL1 risk alleles.” G1 encodes a correlated pair of non-synonymous amino acid 
changes (S342G and I384M), G2 encodes a 2 amino acid deletion (N388del:Y389del) near the 
C-terminus of the protein, and G0 is the ancestral (low risk) allele.3,4  
The APOL1 gene is expressed in multiple organs in humans, including the liver and kidney.5,6 
The biologic function of APOL1 is to protect against parasitic infection (Trypanosoma brucei 
brucei [T. b. brucei]).7 APOL1 is endocytosed by T. b. brucei and transported to lysosomes, 
where it inserts into the lysosomal membrane and forms pores that lead to parasite swelling and 
death.8 While the ability to lyse T. b. brucei is shared by all 3 APOL1 variants (G0, G1, and G2), 
APOL1 G1 and G2 variants confer additional protection against parasite species that have 
evolved a serum resistant associated-protein (SRA) which inhibits APOL1 G0; these species 
cause sleeping sickness. G1 and G2 variants evade inhibition by SRA and G1 confers additional 
protection against T. b. gambiense (which causes West African sleeping sickness), 
and G2 confers additional protection against T. b. rhodesiense (which causes East African 
sleeping sickness).9 
In the kidney, APOL1 is expressed in podocytes, endothelial cells (including glomerular 
endothelial cells), and some tubular cells.6, 10 Podocyte-specific expression of APOL1 G1 or G2 
(but not G0) in transgenic mice induces structural and functional changes, including albuminuria, 
decreased kidney function, podocyte abnormalities, and glomerulosclerosis.11 Consistent with 
these data, G1 and G2 variants of APOL1 play a causative role in inducing FSGS and 
accelerating its progression in humans. Individuals with 2 APOL1 risk alleles (i.e., homozygous 
or compound heterozygous for the APOL1 G1 or APOL1 G2 alleles) have increased risk of 
developing FSGS with an odds ratio of 10 to 17, and they are at risk for rapid decline in kidney 
function if they develop FSGS.3, 4, 12 Thus, inhibition of APOL1 could have a positive impact in 
individuals who harbor 2 APOL1 risk alleles. 
This study is a Phase 2a proof-of-concept study designed to assess the efficacy effects, safety, 
and pharmacokinetics (PK) of VX-147 in subjects with APOL1-mediated FSGS.  
5.2 
VX-147 Background 
VX-147 is a small molecule that inhibits APOL1-induced cell death and inhibits the biological 
function of APOL1, i.e., APOL1-induced lysis of T. b. brucei. These nonclinical data suggest 
that VX-147 has the potential to reduce proteinuria and reverse APOL1-induced podocyte 


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lesions in patients with APOL1-mediated FSGS. Therefore, VX-147 is being developed to treat 
individuals with FSGS who also have 2 APOL1 risk alleles and nephrotic-range proteinuria.  
In vitro studies indicated VX-147 is a weak inducer of CYP3A4; however, in a previous clinical 
study (VX18-147-001; Study 001) an interaction with midazolam, a sensitive substrate of 
CY3A4, indicated that VX-147 has minimal inhibitory effect.  To characterize the CYP3A4-
mediated PK interaction between VX-147 and combined oral contraceptives containing the 
steroids, ethinyl estradiol (EE, 30 µg)/levonorgestrel (LN, 150 µg), a dedicated drug-drug 
interaction (DDI) study was conducted, Study VX19-147-004 (Study 004; analysis complete; 
CSR in preparation). The effect of multiple doses of 45 mg VX-147 was assessed on the steady-
state PK of LN and EE.  The study design was an open label, 2-period, fixed-sequence crossover 
study in 17 healthy female adult subjects. Steady-state plasma levels of EE and LN did not 
decrease in the presence of daily doses of 45 mg VX-147. There were minor (~20%) increases in 
AUC0-24h,ss of both EE and LN.  Geometric mean ratio (GMR) of AUC0-24h for EE at steady state 
was 1.20 (90% confidence interval [CI] of 1.14, 1.27) and that for LN was 1.20 (1.14, 1.27). The 
steady state Cmax of EE and LN also increased with a GMR (90% CI) of 1.23 (1.10, 1.38) for EE 
and 1.08 (1.00, 1.17) for LN. VX-147 was safe and well tolerated in this study, and there were no 
discontinuations. There were no serious adverse events (SAEs), and all AEs were mild in 
severity. Based on these results the magnitude of these interactions are not deemed clinically 
significant; therefore, coadministration of VX-147 and combined oral contraceptives containing 
EE and LN is unlikely to result in contraceptive failure.  
In vitro studies indicated VX-147 is substrate for CYP3A4 and P-gp.  Therefore, it is anticipated 
that drugs that inhibit or induce CYP3A4 and P-gp could have an impact on the PK of VX-147. 
A dedicated DDI study (Study VX19-147-005; analysis complete; clinical study report [CSR] in 
preparation) was done to evaluate the effect of rifampin, a strong CYP3A and P-gp inducer, and 
itraconazole, a strong CYP3A4 and P-gp inhibitor, on single dose PK of VX-147 in an open-
label, fixed-sequence, crossover, DDI study in 28 healthy male and female subjects (14 subjects 
in the itraconazole group and 14 subjects in the rifampin group). Administration of rifampin 
resulted in a significant decrease in VX-147 exposure: AUC0-∞ GMR (90% CI) 
0.154 (0.139, 0.170) and Cmax GMR (90% CI) 0.552 (0.498, 0.612) relative to VX-147 
administration alone. These results indicate that strong CYP3A4 inducers have the potential to 
significantly decrease VX-147 exposure.  Administration of itraconazole resulted in a smaller 
change (approximately 2-fold) compared to rifampin.  VX-147 AUC0-∞ increased with a GMR 
(90% CI) of 1.98 (1.79, 2.19), while Cmax increased slightly, GMR of 1.14 (1.07, 1.20) compared 
to VX-147 administration alone. VX-147 was safe and well tolerated in this study. There were 
SAEs, and all AEs were mild or moderate in severity. One subject discontinued study drug due 
to an AE (mild AE of urticaria during dosing with itraconazole alone; considered possibly 
related). These results indicate that strong CYP3A4 inhibitors are unlikely to cause a significant 
increase (>2-fold) in VX-147 exposure, and that a moderate CYP3A4 inhibitor, such as 
cyclosporine, is expected to result in a less than 2-fold increase in AUC0-24h,ss. Hence, 
cyclosporine administration is anticipated to be safe if co-administered with a 45 mg qd dose of 
VX-147. 
Preliminary, blinded safety data are available from VX20-147-008 (Study 008), in which 
36 healthy subjects received single-ascending doses of VX-147 (90 to 165 mg) or placebo, and 
58 healthy subjects received multiple-ascending doses of VX-147 (60 to 120 mg daily doses) or 
placebo for up to 14 days. VX-147 was generally safe and well tolerated at all doses evaluated. 


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There were no serious adverse events (SAEs), and all AEs were mild or moderate in severity. 
Two subjects discontinued due to AEs. Of these, one subject (60 mg qd or placebo) discontinued 
on Day 7 due to a mild AE of tachycardia and another subject (90 mg qd or placebo) 
discontinued due to a moderate AE of COVID-19 infection. Both were reported by the 
investigator to be not related. 
 
In Study 008, the highest dose of 120 mg qd for 14 days was generally safe and well tolerated. 
Preliminary PK analysis demonstrated that the mean (CV%) AUC0-24h,ss achieved at this dose 
was 50.1 (27.5%) µg*h/mL, providing an approximately 3.8-fold exposure margin over the 45 
mg qd clinical dose with a mean (CV%) AUC0-24h,ss of 13.3 (21.5%) µg*h/mL (Study 001). A 
moderate CYP3A4 inhibitor, such as cyclosporine, is expected to result in a less than 2-fold 
increase in AUC0-24h,ss.  
Additional information about the first-in-human (FIH) study (Study 001) and nonclinical studies 
is available in the Investigator’s Brochure.  
6 
STUDY OBJECTIVES 
6.1 
Part A (Treatment Period) 
6.1.1 
Primary Objective 
• To evaluate the ability of VX-147 to reduce proteinuria 
6.1.2 
Secondary Objectives 
• To evaluate the safety and tolerability of VX-147 
• To characterize the PK of VX-147  
6.2 
Part B 
6.2.1 
Exploratory Objective 
• To evaluate the change proteinuria after stopping administration of VX-147 
7 
STUDY ENDPOINTS 
7.1 
Part A 
7.1.1 
Primary Endpoints 
• Percent change from baseline in urine protein to creatinine ratio (UPCR) at Week 13 
7.1.2 
Secondary Endpoints 
• Safety and tolerability based on adverse events (AEs), clinical laboratory values 
(i.e., hematology, serum chemistry, urinalysis, coagulation studies), standard 12-lead ECGs, 
and vital signs 
• Plasma PK of VX-147  
7.1.3 
Exploratory Endpoints 
• Percent change from baseline in UPCR over time during the Treatment Period  


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• Percent change from baseline in urine albumin to creatinine ratio (UACR) at Week 13 
• Percent change from baseline in UACR over time during the Treatment Period 
• Change from baseline in patient-reported outcome (PRO) Short Form Health Survey 36 
(SF-36) over time during the treatment period  
• Change from baseline in SF-36 at 4 weeks after the last dose (Safety Follow-up Visit 
[SFUV]) 
7.2 
Part B (Optional Off-treatment Follow-up Period) 
7.2.1 
Exploratory Endpoints 
• Percent change from baseline in UPCR at the end of the Off-treatment Follow-up Period  
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
8.1 
Inclusion Criteria 
The following criteria are applicable for Cohort 1 and Cohort 2: 
1. Willing to sign and date an informed consent form (ICF).  
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions 
(Section 9.59.4), laboratory tests, contraceptive guidelines (Section 11.6.5), and other study 
procedures. 
3.  An APOL1 genotype of G1/G1, G2/G2, or G1/G2 obtained with a Vertex-approved clinical 
study assay.  
4. Between the ages of 18 and 65 years, inclusive. 
5. Body mass index (BMI) of 18.0 to 40.0 kg/m2, inclusive, and a total body weight >50 kg. 
6. FSGS diagnosed by kidney biopsy, with the exception of the tip variant, as confirmed 
through the eligibility review process.  
7. There should be no plan to start, stop, or modify dosing for an angiotensin converting 
enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), neprilysin inhibitor, 
sodium-glucose co-transporter-2 (SGLT2) inhibitor, renin inhibitor, systemic corticosteroids, 
tacrolimus, mycophenolate, or cyclosporine from 28 days before Screening through the 
Follow-up Period. 
8. Subjects who are on low-dose corticosteroids (prednisone ≤ 10 mg per day or prednisone 
equivalent) or on an allowed immunosuppressant (i.e. tacrolimus, mycophenolate, or 
cyclosporine) must be on a stable dose for 28 days before screening. 
9. Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 (±10%) based on the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.13, 14 


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10. Subjects with eGFR ≥30 (±10%) to <40 mL/min/1.73 m2 must have tubulointerstitial fibrosis 
≤50% or described as no, mild, or moderate on their kidney biopsy. 
The following criterion is applicable for Cohort 1: 
11. A UPCR ratio of ≥3 g/g (±10%) and <10 g/g in the first morning void on 3 measurements 
collected on at least 3 separate days within a 7-day period, during the Screening Period. The 
average of the 3 measurements must meet this criterion. 
The following criterion is applicable for Cohort 2: 
12. A UPCR ratio of ≥0.8 g/g (±10%) and <2.7 g/g in the first morning void on 3 measurements 
collected on at least 3 separate days within a 7-day period, during the Screening Period. The 
average of the 3 measurements must meet this criterion. 
8.2 
Exclusion Criteria 
The following criteria are applicable for Cohort 1 and Cohort 2: 
1. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study drug(s) to 
the subject. This includes, but is not limited to, the following: 
• Solid organ or bone marrow transplantation 
• Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical 
carcinoma in situ  
• Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined 
by the investigator 
• Clinically significant liver disease 
• Ongoing alcohol or drug abuse as determined by the investigator 
• Any condition possibly affecting drug absorption (e.g., gastrectomy, gastrointestinal tract 
surgery except appendectomy and cholecystectomy) 
• Stroke or myocardial infarction within 6 months before Day 1  
2. Evidence of non-APOL1-mediated FSGS. This includes but is not limited to the following: 
• FSGS occurring concomitantly to administration of drugs known to induce FSGS, including 
but not limited to lithium, interferon, and bisphosphonates (e.g., pamidronate), or FSGS 
occurring in a subject using intravenous illicit drugs at the time of diagnosis. 
• Evidence of another underlying kidney disease that can cause FSGS, including evidence of 
congenital anomaly of the kidney or urinary tract (CAKUT) on renal ultrasound, history of 
CAKUT, history of nephrectomy. 
• FSGS occurring in a subject with known sickle cell disease. 
• Known genetic mutation other than APOL1 G1 or G2 that is associated with FSGS. 
• Positive serology for human immunodeficiency virus-1 (HIV-1) or human immunodeficiency 
virus-2 (HIV-2). 


