Clinical trial NCT05034952
Conditions: Acute Pain
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2021-08-30; Completion date: 2021-12-21
Enrollment: 303 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of VX-548 doses in treating acute pain after an abdominoplasty.

Detailed description:

Arms: arm 1: Participants received placebo matched to VX-548 and Hydrocodone bitartrate/ acetaminophen (HB/APAP) for 2 days. arm 2: Participants received HB 5 mg / APAP 325 milligrams (mg) every 6 hours (q6h) for 2 days. arm 3: Participants received VX-548 60 mg as first dose, followed by VX-548 30 mg every 12 hours (q12h) for 2 days. arm 4: Participants received VX-548 100 mg as first dose, followed by VX-548 50 mg q12h for 2 days.
Interventions: intervention 1: VX-548 intervention 2: HB/APAP intervention 3: Placebo (matched to VX-548) 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 VX-548 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 2, Randomized, Double-blind, Placebo-controlled, 
Multi-dose Study Evaluating the Efficacy and Safety of 
VX-548 for Acute Pain After an Abdominoplasty 
Vertex Study Number: VX21-548-102 
 
Date of Protocol: 21 January 2022 (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 VX21-548-102, Version 4.0 
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Summary of Changes to the Protocol  
The previous version of this protocol (Version 3.0, 10 September 2021) was amended to create 
the current version (Version 4.0, 21 January 2022). The protocol history is below. 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 08 June 2021 
Original version 
Version 2.0, 26 July 2021 
To ensure subject safety and assess wound healing, clinical laboratory 
tests were added at 48 hours after the first dose and a focused physical 
examination was added at 48 hours after the first dose and at the Safety 
Follow-up Visit. 
Version 3.0, 10 September 2021 
• 
Clarified abdominoplasty procedure details 
• 
Increased the BMI upper limit from 35.0 to 38.0 kg/m2 in inclusion 
criterion 4 to allow for participation of more subjects 
• 
Updated the permitted analgesic medications to provide adequate 
management of perioperative pain 
• 
Updated the contraceptive requirements based on negative 
genotoxicity data and to align with the Clinical Trials Facilitation 
and Coordination Group guidance related to contraception in clinical 
trials: 
o 
Reduced the required contraceptive period for subjects and their 
partners from 90 to 30 days after the last study drug dose. 
o 
Included hormone-releasing intrauterine devices as an 
acceptable method of contraception for female subjects. 
Version 4.0, 21 January 2022 
Current version 
 
Key changes in the current version of the protocol are summarized below.  
Change and Rationale 
Affected Sections  
Added that pharmacokinetic blood samples may also be used for evaluations of other 
study medications, including acetaminophen and hydrocodone. 
 
Section 11.2.1 
 
Typographical and administrative changes were also made to improve the clarity of the 
document. 


Protocol VX21-548-102, Version 4.0 
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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 2, Randomized, Double-blind, Placebo-controlled, Multi-dose Study Evaluating the 
Efficacy and Safety of VX‑548 for Acute Pain After an Abdominoplasty 
 
 
Brief Title 
A Study Evaluating Efficacy and Safety of VX-548 for Acute Pain After an Abdominoplasty 
 
 
Clinical Phase 
and Clinical 
Study Type  
Phase 2, efficacy and safety 
 
 
Objectives 
Primary Objective 
• 
To evaluate the efficacy of VX-548 doses in treating acute pain after an abdominoplasty 
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 a Numeric Pain 
Rating Scale (NPRS) at rest 0 to 48 hours (SPIDr0-48) after the first dose of study drug 
Secondary Endpoints 
• 
Time-weighted SPID as recorded on an NPRS at rest 0 to 24 hours (SPIDr0-24) after the 
first dose of study drug 
• 
Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at rest at 
48 hours after the first dose of study drug 
• 
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 an NPRS during movement 8 to 24 hours 
(SPIDm8-24) and 8 to 48 hours (SPIDm8-48) after the first dose of study drug 
• 
Time to onset of “confirmed perceptible pain relief” and “meaningful pain relief” after the 
first dose of study drug 
• 
Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at rest at 
24 hours after the first dose of study drug 
• 
Patient Global Assessment (PGA) of study drug at 48 hours after the first dose of study 
drug 
• 
Percentage of subjects using rescue medication, and total rescue medication usage, 0 to 
48 hours after the first dose of study drug 
• 
PK parameter estimates of VX-548 and its metabolite, 
 
 
 
Number of 
Subjects 
Approximately 256 subjects 
 
 
Study 
Population 
Male or female subjects, 18 through 75 years of age (inclusive), with pain that is ≥4 on the 
NPRS at rest and moderate or severe on a Verbal Categorical Rating Scale (VRS) at rest after 
an abdominoplasty 


Protocol VX21-548-102, Version 4.0 
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Investigational 
Drug 
Active substance: VX-548 
Activity: NaV1.8 inhibitor 
Strength and route of administration: 10-mg tablets and matching placebo for oral 
administration 
 
 
Reference 
Drug 
Active substance: hydrocodone bitartrate/acetaminophen (HB/APAP) 
Activity: opioid analgesic 
Strength and route of administration: 5-mg/325-mg capsules and matching placebo for oral 
administration 
 
 
Study 
Duration 
Excluding the Screening Period, each subject will participate in the study for 3 days plus a 
Safety Follow-up Visit 14 ± 2 days after the last dose of study drug. 
 
 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, 4-arm, parallel study design 
evaluating the efficacy and safety of VX-548 doses in treating acute pain after an 
abdominoplasty (Figure 2-1).  
On Day 1, subjects will undergo a standard (“full”) abdominoplasty procedure (as defined in 
Section 8.1). After surgery completion, a subject will be randomized to 1 of 4 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 at rest, and (3) the subject’s pain is ≥4 on the NPRS at rest. If a 
subject does not meet the VRS and NPRS criteria within 4 hours of surgery completion, the 
subject will not be eligible for this study. 
Approximately 256 subjects will be randomized 1:1:1:1 to 4 treatment groups: high-dose 
VX-548 (100 mg/50 mg every 12 hours [q12h]); low-dose VX-548 (60 mg/30 mg q12h); 
HB/APAP (opioid reference); or placebo (Table 2-1). Randomization will be stratified by site 
and baseline NPRS at rest (<8 versus ≥8). To maintain the blind, all subjects will receive the 
same number of tablets and/or capsules every 6 hours (q6h) in a double-dummy design. 
Figure 2-1 
VX21-548-102 Study Design 
 
CRU: clinical research unit; HB/APAP: hydrocodone bitartrate/acetaminophen; NPRS: Numeric Pain 
Rating Scale; VRS: Verbal Categorical Rating Scale 
Notes: After surgery completion, a subject will be randomized to 1 of 4 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 at rest, and (3) the subject’s pain is ≥4 on the NPRS at rest. If a subject does 
not meet the VRS and NPRS criteria within 4 hours of surgery completion, the subject will not be 
eligible for this study. 
 


