Clinical trial NCT05553366
Conditions: Acute Pain
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2022-10-03; Completion date: 2023-12-15
Enrollment: 1075 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of suzetrigine for acute pain after a bunionectomy.

Detailed description:

Arms: arm 1: Participants received placebo matched to suzetrigine (SUZ) and hydrocodone bitartrate/acetaminophen (HB/APAP) for 2 days. arm 2: Participants received HB 5 milligrams (mg)/ APAP 325 mg every 6 hours (q6h) for 2 days. arm 3: Participants received SUZ \[100 mg as first dose, followed by 50 mg every 12 hours (q12h)\] for 2 days.
Interventions: intervention 1: SUZ intervention 2: HB/APAP intervention 3: Placebo (matched to SUZ) intervention 4: Placebo (matched to HB/APAP)
Intervention descriptions: intervention 1: Tablets for oral administration. intervention 2: Capsules for oral administration. intervention 3: Placebo matched to SUZ for oral administration. intervention 4: Placebo matched to HB/APAP for oral administration.

Protocol documents:
Prot_000.pdf: 
Page 1 of 57 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 3, Randomized, Double‑blind, 
Placebo‑controlled Study Evaluating the Efficacy and 
Safety of VX‑548 for Acute Pain After a Bunionectomy 
Vertex Study Number: VX22-548-104 
IND Number: 146185 
Date of Protocol: 12 April 2023 (Version 4.0) 
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 VX22-548-104, Version 4.0 
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Summary of Changes to the Protocol 
The previous version of this protocol (Version 3.0, 09 November 2022) was amended to create 
the current version (Version 4.0, 12 April 2023). The protocol history is below.  
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 05 August 2022 
Original version 
Version 2.0, 12 October 2022 
• 
Added exclusion criteria for history of QT prolongation or standard 
12-lead ECG demonstrating median QTcF >450 msec at screening or 
baseline. 
• 
Added study drug interruption and stopping rules. 
• 
Clarified procedures for ECG safety monitoring after the first dose of 
study drug. 
Version 3.0, 09 November 2022 
• 
Permitted study drug to be taken with or without food after the first dose. 
• 
Updated the contraception requirement to the use of at least 1 acceptable 
method of contraception based on supporting nonclinical data. 
• 
Specified that numeric pain rating scale (NPRS) responder endpoints will 
be compared to placebo. 
• 
Expanded NPRS window at 48 hours to ± 15 min for operational 
feasibility. 
• 
Added a requirement for medical monitor to authorize all cases of 
screening assessment repetition. 
• 
Restricted inhalational anesthetics use from admission through discharge. 
• 
Clarified that documentation of all medications administered in-clinic, 
including prior medications, will include the time of each administration. 
Version 4.0, 12 April 2023 
Current version 
 
Key changes in the current version of the protocol are summarized below.  
Change and Rationale 
Affected Sections  
Moved the last key secondary endpoint, “time to ≥1-point reduction in NPRS 
from baseline compared to placebo”, to other secondary endpoints. 
Sections 2, 7.2, and 12.3.3.3 
Simplified the order of assessments for operational feasibility. 
Section 3 
Added an exception for Vertex personnel or vendor(s), who are not part of the 
study team, to be unblinded for the analysis of pharmacokinetic (PK)/population 
PK data to support interactions with regulatory authorities, as applicable. 
Section 10.8.1 
Clarified viral load sample collection and reflex testing for human 
immunodeficiency viruses 1 and 2. 
Table 3-1 and Section 11.5.2 
Clarified that Exclusion Criterion 3 applies to standard 12-lead ECGs 
performed at the Screening Visit and on Day -1 (pre-procedure). 
Section 8.2, Exclusion 
Criterion 3 
Clarified the restrictions on analgesic medications, inhalational anesthetics, and 
steroids. 
Table 9-2 and Section 9.4.1 
Clarified that the timing of meals relative to dosing is only required to be 
recorded in the source for the first dose of study drug. 
Section 11.2.1 
 
Typographical and administrative changes were also made to improve the clarity of the 
document. 


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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 3, Randomized, Double‑blind, Placebo‑controlled Study Evaluating the Efficacy and 
Safety of VX‑548 for Acute Pain After a Bunionectomy 
  
Brief Title 
Evaluation of Efficacy and Safety of VX-548 for Acute Pain After a Bunionectomy 
 
 
Clinical Phase 
and Clinical 
Study Type  
Phase 3, efficacy and safety 
 
 
Objectives 
Primary Objective 
To evaluate the efficacy of VX-548 in treating acute pain after a bunionectomy  
Secondary Objective 
To evaluate the safety and tolerability of VX-548 
Other Objective 
To evaluate the pharmacokinetics (PK) of VX-548 and its metabolite, 
 
 
 
 
Endpoints 
Primary Endpoint 
• 
Time-weighted sum of the pain intensity difference (SPID) as recorded on the numeric 
pain rating scale (NPRS) from 0 to 48 hours (SPID48) compared to placebo 
Key Secondary Endpoints 
• 
SPID48 compared to hydrocodone bitartrate/acetaminophen (HB/APAP) 
• 
Time to ≥2-point reduction in NPRS from baseline compared to placebo 
Other Secondary Endpoints 
• 
Time to ≥1-point reduction in NPRS from baseline compared to placebo 
• 
Proportion of subjects reporting good or excellent on the Patient Global Assessment 
(PGA) at 48 hours compared to placebo 
• 
Incidence of vomiting or nausea compared to HB/APAP 
• 
Time-weighted SPID as recorded on the NPRS from 0 to 24 hours (SPID24) compared 
to placebo 
• 
Time to first use of rescue medication compared to placebo 
• 
Proportion of subjects using rescue medication from 0 to 48 hours compared to placebo 
• 
Total rescue medication usage from 0 to 48 hours compared to placebo 
• 
Safety and tolerability based on the incidence and type of adverse events (AEs), changes 
from baseline in clinically significant laboratory test results, vital signs, and ECGs 
Other Endpoints 
• 
Time-weighted SPID as recorded on the NPRS from 0 to 36 hours (SPID36) compared 
to placebo 
• 
Time-weighted SPID as recorded on the NPRS from 0 to 12 hours (SPID12) compared 
to placebo 
• 
Proportion of subjects with ≥30% reduction in NPRS at 48 hours compared to placebo 
• 
Proportion of subjects with ≥50% reduction in NPRS at 48 hours compared to placebo 
• 
Proportion of subjects with ≥70% reduction in NPRS at 48 hours compared to placebo 
• 
Proportion of subjects using rescue medication from 0 to 24 hours compared to placebo 


Protocol VX22-548-104, Version 4.0 
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• 
Time to first use of rescue medication in the first 12 hours compared to placebo 
• 
Proportion of subjects using rescue medication from 0 to 12 hours compared to placebo 
• 
Proportion of subjects using rescue medication from 24 to 48 hours compared to placebo 
• 
PK parameter estimates of VX-548 and its metabolite, 
 
 
 
Number of 
Subjects 
Approximately 1000 subjects 
 
 
Study 
Population 
Male and female subjects, 18 through 80 years of age (inclusive), with pain that is moderate 
or severe on the verbal categorical rating scale (VRS) and ≥4 on the NPRS after a 
bunionectomy 
 
 
Investigational 
Drug 
Active substance: VX-548 
Activity: voltage-gated sodium channel 1.8 (NaV1.8) inhibitor 
Strength and route of administration: 50-mg tablets and matching placebo for oral 
administration 
 
 
Reference Drug 
Active substance: HB/APAP 
Activity: opioid analgesic 
Strength and route of administration: 5-mg/325-mg capsules (over-encapsulated tablets) and 
matching placebo for oral administration 
 
 
Study Duration 
Excluding the Screening Visit, each subject will participate in the study for 4 days plus a 
Safety Follow-up Visit 14 ± 2 days after the last dose of study drug. 
 
 
Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, 3-arm, parallel study design 
evaluating the efficacy and safety of VX-548 in treating acute pain after a bunionectomy 
(Figure 2-1). 
On Day -1, subjects will undergo a primary unilateral bunionectomy with distal first 
metatarsal osteotomy (i.e., Austin procedure) and internal fixation under regional anesthesia 
(Mayo and popliteal sciatic block). A continuous popliteal sciatic block infusion 
(0.2% ropivacaine) will be started after surgery and remain in place until approximately 
3AM, but no later than 5AM, on Day 1. After removal of the popliteal sciatic block, a subject 
will be randomized to 1 of 3 treatment groups 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 9 hours after removal of the popliteal sciatic block, the subject will not be eligible for 
this study. 
Approximately 1000 subjects will be randomized 2:2:1 to 3 treatment groups: VX-548 
(100 mg first dose, then 50 mg every 12 hours [q12h]), HB/APAP (5 mg/325 mg every 
6 hours [q6h]; opioid reference), or placebo (Table 2-1). Randomization will be stratified by 
site and baseline NPRS (<8 versus ≥8). To maintain the blind, all subjects will receive the 
same number of tablets and capsules q6h in a double-dummy design. 


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Figure 2-1 
VX22-548-104 Study Design 
 
HB/APAP: hydrocodone bitartrate/acetaminophen; NPRS: numeric pain rating scale; VRS: verbal 
categorical rating scale 
Notes: After removal of the popliteal sciatic block, a subject will be randomized to 1 of 3 treatment 
groups 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 9 hours after removal of the popliteal sciatic block, 
the subject will not be eligible for this study. Figure is not drawn to scale. 
 
Table 2-1 
Study VX22-548-104 Treatment Groups 
Treatment 
Active Dose 
Number of Subjects 
VX-548 
100 mg first dose, then 50 mg q12h 
400 
HB/APAP 
5 mg/325 mg q6h 
400 
Placebo 
– 
200 
HB/APAP: hydrocodone bitartrate/acetaminophen; q6h: every 6 hours; q12h: every 12 hours 
Notes: To maintain the blind, all subjects will receive the same number of tablets and capsules in a 
double-dummy design. VX-548 active or VX-548 placebo tablets will be administered to all 
subjects q12h as follows: 0 hours (first dose) and at 12, 24, and 36 hours after the first dose of 
study drug. HB/APAP active or HB/APAP placebo capsules will be administered to all subjects 
q6h as follows: 0 hours (first dose) and at 6, 12, 18, 24, 30, 36, and 42 hours after the first dose 
of study drug. 
Subjects will report their pain intensity on the NPRS at each scheduled time point through 
48 hours after the first dose of study drug. In addition, pain intensity will be recorded on the 
NPRS immediately before each administration of rescue medication.  
Ibuprofen (400 mg orally q6h as needed) is permitted as a rescue medication for pain relief 
upon the subject’s request starting any time after the first dose of study drug through 48 hours 
after the first dose of study drug. Subjects are encouraged to wait 90 minutes after the first 
dose of study drug to request rescue medication, and subjects should generally not receive 
rescue medication unless their NPRS score is ≥4. 
 
 
Assessments 
Efficacy: NPRS, use of rescue medications, and PGA of study drug 
Safety: AEs, clinical laboratory assessments, clinical evaluation of vital signs, standard 
12-lead ECGs, and physical examinations 
Other: DNA blood sample (optional) and PK parameters of VX-548 and 
 
 
 
Statistical 
Analyses 
Assuming a standardized effect size of 0.40 for VX-548 compared to placebo and 0.25 for 
VX-548 compared to HB/APAP, 338 evaluable subjects per group for VX-548 and 
HB/APAP and 169 evaluable subjects for placebo will provide more than 90% power for the 
primary endpoint of VX-548 versus placebo on SPID48 and 90% power for the key 
secondary endpoint of VX-548 versus HB/APAP on SPID48, based on 2-sample t-tests with 


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significance level 0.05. To allow for about 15% dropout, a total of approximately 
1000 subjects are planned to be enrolled. 
The primary efficacy analysis will be based on an analysis of covariance (ANCOVA) model. 
The model will include SPID48 as the dependent variable and treatment as a fixed effect, 
with site and baseline NPRS as covariates. If the model estimation does not converge, then 
site will be removed from the model. The least squares mean difference from placebo for 
VX-548 will be provided along with the 95% CI and P value. 