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3. Evidence of kidney disease other than FSGS on kidney biopsy, as assessed by the eligibility 
review process. 
4. Kidney biopsy showing the tip variant of FSGS, as assessed by the eligibility review process. 
5. Abnormal laboratory values at screening that present a risk to subject safety in the opinion of 
the investigator, or any of the following abnormal laboratory values at screening: 
• Total bilirubin ≥1.5 × upper limit of normal (ULN) 
• Aspartate transaminase (AST) or alanine transaminase (ALT) ≥2 × ULN  
• Serum albumin <1 g/dL 
• Hemoglobin <10 g/dL.  
6. Positive for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) nucleic acid 
during screening.  
7. Risk factors for Torsade de Pointes (e.g., familial long QT syndrome, chronic hypokalemia, 
heart failure) or concomitant medications that prolong the QT/QTc interval or any history of 
cardiac disorders that, in the opinion of the investigator, might put the subject at risk or may 
confound the results of the study.  
8. Any clinically significant ECG abnormality (as determined by the investigator) or median 
QTcF of triplicate standard 12 ECGs >450 msec at screening. 
9. Screening blood pressure ≥160 mm Hg (systolic) or ≥100 mm Hg (diastolic), based on the 
average of 3 measurements.  
10. Pregnant or nursing female subjects. 
11. Subjects of reproductive potential who are not willing to follow the contraception 
requirements outlined in Section 11.6.5.1. 
12. Plan to travel to countries where sleeping sickness is endemic, from the Screening Visit 
through 1 week after the last dose of study drug. 
13. Subject, or 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 at that site. 
14. Hypersensitivity to investigational medicinal product or to any of its excipients. 
15. Use of the substances or activities as indicated in Section 9.5 during the specified times, 
including but not limited to ongoing treatment with high doses of corticosteroids 
(>10 mg/day of prednisone or prednisone equivalent) or an immunosuppressive drug other 
than tacrolimus, mycophenolate, or cyclosporine. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a single-arm, open-label, 2-part study. In Part A, all subjects will receive VX-147 at a 
dosage of 15 mg qd for 2 weeks and VX-147 at a dosage of 45 mg qd for 11 weeks. Part A will 
be enrolled in 2 cohorts: Cohort 1 and an optional Cohort 2. Cohort 1 includes up to 10 subjects 




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With the exception of genotyping, all screening assessments will occur within 28 days before 
administration of study drug. The investigator (or an appropriate authorized designee at the study 
site) will obtain informed consent in person or remotely (Section 13.2.2) from each subject 
before conducting any study-related procedure.  
The Screening Visit and informed consent should occur in the clinic if possible. If the subject is 
unable or unwilling to visit the clinic for screening due to extenuating circumstances, the 
Screening visit may occur using a home health nurse. Remote informed consent may be obtained 
before the home health visit.  
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.5). 
9.1.1.1 
Repetition of Screening Assessments 
Screening assessments may be repeated once per screening to establish study eligibility. If repeat 
values of the individual assessment(s) are within the eligibility criteria and completed within the 
screening window, then the subject is eligible for the study. 
Additional repetition of any individual screening assessment that did not meet eligibility criteria 
is not permitted, unless there is clear evidence of a laboratory error (e.g., hemolysis of sample) or 
equipment failure, or if the investigator believes the result is not consistent with the subject’s 
current medical condition. 
9.1.1.2 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 2 weeks for the following 
reasons: 
• Repetition of the Screening Period assessments (Section 9.1.1.1), 
• Unexpected operational or logistic delays, or 
If more than 42 days have elapsed from screening before first dose of study drug, all screening 
assessments need to be repeated. 
9.1.1.3 
Rescreening 
Individuals who do not meet the eligibility criteria for participation upon initial screening can be 
rescreened up to 3 times. All screening tests should be repeated to determine eligibility except 
for APOL1 genotyping, confirmation of biopsy-proven APOL1-mediated FSGS by the eligibility 
review process (Section 9.3.6), and follicle-stimulating hormone (FSH).  
Rescreened participants will keep the same subject identification number assigned during the 
initial screening process. The rescreening period will start from the date of the first assessment of 
the rescreen. Rescreening assessments may be done in the clinic or using home health. If home 
health is used for rescreening, abbreviated PE may be done. 
9.1.2 
Part A 
9.1.2.1 
Treatment Period  
Subjects will be enrolled in Cohort 1 and optional Cohort 2. Treatment Period assessments are 
listed in Table 3-2. During Treatment Period 1, subjects will receive VX-147 at a dosage 


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of 15 mg qd for 2 weeks. During Treatment Period 2, subjects will receive VX-147 at a dosage 
of 45 mg qd for 11 weeks. Dosing details are in Section 9.6. 
9.1.2.2 
Safety Follow-up 
Subjects will have a SFUV 28 (± 7) days after the last dose of study drug. SFUV assessments are 
listed in Table 3-3.  
9.1.2.3 
Early Termination of Treatment or Early Discontinuation 
If a subject prematurely discontinues study treatment, an Early Termination of Treatment (ETT) 
Visit should be scheduled as soon as possible after the subject decides to terminate study 
treatment. Subjects who prematurely discontinue treatment will also be required to complete the 
SFUV, approximately 28 (± 7) days after their last dose of study drug. The assessments 
performed at the SFUV are listed in Table 3-3. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the SFUV, and a separate SFUV will not be required.  
After the ETT Visit, subjects will not complete further Part A Visits; these subjects will not 
continue to Part B.  
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue to use any data and samples collected before such withdrawal of 
consent. 
9.1.3 
Part B 
Participation in Part B is optional. After the last Part A Visit, subjects will be followed 
off-treatment at a visit scheduled every 4 weeks (± 2 weeks) to assess the change in proteinuria 
after stopping administration of VX-147 (Table 3-3). Part B visits will continue until the UPCR 
level reaches ≥90% of baseline levels or 3 months after the last dose of study drug, whichever 
occurs first.  If a subject has not achieved ≥90% of baseline UPCR by the Part B Week 12 Visit, 
the Part B Week 12 Visit will be the last study visit.  
Subjects will not be allowed to participate in Part B if (1) their UPCR level during Part A 
remained ≥90% of baseline or (2) their UPCR level reached ≥90% of baseline before the Part A 
Week 13 Visit and remained at that level through the Week 13 Visit. 
The SFUV and Part B Week 4 Off-treatment Follow-up Visit may occur on the same day, 
provided the visit windows for both visits are met.  
9.2 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study. All subjects will receive VX-147. 
9.2.1 
Replacement Subjects 
Subjects may be replaced at the discretion of Vertex. 
9.3 
Rationale for Study Elements 
9.3.1 
Study Design  
The study will be single-arm and open-label. All subjects will receive VX-147 for a total of 
13 weeks. A placebo arm was not included because FSGS is a rare, severe disease with a very 
low likelihood of spontaneous remission.15-17 This is the first study targeting the APOL1 pathway 


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in patients with FSGS, so the duration required for proteinuria levels to reach nadir is unknown. 
Clinical practice guidelines18 for other therapies indicate that ≥4 months of therapy may be 
required for patients with nephrotic-range proteinuria to achieve complete remission (defined as 
UPCR <0.3 g/g). The duration of 13 weeks for this study was selected to allow the maximum 
treatment time supported by nonclinical data.  
This is the first study in patients with FSGS, therefore subjects will receive 2 dose levels of 
VX-147 to characterize PK of VX-147 at 2 dose levels in this population. As shown in 
Figure 9-1, the 15 mg qd dose will be administered for 2 weeks and the 45 mg qd dose will be 
administered for 11 weeks. The 2-week duration for the 15 mg qd dose was selected based on an 
exposure-response model suggesting that a measurable decrease in proteinuria may be observed 
after 2 weeks of dosing. The 11-week additional duration for the 45 mg qd dose, provides a total 
of 13 weeks continuous dosing, which is the longest observation period supported by available 
nonclinical data. 
9.3.2 
Study Population 
The study will enroll male and female subjects, aged 18 to 65 years old, with biopsy proven 
FSGS, 2 APOL1-risk alleles, and nephrotic-range proteinuria. These patients have need for new 
treatments, because patients with FSGS and nephrotic-range proteinuria have rapid progression 
to kidney failure, with mean renal survival less than 10 years.15, 16, 19-21 The presence of FSGS on 
biopsy will be confirmed by an independent, external expert (Section 9.3.6) to determine 
eligibility.  
9.3.3 
Study Drug Dose 
The administration of once daily doses of 15 mg and 45 mg were selected on the totality of 
clinical safety, tolerability, and PK from the FIH study (Study 001); as well as toxicology and 
non-clinical pharmacodynamic (PD) data. 
In Study 001, single ascending oral doses of VX-147 up to 50 mg and multiple ascending doses 
of VX-147 up to 45 mg once daily for 14 days were evaluated. The doses were well-tolerated 
and no clinically significant safety concerns were identified. In this study, a low dose of 15 mg 
once daily is selected to characterize the PK in FSGS patients and to assess any measurable 
decrease in proteinuria. Based on an exposure-response model, the exposures from the 15 mg 
dose are expected to result in approximately 90% inhibition in the in vitro ion flux model. This 
level of inhibition may result in a measurable decrease in proteinuria after 2 weeks of dosing.  
A high dose of 45 mg once daily is selected to maximize the probability of reduction in 
proteinuria over the 11-week dosing period. Based on the exposure-response model referenced 
above, exposures from this dose are expected to result in over 96% inhibition in the in vitro ion 
flux model. VX-147 exposure from the 2 doses are expected to be well differentiated based on 
data from the FIH healthy subject study (Study 001). Thus, the doses selected will provide an 
adequate assessment of the dose-response relationship and safety profile of VX-147 in the 
exposure range of interest.  
Additional information about FIH and nonclinical data are available in the Investigator’s 
Brochure.  


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9.3.4 
Study Assessments 
All efficacy, safety, and PK assessments are common assessments for clinical studies, with the 
exception of those described below.  
9.3.4.1 
UPCR  
Percent change from baseline in UPCR at Week 13 was chosen as the primary endpoint because 
proteinuria is a characteristic feature of FSGS and 1 of its main prognostic factors. Urine samples 
will be collected for UPCR using the first morning void, which is standardly used in clinical 
practice to determine accurate urine protein levels. As UPCR is variable within an individual, 
3 samples will be taken during screening, Week 5, Week 9, and Week 13; and the average of the 
3 values will be used to determine baseline, Week 5, Week 9, and end-of-treatment UPCR 
values, respectively.  
9.3.4.2 
SF-36 
Change in SF-36 from baseline over the study treatment period will be assessed as an 
exploratory outcome. SF-36 is a patient-reported generic measure of health status. It has been 
previously used to evaluate health-related quality of life in patients with chronic kidney disease, 
including FSGS.22,23 
9.3.5 
Use of Telemedicine for Study Visits  
Telemedicine may be used for a number of study visits as detailed in Table 3-1 through 
Table 3-3. These visits will include home health nurse visits to the subject’s home to complete 
assessments. All visits must have a consultation between the subject and investigator (i.e., in 
person, phone, or telemedicine video conference) within 1 business day after the home health 
visit, in order to check-in and collect AEs. Subjects and investigators may choose to conduct 
individual visits in the clinic or through use of home health. Periodic phone or telemedicine 
video visits may also be done to allow the investigator and subject to communicate directly; 
these visits may be done face-to-face in the clinic at the discretion of the investigator. 
If local regulations or site practice do not allow telemedicine, all visits will be conducted at the 
site.  
9.3.6 
Eligibility Review 
An independent, external expert with appropriate clinical and scientific background will evaluate 
the histopathological eligibility criteria to ensure that the subjects meet the study’s definition of 
FSGS. Details of the process will be included in a separate procedure manual. 
9.4 
Prior and Concomitant Medications 
Information about all prior and concomitant medications, including the subject’s FSGS 
medications, other medications, and herbal and naturopathic remedies administered from 28 days 
before the Screening Visit through the SFUV or last off-treatment Follow-up Visit in Part B, 
whichever is later, will be recorded in each subject’s source documents. For subjects who are 
screened but not subsequently enrolled, details of prior medication will only be documented in 
the subjects’ source documents. 
Subjects in Cohort 1 and Cohort 2 who are taking low dose systemic corticosteroids (i.e., 
≤ 10 mg/day of prednisone or prednisone equivalent), ACE inhibitors, ARB, neprilysin inhibitor, 
SGLT2 inhibitor, a renin inhibitor, or certain immunosuppressants (tacrolimus, mycophenolate, 


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or cyclosporine) must remain on a stable medication regimen at least 28 days before the 
Screening Visit through the Week 13 or ETT (if applicable) Visit. Subjects in Cohorts 1 and 2 
who are taking systemic corticosteroids must remain on a stable low dose from at least 28 days 
before the Screening Visit through the Week 13 or ETT (if applicable) Visit. Use of higher doses 
of corticosteroids are permitted to treat urgent comorbid medical conditions. During the Part B 
Off-Treatment Period, every effort should be made to avoid starting, stopping, or modifying 
doses of these medications. If it becomes clinically necessary to alter a subject’s antihypertensive 
regimen during the study, changes to an antihypertensive medication dose or addition of a new 
antihypertensive medication are recommended before changes are made to any ACE inhibitor, 
ARB, neprilysin inhibitor, or renin inhibitor. 
9.5 
Study Restrictions 
Study restrictions are summarized in Table 9-1. A nonexhaustive list of medications is provided 
in the Study Reference Manual. 
Table 9-1 
Study Restrictions  
Restricted 
Medication/Food/Activitya 
Timing of Restriction 
Start 
Stop 
Moderate and strong CYP3A4 
inhibitors or inducers, including 
consumption of herbal medications 
(e.g., St. John’s Wort) 
None allowed within 14 days 
before the first dose of the 
study drug 
Completion of Safety Follow-up 
Visit assessments 
Nonpermitted Immunosuppressants 
Note: This includes all 
immunosuppressants except 
tacrolimus, mycophenolate, and 
cyclosporine, which are permitted. 
None allowed within 12 weeks 
before the first dose of study 
drug 
Completion of the last study 
assessment 
Rituximab 
None allowed within 6 months 
before the first dose of study 
drug 
Completion of the last study 
assessment 
Other investigational drugs or devices 
28 days before first dose of 
study drug, 5 half-lives before 
first dose of study drug dose, or 
time determined by local 
requirements (whichever is 
longer) 
Completion of the last study 
assessment 
Creatine or creatine-containing dietary 
supplements  
7 days before first dose of 
study drug  
Completion of Safety Follow-up 
Visit assessments  
Grapefruit, grapefruit juice, pomelos, 
orange marmalade, Seville/blood 
oranges 
7 days before first dose of 
study drug  
Until last PK sample is taken 
a 
See Section 9.4 for guidance on concomitant medications. 
9.6 
Administration  
VX-147 will be administered as 15 mg tablets, orally, as shown in Table 3-2.  