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Table 2-1 
VX21-548-102 Treatment Groups 
Treatment 
Active Dose 
Number of Subjects 
VX-548 (high dose) 
100 mg first dose, then 50 mg q12h 
64 
VX-548 (low dose) 
60 mg first dose, then 30 mg q12h 
64 
HB/APAP 
5 mg/325 mg q6h 
64 
Placebo 
 
64 
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/or capsules q6h 
in a double-dummy design. VX-548 active and/or VX-548 placebo 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. 
HB/APAP active or HB/APAP placebo 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. 
Subjects will report their pain intensity on the NPRS at rest at each scheduled time point 
through 48 hours after the first dose of study drug. Starting 8 hours after the first dose of study 
drug, subjects will also report their pain intensity on the NPRS during movement. In addition, 
pain intensity will be recorded on the NPRS at rest 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 at rest score is ≥4. 
 
 
Assessments 
Efficacy: NPRS at rest and during movement, double-stopwatch assessment, and use of rescue 
medications 
Safety: adverse events (AEs), clinical laboratory assessments, clinical evaluation of vital signs, 
standard 12-lead ECGs, and physical examinations 
PK: plasma PK parameters of VX-548 and its metabolite, 
 
Other: VRS at rest, PGA of study drug, and DNA blood sample (optional) 
 
  
Statistical 
Analyses 
The sample size calculation is based on the comparison between VX-548 and placebo on the 
primary endpoint. Assuming a standardized effect size of 0.8 for VX-548 (high or low dose) 
compared to placebo, 54 evaluable subjects per group would provide at least 90% power at a 
2-sided significance level of 0.05. This sample size would allow a minimal detectable 
standardized effect size of 0.38 to achieve statistical significance between VX-548 (high or 
low dose) and placebo. With this sample size, a two-sided 95% CI for the estimated standard 
effect size will extend 0.38 from the observed standardized effect size, assuming the CI is 
based on the large sample z statistic. To allow for withdrawal of up to 15% of randomized 
subjects over 48 hours of treatment, the study will enroll and randomize approximately 256 
subjects in total. 
The primary efficacy analysis will be based on an analysis of covariance (ANCOVA) model. 
The model will include SPIDr0-48 as the dependent variable and treatment as a fixed effect, 
with stratification factors (i.e., site and baseline NPRS at rest) as covariates. If the model 
estimation does not converge, site will be removed from the model. The least squares means of 
difference versus placebo and the corresponding 95% CIs and P values will be presented. 


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are in Table 3-1, Table 3-2, and Table 3-3.


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Table 3-1 
Study VX21-548-102: Screening Through Admission 
Event/Assessmenta 
Day -28 to Day -1 
Day 1 
Comments 
Screening Visit 
Pre-procedure 
Outpatient visit 
X 
 
 
CRU admission 
 
X 
Upon completion of pre-procedure eligibility 
assessments; Section 8. 
Informed consent  
X 
 
Section 13.2.3 
Demographics 
X 
 
 
Medical and surgical history 
X 
 
 
History of drug and alcohol use 
X 
 
Section 8.2 
Prior use of opioid medications 
X 
X 
Any use within 12 months of the Screening Visit 
through admission will be recorded; Section 9.5.  
Vital signs 
X 
X 
Complete after ≥5-minute rest; Section 11.5.3. 
Standard 12-lead ECG 
X 
X 
Complete after ≥5-minute rest in the supine position. 
ECGs must be performed before blood draws or any 
procedures that may affect heart rate. Section 11.5.4. 
Complete PE 
X 
 
Section 11.5.3 
Weight, height, and BMI 
X 
 
Weight and height will be measured with shoes off. 
BMI = weight (kg) / [height (cm/100)]2 
Serology (HBsAg, HCV Ab, 
and HIV-1/HIV-2 Abs) 
X 
 
Section 11.5.2 
Serum β-hCG 
X 
 
All female subjects; Section 11.5.2. 
Serum FSH 
X 
 
Postmenopausal female subjects only; 
Section 11.5.5.1 
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 
Drug test 
X 
X 
Urine; Section 11.5.2. 
Day 1: Testing kit assessed by staff onsite. 
Urine β-hCG 
 
X 
All female subjects of childbearing potential. 
Assessed by staff onsite. Section 11.5.2. 
Alcohol test 
 
X 
Urine, blood, or breath. Breath testing kit assessed 
by staff onsite. Section 11.5.2. 
Placebo and pain assessment 
video training 
X 
X 
Section 11.4.1 
Blood sampling for PK 
 
X 
Collect after completion of pre-procedure eligibility 
assessments; Section 11.2.1. 
Medications review 
Continuous from signing of ICF 
through Safety Follow-up 
All medications taken within 14 days before the 
Screening Visit through end of the study; 
Section 9.5. 
Treatment and procedures 
review 
Continuous from signing of ICF 
through Safety Follow-up 
 
Adverse events 
Continuous from signing of ICF 
through Safety Follow-up 
Section 11.5.1 
β-hCG: beta-human chorionic gonadotropin; BMI: body mass index; CRU: clinical research unit; FSH: follicle-stimulating 
hormone; HBsAg: hepatitis B surface antigen; HCV Ab: hepatitis C virus antibody; HIV-1/HIV-2 Abs: antibodies 
against human immunodeficiency viruses 1 and 2; ICF: informed consent form; PE: physical examination; 
PK: pharmacokinetics 
 
a  
When assessment time points coincide, assessments will be performed in this order: vital signs, 12-lead ECG, PE, and blood 
sample collection. 