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are in Table 3-1, Table 3-2, and Table 3-3. 
Table 3-1 
Study VX22-548-104: Screening Visit Through Admission 
Event/Assessment 
Day -28 to Day -2 
Day -1 
Comments 
Screening Visit 
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 occur before the day of surgery) and may 
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 9.1.5 
Admission 
 
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 
Prior use of opioid medications 
X 
X 
Any use within 12 months before the Screening 
Visit through admission will be recorded; Section 
9.5.  
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 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 before any procedures that may affect 
heart rate (e.g., blood sampling). Section 11.5.4 
PE 
X 
(X) 
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. 
Section 11.5.3 
Weight, height, and BMI 
X 
 
Weight and height will be measured with shoes off. 
BMI = weight (kg) / [height (cm/100)]2 
Serology (HbsAg, HCV Ab, 
HCV RNA, HIV-1/HIV-2 
Ab/Ag, and HIV-1/HIV-2 
RNA) 
X 
 
RNA samples will only be analyzed as a reflex test 
following a positive antibody or antibody/antigen 
test; Section 11.5.2 
Serum β-hCG 
X 
 
All biologically female subjects; Section 11.5.2. 
Serum FSH 
X 
 
Suspected postmenopausal female subjects only; 
Section 11.5.2 
Serum chemistry 
X 
 
Section 11.5.2 
Hematology 
X 
 
Section 11.5.2 


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Table 3-1 
Study VX22-548-104: Screening Visit Through Admission 
Event/Assessment 
Day -28 to Day -2 
Day -1 
Comments 
Screening Visit 
Pre-procedure 
Coagulation 
X 
 
Section 11.5.2 
Urinalysis 
X 
 
Section 11.5.2 
Urine β-hCG 
 
X 
All female subjects of childbearing potential. 
Assessed by staff onsite. Section 11.5.2 
Drug test 
X 
X 
Urine; Section 11.5.2. 
Day -1: Testing kit assessed by staff onsite. 
Alcohol test 
 
X 
Urine, blood, or breath. Assessed by staff onsite. 
Section 11.5.2 
Research subject 
responsibilities, placebo, 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 9.5. 
Non-pharmacological 
treatment and procedures 
review 
Continuous from signing of ICF 
through completion of study 
participation 
All non-pharmacological 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; FSH: follicle-stimulating hormone; HbsAg: hepatitis B 
surface antigen; HCV Ab: hepatitis C virus antibody; HIV-1/HIV-2 Ab/Ag: human immunodeficiency viruses 1 and 2 
antibody/antigen; 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.  


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Table 3-2 
Study VX22-548-104: Procedure Through Randomization 
Event/Assessment 
Day -1 
Day 1 
Comments 
Procedure and 
Post-procedure 
Block Removal Through 
Randomization / Predosea 
Inpatient period 
X 
X 
 
Bunionectomy 
X 
 
Section 9.1 
Record supplemental 
analgesic medication 
X 
X 
Record pain medications given postoperatively 
through time of block removal. Type of pain 
medication allowed is based on NPRS. 
Section 9.4.1.1 
Clear liquid diet 
 
X 
Starting 2 hours before block removal through 
2 hours after the first dose of study drug. 
Section 9.4.2 
Removal of popliteal 
sciatic block (block 
removal)  
 
X 
Defined as removal of infusion catheter and/or 
completion of ropivacaine infusion. Timing is 
expected between 3AM and 5AM (Day 1) after 
surgical procedure. Section 9.4.1.1 
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 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 before any procedures that may affect 
heart rate (e.g., blood sampling). Section 11.5.4 
Blood sampling for PK 
 
X 
Collect any time prior to first study drug dose on 
Day 1; Section 11.2.1. 
VRS 
 
X 
Complete after block removal upon request for the 
first dose of study drug for pain relief; 
Section 9.1.1. 
NPRS 
X 
X 
Before block removal: Complete before 
administration of supplemental analgesic 
medication (Section 9.4.1.1). 
After block removal: Complete after VRS, only if 
pain is rated moderate or severe on the VRS. 
Section 11.4.1 
Randomization 
 
X 
Subject must request study drug for pain relief and 
meet pain criteria (moderate or severe on VRS and 
≥4 on NPRS) within 9 hours after block removal to 
be eligible for randomization (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 9.5. 
Non-pharmacological 
treatment and 
procedures review 
Continuous from signing of ICF through 
completion of study participation 
All non-pharmacological 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; PK: pharmacokinetics; VRS: verbal categorical rating scale 
   
a  
Subject must complete all Day 1 predose assessments before the first dose of study drug is administered. 


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Table 3-3 
Study VX22-548-104: Treatment Period and Safety Follow-up 
Event/ 
Assessmenta 
Hours After First Dose of Study Drug 
SFUb 
Comments 
0c 0.5 1 1.5 2 
3 
4 
5 
6 
8 12 14 16 18 20 24 26 to 32 36 38 to 44 48 
Inpatient period 
Continuous from admission through completion of 48-hour assessments 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
After completion of all study assessments. 
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. Sections 9.1.3 and 9.1.5. 
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 (can be outside the visit window) and may 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 9.1.5 
PGA of study drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Complete before the start of any other assessments scheduled at the 
same time point. Section 11.4.3 
Vital signs 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
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 blood sampling. 
Acceptable window is ± 1 hour from the scheduled time point. 
Section 11.5.3 
Standard 12-lead 
ECG 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
26 h 
 
38 h 
 
 
Performed in triplicate after the subject has been at rest (supine) for at 
least 5 minutes; 12-lead ECGs will be done before any procedures that 
may affect heart rate (e.g., blood sampling). Acceptable window is 
± 1 hour from the scheduled time point. Section 11.5.4 
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 
Focused PE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Assess wound healing at the operative site. Section 11.5.3 
NPRS 
 
X X X X X X X X X X 
 
X 
 
X X 
28 h 
32 h 
X 
40 h 
44 h 
X 
 
Complete before any blood sampling when time points coincide. 
Acceptable windows for scheduled time points are: 
• <48 hours after first dose: ± 5 minutes  
• 48 hours after first dose: ± 15 minutes 
An unscheduled NPRS will be completed immediately before each 
administration of rescue medication. Section 11.4.1 
Blood sampling for 
PK 
 
 
 
 
X 
 
X 
 
 
 
X X 
 
 
 
X 
26 h 
 
X 
38 h 
 
X 
 
12, 24, and 36 hours after first dose: Collect within 15 minutes 
before the next study drug dose. 
All other time points after first dose: Collect within ± 30 minutes of 
scheduled time point. Section 11.2.1 
DNA blood sample 
(optional) 
X 
 
May be collected any time during confinement after randomization. 
Section 11.3.1 
 
a 
Assessments that coincide with study drug administration will be performed before dosing, unless noted otherwise. 
b 
All subjects will have a SFU Visit 14 ± 2 days after the last dose of study drug (Section 9.1.3), including those who prematurely discontinue study drug dosing (Section 9.1.4). 
c  
Time 0 hours is defined as the time of administration for the first dose of study drug, which must occur within 25 minutes after randomization (ideally within 15 minutes). 


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Table 3-3 
Study VX22-548-104: Treatment Period and Safety Follow-up 
Event/ 
Assessmenta 
Hours After First Dose of Study Drug 
SFUb 
Comments 
0c 0.5 1 1.5 2 
3 
4 
5 
6 
8 12 14 16 18 20 24 26 to 32 36 38 to 44 48 
Serum chemistry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 11.5.2 
Hematology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 11.5.2 
Coagulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 11.5.2 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 11.5.2 
Clear liquid diet 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Starting 2 hours before block removal through 2 hours after the first 
dose of study drug. Section 9.4.2 
Study drug 
administration 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
30 h 
X 
42 h 
 
 
To maintain the blind, all subjects receive the same number of tablets 
and capsules q6h. Section 9.6 
Rescue medication 
use 
Ibuprofen 400 mg orally q6h prn (upon request) after first dose of study drug 
 
Record NPRS (Section 11.4.1) immediately before each 
administration. Record date and time of administration. Section 9.4.1.2 
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 9.5 
Non-
pharmacological 
treatment and 
procedures review 
Continuous from signing of ICF through completion of study participation 
All non-pharmacological 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; LIP: licensed independent practitioner; NPRS: numeric pain rating scale; PE: physical examination; PGA: Patient Global Assessment; PK: pharmacokinetic; prn: as 
needed; q6h: every 6 hours; SFU: Safety Follow-up 
Note: Assessments denoted by “(X)” are performed in the situations defined in the Comments column. 
 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
Summary of Changes to the Protocol......................................................................................... 2 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 7 
4 
Table of Contents ................................................................................................................. 12 
List of Tables............................................................................................................................ 15 
List of Figures .......................................................................................................................... 15 
List of Abbreviations................................................................................................................ 16 
5 
Introduction.......................................................................................................................... 18 
5.1 
Background ..................................................................................................................... 18 
5.2 
Study Rationale .............................................................................................................. 18 
6 
Study Objectives .................................................................................................................. 19 
6.1 
Primary Objective ........................................................................................................... 19 
6.2 
Secondary Objective ....................................................................................................... 19 
6.3 
Other Objective .............................................................................................................. 19 
7 
Study Endpoints ................................................................................................................... 19 
7.1 
Primary Endpoint ............................................................................................................ 19 
7.2 
Secondary Endpoints ...................................................................................................... 19 
7.2.1 
Key Secondary Endpoints ...................................................................................... 19 
7.2.2 
Other Secondary Endpoints .................................................................................... 19 
7.3 
Other Endpoints .............................................................................................................. 19 
8 
Study Population .................................................................................................................. 20 
8.1 
Inclusion Criteria ............................................................................................................ 20 
8.2 
Exclusion Criteria ........................................................................................................... 20 
9 
Study Implementation ......................................................................................................... 22 
9.1 
Study Design .................................................................................................................. 22 
9.1.1 
Screening ................................................................................................................ 24 
9.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 24 
9.1.1.2 
Rescreening ...................................................................................................... 24 
9.1.2 
Treatment Period .................................................................................................... 25 
9.1.3 
Follow-up................................................................................................................ 25 
9.1.4 
Early Discontinuation ............................................................................................. 25 
9.1.5 
Home Health Visits ................................................................................................ 26 
9.1.6 
Completion of Study Participation ......................................................................... 26 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 26 
9.3 
Rationale for Study Elements ......................................................................................... 26 
9.3.1 
Study Design........................................................................................................... 26 
9.3.2 
Study Drug Dose and Duration .............................................................................. 27 
9.3.3 
Rationale for Study Assessments ........................................................................... 27 
9.4 
Study Restrictions ........................................................................................................... 27 
9.4.1 
Analgesic Medications ........................................................................................... 28 
9.4.1.1 
Perioperative Pain Management ...................................................................... 28 
9.4.1.2 
Rescue Medication ........................................................................................... 29 
9.4.2 
Additional Dietary Restrictions .............................................................................. 29 


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9.5 
Prior and Concomitant Medications ............................................................................... 30 
9.6 
Administration ................................................................................................................ 30 
9.7 
Dose Modification for Toxicity ...................................................................................... 30 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 31 
9.9 
Removal of Subjects ....................................................................................................... 31 
9.10 Replacement of Subjects ................................................................................................ 31 
10 Study Drug Information and Management ....................................................................... 31 
10.1 Preparation and Dispensing ............................................................................................ 32 
10.2 Packaging and Labeling ................................................................................................. 32 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 32 
10.4 Drug Accountability ....................................................................................................... 32 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 33 
10.6 Compliance ..................................................................................................................... 33 
10.7 Rescue Medication ......................................................................................................... 33 
10.8 Blinding and Unblinding ................................................................................................ 33 
10.8.1 
Blinding .................................................................................................................. 33 
10.8.2 
Unblinding .............................................................................................................. 34 
11 Assessments .......................................................................................................................... 34 
11.1 Subject and Disease Characteristics ............................................................................... 34 
11.2 Pharmacokinetics ............................................................................................................ 35 
11.2.1 
Blood Sampling ...................................................................................................... 35 
11.2.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 35 
11.2.3 
Bioanalysis.............................................................................................................. 35 
11.3 Other Assessments .......................................................................................................... 35 
11.3.1 
Exploratory Assessments: Pharmacogenomics ...................................................... 35 
11.4 Efficacy ........................................................................................................................... 36 
11.4.1 
Numeric Pain Rating Scale ..................................................................................... 36 
11.4.2 
Use of Rescue Medications .................................................................................... 36 
11.4.3 
Patient Global Assessment of Study Drug ............................................................. 36 
11.5 Safety .............................................................................................................................. 36 
11.5.1 
Adverse Events ....................................................................................................... 36 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 36 
11.5.3 
Physical Examinations and Vital Signs .................................................................. 38 
11.5.4 
Electrocardiograms ................................................................................................. 39 
11.5.5 
Contraception and Pregnancy ................................................................................. 39 
11.5.5.1 Contraception ................................................................................................... 39 
11.5.5.2 Pregnancy ......................................................................................................... 41 
12 Statistical Analysis ............................................................................................................... 41 
12.1 Sample Size and Power .................................................................................................. 41 
12.2 Analysis Sets .................................................................................................................. 41 
12.3 Statistical Analysis ......................................................................................................... 42 
12.3.1 
General Considerations ........................................................................................... 42 
12.3.2 
Background Characteristics .................................................................................... 42 
12.3.3 
Efficacy Analysis .................................................................................................... 42 
12.3.3.1 Analysis of Primary Endpoints ........................................................................ 42 
12.3.3.2 Analysis of Secondary Endpoints .................................................................... 42 