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Study drug will be administered according to the following guidelines: 
• The first dose in each period must be administered under the supervision of site medical staff 
or a home health nurse. Subjects will be monitored for 4 hours after receiving the first dose 
of each Treatment Period 
• On days of scheduled visits, the dose of study drug will be administered after predose 
assessments have been completed. 
• Study drug will be taken at approximately the same time on each dosing occasion. For 
example, subjects that administer VX-147 dose at 8AM on Day 1 should administer all 
subsequent doses at 08:00AM ± 2 hours. 
• Study drug may be taken with or without food. 
• Subjects will swallow the study drug whole, with a full glass of water and will not chew it 
before swallowing. 
• On days of intensive PK sampling, the date, dose taken, and time of study drug 
administration will be recorded for the 2 doses before PK sample collection and on the 
morning of PK sample collection. 
•  Subjects will be instructed to bring all used and unused materials associated with the study 
drug to the site or the nurse will take these materials at each study visit; 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, the subject should take 
his/her dose according to the guidance above. If more than 6 hours have elapsed after his/her 
usual dosing time, the subject should skip that dose and resume his/her normal schedule for the 
following dose. An example is provided below: 
• If the morning dose of study drug should have been taken at approximately 08:00AM, and 
the subject remembers at 12:00PM that he/she forgot to take his/her dose, he/she should take 
the dose as soon as possible. If they remember after 2:00PM that they forgot to take the 
morning dose, they should skip that dose and resume the normal schedule the next day. 
Additional information is provided in the Pharmacy Manual. 
9.7 
Dose Modification 
No dose modifications are allowed. Treatment may be interrupted as outlined in Section 9.8. If 
any unacceptable toxicity arises in the opinion of the investigator, individual subjects may 
discontinue dosing. The Vertex medical monitor must be notified immediately.  
9.8 
Study Drug Interruption 
Study drug may be interrupted for safety concerns by the investigator. The Vertex medical 
monitor should be notified of an interruption of study drug and of the resumption of study drug 
after such interruption. 
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 


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for safety, behavior, noncompliance with study procedures, or administrative reasons. A subject 
who withdraws from study drug treatment will continue to be followed unless the subject 
withdraws consent.  
Subjects who discontinue study treatment early should complete the ETT and SFUV, as noted in 
Sections 9.1.2.2 and 9.1.2.3.  
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a SFUV, if applicable (see 
Section 9.1.2.3), and follow up with the subject regarding any unresolved AEs. 
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a 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. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period(s) may be replaced at Vertex’s discretion. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
10.2 
Packaging and Labeling 
Vertex will supply the 15-mg VX-147 tablets. Study drug labeling will be in compliance with 
applicable local and national regulations. Additional details about packaging, labeling, and 
dispensing for VX-147 will be in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
The investigator, or an authorized designee (e.g., a licensed pharmacist), will ensure that all 
investigational product is stored in a secured area, under recommended storage conditions, and in 
accordance with applicable regulatory requirements. To ensure adequate records, all study drugs 
will be accounted for in the drug accountability forms as instructed by Vertex. 
Detailed instructions regarding the storage, handling, and dispensation of the study drug will be 
provided in the Pharmacy Manual. 


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Table 10-1 
Study Drug  
Drug Name 
Dosing Form/ 
Route 
Dosage 
How Supplied 
VX-147 
Tablet/ 
oral 
15-mg  
Supplied as 15-mg tablets  
VX-147 
Tablet/ 
oral 
45-mg  
Supplied as 3 × 15-mg 
tablets 
 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information about the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. A central pharmacy will be used. Subjects will be instructed to return all 
used and unused materials associated with the study drug to the home health nurse or site. These 
materials will be retained at the site or central pharmacy according to instructions provided by 
Vertex or its designee. The study monitor will review study drug records and inventory 
throughout the study. If a site or central pharmacy uses a site-specific drug accountability system 
and/or process, including processes associated with the destruction of returned materials, the 
process must be documented and approved by Vertex. The study monitor must review the drug 
accountability documentation on a regular basis. The study monitor will promptly communicate 
to Vertex any discrepancies he/she is unable to resolve with the site. 
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. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site or in the subject’s home at required study visits. At each visit, site 
personnel/home health care nurses 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 should consider discontinuing the subject from the study  
10.7 
Blinding and Unblinding 
This is an open-label study.  


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11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1 through Table 3-3. 
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 
Medical history will be elicited from each subject and extracted from medical records during 
screening. Based on the medical history, the subject will be assessed for any disqualifying 
medical conditions as specified in the inclusion and exclusion criteria. The medical history will 
include a complete review of systems, past medical and surgical histories, and any allergies. 
Height and weight will be measured with shoes off with light weight clothing (no outerwear). 
BMI will be calculated from weight and height. 
11.2 
Pharmacokinetics 
11.2.1 
Blood Sampling  
Blood samples will be collected to determine plasma concentrations of VX-147. Metabolites of 
VX-147 may be analyzed, if necessary. These samples may also be used for further evaluation of 
the bioanalytical method, evaluation of unbound concentration of VX‑147, and for exploratory 
analyses that provide information on the metabolic pathways used by or affected by VX-147; 
these results may not be included in the clinical study report. 
All efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
Acceptable windows for sampling times are shown in Table 11-1. Samples collected outside of 
these acceptable windows will be considered protocol deviations.  
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Sampling Time 
Time From Scheduled Sampling Allowed 
Predose 
Up to 60 minutes before dose 
From 0.25 up to ≤4 hours after study drug dosing 
± 15 minutes 
> 4 hours after study drug dosing 
± 120 minutes 
48 hours after study drug dosing 
± 180 minutes 
 
For each visit with a PK blood draw, a record of study drug administration will be collected. 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. 
11.2.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of samples and further procedures for processing and 
handling of samples for PK analysis will be in a separate document.  


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11.2.3 
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. 
11.3 
Urine Sampling for UPCR, UACR, and Safety Laboratory Panel 
Urine will be collected from the first morning void (predose) for use in efficacy and safety 
analyses. Efficacy analyses will include UPCR (primary endpoint) and UACR (exploratory 
endpoint), as calculated from protein, albumin, and creatinine measured in the urine. Safety 
assessments will include the urine laboratory parameters in Section 11.6.2. During the Screening, 
Week 5, Week 9, and Week 13 Visits, when 3 samples are collected on 3 separate days within a 
7-day period, the third sample collected will be used for the safety laboratory and biomarker 
assessments; all 3 samples will be used for UPCR and UACR.  
If the subject does not remember to collect their first morning void on the scheduled visit day, 
the subject may provide the sample on another day within the visit window.  
Details about the collection and processing of urine samples will be provided in the Laboratory 
Manual.  
11.4 
APOL1 Genotyping 
A blood sample will be collected for determining APOL1 genotype during screening. This 
sample is not required if a genotype result is available from a previous Vertex study using a 
Vertex-approved clinical study assay.  
The results of the genotyping test will be provided to the investigator. The investigator will 
inform the subject of the APOL1 genotype. Vertex will ensure that subjects can obtain the 
services of a genetic counselor, if desired. The site will be responsible for managing the 
corresponding logistics.  
11.5 
Exploratory Assessments 
These data will be used for internal exploratory purposes. Detailed procedures for the collection 
of blood and urine, as well as additional procedures for processing and handling samples, will be 
provided in a separate document. 
11.5.1 
Blood Biomarker Samples 
Blood samples will be collected for potential exploratory evaluation of correlations between 
blood markers (e.g., post-translational APOL1 protein modification, peptides, lipids, endogenous 
metabolites, etc.) with PK and AEs observed in the study. The samples may also be used for the 
evaluation of safety biomarkers.  
11.5.2 
Urine Biomarker Samples 
Urine samples will be collected from the first morning void for potential exploratory evaluation 
of correlations between urine biomarkers (e.g., exosomes) with PK treatment response, and AEs 
observed in the study. At visits where triplicate urine samples are collected, only the third urine 
sample will be used for urine biomarker analysis. Additional details will be provided in the 
Laboratory Manual. 


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11.5.3 
SF-36 
Subjects will complete the SF-36 in their native language (if validated translations are available) 
before all other study assessments at each scheduled time point. If there is no validated 
translation available in the subject’s native language, the subject will not complete the 
questionnaire. The questionnaire provides information about functional health and wellbeing, as 
well as 2 psychometrically based physical and mental health summary measures. 
11.6 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, and physical examinations (PEs). 
11.6.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP Guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF completion 
guidelines for investigators as well as training will be provided. 
11.6.2 
Clinical Laboratory Assessments 
The safety laboratory test panels are shown in Table 11-2. For purposes of study conduct, blood 
and urine samples will be analyzed at a central laboratory, with the exception of urine pregnancy 
tests and if there are extenuating circumstances due to COVID-19, as described below.  
Urine samples for safety laboratory assessments may be collected at the same time as the urine 
samples for efficacy and biomarker assessments (See Section 11.3). Refer to sample handling 
guidelines to ensure that each sample collected is submitted appropriately to the lab for analysis 
at each visit. At the Screening, Week 5, Week 9, and Week 13 Visits, only the third urine sample 
will be used for safety urinalysis and biomarker assessments; urine protein, creatinine, and 
albumin will be assessed for all 3 samples collected during this visit. 
On days when overnight fasts are required (see Table 3-2 and Table 3-3), subjects will abstain 
from food and beverages for 8 hours before the start of the visit. During this period, water may 
be consumed up to 1 hour before study drug administration.  
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. Laboratory test results that are abnormal and 
considered clinically significant will be reported as AEs (see Section 13.1).  
The central laboratory should be used for all assessments when possible, and Vertex should be 
notified if a local laboratory is to be used. If the subject is unable to have a clinic or home health 
visit due to extenuating circumstance of the COVID-19 global pandemic, local laboratories may 
be used after Day 1 for blood safety samples.  When local labs are used for blood safety sample 
collection, the site will obtain the results from the local lab and ensure data are captured in the 
electronic data capture (EDC) per Section 13.5. Local labs may not be used for screening 
assessments. 


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Table 11-2 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Creatine kinase 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Total bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate transaminase 
Alanine transaminase 
Amylase  
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Cholesterold  
Triglyceridesd 
Low-density lipoprotein-directd  
High-density lipoproteind  
Hemoglobin  
Hematocrit 
Erythrocytes 
Mean corpuscular volume 
Platelets  
Reticulocytes  
Leukocytes  
Differential (absolute and percent): 
Eosinophils 
Basophils  
Neutrophils 
Lymphocytes 
Monocytes  
Blood smeare 
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
Leukocyte esterase  
Nitrite  
Urine proteinc  
Urine creatininec 
Urine albuminc 
Urine blood 
  
  
Urine ketones 
Urine glucose 
Urobilinogen 
Urine pH 
Specific gravity 
 
 
a 
For the Day 1 predose sample, microscopic examination of urine will be done, and results will be provided 
for leukocytes, erythrocytes, crystals, bacteria, and casts. 
b 
If blood urea nitrogen cannot be measured, urea may be substituted. 
c 
eGFR will be calculated using the CKD-EPI equation, and AKI will be determined using KDIGO criteria.24 
Urine protein, creatinine, and albumin measurements will be used for efficacy  and safety. 
d 
Lipid profile will only be measured at the visits with fasting: Day 1, Week 3, Week 13, ETT, and SFUV. 
e 
A blood smear will be collected on Day 1, Week 13, and the ETT Visit. 
Additional Tests at Screening: The following additional tests will be performed during screening 
to assess eligibility: 
• Serum beta-human chorionic gonadotropin (β-hCG) for all subjects: Serum samples will be 
analyzed for β-hCG at the central laboratory.  
• Follicle-stimulating Hormone (Screening Period only): Blood sample for FSH will be 
measured for any suspected postmenopausal female with at least 12 months of continuous 
spontaneous amenorrhea. Serum FSH levels must be within the postmenopausal reference 
range of the performing laboratory to be considered postmenopausal. 
• APOL1: A blood sample will be collected to determine APOL1 genotype, if required per 
Table 3-1. 
• HIV-1 and HIV-2 antibodies: A blood sample will be collected for serology. 
• Hepatitis B surface antigen: A blood sample will be collected for serology. 