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Table 3-2 
Study VX21-548-102: Procedure Through Randomization 
Event/Assessment 
Day 1 
Comments 
Procedure Through 
Randomization / Predosea 
Inpatient CRU 
X 
 
Abdominoplasty 
X 
Section 9.1 
Fasting period 
X 
No food or drink (except water) from time of surgery completion 
through 4 hours after the first dose of study drug; Section 9.4.2. 
Record supplemental 
analgesia medication 
X 
Record pain medications given postoperatively through time 
subject is randomized. Refer to Section 9.4.1.1 for permitted pain 
medication. 
Vital signs 
X 
Perform after surgery completion (at least 1 hour after surgery 
completion is recommended unless the subject requests study drug 
within 1 hour) and before the first dose of study drug. 
Complete after a ≥5-minute rest and before blood draws or ECG 
assessments. Section 11.5.3. 
Standard 12-lead ECG 
X 
Perform after surgery completion (at least 1 hour after surgery 
completion is recommended unless the subject requests study drug 
within 1 hour) and before the first dose of study drug. 
Complete after a ≥5-minute rest in the supine position and before 
blood draws or any procedures that may affect heart rate. 
Section 11.5.4. 
VRS at rest 
X 
Complete upon request for the first dose of study drug for pain 
relief after surgery completion. 
Pain intensity will be recorded after a ≥3-minute rest in bed in 
either the supine or up to approximately 15-degree head-up 
position; Section 11.3. 
NPRS at rest 
X 
Complete immediately after VRS at rest only if pain is rated 
moderate or severe on VRS at rest. 
Pain intensity will be recorded after a ≥3-minute rest in bed in 
either the supine or up to approximately 15-degree head-up 
position; Section 11.4.2. 
Randomization 
X 
Subject must request study drug for relief of pain meeting criteria 
(≥4 on NPRS at rest and moderate or severe on VRS at rest) 
within 4 hours after surgery completion to be eligible for 
randomization (Section 8.1). 
Medications review 
Continuous from signing of 
ICF through Safety Follow-up 
All medications taken within 14 days before the Screening Visit 
through end of the study; Section 9.5. 
Treatment and 
procedures review 
Continuous from signing of 
ICF through Safety Follow-up 
 
Adverse events 
Continuous from signing of 
ICF through Safety Follow-up 
Section 11.5.1 
CRU: clinical research unit; ICF: informed consent form; NPRS: Numeric Pain Rating Scale; VRS: Verbal Categorical Rating 
Scale 
 
a  
Subject must complete all Day 1 predose assessments before the first dose of study drug is administered.  


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Table 3-3 
Study VX21-548-102: Treatment Period and Safety Follow-up 
Event/ 
Assessmenta 
Hours After First Dose 
SFUb 
Comments 
0c 0.5 
1 
1.5 2 
3 
4 
5 
6 
8 
12 
16 
18 
20 
24 
25 to 32 
35 to 44 
48 
Inpatient CRU 
Continuous from admission through completion of 48-hour assessments 
 
 
Discharge from CRU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Upon completion of all study assessments. 
Outpatient Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Section 9.1.4 
PGA of study drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Complete before the start of any other assessments scheduled at 
the same time point; Section 11.3.2 
Vital signs 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Complete after ≥5-minute rest (Section 11.5.3). Acceptable 
window is ± 1 hour from the scheduled time point. 
Standard 12-lead ECG 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
28 h 
40 h 
 
 
Complete after ≥5-minute rest in the supine position. ECGs must 
be performed before blood draws or any procedures that may 
affect heart rate (Section 11.5.4). Acceptable window is ± 1 hour 
from the scheduled time point. 
Complete PE 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Section 11.5.3 
Focused PE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Assess wound healing at the operative site; Section 11.5.3. 
NPRS at rest 
 
X 
X 
X 
X X X X X X 
X 
X 
 
X 
X 
28 h 
32 h 
36 h 
40 h 
44 h 
X 
 
Pain intensity will be recorded after a ≥3-minute rest in bed in 
either the supine or up to approximately 15-degree head-up 
position. Acceptable window is ± 5 minutes from the scheduled 
time point; Section 11.4.2. 
NPRS during 
movement 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
28 h 
32 h 
36 h 
40 h 
44 h 
X 
 
Perform immediately after completion of NPRS at rest. 
Pain intensity will be recorded after the subject sits up in bed, 
unassisted, at an angle of approximately 45 degrees or more; 
Section 11.4.2. 
DNA blood sample 
(optional) 
X 
 
May be collected anytime during CRU confinement after 
randomization; Section 11.3.3. 
Blood sampling for PK 
 
 
X 
 
X 
 
X 
 
X X 
X 
 
 
 
X 
25, 26, 
28, 30, 
and 32 h 
36 h 
X 
 
At 12, 24, and 36 hours after first dose: Collect within 
15 minutes before the next study drug dose. 
At all other time points after first dose: Collect within 
± 30 minutes of scheduled time point. Section 11.2.1. 
Serum chemistry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 11.5.2 
Hematology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 11.5.2 
Coagulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 11.5.211.5.2 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 11.5.2 
Fasting period 
0 to 4 h 
 
 
11 to 15 h 
 
23 to 27 h 
35 to 39 h 
 
 
No food or drink (except water); Section 9.4.2. 
Study drug 
administration 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
30 h 
36 h 
42 h 
 
 
To maintain the blind, all subjects receive the same number of 
tablets and/or capsules q6h; Section 9.6. 
 
a 
When assessment time points coincide, assessments will be performed in this order: PGA of study drug, vital signs, 12-lead ECG, PE, NPRS at rest, NPRS during movement, and blood sample 
collection. Assessments that coincide with study drug administration will be performed before dosing unless noted otherwise. 
b 
Safety Follow-up Visit is 14 ± 2 days after the last dose of study drug. 
c 
Time 0 hours is defined as the first dose of study drug. The first dose of study drug should be administered immediately after completion of all Day 1 predose assessments (Table 3-2). 