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12.3.3.3 Multiplicity Adjustment ................................................................................... 43 
12.3.4 
Safety Analysis ....................................................................................................... 43 
12.4 Interim Analysis ............................................................................................................. 43 
12.5 Independent Data Monitoring Committee Analysis ....................................................... 43 
12.6 Clinical Pharmacology Analysis .................................................................................... 43 
12.6.1 
Pharmacokinetic Analysis ...................................................................................... 43 
12.6.2 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 44 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 44 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 44 
13.1.1 
Adverse Events ....................................................................................................... 44 
13.1.1.1 Definition of an Adverse Event........................................................................ 44 
13.1.1.2 Clinically Significant Assessments .................................................................. 44 
13.1.1.3 Documentation of Adverse Events................................................................... 45 
13.1.1.4 Adverse Event Severity .................................................................................... 45 
13.1.1.5 Adverse Event Causality .................................................................................. 46 
13.1.1.6 Study Drug Action Taken ................................................................................ 46 
13.1.1.7 Adverse Event Outcome .................................................................................. 46 
13.1.1.8 Treatment Given............................................................................................... 47 
13.1.2 
Serious Adverse Events .......................................................................................... 47 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 47 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 48 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 48 
13.2 Administrative Requirements ......................................................................................... 49 
13.2.1 
Product Complaints ................................................................................................ 49 
13.2.2 
Ethical Considerations ............................................................................................ 49 
13.2.3 
Subject Information and Informed Consent ........................................................... 49 
13.2.4 
Investigator Compliance ......................................................................................... 49 
13.2.5 
Access to Records ................................................................................................... 50 
13.2.6 
Subject Privacy ....................................................................................................... 50 
13.2.7 
Record Retention .................................................................................................... 50 
13.2.8 
Study Termination .................................................................................................. 50 
13.2.9 
End of Study ........................................................................................................... 51 
13.3 Data Quality Assurance .................................................................................................. 51 
13.4 Monitoring ...................................................................................................................... 51 
13.5 Data Capture ................................................................................................................... 51 
13.6 Confidentiality and Disclosure ....................................................................................... 52 
13.7 Publications and Clinical Study Report .......................................................................... 52 
13.7.1 
Publication of Study Results ................................................................................... 52 
13.7.2 
Clinical Study Report ............................................................................................. 53 
14 References ............................................................................................................................. 54 
15 Protocol Signature Pages .................................................................................................... 56 
15.1 Sponsor Signature Page .................................................................................................. 56 
15.2 Investigator Signature Page ............................................................................................ 57 
 


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List of Tables 
Table 2-1 
Study VX22-548-104 Treatment Groups................................................................ 5 
Table 3-1 
Study VX22-548-104: Screening Visit Through Admission .................................. 7 
Table 3-2 
Study VX22-548-104: Procedure Through Randomization ................................... 9 
Table 3-3 
Study VX22-548-104: Treatment Period and Safety Follow-up .......................... 10 
Table 9-1 
Study VX22-548-104 Treatment Groups.............................................................. 23 
Table 9-2 
Study Restrictions ................................................................................................. 27 
Table 10-1 
Study Drug ............................................................................................................ 32 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 35 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 37 
Table 11-3 
Acceptable Methods of Contraception.................................................................. 40 
Table 13-1 
Grading of AE Severity ........................................................................................ 45 
Table 13-2 
Classifications for AE Causality ........................................................................... 46 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 46 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 47 
List of Figures 
Figure 2-1 
VX22-548-104 Study Design ................................................................................. 5 
Figure 9-1 
VX22-548-104 Study Design ............................................................................... 23 
 


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List of Abbreviations 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ANCOVA 
analysis of covariance 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
DRG 
dorsal root ganglia 
ECG 
electrocardiogram 
EDC 
electronic data capture 
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 
h 
hour 
HB/APAP 
hydrocodone bitartrate/acetaminophen 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HCV Ab 
hepatitis C virus antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV-1/HIV-2 Ab/Ag 
human immunodeficiency viruses 1 and 2 antibody/antigen 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
institutional review board 
IV 
intravenous 
IXRS 
interactive response system in which X represents voice or web, such as IWRS 
LIP 
licensed independent practitioner 
max 
maximum value 
min 
minimum value 


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Abbreviation 
Definition 
n 
size of subsample 
N 
number of subjects 
N2O 
nitrous oxide 
NaV 
voltage-gated sodium channel 
NPRS 
numeric pain rating scale 
NSAID 
nonsteroidal anti-inflammatory drug 
P 
probability 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PGA 
Patient Global Assessment 
PK 
pharmacokinetic, pharmacokinetics 
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 
SPID 
sum of the pain intensity difference 
SPID12 
sum of the pain intensity difference as recorded on the numeric pain rating scale 
from 0 to 12 hours 
SPID24 
sum of the pain intensity difference as recorded on the numeric pain rating scale 
from 0 to 24 hours 
SPID36 
sum of the pain intensity difference as recorded on the numeric pain rating scale 
from 0 to 36 hours 
SPID48 
sum of the pain intensity difference as recorded on the numeric pain rating scale 
from 0 to 48 hours 
SpO2 
oxygen saturation 
SUSAR 
suspected, unexpected, serious adverse reaction 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
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 77,000 overdose deaths in the US in 2021 and in approximately 74% of 
fatal drug overdoses in the EU in 2020.3, 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 is preferentially expressed in peripheral pain-sensing neurons (e.g., the dorsal root 
ganglia [DRG])11, 13, NaV1.8 inhibitors are not expected to be associated with the side effects 
commonly observed with other sodium channel modulators and are not expected to have the 
abuse liability associated with opioid therapies. Therefore, targeting the underlying biology of 
pain through selective NaV1.8 inhibition represents a scientific 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. 
VX-548 is being developed for the treatment of pain. VX-548 is a NaV1.8 inhibitor that is highly 
selective for NaV1.8 relative to other NaV channels. Clinical data from Phase 1 studies in healthy 
subjects and Phase 2 proof-of-concept studies in subjects with moderate to severe acute pain 
demonstrate that VX-548 is generally safe and well tolerated. Refer to the VX-548 Investigator’s 
Brochure for additional details.25 
5.2 
Study Rationale 
This study will evaluate the efficacy and safety of VX-548 in treating acute pain after a 
bunionectomy. 


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6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
• To evaluate the efficacy of VX-548 in treating acute pain after a bunionectomy  
6.2 
Secondary Objective 
• To evaluate the safety and tolerability of VX-548 
6.3 
Other Objective 
• To evaluate the pharmacokinetics (PK) of VX-548 and its metabolite, 
 
 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
• Time-weighted sum of the pain intensity difference (SPID) as recorded on the numeric pain 
rating scale (NPRS) from 0 to 48 hours (SPID48) compared to placebo 
7.2 
Secondary Endpoints 
7.2.1 
Key Secondary Endpoints 
• SPID48 compared to hydrocodone bitartrate/acetaminophen (HB/APAP) 
• Time to ≥2-point reduction in NPRS from baseline compared to placebo 
7.2.2 
Other Secondary Endpoints 
• Time to ≥1-point reduction in NPRS from baseline compared to placebo 
• Proportion of subjects reporting good or excellent on the Patient Global Assessment (PGA) 
at 48 hours compared to placebo 
• Incidence of vomiting or nausea compared to HB/APAP 
• Time-weighted SPID as recorded on the NPRS from 0 to 24 hours (SPID24) compared to 
placebo 
• Time to first use of rescue medication compared to placebo 
• Proportion of subjects using rescue medication from 0 to 48 hours compared to placebo 
• Total rescue medication usage from 0 to 48 hours compared to placebo 
• Safety and tolerability based on the incidence and type of AEs, changes from baseline in 
clinically significant laboratory test results, vital signs, and ECGs 
7.3 
Other Endpoints 
• Time-weighted SPID as recorded on the NPRS from 0 to 36 hours (SPID36) compared to 
placebo 
• Time-weighted SPID as recorded on the NPRS from 0 to 12 hours (SPID12) compared to 
placebo 


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• Proportion of subjects with ≥30% reduction in NPRS at 48 hours compared to placebo 
• Proportion of subjects with ≥50% reduction in NPRS at 48 hours compared to placebo 
• Proportion of subjects with ≥70% reduction in NPRS at 48 hours compared to placebo 
• Proportion of subjects using rescue medication from 0 to 24 hours compared to placebo 
• Time to first use of rescue medication in the first 12 hours compared to placebo 
• Proportion of subjects using rescue medication from 0 to 12 hours compared to placebo 
• Proportion of subjects using rescue medication from 24 to 48 hours compared to placebo 
• PK parameter estimates of VX-548 and its metabolite, 
 
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 
Before Surgery: 
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, inclusive. 
5. Subject scheduled to undergo a primary unilateral bunionectomy with distal first metatarsal 
osteotomy (i.e., Austin procedure) and internal fixation under regional anesthesia (Mayo and 
popliteal sciatic block). 
After Surgery: 
6. Subject reported pain that is moderate or severe on the verbal categorical rating scale (VRS) 
and ≥4 on the NPRS within 9 hours after removal of the popliteal sciatic block on Day 1. 
7. Subject is lucid and able to follow commands. 
8. All analgesic guidelines (Section 9.4.1) were followed during and after the bunionectomy. 
8.2 
Exclusion Criteria 
Before Surgery: 
1. Prior history of bunionectomy or other foot surgery on the index foot; or bunionectomy on 
the opposite foot as part of this study. 
2. 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; 


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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. 
3. 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 the Screening Visit or on Day -1 (pre-procedure). 
4. Presence of an automated implantable cardioverter defibrillator, cardiac resynchronization 
therapy device, or pacemaker. 
5. History of significant hepatic disease, including but not limited to hepatic cirrhosis, portal 
hypertension, moderate or severe hepatic impairment (defined as Child-Pugh Class B or C).26 
6. Alanine transaminase or aspartate transaminase values >2.5 × upper limit of normal. 
7. History of severe renal impairment defined as estimated glomerular filtration rate (eGFR) of 
<30 mL/min/1.73m2 calculated using the subject’s measured serum creatinine; the suggested 
calculation method for eGFR is the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation. 
8. 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. 
9. History of any sensory abnormality that, in the opinion of the investigator, may confound the 
ability of the subject to assess postoperative pain. 
10. Subjects who have a painful physical condition that, in the opinion of the investigator, may 
confound the assessments of postoperative pain. 
11. A known or clinically suspected active infection with human immunodeficiency virus or 
hepatitis B or C viruses. 
12. Any prior surgery within 1 month before the first study drug dose, unless approved by the 
medical monitor. 
13. American Society of Anesthesiologists physical status classification27 of ≥3. 
14. Chronic use of opioids (pure agonists, agonist/antagonists, partial agonists, antagonists) or 
NSAIDs with dose escalation within 30 days before admission; or unwilling or unable to stop 
analgesics at least 5 half-lives or 2 days (whichever is longer) before admission. 
15. Subjects who have started new medications that have not been at a stable dose for at least 
14 days prior to the scheduled bunionectomy procedure and before dosing with 
investigational product. 
16. Subjects unwilling to receive any protocol-related medicine (e.g., ibuprofen, acetaminophen, 
fentanyl, hydrocodone). 