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• Hepatitis C Virus (HCV): A blood sample will be collected for serology and nucleic acid 
testing. If the antibody test is positive, a nucleic acid test will be done.  
Algorithm for assessing out of range laboratory values at Screening: 
If one or more lab values NOT specified in the eligibility criteria (Section 8) are outside the 
normal range, the following choices are available: 
• The subject may be excluded. 
• The subject may be included if the lab value(s) are not clinically significant, as 
determined by the principal investigator (PI). 
• The subject may be included if the lab abnormality is consistent with a pre-existing 
medical condition that is NOT excluded per protocol. 
• Repeat the test for the individual lab assessment per the guidance in Section 9.1.1.1. 
Pregnancy Testing for Female Subjects of Childbearing Potential (Section 11.6.5): 
• Urine pregnancy tests will either be performed and analyzed at the site or, when there is a 
home health visit, at home using a home kit provided by the site/home health nurse. The 
urine pregnancy test on Day 1 must be negative before the first dose of study drug. 
Additional pregnancy tests may be required according to local regulations and/or 
requirements. 
If a urine pregnancy test is positive, all study drug dosing will stop, and the pregnancy will be 
confirmed with a serum β-hCG test. If pregnancy is confirmed, the procedures outlined in 
Section 11.6.5.2 will be followed. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate. 
11.6.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening visits in the 
clinic. Screening visits done with a home health nurse will have an abbreviated PE. At other 
visits, an abbreviated PE will be done. Symptom-directed PEs and symptom-directed vital signs 
assessments can be performed by the investigator or healthcare provider at any time if deemed 
necessary by the investigator. 
A complete PE includes a review of the following systems: head, neck, and 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. 
The abbreviated PE will include an assessment of the following body systems: cardiovascular 
system; respiratory system; skin; and abdomen. 
Vital signs include blood pressure (systolic and diastolic), oral temperature, pulse rate, and 
respiration rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed. At each scheduled timepoint, blood pressure will be recorded in triplicate. 


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11.6.4 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines: 
• The ECG will be done before any other procedures that may affect heart rate, such as blood 
draws. 
• The subject will be instructed to rest for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position 
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 SFUV will be recorded as AEs.  
If study sites cannot use QTcF they should discuss alternatives with the medical monitor. 
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. A subject with a 
confirmed QTcF value above the threshold value will discontinue dosing. 
11.6.5 
Contraception and Pregnancy 
The effects of VX-147 on conception, pregnancy, and lactation in humans are not known. Refer 
to the VX-147 Investigator’s Brochure for additional details. 
11.6.5.1 
Contraception 
Study participation requires compliance with the contraception guidelines outlined below: 
Contraception for the couple is waived for the following: 
• True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and post-ovulation 
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 the female is of non-childbearing potential. To be considered of non-childbearing potential, 
the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH 
level within the laboratory’s reference range for postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
Note: All other females (including females with tubal ligations and females who do 
not have a documented hysterectomy or bilateral oophorectomy/salpingo-
oophorectomy) will be considered to be of childbearing potential. 


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• Same sex relationships. 
For subjects for whom the contraception requirement is not waived: 
For male subjects with female partners of childbearing potential, in addition to wearing a 
condom, study participation requires a commitment from the subject that at least 1 allowed 
method of contraception (in addition to a condom) will be used as a couple. Refer to Table 11-3 
for allowed methods of contraception. 
For female subjects with childbearing potential, study participation requires a commitment 
from the subject that at least 1 allowed method of contraception is used as a couple. Allowed 
methods of contraception are listed in Table 11-3. 
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.  
Table 11-3 
Allowed Methods of Contraception 
Method 
Male Subjects and 
Their Female 
(Non-study) Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy 6 months or more previously, with a 
documented negative postvasectomy semen 
analysis for sperm 
Yes 
Yes 
Documented tubal ligation 4 weeks or more 
previously 
Yes 
Yes 
Continuous use of an intrauterine device for at 
least 90 days before the first dose of study drug  
Yes 
Yes  
Oral, patch, implanted, injected, or vaginal 
hormonal contraceptives, if used consistently and 
correctly for at least 60 days before the first dose 
of study drug 
Yes  
Yes 
 
Additional notes: 
• Male subjects must use a condom to avoid exposing a potential fetus to study drug via the 
seminal fluid. The female condom is not an acceptable method due to the increased risk of 
tearing when the female and male condoms are used at the same time. 
• Male and female subjects who are not sexually active at the time of screening must agree to 
follow the contraceptive requirements of this study if they become sexually active with a 
partner of the opposite sex.  
• Male subjects must not donate sperm from the first study drug dose until 90 days after the 
last dose of study drug. 
• Female subjects of childbearing potential should not plan to become pregnant during the 
study or within 90 days after the last dose of study drug.  
• For male subjects with a female partner of childbearing potential, the couple should not plan 
to become pregnant during the study or within 90 days after the last dose of study drug. 


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• If applicable, additional contraception requirements may need to be followed according to 
local regulations and/or requirements. 
• Unique situations that may not fall within the above specifications may be discussed with the 
Vertex medical monitor or designee on an individual basis. 
11.6.5.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a female subject, or the female partner of a male subject, becomes pregnant while participating 
in the study, the study drug will be permanently discontinued immediately. The investigator will 
notify the medical monitor and Vertex Global Patient Safety (GPS) within 24 hours of the site’s 
knowledge of the subject’s (or partner’s) pregnancy, and send the Pregnancy Information 
Collection Form to Vertex GPS. 
A subject (or their partner, if relevant) who becomes pregnant while on study will be followed 
until the end of the pregnancy. The infant will be followed for 1 year after birth, provided 
informed consent is obtained. A separate ICF, which may be obtained in person or remotely, will 
be provided to explain these follow-up activities. Pregnancy itself is not an AE.  
12 
STATISTICAL AND ANALYTICAL PLANS 
This section presents a summary of the planned final analyses for efficacy, safety, and clinical 
pharmacology. Efficacy and safety statistical analysis details will be provided in the statistical 
analysis plan (SAP) for this study, and clinical pharmacology analysis details will be provided in 
the clinical pharmacology analysis plan (CPAP), both of which will be finalized before last 
subject last visit for the treatment period (Part A). 
12.1 
Sample Size and Power 
The sample size was not calculated based on power assumptions, because this is an estimation 
study. The primary endpoint is percent change from baseline in UPCR at Week 13. Assuming an 
SD of 0.672 (in log scale),25 a sample size of 10 subjects will provide a precision of 0.294 (in log 
scale) for the estimation of the Geometric Mean Percent Change (GMPC) from baseline in 
UPCR. The precision of the estimate corresponds to the half width of its 80% CI, in log scale. 
Table 12-1 displays the expected size of the 80% CIs for the GMPC at various values of the 
observed GMPC. Up to 10 subjects will be enrolled in Cohort 1, and approximately 10 subjects 
will be enrolled in Cohort 2. 
Table 12-1 
Two-sided 80% Confidence Interval for GMPC from Baseline in UPCR  
Number of 
Subjects 
Completing 
Assumption for 
SD in Log Scale 
Observed Geometric Mean (corresponding percent reduction from 
baseline) 
0.5 (-50%) 
0.6 (-40%) 
0.7 (-30%) 
0.8 (-20%) 
10 
0.672 
0.37, 0.67  
(-63%, -33%) 
0.45, 0.81  
(-55%, -19%) 
0.52, 0.94  
(-48%, -6%) 
0.60, 1.07  
(-40%, 7%) 
 


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12.2 
Analysis Sets 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), Safety Set, 
and Follow-up Set. 
The All Subjects Set will include all subjects who were enrolled in the study. This analysis set 
will be used for all individual subject data listings and disposition summary tables, unless 
otherwise specified.  
The FAS will include all subjects who received at least 1 dose of study drug in the Treatment 
Period and have at least 1 post-baseline efficacy assessment. The FAS will be used to summarize 
subject demographics and baseline characteristics, and for all efficacy analyses in the Treatment 
Period, unless otherwise specified. 
The Follow-up Set will include all subjects who entered the Off-treatment Follow-up Period 
(Part B) and have at least 1 efficacy assessment in that period. The Follow-up Set will be used 
for all efficacy analyses in the Follow-up Period, unless otherwise specified.  
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. 
12.3 
Statistical Analysis 
This section presents a summary of the planned statistical analyses of efficacy, safety and PK 
endpoints of the study. Statistical analysis details will be provided in the SAP. 
12.3.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). 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, and SD 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. 
Baseline value, unless specified otherwise, 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., the Day 1 Visit). For ECGs, 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., the Day 1 visit). For UPCR (and UACR) data baseline value will be the 
average of UPCR (UACR) values from the 3 urine samples collected during screening for the 
purpose of assessing eligibility. 
Change (absolute change) from baseline will be calculated as Post-baseline value − Baseline 
value. 


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Treatment emergent (TE) Period will include the time from the first dose of study drug in the 
Treatment Period to either (1) the SFUV, (2) ETT Visit if it replaces the SFUV, or (3) the date of 
the last dose + 28 days for subjects who do not have a SFUV. The TE Period will be used for 
safety analyses unless specified otherwise. 
The analysis visit windows for protocol-defined visits will be described in the SAP. 
The rules for handling missing data due to treatment or study discontinuation will be described in 
the SAP.  
Data will be analyzed separately for the Treatment Period (Part A) and the Off-treatment Follow-
up Period (Part B), unless specified otherwise. 
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
The number and percentage of subjects in each disposition category in the Treatment Period 
(e.g., included in the All Subjects Set, included in the Safety Set, completed Treatment Period, 
completed SFUV, and discontinued treatment or study with a breakdown of the reasons for 
discontinuation) will be summarized. 
The number and percentage of subjects in each disposition category in the Off-treatment Follow-
up Period (e.g., included in the Follow-up Set, completed Follow-up Period, and discontinued 
study/Follow-up Period with a breakdown of the reasons for discontinuation) will be 
summarized. 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographics, background (e.g. medical history), and baseline characteristics will be 
summarized using descriptive summary statistics. 
The following demographics and baseline characteristics will be summarized and will include 
(but not limited to): sex, race, age, weight, height, BMI, UPCR, UACR, and eGFR. 
12.3.2.3 
Prior and Concomitant Medications 
Medications used will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) and categorized as the following: 
Prior medication: any medication that started before the date of the first dose of study drug, 
regardless of when the medication ended 
Concomitant medication: medication continued or newly received on or after the date of the 
first dose of study drug through the end of the TE Period 
A given medication may be classified as prior, concomitant, or both prior and concomitant.  
If a medication start date is on or after the first dose date of study drug, then the medication will 
be categorized as concomitant medication regardless of whether the medication end date is 
missing or not. If a medication end date is before the first dose date of study drug, then the 
medication will be categorized as prior medication regardless of whether the medication start 
date is missing or not. Note that medication that started before the first dose of study drug and 
continued after the first dose will be categorized as prior medication and separately as 
concomitant medication.  


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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, or concomitantly, it will be 
considered in both categories of prior and concomitant medication. 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by Preferred Name.  
Details for imputing missing or partial start and/or stop dates of medication will be in the SAP. 
12.3.2.4 
Study Drug Exposure and Compliance 
Exposure to study drug will be summarized in terms of duration of treatment a subject received 
(in days), defined as: last dose date – first dose date + 1 day, regardless of study drug 
interruption. 
Study drug compliance based on study drug exposure, will be summarized, and will be 
calculated as: 100  [1 – (total number of days of any study drug interruption)/(duration of study 
drug exposure in days)].  
12.3.2.5 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. The rules for identifying an IPD will be described in the SAP. 
IPDs will be provided in an individual subject data listing. 
12.3.3 
Efficacy Analysis 
Analyses will be done separately for Cohort 1 and Cohort 2, as well as combined. 
12.3.3.1 
Analysis of Primary Variables 
The primary efficacy endpoint is percent change from baseline in UPCR at Week 13. The 
Week 13 UPCR value will be calculated as the average of the available UPCR measurements 
(maximum 3) taken during Week 13. The baseline value will be the average of the 3 UPCR 
values from the urine samples collected during screening. 
The percent change from baseline in UPCR at Week 13 will be analyzed by first log 
transforming the UPCR data before analyses to reduce skewness and calculating the change from 
baseline in log-transformed values. The GMPC from baseline in UPCR will be estimated along 
with the corresponding 2-sided 80% CI. The GMPC from baseline and associated confidence 
limits will be calculated by back-transforming the estimated simple mean of change from 
baseline in log-transformed data. 
Sensitivity analyses for handling missing data due to treatment or study discontinuation will be 
described in the SAP. 
12.3.3.2 
Analysis of Other Variables 
In all exploratory analyses of UPCR and UACR related data, the Week 5, Week 9, and Week 13 
UPCR/UACR value will be calculated as the average of the available UPCR/UACR 
measurements (maximum 3) taken during these weeks, and the baseline value will be the average 
of the 3 UPCR/UACR values from the urine samples collected for this purpose during screening. 