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Table 3-3 
Study VX21-548-102: Treatment Period and Safety Follow-up 
Event/ 
Assessmenta 
Hours After First Dose 
SFUb 
Comments 
0c 0.5 
1 
1.5 2 
3 
4 
5 
6 
8 
12 
16 
18 
20 
24 
25 to 32 
35 to 44 
48 
Double-stopwatch 
X 
 
 
 
 
 
 
 
 
 
 
At the time of first dose, 2 stopwatches will be started by the 
appropriate study site staff and given to the subject. The subject 
will stop the first watch when/if they feel the “first perceptible 
pain relief” and stop the second watch when/if they feel 
“meaningful pain relief”. Section 11.4.3. 
Rescue medication use 
Ibuprofen 400 mg orally q6h prn (upon request) after first dose of study drug 
 
Record NPRS at rest immediately before each administration. 
Record date and time of administration. Sections 9.4.1.2 
and 11.4.4. 
Adverse events 
Continuous from signing of ICF through Safety Follow-up 
Section 11.5.1 
Medications review 
Continuous from signing of ICF through Safety Follow-up 
All medications taken within 14 days before the Screening Visit 
through the end of the study; Section 9.5. 
Treatment and 
procedures review 
Continuous from signing of ICF through Safety Follow-up 
 
CRU: clinical research unit; ICF: informed consent form; 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 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
Summary of Changes to the Protocol......................................................................................... 2 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 6 
4 
Table of Contents ................................................................................................................. 11 
List of Tables............................................................................................................................ 14 
List of Figures .......................................................................................................................... 14 
List of Abbreviations................................................................................................................ 15 
Abbreviation of Study Numbers .............................................................................................. 16 
5 
Introduction.......................................................................................................................... 17 
5.1 
Background ..................................................................................................................... 17 
5.2 
Study Rationale .............................................................................................................. 17 
6 
Study Objectives .................................................................................................................. 18 
6.1 
Primary Objective ........................................................................................................... 18 
6.2 
Secondary Objective ....................................................................................................... 18 
6.3 
Other Objective .............................................................................................................. 18 
7 
Study Endpoints ................................................................................................................... 18 
7.1 
Primary Endpoint ............................................................................................................ 18 
7.2 
Secondary Endpoints ...................................................................................................... 18 
7.3 
Other Endpoints .............................................................................................................. 18 
8 
Study Population .................................................................................................................. 18 
8.1 
Inclusion Criteria ............................................................................................................ 19 
8.2 
Exclusion Criteria ........................................................................................................... 19 
9 
Study Implementation ......................................................................................................... 21 
9.1 
Study Design .................................................................................................................. 21 
9.1.1 
Screening ................................................................................................................ 23 
9.1.1.1 
Repetition of Screening Assessments .............................................................. 23 
9.1.1.2 
Rescreening ...................................................................................................... 23 
9.1.2 
Abdominoplasty Procedure to Randomization ....................................................... 23 
9.1.3 
Treatment Period .................................................................................................... 24 
9.1.4 
Follow-up................................................................................................................ 24 
9.1.5 
Early Discontinuation ............................................................................................. 24 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 24 
9.3 
Rationale for Study Elements ......................................................................................... 24 
9.3.1 
Study Design........................................................................................................... 24 
9.3.2 
Study Drug Dose and Duration .............................................................................. 25 
9.3.3 
Rationale for Study Assessments ........................................................................... 25 
9.4 
Study Restrictions ........................................................................................................... 26 
9.4.1 
Analgesic Medications ........................................................................................... 27 
9.4.1.1 
Perioperative Pain Management ...................................................................... 27 
9.4.1.2 
Rescue Medication ........................................................................................... 28 
9.4.2 
Additional Dietary Restrictions .............................................................................. 28 
9.5 
Prior and Concomitant Medications ............................................................................... 28 
9.6 
Administration ................................................................................................................ 29 


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9.7 
Dose Modification for Toxicity ...................................................................................... 29 
9.8 
Removal of Subjects ....................................................................................................... 29 
9.9 
Replacement of Subjects ................................................................................................ 30 
10 Study Drug Information and Management ....................................................................... 30 
10.1 Preparation and Dispensing ............................................................................................ 30 
10.2 Packaging and Labeling ................................................................................................. 30 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 30 
10.4 Drug Accountability ....................................................................................................... 31 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 31 
10.6 Compliance ..................................................................................................................... 31 
10.7 Blinding and Unblinding ................................................................................................ 31 
10.7.1 
Blinding .................................................................................................................. 31 
10.7.2 
Unblinding .............................................................................................................. 32 
11 Assessments .......................................................................................................................... 33 
11.1 Subject and Disease Characteristics ............................................................................... 33 
11.2 Pharmacokinetics ............................................................................................................ 33 
11.2.1 
Blood Sampling ...................................................................................................... 33 
11.2.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 33 
11.2.3 
Bioanalysis.............................................................................................................. 33 
11.3 Other Assessments .......................................................................................................... 34 
11.3.1 
Verbal Categorical Rating Scale............................................................................. 34 
11.3.2 
Patient Global Assessment of Study Drug ............................................................. 34 
11.3.3 
Exploratory Assessments: Pharmacogenomics ...................................................... 34 
11.4 Efficacy ........................................................................................................................... 34 
11.4.1 
Placebo and Pain Assessment Video Training ....................................................... 34 
11.4.2 
Numeric Pain Rating Scale ..................................................................................... 34 
11.4.3 
Double-stopwatch Assessment ............................................................................... 35 
11.4.4 
Use of Rescue Medications .................................................................................... 35 
11.5 Safety .............................................................................................................................. 35 
11.5.1 
Adverse Events ....................................................................................................... 35 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 35 
11.5.3 
Physical Examinations and Vital Signs .................................................................. 37 
11.5.4 
Electrocardiograms ................................................................................................. 37 
11.5.5 
Contraception and Pregnancy ................................................................................. 38 
11.5.5.1 Contraception ................................................................................................... 38 
11.5.5.2 Pregnancy ......................................................................................................... 40 
12 Statistical Analysis ............................................................................................................... 40 
12.1 Sample Size and Power .................................................................................................. 40 
12.2 Analysis Sets .................................................................................................................. 41 
12.3 Statistical Analysis ......................................................................................................... 41 
12.3.1 
General Considerations ........................................................................................... 41 
12.3.2 
Background Characteristics .................................................................................... 41 
12.3.3 
Efficacy Analysis .................................................................................................... 42 
12.3.3.1 Analysis of Primary Endpoint .......................................................................... 42 
12.3.3.2 Analysis of Secondary Efficacy Endpoints ...................................................... 42 
12.3.3.3 Multiplicity Adjustment ................................................................................... 42 