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17. Subjects with a history of allergy or significant 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. 
18. Subjects with sleep apnea and/or on a home positive airway pressure device. 
19. 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. 
20. For female subjects: Pregnant, nursing, or planning to become pregnant during the study or 
within 30 days after the last dose of study drug. 
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 dose of study drug. 
21. Participation in a previous study investigating VX-548. 
22. Participated in another investigational study within 30 days of the first dose of study drug. 
23. 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. 
24. Use of the substances, activities, or devices, as defined in Section 9.4, during the specified 
times. 
25. 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. 
After Surgery: 
26. Subject had a Type 3 deformity requiring a base wedge osteotomy, concomitant surgery such 
as hammertoe repair, or any surgical complications during the bunionectomy. 
27. Subject had a medical complication during the bunionectomy that, in the opinion of the 
investigator, should preclude randomization. 
28. 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, randomized, double-blind, placebo-controlled, 3-arm, parallel study design 
evaluating the efficacy and safety of VX-548 in treating acute pain after a bunionectomy 
(Figure 9-1). 
On Day -1, subjects will undergo a primary unilateral bunionectomy with distal first metatarsal 
osteotomy (i.e., Austin procedure) and internal fixation under regional anesthesia (Mayo and 
popliteal sciatic block). A continuous popliteal sciatic block infusion (0.2% ropivacaine) will be 
started after surgery and remain in place until approximately 3AM, but no later than 5AM, on 
Day 1. After removal of the popliteal sciatic block, a subject will be randomized to 1 of 


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3 treatment groups 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 9 hours after removal of the popliteal 
sciatic block, the subject will not be eligible for this study. 
Approximately 1000 subjects will be randomized 2:2:1 to 3 treatment groups: VX-548 (100 mg 
first dose, then 50 mg every 12 hours [q12h]), HB/APAP (5 mg/325 mg every 6 hours [q6h]; 
opioid reference), or placebo (Table 9-1). Randomization will be stratified by site and baseline 
NPRS (<8 versus ≥8). To maintain the blind, all subjects will receive the same number of tablets 
and capsules q6h in a double-dummy design. 
Figure 9-1 
VX22-548-104 Study Design 
 
HB/APAP: hydrocodone bitartrate/acetaminophen; NPRS: numeric pain rating scale; VRS: verbal categorical 
rating scale 
Notes: After removal of the popliteal sciatic block, a subject will be randomized to 1 of 3 treatment groups 
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 9 hours after removal of the popliteal sciatic block, the subject will not be eligible for 
this study. Figure is not drawn to scale. 
 
Table 9-1 
Study VX22-548-104 Treatment Groups 
Treatment 
Active Dose 
Number of Subjects 
VX-548 
100 mg first dose, then 50 mg q12h 
400 
HB/APAP 
5 mg/325 mg q6h 
400 
Placebo 
– 
200 
HB/APAP: hydrocodone bitartrate/acetaminophen; q6h: every 6 hours; q12h: every 12 hours 
Notes: To maintain the blind, all subjects will receive the same number of tablets and capsules in a 
double-dummy design. VX-548 active or VX-548 placebo tablets will be administered to all subjects q12h as 
follows: 0 hours (first dose) and at 12, 24, and 36 hours after the first dose of study drug. HB/APAP active or 
HB/APAP placebo capsules will be administered to all subjects q6h as follows: 0 hours (first dose) and at 6, 
12, 18, 24, 30, 36, and 42 hours after the first dose of study drug. 
Subjects will report their pain intensity on the NPRS at each scheduled time point through 
48 hours after the first dose of study drug. In addition, pain intensity will be recorded on the 
NPRS immediately before each administration of rescue medication.  
Ibuprofen (400 mg orally q6h as needed [prn]) is permitted as a rescue medication for pain relief 
upon the subject’s request starting any time after the first dose of study drug through 48 hours 


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after the first dose of study drug. Subjects are encouraged to wait 90 minutes after the first dose 
of study drug to request rescue medication, and subjects should generally not receive rescue 
medication unless their NPRS score is ≥4. 
9.1.1 
Screening 
All study periods will be conducted as described in Section 9.1. 
Screening Visit through Admission 
Assessments from the Screening Visit through admission (pre-procedure) are listed in Table 3-1. 
The Screening Visit will occur within 27 days before the scheduled bunionectomy 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 visit window. 
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.4). 
At the Screening Visit, subjects will receive trainings on appropriate expectations around their 
participation in a clinical study, placebo response reduction, and the importance of accurately 
reporting their post-procedural pain. On Day -1 (pre-procedure), these trainings will be repeated. 
Additional review of these educational materials may be repeated for some or all subjects, as 
needed. 
Surgical Procedure Through Randomization 
Assessments from the surgical procedure through randomization are listed in Table 3-2. 
VRS will be completed upon request for the first dose of study drug for pain relief after removal 
of the popliteal sciatic block. 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 
(Section 8.1) within 9 hours after removal of the popliteal sciatic block, the subject will not be 
eligible for this study. 
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 
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 


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• 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 the 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 
Treatment Period 
Treatment Period assessments are listed in Table 3-3. 
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 conclusion of the 
scheduled inpatient portion of the study, the medical monitor (or authorized designee) will be 
notified, and the subject will be asked to remain at the study site until such abnormalities resolve. 
If the subject is unable or unwilling to remain at the study site, the medical monitor (or 
authorized designee) will be notified, and the investigator will make every effort to arrange 
follow-up evaluations at appropriate intervals to document the course of the abnormalities. 
9.1.3 
Follow-up 
Subjects will have a Safety Follow-up Visit 14 (± 2) days after the last dose of study drug. Safety 
Follow-up Visit assessments are listed in Table 3-3. 
9.1.4 
Early Discontinuation 
Subjects who prematurely discontinue study drug dosing for any reason will remain under 
observation at the study site for at least 48 hours after the first dose of study drug and complete 
(1) all scheduled vital signs and 12-lead ECG assessments through 48 hours after the first dose of 
study drug and (2) all safety assessments listed for the 48-hour time point (Table 3-3), after 
which point they can be discharged. The reason, date, and time of discontinuation will be 
recorded for all subjects who prematurely discontinue study drug. All concomitant medications 
will continue to be recorded through completion of study participation as indicated in 
Section 9.5. 
If a subject has any clinically significant, study-related abnormalities, the medical monitor (or 
authorized designee) will be notified, and the subject will be asked to remain at the study site 
until such abnormalities resolve. If the subject is unable or unwilling to remain at the study site, 
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. 
Subjects who prematurely discontinue study drug dosing will be required to complete the 
Safety Follow-up Visit 14 (± 2) days after the last dose of study drug. Safety Follow-up Visit 
assessments are listed in Table 3-3. 


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If a subject withdraws consent for the study, no further assessments will be performed; refer to 
Section 9.8 for information on the use of study data and samples already collected. 
9.1.5 
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. 
9.1.6 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as 1 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 
Approximately 1000 subjects will be randomized 2:2:1 to 3 treatment groups: VX-548, 
HB/APAP (opioid reference), or placebo. The randomization ratio of 2:2:1 will be controlled for 
the overall study, and the details of the randomization implementation will be specified in 
separate documents. 
Each randomized subject will be assigned a unique subject number. Randomization will be 
stratified by site and baseline NPRS (<8 versus ≥8). 
An interactive web or voice response system (IXRS) will be used to assign subjects to treatment. 
The randomization code will be produced by Vertex Biostatistics or a qualified randomization 
vendor. The Vertex study biostatistician will review and approve the production of the final 
randomization list, which will be reviewed and approved by a designated unblinded 
biostatistician who is not a member of the Study Team.  
9.3 
Rationale for Study Elements 
9.3.1 
Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, 3-arm, parallel study design 
evaluating the efficacy and safety of VX-548 in treating acute pain after a bunionectomy. 
Bunionectomy is a well-established, multi-dose, surgical, acute pain model. A randomized, 
double-blind study design was selected to avoid observer bias and reduce symptoms or outcomes 
arising from the subjects’ knowledge of treatment. A parallel design is considered most 
appropriate given the acute nature of bunionectomy surgery. 
An opioid reference group assessing a standard-of-care treatment (HB/APAP 5 mg/325 mg q6h) 
was included to establish the ability of the study, as executed, to successfully observe a treatment 
effect. 
Following a standard study design, subjects will be randomized after removal of the popliteal 
sciatic block and after the subject’s pain meets the pain threshold criteria. The pain threshold 
criteria are designed to ensure subjects have sufficient pain to determine if the drug is effective. 


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Ibuprofen was selected as the rescue medication because it is a commonly used, short-acting, 
standard-of-care treatment 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 PK 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 duration of dosing (48 hours) is a standard duration for postsurgical, acute pain models and 
is of sufficient length to assess efficacy and safety. 
9.3.3 
Rationale for Study Assessments 
VRS: A 4-point VRS (none, mild, moderate, or severe) is included as part of the pain threshold 
inclusion criterion to ensure that all subjects have moderate or severe pain at baseline, which 
ensures subjects have sufficient pain to determine if the study drug is effective. 
NPRS: NPRS is frequently used in bunionectomy studies and is recognized by the FDA as a 
valid pain intensity measure.28 Pain rated ≥4 on an 11-point (0 to 10) NPRS at baseline ensures 
subjects have sufficient pain to determine if the study drug is effective. 
Use of rescue medications: The use of rescue medications is an important covariate in pain 
studies that can impact the analysis of other efficacy assessments. 
PGA of study drug: The PGA of study drug is a single-item assessment of patient perceptions 
of pain control with the study drug and is evaluated on a 4-point Likert scale (poor, fair, good, or 
excellent).29 The PGA of study drug provides subjects the ability to state their perceptions of the 
treatment that may not be captured by measuring pain intensity alone. 
9.4 
Study Restrictions 
Study restrictions are summarized in Table 9-2. Additional details on study restrictions will be 
provided in the Study Reference Manual. 
Table 9-2 
Study Restrictions 
Restricted 
Medication/Food/Activity a 
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 
longer) 
Completion of SFU assessments 
Analgesic medications (per 
guidelines in Section 9.4.1) 
5 half-lives or 2 days (whichever is 
longer) before admission 
Completion of 48-hour 
assessments (or after early 
discontinuation, if applicable) 
Inhalational anesthetics (e.g., N2O, 
sevoflurane, desflurane, isoflurane) 
Admission 
Completion of 48-hour 
assessments (or after early 
discontinuation, if applicable) 


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Table 9-2 
Study Restrictions 
Restricted 
Medication/Food/Activity a 
Timing of Restriction 
Start 
Stop 
Oral steroids 
5 half-lives or 2 days (whichever is 
longer) before admission 
Completion of 48-hour 
assessments (or after early 
discontinuation, if applicable) 
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, Seville oranges, 
and 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 discharge 
Alcohol 
24 hours before first dose of study 
drug 
Until discharge 
Strenuous exercise (e.g., heavy 
lifting, weight training, and 
aerobics) 
48 hours before first clinical 
laboratory testing  
Completion of SFU assessments 
N2O: nitrous oxide; 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 9.5 for guidance on concomitant medications. 
9.4.1 
Analgesic Medications 
All medications with analgesic properties (e.g., opioids, NSAIDs, IV steroids) are prohibited for 
5 half-lives or 2 days (whichever is longer) before admission through completion of 48-hour 
assessments (or after early discontinuation, if applicable), except for those permitted for 
perioperative pain management (Section 9.4.1.1) and ibuprofen rescue (Section 9.4.1.2). 
9.4.1.1 
Perioperative Pain Management 
Pre- and intra-operative: 
• Intravenous (IV) midazolam and/or fentanyl will be administered, followed by IV propofol, a 
popliteal sciatic block (≤0.5% ropivacaine), and a Mayo block (2% lidocaine without 
epinephrine). NSAIDs may not be administered. 
Postoperative: 
• A continuous popliteal sciatic block infusion (0.2% ropivacaine) will be started at an initial 
rate between 1 to 3 mL/h after surgery and will remain in place until approximately 3AM, 
but no later than 5AM on Day 1. Removal of the popliteal sciatic block (“block removal”) is 
defined as removal of the infusion catheter and/or completion of the ropivacaine infusion. 