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The percent change from baseline in UPCR over time during the Treatment period is an 
exploratory efficacy endpoint. Similar to the primary endpoint analysis, UPCR data will be 
log-transformed and change from baseline at each planned visit, up to Week 13, will be analyzed 
using the log-transformed UPCR values. The GMPC from baseline and associated 2-sided 
80% CI at each planned visit will be calculated by back-transforming the corresponding 
estimated simple mean and CI from the log-transformed data. 
Other exploratory efficacy endpoints include percent change from baseline in urinary albumin  
to-creatinine ratio (UACR) at Week 13, and percent change from baseline in UACR over time 
during the Treatment period. Analysis of these 2 endpoints will be similar to that performed for 
the corresponding UPCR endpoints. 
Off-treatment Follow-up Period (Part B): The exploratory endpoint of percent change from 
baseline in UPCR at the end of the Off-treatment Follow-up Period will be analyzed similarly to 
the primary efficacy endpoint. 
Additional details of these analyses will be provided in the SAP. 
12.3.4 
Safety Analysis 
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 in terms of the following safety and 
tolerability endpoints:  
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (hematology, serum chemistry, coagulation studies, and urinalysis) 
• Standard 12-lead ECG outcomes 
• Vital signs  
Only a descriptive analysis of safety will be performed. 
All safety data will be presented in individual subject data listings. 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs or TEAEs, defined as follows:  
Pretreatment AE: any AE that started before the first dose date of study drug 
TEAE: any AE that worsened (either in severity or seriousness) or that was newly developed on 
or after the first dose date of study drug through the end of the TE Period  
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs started before or after study treatment, the AEs will be classified as TEAEs. 
AE summary tables will be presented for TEAEs only and will include the following: 
• All TEAEs 
• TEAEs by strongest relationship  
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 


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• Serious TEAEs 
• TEAEs leading to death 
Summaries will be presented by MedDRA System Organ Class (SOC) and Preferred Term (PT) 
using frequency counts and percentages (i.e., number and percentage of subjects with an event). 
When summarizing the number and percentage of subjects with an event, subjects with multiple 
occurrences of the same AE or a continuing AE will be counted once. Only the maximum 
severity level will be presented in the severity summaries, and the strongest relationship level 
will be presented in the relationship summaries.  
In addition, a listing of individual subject level AE data for TEAEs leading to treatment 
discontinuation, SAEs, and deaths will be provided separately. All AEs, including pretreatment 
AEs, will be in individual subject data listings. 
12.3.4.2 
Clinical Laboratory Assessments 
For 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 by visit.  
The number and percentage of subjects with at least 1 laboratory event outside threshold criteria 
for the event during the TE Period will be summarized, including a shift of the event from 
baseline to post-baseline. The threshold criteria will be in the SAP. 
Results of urinalysis and the urine/serum pregnancy test will be in individual subject data listings 
only.  
In addition, a listing of 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. 
12.3.4.3 
Electrocardiogram 
For treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided by visit and time point, as applicable, for the following ECG 
measurements: RR (msec), heart rate (HR; beats per minute [bpm]), PR (msec), QRS duration 
(msec), QT (msec), and QT corrected for HR intervals (QTcF [msec]).  
The number and percentage of subjects meeting a threshold analysis criterion during the 
TE Period will be summarized. The threshold analysis criteria will be provided in the SAP. 
Clinically significant abnormal findings will be reported as AEs. 
Additional ECG analyses may be described in the SAP. 
12.3.4.4 
Vital Signs 
For treatment-emergent vital signs measurements, the observed values and change from baseline 
values will be summarized by visit: systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), pulse rate (bpm), and respiratory rate (breaths per minute). 
The number and percentage of subjects with at least 1 event outside the threshold criteria for a 
vital sign during the TE Period will be summarized. The threshold analysis criteria will be 
provided in the SAP. 


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Clinically significant abnormal findings in vital signs will be reported as AEs. 
Additional vital signs analyses may be described in the SAP. 
12.3.4.5 
Physical Examination 
PE findings will be presented in individual subject data listings only. 
12.3.4.6 
Other Safety Analysis 
Change from baseline in weight will be summarized by visit. 
12.3.5 
Other Analyses 
Analysis of the exploratory endpoints for SF-36 will be provided in the SAP. 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses 
Interim analyses may be done at the discretion of the sponsor to allow for regulatory interactions 
and clinical development planning. There is no independent Data Monitoring Committee for this 
study.  
12.4 
Clinical Pharmacology Analysis 
The following systemic exposure parameters will be estimated using noncompartmental and 
population PK analysis: AUCτ during a dosing interval, Cmax and Ctrough will be estimated for all 
subjects who provide adequate number of PK samples: 
• on Day 1 after single administration of the lower dose;  
• at Week 2 after the first administration of the higher dose; 
• at Week 5 after multiple administrations of the higher dose. 
In addition, observed Ctrough will be reported at Weeks 1, 3, 9, and 13. Based on availability of 
data after the last administration of the higher dose, half-life will be reported after multiple 
administrations of the higher dose.  
12.4.1 
Pharmacokinetic Analysis 
Mean and/or median plasma concentrations versus time will be plotted on log and linear scales. 
The PK parameters (Cmax, Ctrough, AUCτ, and other parameters as needed) of VX-147 estimated 
by noncompartmental analysis will be listed and summarized using summary statistics. Ongoing 
analyses of plasma concentrations of VX-147 may be conducted before database lock. 
Details of the analyses will be in the CPAP. 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses 
A population PK analysis of plasma concentration versus time data of VX-147 will be performed 
using the nonlinear mixed-effects modeling approach. Population and individual PK parameters: 
clearance after oral administration (CL/F) and apparent volume of distribution at steady state 
(Vss/F) will be estimated and the influence of various covariates (such as age, gender, and body 
weight) on these parameters will be investigated in an exploratory way. If deemed necessary, 
data may be pooled with data from other studies with VX-147 in order to improve the parameter 
estimates from the model.  


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Plasma concentration response relationship (PD markers and AEs, if any) will be explored. A 
more detailed description of the methodology to be followed will be in either the CPAP or the 
population PK/PD analysis plan. Listings of VX-147 plasma concentration data will be in the 
bioanalytical report. The population PK analysis will be in a stand-alone report.  
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the following times: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, withdrawal of 
consent) 
• For enrolled subjects who have a SFUV: through the SFUV 


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• For enrolled subjects who do not have a SFUV, 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 9.1.2.3) 
As noted in Table 3-1, for subjects undergoing a 2-step screening process, AEs related to 
phlebotomy will be collected for up to 24 hours after the blood collection; AEs will not be 
collected during the time between a subject undergoing genotype screening and the start of the 
Screening Visit. 
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 will be 
recorded only in the subject’s source documents. The following data will be documented for 
each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
February 2020). The severity of an AE described by a term that does not appear in the CTCAE 
will be determined according to the definitions in Table 13-1. 
Table 13-1 
Grading of AE Severity  
Classification 
Description 
Mild (Grade 1) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Moderate (Grade 2) 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADLa 
Severe (Grade 3) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADLb 
Life-threatening (Grade 4) 
Life-threatening consequences, urgent intervention indicated  


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Table 13-1 
Grading of AE Severity  
Classification 
Description 
Death (Grade 5) 
Death related to AE 
Source: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
ADL: activities of daily living; AE: adverse event 
Note: A semi-colon indicates ‘or’ within the description of the grade. 
a 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
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 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 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 in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
 


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13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation and is suspected of being a delayed toxicity due to administration of the study 
drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 


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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 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent through the SFUV, regardless of causality, 
will be reported by the investigator to Vertex GPS within 24 hours of identification. In 
addition, all SAEs that occur after the SFUV and are considered related to study drug(s) will be 
reported to Vertex GPS within 24 hours of identification.  
For SAEs that occur after obtaining informed consent through the SFUV, 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: 
 
  
For technical issues related to submitting the form, contact telephone: 
 
SAEs that occur after the SFUV and are considered related to study drug(s) will be recorded on 
the Vertex Clinical Trial 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 the outcome to Vertex using the SAE Form. 
13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IECs, and 
participating investigators in accordance with ICH Guidelines and/or local regulatory 
requirements, as applicable. In addition, Vertex, or authorized designee, will be responsible for 
the submission of safety letters to central IECs.  


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It is the responsibility of the investigator or designee to promptly notify the local IRB/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 be 
conducted only 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 and before performing any study-related procedures. Remote 
consent may be used. Remote consent would include a phone call or telemedicine visit between 
the site and subject for the consent discussion. The method of obtaining and documenting the 
informed consent and the contents of the consent will comply with ICH GCP and all applicable 
laws and regulations and will be subject to approval by Vertex or its designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
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.  


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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 will be limited to the site and the study physician and will 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 US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will 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 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 


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13.2.8 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
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 subject. Study 
data for each enrolled subject will be entered into a CRF by study site personnel using a secure, 
validated, web-based 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 or remote (as applicable by local regulation) checking of 
the CRFs/SAE Forms for completeness and clarity, cross-checking with source documents, and 
clarification of administrative matters will be performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application is 
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 them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  


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Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc (CD) or other electronic media will be placed in the investigator’s 
study file. 
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator's employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 
13.7.1 
Publication of Study Results 
Vertex is committed to reporting the design and results of all clinical studies in a complete, 
accurate, balanced, transparent, and timely manner, consistent with Good Publication Practices 
(GPP3).26  
Publication Planning: Vertex staff along with the lead PIs, the steering committee (SC), and/or 
the publication committee (PC) will work together to develop a publication plan.  
Authorship: Authorship of publications will be determined based on the Recommendations for 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, which 
states that authorship should be based on the following 4 criteria27: 
1. Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data;  
2. Drafting of the article or revising it critically for important intellectual content;  
3. Final approval of the version to be published; and 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved. 
All authors must meet conditions 1, 2, 3, and 4. All persons designated as authors should qualify 
for authorship, and all those who qualify should be listed. Contributions such as medical writing, 
enrollment of subjects, acquisition of funding, collection of data, or general supervision of the 
research group, alone, do not justify authorship.  


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Contributors: Contributors who meet fewer than all 4 of International Committee of Medical 
Journal Editors (ICMJE) criteria for authorship will not be listed as authors, but their 
contribution will be acknowledged and specified either as a group (e.g., “study investigators”) or 
individually (e.g., “served as scientific advisor”).  
Publication Review: As required by a separate clinical study agreement, Vertex must have the 
opportunity to review all publications, including any manuscripts, abstracts, oral/slide 
presentations, and book chapters regarding this study before submission to congresses or journals 
for consideration.  
13.7.2 
Clinical Study Report  
A clinical study report (CSR), written in accordance with the ICH E3 Guideline, will be 
submitted in accordance with local regulations. 


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14 
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Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, et al. Missense 
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Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A 
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Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. 
Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C. New 
England Journal of Medicine. 2012;367(1):20-29. 
15 
Chun MJ, Korbet SM, Schwartz MM, Lewis EJ. Focal segmental glomerulosclerosis in 
nephrotic adults: presentation, prognosis, and response to therapy of the histologic 
variants. J Am Soc Nephrol. 2004;15(8):2169-77. 
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Stirling CM, Mathieson P, Boulton-Jones JM, Feehally J, Jayne D, Murray HM, et al. 
Treatment and outcome of adult patients with primary focal segmental glomerulosclerosis 
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Cattran DC, Rao P. Long-term outcome in children and adults with classic focal 
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(KDIGO) KDIGO. 2012 Clinical Practice Guideline for the Evaluation and Management 
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19 
Korbet SM, Schwartz MM, Lewis EJ. Primary focal segmental glomerulosclerosis: 
clinical course and response to therapy. Am J Kidney Dis. 1994;23(6):773-83. 
20 
Troyanov S, Wall CA, Miller JA, Scholey JW, Cattran DC, Toronto Glomerulonephritis 
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21 
Rydel JJ, Korbet SM, Borok RZ, Schwartz MM. Focal segmental glomerular sclerosis in 
adults: presentation, course, and response to treatment. Am J Kidney Dis. 
1995;25(4):534-42. 
22 
Gipson DS, Trachtman H, Kaskel FJ, Radeva MK, Gassman J, Greene TH, et al. Clinical 
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Kidney International. 2011;79(6):678-85. 
23 
Komers R, Gipson DS, Nelson P, Adler S, Srivastava T, Derebail VK, et al. Efficacy and 
Safety of Sparsentan Compared With Irbesartan in Patients With Primary Focal 
Segmental Glomerulosclerosis: Randomized, Controlled Trial Design (DUET). Kidney 
International Reports. 2017;2(4):654-64. 
24 
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Clinical Practice Guideline for Acute Kidney Injury. Kidney International Supplement. 
2012;2(1)  
25 
Trachtman H, Nelson P, Adler S, Campbell KN, Chaudhuri A, Derebail VK, et al. 
DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients 
with FSGS. Journal of the American Society of Nephrology. 2018;29(11):2745-54. 
26 
Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
Publication Practice for Communicating Company-Sponsored Medical Research: GPP3. 
Ann Intern Med. 2015;163(6):461-4. 
27 
(ICMJE) ICoMJE. International Committee of Medical Journal Editors (ICMJE). 
Recommendations for conduct, reporting, editing, and publication of scholarly work in 
medical journals. [Internet]. Available from: http://www.icmje.org/recommendations. 
Accessed 06 September. 
 


