Clinical trial NCT05661734
Conditions: Pain
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2023-01-09; Completion date: 2023-12-12
Enrollment: 258 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety and effectiveness of VX-548 in treating acute pain.

Detailed description:

Arms: arm 1: Participants received SUZ 100 milligram (mg) as first dose, followed by SUZ 50 mg every 12 hours (q12h) for 14 days or until pain resolves, whichever occurs first.
Interventions: intervention 1: Suzetrigine
Intervention descriptions: intervention 1: Tablets for oral administration.

Protocol documents:
Prot_000.pdf: 
Page 1 of 62 
 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 3, Single-arm Study Evaluating the Safety 
and Effectiveness of VX‑548 for Acute Pain 
Vertex Study Number: VX22-548-107 
IND Number: 146185 
Date of Protocol: 09 November 2022 (Version 2.0) 
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 
 
 
 
 
 


Protocol VX22-548-107, Version 2.0 
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Summary of Changes to the Protocol 
The previous version of this protocol (Version 1.1, 21 September 2022) was amended to create 
the current version (Version 2.0, 09 November 2022). The protocol history is below. 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.1, 21 September 2022 
Original version 
Version 2.0, 09 November 2022 
Current version 
 
Key changes in the current version of the protocol are summarized below. 
Change and Rationale 
Affected Sections  
Added postdose ECGs at additional study visits and provided 
instructions on withholding a study drug dose on these days if 
needed. 
Section 3 and Section 9.6 
Added exclusion criteria for history of QT prolongation or 
standard 12-lead ECG demonstrating median QTcF >450 msec 
at screening or baseline. 
Section 8.2, Exclusion Criteria 4 and 30 
Added study drug interruption and stopping rules. 
Section 9.8 
Based on available clinical data from Study VX21-548-011, 
updated to allow study drug to be taken with or without food 
after the first dose. 
Section 3 (Table 3-4), Section 9.4, and 
Section 9.6 
Added telephone contact on Day 4 to assess the subject’s 
status, any adverse events, concomitant medications, 
treatments, and procedures at an additional time point. 
Section 3 (Table 3-4) 
Updated End of Dosing Visit to occur as soon as possible after 
pain resolution criteria are met instead of as soon as possible 
after the subject decides to stop study drug treatment. 
Section 3 (Table 3-4) 
Clarified that discharge assessments should be completed for 
all surgical subjects and for any non-surgical subjects who 
required inpatient admission. 
Section 3 (Table 3-4) 
Clarified that PGA should still be completed even if a study 
drug dose is missed (e.g., forgotten). 
Section 3 (Table 3-4) and Section 11.5.4 
Clarified definition of study drug treatment completion for 
subjects who stop less than 48 hours before the last scheduled 
dose of study drug. 
Section 9.1 
Added a requirement for medical monitor to authorize all cases 
of screening assessment repetition. 
Section 9.1.1.1 
Updated rescue medication documentation such that subjects 
will continue documentation through Study Day 14 or the End 
of Dosing Visit, whichever occurs first.  
9.4.1.2 
Updated such that documentation of all medications 
administered in-clinic, including prior medications, will 
include the time of each administration. Also specified that 
non-surgical subjects should provide the estimated time of 
administration for any medications taken on Day 1 before 
arriving at the medical facility. 
Section 9.4.2 


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Change and Rationale 
Affected Sections  
Updated study drug dosing window of ± 1 hour around q12h to 
be with respect to the most recent dose rather than based on the 
first dose of study drug. 
Section 9.6 
Clarified procedures for ECG safety monitoring after the first 
dose of study drug and added a window for postdose ECGs. 
Section 11.5.4 
Updated the contraception requirements to use of at least 
1 acceptable method of contraception based on supporting 
nonclinical data; updated requirements for suspected 
postmenopausal subjects with pending FSH data, accordingly.  
Section 11.5.6.1; Section 3 (Table 3-3) and   
Section 11.5.2 
Updated list of representative ineligible surgical procedures. 
Appendix A 
PGA: patient global assessment; q12h: every 12 hours 
Typographical and administrative changes were also made to improve the clarity of the 
document. 


Protocol VX22-548-107, Version 2.0 
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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3, Single-arm Study Evaluating the Safety and Effectiveness of VX‑548 
for Acute Pain 
  
Brief Title 
A Single-arm Study to Evaluate Safety and Effectiveness of VX-548 for Acute 
Pain 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 3, safety and effectiveness 
 
 
Objectives 
Primary Objective 
To evaluate the safety and tolerability of VX-548 
Secondary Objective 
To evaluate the effectiveness of VX-548 in treating acute pain 
 
 
Endpoints 
Primary Endpoint 
Safety and tolerability based on treatment-emergent adverse events (TEAEs), 
laboratory test results, vital signs, and ECGs 
Secondary Endpoint 
Subject perception of VX-548 effectiveness in treating pain at the end of treatment 
as measured by the proportion of subjects reporting good, very good, or excellent 
on a patient global assessment (PGA)  
 
 
Number of Subjects 
Approximately 250 subjects 
 
 
Study Population 
Male and female subjects between the ages of 18 and 80 years, inclusive, with 
pain that is moderate or severe on a verbal categorical rating scale (VRS) and 
≥4 on a numeric pain rating scale (NPRS) resulting from any of the 
protocol-defined representative ambulatory surgical procedures (e.g., inguinal 
hernia repair, hemorrhoidectomy, or shoulder arthroscopy) or non-surgical 
conditions (e.g., traumatic acute musculoskeletal pain), with pain that is expected 
to last for at least 72 hours and that is expected to require no more than a 
short-term (i.e., <24-hour) admission, if any. 
 
 
Investigational Drug 
Active substance: VX-548 
 
Activity: voltage-gated sodium channel 1.8 (NaV1.8) inhibitor 
 
Strength and route of administration: 50-mg tablets for oral administration 
 
 
Study Duration 
Excluding the Screening Period, each subject will participate in the study for 
28 ± 2 days, including up to 14 days of treatment with VX-548. 
 
 


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Study Design 
This is a Phase 3, single-arm study evaluating the safety and effectiveness of 
VX-548 in treating acute pain (Figure 2-1 [surgical subjects] and Figure 2-2 
[non-surgical subjects]). 
Figure 2-1 
VX22-548-107 Study Design (Surgical Subjects) 
 
NPRS: numeric pain rating scale; VRS: verbal categorical rating scale 
Notes: After surgery completion, a subject will be assigned to treatment if (1) the subject 
requests the first dose of study drug for pain relief, (2) the subject’s pain is moderate 
or severe on the VRS, and (3) the subject’s pain is ≥4 on the NPRS. If a subject does 
not meet the VRS and NPRS criteria within the protocol-specified, procedure-specific 
time period, the subject will not be eligible for this study. Figure is not drawn to scale. 
 
Figure 2-2 
VX22-548-107 Study Design (Non-surgical Subjects) 
 
NPRS: numeric pain rating scale; VRS: verbal categorical rating scale 
Notes: After completion of screening assessments and confirmation of eligibility, a subject 
will be assigned to treatment if (1) the subject’s pain is moderate or severe on the 
VRS, and (2) the subject’s pain is ≥4 on the NPRS. Figure is not drawn to scale. 
Surgical Subjects 
On Day 1, subjects will undergo a scheduled ambulatory surgical procedure with 
pain that is expected to last for at least 72 hours and that is expected to require no 
more than a short-term (i.e., <24-hour) admission. After surgery completion, a 
subject will be assigned to treatment if (1) the subject requests the first dose of 
study drug for pain relief, (2) the subject’s pain is moderate or severe on the VRS, 
and (3) the subject’s pain is ≥4 on the NPRS. If a subject does not meet the VRS 
and NPRS criteria within the protocol-specified time period for the surgical 
procedure they underwent (e.g., 4 hours for most procedures), the subject will not 
be eligible for this study. 
 


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Non-surgical Subjects 
On Day 1, after completion of screening assessments and confirmation of 
eligibility, a subject will begin treatment if (1) the subject’s pain is moderate or 
severe on the VRS, and (2) the subject’s pain is ≥4 on the NPRS. For a subject to 
be eligible, their pain must have been ongoing for ≤48 hours at presentation. 
All Subjects 
Approximately 250 subjects will receive VX-548 (100 mg first dose, then 50 mg 
every 12 hours [q12h]). Subjects will continue to receive VX-548 for 14 days or 
until their pain resolves, whichever occurs first. An acetaminophen/ibuprofen 
combination may be used as a rescue medication for pain relief as needed (prn), 
starting any time after the first dose of study drug through Day 14, completion of 
study drug treatment due to pain resolution, or study drug discontinuation, 
whichever occurs first. Subjects will be permitted to take acetaminophen 
650 mg/ibuprofen 400 mg every 6 hours (q6h) prn, up to a maximum of 
2600 mg/1600 mg in any 24-hour period. 
The following approach will be used to define pain resolution and completion of 
study drug treatment: 
1. Pain is considered to be resolved and the study drug treatment will be 
considered completed if 
a. 
a subject takes no study drug during a 48-hour period (i.e., skipped at 
least 4 consecutive doses due to pain resolution); and 
b. a subject takes no more than 1 dose of acetaminophen/ibuprofen during 
each 24-hour period within the 48-hour period (i.e., no more than 2 doses 
in 48 hours). 
2. If a subject stops taking study drug per Criterion 1a but does not meet 
Criterion 1b, they will be instructed to restart study drug (and prn rescue 
medication). 
3. If a subject stops and restarts study drug (Criterion 2 above) and subsequently 
believes their pain is resolving and stops study drug a second time, they will 
be instructed to not restart study drug, regardless of whether the above 
criteria are met. 
4. If a subject stops study drug a second time after the restart of dosing 
(Criterion 3 above) and then fulfills both Criterion 1a and 1b, the pain is 
considered resolved and study drug treatment will be considered completed. 
If the subject fulfills only Criterion 1a but not Criterion 1b after the restart of 
dosing, the pain is considered not resolved and study drug will be considered 
discontinued. 
Note: If subject stops study drug due to pain resolution less than 48 hours before 
the last scheduled dose of study drug (i.e., stops after the second dose on Day 12) 
and therefore cannot meet Criterion 1a by Day 14, the subject will be considered 
to have completed study drug dosing as long as they also meet Criterion 1b. 
 
 
Assessments 
Safety: adverse events (AEs); clinical laboratory assessments; clinical evaluation 
of vital signs, standard 12-lead ECGs, and physical examinations; and 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Effectiveness: PGA of study drug  
Other: use of rescue medications 
 
 


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Statistical Analyses 
Sample size: Approximately 250 subjects are planned to be enrolled. With 
250 subjects, there is a 92% probability of observing an AE in at least 1 subject if 
the true incidence is 1% and a 99% probability of observing an AE in at least 
1 subject if the true incidence is 2%.   
Descriptive summary analyses will be performed. 


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are in Table 3-1 (surgical subjects), Table 3-2 (surgical subjects), 
Table 3-3 (non-surgical subjects), and Table 3-4 (all subjects). 
Table 3-1 
Study VX22-548-107: Screening Through Admission (Surgical Subjects) 
Event/Assessmenta 
Day -28 to Day -1 
Day 1 
 
Comments 
Screening 
Pre-procedure 
Informed consent  
X 
 
Must be obtained before performing any 
study-related procedures. Remote consent may 
be used if permitted by local regulations; 
Section 13.2.3. 
Clinic or home health visit 
X 
 
Subjects will have the option to complete this 
visit in the clinic or to have a home health visit. 
Home health visits are only an option if 
permitted by local regulations; Section 9.1.1. 
Telemedicine video conference 
or telephone contact 
(X) 
 
A consultation between the subject and 
investigator or qualified delegate (LIP) must be 
performed within 2 business days after the 
home health visit (must be within screening 
window) and may also include a separate follow-
up with the study coordinator. Required only for 
subjects who have a home health visit; not 
required for subjects who have a clinic visit; 
Section 9.1.6. 
Admission for surgery 
(e.g., hospital or ambulatory 
surgical center) 
 
X 
Upon completion of pre-procedure eligibility 
assessments; Section 8. 
Demographics 
X 
 
Section 11.1 
Medical and surgical history 
X 
 
Section 11.1 
History of drug and alcohol use 
X 
 
Section 8.2 
Vital signs 
X 
X 
Vital signs will be collected after the subject has 
been at rest (seated or supine) for at least 
5 minutes and before any 12-lead ECG 
assessment or blood sampling; Section 11.5.3. 
Standard 12-lead ECG 
X 
X 
Performed in triplicate after the subject has been 
at rest (supine) for at least 5 minutes; 12-lead 
ECGs will be done after taking vital signs and 
before any procedures that may affect heart rate 
(e.g., blood sampling); Section 11.5.4. 
PE 
X 
(X) 
Section 11.5.3 
Screening Visit: A complete PE will be 
performed if the visit occurs in clinic. An 
abbreviated PE will be performed if the visit 
occurs via home health. 
Day 1: A complete PE will be performed only if 
the Screening Visit occurs via home health. 
Otherwise, no PE is required. 
Weight, height, and BMI 
X 
 
Weight and height will be measured with shoes 
off. 
C-SSRS 
 
X 
Section 11.5.5 
Serology (HBsAg, HCV Ab, 
HCV RNA, and HIV-1/HIV-2 
Abs) 
X 
 
Section 11.5.2 
Serum β-hCG 
X 
 
All biologically female subjects; Section 11.5.2. 


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Table 3-1 
Study VX22-548-107: Screening Through Admission (Surgical Subjects) 
Event/Assessmenta 
Day -28 to Day -1 
Day 1 
 
Comments 
Screening 
Pre-procedure 
Serum FSH  
X 
 
Suspected postmenopausal female subjects only; 
Section 11.5.2 
Serum chemistry 
X 
 
Section 11.5.2 
Hematology 
X 
 
Coagulation 
X 
 
Urinalysis 
X 
 
Drug test  
X 
X 
Urine; Section 11.5.2 
Day 1: Testing kit assessed by staff onsite.  
Urine β-hCG  
 
X 
All female subjects of childbearing potential. 
Assessed by staff onsite; Section 11.5.2. 
Alcohol test  
 
X 
Urine, blood, or breath. Assessed by staff onsite; 
Section 11.5.2. 
Research subject 
responsibilities and pain 
assessment trainings 
X 
X 
Section 9.1.1 
Medications review 
Continuous from signing of ICF 
through completion of study 
participation 
All medications taken within 14 days before the 
Screening Visit through completion of study 
participation; Section 9.4.2. 
Nonpharmacological treatment 
and procedures review 
Continuous from signing of ICF 
through completion of study 
participation 
All nonpharmacological treatments and 
procedures starting from the Screening Visit. 
Adverse events 
Continuous from signing of ICF 
through completion of study 
participation 
Section 11.5.1 
β-hCG: beta-human chorionic gonadotropin; BMI: body mass index; C-SSRS: Columbia-Suicide Severity Rating Scale; 
FSH: follicle-stimulating hormone; HbsAg: hepatitis B surface antigen; HCV Ab: hepatitis C virus antibody; 
HIV-1/HIV-2 Abs: antibodies against human immunodeficiency viruses 1 and 2; ICF: informed consent form; 
LIP: licensed independent practitioner; PE: physical examination 
Note: Assessments denoted by “(X)” are performed in the situations defined in the Comments column. 
a 
When assessment time points coincide, assessments will be performed in the following order: vital signs, 12-lead ECG, 
PE, and blood sample collection. 
 