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• Postoperative supplemental analgesic medications are permitted before the time of popliteal 
block removal per the following guidelines: 
o Acetaminophen (975 to 1000 mg) can be administered q6h prn until 6 hours before 
removal of the popliteal block for subjects with NPRS score of 4 through 6 after 
surgery. 
o Fentanyl citrate (12.5 to 25 µg IV) can be administered every 2 hours prn until 
1.5 hours before removal of the popliteal block for subjects with NPRS score of 7 or 
above after surgery. 
o Ropivacaine boluses and/or infusion rate changes can be used prn prior to removal of 
the popliteal block for subjects with NPRS score of ≥4; boluses should not be used at 
the time of block removal. 
• The use of ice packs is NOT permitted. 
• A record (date and time of administration) will be kept of all medication use prior to removal 
of the popliteal block. An unscheduled NPRS will be completed immediately before each 
administration of supplemental analgesic medication except when an administration of 
supplemental analgesic medication occurs within 30 minutes after a preceding 
administration. 
• No pain treatments are allowed from the time of block removal through the first dose of 
study drug. 
9.4.1.2 
Rescue Medication 
• Ibuprofen (400 mg orally q6h prn) is permitted as a rescue medication for pain relief upon 
the subject’s request starting any time after the first dose of study drug through 48 hours after 
the first dose of study drug. 
• Subjects are encouraged to wait 90 minutes after the first dose of study drug to request rescue 
medication, and subjects should generally not receive rescue medication unless their NPRS 
score is ≥4. 
• 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. 
• An unscheduled NPRS will be completed immediately before each administration of rescue 
medication (Section 11.4.1). 
9.4.2 
Additional Dietary Restrictions 
Subjects will be on a clear liquid diet (≤8 fluid ounces per hour) starting 2 hours before block 
removal through 2 hours after the first dose of study drug (Table 3-2 and Table 3-3). Refer to the 
Study Reference Manual for a list of permitted liquids. After this period, study drug may be 
taken with or without food. 


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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 opioid medications taken within 12 months before the Screening Visit through admission 
will be recorded with indication, route of administration, and start and stop dates of 
administration. 
• All medications taken within 14 days before the Screening Visit through completion of study 
participation (Section 9.1.6) will be recorded with indication, route of administration, and 
start and stop dates of administration. In addition, all medications administered in-clinic will 
also be recorded with the time of each administration, and analgesic concomitant medications 
will be recorded with the dose. All subjects will be questioned about medications at each 
visit. 
9.6 
Administration 
Study drug will be administered according to the following guidelines: 
• To maintain the blind, all subjects will receive the same number of tablets and capsules q6h 
in a double-dummy design: 
o VX-548 active or VX-548 placebo tablets will be administered to all subjects q12h: 
0 hours (first dose) and at 12, 24, and 36 hours after the first dose of study drug. 
o HB/APAP active or HB/APAP placebo capsules will be administered to all subjects 
q6h: 0 hours (first dose) and at 6, 12, 18, 24, 30, 36, and 42 hours after the first dose 
of study drug. 
• The first dose of study drug must be administered within 25 minutes after randomization 
(ideally within 15 minutes). The acceptable window for each subsequent dose of study drug 
is ± 45 minutes from the scheduled time point. 
• 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. All doses 
will be administered by authorized study site personnel and following national and local laws 
and regulations. 
• When assessment time points coincide with study drug administration, study drug will be 
administered after completing all assessments unless noted otherwise. 
• Study drug must be administered following the dietary restrictions outlined in Table 9-2 and 
Section 9.4.2. 
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 9.1.4). 


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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 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 
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.  
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 for a 
Safety Follow-up Visit, if applicable (see Section 9.1.4), 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, VX-548 placebo, HB/APAP, and HB/APAP placebo 
(Sections 10.1 through 10.6). Vertex will also supply the commercially available rescue 
medication (Section 10.7). 


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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.  
Study drug will be dispensed at the study site to blinded 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, 5-mg/325-mg HB/APAP capsules, and matching 
placebos. Study drug labeling will be in compliance with applicable local and national 
regulations. Additional details about study drug packaging, labeling, and dispensing 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. Specifically, study drug will be stored in a 
securely locked, substantially constructed cabinet or other securely locked, substantially 
constructed enclosure. Access to study drug will be limited to prevent theft or diversion of the 
study drug. To ensure adequate records, all study drugs will be accounted for via the drug 
accountability forms as instructed by Vertex. 
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 
How Supplied 
VX-548 
Tablet 
Oral 
Supplied as 50-mg tablets 
VX-548 placebo 
Tablet 
Oral 
Supplied as tablets 
HB/APAP 
Capsule 
Oral 
Supplied as over-encapsulated 5-mg/325-mg tablets 
HB/APAP placebo 
Capsule 
Oral 
Supplied as capsules 
HB/APAP: hydrocodone bitartrate/acetaminophen 
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 
dispensed but not administered. 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. 


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10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials until the study monitor has 
performed drug accountability. If the study monitor authorizes destruction at the study site, the 
investigator will ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by Vertex. 
Destruction will be adequately documented. 
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  
Study drug doses will be administered under the direct supervision of the investigator or 
designee. A hand-and-mouth check will be done after each dose administration at the study site 
to ensure 100% study treatment compliance. 
10.7 
Rescue Medication 
Vertex will supply ibuprofen for use as rescue medication during the Treatment Period. Drug 
accountability will be performed in a similar manner as for study drug. 
10.8 
Blinding and Unblinding 
This is a double-blind study. 
10.8.1 
Blinding  
All study personnel will be blinded to subject treatment assignments except for the following 
individuals:  
• Any site personnel for whom this information is important to ensure the safety of a subject in 
the event of a life-threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of a subject 
and a fetus in the event of a pregnancy 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy serious 
adverse event (SAE) processing and reporting regulations 
• External vendor (unblinded) statistician preparing the final (production) randomization list 
who is not part of the study team 
• Vertex IXRS Management for IXRS oversight and system administration 
• Vertex Clinical Supply Chain 
• The bioanalytical laboratory/vendor personnel responsible for the sample testing (Vertex or 
external) 
• The Vertex bioanalytical personnel responsible for reviewing raw data from the bioanalytical 
contract research organization (CRO), who is not a member of the Study Team (the Vertex 
bioanalytical Study Team member will continue to be blinded) 


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• Vertex personnel or vendor(s), who are not part of the study team, and are responsible for 
analyzing PK/population PK data to support interactions with regulatory authorities, as 
applicable. 
Vertex medical monitor may, for matters relating to safety, unblind individual subjects at any 
time. 
10.8.2 
Unblinding 
At the initiation of the study, study site personnel will be instructed on the method for breaking 
the blind. The unblinding method will be either manual or electronic. 
Unblinding of the individual subject’s treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject’s study treatment is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the medical monitor to discuss unblinding. 
If investigators deem it unnecessary to unblind immediately, they will first attempt to contact the 
medical monitor to discuss unblinding. If investigators have tried but are unable to reach the 
medical monitor, they will use their best judgment, based on the nature and urgency of the 
clinical situation, and may proceed with unblinding. 
Contact information for the medical monitor (or appropriate backup) will be in a separate 
document. 
If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding event. 
The reason and the date of the unblinding will be documented clearly in the subject’s study file. 
Information about the treatment assignment obtained from the unblinding will be maintained in a 
secure location with controlled access and will not be shared with Vertex, the CRO, or any site 
personnel (other than the physician treating the subject). In addition, the investigator will 
consider whether the clinical event that prompted unblinding will be considered an SAE, 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report to 
Vertex GPS or designee, per Section 13.1.2. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety, unblind individual 
subjects at any time.  
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1, Table 3-2, and Table 3-3.  
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical and surgical 
history, baseline VRS and NPRS scores, height, weight, and BMI. 
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. 


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11.2 
Pharmacokinetics 
11.2.1 
Blood Sampling 
Blood samples will be collected from subjects for the evaluation of plasma concentrations of 
VX-548 and 
 
These samples may also be used for evaluations of other study medications (e.g., rescue 
medication, acetaminophen, hydrocodone), other metabolites of VX-548, for further evaluation 
of the bioanalytical method, and for analyses that provide information on the metabolic pathways 
used or impacted by VX-548. 
Plasma concentration samples collected from subjects in the placebo treatment group will not be 
routinely analyzed. 
All efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
Acceptable windows for sampling times are shown in Table 11-1. The following details will be 
recorded accurately in the source document on days of PK blood sample collection: date and 
time of administration of each dose; date and time of each of the PK blood samples; and date and 
time of the last meal taken before the first dose (Day 1 only). 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Sampling Time 
Time From Scheduled Sampling Allowed 
Predose  
Any time before the first study drug dose on Day 1 
At 12, 24, and 36 hours after the first dose of study 
drug 
Within 15 minutes before the next study drug dose 
At all other time points after the first dose of study 
drug 
Within ± 30 minutes of scheduled time point 
Note: Refer to Table 3-2 and Table 3-3 for pharmacokinetic sampling time points. 
11.2.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be in the Laboratory Manual. 
11.2.3 
Bioanalysis 
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee standard operating procedures. A description of the assay and validation data will be 
provided in separate reports. 
11.3 
Other Assessments 
11.3.1 
Exploratory Assessments: Pharmacogenomics 
A blood sample (optional DNA sample) will be collected for potential exploratory evaluation of 
associations between DNA markers with other endpoints, PK, treatment response, AEs, and 
biomarkers related to health and disease, including pain, for subjects who choose to participate in 
this assessment. 
These data will be used for internal exploratory purposes. Detailed procedures for the collection 
of blood samples and additional procedures for processing and handling samples for 
pharmacogenomics analysis will be provided in a separate document. 


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11.4 
Efficacy 
11.4.1 
Numeric Pain Rating Scale 
Before removal of the popliteal sciatic block, an unscheduled NPRS will be completed before 
administration of supplemental analgesic medication (Section 9.4.1.1). The type of supplemental 
analgesic allowed is based on the NPRS score. 
After removal of the popliteal sciatic block, 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 (Section 8.1) within 9 hours after removal of the popliteal sciatic block, the 
subject will not be eligible for this study. 
During the Treatment Period, subjects will report their pain intensity on the NPRS at each 
scheduled time point through 48 hours after the first dose of study drug. In addition, pain 
intensity will be recorded on the NPRS immediately before each administration of rescue 
medication (Section 9.4.1.2). 
11.4.2 
Use of Rescue Medications 
Rescue medication is permitted for pain relief upon subject’s request. Guidelines on 
administration of ibuprofen as rescue medication are included in Section 9.4.1.2. A record will 
be kept of all rescue medication use. An unscheduled NPRS will be completed immediately 
before each administration of rescue medication. 
11.4.3 
Patient Global Assessment of Study Drug 
The PGA of study drug must be completed before the start of any other assessments scheduled at 
the same time point. Detailed procedures for the administration of the PGA of study drug will be 
provided in a separate document. 
11.5 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, standard 12-lead ECGs, and physical examinations (PEs). 
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.  
11.5.2 
Clinical Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table 3-1 and Table 3-3. 
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 11-2. 


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Table 11-2 
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 
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Urate  
Hemoglobin  
Platelets  
Leukocytes  
Differential (percent): 
Eosinophils 
Basophils  
Neutrophils 
Lymphocytes 
Monocytes  
Urobilinogen  
Urine protein  
pH 
Urine blood  
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose 
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio 
a 
If urinalysis results are positive for protein or blood, microscopic examination of urine will be performed and 
results 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.  
Additional Screening Tests: The following additional tests will be performed at the Screening 
Visit and/or pre-procedure to assess eligibility: 
• Serology: Hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), HCV 
RNA, human immunodeficiency viruses 1 and 2 antibody/antigen (HIV-1/HIV-2 Ab/Ag), 
and HIV-1/HIV-2 RNA. RNA samples will only be analyzed as a reflex test following a 
positive antibody or antibody/antigen test. Subjects with detectable viral load for HIV 
(≥200 copies/mL) or HCV 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 11.5.5.1). 
For a subject to be considered of non-childbearing potential, the serum FSH levels will be 
within the laboratory range for postmenopausal females. 
• Pregnancy Testing: 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 11.5.5.1) will also have a urine β-hCG test before admission on Day -1. 
Both the serum and urine β-hCG tests (as applicable per Table 3-1) must be negative to 
receive study drug. 