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15.2 
Investigator Signature Page 
Protocol #:  
VX19-147-101 Version #: 
6.0 
Version Date: 26 July 2021 
Study Title: A Phase 2a, Open-label, Single-arm, 2-Part Study to Evaluate the Efficacy, 
Safety, and Pharmacokinetics of VX‑147 in Adults With APOL1-mediated Focal Segmental 
Glomerulosclerosis 
 
 
I have read Protocol VX19-147-101, Version 6.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-147 and this protocol supplied to me by 
Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods)  
Page 1 of 31 
Protocol Number: VX19-147-101 
 
 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Statistical Analysis Plan 
(Methods) 
Protocol Number VX19-147-101, Version 5.0 
(Interim and Final Analysis) 
 
A Phase 2a, Open-label, Single-arm, 2-Part Study to Evaluate the 
Efficacy, Safety, and Pharmacokinetics of VX-147 in Adults With 
APOL1-mediated Focal Segmental Glomerulosclerosis 
 
Author of SAP: 
 
 
Version: 1.0 
Version Date of SAP: 20 JULY 2021 
 
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. 


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2 
TABLE OF CONTENTS 
1 
Title Page .............................................................................................................................. 1 
2 
Table of contents ................................................................................................................ 2 
3 
Modifications........................................................................................................................ 5 
3.1 
Modifications to the Approved Clinical Study Protocol .................................................. 5 
3.2 
Modifications to the Approved Statistical Analysis Plan ................................................. 5 
3.3 
Modifications to the Approved IDMC Charter ................................................................ 5 
4 
Introduction .......................................................................................................................... 6 
5 
Study Objectives ................................................................................................................. 6 
5.1 
Part A (Treatment Period) ................................................................................................ 6 
5.1.1 Primary Objective ............................................................................................................. 6 
5.1.2 Secondary Objectives ....................................................................................................... 6 
5.2 
Part B ................................................................................................................................ 6 
5.2.1 Exploratory Objective ...................................................................................................... 6 
6 
Study Endpoints.................................................................................................................. 7 
6.1 
Part A ................................................................................................................................ 7 
6.1.1 Primary Endpoints ............................................................................................................ 7 
6.1.2 Secondary Endpoints ........................................................................................................ 7 
6.1.3 Exploratory Endpoints ...................................................................................................... 7 
6.2 
Part B (Optional Off-treatment Follow-up Period) .......................................................... 7 
6.2.1 Exploratory Endpoints ...................................................................................................... 7 
7 
Study Design ........................................................................................................................ 7 
7.1 
Overall Design .................................................................................................................. 7 
7.2 
Sample Size and Power .................................................................................................... 8 
7.3 
Randomization .................................................................................................................. 9 
7.4 
Blinding and Unblinding .................................................................................................. 9 
8 
Analysis Sets ....................................................................................................................... 9 
8.1 
All Subjects Set ................................................................................................................ 9 
8.2 
Full Analysis Set ............................................................................................................... 9 
8.3 
Follow-up Set ................................................................................................................... 9 
8.4 
Safety Set ........................................................................................................................ 10 
9 
Statistical Analysis ........................................................................................................... 10 
9.1 
General Considerations .................................................................................................. 10 
9.2 
Background Characteristics ............................................................................................ 11 


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9.2.1 
Subject Disposition ................................................................................................. 11 
9.2.2 
Demographics and Baseline Characteristics ........................................................... 12 
9.2.3 
Medical History ...................................................................................................... 13 
9.2.4 
Prior and Concomitant Medications ....................................................................... 13 
9.2.5 
Study Drug Exposure and Compliance .................................................................. 14 
9.2.6 
Important Protocol Deviations ................................................................................ 14 
9.3 
Efficacy Analysis ............................................................................................................ 14 
9.3.1 
Analysis of the Primary Efficacy Variable ............................................................. 15 
9.3.1.1 Definition of the Primary Efficacy Variable .......................................................... 15 
9.3.1.2 Analysis of the Primary Efficacy Variable ............................................................. 15 
9.3.2 
Analysis of Exploratory Efficacy Variables ........................................................... 16 
9.3.2.1 Definition of Exploratory Efficacy Variable .......................................................... 16 
9.3.2.2 Analyses of Exploratory Efficacy Variable ............................................................ 16 
9.4 
Safety Analysis ............................................................................................................... 17 
9.4.1 
Adverse Events ....................................................................................................... 17 
9.4.2 
Clinical Laboratory ................................................................................................. 18 
9.4.3 
Electrocardiogram .................................................................................................. 18 
9.4.4 
Vital Signs .............................................................................................................. 19 
9.4.5 
Physical Examination ............................................................................................. 19 
9.4.6 
Other Safety Analysis ............................................................................................. 19 
9.4.7 
COVID-19 Impacted Visits .................................................................................... 19 
9.5 
Other Analyses ............................................................................................................... 19 
9.5.1 Analysis of SF-36 ........................................................................................................... 19 
10 Interim and IDMC Analyses ............................................................................................ 20 
10.1 Interim Analysis ............................................................................................................. 20 
10.1.1 
General Consideration ............................................................................................ 20 
10.1.2 
Background Characteristics .................................................................................... 20 
10.1.3 
Efficacy Analysis .................................................................................................... 20 
10.1.4 
Safety Analysis ....................................................................................................... 20 
10.1.5 
Other Analysis ........................................................................................................ 21 
10.2 Independent Data Monitoring Committee Analysis ....................................................... 21 
11 References .......................................................................................................................... 21 
12 Appendices ......................................................................................................................... 22 
Appendix A: Analysis Visit Windows for Efficacy, Safety, and Exploratory Assessments ... 22 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 25 
Appendix C: Imputation Rules for Missing AE dates ............................................................. 26 


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Appendix D: Criteria for Threshold Analysis .......................................................................... 27 
 
 


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3 
MODIFICATIONS 
3.1 
Modifications to the Approved Clinical Study Protocol 
Not applicable. 
3.2 
Modifications to the Approved Statistical Analysis Plan 
Not applicable. 
3.3 
Modifications to the Approved IDMC Charter 
Not applicable. 
 
 


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4 
INTRODUCTION 
This statistical analysis plan (SAP) describes the efficacy and safety analyses and is based on the 
most recent approved clinical study protocol (CSP), the most recent approved electronic case 
report form (eCRF), and the most recent approved eCRF completion guidelines. It also 
documents analyses not specified in the protocol, which will provide supportive information for 
the scientific understanding of the drug entity.  
The Vertex Biometrics Department will perform the statistical analysis of the efficacy and safety 
data; SAS® Version 9.4 Software (SAS Institute, Cary, North Carolina, USA) or higher will be 
used to generate all statistical outputs (tables, figures, listings and datasets).   
The SAP (Methods) will be finalized and approved before the interim analysis datacut (if 
applicable) or clinical database lock, whichever occurs earlier. Any revisions to the approved 
SAP will be documented and approved in an amendment to the SAP prior to the clinical database 
lock. Any revisions made to the SAP after the clinical database lock will be documented in the 
clinical study report for this study. 
The analysis addressing the pharmacokinetic (PK) objective of the study will be described in the 
Clinical Pharmacology Analysis Plan (CPAP) which will be developed separately by the Clinical 
Pharmacology department at Vertex Pharmaceuticals Incorporated (Vertex). 
5 
STUDY OBJECTIVES 
5.1 
Part A (Treatment Period) 
5.1.1 
Primary Objective 
• To evaluate the ability of VX-147 to reduce proteinuria  
5.1.2 
Secondary Objectives 
• To evaluate the safety and tolerability of VX-147 
• To characterize the PK of VX-147 
5.2 
Part B 
5.2.1 
Exploratory Objective 
• To evaluate the change proteinuria after stopping administration of VX-147 


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6 
STUDY ENDPOINTS 
6.1 
Part A 
6.1.1 
Primary Endpoints 
• Percent change from baseline in urine protein to creatinine ratio (UPCR) at Week 13 
6.1.2 
Secondary Endpoints 
• Safety and tolerability based on adverse events (AEs), clinical laboratory values (i.e., 
hematology, serum chemistry, urinalysis, coagulation studies), standard 12-lead ECGs, 
and vital signs 
• Plasma PK of VX-147 
6.1.3 
Exploratory Endpoints 
• Percent change from baseline in UPCR over time during the Treatment Period 
• Percent change from baseline in urine albumin to creatinine ratio (UACR) at Week 13 
• Percent change from baseline in UACR over time during the Treatment Period 
• Change from baseline in patient-reported outcome (PRO) Short Form Health Survey 36 
(SF-36) over time during the Treatment period 
• Change from baseline in SF-36 at 4 weeks after the last dose (Safety Follow-up Visit 
[SFUV]) 
6.2 
Part B (Optional Off-treatment Follow-up Period) 
6.2.1 
Exploratory Endpoints 
• Percent change from baseline in UPCR at the end of the Off-treatment Follow-up Period 
7 
STUDY DESIGN 
7.1 
Overall Design 
This is a single-arm, open-label, 2-part study. In Part A, all subjects will receive VX-147 at a 
dosage of 15 mg qd for 2 weeks and VX-147 at a dosage of 45 mg qd for 11 weeks. Part A will 
be enrolled in 2 cohorts: Cohort 1 and an optional Cohort 2. Cohort 1 includes approximately 
10 subjects with UPCR approximately ≥3 g/g and <10 g/g and eGFR approximately 
≥30 mL/min/1.73 m2. Optional Cohort 2 includes approximately 10 subjects with UPCR 
approximately ≥0.8 g/g and < 2.7g/g and eGFR approximately ≥30 mL/min/1.73 m2.  


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Subjects in Cohort 1 and Cohort 2 are permitted to take a stable low dose of systemic 
corticosteroid (prednisone ≤10 mg per day or prednisone equivalent) and/or an allowed 
immunosuppressant (i.e., tacrolimus, mycophenolate, or cyclosporine). 
Enrollment of Cohort 1 and Cohort 2 will be managed through the interactive web response 
system (IWRS).  
In Optional Part B, subjects will be followed for up to 12 weeks for evaluation of proteinuria off-
treatment (Section 9.1.3 of the CSP). 
All subjects will complete a SFUV at 28 (± 7) days after the last dose of study drug. 
Figure 7-1 
VX19-147-101 Study Design 
 
D: Day; PK: pharmacokinetics; qd: once daily; UPCR: urine protein to creatinine ratio; W: Week 
Notes: The figure is not drawn to scale. After completing Part A, subjects will be followed monthly for up to 
12 weeks or until UPCR returns to baseline, whichever occurs first. All subjects will be required to complete a 
SFUV at 28 (± 7) days after the last dose of study drug. 
a 
Proteinuria will be assessed at multiple timepoints throughout the Treatment Period and Off-treatment 
Follow-up. Triangles represent timepoints for the primary analysis. 
7.2 
Sample Size and Power 
The sample size was not calculated based on power assumptions, because this is an estimation 
study. The primary endpoint is percent change from baseline in UPCR at Week 13. Assuming an 
SD of 0.672 (in log scale), a sample size of 10 subjects will provide a precision of 0.294 (in log 
scale) for the estimation of the Geometric Mean Percent Change (GMPC) from baseline in 
UPCR. The precision of the estimate corresponds to the half width of its 80% confidence interval 
(CI), in log scale. 


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Table 7-1 displays the expected size of the 80% CIs for the GMPC at various values of the 
observed GMPC. Approximately 10 subjects will be enrolled in each cohort. 
Table 7-1         Two-sided 80% Confidence Interval for GMPC from Baseline in UPCR 
Number of 
Subjects 
Completing 
Assumption for 
SD in Log Scale 
Observed Geometric Mean  (corresponding percent reduction from 
baseline) 
0.5 (-50%) 
0.6 (-40%) 
0.7 (-30%) 
0.8 (-20%) 
10 
0.672 
0.37, 0.67  
(-63%, -33%) 
0.45, 0.81  
(-55%, -19%) 
0.52, 0.94  
(-48%, -6%) 
0.60, 1.07  
(-40%, 7%) 
 
7.3 
Randomization 
This is an open-label study. Randomization is not required because all subjects will receive VX-
147. 
7.4 
Blinding and Unblinding 
This is an open-label study. Refer to Section 10.7 of CSP for details. 
8 
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), Follow-up Set 
and Safety Set. 
8.1 
All Subjects Set 
The All Subjects Set will include all subjects who were enrolled in the study. This analysis set 
will be used for all individual subject data listings and disposition summary tables, unless 
otherwise specified. 
8.2 
Full Analysis Set 
The Full Analysis Set (FAS) will include all subjects who received at least 1 dose of study drug 
in the Treatment Period and with at least 1 post-baseline efficacy assessment. The FAS will be 
used to summarize subject demographics and baseline characteristics, and for all efficacy 
analyses in the Treatment Period, unless otherwise specified. 
8.3 
Follow-up Set 
The Follow-up Set will include all subjects who entered the Off-treatment Follow-up Period 
(Part B) and have at least 1 efficacy assessment in that period. The Follow-up Set will be used 
for all efficacy analyses in the Off-treatment Follow-up Period, unless otherwise specified. 