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Table 3-2 
Study VX22-548-107: Procedure Through Treatment Assignment 
(Surgical Subjects) 
Event/Assessment 
Day 1 
Comments 
Procedure Through 
Treatment Assignment/ 
Predosea 
Inpatient (e.g., hospital or 
ambulatory surgical center) 
X 
 
Procedure 
X 
Section 9.1 and Appendix A 
Fasting period 
X 
No food or drink (except ≤8 fluid ounces of water per hour) 
from time of surgery completion through 2 hours after the first 
dose of study drug; Section 9.4.2. 
Record supplemental 
analgesic medication 
X 
Pain medications given postoperatively through time subject is 
assigned to treatment will be recorded. Refer to Section 9.4.1 
for permitted pain medication. 
Vital signs 
X 
Performed after surgery completion (at least 1 hour after 
surgery completion is recommended) before the first dose of 
study drug. Vital signs will be collected after a ≥5-minute rest 
(seated or supine) and before any 12-lead ECG assessment or 
blood sampling; Section 11.5.3. 
Standard 12-lead ECG 
X 
Performed after surgery completion (at least 1 hour after 
surgery completion is recommended) before the first dose of 
study drug. Standard 12-lead ECGs will be performed in 
triplicate after a ≥5-minute rest (supine); these will be done 
after taking vital signs and before any procedures that may 
affect heart rate (e.g., blood sampling); Section 11.5.4. 
VRS 
X 
Completed upon request for the first dose of study drug for 
pain relief after surgery completion; Section 9.1.2. 
NPRS 
X 
Completed immediately after the VRS only if the subject’s 
pain is rated moderate or severe on the VRS; Section 9.1.2. 
Medications review 
Continuous from signing of 
ICF through completion of 
study participation  
All medications taken within 14 days before the Screening 
Visit through completion of study participation; Section 9.4.2. 
Nonpharmacological 
treatment and procedures 
review 
Continuous from signing of 
ICF through completion of 
study participation 
All nonpharmacological treatments and procedures starting 
from the Screening Visit. 
Adverse events 
Continuous from signing of 
ICF through completion of 
study participation 
Section 11.5.1 
ICF: informed consent form; NPRS: numeric pain rating scale; VRS: verbal categorical rating scale 
a 
Subject must complete all Day 1 predose assessments before the first dose of study drug is administered. When 
assessment time points coincide, assessments will be performed in the following order: vital signs, 12-lead ECG, and 
blood sample collection. 


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Table 3-3 
Study VX22-548-107: Screening Through Treatment Assignment 
(Non-surgical Subjects) 
Event/Assessmenta 
Screening Visit/Day 1 
 
Comments 
Screening Through 
Treatment Assignment 
Presents with pain at medical 
facility (e.g., hospital, clinic, or 
ambulatory center) 
X 
Section 9.1 
Informed consent  
X 
Must be obtained before performing any study-related 
procedures; Section 13.2.3. 
Demographics 
X 
Section 11.1 
Medical and surgical history 
X 
Section 11.1 
History of drug and alcohol use 
X 
Section 8.2 
Vital signs 
X 
Vital signs will be collected after the subject has been at 
rest (seated or supine) for at least 5 minutes and before 
any 12-lead ECG assessment or blood sampling; 
Section 11.5.3. 
Standard 12-lead ECG 
X 
Performed in triplicate after the subject has been at rest 
(supine) for at least 5 minutes; 12-lead ECGs will be 
done after taking vital signs and before any procedures 
that may affect heart rate (e.g., blood sampling); 
Section 11.5.4. 
Complete PE 
X 
Section 11.5.3 
Weight, height, and BMI 
X 
Weight and height will be measured with shoes off. 
C-SSRS 
X 
Section 11.5.5 
Urine β-hCG 
X 
All biologically female subjects. Assessed by staff 
onsite; Section 11.5.2. 
Serum FSH  
X 
Suspected postmenopausal female subjects only; 
Section 11.5.2. A test result is not required for eligibility; 
however, until the test result is received, a subject will be 
considered to be of childbearing potential and must 
follow contraception requirements (Section 11.5.6.1) 
until postmenopausal status is confirmed. 
Serum chemistry 
X 
Section 11.5.2. Test results are required for eligibility; a 
local laboratory will be used. Previous test results from 
the facility’s local laboratory may be used to establish 
eligibility if collected within 2 hours before ICF signing. 
Hematology 
X 
Coagulation 
X 
Urinalysis 
X 
Drug test  
X 
Urine. Testing kit assessed by staff onsite; Section 11.5.2 
Alcohol test  
X 
Urine, blood, or breath. Assessed by staff onsite; 
Section 11.5.2. 
Research subject responsibilities 
and pain assessment trainings 
X 
Section 9.1.1 
VRS 
X 
Completed before treatment assignment; Section 9.1.1. 
NPRS 
X 
Completed immediately after the VRS and before 
treatment assignment only if the subject’s pain is rated 
moderate or severe on the VRS; Section 9.1.1. 
Medications review 
Continuous from signing 
of ICF through completion 
of study participation 
All medications taken within 14 days before the 
Screening Visit through completion of study 
participation; Section 9.4.2. 


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Table 3-3 
Study VX22-548-107: Screening Through Treatment Assignment 
(Non-surgical Subjects) 
Event/Assessmenta 
Screening Visit/Day 1 
 
Comments 
Screening Through 
Treatment Assignment 
Nonpharmacological treatment and 
procedures review 
Continuous from signing 
of ICF through completion 
of study participation 
All nonpharmacological treatments and procedures 
starting from the Screening Visit. 
Adverse events 
Continuous from signing 
of ICF through completion 
of study participation 
Section 11.5.1 
β-hCG: beta-human chorionic gonadotropin; BMI: body mass index; C-SSRS: Columbia-Suicide Severity Rating Scale; 
FSH: follicle-stimulating hormone; ICF: informed consent form; PE: physical examination 
a 
When assessment time points coincide, assessments will be performed in the following order: vital signs, 12-lead ECG, 
PE, and blood sample collection. 
 


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Table 3-4 
Study VX22-548-107: Treatment Period and Safety Follow-up Visit (All Subjects) 
Event/Assessmenta 
Day 1 
Day 2 
Dischargeb 
Day 4 
(± 1 day) 
Day 7  
(± 1 day) 
Day 14 
(+ 3 days) 
End of 
Dosing Visitc 
Safety 
Follow-up Visit 
Day 28 
(± 2 days) 
Comments 
Inpatient (e.g., hospital or 
ambulatory center), if required, 
or visit at medical facility 
X 
(X) 
 
 
 
 
 
 
Non-surgical subjects are generally 
not anticipated to require 
admission. 
Discharge (e.g., from hospital or 
ambulatory center), if required, 
or leaving medical facility 
X 
 
 
 
 
 
Discharge/leaving will be per 
clinical judgement. Although the 
inpatient period, if any, is generally 
expected to be <24 hours, subjects 
who turn out to require a stay of 
≥24 hours do not need to 
discontinue study drug treatment or 
the study; Section 9.1.3. 
Telephone contact 
 
 
 
X 
 
 
 
 
Assess the subject’s status, any 
AEs, concomitant medications, 
treatments, and procedures 
Clinic or home health visit 
 
 
 
 
X 
 
 
X 
Subjects will have the option to 
complete these visits in the clinic 
or to have a home health visit. 
Home health visits are only an 
option if permitted by local 
regulations; Section 9.1.6. 
Telemedicine video conference 
or telephone contact 
 
 
 
 
(X) 
 
 
(X) 
A consultation between the subject 
and investigator or qualified 
delegate (LIP) must be performed 
within 2 business days after the 
home health visit (can be outside 
the visit window) and may also 
include a separate follow-up with 
the study coordinator. Required 
only for subjects who have a home 
health visit; not required for 
subjects who have a clinic visit; 
Section 9.1.6. 
Clinic visit 
 
 
 
 
 
X 
X 
 
 


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Table 3-4 
Study VX22-548-107: Treatment Period and Safety Follow-up Visit (All Subjects) 
Event/Assessmenta 
Day 1 
Day 2 
Dischargeb 
Day 4 
(± 1 day) 
Day 7  
(± 1 day) 
Day 14 
(+ 3 days) 
End of 
Dosing Visitc 
Safety 
Follow-up Visit 
Day 28 
(± 2 days) 
Comments 
PGA  
 
X 
 
 
X 
X 
X 
 
Recorded in the e-diaryd; 
Section 11.4.1. Subjects should 
still complete the PGA even if the 
specified dose is not taken. 
Day 2: To be completed after the 
third study drug dose 
(approximately 24 hours after the 
first dose). 
Day 7: Completed after the first 
study drug dose on Study Day 7 
(whether or not this coincides with 
the date of the Day 7 Visit). 
Day 14 or EDV: Completed after 
final study drug dose for subjects 
still taking study drug on Day 14. 
Subjects who have discontinued or 
completed study drug treatment 
should complete the PGA at home 
within approximately 24 hours 
after the last (or presumed last) 
dose of study drug rather than 
waiting for their scheduled visit.  
Vital signs 
 
 
X 
(postdose)b 
 
X 
X 
X 
X 
Vital signs will be collected after a 
≥5-minute rest (seated or supine) 
and before any 12-lead ECG 
assessment or blood sampling; 
Section 11.5.3. 
Standard 12-lead ECG 
X (4 hours after first dose and  
at discharge or before leaving medical 
facility, as applicable) 
 
X  
(4 hours 
after a 
dose)e 
X  
(4 hours 
after a 
dose)e,f 
X 
(X) 
Required at SFU only if any 
clinically significant abnormalities 
were noted on a prior ECG. 
Standard 12-lead ECGs will be 
performed in triplicate after a 
≥5-minute rest (supine); these will 
be done after taking vital signs and 
before any procedures that may 
affect heart rate (e.g., blood 
sampling); Section 11.5.4. 


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Table 3-4 
Study VX22-548-107: Treatment Period and Safety Follow-up Visit (All Subjects) 
Event/Assessmenta 
Day 1 
Day 2 
Dischargeb 
Day 4 
(± 1 day) 
Day 7  
(± 1 day) 
Day 14 
(+ 3 days) 
End of 
Dosing Visitc 
Safety 
Follow-up Visit 
Day 28 
(± 2 days) 
Comments 
Symptom-directed PE 
As applicable 
 
Symptom-directed PEs will occur 
at any time during the study if 
triggered by AEs or if deemed 
necessary by the investigator; 
Section 11.5.3. 
Focused PE (surgical subjects 
only) 
 
X 
Assessment of wound healing at 
the operative site; Section 11.5.3. 
Complete PE 
 
(X) 
Required at SFU only if a clinical 
finding during the Treatment 
Period requires follow up, in which 
case the subject must have a clinic 
visit; Section 11.5.3. 
C-SSRS 
 
 
X 
(postdose)b 
 
X 
X 
X 
 
Section 11.5.5 
Urine β-hCG 
 
 
 
 
 
X 
X 
X 
All female subjects of childbearing 
potential; Section 11.5.2. 
Serum chemistry 
 
 
X 
(postdose)b 
 
 
X 
X 
(X) 
Required at SFU only if a clinical 
finding during the Treatment 
Period requires follow up; 
Section 11.5.2. 
Hematology  
 
 
X 
(postdose)b 
 
 
X 
X 
(X) 
Coagulation 
 
 
X 
(postdose)b 
 
 
X 
X 
(X) 
Urinalysis 
 
 
X 
(postdose)b 
 
 
X 
X 
(X) 
Fasting period 
X (first 
dose only) 
 
 
 
 
 
 
 
First dose: for at least 1 hour 
before (surgical subjects: starting 
from time of surgery completion) 
through 2 hours after, no food or 
drink (except ≤8 fluid ounces of 
water per hour); Section 9.4.2.  
VX-548 dosing  
Day 1 through Day 14g (q12h) or until pain resolves, whichever occurs first 
 
Subjects will record the date and 
time of administration in an 
e-diaryd; Section 9.6. 
Rescue medication use 
Day 1 through Day 14, completion of study drug treatment due to pain resolution, or study drug 
discontinuation, whichever occurs first 
 
Subjects will record the date and 
time of administration in an 
e-diaryd; Section 9.4.1.2. 
Study drug count 
 
 
X 
X 
X 
 
 
Adverse events 
Continuous from signing of ICF through completion of study participation 
Section 11.5.1 


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Table 3-4 
Study VX22-548-107: Treatment Period and Safety Follow-up Visit (All Subjects) 
Event/Assessmenta 
Day 1 
Day 2 
Dischargeb 
Day 4 
(± 1 day) 
Day 7  
(± 1 day) 
Day 14 
(+ 3 days) 
End of 
Dosing Visitc 
Safety 
Follow-up Visit 
Day 28 
(± 2 days) 
Comments 
Medications review 
Continuous from signing of ICF through completion of study participation 
All medications taken within 
14 days before the Screening Visit 
through completion of study 
participation; Section 9.4.2. 
Nonpharmacological treatment 
and procedures review 
Continuous from signing of ICF through completion of study participation 
All nonpharmacological treatments 
and procedures starting from the 
Screening Visit. 
AE: adverse event; β-hCG: beta-human chorionic gonadotropin; C-SSRS: Columbia-Suicide Severity Rating Scale; e-diary: electronic diary; EDV: End of Dosing Visit; ICF: informed consent form; 
LIP: licensed independent practitioner; PE: physical examination; PGA: patient global assessment; q12h: every 12 hours; SFU: Safety Follow-up 
Note: Assessments denoted by “(X)” are performed in the situations defined in the Comments column. 
a 
When assessment time points coincide, assessments will be performed the following order: C-SSRS, vital signs, 12-lead ECG, PE, and blood sample collection. 
b 
Discharge assessments should be completed for all surgical subjects and for any non-surgical subjects who required inpatient admission. 
c 
If a subject discontinues or completes study drug treatment for any reason before Day 14, including AEs (considered treatment discontinuation) or reaching pain resolution (considered treatment 
completion), an EDV should be scheduled to occur as soon as possible after treatment discontinuation or after pain resolution criteria are met (as applicable), and the Day 14 Visit will not be 
required. If the EDV occurs within or prior to the Day 7 visit window, the Day 7 Visit will also not be required. Subjects who discontinue or complete study drug treatment before Day 14 will be 
required to complete the Safety Follow-up Visit. In the unlikely event that the EDV is delayed and occurs 28 days or later following the first dose of study drug, then a separate Safety Follow up 
Visit will not be required. 
d 
For all e-diary assessments, a paper version will be available as a back-up option. 
e 
Refer to Section 9.6 for instructions on dose and visit scheduling on days of postdose ECGs. 
f 
Subjects who have their Day 14 Visit after Study Day 14 (per the visit window) and thus are no longer taking study drug will have an ECG any time that day rather than 4 hours postdose.  
g 
For subjects who remain on study drug treatment at Day 14, only 1 dose of study drug should be taken on that day, and it will be the last dose of study drug for these subjects. 
 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
Summary of Changes to the Protocol......................................................................................... 2 
2 
Protocol Synopsis ................................................................................................................... 4 
3 
Schedule of Assessments........................................................................................................ 8 
4 
Table of Contents ................................................................................................................. 17 
List of Tables............................................................................................................................ 20 
List of Figures .......................................................................................................................... 20 
List of Abbreviations................................................................................................................ 21 
5 
Introduction.......................................................................................................................... 23 
5.1 
Background ..................................................................................................................... 23 
5.2 
Study Rationale .............................................................................................................. 23 
6 
Study Objectives .................................................................................................................. 23 
6.1 
Primary Objective ........................................................................................................... 23 
6.2 
Secondary Objective ....................................................................................................... 23 
7 
Study Endpoints ................................................................................................................... 24 
7.1 
Primary Endpoint ............................................................................................................ 24 
7.2 
Secondary Endpoint ........................................................................................................ 24 
8 
Study Population .................................................................................................................. 24 
8.1 
Inclusion Criteria ............................................................................................................ 24 
8.2 
Exclusion Criteria ........................................................................................................... 25 
9 
Study Implementation ......................................................................................................... 27 
9.1 
Study Design .................................................................................................................. 27 
9.1.1 
Screening ................................................................................................................ 29 
9.1.1.1 
Repetition of Screening Assessment(s) ........................................................... 30 
9.1.1.2 
Rescreening (Surgical Subjects Only) ............................................................. 30 
9.1.2 
Surgical Procedure Through Treatment Assignment (Surgical Subjects) .............. 30 
9.1.3 
Treatment Period .................................................................................................... 31 
9.1.4 
Follow-up................................................................................................................ 31 
9.1.5 
Study Drug Completion or Discontinuation ........................................................... 31 
9.1.6 
Home Health Visits ................................................................................................ 32 
9.1.7 
Completion of Study Participation ......................................................................... 32 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 32 
9.3 
Rationale for Study Elements ......................................................................................... 32 
9.3.1 
Study Design and Population ................................................................................. 32 
9.3.2 
Study Drug Dose and Duration .............................................................................. 33 
9.3.3 
Rationale for Study Assessments ........................................................................... 33 
9.4 
Study Restrictions ........................................................................................................... 33 
9.4.1 
Analgesic Medications ........................................................................................... 35 
9.4.1.1 
Perioperative Pain Management (Surgical Subjects Only) ............................. 35 
9.4.1.2 
Rescue Medication .......................................................................................... 36 
9.4.2 
Additional Dietary Restrictions .............................................................................. 36 
9.5 
Prior and Concomitant Medications ............................................................................... 36 
9.6 
Administration ................................................................................................................ 36 
9.7 
Dose Modification for Toxicity ...................................................................................... 37 