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• 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. Alcohol screening will be 
assessed before admission 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 drug and alcohol tests and urine β-hCG pregnancy tests will be assessed by staff 
onsite. 
• Local laboratories may be used to repeat a screening assessment to determine eligibility on 
Day -1 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 assessments will be performed during screening and at 
select study visits. At other visits, symptom-directed PEs and symptom-directed vital signs 
assessments can be performed at the discretion of the investigator or healthcare provider. If the 
Screening Visit occurs via home health, an abbreviated PE will be performed at the Screening 
Visit and a complete PE will be performed on Day -1. 
A complete PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, 
nose, and throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; 
musculoskeletal; and neurological. Breast, anorectal, and genital examinations will be performed 
when medically indicated. After the complete PE during 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 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. 


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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 for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position. 
A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. 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.  
11.5.5 
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.25 
11.5.5.1 
Contraception 
Study participation requires compliance with the contraception guidelines outlined below. 
Contraception for the couple is waived for the following: 
• True abstinence for the subject. 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. 


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• 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 11-3, is used as a couple from the Screening Visit through 30 days after the last 
dose of study drug. 
Table 11-3 
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 11-3. 
• 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 the Screening Visit 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. 


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Unique situations that may not fall within the above specifications may be discussed with the 
Vertex medical monitor or designee on an individual basis. 
11.5.5.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a 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. 
A subject (or their partner, if relevant) who becomes pregnant while on study will be followed 
until the end of the pregnancy only if on blinded treatment, or if they have been unblinded and 
have received active drug. 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 
This section presents a summary of the principal features of the planned efficacy, safety, and PK 
analyses for the study. Safety and efficacy analysis details will be provided in the statistical 
analysis plan (SAP), and PK analysis details will be provided in the clinical pharmacology 
analysis plan (CPAP). Both the SAP and CPAP will be finalized before clinical data lock.  
Final analyses will take place after all subjects have completed the study, all data have been 
entered in the clinical study database, and the clinical data have been locked. 
12.1 
Sample Size and Power 
Assuming a standardized effect size of 0.40 for VX-548 compared to placebo and 0.25 for 
VX-548 compared to HB/APAP, 338 evaluable subjects per group for VX-548 and HB/APAP 
and 169 evaluable subjects for placebo will provide more than 90% power for the primary 
endpoint of VX-548 versus placebo on SPID48 and 90% power for the key secondary endpoint 
of VX-548 versus HB/APAP on SPID48, based on 2-sample t-tests with significance level 0.05. 
To allow for about 15% dropout, a total of approximately 1000 subjects are planned to be 
enrolled. 
12.2 
Analysis Sets 
The All Subjects Set is defined as all subjects who have been randomized or have received at 
least 1 dose of study drug. This analysis set will be used in subject listings and disposition 
summary tables, unless otherwise specified. 
The Full Analysis Set (FAS) is defined as all randomized subjects who have received at least 
1 dose of study drug. The FAS is to be used in efficacy analyses in which subjects will be 
analyzed according to their randomized treatment group, unless otherwise specified. 
The Safety Set is defined as all subjects who have received at least 1 dose of study drug. The 
Safety Set is to be used for all safety analyses in which subjects will be analyzed according to the 
treatment they received. 


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12.3 
Statistical Analysis 
12.3.1 
General Considerations 
All individual subject data for subjects who were randomized or 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 pretreatment measurements 
(triplicate) 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 9.1.6), 
whichever occurs first.  
12.3.2 
Background Characteristics 
Unless otherwise specified, subject disposition, demographic and baseline characteristics, prior 
and concomitant medications, and important protocol deviations will be summarized. 
12.3.3 
Efficacy Analysis 
Only the principal features of the efficacy analysis will be presented in this section. For more 
details, please refer to the SAP. 
12.3.3.1 
Analysis of Primary Endpoints 
The primary efficacy analysis will be based on an analysis of covariance (ANCOVA) model. 
The model will include SPID48 as the dependent variable and treatment as a fixed effect, with 
site and baseline NPRS as covariates. If the model estimation does not converge, then site will be 
removed from the model. The least squares mean difference from placebo for VX-548 will be 
provided along with the 95% CI and P value. 
12.3.3.2 
Analysis of Secondary Endpoints 
SPID48 compared to HB/APAP and SPID24 compared to placebo will be analyzed in a similar 
manner as the primary endpoint. 
The time to ≥2-point (or ≥1-point) reduction in NPRS from baseline is the time elapsed from the 
first dose of study drug to the first time the subject has at least a 2-point (or 1-point) reduction in 
the NPRS from baseline. These endpoints will be analyzed using the Kaplan-Meier method to 
estimate the median time to event and survival curve for each treatment group. The log-rank test 
will be used to compare the survival curves between VX-548 and placebo. The time to first use 
of rescue medication will be analyzed similarly. 


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The proportion of subjects reporting good or excellent on the PGA at 48 hours compared to 
placebo will be analyzed by the Cochran-Mantel-Haenszel test, stratified by baseline NPRS. The 
proportion of subjects using rescue medication from 0 to 48 hours compared to placebo will be 
analyzed similarly. 
The incidence of vomiting or nausea compared to HB/APAP will be analyzed using Pearson’s 
chi-squared test. If any expected counts are too small, Fisher’s exact test will be used instead. 
The total rescue medication usage from 0 to 48 hours will be analyzed by the Wilcoxon 
rank-sum test, stratified by baseline NPRS.  
12.3.3.3 
Multiplicity Adjustment 
The following primary and key secondary efficacy endpoints will be tested using a hierarchical 
testing procedure. Each endpoint will be tested in the following order at the 2-sided significance 
level of 0.05: 
• SPID48 compared to placebo 
• SPID48 compared to HB/APAP 
• Time to ≥2-point reduction in NPRS from baseline compared to placebo 
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 treatment-emergent adverse events (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. For safety analyses, 
no statistical hypothesis testing will be conducted. Additional details will be provided in the 
SAP. 
12.4 
Interim Analysis 
Not applicable 
12.5 
Independent Data Monitoring Committee Analysis 
Not applicable 
12.6 
Clinical Pharmacology Analysis 
12.6.1 
Pharmacokinetic Analysis 
The PK of VX-548 and 
 will be described using summary statistics. Preliminary review 
and analyses of the drug concentrations may be done before database lock under the conditions 
of masked identifications of the subject concentrations. 
Details of the analyses will be in the CPAP. 


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12.6.2 
Pharmacokinetic/Pharmacodynamic Analyses 
A population PK analysis of plasma concentration versus time data of VX-548 and 
may 
be performed using the nonlinear mixed-effects modeling approach. A population approach may 
also be used to investigate the exposure-response relationship for the efficacy and safety 
variables. A more detailed description of the methodology to be followed will be presented in the 
modeling and simulation analysis plan. The results of the population PK and 
PK/pharmacodynamic (PD) analysis (if done) will be reported in a separate document. 
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 


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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 9.1.6). 
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in 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 
July 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.  
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 AE 
Source: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed July 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. 


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13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the subject’s medical record). 
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.  
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. 


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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  
• 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. 


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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 
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. 


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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, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  


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13.2.5 
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 case report forms 
(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. 
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 


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• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.2.9 
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. 
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.  


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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).30  
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.  
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, 


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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 2022: 
trends and developments. 2022. 
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. Molecular Interventions. 2007;7(4):192-
5. 
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 
Vertex Pharmaceuticals Incorporated. VX-548 Investigator's Brochure.  
26 
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. 
27 
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. 
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. 
30 
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 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol #: 
VX22-548-104 
Version #: 
4.0 
Version Date: 
12 April 2023 
Study Title: A Phase 3, Randomized, Double‑blind, Placebo‑controlled Study Evaluating the 
Efficacy and Safety of VX‑548 for Acute Pain After a Bunionectomy 
This clinical study protocol has been reviewed and approved by the sponsor. 
Printed Name 
 
Title 
Signature 
 
Date 


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15.2 
Investigator Signature Page 
Protocol #:  
VX22-548-104 
Version #: 
4.0 
Version Date: 
12 April 2023 
Study Title: A Phase 3, Randomized, Double‑blind, Placebo‑controlled Study Evaluating the 
Efficacy and Safety of VX‑548 for Acute Pain After a Bunionectomy 
 
 
I have read Protocol VX22-548-104, Version 4.0, 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 28 
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1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX22-548-104 
(Final Analysis) 
 
A Phase 3, Randomized, Double-blind, Placebo-controlled Study 
Evaluating the Efficacy and Safety of VX‑548 for Acute Pain After a 
Bunionectomy  
Author of SAP: 
 
 
Date of SAP: 19 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)  
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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 Objectives ................................................................................................. 5 
5.3 
Other Objectives ......................................................................................................... 5 
6 
Study Endpoints ............................................................................................................... 5 
6.1 
Primary Endpoint ........................................................................................................ 5 
6.2 
Secondary Endpoints .................................................................................................. 5 
6.2.1 
Key Secondary Endpoints .................................................................................. 5 
6.2.2 
Other Secondary Endpoints ................................................................................ 5 
6.3 
Other Endpoints .......................................................................................................... 6 
7 
Overall Design .................................................................................................................. 6 
7.1 
Sample Size and Power .............................................................................................. 8 
7.2 
Randomization ............................................................................................................ 8 
7.3 
Blinding and Unblinding ............................................................................................ 8 
8 
Analysis Sets ..................................................................................................................... 8 
8.1 
All Subjects Set .......................................................................................................... 8 
8.2 
Full Analysis Set ......................................................................................................... 8 
8.3 
Safety 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 ..................................................... 10 
9.2.3 
Medical History ................................................................................................ 11 
9.2.4 
Prior and Concomitant Medications ................................................................. 11 
9.2.5 
Study Drug Exposure and Study Drug Compliance ......................................... 11 
9.2.6 
Important Protocol Deviations .......................................................................... 12 
9.3 
Efficacy Analysis ...................................................................................................... 12 
9.3.1 
Analysis of Primary Endpoint .......................................................................... 12 
9.3.1.1 
Definition of Primary Endpoint ................................................................. 12 
9.3.1.2 
Definition of Primary Estimand ................................................................. 12 
9.3.1.3 
Primary Analysis ........................................................................................ 13 
9.3.1.5 
Subgroup Analysis ..................................................................................... 14 
9.3.2 
Analysis of Key Secondary Efficacy Variables ............................................... 14 
9.3.2.1 
Definitions and Analysis Methods ............................................................. 14 


Statistical Analysis Plan (Methods)  
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9.3.2.2 
Multiplicity Adjustment ............................................................................. 15 
9.3.3 
Analysis of Other Secondary Efficacy Variables ............................................. 15 
9.4 
Safety Analysis ......................................................................................................... 17 
9.4.1 
Adverse Events ................................................................................................. 18 
9.4.2 
Clinical Laboratory Assessments ..................................................................... 18 
9.4.3 
Electrocardiogram ............................................................................................ 19 
9.4.4 
Vital Signs ........................................................................................................ 19 
9.4.5 
Physical Examination ....................................................................................... 20 
10 Summary of Interim and IDMC Analyses .................................................................. 20 
11 References ....................................................................................................................... 20 
12 List of Appendices.......................................................................................................... 21 
Appendix A 
: Analysis Visit Windows for Safety and Efficacy Assessments ............... 21 
Appendix B 
: Imputation Rules for Missing Medication and Dates/Times ................... 23 
Appendix C 
: Imputation Rules for Missing AE Dates and Times ................................ 24 
Appendix D 
: Threshold Value Criteria .......................................................................... 25 
 


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 efficacy and safety endpoints defined in the study protocol of VX22-
548-104 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. 
Analyses addressing the pharmacokinetic (PK) objective of the study will be described in the 
Clinical Pharmacology Analysis Plan (CPAP) which will be developed separately by the 
Vertex Clinical Pharmacology department. 
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
• To evaluate the efficacy of VX-548 in treating acute pain after a bunionectomy 
5.2 
Secondary Objectives  
• To evaluate the safety and tolerability of VX-548 
5.3 
Other Objectives  
• To evaluate the pharmacokinetics of VX-548 and its metabolite, 
 