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8.4 
Safety Set 
The Safety Set will include all subjects who received at least 1 dose of study drug. The Safety 
Set will be used to summarize subject demographics and baseline characteristics, and used for all 
safety analyses, unless otherwise specified. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of the CSP. The precision standards for 
reporting variables are provided in an internal Biometrics document that specifies the 
programming rules including the precision for derived variables.  
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). 
Categorical variables will be summarized using counts and percentages. 
Baseline value, unless specified otherwise, 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. For ECGs, 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. 
For systolic and diastolic blood pressure, 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. 
For UPCR (and UACR) data baseline value will be the average of UPCR (UACR) values from 
the 3 urine samples collected during screening for the purpose of assessing eligibility. 
Change (absolute change) from baseline will be calculated as Post-baseline value – Baseline 
value. 
Treatment-emergent (TE) Period will include the time from the first dose of study drug in the 
Treatment Period to either (1) the Safety Follow-up Visit, (2) ETT Visit if it replaces the Safety 
Follow-up Visit, or (3) the date of the last dose + 28 days for subjects who do not have a Safety 
Follow-up Visit. The TE Period will be used for safety analyses unless specified otherwise. 
Unscheduled visits: Data obtained from unscheduled visits will be included in the analysis as 
follows: 


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x In scheduled visit windows per specified visit windowing rules 
x In the derivation of baseline 
x In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values during TE period for safety analyses 
x In individual subject data listings as appropriate 
Visit Window: The analysis visit windows for the protocol-defined visits are provided in 
Appendix A. 
Incomplete or missing data will not be imputed, unless specified otherwise. 
Outliers: No formal statistical analyses will be performed to detect and/or remedy the presence 
of statistical outliers, unless specified otherwise. 
Multiplicity: No multiplicity adjustment will be performed.    
9.2 
Background Characteristics 
9.2.1 
Subject Disposition 
Disposition summary will be provided by cohort and overall.
The number of subjects, based on the All Subject Set, in the following disposition categories, 
will be summarized:
x All Subjects Set 
x Full Analysis Set 
x Safety Set 
x Follow-up Set 
Treatment Period (Part A): The number and percentage of subjects, based on the FAS, in each of 
the following disposition categories, will be summarized: 
x Completed treatment 
x Prematurely discontinued treatment and the reason for discontinuation from treatment 
x Completed Safety Follow-up Visit 
x Completed study 
x Prematurely discontinued the study and the reason for discontinuation from study 
Off-treatment Follow-up Period (Part B): The number and percentage of subjects, based on the 
FAS, in the following disposition categories, will be summarized: 


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x Completed study  
x Prematurely discontinued the study and the reason for discontinuation from study  
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. 
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the FAS by cohort and 
overall.
Demographic data will include the following: 
x Age (in years) 
x Sex (female and male) 
x Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
x Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other, Not collected per local regulations, 
Other, and Multiracial [if more than 2 races reported from a subject]) 
Baseline and disease characteristics will include the following: 
x Weight (kg) 
x Height (cm) 
 
x BMI (kg/m2) 
x APOL1 genotype (G1/G1, G2/G2, or G1/G2) 
x UPCR (g/g) 
x UACR (g/g) 
x eGFR (mL/min/1.73 m2) 
x eGFR (mL/min/1.73 m2) category (<40, ≥40 to <60, ≥60) 
x Systolic blood pressure (mmHg) 
x Diastolic blood pressure (mmHg) 
x Prior medication of any systemic corticosteroid (Yes, No) 
x Prior medication of any immunosuppressants (Yes, No) 


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• Prior medication of any angiotensin converting enzyme (ACE) inhibitor (Yes, No)  
• Prior medication of any angiotensin II receptor blocker (ARB) (Yes, No) 
• Prior medication of any neprilysin inhibitor (Yes, No) 
• Prior medication of any sodium-glucose cotransporter-2 (SGLT2) inhibitor (Yes, No) 
• Prior medication of any diuretic (Yes, No) 
• Prior medication of any renin inhibitor (Yes, No) 
• Prior medication of any statin (Yes, No) 
• Medical history of diabetes  (Yes, No) 
In addition, data listings will also be provided for: 
• Informed consent 
• Inclusion/Exclusion criteria violation for subjects with any such violations 
9.2.3 
Medical History  
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). Medical history will be summarized descriptively based on the FAS by MedDRA 
system organ class (SOC) and preferred term (PT). This summary will be provided by cohort and 
overall. The corresponding data listing will also be provided. 
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary and 
categorized as the following for the purpose of analysis: 
Prior medication: Medication that started before the first dose of study drug, regardless of when 
dosing of the medication ended 
Concomitant medication: Medication continued or newly received on or after the date of the 
first dose of study through the end of 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 a prior and a concomitant; both concomitant and post-treatment; or 
prior, concomitant, and post-treatment medication.  
Note that medication that started before the first dose of study drug and continued after the first 
dose will be categorized as prior medication and separately as concomitant medication. If a 


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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 
medication, and post-treatment medication. 
Missing or partial dates will be imputed for medication. Details for imputing missing or partial 
start and/or stop dates of medication are described in Appendix B. 
Prior medications and Concomitant medications will be summarized based on the FAS by 
Preferred Name. This summary will be provided by cohort and overall. Post-treatment 
medications will only be listed. 
9.2.5 
Study Drug Exposure and Compliance  
Study drug exposure (in days) will be calculated as (last date of dosing – first date of dosing) + 1, 
regardless of study drug interruption, and will be summarized descriptively based on the Safety 
Set by cohort and overall. Study drug exposure (in weeks) will be summarized in categories for 
Treatment Period: ≤1 week, >1 to ≤2 weeks, >2 to ≤3 weeks, >3 to ≤5 weeks, >5 to ≤9 weeks, 
>9 to ≤12 weeks, and >12 weeks using counts and percentages. 
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 is defined as any interruption of the study drug on that day. A study drug interruption that 
continues through the end of the study participation (i.e., subject does not resume study drug 
before the end of the study participation) will not be included in the compliance calculation. 
Study drug compliance will be summarized descriptively based on the FAS by cohort and 
overall. It will also be summarized in categories: <80% and ≥80%, using counts and percentages. 
9.2.6 
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. 
IPDs will be identified by the PD review team according to the protocol deviation plan.  
IPDs will be summarized descriptively by cohort and overall. 
9.3 
Efficacy Analysis 
Efficacy analyses for Treatment Period (Part A) will be based on FAS and efficacy analyses for 
Off-treatment Follow-up Period (Part B) will be based on Follow-up Set, unless specified 


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otherwise. All efficacy analyses will be conducted separately for Cohort 1 and Cohort 2, as well 
as combined. 
9.3.1 
Analysis of the Primary Efficacy Variable 
9.3.1.1 
Definition of the Primary Efficacy Variable 
The primary efficacy endpoint is percent change from baseline in UPCR at Week 13. The Week 
13 UPCR value will be calculated by averaging a maximum of 3 nonmissing UPCR values 
measured within a 7-day period as described in Appendix A. 
9.3.1.2 
Analysis of the Primary Efficacy Variable 
The primary efficacy endpoint will be analyzed based on combined Cohort 1 and Cohort 2. 
Subjects non-compliant with study drug will not be included in the analysis. 
The primary analysis of the primary efficacy endpoint will be based on the following steps: (1) 
Log-transform the UPCR values to reduce skewness; (2) Calculate the mean of the change from 
baseline in log-transformed UPCR, corresponding standard error (SE) and 2-sided 80% CI; (3) 
The geometric mean and geometric standard error (GSE) will be calculated by back-transforming 
(exponential-transform) the corresponding estimates obtained in step (2). GMPC from baseline 
will be obtained as [geometric mean – 1]*100%. The corresponding 2-sided 80% CI will be 
calculated by [back-transforming (exponential-transform) the CI obtained in step (2) – 1]*100%. 
The GMPC from baseline in UPCR at Week 13, GSE (%), along with the corresponding 2-sided 
80% CI will be provided. In addition, the corresponding 2-sided 95% CI will be provided for 
descriptive purposes. 
In addition, the primary efficacy endpoint will also be summarized in a similar way separately 
for Cohort 1 and Cohort 2.  
9.3.1.3 
Supportive Analyses 
There will be no supportive analysis for the primary efficacy endpoint. 
9.3.1.4 
Sensitivity Analysis 
No sensitivity analysis for the primary efficacy variable is planned. 
9.3.1.5 
Subgroup Analysis 
No subgroup analysis for the primary efficacy variable is planned. 


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9.3.2 
Analysis of Exploratory Efficacy Variables 
9.3.2.1 
Definition of Exploratory Efficacy Variable 
UPCR (and UACR) values at Week 5, Week 9 and Week 13 will be calculated as the average of 
the available UPCR (and UACR) measurements (maximum 3) taken during Week 5, Week 9 or 
Week 13 within a 7-day period as described in Appendix A. 
9.3.2.2 
Analyses of Exploratory Efficacy Variable 
Percent change from baseline in UPCR over time during the Treatment Period: Analysis of this 
variable will be based on steps as described for primary analyses in Section 9.3.1.2. Subjects 
non-compliant with study drug will not be included in the analysis. The GMPC from baseline in 
UPCR, GSE (%) along with the corresponding 2-sided 80% CI and 95% CI at each post-baseline 
visit (Week 1, Day 15, Week 3, Week 5, Week 9, and Week 13) will be provided. The GMPC 
from baseline in UPCR at each post-baseline visit during the Treatment Period will also be 
presented in a figure. 
Percent change from baseline in urine albumin-to-creatinine ratio (UACR) at Week 13: Analysis 
of this variable will be conducted in the same way as described for primary analyses 
Section 9.3.1.2. Subjects non-compliant with study drug will not be included in the analysis. The 
GMPC from baseline in UACR at Week 13, GSE (%) along with the corresponding 2-sided 80% 
CI will be provided. 
Percent change from baseline in UACR over time during the Treatment Period: Analysis of this 
variable will be based on steps as described for primary analyses in Section 9.3.1.2. Subjects 
non-compliant with study drug will not be included in the analysis. The GMPC from baseline in 
UACR, GSE (%) along with the corresponding 2-sided 80% CI at each post-baseline visit (Week 
1, Day 15, Week 3, Week 5, Week 9, and Week 13) will be provided. The GMPC from baseline 
in UACR at each post-baseline visit during the Treatment Period will also be presented in a 
figure. 
Percent change from baseline in UPCR at the end of the Off-treatment Follow-up Period: 
Analysis of this variable will be based on steps as described for primary analyses in Section 
9.3.1.2. Subjects non-compliant with study drug will not be included in the analysis. The GMPC 
from baseline in UPCR, GSE (%) along with the corresponding 2-sided 80% CI and 95% CI at 
each visit in Off-treatment Follow-up Period (Part B Week 4, Week 8, and Week 12) will be 
provided. The GMPC from baseline in UPCR at each post-baseline visit during the Off-treatment 
Period will also be presented in a figure. 