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9.8 
Study Drug Interruption and Stopping Rules ................................................................. 37 
9.9 
Removal of Subjects ....................................................................................................... 37 
9.10 Replacement of Subjects ................................................................................................ 38 
10 Study Drug Information and Management ....................................................................... 38 
10.1 Preparation and Dispensing ............................................................................................ 38 
10.2 Packaging and Labeling ................................................................................................. 38 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 38 
10.4 Drug Accountability ....................................................................................................... 39 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 39 
10.6 Compliance ..................................................................................................................... 39 
10.7 Blinding and Unblinding ................................................................................................ 39 
10.8 Rescue Medication ......................................................................................................... 40 
11 Assessments .......................................................................................................................... 40 
11.1 Subject and Disease Characteristics ............................................................................... 40 
11.2 Pharmacokinetics ............................................................................................................ 40 
11.3 Other Assessments .......................................................................................................... 40 
11.3.1 
Use of Rescue Medications .................................................................................... 40 
11.4 Effectiveness ................................................................................................................... 40 
11.4.1 
Patient Global Assessment of Study Drug ............................................................. 40 
11.5 Safety .............................................................................................................................. 40 
11.5.1 
Adverse Events ....................................................................................................... 40 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 41 
11.5.3 
Physical Examinations and Vital Signs .................................................................. 42 
11.5.4 
Electrocardiograms ................................................................................................. 43 
11.5.5 
Columbia-Suicide Severity Rating Scale ............................................................... 44 
11.5.6 
Contraception and Pregnancy ................................................................................. 44 
11.5.6.1 
Contraception................................................................................................... 44 
11.5.6.2 
Pregnancy ........................................................................................................ 45 
12 Statistical Analysis ............................................................................................................... 46 
12.1 Sample Size and Power .................................................................................................. 46 
12.2 Analysis Sets .................................................................................................................. 46 
12.3 Statistical Analysis ......................................................................................................... 46 
12.3.1 
General Considerations ........................................................................................... 46 
12.3.2 
Background Characteristics .................................................................................... 47 
12.3.3 
Effectiveness Analysis ............................................................................................ 47 
12.3.4 
Safety Analysis ....................................................................................................... 47 
12.4 Interim Analysis ............................................................................................................. 47 
12.5 Independent Data Monitoring Committee Analysis ....................................................... 47 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 47 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 47 
13.1.1 
Adverse Events ....................................................................................................... 47 
13.1.1.1 
Definition of an Adverse Event ....................................................................... 47 
13.1.1.2 
Clinically Significant Assessments ................................................................. 47 
13.1.1.3 
Documentation of Adverse Events .................................................................. 48 
13.1.1.4 
Adverse Event Severity ................................................................................... 48 


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13.1.1.5 
Adverse Event Causality ................................................................................. 49 
13.1.1.6 
Study Drug Action Taken ................................................................................ 49 
13.1.1.7 
Adverse Event Outcome .................................................................................. 50 
13.1.1.8 
Treatment Given .............................................................................................. 50 
13.1.2 
Serious Adverse Events .......................................................................................... 50 
13.1.2.1 
Definition of a Serious Adverse Event ............................................................ 50 
13.1.2.2 
Reporting and Documentation of Serious Adverse Events ............................. 51 
13.1.2.3 
Expedited Reporting and Investigator Safety Letters ...................................... 52 
13.2 Administrative Requirements ......................................................................................... 52 
13.2.1 
Product Complaints ................................................................................................ 52 
13.2.2 
Ethical Considerations ............................................................................................ 52 
13.2.3 
Subject Information and Informed Consent ........................................................... 52 
13.2.4 
Investigator Compliance ......................................................................................... 52 
13.2.5 
Access to Records ................................................................................................... 53 
13.2.6 
Subject Privacy ....................................................................................................... 53 
13.2.7 
Record Retention .................................................................................................... 53 
13.2.8 
Study Termination .................................................................................................. 54 
13.2.9 
End of Study ........................................................................................................... 54 
13.3 Data Quality Assurance .................................................................................................. 54 
13.4 Monitoring ...................................................................................................................... 54 
13.5 Data Capture ................................................................................................................... 55 
13.6 Confidentiality and Disclosure ....................................................................................... 55 
13.7 Publications and Clinical Study Report .......................................................................... 55 
13.7.1 
Publication of Study Results ................................................................................... 55 
13.7.2 
Clinical Study Report ............................................................................................. 56 
14 References ............................................................................................................................. 57 
15 Appendix A: Guidance on Surgical Procedures and Non-surgical Acute Pain 
Conditions ............................................................................................................................. 60 
16 Protocol Signature Pages .................................................................................................... 61 
16.1 Sponsor Signature Page .................................................................................................. 61 
16.2 Investigator Signature Page ............................................................................................ 62 
 


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List of Tables 
Table 3-1 
Study VX22-548-107: Screening Through Admission (Surgical Subjects) ........... 8 
Table 3-2 
Study VX22-548-107: Procedure Through Treatment Assignment (Surgical 
Subjects) ................................................................................................................ 10 
Table 3-3 
Study VX22-548-107: Screening Through Treatment Assignment (Non-surgical 
Subjects) ................................................................................................................ 11 
Table 3-4 
Study VX22-548-107: Treatment Period and Safety Follow-up Visit (All 
Subjects) ................................................................................................................ 13 
Table 9-1 
Study Restrictions ................................................................................................. 34 
Table 9-2 
Guidance on Pre- and Intraoperative Anesthesia and Analgesic Agents .............. 35 
Table 10-1 
Study Drug ............................................................................................................ 39 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 41 
Table 11-2 
Acceptable Methods of Contraception.................................................................. 45 
Table 13-1 
Grading of AE Severity ........................................................................................ 49 
Table 13-2 
Classifications for AE Causality ........................................................................... 49 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 50 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 50 
Table 15-1 
Representative Ineligible Surgical Procedures and Non-surgical Conditions 
Resulting in Acute Pain ........................................................................................ 60 
List of Figures 
Figure 2-1 
VX22-548-107 Study Design (Surgical Subjects) .................................................. 5 
Figure 2-2 
VX22-548-107 Study Design (Non-surgical Subjects) .......................................... 5 
Figure 9-1 
VX22-548-107 Study Design (Surgical Subjects) ................................................ 27 
Figure 9-2 
VX22-548-107 Study Design (Non-surgical Subjects) ........................................ 28 
 


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List of Abbreviations 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRF 
case report form 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DIEP 
deep inferior epigastric perforator 
DRG 
dorsal root ganglia 
e-diary 
electronic diary 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EDV 
End of Dosing Visit 
EENT 
eyes, ears, nose, and throat 
eGFR 
estimated glomerular filtration rate 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GPP3 
Good Publication Practices 
GPS 
Global Patient Safety 
H2 
histamine type 2 receptor 
HBsAg 
hepatitis B surface antigen 
HCV Ab 
hepatitis C virus antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV-1/HIV-2 Abs 
antibodies against human immunodeficiency viruses 1 and 2 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IV 
intravenous 
LIP 
licensed independent practitioner 
max 
maximum value 
min 
minimum value 
n 
size of subsample 
NaV1.8 
voltage-gated sodium channel 1.8 


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Abbreviation 
Definition 
N2O 
nitrous oxide 
NPRS 
numeric pain rating scale 
NSAID 
nonsteroidal anti-inflammatory drug 
PE 
physical examination 
PGA 
patient global assessment 
prn 
as needed 
q6h 
every 6 hours 
q12h 
every 12 hours 
QTcF 
QT interval corrected by Fridericia’s formula 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCN10A 
sodium voltage-gated channel alpha subunit 10 
SD 
standard deviation 
SFU 
Safety Follow-up (Visit) 
SpO2 
oxygen saturation 
SUSAR 
suspected, unexpected, serious adverse reaction 
TE 
Treatment-emergent (Period) 
TEAE 
treatment-emergent adverse event 
TRAM 
traverse rectus abdominal muscle 
US 
United States 
VRS 
verbal categorical rating scale 


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5 
INTRODUCTION 
5.1 
Background 
Pain is one of the most common symptoms for which patients seek medical attention. Current 
treatment options for pain are limited by poor efficacy and high rates of adverse events (AEs), 
leaving many patients without adequate pain control. Nonsteroidal anti-inflammatory drugs 
(NSAIDs) pose a potentially serious risk of gastrointestinal toxicity with acute and chronic use, 
hematologic toxicity with acute use, and nephrotoxicity with chronic use.1 Opioids are 
significantly limited by safety and tolerability issues and have a high abuse liability. 
Opioid-associated deaths have increased in frequency over the past 2 decades.2 Opioids were 
involved in more than 70,000 overdose deaths in the US in 2020 and in approximately 76% of 
fatal drug overdoses in the EU in 2019.3, 4 
Given the limited treatment options, combined with the risks and constrained utility of current 
treatments, the development of new analgesics with improved efficacy and safety profiles is vital 
for better pain management and patient health outcomes. Despite the need for new analgesics, 
clinical development has exhibited a considerable lack of recent progress and innovation of new 
medications to treat pain.5 Over the last decade, the majority of approved analgesic drugs either 
act on the opioid receptor system or are NSAIDs6; few new molecular entity drugs for moderate 
to severe pain have been approved.7, 8 The majority of research activity focuses on developing 
abuse-deterrent reformulations of existing narcotic pain drugs, or combinations with NSAIDs. 
The resultant compounds do not have substantially improved efficacy or safety.  
Voltage-gated sodium channel 1.8 (NaV1.8) plays a critical role in pain signaling.9, 10 Support for 
this assertion arises from (1) evaluation of the role NaV1.8 plays in normal physiology11-15, 
(2) pathological states arising from mutations in the NaV1.8 gene (SCN10A)16, 17, (3) animal 
models18-21, and (4) pharmacology of known NaV1.8-modulating agents.22-24 In addition, because 
NaV1.8 expression is restricted to peripheral neurons, particularly those that sense pain (e.g., the 
dorsal root ganglia [DRG])11, 13, NaV1.8 inhibitors are less likely to be associated with the side 
effects commonly observed with other sodium channel modulators and the abuse liability 
associated with opioid therapies. Therefore, targeting the underlying biology of pain through 
selective NaV1.8 inhibition represents a novel approach to analgesic drug development that has 
the potential to address an urgent unmet need for safe and effective acute and chronic pain 
therapies. These therapies include treatment where the primary mechanisms underlying pain are 
nociceptor hyperexcitability. 
5.2 
Study Rationale 
This study will evaluate the safety and effectiveness of up to 14 days of treatment with VX-548 
for acute pain.   
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the safety and tolerability of VX-548 
6.2 
Secondary Objective 
To evaluate the effectiveness of VX-548 in treating acute pain 


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7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Safety and tolerability based on treatment-emergent adverse events (TEAEs), laboratory test 
results, vital signs, and ECGs 
7.2 
Secondary Endpoint 
Subject perception of VX-548 effectiveness in treating pain at the end of treatment as measured 
by the proportion of subjects reporting good, very good, or excellent on a patient global 
assessment (PGA) 
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 
All Subjects (Before Surgery, If Applicable) 
1. Subject will sign and date an informed consent form (ICF). 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Subjects (male and female) between the ages of 18 and 80 years, inclusive. 
4. Body mass index (BMI) of ≥18.0 to <40.0 kg/m2. 
5. Surgical subjects: Scheduled to undergo an ambulatory orthopedic, plastic, breast, 
otorhinolaryngologic, colorectal, gynecologic, urologic, or general surgical procedure with 
pain that is expected to last for at least 72 hours and that is expected to require no more than 
short-term (i.e., <24-hour) admission (additional details on ineligible procedures are provided 
in Appendix A). 
Non-surgical subjects: Present to medical facility with pain of new origin (not related to a 
prior known condition) that is moderate or severe on the verbal categorical rating scale 
(VRS) and ≥4 on the numeric pain rating scale (NPRS), has been ongoing for ≤48 hours, is 
expected to last for at least 72 hours, and is expected to require no more than a short-term 
(i.e., <24-hour) admission, if any. Representative conditions include traumatic and atraumatic 
acute musculoskeletal pain, orofacial pain, burns, and cutaneous and soft tissue pain 
(additional details on ineligible conditions are provided in Appendix A). 
After Surgery (Surgical Subjects Only) 
6. Subject reported pain at the surgical site that is moderate or severe on the VRS and ≥4 on the 
NPRS within the following procedure-specific time periods: 
o 
Procedures performed with regional anesthesia: within 12 hours after surgery 
completion 
o 
All other procedures: within 4 hours after surgery completion 


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7. Subject is lucid, able to follow commands, and able to swallow oral medications. 
8. All analgesic guidelines (Section 9.4.1) were followed during and after the procedure. 
8.2 
Exclusion Criteria 
All Subjects (Before Surgery, If Applicable) 
1. Surgical subjects only: History of previous surgery due to the same condition, except for 
procedures for which a previous surgery on the contra-lateral limb or organ is allowed. 
2. Surgical subjects only: History of a prior surgical procedure in the same region of the body 
that resulted in any perioperative complications or that, in the opinion of the investigator or 
medical monitor, would preclude participation in the study. 
3. 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 to the 
subject. This may include, but is not limited to, history of relevant drug or food allergies; 
history of significant respiratory, cardiovascular, metabolic, hematologic, neurologic, or 
psychiatric disease; history or presence of clinically significant pathology; and history of 
cancer. Note that this criterion does not apply to squamous cell skin cancer, basal cell skin 
cancer, and Stage 0 cervical carcinoma in situ (i.e., no adjudication by the investigator is 
needed), so long as there has been no recurrence for the last 5 years. 
4. Cardiac dysrhythmias requiring anti-arrhythmic treatment(s) within the last 2 years; history 
or evidence of abnormal study ECGs that in the opinion of the investigator or medical 
monitor would preclude the subject’s participation in the study; or history of 
QT prolongation or standard 12-lead ECG (performed in triplicate) demonstrating median 
QTcF >450 msec at screening. 
5. Presence of an automated implantable cardioverter defibrillator, cardiac resynchronization 
therapy device, or pacemaker. 
6. History of significant hepatic disease, including but not limited to hepatic cirrhosis, portal 
hypertension, or moderate or severe hepatic impairment (defined as Child Pugh Class B 
or C25). 
7. Alanine transaminase or aspartate transaminase values >2.5 × upper limit of normal. 
8. History of severe renal impairment defined as estimated glomerular filtration rate (eGFR) 
<30 mL/min/1.732 calculated using the subject’s measured serum creatinine; the suggested 
calculation method for eGFR is the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation 
9. Any other abnormal laboratory results indicative of significant medical disease that, in the 
opinion of the investigator, would preclude the subject’s participation in the study. 
10. History of any sensory abnormality that, in the opinion of the investigator, may confound the 
ability of the subject to assess pain. 
11. Subjects who have a painful physical condition that, in the opinion of the investigator, may 
confound the assessments of pain. 