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12.3.3.4 Missing Data Handling .................................................................................... 42 
12.3.4 
Safety Analysis ....................................................................................................... 42 
12.4 Interim Analysis ............................................................................................................. 43 
12.5 Data Monitoring Committee Analysis ............................................................................ 43 
12.6 Clinical Pharmacology Analysis .................................................................................... 43 
12.6.1 
Pharmacokinetic Analysis ...................................................................................... 43 
12.6.2 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 43 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 43 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 43 
13.1.1 
Adverse Events ....................................................................................................... 43 
13.1.1.1 Definition of an Adverse Event........................................................................ 43 
13.1.1.2 Clinically Significant Assessments .................................................................. 43 
13.1.1.3 Documentation of Adverse Events................................................................... 44 
13.1.1.4 Adverse Event Severity .................................................................................... 44 
13.1.1.5 Adverse Event Causality .................................................................................. 45 
13.1.1.6 Study Drug Action Taken ................................................................................ 45 
13.1.1.7 Adverse Event Outcome .................................................................................. 46 
13.1.1.8 Treatment Given............................................................................................... 46 
13.1.2 
Serious Adverse Events .......................................................................................... 46 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 46 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 47 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 48 
13.2 Administrative Requirements ......................................................................................... 48 
13.2.1 
Product Complaints ................................................................................................ 48 
13.2.2 
Ethical Considerations ............................................................................................ 48 
13.2.3 
Subject Information and Informed Consent ........................................................... 48 
13.2.4 
Investigator Compliance ......................................................................................... 48 
13.2.5 
Access to Records ................................................................................................... 49 
13.2.6 
Subject Privacy ....................................................................................................... 49 
13.2.7 
Record Retention .................................................................................................... 49 
13.2.8 
Study Termination .................................................................................................. 49 
13.2.9 
End of Study ........................................................................................................... 50 
13.3 Data Quality Assurance .................................................................................................. 50 
13.4 Monitoring ...................................................................................................................... 50 
13.5 Electronic Data Capture ................................................................................................. 50 
13.6 Confidentiality and Disclosure ....................................................................................... 51 
13.7 Publications and Clinical Study Report .......................................................................... 51 
13.7.1 
Publication of Study Results ................................................................................... 51 
13.7.2 
Clinical Study Report ............................................................................................. 52 
14 References ............................................................................................................................. 53 
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 
VX21-548-102 Treatment Groups .......................................................................... 5 
Table 3-1 
Study VX21-548-102: Screening Through Admission........................................... 7 
Table 3-2 
Study VX21-548-102: Procedure Through Randomization ................................... 8 
Table 3-3 
Study VX21-548-102: Treatment Period and Safety Follow-up ............................ 9 
Table 9-1 
VX21-548-102 Treatment Groups ........................................................................ 22 
Table 9-2 
Study Restrictions ................................................................................................. 27 
Table 10-1 
Study Drug ............................................................................................................ 30 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 33 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 36 
Table 11-3 
Contraceptive Requirements ................................................................................. 39 
Table 13-1 
Grading of AE Severity ........................................................................................ 45 
Table 13-2 
Classifications for AE Causality ........................................................................... 45 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 46 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 46 
List of Figures 
Figure 2-1 
VX21-548-102 Study Design ................................................................................. 4 
Figure 9-1 
VX21-548-102 Study Design ............................................................................... 22 
 


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List of Abbreviations 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
AMSAP 
abbreviated modeling and simulation analysis plan 
ANCOVA 
analysis of covariance 
AUC0-24 
area under the concentration versus time curve from the time of dosing to 24 hours 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
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 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GPS 
Global Patient Safety 
h 
hour 
HB/APAP 
hydrocodone bitartrate/acetaminophen 
HBsAg 
hepatitis B surface antigen 
HCV Ab 
hepatitis C virus antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV-1/HIV-2 Abs 
antibodies against human immunodeficiency viruses 1 and 2 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) (US) 
IRB 
institutional review board 
IV 
intravenous 
IXRS 
interactive response system in which X represents voice or web, such as IWRS 
max 
maximum value 
min 
minimum value 
n 
size of subsample 
NaV 
voltage-gated sodium channel 
NOAEL 
no-observed-adverse-effect-level 


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Abbreviation 
Definition 
NPRS 
Numeric Pain Rating Scale 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
P 
probability 
PE 
physical examination 
PGA 
Patient Global Assessment 
PK 
pharmacokinetic, pharmacokinetics 
prn 
as needed 
q6h 
every 6 hours 
q12h 
every 12 hours 
q24h 
every 24 hours 
QTcF 
QT interval corrected by Fridericia's formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SET 
Study Execution Team 
SFU 
Safety Follow-up 
SPID 
sum of the pain intensity difference 
SPIDm8-24 
sum of the pain intensity difference during movement from 8 to 24 hours 
SPIDm8-48 
sum of the pain intensity difference during movement from 8 to 48 hours 
SPIDr0-24 
sum of the pain intensity difference at rest from 0 to 24 hours 
SPIDr0-48 
sum of the pain intensity difference at rest from 0 to 48 hours 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
US 
United States 
VRS 
Verbal Categorical Rating Scale 
 
Abbreviation of Study Numbers 
Abbreviation 
Study Number 
Study 001 
Study VX19-548-001 
Study 002 
Study VX20-548-002 
 


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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, commonly 
prescribed for moderate-to-severe pain, 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 More than 50,000 deaths attributable to opioids occurred in the US from 2019 to 
2020, and more than 80% of fatal drug overdoses in Europe involved opioids.3, 4 
Given the limited treatment options, combined with the risks and relative ineffectiveness of 
current treatments, the development of new analgesics with improved efficacy and safety profiles 
is vital for better patient management and 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. The majority of analgesic drugs approved over the last decade either 
act on the opioid receptor system or are NSAIDs5; only 3 new molecular entity drugs for 
moderate to severe pain have been approved by the FDA since 2008.6-10 The majority of research 
activity focuses on developing abuse-deterrent reformulations of existing narcotic pain drugs; 
however, these drugs do not substantially improve efficacy or safety.  
Voltage-gated sodium channel 1.8 (NaV1.8) plays a critical role in pain signaling.11, 12 Support 
for this assertion arises from (1) evaluation of the role NaV1.8 plays in normal physiology13-17, 
(2) pathological states arising from mutations in the NaV1.8 gene (SCN10A)18, 19, (3) animal 
models20-23, and (4) pharmacology of known NaV1.8-modulating agents.24-26 In addition, because 
NaV1.8 expression is restricted to peripheral neurons, particularly those that sense pain (e.g., the 
dorsal root ganglia [DRG])13, 15, NaV1.8 inhibitors are less likely to be associated with the side 
effects commonly observed with other sodium channel modulators and the abuse liability 
associated with opioid therapies. Therefore, targeting the underlying biology of pain through 
selective NaV1.8 inhibition represents a novel approach to analgesic drug development that has 
the potential to address an urgent unmet need for safe and effective acute and chronic pain 
therapies. These therapies include treatment where the primary mechanisms underlying pain are 
nociceptor hyperexcitability. 
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. Refer to the VX-548 Investigator’s Brochure 
for additional details.27 
5.2 
Study Rationale 
Clinical data from 2 Phase 1 studies evaluating single and multiple ascending doses of VX-548 
demonstrated that VX-548 is generally safe and well tolerated in healthy subjects (Studies 001 
and 002).27 
This study will evaluate the efficacy and safety of 2 VX-548 doses in treating acute pain after an 
abdominoplasty. 