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9.4 
Safety Analysis 
All safety analyses will be performed based on the Safety Set by cohort and overall.  
The overall safety profile of VX-147 will be assessed in terms of the following safety and 
tolerability endpoints:  
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (hematology, serum chemistry, coagulation studies, and 
urinalysis) 
• Standard 12-lead ECG outcomes 
• Vital signs 
Only descriptive analyses of safety will be performed, and no statistical hypothesis testing will 
be performed. 
9.4.1 
Adverse Events 
AEs will be coded according to MedDRA. For analysis purposes, AEs will be classified as 
pretreatment AEs and TEAEs as follows: 
Pretreatment AEs: AEs that occurred before the first dose of study drug 
Treatment-emergent AEs: AEs that worsened or started on or after the first dose date of study 
drug through the end of the TE Period 
For AEs with completely missing or partial start dates, if there is no clear evidence that the AEs 
started before or after the first dose of study drug, the AEs will be classified as TEAEs. 
Imputation rules for missing or partial AE start date are defined as Appendix C. 
AE summary tables will be presented only for TEAEs, and will include the following: 
• All TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Related TEAEs 
• Serious TEAEs 


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• Related serious TEAEs 
• TEAEs leading to death 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same AE or a 
continuing AE will be counted once, and only the maximum severity level will be presented in 
the severity summaries, and the strongest relationship level in the relationship summaries.  
All AEs, including pretreatment AEs and TEAEs will be presented in an individual subject data 
listing based on the All Subjects Set. In addition, a listing containing individual subject adverse 
event data for TEAEs leading to treatment discontinuation, TEAEs leading to treatment 
interruption, SAEs and all deaths will be provided separately. 
9.4.2 
Clinical Laboratory  
All statistical analyses of laboratory values will be performed using SI units. For treatment-
emergent laboratory measurements, the observed values and change from baseline values of the 
continuous hematology, chemistry, and coagulation results will be summarized at each visit. 
The number and percentage of subjects with selected test values meeting at least 1 threshold 
analysis criterion event during the TE period will be summarized. The threshold analysis 
criterion shift from baseline will also be summarized for selected laboratory test values. The 
threshold analysis criteria are provided in Appendix D.  
Results of urinalysis and the urine/serum pregnancy test will be in individual subject data listings 
only.  
In addition, a listing of 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. 
9.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided at each visit and time point, as applicable, for the following 
ECG measurements: heart rate (HR; beats per minute [bpm]), PR (msec), RR (msec), QRS 
duration (msec), QT (msec), and QT corrected for HR intervals (QTcF [msec]). In addition, the 
number and percentage of subjects by maximum treatment-emergent value of QT/QTcF 
intervals, categorized as ≤450 msec, >450 msec and ≤480 msec, >480 msec and ≤500 msec, and 
>500 msec, as well as maximum treatment-emergent change from baseline value of QT/QTcF 


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intervals, categorized ≤0 msec, >0 to ≤30 msec, >30 and ≤60 msec, and >60 msec will be 
provided. 
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period will be summarized. The threshold analysis criteria are provided in Appendix D. 
In addition, a listing containing individual subject ECG values will be provided. This listing will 
include data from both scheduled and unscheduled visits. 
9.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each visit. The following vital signs parameters will be 
summarized: systolic and diastolic blood pressure (mm Hg), pulse rate (beats per minute), body 
temperature (°C), and respiratory rate (breaths per minute). 
The number and percentage of subjects meeting a threshold analysis criterion during the TE 
Period will be summarized. The threshold analysis criteria are provided in Appendix D. 
In addition, a listing containing individual subject vital signs values will be provided. This listing 
will include data from both scheduled and unscheduled visits. 
9.4.5 
Physical Examination 
Physical examination (PE) results will be presented in individual subject data listings only. 
9.4.6 
Other Safety Analysis 
Change from baseline in weight (kg) will be summarized at each visit.  
9.4.7 
COVID-19 Impacted Visits  
A listing containing subjects’ visits impacted due to COVID-19 will be provided. 
9.5 
Other Analyses 
9.5.1 
Analysis of SF-36 
SF-36 is a patient-reported generic measure of health status. The questionnaire provides 
information about functional health and wellbeing, as well as 2 psychometrically based physical 
and mental health summary measures. Physical and mental component summary scores will be 
provided by commercially available software, i.e., QualityMetric Health OutcomesTM Scoring 
Software. Analysis of SF-36 will be conducted separately for Cohort 1 and Cohort 2, as well as 
combined. 


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Change from baseline in patient-reported outcome (PRO) Short Form Health Survey 36 (SF-36) 
over time during the Treatment Period: The change from baseline in the SF-36 physical 
component summary scores and the change from baseline in the SF-36 mental component 
summary scores will be summarized descriptively at Week 5 and Week 13. 
Change from baseline in SF-36 at 4 weeks after the last dose (SFUV): The change from baseline 
in the SF-36 physical component summary scores and the change from baseline in the SF-36 
mental component summary scores will be summarized descriptively at 4 weeks after the last 
dose of VX-147. 
10 
INTERIM AND IDMC ANALYSES 
10.1 
Interim Analysis 
Interim analyses may be done at the discretion of the sponsor to allow for regulatory interactions 
and clinical development planning. Interim analyses will be performed and reviewed by an 
independent Vertex team not involved in the conduct of the study. 
Interim analyses will be based on all data included in the IA data cuts.
10.1.1 
General Consideration 
General considerations, reporting conventions, and analysis methods specified for the final 
analysis apply to the IA, unless otherwise specified. 
For the IA, the TE period will include the time period starting from the date of the first dose of 
study drug to either (1) the Safety Follow-up Visit, (2) ETT Visit if it replaces the Safety Follow-
up Visit, (3) the date of the last dose + 28 days for subjects who do not have a Safety Follow-up 
Visit, or (4) the IA data cut date if subjects haven’t completed the Treatment Period or haven’t 
discontinued the study at the time of the IA data cut. 
10.1.2 
Background Characteristics 
Refer to Section 9.2 for summary of background characteristics for IA. In addition, treatment 
ongoing will be summarized as disposition categories for IA.
10.1.3 
Efficacy Analysis 
Refer to Section 9.3 for efficacy analysis for IA. 
10.1.4 
Safety Analysis 
Refer to Section 9.4 for safety analysis for IA. 


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10.1.5 
Other Analysis 
Refer to Section 9.59.4 for other analysis for IA. 
10.2 
Independent Data Monitoring Committee Analysis 
Not applicable. 
11 
REFERENCES 
Not applicable. 
 
 


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12 
APPENDICES 
Appendix A: Analysis Visit Windows for Efficacy, Safety, and Exploratory 
Assessments 
Table 12-1  
Analysis Visit Windows for Efficacy, Safety, and Exploratory Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2, 3, 4, 5 
Efficacy Assessments  
x UPCR 
Baseline 
Week 1 
Day 15 
Week 3 
Week 5 
Week 9 
Week 13 
Part B Week 4 
Part B Week 8 
Part B Week 12 
Not applicable 
8 
15 
22 
36 
64 
92 
120 
148 
176 
൏1 
(1, 11] 
(11, 18] 
(18, 29] 
(29, 50] 
(50, 78] 
(78, 106] 
(106, 134] 
(134, 162] 
(162, 190] 
x UACR 
Baseline 
Week 1 
Day 15 
Week 3 
Week 5 
Week 9 
Week 13 
Not applicable 
8 
15 
22 
36 
64 
92 
൏1  
(1, 11] 
(11, 18] 
(18, 29] 
(29, 50] 
(50, 78] 
(78, 106] 
Safety Assessments  
x Serum Chemistry 
x Hematology 
x Coagulation 
Baseline 
Week 1 
Day 15 
Week 3 
Week 5 
Week 9 
Week 13 
Safety Follow-up 
1 
8 
15 
22 
36 
64 
92 
Not applicable 
൑1 Pre-dose 
[1 Post-dose, 11] 
(11, 18] 
(18, 29] 
(29, 50] 
(50, 78] 
(78, 106] 
Use nominal visit 
x Standard 12-lead 
ECG 
Baseline 
Day 1 (2 hours post dose) 
Week 1  
Day 15 predose 
Day 15 (2 hours post dose) 
Week 3  
Week 5  
Week 9 
Week 13 
Safety Follow-up 
1 
1 
8 
15 
15 
22 
36 
64 
92 
Not applicable 
൑1 Pre-dose 
Nominal visit for all visits  
 


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x Vital Signs 
x Weight 
Baseline 
Week 1 
Day 15 
Week 3 
Week 5 
Week 9 
Week 13 
Safety Follow-up 
1 
8 
15 
22 
36 
64 
92 
Not applicable 
൑1 
[1 Post-dose, 11] 
(11, 18] 
(18, 29] 
(29, 50] 
(50, 78] 
(78, 106] 
Use nominal visit 
Exploratory Assessments 
x SF-36 
Baseline 
Week 5 
Week 13 
Safety Follow-up 
1 
36 
92 
Not applicable 
≤1 
[1 Post-dose, 64] 
(64, 106] 
Use nominal visit 
Notes: 
1Visit name for analysis purpose is used to report data in tables and figures. 
 
2The analysis visit windows will be applied using the following rules for both scheduled and unscheduled 
visits: 
a. If no numerical measurement is available within a visit window, the measurement will be 
considered missing for the visit. 
b. If there is more than 1 numerical measurement available within a visit window, use the following 
rules:  
i. 
The measurement closest to the target day will be used; or  
ii. 
If there are multiple measurements with the same distance from the target day, the latest 
measurement will be used. If the latest measurement cannot be determined, then 
unscheduled visit will be selected. 
iii. 
If there are multiple measurements from the central laboratory and local laboratory with 
the same distance from the target day, the measurement from the central laboratory will 
be used.  
3For measurements collected on the date of first dose of study drug in Treatment Period, if it cannot be 
determined whether the measurement is before or after the first dose: 
a. Scheduled measurement will be treated as pre-dose observation; 
b. Unscheduled measurement will be treated as post-dose observation. 
4For safety assessment, the Safety Follow-up analysis visit will be based on nominal Safety Follow-up 
visit. If a subject doesn’t have a nominal Safety Follow-up visit but has an ETT visit occurs 3 weeks (21 
days) or later following the last dose of study drug, then the ETT visit will be mapped into Safety Follow-
up analysis visit. 
5UPCR and UACR at Week 5, Week 9 and Week 13 will be calculated by averaging maximum 3 
nonmissing UPCR and UACR values measured within a 7-day period within the visit window.  


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a. If there is only 1 assessment within the visit window, use the single value 
b. If there are more than 1 assessment within the visit window:  
i. 
find the earliest assessment within the visit window, and then find the number of 
assessments within 7 days after the earliest assessment;  
ii. 
find the second assessment within the visit window, and then find the number of 
assessments within 7 days after the second assessment;  
iii. 
find the third assessment within the visit window, and then find the number of assessments 
within 7 days after the third assessment, if applicable;  
iv. 
Compare the number of assessments from step i to iii, use the assessments from the step 
that has the maximum number. If number of assessments are the same from multiple steps, 
then use the step with the first assessment closest to target study day. 
 
Derived Variable: 
1. Missing first dose date or last dose date 
• 
If the first dose date is missing, use Day 1 visit date to impute. 
• 
If the last dose date is missing or partial date is reported, the last dose date will be 
imputed based on, in descending order priority, the Early Treatment Termination (ETT) 
visit date, last visit date before the Safety Follow-up, or the last study drug administration 
date from EC SDTM domain, as appropriate. The imputation algorithm will ensure the 
imputed last dose date does not exceed the study participation end date. 
2. Electrocardiogram: 
If ECGs are performed in triplicate at any visit and timepoint: 
• 
For summary purpose, the average of these ECGs at a specific visit and time point will be 
used as the ECG for that specific visit and time point. 
• 
For threshold analysis purpose, all reported ECG values will be used. 
3. Systolic and diastolic blood pressures: 
If systolic and diastolic blood pressures are performed in triplicate at any visit: 
• 
For summary purpose, the average of these systolic and diastolic blood pressures at a 
specific visit will be used as the systolic and diastolic blood pressures for that specific 
visit. 
• 
For threshold analysis purpose, all reported systolic and diastolic blood pressures will be 
used. 
 




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Appendix C: Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date are defined below. If the imputed AE start 
date is before the study informed consent date, the AE start date will be imputed using the study 
informed consent date. 
• If only Day of AE start date is missing:  
o If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then  
 if AE start year and month are equal to the month and year of first dose date, 
then impute the AE start day as the day of first dose date;  
 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 or TEAE. 
• 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 or AE end date is 
missing, then  
  
if AE start year is equal to the year of first dose date, then impute the AE 
start month and day as the month and day of first dose date;  
  
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 or TEAE. 
• 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. 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the first dose date.  
o else impute the AE start date as the informed consent date. 
Missing or partially missing AE end date will not be imputed. 
 
 


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Appendix D: Criteria for Threshold Analysis 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry 
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>20xULN 
FDA DILI Guidance Jul 2009. 
Alkaline Phosphatase 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5 - ≤5.0xULN 
>5.0 - ≤20.0xULN 
>20.0xULN 
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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Table 12-3 
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 
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 
Creatine kinase 
>ULN - ≤2.5xULN 
>2.5 - ≤5xULN 
>5 - ≤10xULN  
>10xULN 
CTCAE grades 1-4 
 
Cholesterol 
<5.18 mmol/L 
≥5.18 - <6.22 mmol/L 
≥6.22 mmol/L 
ATP III guideline 
Triglycerides 
<1.70 mmol/L 
≥1.70 - <2.26 mmol/L 
≥2.26 - <5.65 mmol/L 
≥5.65 mmol/L 
ATP III guideline 
HDL Cholesterol 
<1.04 mmol/L 
≥1.04 - <1.55 mmol/L 
≥1.55 mmol/L 
ATP III guideline 
LDL Cholesterol 
<2.59 mmol/L 
≥2.59 - <3.37 mmol/L 
≥3.37 - <4.14 mmol/L 
≥4.14 - <4.92 mmol/L 
≥4.92 mmol/L 
ATP III guideline 
Hematology 


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Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥100 g/L 
<100 - ≥80 g/L  
<80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤20 g/L above ULN 
>20 g/L above ULN - ≤40 g/L above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥75.0 x 10e9 /L 
<75.0 - ≥50.0 x 10e9 /L  
<50.0 - ≥25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 
Reticulocytes/Erythrocytes (%)    
<LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated partial thromboplastin 
time (PTT)  
 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5xULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5 x ULN* 
CTCAE grade 1-3 
* ULN for patient taking oral anticoagulant will be used. 
Table 12-4 
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 
 
 


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Table 12-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
 
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 
 
>450 to <500ms (Male) or >470 to <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.  
 
 
 
 
 
Table 12-5    Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Pulse Rate 
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 


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Table 12-5    Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
SBP decrease 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from baseline 
<90 mmHg and >20 mmHg decrease from baseline 
<80 mmHg and >10 mmHg decrease from baseline 
<80 mmHg and >20 mmHg decrease from baseline 
Per HV grade 1, 3, plus shift change 
DBP 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