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12. A known or clinically suspected active infection with human immunodeficiency virus or 
hepatitis B or C viruses. (Note: Testing in the absence of suspected active infection is 
required for surgical subjects only.) 
13. Any surgery (except the protocol surgery for surgical subjects) within 1 month before the 
first study drug dose, unless approved by the medical monitor. 
14. American Society of Anesthesiologists physical status classification26 of ≥3. 
15. Chronic use of opioids (pure agonists, agonist/antagonists, partial agonists, antagonists) or 
NSAIDs with dose escalation within 30 days before first dose of study drug. 
16. Unwilling or unable to stop analgesics at least 5 half-lives or 2 days (whichever is longer) 
before first dose of study drug, with the following exception: for non-surgical subjects, use of 
a limited amount of pain medications before presentation at the medical facility and/or single 
use of any medication in the medical facility within the past 4 hours is not exclusionary. 
17. Subjects who have started any non-analgesic new medications that have not been at a stable 
dose for at least 14 days before first dose of study drug. 
18. Subjects unwilling to receive any protocol-related medicine (e.g., ibuprofen, acetaminophen, 
fentanyl). 
19. Subjects with a history of allergy or significant adverse event (AE) to any opioid and/or 
NSAID that, in the opinion of the investigator, would significantly increase the chance of 
AEs from medicines used in the study. 
20. Subjects with sleep apnea and/or on a home positive airway pressure device. 
21. History of peptic ulcer disease or gastrointestinal bleeding that, in the opinion of the 
investigator or medical monitor, would preclude the subject’s participation in the study. 
22. For female subjects: Pregnant, nursing, or planning to become pregnant during the study or 
within 30 days after the last study drug dose.  
For male subjects: Male subjects with a female partner who is pregnant, nursing, or planning 
to become pregnant during the study or within 30 days after the last study drug dose. 
23. Participation in a previous study investigating VX-548. 
24. Participated in another investigational study within 30 days of the first dose of study drug. 
25. Evidence of misuse, aberrant use, or addiction to alcohol or an illicitly used drug of abuse in 
the past 3 years, or a positive test for drugs of abuse as defined in Section 11.5.2. 
o 
A positive drug screen for a known prescribed concomitant medication that is not 
otherwise exclusionary (e.g., benzodiazepines) will not disqualify subjects. 
26. Use of the substances, activities, or devices, as indicated in Section 9.4, during the specified 
times. 
27. 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. 


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After Surgery (Surgical Subjects Only) 
28. Subject had any surgical complications during the procedure. 
29. Subject had a medical complication during the procedure that, in the opinion of the 
investigator, should preclude assignment to treatment. 
30. Standard 12-lead ECG (performed in triplicate) demonstrating median QTcF >450 msec at 
baseline (Day 1 predose). 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 3, single-arm study evaluating the safety and effectiveness of VX-548 in treating 
acute pain (Figure 9-1 [surgical subjects] and Figure 9-2 [non-surgical subjects]). 
Figure 9-1 
VX22-548-107 Study Design (Surgical Subjects) 
 
NPRS: numeric pain rating scale; VRS: verbal categorical rating scale 
Notes: After surgery completion, a subject will be assigned to treatment if (1) the subject requests the first dose of 
study drug for pain relief, (2) the subject’s pain is moderate or severe on the VRS, and (3) the subject’s pain is 
≥4 on the NPRS. If a subject does not meet the VRS and NPRS criteria within the protocol-specified, 
procedure-specific time period, the subject will not be eligible for this study. Figure is not drawn to scale. 
 


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Figure 9-2 
VX22-548-107 Study Design (Non-surgical Subjects) 
 
NPRS: numeric pain rating scale; VRS: verbal categorical rating scale 
Notes: After completion of screening assessments and confirmation of eligibility, a subject will be assigned to 
treatment if (1) the subject’s pain is moderate or severe on the VRS, and (2) the subject’s pain is ≥4 on the 
NPRS. Figure is not drawn to scale. 
Surgical Subjects 
On Day 1, subjects will undergo a scheduled ambulatory surgical procedure with pain that is 
expected to last for at least 72 hours and that is expected to require no more than a short-term 
(i.e., <24-hour) admission. After surgery completion, a subject will be assigned to treatment if 
(1) the subject requests the first dose of study drug for pain relief, (2) the subject’s pain is 
moderate or severe on the VRS, and (3) the subject’s pain is ≥4 on the NPRS. If a subject does 
not meet the VRS and NPRS criteria within the protocol-specified time period for the surgical 
procedure they underwent (e.g., 4 hours for most procedures; Section 8.1), the subject will not be 
eligible for this study. 
Non-surgical Subjects 
On Day 1, after completion of screening assessments and confirmation of eligibility, a subject 
will begin treatment if (1) the subject’s pain is moderate or severe on the VRS, and (2) the 
subject’s pain is ≥4 on the NPRS. For a subject to be eligible, their pain must have been ongoing 
for ≤48 hours at presentation. 
All Subjects 
Approximately 250 subjects will receive VX-548 (100 mg first dose, then 50 mg every 12 hours 
[q12h]). Subjects will continue to receive VX-548 for 14 days or until their pain resolves, 
whichever occurs first. An acetaminophen/ibuprofen combination may be used as a rescue 
medication for pain relief as needed (prn), starting any time after the first dose of study drug 
through Day 14, completion of study drug treatment due to pain resolution, or study drug 
discontinuation, whichever occurs first. Subjects will be permitted to take acetaminophen 
650 mg/ibuprofen 400 mg every 6 hours (q6h) prn, up to a maximum of 2600 mg/1600 mg in 
any 24-hour period. 


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The following approach will be used to define pain resolution and completion of study drug 
treatment: 
1. Pain is considered to be resolved and the study drug treatment will be considered completed 
if 
a. a subject takes no study drug during a 48-hour period (i.e., skipped at least 4 consecutive 
doses due to pain resolution); and 
b. a subject takes no more than 1 dose of acetaminophen/ibuprofen during each 24-hour 
period within the 48-hour period (i.e., no more than 2 doses in 48 hours).  
2. If a subject stops taking study drug per Criterion 1a but does not meet Criterion 1b, they will 
be instructed to restart study drug (and prn rescue medication). 
3. If a subject stops and restarts study drug (Criterion 2 above) and subsequently believes their 
pain is resolving and stops study drug a second time, they will be instructed to not restart 
study drug, regardless of whether the above criteria are met. 
4. If a subject stops study drug a second time after the restart of dosing (Criterion 3 above) and 
then fulfills both Criterion 1a and 1b, the pain is considered resolved and study drug 
treatment will be considered completed. If the subject fulfills Criterion 1a but not 
Criterion 1b after the restart of dosing, the pain is considered not resolved and study drug 
will be considered discontinued.  
Note If a subject stops study drug due to pain resolution less than 48 hours before the last 
scheduled dose of study drug (i.e., stops after the second dose on Day 12) and therefore cannot 
meet Criterion 1a by Day 14, the subject will be considered to have completed study drug dosing 
as long as they also meet Criterion 1b.  
9.1.1 
Screening 
Surgical Subjects 
Assessments from screening through admission (pre-procedure) are listed in Table 3-1. 
The Screening Visit will occur within 28 days before the scheduled surgical procedure and may 
occur in the clinic or as a home health visit with a qualified visiting nurse if permitted by local 
regulations. The investigator (or an appropriate authorized designee at the study site) will obtain 
informed consent from each subject in person or remotely (Section 13.2.3) before performing 
any study-related procedure. If needed, Screening Visit assessments may be performed on 
different days within the screening period (e.g., informed consent may be obtained before the 
home health visit, if applicable). 
Non-surgical Subjects 
Assessments from screening through treatment assigned are listed in Table 3-3. 
The Screening Visit will occur on Day 1 after the subject presents with pain at a medical facility. 
The investigator (or an appropriate authorized designee at the study site) will obtain informed 
consent from each subject before performing any study-related procedure. However, previous 
test results from the facility’s local laboratory may be used to establish eligibility if collected 
within 2 hours before ICF signing. All screening assessments must be completed, confirming 


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subject eligibility, before treatment assignment may occur, including VRS and (if the subject’s 
pain is rated moderate or severe on the VRS) NPRS. 
All Subjects 
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.4). 
Subjects will be instructed during screening on appropriate expectations around their 
participation in a clinical study and the importance of accurately reporting their post-procedural 
pain. At the Screening Visit, subjects will receive trainings on accurate pain reporting, clinical 
study participation, and use of the electronic diary (e-diary) for recording study drug 
administration, rescue medication use, and the PGA. On Day 1 (pre-procedure), these trainings 
will be repeated for surgical subjects; for non-surgical subjects, only 1 training is required 
because the Screening Visit is on Day 1. Additional review of these educational materials may be 
repeated for some or all subjects, as needed. 
9.1.1.1 
Repetition of Screening Assessment(s) 
Repetition of any 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, equipment error). 
In all cases, the medical monitor must authorize retesting. 
9.1.1.2 
Rescreening (Surgical Subjects Only) 
Subjects who do not meet the eligibility criteria may not be rescreened, with the following 
exceptions: 
• Subjects who met all eligibility criteria but had an intercurrent illness (e.g., upper respiratory 
infection with fever) in the 5 days before the first dose of study drug that was properly 
evaluated and which resolved fully 
• Subjects who met all eligibility criteria but were not able to obtain required documentation 
within the allotted screening window 
• Subjects who met all eligibility criteria but transiently (for personal reasons) are unable to 
commit to all study procedures 
• Subjects who were screened under a prior version of the protocol and did not meet any 
exclusion criterion, with the exception of a criterion that was updated in a subsequent version 
of the protocol 
Any subject who is rescreened for any of the exceptions listed above may have the screening 
window extended by 1 week before needing to undergo any rescreening assessments. If more 
than 35 days have elapsed from the Screening Visit before first dose of study drug, all screening 
assessments need to be repeated. The medical monitor must approve all rescreening and/or 
screening window extension requests before these occur. 
9.1.2 
Surgical Procedure Through Treatment Assignment (Surgical 
Subjects) 
Assessments to be completed after the surgical procedure through treatment assignment are listed 
in Table 3-2.  
All study periods will be conducted as described in Section 9.1. 


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Use of drains for all relevant procedures will be at the discretion of the surgical team. 
In the perioperative period, pain management agents will be used according to Section 9.4.1.1. 
All other standard-of-care agents (e.g., anti-emetics) are allowed except those which are 
specifically restricted (Table 9-1). Section 9.4 provides additional details on allowed and 
restricted agents. 
Treatment assignment may not occur until at least 15 minutes after the last administration of 
supplemental analgesia (i.e., fentanyl; Section 9.4.1.1).  
In the postoperative period before treatment assignment, VRS will be completed upon request for 
the first dose of study drug for pain relief. NPRS will be completed after VRS only if the 
subject’s pain is rated moderate or severe on the VRS. If a subject does not meet the VRS and 
NPRS criteria within the protocol-specified time period for the surgical procedure they 
underwent (Section 8.1), the subject will not be eligible for this study.  
9.1.3 
Treatment Period 
Treatment Period assessments are listed in Table 3-4 (surgical and non-surgical subjects). 
All study periods will be conducted as described in Section 9.1. Dosing details are in Section 9.6. 
If a subject has any clinically significant, study-related abnormalities at the time that they meet 
discharge/leaving criteria from where the surgical procedure was conducted or non-surgical 
condition was treated (e.g., hospital, clinic, or ambulatory center), the medical monitor (or 
authorized designee) will be notified, and the subject will be asked to remain (e.g., in the 
hospital, clinic, or ambulatory center) until such abnormalities resolve. If the subject is unable or 
unwilling to remain, the medical monitor (or authorized designee) will be notified, and the 
investigator will make every effort to arrange follow-up evaluations at appropriate intervals to 
document the course of the abnormalities. 
Although the inpatient period, if any, is generally expected to be <24 hours (Section 8.1), 
subjects who turn out to require a stay of ≥24 hours do not need to discontinue study drug 
treatment or the study. 
Subjects who complete or discontinue study drug treatment before Day 14 will remain in the 
study from the time of stopping study drug treatment through the last scheduled study visit and 
complete assessments for all study visits, as described in Section 9.1.5. 
9.1.4 
Follow-up 
Subjects will have a Safety Follow-up Visit approximately 28 days after the first dose of study 
drug (Day 28 ± 2 days). Safety Follow-up Visit assessments are listed in Table 3-4.  
9.1.5 
Study Drug Completion or Discontinuation 
Subjects will receive VX-548 for 14 days or until their pain resolves, whichever occurs first, 
with pain resolution and study drug treatment completion as defined in Section 9.1. Subjects may 
also choose to discontinue study drug for other reasons. 
If a subject discontinues or completes study drug treatment for any reason before Day 14, 
including AEs (considered treatment discontinuation) or reaching pain resolution (considered 
treatment completion), an End of Dosing Visit (EDV) should be scheduled to occur as soon as 
possible after treatment discontinuation or after pain resolution criteria are met (as applicable), 


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and the Day 14 Visit will not be required. If the EDV occurs within or prior to the Day 7 visit 
window, the Day 7 Visit will also not be required. The EDV should ideally occur within 
72 hours after the last dose of study drug. 
Subjects who discontinue or complete study drug treatment before Day 14 will also be required 
to complete the Safety Follow-up Visit (Section 9.1.4). In the unlikely event that the EDV is 
delayed and occurs 28 days or later following the first dose of study drug, then a separate Safety 
Follow-up Visit will not be required. 
If a subject withdraws consent for the study, no further assessments will be performed; the study 
data and samples collected will remain part of the study (Section 9.8). 
9.1.6 
Home Health Visits 
Home health visits are only an option if permitted by local regulations. Any visits that occur via 
home health must have a consultation (i.e., telemedicine video conference or telephone contact) 
between the subject and investigator or qualified delegate (licensed independent practitioner 
[LIP]) within 2 business days after the home health visit in order to check-in and collect AEs, 
and may also include a separate follow up with the study coordinator. 
9.1.7 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as one of the following: 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up Visit 
• For enrolled subjects who do not have a Safety Follow-up Visit: the date of last contact 
The end of study is defined in Section 13.2.9. 
9.2 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study.  
9.3 
Rationale for Study Elements 
9.3.1 
Study Design and Population 
The study is designed to evaluate longer-term safety and sustained effect of VX-548 after 
multiple kinds of surgeries and non-surgical conditions resulting in acute pain; broad categories 
of surgeries and non-surgical acute pain conditions were included to obtain comprehensive safety 
data. Moreover, the use of VX-548 will be primarily in an outpatient setting as the selected 
surgeries/conditions generally require no more than a short-term (i.e., <24-hour) admission. For 
the surgical subjects, the procedures and postoperative care, including methods for acute pain 
management, follow standard of care with minimal restrictions on the surgical and anesthetic 
parameters for the specified procedures. Clinicians may generally use what they consider to be 
standard of care in the US, while remaining within protocol specifications. Given that the study 
is intended primarily to collect safety information, an open-label, single-arm study design is 
appropriate. 
The guiding considerations for the eligible surgical models and non-surgical pain conditions are 
that (1) they result in at least a moderate level of pain that lasts between 7 and 14 days; and 
(2) the surgical procedures (where applicable) historically are performed on an ambulatory basis. 
Consistent with the FDA requirements for premarketing safety databases, the proposed 
population adequately represents the target population (i.e., patients with moderate to severe 