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6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
• To evaluate the efficacy of VX-548 doses in treating acute pain after an abdominoplasty 
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 a Numeric Pain 
Rating Scale (NPRS) at rest 0 to 48 hours (SPIDr0-48) after the first dose of study drug 
7.2 
Secondary Endpoints 
• Time-weighted SPID as recorded on an NPRS at rest 0 to 24 hours (SPIDr0-24) after the first 
dose of study drug 
• Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at rest at 48 hours 
after the first dose of study drug 
• 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 an NPRS during movement 8 to 24 hours (SPIDm8-24) 
and 8 to 48 hours (SPIDm8-48) after the first dose of study drug 
• Time to onset of “confirmed perceptible pain relief” and “meaningful pain relief” after the 
first dose of study drug 
• Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at rest at 24 hours 
after the first dose of study drug 
• Patient Global Assessment (PGA) of study drug at 48 hours after the first dose of study drug 
• Percentage of subjects using rescue medication, and total rescue medication usage, 0 to 
48 hours after the first dose of study drug 
• 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. 


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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 or female) between the ages of 18 and 75 years, inclusive. 
4. Body mass index (BMI) of 18.0 to 38.0 kg/m2, inclusive. 
5. Subject scheduled to undergo a standard (“full”) abdominoplasty procedure that: 
o includes a horizontally oriented incision approximately extending to (but not 
exceeding) each anterior superior iliac spine; 
o includes umbilical dissection and relocation, and plication of the fascia of the rectus 
muscle above and/or below the umbilical stalk; 
o does NOT include a vertically oriented supra-umbilical incision or collateral 
procedures (e.g., liposuction); and 
o can include drain placement and skin closure at the discretion of the surgeon 
After Surgery: 
6. Subject reported pain of ≥4 on the NPRS at rest and moderate or severe pain on the Verbal 
Categorical Rating Scale (VRS) at rest within 4 hours after surgery completion on Day 1. 
7. Subject is lucid, able to follow commands, and able to swallow oral medications. 
8. All analgesic guidelines (Section 9.4.1) were followed during and after the abdominoplasty. 
9. Abdominoplasty procedure duration ≤3 hours. 
8.2 
Exclusion Criteria 
Before Surgery: 
1. Prior history of abdominoplasty. 
2. History of intra-abdominal and/or pelvic surgery (including hysterectomy and Cesarean 
section) that resulted in any complications (e.g., postoperative infections, incisional 
infections or dehiscence, wound infections, or re-exploration/redo surgery for the same 
condition) or, in the opinion of the investigator or medical monitor, would preclude 
participation in the study. 
3. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study drug to the 
subject. This may include, but is not limited to, history of relevant drug or food allergies; 
history of significant respiratory, renal, hepatic, cardiovascular, metabolic, neurologic, or 
psychiatric disease; history or presence of clinically significant pathology; and history of 
cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical 
carcinoma in situ (all 3 with no recurrence for the last 5 years). 


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4. History of cardiac dysrhythmias requiring anti-arrhythmia treatment(s); or 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. 
5. Alanine aminotransferase or aspartate aminotransferase values >2.5 × upper limit of normal. 
6. 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. 
7. History of any sensory abnormality that, in the opinion of the investigator, may confound the 
ability of the subject to assess postoperative pain. 
8. Subjects who have a painful physical condition that, in the opinion of the investigator, may 
confound the assessments of postoperative pain. 
9. A known or clinically suspected infection with human immunodeficiency virus or hepatitis B 
or C viruses. 
10. Any prior surgery within 1 month before the first study drug dose unless approved by the 
medical monitor. 
11. American Society of Anesthesiologists physical status classification of ≥3. 
12. Chronic use of opioids or NSAIDs with dose escalation within 30 days before admission 
and/or unwilling or unable to stop analgesics at least 5 half-lives or 2 days (whichever is 
longer) before admission. 
13. Subjects who have started new medications that have not been at a stable dose for at least 
14 days prior to the scheduled abdominoplasty procedure and before dosing with 
investigational product. 
14. Subjects unwilling to receive any protocol-related medicine (e.g., ibuprofen, acetaminophen, 
fentanyl, hydrocodone). 
15. 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. 
16. Subjects with sleep apnea and/or on a home continuous positive airway pressure machine. 
17. 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. 
18. For female subjects: Pregnant, nursing, or planning to become pregnant during the study or 
within 30 days after the last study drug dose. 
For male subjects: Male subjects with a female partner who is pregnant, nursing, or planning 
to become pregnant during the study or within 30 days after the last study drug dose. 
19. Participation in a previous study investigating VX-548. 
20. Participated in another investigational study within 30 days of the first dose of study drug. 
21. 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. 