 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
• Time-weighted sum of the pain intensity difference (SPID) as recorded on the numeric 
pain rating scale (NPRS) from 0 to 48 hours (SPID48) compared to placebo 
6.2 
Secondary Endpoints 
6.2.1 
Key Secondary Endpoints 
• SPID48 compared to hydrocodone bitartrate/acetaminophen (HB/APAP) 
• Time to ≥2-point reduction in NPRS from baseline compared to placebo 
6.2.2 
Other Secondary Endpoints 
• Time to ≥1-point reduction in NPRS from baseline compared to placebo 


Statistical Analysis Plan (Methods)  
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• Proportion of subjects reporting good or excellent on the Patient Global Assessment 
(PGA) at 48 hours compared to placebo 
• Incidence of vomiting or nausea compared to HB/APAP 
• Time-weighted SPID as recorded on the NPRS from 0 to 24 hours (SPID24) compared to 
placebo 
• Time to first use of rescue medication compared to placebo 
•  Proportion of subjects using rescue medication from 0 to 48 hours compared to placebo 
• Total rescue medication usage from 0 to 48 hours compared to placebo 
• Safety and tolerability based on the incidence and type of adverse events (AEs), changes 
from baseline in clinically significant laboratory test results, vital signs, and ECGs 
6.3 
Other Endpoints 
• Time-weighted SPID as recorded on the NPRS from 0 to 36 hours (SPID36) compared to 
placebo 
• Time-weighted SPID as recorded on the NPRS from 0 to 12 hours (SPID12) compared to 
placebo 
• Proportion of subjects with ≥30% reduction in NPRS at 48 hours compared to placebo 
• Proportion of subjects with ≥50% reduction in NPRS at 48 hours compared to placebo 
• Proportion of subjects with ≥70% reduction in NPRS at 48 hours compared to placebo 
•  Proportion of subjects using rescue medication from 0 to 24 hours compared to placebo 
• Time to first use of rescue medication in the first 12 hours compared to placebo 
• Proportion of subjects using rescue medication from 0 to 12 hours compared to placebo 
• Proportion of subjects using rescue medication from 24 to 48 hours compared to placebo 
• PK parameter estimates of VX-548 and its metabolite, 
 
7 
OVERALL DESIGN  
This is a Phase 3, randomized, double-blind, placebo-controlled, 3-arm, parallel study design 
evaluating the efficacy and safety of VX-548 in treating acute pain after a bunionectomy 
(Figure 7-1).  
On Day -1, subjects will undergo a primary unilateral bunionectomy with distal first 
metatarsal osteotomy (i.e., Austin procedure) and internal fixation under regional anesthesia 
(Mayo and popliteal sciatic block). A continuous popliteal sciatic block infusion (0.2% 
ropivacaine) will be started after surgery and remain in place until approximately 3AM, but 
no later than 5AM, on Day 1. After removal of the popliteal sciatic block, a subject will be 
randomized to 1 of 3 treatment groups 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 


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pain is ≥4 on the NPRS. If a subject does not meet the VRS and NPRS criteria within 9 hours 
of removal of the popliteal sciatic block, the subject will not be eligible for this study. 
Figure 7-1 
VX22-548-104 Study Design 
 
HB/APAP: hydrocodone bitartrate/acetaminophen; NPRS: numeric pain rating scale; VRS: verbal 
categorical rating scale 
Notes: After removal of the popliteal sciatic block, a subject will be randomized to 1 of 3 treatment groups 
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 9 hours after removal of the popliteal sciatic block, the subject will not be eligible 
for this study. Figure is not drawn to scale. 
 
Approximately 1000 subjects will be randomized 2:2:1 to 3 treatment groups: VX-548 (100 
mg first dose, then 50 mg every 12 hours [q12h]); HB/APAP (5 mg/325 mg every 6 hours 
[q6h]; opioid reference); or placebo (Table 7-1). Randomization will be stratified by site and 
baseline NPRS (<8 versus ≥8). To maintain the blind, all subjects will receive the same 
number of tablets and capsules q6h in a double-dummy design. 
 
Table 7-1          VX22-548-104 Treatment Groups 
Treatment 
Active Dose 
Number of Subjects 
VX-548  
100 mg first dose, then 50 mg q12h 
400 
HB/APAP 
5 mg/325 mg q6h 
400 
Placebo 
--  
200 
HB/APAP: hydrocodone bitartrate/acetaminophen; q6h: every 6 hours; q12h: every 12 hours 
Note: To maintain the blind, all subjects will receive the same number of tablets and capsules in a double-dummy 
design. VX-548 active or VX-548 placebo tablets will be administered to all subjects q12h as follows: 0 hours 
(first dose) and at 12, 24 and 36 hours after the first dose of study drug. HB/APAP active or HB/APAP placebo 
capsules will be administered to all subjects q6h as follows: 0 hours (first dose) and at 6, 12, 18, 24, 30, 36 and 
42 hours after the first dose of study drug. 
Subjects will report their pain on the NPRS at each scheduled time point through 48 hours 
after the first dose of study drug. In addition, pain intensity will be recorded on the NPRS 
immediately before each administration of rescue medication.  
Ibuprofen (400 mg orally q6h as needed [prn]) is permitted as a rescue medication for pain 
relief upon the subject’s request starting any time after the first dose of study drug through 


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48 hours after the first dose of study drug. Subjects are encouraged to wait 90 minutes after 
the first dose of study drug to receive rescue medication, and subjects should generally not 
receive rescue medication unless their NPRS is ≥4. 
7.1 
Sample Size and Power 
Assuming a standardized effect size of 0.40 for VX-548 compared to placebo and 0.25 for 
VX-548 compared to HB/APAP, 338 evaluable subjects per group for VX-548 and 
HB/APAP and 169 evaluable subjects for placebo will provide more than 90% power for the 
primary endpoint of VX-548 versus placebo on SPID48 and 90% power for the key 
secondary endpoint of VX-548 versus HB/APAP on SPID48, based on 2-sample t-tests with 
significance level 0.05. To allow about 15% dropout, a total of approximately 1000 subjects 
are planned to be enrolled. 
7.2 
Randomization 
Refer to Section 9.2 of the CSP for details. 
7.3 
Blinding and Unblinding 
Refer to Section 10.8 of the CSP for details. 
8 
ANALYSIS SETS 
8.1 
All Subjects Set 
The All Subjects Set is defined as all subjects who have been randomized or have received 
at least 1 dose of study drug. This analysis set will be used in subject listings and the 
disposition summary table, unless otherwise specified. 
8.2 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all randomized subjects who have received at 
least 1 dose of study drug. The FAS is to be used to summarize subject demographics and 
baseline characteristics, and for all efficacy analyses, unless otherwise specified, in which 
subjects will be analyzed according to their randomized treatment group. 
8.3 
Safety Set 
The Safety Set is defined as all subjects who have received at least 1 dose of study drug. The 
Safety Set is to be used for all safety analyses in which subjects will be analyzed according to 
the treatment they received. 
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 were randomized or received at least 1 dose of 
study drug will be presented in individual subject data listings. 


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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), unless otherwise specified.  
Categorical variables will be summarized using counts and percentages.  
Baseline value will be defined as the most recent non-missing measurement (scheduled or 
unscheduled) collected before the first dose of study drug, unless otherwise specified.  
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 in 
the Treatment Period to the Safety Follow-up Visit or to the completion of study participation 
(as defined in Section 9.1.6 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 
• 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 visits are provided 
in Appendix A.  
Incomplete/missing data: Details on how to handle missing data are described in 
subsequent sections when applicable. 
Outliers: No formal statistical analyses will be performed to detect and/or remedy the 
presence of statistical outliers. 
Multiplicity: The multiplicity adjustment procedure for the primary and key secondary 
endpoints is described in Section 9.3.2.2. All other P values are nominal. 
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
The disposition summary will be provided by treatment group and overall. 
The number of subjects in the following categories will be summarized:  
• All Subjects Set 
• Randomized 
• Full Analysis Set (FAS) 


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• Safety Set 
• Randomized 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 
• 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 and a randomization listing of subjects will be provided.  
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the FAS by 
treatment group and overall. 
Demographic data will include the following: 
• Age at screening (in years) 
• Age at screening category (≥18 to <65, ≥65) 
• Sex (male, female) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, 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) 
• Site  
• NPRS 
• NPRS category (<8, ≥8) 
• VRS (moderate, severe) 
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 


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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). This summary will be provided 
by treatment group and overall. The corresponding data listing will also be provided. 
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary and 
categorized as the following for the purposes 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 
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. This summary will be provided by treatment group and overall. Pre- and intra-
operative medications will be included in the summary of prior medications and will be listed 
separately. Similarly, supplemental analgesic medications administered after surgery and 
before removal of the popliteal sciatic block will be included in the summary of prior 
medications and will also be summarized and listed separately. Concomitant analgesic 
medications will be included in the summary of concomitant medications and will be listed 
separately. Rescue medication will be included in the summary of concomitant medications 
and will be listed separately.   
Prior and concomitant non-pharmacological treatments or procedures will also be listed. 
9.2.5 
Study Drug Exposure and Study Drug Compliance 
Study drug will be administered to the subjects by site personnel at time points specified in 
the CSP (Table 3-2 and Section 9.6) during a period of 42 hours. Therefore, calculations of 
compliance are not needed.  


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Study drug exposure will be summarized descriptively by treatment group in terms of the 
total number of tablets (VX-548 or placebo) and total number of capsules (HB/APAP or 
placebo) administered. Separate exposure summaries will be planned based on the Safety Set 
and the FAS. 
All data collected during dispensation of study drug (e.g., time of administration and number 
of tablets/capsules 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 by treatment group and overall, as well as presented 
in an individual data listing. 
9.3 
Efficacy Analysis 
All efficacy analyses described in this section will be based on the FAS, unless specified 
otherwise. Subjects will be analyzed according to their randomized treatment assignment. 
9.3.1 
Analysis of Primary Endpoint 
9.3.1.1 
Definition of Primary Endpoint 
The primary endpoint is SPID48 compared to placebo. In general, SPID is calculated as:  
∑(𝑡𝑡𝑖𝑖−1 −𝑡𝑡𝑖𝑖) × 𝑃𝑃𝑃𝑃𝐷𝐷𝑡𝑡𝑖𝑖 where:  
• 𝑡𝑡𝑖𝑖  = scheduled time since first dose (in hours) for time point 𝑖𝑖 (𝑡𝑡0 = 0 hours; 𝑡𝑡1 = 0.5 
hour, etc.) 
• 𝑃𝑃𝑃𝑃𝐷𝐷𝑡𝑡𝑖𝑖 = pain intensity (NPRS) at time point 𝑖𝑖 - pain intensity (NPRS) at baseline 
Hence: 
• SPID48 = -(0.5 × PID0.5 + 0.5 × PID1 + 0.5 × PID1.5 + 0.5 × PID2 + PID3 + PID4 + 
PID5 + PID6 + 2 × PID8 + 4 × PID12 + 4 × PID16 + 4 × PID20 + 4 × PID24 + 4 × PID28 
+ 4 × PID32 + 4 × PID36 + 4 × PID40 + 4 × PID44 + 4 × PID48) 
In this definition of SPID48, a higher value of SPID48 indicates greater pain reduction from 
baseline. 
9.3.1.2 
Definition of Primary Estimand 
The primary estimand is defined as the following: 
• Treatment: VX-548 versus placebo 
• Population: Study population meeting the study inclusion and exclusion criteria 
• Variable: SPID48  