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acute pain).27 To approximate use in a “real-world” setting, inclusion and exclusion criteria were 
designed to enroll a clinically diverse population that is more generalizable to clinical practice. 
The eligible surgical procedures and non-surgical conditions support an evaluation of VX-548 in 
subjects with sufficiently diverse sources of acute pain (e.g., both bony and soft tissue) for the 
expected duration of use. The surgical procedures represent the broad categories of general, 
orthopedic, otolaryngology, breast, colorectal, gynecologic, urologic, and plastic and 
reconstructive surgery. The non-surgical conditions include traumatic and atraumatic acute 
musculoskeletal pain, orofacial pain, burns, and cutaneous and soft tissue pain. 
Following the scheduled surgical procedure or presentation at a medical facility with acute pain, 
subjects will be assigned to treatment after their pain meets threshold criteria using both a VRS 
and an NPRS. The pain threshold criteria are designed to ensure subjects have moderate to 
severe pain. A 4-point VRS (none, mild, moderate, or severe) is included as part of the pain 
threshold inclusion criterion to allow rapid assessment of subjects’ baseline pain on a repeated 
basis in the immediate postoperative period. The NPRS, a frequently used, valid pain intensity 
measure recognized by the FDA28, is included at baseline to further define and quantify subjects 
as having moderate to severe pain (i.e., ≥4 on an 11-point [0 to 10] scale). 
Ibuprofen and acetaminophen were selected as the rescue medications because they are 
commonly used, short-acting, standard-of-care treatments for acute pain. 
9.3.2 
Study Drug Dose and Duration 
The VX-548 dosing regimen of 100 mg first dose (loading dose), then 50 mg q12h was selected 
based on favorable safety and pharmacokinetic data from healthy subjects and subjects with pain 
after bunionectomy or abdominoplasty. Exposures at the selected VX-548 dose are predicted to 
achieve NaV1.8 inhibition levels of approximately 90% by 2 hours after administration of the 
100 mg loading dose. Exposures corresponding to approximately IC90 are sustained with the 
administration of 50 mg q12h maintenance doses starting 12 hours after the loading dose. 
The dosing duration for each subject will be determined by the clinical need for postoperative 
analgesic therapy. In current practice, analgesics are used as needed for at least several days and 
up to approximately 2 weeks for acute pain. 
9.3.3 
Rationale for Study Assessments 
PGA of study drug: The PGA captures subjects’ perceptions of the study drug’s effectiveness in 
treating pain using a validated, single-item questionnaire.29 This study will use a 5-point Likert 
scale (poor, fair, good, very good, or excellent) for the PGA evaluation.30 
9.4 
Study Restrictions 
Study restrictions that apply to all subjects are summarized in Table 9-1. Additional details on 
study restrictions will be provided in the Study Reference Manual. 


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Table 9-1 
Study Restrictions 
Restricted 
Medication/Food/Activitya 
Timing of Restriction 
Start 
Stop 
Other investigational drugs or 
devices 
30 days before first dose of study drug, 
5 half-lives before first dose of study 
drug, or time determined by local 
requirements (whichever is longest) 
Completion of SFU assessments 
Analgesic medications  
Surgical subjects: 5 half-lives or 2 days 
(whichever is longer) before admission 
for surgery and per guidelines in 
Section 9.4.1.1 and Section 9.4.1.2 
Non-surgical subjects: at presentation 
with acute non-surgical pain (see also 
Section 8.2 and Section 9.4.1.2) 
Until last dose of study drug is taken 
Oral steroids 
5 half-lives or 2 days (whichever is 
longer) before admission for surgery or 
at presentation with non-surgical pain 
Until last dose of study drug is taken 
Medications, herbal and 
dietary supplements 
(including St. John’s wort) 
known to be moderate or 
strong inducers of CYP3A 
14 days before first dose of study drug  
Completion of SFU assessments 
Medications, herbal and 
dietary supplements known 
to be moderate or strong 
inhibitors of CYP3A 
7 days before first dose of study drug  
Completion of SFU assessments 
Grapefruit or grapefruit juice; 
pomelos, star fruit, and 
Seville oranges or their juices 
7 days before first dose of study drug  
Completion of SFU assessments 
H2 blockers and proton pump 
inhibitors 
72 hours before first dose of study drug 
Until last dose of study drug is taken 
Alcohol 
24 hours before first dose of study drug 
Until last dose of study drug is taken 
Strenuous exercise 
(e.g., heavy lifting, weight 
training, and aerobics) 
48 hours before first clinical laboratory 
testing  
Completion of SFU assessments 
H2: histamine type 2 receptor; SFU: Safety Follow-up 
a 
Refer to the Study Reference Manual for a more complete list of medications prohibited/restricted in the 
study. See Section 9.4.2 for guidance on concomitant medications. 
Surgical Subjects Only 
Excluding agents for pain management (see Section 9.4.1.1), all perioperative standard-of-care 
agents are allowed at the discretion of surgical and anesthesia teams except those which are on 
the restricted medication list (Table 9-1). Commonly used medications may include those falling 
into the general categories of short-acting anxiolytics/sedatives (e.g., midazolam), 
antisialagogues (e.g., glycopyrrolate), anti-emetic or anti-nausea agents (e.g., ondansetron, 
metoclopramide), neuromuscular blockers (e.g., rocuronium), neuromuscular blockade reversal 
(e.g., neostigmine, sugammadex), hemodynamic control (i.e., positive/negative inotropes or 
chronotropes, vasopressors, antihypertensives), oxygen/air, IV fluids, antibiotics, anticoagulants 
(e.g., heparin), or antifibrinolytics (e.g., tranexamic acid). 


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9.4.1 
Analgesic Medications 
Non-surgical subjects do not have additional restrictions on analgesic medications besides those 
in the study restrictions table (Table 9-1). Additional restrictions for surgical subjects are 
described in Section 9.4.1.1. 
9.4.1.1 
Perioperative Pain Management (Surgical Subjects Only) 
Pre- and Intraoperative Pain Management 
Table 9-2 summarizes the allowed and prohibited anesthesia and analgesic agents during the 
pre- and intraoperative period. 
Table 9-2 
Guidance on Pre- and Intraoperative Anesthesia and Analgesic Agents 
Agent Type 
Allowed Agents 
Prohibited Agents 
General anesthesia 
• 
Induction: propofol, etomidate, 
thiopental 
• 
Maintenance: propofol, desflurane, 
sevoflurane, N2O 
• 
Analgesia: opioids (e.g., fentanyl), 
NSAIDs, acetaminophen 
• 
Induction: ketamine 
• 
Maintenance: ketamine, isoflurane, 
dexmedetomidine 
• 
Analgesia: ketamine, gabapentinoids, 
dexamethasone 
Local anesthetic 
infiltration or injection 
(non-catheter-based) 
Any non-extended-release agent, with or 
without epinephrinea 
• 
Liposomal bupivacaine 
• 
Bupivacaine/meloxicam 
• 
Clonidine 
Neuraxial anesthesia 
(non-catheter-based) 
Any non-extended-release local 
anesthetic, with or without epinephrinea 
• 
Liposomal bupivacaine 
• 
Bupivacaine/meloxicam 
• 
Clonidine 
Nerve block 
(non-catheter-based) 
Any non-extended-release local 
anesthetic, with or without epinephrinea 
• 
Liposomal bupivacaine 
• 
Clonidine 
N2O: nitrous oxide; NSAID: nonsteroidal anti-inflammatory drug 
a 
The maximum dose should be calculated using ideal body weight and accepted standard-of-care 
recommendations for the specific agent and mode of administration. For example, for lidocaine the 
maximum doses would be 4 mg/kg ideal weight without epinephrine or 7 mg/kg ideal weight with 
epinephrine. 
Postoperative Pain Management 
Postoperative supplemental analgesic medication is permitted per the following guidelines until 
the first dose of study drug is administered: 
• Intravenous (IV) fentanyl citrate (dosing at the discretion of the surgical and/or anesthesia 
teams) can be administered if the subject is (1) not lucid enough for treatment assignment but 
deemed to be in severe pain per clinical judgement; and/or (2) unable to swallow oral 
medications. 
• Treatment assignment may not occur until at least 15 minutes after the last administration of 
supplemental fentanyl. 


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9.4.1.2 
Rescue Medication 
Rescue medication may be used per the following guidelines: 
• Rescue medication for pain relief may be used prn any time after the first dose of study drug 
through Day 14, completion of study drug treatment due to pain resolution, or study drug 
discontinuation (e.g., due to AE), whichever occurs first. Subjects will continue to document 
rescue medication use through Study Day 14 or the EDV, whichever occurs first. 
• Subjects will be permitted to take acetaminophen 650 mg/ibuprofen 400 mg q6h prn, up to a 
maximum of 2600 mg/1600 mg in any 24-hour period.  
• No other analgesic medications (e.g., NSAIDs other than ibuprofen, opioids) are allowed 
from the start of the treatment period through the last dose of study drug. 
• A record (date and time of administration) will be kept of all rescue medication use. 
9.4.2 
Additional Dietary Restrictions 
Surgical subjects will abstain from all food and drink (except ≤8 fluid ounces per hour of water) 
from the time of surgery completion through 2 hours after the first dose of study drug (Table 3-2 
and Table 3-4). After this period, study drug may be taken with or without food. 
Non-surgical subjects will abstain from all food and drink (except ≤8 fluid ounces per hour of 
water) for 1 hour before through 2 hours after the first dose of study drug (Table 3-4). After this 
period, study drug may be taken with or without food. 
9.5 
Prior and Concomitant Medications 
• Subjects will abstain from all concomitant medications as described in the exclusion criteria 
(Section 8.2) and study restrictions (Section 9.4). 
• All medications taken within 14 days before the Screening Visit through completion of study 
participation will be recorded with indication, route of administration, and start and stop 
dates of administration. All medications administered in-clinic will also be recorded with the 
time of each administration. Non-surgical subjects should provide the estimated time of 
administration for any medications taken on Day 1 before arriving at the medical facility. All 
subjects will be questioned about medications at each visit or telephone contact. 
9.6 
Administration 
VX-548 will be administered to all subjects q12h.  
Study drug will be administered according to the following guidelines: 
• Study drug will be administered orally with approximately 240 mL (8 fluid ounces) of water. 
• Subjects will swallow the study drug whole and will not chew it before swallowing. 
• The date and time of administration of each dose of study drug will be recorded.  
• Study drug must be administered following the dietary restrictions outlined in Table 9-1 and 
Section 9.4.2. Starting from the second dose of study drug, VX-548 may be taken with or 
without food. 
• Study drug will be administered after baseline vital signs and ECGs are performed.  


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• Study drug should be administered q12h, with a window of ± 1 hour with respect to the most 
recent dose. For example, if the first dose of study drug is administered at 10:00 on Day 1, 
the next dose should be administered between 21:00 and 23:00 on Day 1; if the second dose 
is taken at 21:00 on Day 1, the next dose should be taken between 8:00 and 10:00 on Day 2. 
Depending on the timing of their visit and initial dose, the subject may take either 1 or 
2 doses on Day 1.  
o 
If a subject forgets a dose and exceeds the suggested window but remembers within 
an additional 4 hours beyond the +1-hour window, they will take the dose at that 
time. 
o 
If a subject forgets a dose and more than 5 hours have elapsed, they are to skip that 
dose and resume at the next scheduled dose (i.e., a window of 24 hours ± 1 hour with 
respect to the prior dose before the one that was missed). 
• On the date of the Day 7 Visit and on Study Day 14 (if applicable; Table 3-4), administration 
of a study drug dose should be timed so as to complete 4-hour postdose ECGs at the visit 
(clinic or home health, as applicable). The visit should ideally be scheduled to occur within 
approximately 4 hours after either the first or second planned daily dose of study drug, 
whichever is more convenient. If necessary for scheduling reasons, the subject may withhold 
a study drug dose for up to 3 hours after the planned dosing time point in order to align 
postdose ECGs with the scheduling visit timing. 
• Subjects who choose to stop study drug before Day 14 may restart and stop 1 additional time 
per Section 9.1. For subjects who remain on treatment at Day 14, only 1 dose of study drug 
should be taken on that day, and it will be the last dose of study drug for these subjects.  
Additional information is provided in the Pharmacy Manual. 
9.7 
Dose Modification for Toxicity 
No dose modifications for toxicity are allowed. If any unacceptable toxicity arises, individual 
subjects will discontinue dosing (Section 9.1.5). 
9.8 
Study Drug Interruption and Stopping Rules 
Enrollment and dosing will be paused if any of the following events occur and are considered 
related or possibly related to VX-548 by the investigator or Vertex: 
• ≥3 serious adverse events (SAEs) of QTc prolongation 
• 1 SAE of Torsades de Pointes 
• Death 
Vertex will notify regulatory authorities according to applicable regulations. A review of safety 
data will be conducted by Vertex to determine whether to: (1) continue to pause enrollment and 
dosing for further evaluation; (2) resume enrollment and dosing without modification to study 
conduct; (3) resume enrollment and dosing with modification to study conduct; or (4) terminate 
the study. 
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 complete or discontinue study treatment before Day 14 should continue to return 
for study assessments, as noted in Section 9.1.5.  
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a Safety Follow-up Visit, if 
applicable (see Section 9.1.5), 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 during the study drug Treatment Period will not be 
replaced. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
Study drug refers to VX-548 (Section 10.1 through Section 10.7). Vertex will also supply the 
commercially available rescue medication (Section 10.8). 
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. 
Tablets will be dispensed at the site to individual dosing containers by a qualified pharmacist or 
designated study site staff, and following national and local laws and regulations. 
10.2 
Packaging and Labeling 
Vertex will supply the 50-mg VX-548 tablets. Study drug labeling will be in compliance with 
applicable local and national regulations. Additional details about packaging, labeling, and 
dispensing for VX-548 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 via the drug accountability forms as instructed by Vertex. 