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o A positive drug screen for a known prescribed concomitant medication that is not 
otherwise exclusionary (e.g., benzodiazepines) will not disqualify subjects; however, 
marijuana (or any cannabis derivative) will not be allowed. 
22. Use of the substances, activities, or devices, as defined in Section 9.4, during the specified 
times. 
23. Subject, or close relative of the subject, is the investigator or a sub-investigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study at that site. 
After Surgery: 
24. Subject had medical complications during the abdominoplasty that, in the opinion of the 
investigator, should preclude randomization. 
25. Subject had a non-standard abdominoplasty and/or collateral procedures during the 
abdominoplasty. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, 4-arm, parallel study design 
evaluating the efficacy and safety of VX-548 doses in treating acute pain after an 
abdominoplasty (Figure 9-1).  
On Day 1, subjects will undergo a standard (“full”) abdominoplasty procedure (as defined in 
Section 8.1). After surgery completion, a subject will be randomized to 1 of 4 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 at rest, and (3) the subject’s pain is ≥4 on the NPRS at rest. If a 
subject does not meet the VRS and NPRS criteria within 4 hours of surgery completion, the 
subject will not be eligible for this study. 
Approximately 256 subjects will be randomized 1:1:1:1 to 4 treatment groups: high-dose 
VX-548 (100 mg/50 mg every 12 hours [q12h]); low-dose VX-548 (60 mg/30 mg q12h); 
hydrocodone bitartrate/acetaminophen (HB/APAP;opioid reference); or placebo (-1). 
Randomization will be stratified by site and baseline NPRS at rest (<8 versus ≥8). To maintain 
the blind, all subjects will receive the same number of tablets and/or capsules every 6 hours 
(q6h) in a double-dummy design. 


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Figure 9-1 
VX21-548-102 Study Design 
 
CRU: clinical research unit; HB/APAP: hydrocodone bitartrate/acetaminophen; NPRS: Numeric Pain Rating 
Scale; VRS: Verbal Categorical Rating Scale 
Notes: After surgery completion, a subject will be randomized to 1 of 4 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 at 
rest, and (3) the subject’s pain is ≥4 on the NPRS at rest. If a subject does not meet the VRS and NPRS 
criteria within 4 hours of surgery completion, the subject will not be eligible for this study. 
 
Table 9-1 
VX21-548-102 Treatment Groups 
Treatment 
Active Dose 
Number of Subjects 
VX-548 (high dose) 
100 mg first dose, then 50 mg q12h 
64 
VX-548 (low dose) 
60 mg first dose, then 30 mg q12h 
64 
HB/APAP 
5 mg/325 mg q6h 
64 
Placebo 
 
64 
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/or capsules q6h in a double-
dummy design. VX-548 active and/or VX-548 placebo 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. HB/APAP active or HB/APAP 
placebo 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. 
Subjects will report their pain intensity on the NPRS at rest at each scheduled time point through 
48 hours after the first dose of study drug. Starting 8 hours after the first dose of study drug, 
subjects will also report their pain intensity on the NPRS during movement. In addition, pain 
intensity will be recorded on the NPRS at rest immediately before each administration of rescue 
medication (Section 9.4.1.2). 
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 
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 at rest score is ≥4. 


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9.1.1 
Screening 
Screening assessments are listed in Table 3-1. Screening includes Screening Visit assessments 
required before the day of surgery and pre-procedure assessments required on the day of surgery. 
The Screening Visit will occur within 28 days before the scheduled abdominoplasty procedure. 
The investigator (or an appropriate authorized designee at the study site) will obtain informed 
consent from each subject. 
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.4). 
9.1.1.1 
Repetition of Screening Assessments 
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). 
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 
• Subjects who met all eligibility criteria but transiently (for personal reasons) are unable to 
commit to all study procedures 
• Subjects who were screened under a prior version of the protocol and did not meet any 
exclusion criterion, with the exception of a criterion that was updated in a subsequent version 
of the protocol 
Any subject who is rescreened for any of the exceptions listed above may have the screening 
window extended by 1 week before needing to undergo any rescreening assessments. If more 
than 35 days have elapsed from the Screening Visit before first dose of study drug, all screening 
assessments need to be repeated. 
9.1.2 
Abdominoplasty Procedure to Randomization 
Assessments to be completed after the abdominoplasty procedure through randomization are 
listed in Table 3-2. 
Subjects will receive 4 mg of intravenous (IV) ondansetron once at the beginning of surgery. 
After surgery, subjects may receive 4 mg of IV ondansetron every 8 hours prn for nausea and/or 
vomiting. Refer to Section 9.4.1.1 for details on perioperative pain management. 
All study periods will be conducted as described in Section 9.1. If a subject does not meet the 
VRS and NPRS criteria (Section 8.1) within 4 hours of surgery completion, the subject will not 
be eligible for this study. 


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9.1.3 
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 in the clinical research unit (CRU) until such 
abnormalities resolve. If the subject is unable or unwilling to remain in the CRU, the medical 
monitor (or authorized designee) will be notified, and the investigator will make every effort to 
arrange follow-up evaluations at appropriate intervals to document the course of the 
abnormalities. 
9.1.4 
Follow-up 
Subjects will have an in-person Safety Follow-up Visit 14 (± 2) days after the last dose of study 
drug. Safety Follow-up assessments are listed in Table 3-3. 
9.1.5 
Early Discontinuation 
Subjects who prematurely discontinue study drug dosing will remain under observation for at 
least 12 hours after the last dose of study drug, after which point they can be discharged from the 
CRU. 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 in the CRU 
until such abnormalities resolve. If the subject is unable or unwilling to remain in the CRU, the 
medical monitor (or authorized designee) will be notified, and the investigator will make every 
effort to arrange follow-up evaluations at appropriate intervals to document the course of the 
abnormalities. 
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. 
9.2 
Method of Assigning Subjects to Treatment Groups 
Approximately 256 subjects will be randomized 1:1:1:1 to 4 treatment groups: VX-548 (high 
dose); VX-548 (low dose); HB/APAP (opioid reference); or placebo. The randomization ratio of 
1:1:1:1 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 at rest (<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 Execution Team (SET).  
9.3 
Rationale for Study Elements 
9.3.1 
Study Design 
Abdominoplasty 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 