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• Handling of intercurrent events:  
o The hypothetical strategy will be used to handle the use of rescue medication, 
which means that the observed NPRS scores during the rescue period will not be 
used and will instead be replaced by imputed values.  
o The hypothetical strategy will be used to handle treatment discontinuation, which 
means that missing NPRS scores after treatment discontinuation will be imputed.  
• Population level summary: Difference in variable means 
9.3.1.3 
Primary Analysis  
The primary analysis for the primary estimand will be based on an analysis of covariance 
(ANCOVA) model. The model will include SPID48 as the dependent variable and treatment 
as a fixed effect, with site and baseline NPRS as covariates. If model estimation does not 
converge, then site will be removed from the model. The Least Squares (LS) mean difference 
for VX-548 versus placebo will be provided along with the SE, 95% confidence interval (CI) 
and 2-sided P value. In addition, the LS mean with SE and 95% CI will be provided for each 
treatment group. Analogous results for HB/APAP versus placebo will be reported as well. 
The following imputation scheme will be applied for the primary analysis: 
1) NPRS scores during the rescue period (within 6 hours after rescue medication) will be 
replaced by the pre-rescue NPRS score.  
• The pre-rescue NPRS score will be the NPRS score collected immediately 
before the administration of rescue medication, or the previous NPRS score if 
that score is missing. The previous NPRS score can be a score from a 
regularly scheduled measurement or the previous pre-rescue NPRS score but 
cannot be any observed score during the previous rescue period. 
• If there are multiple administrations of rescue medication leading to 
overlapping rescue periods, the pre-rescue NPRS score for the first rescue 
period will replace all NPRS scores from the start of the first rescue period 
through the end of the last overlapping rescue period (i.e., 6 hours after the 
corresponding use of rescue medication). 
2) Missing NPRS scores following treatment discontinuation due to an AE will be 
imputed using the baseline NPRS score; missing NPRS scores following treatment 
discontinuation due to other reasons will be imputed with the last NPRS score prior to 
discontinuation. 
3) Missing NPRS scores for subjects who completed the treatment but with missing data 
from a certain time point to 48 hours will be imputed with the last NPRS score.  
4) Intermittently missing NPRS scores will be imputed using linear interpolation. 
In addition, NPRS scores and change from baseline in NPRS scores (i.e., pain intensity 
difference) will be summarized descriptively, including SE, by treatment group at each 
scheduled time point. The mean NPRS scores and SEs over time by treatment group, as well 


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as the mean pain intensity differences and SEs over time by treatment group, will be 
presented in separate figures.  
9.3.1.5 
Subgroup Analysis 
Subgroup analyses of the primary efficacy endpoint will be performed for age, sex and race 
according to the following categories. The analyses will be performed using the same 
imputation scheme and the same ANCOVA model as in Section 9.3.1.3: 
• Age at screening (≥18 to <65, ≥65) 
• Sex (male, female) 
• Race (White, Non-White) 
Each of these subgroup analyses will only be performed if ≥10% of subjects in the FAS are 
members of both subgroups. 
9.3.2 
Analysis of Key Secondary Efficacy Variables 
9.3.2.1 
Definitions and Analysis Methods 
SPID48 compared to HB/APAP: SPID48 is defined the same way as in Section 9.3.1.1. 
The estimand for SPID48 compared to HB/APAP is identical to the primary estimand 
described in Section 9.3.1.2 except that the treatment attribute is VX-548 versus HB/APAP.  
SPID48 compared to HB/APAP will be analyzed using the same imputation scheme and 
model as for the primary analysis (as described in Section 9.3.1.3). The LS mean difference 
for VX-548 versus HB/APAP will be provided along with the 95% CI and 2-sided P value. 
Time to ≥2-point reduction in NPRS from baseline compared to placebo: Time to ≥2-point 
reduction in NPRS from baseline is the time elapsed from the first dose of study drug until 
the first time the subject has at least a 2-point reduction in the NPRS from baseline. Subjects 
who have not reached at least a 2-point reduction in NPRS from baseline by 48 hours will be 
censored at 48 hours. 


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The estimand for the time to ≥2-point reduction in NPRS from baseline is defined as the 
following: 
• Treatment: VX-548 versus placebo 
• Population: Study population meeting the study inclusion and exclusion criteria 
• Variable: Time to ≥2-point reduction in NPRS from baseline 
• Handling of intercurrent events: Same as the primary estimand, with the hypothetical 
strategy applied to handle rescue medication use and treatment discontinuation 
• Population level summary: Medians of the variable for each treatment group 
This endpoint will be calculated based on NPRS scores collected at scheduled time points 
(using the same imputation scheme as described in Section 9.3.1.3).  The Kaplan-Meier 
method will be used to estimate the median time and the survival curve for each treatment 
group. A log-rank test will be used to compare the survival curves between VX-548 and 
placebo. The median time along with the 95% CI for each treatment group from the Kaplan-
Meier analysis and the P value for the comparison to placebo from the log-rank test will be 
provided. 
9.3.2.2 
Multiplicity Adjustment  
A hierarchical testing procedure will be used to control the overall type 1 error at a 
significance level of 0.05 for the primary endpoint and the key secondary endpoints tested.  
For a test at any step to be considered statistically significant within the testing hierarchy, 
that test and all previous tests (if any) within the hierarchy must be statistically significant at 
the 0.05 level. The testing order of the primary and key secondary endpoints is as follows: 
• SPID48 compared to placebo 
• SPID48 compared to HB/APAP 
• Time to ≥2-point reduction in NPRS from baseline compared to placebo 
9.3.3 
Analysis of Other Secondary Efficacy Variables 
Time to ≥1-point reduction in NPRS from baseline compared to placebo: Time to ≥1-point 
reduction in NPRS from baseline is the time elapsed from the first dose of study drug until 
the first time the subject has at least a 1-point reduction in the NPRS from baseline. Subjects 
who have not reached at least a 1-point reduction in NPRS from baseline by 48 hours will be 
censored at 48 hours. This variable will be analyzed the same way as described in Section 
9.3.2.1 for the time to ≥2-point reduction in NPRS from baseline. 
Proportion of subjects reporting good or excellent on the PGA at 48 hours compared to 
placebo: The PGA of study drug is a single-item assessment of patient perceptions of the 
method of pain control with the study drug and is evaluated on a 4-point Likert scale (poor, 
fair, good, or excellent). Subjects who discontinue study drug treatment for any reason prior 
to 48 hours and subjects with missing PGA at 48 hours will be considered as non-responders 
(i.e., not reporting good or excellent on the PGA). This variable will be summarized 


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descriptively, and the Cochran-Mantel-Haenszel test, stratified by the baseline NPRS 
category (<8, ≥8), will be conducted to compare VX-548 and placebo. 
Incidence of vomiting or nausea compared to HB/APAP: This endpoint will be analyzed 
based on the Safety Set. The incidence of vomiting or nausea is the proportion of subjects 
reporting the treatment-emergent adverse events of vomiting or nausea from the first dose of 
study drug through completion of study participation. When computing these proportions, 
subjects with multiple occurrences of either event will be counted once. Subjects who 
experience both vomiting and nausea will only be counted once. This variable will be 
summarized descriptively, and Pearson’s chi-squared test will be conducted to compare VX-
548 and HB/APAP. If any expected counts are <5, Fisher’s exact test will be used instead. 
SPID24 compared to placebo: SPID24 is calculated using the following formula: 
• SPID24 = -(0.5 × PID0.5 + 0.5 × PID1 + 0.5 × PID1.5 + 0.5 × PID2 + PID3 + PID4 + 
PID5 + PID6 + 2 × PID8 + 4 × PID12 + 4 × PID16 + 4 × PID20 + 4 × PID24) 
SPID24 will be analyzed in the same way as described in Section 9.3.1.3 for the primary 
endpoint. 
Time to first use of rescue medication compared to placebo: Time to first use of rescue 
medication is the time from the first dose of study drug until the first use of rescue 
medication. Subjects who do not take any rescue medication within 48 hours will be 
censored at 48 hours. The Kaplan-Meier method will be used to estimate the median time to 
first use of rescue medication and the survival curve for each treatment group. A log-rank test 
will be used to compare the survival curves between VX-548 and placebo. The median time 
to first use of rescue medication along with the 95% CI for each treatment group from the 
Kaplan-Meier analysis and the P value for the comparison to placebo from the log-rank test 
will be provided. 
Proportion of subjects using rescue medication from 0 to 48 hours compared to placebo: This 
variable will be summarized descriptively, and the Cochran-Mantel-Haenszel test, stratified 
by the baseline NPRS category (<8, ≥8), will be conducted to compare VX-548 and placebo. 
Total rescue medication usage from 0 to 48 hours compared to placebo: This variable will be 
summarized descriptively, and the Wilcoxon rank-sum test, stratified by the baseline NPRS 
category (<8, ≥8), will be conducted to compare VX-548 and placebo. 


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9.4 
Safety Analysis 
The overall safety profile of VX-548 will be assessed in terms of the following safety and 
tolerability endpoints:  
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (hematology, serum chemistry, coagulation, and urinalysis) 
• ECG outcomes 
• Vital signs 
All safety analyses will be performed based on the Safety Set based on actual treatment. In 
the unexpected scenario that a subject receives more than one treatment in the study, the 
following algorithm will be used to define actual treatment: for any dosed subjects, the actual 
treatment is defined as VX-548 if the subject received any VX-548 treatment, regardless of 
the randomized treatment assignment; the actual treatment is defined as HB/APAP if the 
subject did not receive any VX-548 treatment but did receive any HB/APAP; the actual 
treatment is defined as placebo only if the subject received placebo on all dosing occasions. 
Only descriptive analyses of safety will be performed, and no statistical hypothesis testing 
will be performed. 


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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 at or 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 as Appendix C. 
AE summary tables will be presented only for TEAEs by treatment group, 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 
• 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, listings 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. 


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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 
≤500 msec, and >500 msec, as well as maximum treatment-emergent change from baseline 
value of QT/QTcF intervals, categorized as ≤0 msec, and >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. 


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9.4.5 
Physical Examination  
Physical examination (PE) results will be presented in an individual subject data listing only. 
10 
SUMMARY OF INTERIM AND IDMC ANALYSES 
Not applicable. 
11 
REFERENCES 
Not applicable. 
 


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12 
LIST OF APPENDICES 
Appendix A : Analysis Visit Windows for Safety and Efficacy Assessments  
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit/Time point1 
Target Study Day 
/Time point per 
the protocol 
Analysis Visit Window 
(in study days/time points) 2, 
3, 4 
Safety Assessment 
Hematology 
Serum Chemistry 
Coagulation 
Baseline 
Day 1 
≤ Day 1 predose 
48 hours 
48 hours 
Nominal visit  
Standard 12-Lead ECG 
 
Baseline 
Day 1 
≤ Day 1 predose 
4 hours 
4 hours  
Nominal visit for all visits 
14 hours 
14 hours 
 
26 hours 
26 hours 
 
38 hours 
38 hours 
 
Vital Signs 
Baseline 
Day 1 
≤ Day 1 predose 
2 hours 
2 hours  
Nominal visit for all visits 
4 hours 
4 hours 
 
24 hours 
24 hours 
 
48 hours 
48 hours 
 
Safety Follow-up 
Not applicable 
 
Efficacy Assessment 
NPRS 
Baseline  
Day 1 
≤ Day 1 predose 
At 0.5, 1, 1.5, 2, 3, 4, 5, 
6, 8, 12, 16, 20, 24, 28, 
32, 36, 40, 44, and 48 
hours  
At 0.5, 1, 1.5, 2, 3, 
4, 5, 6, 8, 12, 16, 
20, 24, 28, 32, 36, 
40, 44, and 48 
hours 
± 10 minutes for 0.5 to 2 
hours 
± 15 minutes for 3 to 8 hours 
± 30 minutes for 12 to 48 
hours 
 
VRS 
Baseline  
Day 1 
≤ Day 1 predose 
Rescue Medication 
N/A 
N/A 
[Day 1 post-dose, 48 hours]  
 
Notes:  
1 Visit/time point names for analysis purposes are used to report data in tables and figures. 
2The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered 
missing for the visit.  
b. If there is more than 1 numerical measurement available within the same visit window, use the 
following rules:  


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i. 
The measurement closest to the target day/time point will be used; or  
ii. 
If there are multiple measurements within the same distance from the target day/time point, 
the latest measurement will be used. 
3For measurements collected on the date of the first dose of study drug, if it cannot be determined whether the 
measurement is before or after the first dose: 
a. 
If a scheduled measurement is pre-dose in the CSP, it will be treated as a pre-dose observation. If a 
scheduled measurement is post-dose in the CSP, it will be treated as a post-dose observation. 
b. Unscheduled measurements will be treated as post-dose observations. 
4When defining baseline for efficacy and safety, refer to the generic baseline definition in Section 9.1.  
 
 


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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 


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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.  
 
 
 
 
 


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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