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Study drug supply details are listed in Table 10-1. 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-548 
Tablet/ 
oral 
100 mg first dose; all other 
doses 50 mg 
Supplied as 50-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. Subjects will be instructed to return all used and unused materials 
associated with the study drug to the site. These materials will be retained at the site according to 
instructions provided by Vertex or its designee. The study monitor will review study drug 
records and inventory throughout the study. If a site 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. 
The principal investigator, study site staff, including pharmacy personnel will assist Vertex with 
any recall activities (as applicable) and place impacted investigational medicinal product (IMP) 
in quarantine when requested. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel or approved home nurse 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 in the clinic or 
checked by home nurse during home visits. 
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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10.8 
Rescue Medication 
Vertex will supply acetaminophen and ibuprofen for use as rescue medication during the 
Treatment Period. Drug accountability will be performed in a similar manner as for study drug. 
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1, Table 3-2, Table 3-3, and Table 3-4.  
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical and surgical 
history, baseline VRS and NPRS scores, type of surgical procedure (for surgical subjects only), 
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 (Section 8). The medical 
history will include a complete review of systems, past medical and surgical histories, 
concomitant medications, and any allergies. 
11.2 
Pharmacokinetics 
Not applicable 
11.3 
Other Assessments 
11.3.1 
Use of Rescue Medications 
Rescue medication is permitted for pain relief if needed. Guidelines on administration of 
ibuprofen and acetaminophen in combination as rescue medications are included in 
Section 9.4.1.2. Subjects will record rescue medication use in an e-diary; a paper back-up option 
will be available. 
11.4 
Effectiveness 
11.4.1 
Patient Global Assessment of Study Drug 
The PGA of study drug is completed after taking a dose of study drug, at the indicated time 
points. Subjects should still complete the PGA even if the specified dose is not taken 
(e.g., forgotten dose). Detailed procedures for the administration of the PGA of study drug will 
be provided in a separate document. Subjects will record their PGA responses in an e-diary; a 
paper back-up option will be available. 
11.5 
Safety 
Safety evaluations will include AEs; clinical laboratory assessments; clinical evaluation of vital 
signs, standard 12-lead ECGs, and physical examinations (PEs); and Columbia-Suicide Severity 
Rating Scale (C-SSRS). 
11.5.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with current ICH E6 GCP 
Guidelines. Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs.  


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11.5.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, unless otherwise specified. 
Laboratory test results that are abnormal and considered clinically significant will be reported as 
AEs (see Section 11.5.1). 
The safety laboratory test panels are shown in Table 11-1. 
Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Total bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate transaminase 
Alanine transaminase 
Amylase  
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Urate  
Hemoglobin  
Platelets  
Leukocytes  
Differential (percent): 
Eosinophils 
Basophils  
Neutrophils 
Lymphocytes 
Monocytes  
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
Urobilinogen  
Urine protein  
pH 
Urine blood  
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose  
a 
If urinalysis results are positive for protein or blood, 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 collected, urea may be substituted. 
Clinical laboratory assessments during screening must have no clinically significant findings that 
preclude participation in the study, as judged by the investigator, for a subject to receive study 
drug on Day 1. For non-surgical subjects, local laboratory results will be used during screening; 
previous test results from the facility’s local laboratory may be used to establish eligibility if 
collected within 2 hours before ICF signing. 
Additional Screening Tests: The following additional tests will be performed at the Screening 
Visit and/or pre-procedure to assess eligibility: 
• Serology (surgical subjects only): Hepatitis B surface antigen (HBsAg), hepatitis C virus 
antibody (HCV Ab), HCV RNA, and antibodies against human immunodeficiency viruses 1 
and 2 (HIV-1/HIV-2 Abs). Subjects with detectable viral load will be excluded (Section 8.2). 
• Serum Follicle-stimulating Hormone (FSH): Serum FSH will be tested at the Screening Visit 
for female subjects who are suspected to be postmenopausal (as defined in Section 11.5.6.1). 
For a subject to be considered of non-childbearing potential, the serum FSH levels will be 


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within the laboratory range for postmenopausal females. For non-surgical subjects, a test 
result is not required for eligibility; however, until the test result is received, a subject will be 
considered to be of childbearing potential and must follow contraception requirements 
(Section 11.5.6.1) until postmenopausal status is confirmed. 
• Pregnancy Testing: Surgical subjects: All biologically female subjects will have a serum 
beta-human chorionic gonadotropin (β-hCG) test during the Screening Visit. Female subjects 
of childbearing potential (Section 11.5.6.1) will also have a urine β-hCG test before 
admission on Day 1. Both the serum and urine β-hCG test must be negative to receive study 
drug. Non-surgical subjects: All biologically female subjects will have a urine β-hCG test 
during the Screening Visit, which occurs on Day 1; the test must be negative to receive study 
drug. 
• Drug and Alcohol Screening: Drug screening for opioids, methadone, cannabinoids, cocaine, 
amphetamines/methamphetamines, barbiturates, and benzodiazepines will be assessed by a 
urine test at the Screening Visit and before admission on Day 1; for non-surgical subjects, 
only 1 test is required because the Screening Visit is on Day 1. Alcohol screening will be 
assessed before admission (surgical subjects) or treatment assignment (non-surgical subjects) 
on Day 1 by a urine, blood, or breath test. Subjects may undergo random urine drug screen 
and alcohol testing if deemed appropriate by the investigator. Drug and alcohol screen results 
must be negative for a subject to receive study drug; a positive marijuana screen will only be 
exclusionary on Day 1. A positive drug screen for a known prescribed concomitant 
medication that is not otherwise exclusionary (e.g., benzodiazepines) will not disqualify 
subjects. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate. 
For purposes of study conduct, only laboratory tests done in the central laboratory may be used, 
with the following exceptions: 
• Day 1 (pre-procedure, if applicable) drug and alcohol tests and urine β-hCG pregnancy tests 
will be assessed by staff onsite. 
• For non-surgical subjects, local laboratories will be used for safety laboratory tests at 
screening. 
• For surgical subjects, local laboratories may be used to repeat a screening assessment to 
determine eligibility on Day 1 (pre-procedure) if there is clear evidence of laboratory error 
(Section 9.1.1.1) in the central laboratory assessment. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 
becomes aware of the abnormal result. If it is not possible to send a timely specimen to the 
central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base the 
assessment of an AE on the local laboratory value. 
11.5.3 
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 


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can be performed at the discretion of the investigator or healthcare provider. If the Screening 
Visit occurs via home health (surgical subjects only), an abbreviated PE will be performed at 
screening and a complete PE will be performed on Day 1. 
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: general; 
cardiovascular system; respiratory system; skin; and abdomen. 
A focused PE of the operative site (surgical subjects only) will be performed in order to assess 
wound healing. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, respiration 
rate, and oxygen saturation (SpO2). The subject will be instructed to rest (seated or supine) for at 
least 5 minutes before vital signs are assessed.  
If there is an abnormal clinical assessment during a home visit, depending on its severity and at 
investigator discretion, the subject may be instructed to have a PE or other evaluation in the 
clinic. 
11.5.4 
Electrocardiograms 
Standard 12-lead ECGs will be performed in triplicate 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 blood draws or any other procedures that may affect heart rate. 
• The subject will be instructed to rest (supine) for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position. 
The acceptable window for the 4-hour postdose ECG is ± 30 minutes relative to the scheduled 
nominal time. 
A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. All traces will be centrally evaluated by a qualified cardiologist. 
Clinically significant ECG abnormalities occurring during the study through the Safety 
Follow-up Visit will be recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the median QTcF is increased by >60 msec from the baseline or the 
median absolute QTcF value is ≥500 msec for any scheduled or unscheduled ECGs (performed 
in triplicate), 2 additional ECGs (performed in triplicate) will be performed approximately 2 to 
4 minutes apart to confirm the original measurement. If the median QTcF value from either of 
these repeated ECGs remains above the threshold value (>60 msec from baseline or ≥500 msec), 
the subject should discontinue dosing. For safety monitoring after discontinuation, 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.  


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11.5.5 
Columbia-Suicide Severity Rating Scale 
The C-SSRS, a series of questions about suicidal thoughts and behaviors, will be included (per 
Table 3-1, Table 3-3, and Table 3-4) for prospective assessment in accordance with regulatory 
guidance.31 
11.5.6 
Contraception and Pregnancy 
The effects of VX‑548 on conception, pregnancy, and lactation in humans are not known. Refer 
to the VX‑548 Investigator’s Brochure for additional details. 
11.5.6.1 
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. The subject must confirm that they will practice true 
abstinence from the Screening Visit through 30 days after the last dose of study drug. True 
abstinence is important to differentiate from periodic abstinence (e.g., calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal, which are not acceptable methods of 
contraception.  
• If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented through 
examination of a semen specimen. 
• 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 bilateral oophorectomy and/or hysterectomy 
• Same biological sex relationships. 
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception, as 
outlined in Table 11-2, is used as a couple from the Screening Visit through 30 days after the last 
dose of study drug. 


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Table 11-2 
Acceptable Methods of Contraception 
Subjects and their 
non-study partnersa 
At least 1 of the following acceptable methods must be used as a couple from the 
Screening Visit through 30 days after the last dose of study drug: 
• 
Male vasectomy 6 months or more previously, with a documented negative 
post-vasectomy semen analysis for spermb 
• 
Female bilateral tubal ligation performed at least 6 months previously 
• 
Female continuous use of an intrauterine device for at least 90 days before the first 
dose of study drug, throughout study drug treatment, and until 30 days after the last 
dose of study drug 
• 
Female hormonal contraceptives, if successfully used for at least 60 days before the 
first dose of study drug, throughout study drug treatment, and until 30 days after 
the last dose of study drug 
• 
Male or female condom (with or without spermicide)c 
• 
Female barrier contraception (such as diaphragm, cervical cap, or sponge) with 
spermicide 
a 
Applicable to subjects and their non-study partners of the opposite biological sex for whom the contraception 
requirement is not waived. 
b 
Medical record documentation of contraception for non-study partners is not required. The subject must 
confirm that their partner has documented proof, and the subject’s confirmation should be documented. 
c 
Female condom cannot be used with male condom due to risk of tearing. 
Additional notes: 
• If over the course of the study the subject meets the criteria for waiving the contraception 
requirements, the subject does not need to follow the contraceptive methods listed in 
Table 11-2. 
• Male subjects must not donate sperm from the first dose of study drug, throughout the study, 
and for 30 days following the last dose of study drug. 
• 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 biological sex. 
• Medical record documentation of contraception for non-study partners is not required. 
• 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. 
11.5.6.2 
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 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 
(1) notify the medical monitor and Vertex GPS within 24 hours of the site’s knowledge of the 
subject’s (or partner’s) pregnancy, and (2) send the Pregnancy Information Collection Form to 
Vertex GPS. 


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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 ANALYSIS 
12.1 
Sample Size and Power 
Approximately 250 subjects are planned to be enrolled. With 250 subjects, there is a 
92% probability of observing an AE in at least 1 subject if the true incidence is 1% and a 
99% probability of observing an AE in at least 1 subject if the true incidence is 2%. 
12.2 
Analysis Sets 
The All Subjects Set is defined as all subjects who were enrolled (defined as subject having data 
in the clinical database). The All Subjects Set will be used for individual subject data listings and 
disposition summary tables unless otherwise specified. 
The Safety Set is defined as all subjects who have received at least 1 dose of study drug. The 
Safety Set will be used for all safety analyses. 
The Full Analysis Set (FAS) is defined as all subjects who have received at least 1 dose of study 
drug. The FAS will be used for effectiveness analyses unless otherwise specified. 
12.3 
Statistical Analysis 
This section presents a summary of the principal features of the planned statistical analyses. 
Statistical analysis details will be in the statistical analysis plan (SAP), which will be finalized 
before clinical database lock. 
12.3.1 
General Considerations 
All individual subject data for subjects who have received at least 1 dose of study drug will be 
presented in individual subject data listings. 
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. For 
ECGs, the baseline value will be defined as the average of the non-missing pretreatment 
measurements (triplicate) on Day 1 before the first dose of study drug. 
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 to the 
Safety Follow-up Visit or to the completion of study participation (as defined in Section 9.1.7), 
whichever occurs first. 


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12.3.2 
Background Characteristics 
Subject disposition, demographic and baseline characteristics, and prior and concomitant 
medications will be summarized. 
12.3.3 
Effectiveness Analysis 
The subject perception of VX-548 effectiveness in treating pain as measured via PGA will be 
summarized descriptively. Additional details will be provided in the SAP. 
12.3.4 
Safety Analysis 
The overall safety profile of VX-548 will be assessed in terms of the following safety and 
tolerability endpoints: 
• Incidence of TEAEs 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis) 
• Standard 12-lead ECG outcomes 
• Vital signs 
Safety endpoints will be summarized descriptively based on the Safety Set. Additional details 
will be provided in the SAP. 
12.4 
Interim Analysis 
Interim analyses may be performed during the study. If these occur, the timing and details of the 
interim analysis will be documented in the SAP. 
12.5 
Independent Data Monitoring Committee Analysis 
Not applicable 
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, 


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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 in source documents from the time the ICF is signed until completion 
of study participation (Section 9.1.7). 
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in source documents. 
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 
May 2022). 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.  


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Table 13-1 
Grading of AE Severity  
Classification 
Description 
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 (Moderate) 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADLa 
Grade 3 (Severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADLb 
Grade 4 (Life-
threatening) 
Life-threatening consequences; urgent intervention indicated  
Grade 5 (Death) 
Death related to adverse event 
Source: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed May 2022) 
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). 
AE: adverse event 
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.  


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Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classificationa 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
AE: adverse event 
a 
Refer to Section 9.7 for directions regarding what drug actions are permitted per protocol.  
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) 
AE: adverse event 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE and may include treatments such as other medications, 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  


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• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“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 Safety Follow-up Visit, 
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 Safety Follow-up Visit 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 Safety Follow-up Visit, the 
SAE Form will be completed for new/initial events as well as to report follow-up information on 
previously reported events. Investigators are asked to report follow-up information as soon as it 
becomes available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email: globalpatientsafety@vrtx.com (preferred choice) 
Fax: +1-617-341-6159  
For technical issues related to submitting the form, contact telephone: +1-617-341-6677 
SAEs that occur after the Safety Follow-up Visit 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 


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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, IEC, and 
participating investigators in accordance with current ICH E2A 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, if allowed by local 
regulations. 
13.2 
Administrative Requirements 
13.2.1 
Product Complaints 
A product complaint is defined as any verbal or written communication addressed to Vertex, or 
designee, of inquiry or dissatisfaction with the identity, strength, quality, or purity of a released 
drug product, IMP, or medical device. In addition, suspected counterfeit/falsified product is 
considered a product complaint.   
Product complaints are to be reported to Vertex. 
13.2.2 
Ethical Considerations 
The study will be conducted in accordance with the current ICH E6 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. 
13.2.3 
Subject Information and Informed Consent 
After the study has been fully explained, 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 current ICH E6 GCP Guidelines and all 
applicable laws and regulations and will be subject to approval by Vertex or its designee. 
13.2.4 
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, 


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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.  
13.2.5 
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.  
13.2.6 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all data, 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 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. 
13.2.7 
Record Retention 
The investigator will maintain all study records according to current ICH E6 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. 


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13.2.8 
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. 
13.2.9 
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 per 
current ICH E6 GCP Guidelines. 
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 electronic data capture (EDC) application. The investigator will affirm the 
completeness and accuracy of the data by signing each casebook before data lock. If applicable, 
periodic investigator signatures may also be required. 
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. 
13.4 
Monitoring 
The study will be monitored by Vertex or its designee in accordance with written procedures. 
Monitoring and auditing procedures developed or approved by Vertex for these activities comply 
with GCP regulatory requirements and guidelines.  
The monitoring strategy may include onsite, remote, and central monitoring activities, in 
accordance with local regulations. The study site monitor will ensure that the study is conducted 
according to the protocol design and regulatory requirements. 


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13.5 
Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to 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 
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).32  
Publication Planning: Vertex staff along with the lead principal investigators, the steering 
committee, and/or the publication committee will work together to develop a publication plan.  


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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 criteria: 
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 current ICH E3 Guideline, will be 
submitted in accordance with local regulations. 


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14 
REFERENCES 
1 
Payne R. Limitations of NSAIDs for pain management: toxicity or lack of efficacy? J 
Pain. 2000;1(3 Suppl):14-8. 
2 
Centers for Disease Control and Prevention, Hedegaard H, Minino AM, Warner M. Drug 
overdose deaths in the United States, 1999-2018. NCHS Data Brief. 2020;No. 356:1-8. 
3 
Centers for Disease Control and Prevention. Vital statistics rapid release: provisional 
drug overdose death counts. Available at: https://www.cdc.gov/nchs/nvss/vsrr/drug-
overdose-data.htm#dashboard. Accessed 16 June 2022. 
4 
European Monitoring Centre for Drugs and Drug Addiction. European drug report 2021: 
trends and developments. Lisbon, Portugal: 2021. 
5 
Hijma HJ, Groeneveld GJ. Analgesic drug development: proof-of-mechanism and proof-
of-concept in early phase clinical studies. Medicine in Drug Discovery. 2021;10:1-15. 
6 
Taneja A, Della Pasqua O, Danhof M. Challenges in translational drug research in 
neuropathic and inflammatory pain: the prerequisites for a new paradigm. Eur J Clin 
Pharmacol. 2017;73(10):1219-36. 
7 
United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research. 2015-2021. New Molecular Entity (NME) 
drug and new biologic approvals. Available at: https://www.fda.gov/drugs/nda-and-bla-
approvals/new-molecular-entity-nme-drug-and-new-biologic-approvals. Accessed 14 
July 2022. 
8 
United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research. 1999-2016. New Molecular Entity (NME) 
drug and new biologic approvals. Available at: https://wayback.archive-
it.org/7993/20170404174205/https:/www.fda.gov/Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/NDAandBLA
ApprovalReports/ucm373420.htm. Accessed 14 July 2022. 
9 
England S. Voltage-gated sodium channels: the search for subtype-selective analgesics. 
Expert Opin Investig Drugs. 2008;17(12):1849-64. 
10 
Krafte D, Bannon A. Sodium channels and nociception: recent concepts and therapeutic 
opportunities. Curr Opin Pharmacol. 2008;8(1):50-6. 
11 
Akopian AN, Sivilotti L, Wood JN. A tetrodotoxin-resistant voltage-gated sodium 
channel expressed by sensory neurons. Nature. 1996;379(6562):257-62. 
12 
Shields SD, Ahn HS, Yang Y, Han C, Seal RP, Wood JN, et al. Nav1.8 expression is not 
restricted to nociceptors in mouse peripheral nervous system. Pain. 2012;153(10):2017-
30. 
13 
Amaya F, Decosterd I, Samad TA, Plumpton C, Tate S, Mannion RJ, et al. Diversity of 
expression of the sensory neuron-specific TTX-resistant voltage-gated sodium ion 
channels SNS and SNS2. Mol Cell Neurosci. 2000;15(4):331-42. 
14 
Blair NT, Bean BP. Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant 
Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J 
Neurosci. 2002;22(23):10277-90. 
15 
Bucknill AT, Coward K, Plumpton C, Tate S, Bountra C, Birch R, et al. Nerve fibers in 
lumbar spine structures and injured spinal roots express the sensory neuron-specific 
sodium channels SNS/PN3 and NaN/SNS2. Spine (Phila Pa 1976). 2002;27(2):135-40. 


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16 
Faber CG, Lauria G, Merkies ISJ, Cheng X, Han C, Ahn HS, et al. Gain-of-function 
Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A. 2012;109(47):19444-
49. 
17 
Han C, Vasylyev D, Macala LJ, Gerrits MM, Hoeijmakers JG, Bekelaar KJ, et al. The 
G1662S Nav1.8 mutation in small fibre neuropathy: impaired inactivation underlying 
DRG neuron hyperexcitability. J Neurol Neurosurg Psychiatry. 2014;85(5):499-505. 
18 
Abrahamsen B, Zhao J, Asante CO, Cendan CM, Marsh S, Martinez-Barbera JP, et al. 
The cell and molecular basis of mechanical, cold, and inflammatory pain. Science. 
2008;321(5889):702-5. 
19 
Roza C, Laird JM, Souslova V, Wood JN, Cervero F. The tetrodotoxin-resistant Na+ 
channel Nav1.8 is essential for the expression of spontaneous activity in damaged 
sensory axons of mice. J Physiol. 2003;550(Pt 3):921-6. 
20 
Strickland IT, Martindale JC, Woodhams PL, Reeve AJ, Chessell IP, McQueen DS. 
Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of 
dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint 
pain. Eur J Pain. 2008;12(5):564-72. 
21 
Qiu F, Jiang Y, Zhang H, Liu Y, Mi W. Increased expression of tetrodotoxin-resistant 
sodium channels Nav1.8 and Nav1.9 within dorsal root ganglia in a rat model of bone 
cancer pain. Neurosci Lett. 2012;512(2):61-6. 
22 
Jarvis MF, Honore P, Shieh CC, Chapman M, Joshi S, Zhang XF, et al. A-803467, a 
potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and 
inflammatory pain in the rat. Proc Natl Acad Sci U S A. 2007;104(20):8520-5. 
23 
Rush AM, Cummins TR. Painful research: identification of a small-molecule inhibitor 
that selectively targets Nav1.8 sodium channels. Mol Interv. 2007;7(4):192-5, 80. 
24 
Payne CE, Brown AR, Theile JW, Loucif AJ, Alexandrou AJ, Fuller MD, et al. A novel 
selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates 
nociception and sensory neuron excitability. Br J Pharmacol. 2015;172(10):2654-70. 
25 
United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation 
Research (CBER). Guidance for industry: pharmacokinetics in patients with impaired 
hepatic function: study design, data analysis, and impact on dosing and labeling. 
Rockville, MD: May 2003. 
26 
American Society of Anesthesiologists. 2014. ASA physical status classification system. 
Available at: https://www.asahq.org/standards-and-guidelines/asa-physical-status-
classification-system. Accessed 14 July 2022. 
27 
United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation 
Research (CBER). Premarketing Risk Assessment,. Rockville, MD: March 2005. 
28 
United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research (CDER). Draft guidance for industry: analgesic 
indications: developing drug and biological products. Rockville, MD: February 2014. 
29 
Rothman M, Vallow S, Damaraju CV, Hewitt DJ. Using the patient global assessment of 
the method of pain control to assess new analgesic modalities in clinical trials. Curr Med 
Res Opin. 2009;25(6):1433-43. 


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30 
Minkowitz H, Leiman D, Lu L, Reines S, Ryan M, Harnett M, et al. IV Tramadol - A 
new treatment option for management of post-operative pain in the US: An open-label, 
single-arm, safety trial including various types of surgery. 2020;13:1155-62. 
31 
United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation 
Research (CBER). Draft guidance for industry: suicidal ideation behavior: prospective 
assessment of occurrence in clinical trials. Rockville, MD: August 2012. 
32 
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. 
 
 
 


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15 
APPENDIX A: GUIDANCE ON SURGICAL PROCEDURES AND 
NON-SURGICAL ACUTE PAIN CONDITIONS 
Representative eligible surgical procedures and non-surgical acute pain conditions are defined in 
Inclusion Criterion 5 (Section 8.1). Table 15-1 presents surgical procedures and non-surgical 
conditions representative of those which are NOT eligible. 
Table 15-1 
Representative Ineligible Surgical Procedures and Non-surgical Conditions 
Resulting in Acute Pain 
Surgical Procedures 
Non-surgical Conditions 
Open joint arthroplasty (e.g., THA, TKA, TSA) 
Pain resulting from presumed hollow organ 
obstructive pathology (e.g., pancreatitis, renal colic) 
Thoracic surgery (open or laparoscopic) 
Pain presumed to be primarily visceral in origin 
(e.g., appendicitis, ovarian cysts, diverticulitis) 
Cardiac surgery 
Pain in a subject with active cancer and/or 
undergoing treatment for same 
Surgery in subject with active cancer – curative or 
palliative 
 
Major vascular surgery 
 
Spinal surgery 
 
Austin or Lapidus bunionectomy without concomitant 
surgery 
 
Full abdominoplasty 
 
THA: total hip arthroplasty; TKA: total knee arthroplasty; TSA: total shoulder arthroplasty 
 


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16 
PROTOCOL SIGNATURE PAGES 
16.1 
Sponsor Signature Page 
Protocol #: 
VX22-548-107 
Version #: 
2.0 
Version Date: 
09 November 2022 
Study Title: A Phase 3, Single-arm Study Evaluating the Safety and Effectiveness of VX‑548 
for Acute Pain 
This clinical study protocol has been reviewed and approved by the sponsor. 
Printed Name 
 
Title 
Signature 
 
Date 


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16.2 
Investigator Signature Page 
Protocol #:  
VX22-548-107 
Version #: 
2.0 
Version Date: 
09 November 2022 
Study Title: A Phase 3, Single-arm Study Evaluating the Safety and Effectiveness of VX‑548 
for Acute Pain 
 
 
I have read Protocol VX22-548-107, Version 2.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-548 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 22 
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1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX22-548-107 
(Final Analysis) 
 
A Phase 3, Single-arm Study Evaluating the Safety and 
Effectiveness of VX-548 for Acute Pain 
Author of SAP: 
 
 
Date of SAP: 20 Dec 2023 (v1.0) 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods)  
Page 2 of 22 
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2 
TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
2 
Table of Contents ............................................................................................................. 2 
3 
Modifications .................................................................................................................... 4 
3.1 
Modifications to the Approved Clinical Study Protocol ............................................ 4 
3.2 
Modifications to the Approved Statistical Analysis Plan ........................................... 4 
4 
Introduction...................................................................................................................... 5 
5 
Study Objectives .............................................................................................................. 5 
5.1 
Primary Objective ....................................................................................................... 5 
5.2 
Secondary Objective ................................................................................................... 5 
6 
Study Endpoints ............................................................................................................... 5 
6.1 
Primary Endpoint ........................................................................................................ 5 
6.2 
Secondary Endpoint .................................................................................................... 5 
7 
Overall Design .................................................................................................................. 5 
7.1 
Sample Size and Power .............................................................................................. 7 
7.2 
Randomization ............................................................................................................ 7 
7.3 
Blinding and Unblinding ............................................................................................ 7 
8 
Analysis Sets ..................................................................................................................... 8 
8.1 
All Subjects Set .......................................................................................................... 8 
8.2 
Safety Set .................................................................................................................... 8 
8.3 
Full Analysis Set ......................................................................................................... 8 
9 
Statistical Analysis ........................................................................................................... 8 
9.1 
General Considerations .............................................................................................. 8 
9.2 
Background Characteristics ........................................................................................ 9 
9.2.1 
Subject Disposition ............................................................................................. 9 
9.2.2 
Demographics and Baseline Characteristics ....................................................... 9 
9.2.3 
Medical History ................................................................................................ 10 
9.2.4 
Prior and Concomitant Medications ................................................................. 10 
9.2.5 
Study Drug Exposure and Study Drug Compliance ......................................... 11 
9.2.6 
Important Protocol Deviations .......................................................................... 11 
9.3 
Effectiveness Analysis .............................................................................................. 11 
9.4 
Safety Analysis ......................................................................................................... 12 
9.4.1 
Adverse Events ................................................................................................. 12 
9.4.2 
Clinical Laboratory Assessments ..................................................................... 13 
9.4.3 
Electrocardiogram ............................................................................................ 13 
9.4.4 
Vital Signs ........................................................................................................ 14 
9.4.5 
Physical Examination ....................................................................................... 14 
9.4.6 
Columbia-Suicide Severity Rating Scale ......................................................... 14 
9.5 
Subgroup Analyses ................................................................................................... 14 
10 Summary of Interim and IDMC Analyses .................................................................. 14 
11 References ....................................................................................................................... 15 
12 List of Appendices.......................................................................................................... 16 
Appendix A 
: Analysis Visit Windows for Effectiveness Assessments ......................... 16 


Statistical Analysis Plan (Methods)  
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Appendix B 
: Imputation Rules for Missing Medication and Dates/Times ................... 17 
Appendix C 
: Imputation Rules for Missing AE Dates and Times ................................ 18 
Appendix D 
: Threshold Value Criteria .......................................................................... 19 
 


Statistical Analysis Plan (Methods)  
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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 


Statistical Analysis Plan (Methods)  
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4 
INTRODUCTION 
This statistical analysis plan (SAP) for the final analysis 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. This SAP documents the planned 
statistical analysis of safety and effectiveness endpoints defined in the study protocol of 
VX22-548-107 and provides additional details and clarifications.  
The Vertex Biometrics Department will perform the final 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 clinical data lock for the final 
analysis. 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 data lock will be documented in the clinical study report for this study. 
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
To evaluate the safety and tolerability of VX-548 
5.2 
Secondary Objective 
To evaluate the effectiveness of VX-548 in treating acute pain 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
Safety and tolerability based on treatment-emergent adverse events (TEAEs), laboratory test 
results, vital signs, and ECGs 
6.2 
Secondary Endpoint 
Subject perception of VX-548 effectiveness in treating pain at the end of treatment as 
measured by the proportion of subjects reporting good, very good, or excellent on a patient 
global assessment (PGA) 
7 
OVERALL DESIGN  
This is a Phase 3, single-arm study evaluating the safety and effectiveness of VX-548 in 
treating acute pain (Figure 7-1 [surgical subjects] and Figure 7-2 [non-surgical subjects]). 
Surgical Subjects 
On Day 1, subjects will undergo a scheduled ambulatory surgical procedure with pain that is 
expected to last for at least 72 hours and that is expected to require no more than a short-term 
(i.e., <24-hour) admission. After surgery completion, a subject will be assigned to treatment 
if (1) the subject requests the first dose of study drug for pain relief, (2) the subject’s pain is 
moderate or severe on the VRS (verbal categorical rating scale), and (3) the subject’s pain is 


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≥4 on the NPRS (numeric pain rating scale). If a subject does not meet the VRS and NPRS 
criteria within the protocol-specified time period for the surgical procedure they underwent 
(e.g., 4 hours for most procedures), the subject will not be eligible for this study. 
Non-surgical Subjects 
On Day 1, after completion of screening assessments and confirmation of eligibility, a 
subject will begin treatment if (1) the subject’s pain is moderate or severe on the VRS, and 
(2) the subject’s pain is ≥4 on the NPRS. For a subject to be eligible, their pain must have 
been ongoing for ≤48 hours at presentation. 
All Subjects 
Approximately 250 subjects will receive VX-548 (100 mg first dose, then 50 mg every 12 
hours [q12h]). Subjects will continue to receive VX-548 for 14 days or until their pain 
resolves, whichever occurs first. An acetaminophen/ibuprofen combination may be used as a 
rescue medication for pain relief as needed (prn), starting any time after the first dose of 
study drug through Day 14, completion of study drug treatment due to pain resolution, or 
study drug discontinuation, whichever occurs first. Subjects will be permitted to take 
acetaminophen 650 mg/ibuprofen 400 mg every 6 hours (q6h) prn, up to a maximum of 2600 
mg/1600 mg in any 24-hour period. 
The following approach will be used to define pain resolution and completion of study drug 
treatment: 
1. Pain is considered to be resolved and the study drug treatment will be considered 
completed if 
a. a subject takes no study drug during a 48-hour period (i.e., skipped at least 4 
consecutive doses due to pain resolution); and 
b. a subject takes no more than 1 dose of acetaminophen/ibuprofen during each 24-hour 
period within the 48-hour period (i.e., no more than 2 doses in 48 hours). 
2. If a subject stops taking study drug per Criterion 1a but does not meet Criterion 1b, they 
will be instructed to restart study drug (and prn rescue medication). 
3. If a subject stops and restarts study drug (Criterion 2 above) and subsequently believes 
their pain is resolving and stops study drug a second time, they will be instructed to not 
restart study drug, regardless of whether the above criteria are met. 
4. If a subject stops study drug a second time after the restart of dosing (Criterion 3 above) 
and then fulfills both Criterion 1a and 1b, the pain is considered resolved and study drug 
treatment will be considered completed. If the subject fulfills only Criterion 1a but not 
Criterion 1b after the restart of dosing, the pain is considered not resolved and study drug 
will be considered discontinued. 
Note: If subject stops study drug due to pain resolution less than 48 hours before the last 
scheduled dose of study drug (i.e., stops after the second dose on Day 12) and therefore 
cannot meet Criterion 1a by Day 14, the subject will be considered to have completed study 
drug dosing as long as they also meet Criterion 1b. 


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Figure 7-1 
VX22-548-107 Study Design (Surgical Subjects) 
 
NPRS: numeric pain rating scale; VRS: verbal categorical rating scale 
Notes: After surgery completion, a subject will be assigned to treatment if (1) the subject requests the first dose of study 
drug for pain relief, (2) the subject’s pain is moderate or severe on the VRS, and (3) the subject’s pain is ≥4 on the NPRS. If 
a subject does not meet the VRS and NPRS criteria within the protocol-specified, procedure-specific time period, the subject 
will not be eligible for this study. Figure is not drawn to scale. 
Figure 7-2 
VX22-548-107 Study Design (Non-surgical Subjects) 
 
NPRS: numeric pain rating scale; VRS: verbal categorical rating scale 
Notes: After completion of screening assessments and confirmation of eligibility, a subject will be assigned to treatment if 
(1) the subject’s pain is moderate or severe on the VRS, and (2) the subject’s pain is ≥4 on the NPRS. Figure is not drawn to 
scale. 
 
7.1 
Sample Size and Power 
Approximately 250 subjects are planned to be enrolled. With 250 subjects, there is a 
92% probability of observing an AE in at least 1 subject if the true incidence is 1% and a 
99% probability of observing an AE in at least 1 subject if the true incidence is 2%. 
7.2 
Randomization 
This is a single-arm study with no randomization. 
7.3 
Blinding and Unblinding 
This is an open-label study. 


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8 
ANALYSIS SETS 
8.1 
All Subjects Set 
The All Subjects Set is defined as all subjects who were enrolled (defined as subject having 
data in the clinical database). The All Subjects Set will be used for individual subject data 
listings and disposition summary tables. 
8.2 
Safety Set 
The Safety Set is defined as all subjects who have received at least 1 dose of study drug. The 
Safety Set will be used for all safety analyses. 
8.3 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all subjects who have received at least 1 dose of 
study drug. The FAS will be used for effectiveness analyses. 
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. 
All individual subject data for subjects who have received at least 1 dose of study drug will 
be presented in individual subject data listings. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (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.  
For ECGs, the baseline value will be defined as the average of the most recent non-missing 
measurements (scheduled or unscheduled) collected before the first dose of study drug, 
expected to be the triplicate predose measurements on Day 1.   
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 to 
the Safety Follow-up Visit or to the completion of study participation (as defined in Section 
9.1.7 of the CSP), whichever occurs first. 
Unscheduled visits: Unscheduled visit measurements will be included in the analysis as 
follows: 
• In scheduled visit windows per specified visit windowing rules 


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• In the derivation of baseline 
• In the derivation of maximum and minimum values during the TE period, and maximum 
and minimum change from baseline values during the TE period for safety analyses 
• In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined PGA entries, which 
are provided by the subject in a dosing diary, are provided in Appendix A. All safety 
assessments are analyzed according to their nominal visits. 
Outliers: No formal statistical analyses will be performed to detect and/or remedy the 
presence of statistical outliers. 
Multiplicity: Only descriptive analyses will be performed; no statistical hypothesis testing 
will be performed. 
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized:  
• All Subjects Set/Enrolled 
• Full Analysis Set (FAS) 
• Safety Set 
• Enrolled but not dosed 
The number and percentage (based on the FAS) of subjects in each of the following 
disposition categories will be summarized: 
• Completed treatment and the reason for completion of treatment 
• Prematurely discontinued treatment and the reason for discontinuation from treatment 
• Completed study 
• Prematurely discontinued the study and the reason for discontinuation from study 
A disposition listing of subjects will be provided.  
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the FAS. 
Demographic data will include the following: 
• Age at screening (in years) 
• Age at screening category (≥18 to <65, ≥65 years) 
• Sex (male, female) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 


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• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, not collected per local regulations, Other, and 
Multiracial [if 2 or more races reported from a subject]) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• NPRS 
• NPRS category (<8, ≥8) 
• VRS (moderate, severe) 
• Surgical/non-surgical status 
• Surgery type 
• Site 
In addition to demographic data and baseline characteristics, 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 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). 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 after the date and time 
of the first dose of study drug through the end of the TE Period 
A given medication may be classified as a prior medication, a concomitant medication, or 
both a prior and a concomitant medication.  
If a medication start date/time is on or after the first dose of study drug, then the medication 
will be classified as a concomitant medication regardless of whether the medication end 
date/time is missing. If a medication end date/time is before the first dose of study drug, then 


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the medication will be classified as a prior medication regardless of whether the medication 
start date/time is missing.  
Note that a medication that started before the first dose of study drug and continued after the 
first dose will be classified as a prior medication and separately as a concomitant medication. 
If a medication has a missing or partially missing start or end date/time and it cannot be 
determined whether it was taken before the first dose of study drug or concomitantly, it will 
be classified as a prior and a concomitant medication. 
Details for imputing missing or partial start/end date and time of medication are described in 
Appendix B. 
Prior and concomitant medications will be summarized based on the FAS by Preferred Name 
and listed. Pre- and intra-operative medications and supplemental analgesic medications for 
surgical subjects will be included in the summary of prior medications. Rescue medication 
taken prior to the subject’s last dose of VX-548 will be included in the summary of 
concomitant medications. The proportion of subjects taking any rescue medication will be 
summarized separately. In addition, for acetaminophen and ibuprofen separately, the mean 
dose administered per day of VX-548 exposure (calculated for each subject as the total dose / 
number of days of exposure) will be summarized.  
Prior and concomitant non-pharmacological treatments or procedures will also be listed. 
9.2.5 
Study Drug Exposure and Study Drug Compliance 
Study drug exposure (in days) will be calculated as (last date of dosing – first date of dosing) + 1. 
This will be summarized overall, as well as for those who completed treatment and for those 
who discontinued treatment. Study drug exposure will also be summarized in categories: ≤3 
days, >3 to ≤7 days, and >7 days, using counts and percentages. 
Compliance will not be analyzed due to the complex nature of starting and stopping the study 
drug as explained in Section 9.1 of the CSP. 
All data collected during dispensation of study drug (e.g., time of administration and number 
of tablets taken) will be presented in an individual data listing. 
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 and presented in an individual data listing. 
9.3 
Effectiveness Analysis 
The secondary endpoint is the subject perception of VX-548 effectiveness in treating pain at 
the end of treatment as measured by the proportion of subjects reporting good, very good, or 
excellent on a patient global assessment (PGA). The PGA of study drug is a single-item 
assessment of patient perceptions of the method of pain control with the study drug and will 
be evaluated on a 5-point Likert scale (poor, fair, good, very good, or excellent). The 


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proportion of subjects reporting good, very good, or excellent, at the end of treatment will be 
presented descriptively based on the FAS, as well as the proportion of subjects providing 
each response. The PGA at the end of treatment is defined as either the PGA collected on 
Day 14 or the PGA associated with the End of Dosing Visit for subjects who complete or 
discontinue study drug treatment before Day 14. Missing PGA assessments at the end of 
treatment will be imputed using the previous PGA assessment. Subjects with no previous 
PGA assessments available will be considered non-responders and will be included in the 
denominator when calculating the proportions.  
9.4 
Safety Analysis 
The following safety and tolerability assessments will be used to evaluate the overall safety 
profile of VX-548:  
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (hematology, serum chemistry, coagulation, and urinalysis) 
• ECG outcomes 
• Vital signs 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
All safety analyses will be performed based on the Safety Set.  
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 after the first dose of study drug 
through the end of the TE Period 
For AEs with completely missing or partial start dates/times, 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 dates/times are defined in 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. In addition, a listing containing individual subject AE 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 Assessments 
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 threshold analysis 
criteria during the TE period will be summarized. The number and percentage of subjects 
with shift from baseline in selected test values meeting threshold analysis criteria will also be 
summarized for chemistry measurements. 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, listings of individual subject hematology, chemistry, and coagulation values 
outside the normal reference ranges will be provided. These listings 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 interval (msec), 
RR interval (msec), QRS duration (msec), QT interval (msec), and QT corrected for HR 
intervals (QTcF [msec]).  
The number and percentage of subjects meeting threshold analysis criteria during the TE 
period will be summarized. The threshold analysis criteria are provided in Appendix D. A 
listing containing individual subject measurements meeting the threshold value criteria at any 
time point will be provided. This listing will include data from both scheduled and 
unscheduled visits. 
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 


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≤500 msec, and >500 msec, as well as maximum treatment-emergent change from baseline 
value of QT/QTcF intervals, categorized as ≤0 msec, >0 and ≤30 msec, >30 and ≤60 msec, 
and >60 msec, will be provided.  
ECGs are performed in triplicate. The mean of the ECG measurements will be used as the 
ECG value for summaries of observed values and change from baseline values. All reported 
ECG measurements will be used to conduct threshold analyses and to assess maximum 
treatment-emergent values.  
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), respiratory rate (breaths per minute), and oxygen saturation (%).  
The number and percentage of subjects meeting threshold analysis criteria 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 an individual subject data listing only. 
9.4.6 
Columbia-Suicide Severity Rating Scale 
For each event category on the C-SSRS (suicidal ideation, suicidal behavior, suicidal ideation 
or behavior, self-injurious behavior without suicidal intent), the proportion of subjects with at 
least one event in the category during the TE Period will be summarized. C-SSRS results for 
subjects with responses of "Yes" at any visit will also be presented in an individual subject 
data listing. 
9.5 
Subgroup Analyses 
All summaries of safety, effectiveness, and use of rescue medication will be presented for 
surgical subjects. These summaries will also be presented for non-surgical subjects if they 
constitute at least 10% of the total subjects; otherwise, data for non-surgical subjects will be 
presented in listings only. Due to the underlying differences in the subgroup populations and 
potentially limited sample sizes in the non-surgical subgroup, these analyses should be 
interpreted with caution.  
Additionally, the proportion of subjects receiving fentanyl citrate, the median dose, and time 
from last administration of fentanyl citrate to the first dose of study drug among surgical 
subjects will be summarized in a separate table. 
10 
SUMMARY OF INTERIM AND IDMC ANALYSES 
Interim analyses may be performed during the study. If these occur, the timing and details of 
the interim analyses will be documented in the SAP prior to its finalization. 


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11 
REFERENCES 
Not applicable. 


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12 
LIST OF APPENDICES 
Appendix A : Analysis Visit Windows for Effectiveness Assessments  
Table 12-1 
Analysis Visit Windows for Effectiveness Assessments 
Assessment 
Visit/Timepoint 
Target Study Day  
Analysis Visit Window 
(in study days/timepoints) 
PGA 
EDV 
After treatment 
completion/disconti
nuation 
First assessment between 0 
and 48 hours after subject’s 
last dose of VX-548 
 
Note: If no PGA measurement is available within the EDV visit window, PGA at EDV will be imputed with the 
previous PGA measurement, if available. 
 
 


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Appendix B : Imputation Rules for Missing Medication and Dates/Times 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date and time: 
a. If hour and/or minute are missing, do not impute.   
b. If day is missing, use the first day of the month.  
c. If day and month are both missing, use the first day of the year.  
d. If day, month and year are all missing, use a date before the first dose date. 
2. Missing or partial medication stop date and time: 
a. If hour and/or minute are missing, do not impute.  
b. If day is missing, use the last day of the month. 
c. If day and month are both missing, use the last day of the year. 
d. If day, month and year are all missing, assign ‘continuing’ status to stop date. 
With missing or partial medication start times, only use the imputed start date to categorize 
the prior and/or concomitant medication as described in Table 12-2. If hour and/or minute of 
the first dose time are missing, only use the first dose date to categorize the prior and/or 
concomitant medication. Imputation of missing and/or partial dates for non-pharmacological 
treatments/procedures will follow the same imputation rule.  
Table 12-2 
Prior and/or Concomitant Categorization of a Medication 
Medication Start Date 
Medication Stop Date 
< First Dose Date/Time of 
Study Drug 
≥ First Dose Date/Time 
and ≤ End Date of TE 
Period 
< First dose date/time of study drug 
P 
PC 
≥ First dose date/time and ≤ end date of TE 
period 
- 
C 
C: Concomitant; P: Prior 
 
 


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Appendix C : Imputation Rules for Missing AE Dates and Times 
Imputation rules for missing or partial AE start dates and times are defined below: 
If Hour and/or Minute of AE start time are missing, do not impute:  
• If the AE start date is before the first dose date, the AE will be classified as a 
pretreatment AE. 
• If the AE start date is on or after the first dose date, the AE will be classified as a 
TEAE. 
If only Day of AE start date is missing:  
o If the AE start year and month are the same as that for the first dose date, then: 
 If the full (or partial) AE end date is NOT before the first dose date or AE end 
date is missing, then impute the AE start day as the day of the first dose date 
 Otherwise, impute the AE start day as 1. 
o Otherwise, impute the AE start day as 1. 
Compare the imputed AE start date with the TE period to determine whether the AE is a 
pretreatment AE or TEAE. 
If Day and Month of AE start date are missing: 
o If AE start year is the same as the year of the first dose date, then: 
 If the full (or partial) AE end date is NOT before the first dose date or the AE end 
date is missing, then impute the AE start month and day as the month and day of 
the first dose date; 
 Otherwise, impute the AE start month as January and the day as 1. 
o Otherwise, impute the AE start month as January and the day as 1. 
Compare the imputed AE start date with TE period to determine whether the AE is a 
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 the site 
with no imputation. Compare the full (or partial) AE end date to the first dose date. If the AE 
end date is before the first dose date, then the AE should be considered as a pretreatment AE. 
Otherwise, the AE will be considered as a TEAE. 
If Hour and/or Minute of first dose time are missing: 
• If the AE start date is before the first dose date, the AE will be classified as a 
pretreatment AE. 
• If the AE start date is on or after the first dose date, the AE will be classified as a 
TEAE. 
A missing or partially missing AE end date will not be imputed. 
 


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Appendix D : Threshold Value Criteria 
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 - ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20xULN 
>20xULN 
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 - ≤5xULN 
>5 - ≤20xULN 
>20xULN 
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 - ≤5xULN 
>5 - ≤20xULN  
>20xULN 
CTCAE grade 1-4 
Albumin 
<LLN - ≥30 g/L 
<30 - ≥20 g/L 
<20 g/L 
CTCAE grade 1-3 
Creatinine 
>ULN - ≤1.5xULN 
>1.5 - ≤3xULN 
>3 - ≤6xULN 
>6xULN 
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 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥100 g/L 
<100 - ≥80 g/L  
<80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤20 g/L above ULN 
>20 g/L above ULN - ≤40 g/L above 
ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥75.0 x 10e9 /L 
<75.0 - ≥50.0 x 10e9 /L  
<50.0 - ≥25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 
Coagulation 
 
 
Activated partial thromboplastin 
time (PTT)  
 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5xULN 
CTCAE grade 1-3 


Statistical Analysis Plan (Methods)  
Page 21 of 22 
Protocol Number: VX22-548-107 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5 x ULN 
CTCAE grade 1-3 
 
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 
 
 
 
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.  
 
 
 
 
 


Statistical Analysis Plan (Methods)  
Page 22 of 22 
Protocol Number: VX22-548-107 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
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 
 
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 
 
Oxygen saturation 
decreased 
<88% 
<95% and decrease from baseline >5% of absolute 
oxygen saturation