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arising from the subjects’ knowledge of treatment. A parallel design is considered most 
appropriate given the acute nature of abdominoplasty surgery. 
Two VX-548 doses will be evaluated to help inform dose selection for Phase 3 studies. 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 surgery 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. 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 
VX-548 doses (-1) were selected based on favorable safety and PK data from healthy volunteers 
in Study 001 (single ascending dose study) and Study 002 (multiple ascending dose study). 
Multiple oral doses up to 65 mg administered in solution/suspension every 24 hours (q24h) for 
14 days have been evaluated and found to be safe and well tolerated.27 The selected VX-548 
doses are predicted to achieve concentrations that are able to produce 87% (60 mg/30 mg q12h) 
to 91% (100 mg/50 mg q12h) NaV1.8 inhibition in the in vitro human DRG assay. 
Based on population PK modeling, the mean exposures (AUC0-24 and Cmax) for VX-548 and its 
major metabolite, 
, at the high dose in this study (100 mg/50 mg q12h 
administered as tablets) are predicted to be within the range of exposures observed at the highest 
tested dose found to be safe and well tolerated in humans in Study 001 and Study 002 and 
provide the following safety margins to the no-observed-adverse-effect level (NOAEL) observed 
in monkey in the 28-day GLP toxicity study:27  
• VX-548: 2.8-fold and 3.8-fold below the NOAEL for AUC0-24 and Cmax, respectively 
• 
: 4.0-fold and 6.3-fold below the NOAEL for AUC0-24 and Cmax, respectively 
The population PK model was based on observed PK data for the suspension/solution 
formulation of VX-548 and adjusted based on the relative bioavailability between the tablet and 
solution formulations of VX-548. 
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 abdominoplasty 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. 
Pain at rest is the standard outcome measure in postoperative analgesic trials. However, there is 
evidence that pain during movement, commonly referred to as “movement-evoked pain”, may be 
more sensitive to treatment effects than pain at rest.29, 30 Movement-evoked pain is more intense 
than pain at rest in the first 3 postoperative days,31 providing an opportunity to demonstrate 
differential efficacy among active treatments.29, 32 


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Double-stopwatch assessment: The double-stopwatch assessment is a standardized assessment 
for determining the onset of pain relief.30, 33 Two stopwatches are started by the appropriate study 
site staff and given to the subject at the time of the first dose. Subjects are told to stop the first 
watch when/if they first feel any pain relief (“first perceptible pain relief”) and stop the second 
watch when/if they first feel pain relief they consider meaningful (“meaningful pain relief”). If a 
subject achieves “meaningful pain relief”, the time the first watch was stopped is considered the 
time to “confirmed perceptible pain relief”. 
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 the method of pain control with the study drug and is evaluated on a 4-point Likert scale 
(poor, fair, good, or excellent). 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. A non-exhaustive list of study restrictions will 
be provided in the Study Reference Manual. 


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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 to the CRU 
Until discharge from CRU 
Oral steroids 
5 half-lives or 2 days (whichever is 
longer) before admission to the CRU 
Until discharge from CRU 
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, vegetables from the 
mustard green family (e.g., kale, 
broccoli, watercress, collard greens, 
kohlrabi, Brussels sprouts, mustard), 
and charbroiled meats 
7 days before first dose of study drug  
Completion of SFU 
assessments 
Alcohol 
24 hours before first dose of study drug 
Until discharge from CRU 
Strenuous exercise (e.g., heavy 
lifting, weight training, and 
aerobics) 
48 hours before first clinical laboratory 
testing  
Completion of SFU 
assessments 
CRU: clinical research unit; 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 
Apart from standard-of-care during admission, the following analgesic medications are 
prohibited for 5 half-lives or 2 days (whichever is longer) before admission through discharge 
from CRU: opioids (except fentanyl citrate), NSAIDs (except ibuprofen rescue), acetaminophen, 
ketamine, regional or neuraxial anesthesia, and/or local anesthetic infiltration (except lidocaine 
during the procedure). 
9.4.1.1 
Perioperative Pain Management 
Pre- and perioperative: 
• IV midazolam (≤2 mg) and/or fentanyl citrate (≤50 µg) may be used preoperatively. 
• IV fentanyl citrate and propofol (doses at the discretion of the anesthesia provider) may be 
used for anesthesia induction. 
• IV general anesthesia with propofol and fentanyl citrate will be used for anesthesia 
maintenance.  


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• After completing the rectus plication, the rectus fascia should be infiltrated above and below 
the umbilicus with 1% lidocaine without epinephrine for a total of approximately 4 mg/kg. 
• Total fentanyl citrate from induction through emergence may not exceed 250 µg. 
• A record (date and time of administration) will be kept of all standard-of-care pain 
medication use through surgery completion. 
Postoperative: 
• Postoperative supplemental analgesia medication is permitted in the postanesthesia care unit 
per the following guidelines: 
o Fentanyl citrate (12.5 to 25 µg IV prn) can be administered if the subject is: 1) not 
lucid enough for randomization but deemed to be in severe pain per clinical 
judgement and/or 2) unable to swallow oral medications. 
o Randomization may not occur until at least 15 minutes after the last administration of 
supplemental analgesia medication. 
• The use of abdominal binders is permitted. 
• The use of ice packs is not permitted. 
• No pain treatments (except the permitted supplemental analgesia medication) are allowed 
from surgery completion until the first dose of study drug. 
Refer to Section 9.1.2 for details on perioperative antiemetics. 
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 at 
rest score is ≥4. 
• A record (date and time of administration) will be kept of all rescue medication use. 
• An unscheduled NPRS at rest will be completed immediately before each administration of 
rescue medication. 
9.4.2 
Additional Dietary Restrictions 
• Subjects will abstain from all food and drink (except ≤8 fluid ounces per hour of water) 
during the fasting periods indicated in Table 3-2 and Table 3-3. 
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 of the Screening Visit through admission will 
be recorded with indication, route of administration, and start and stop dates of 
administration. 


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• All medications taken from 14 days before the Screening Visit through the end of the study 
will be recorded with indication, route of administration, and start and stop dates of 
administration. Concomitant medications administered in-clinic will also be recorded with 
the time of each administration. 
• A female subject of childbearing potential using hormonal contraceptives does not need to 
stop taking hormonal contraceptives; however, they are not considered an approved form of 
contraception (Section 11.5.5.1). 
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/or capsules 
q6h in a double-dummy design: 
o VX-548 active and/or VX-548 placebo will be administered to all subjects q12h: 
0 hours (first dose) and at 12, 24, and 36 hours after the first dose. 
o HB/APAP active or HB/APAP placebo 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. 
• 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.  
• 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 9.1.5). 
9.8 
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 participate in a 
Safety Follow-up Visit, if applicable (see Section 9.1.5), and follow up with the subject 
regarding any unresolved AEs. 


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If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends, and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study, the study data and samples collected will remain part of the study. A subject will 
not be able to request the withdrawal of his/her information from the study data. A subject may 
request destruction of the samples collected from him/her during the study as long as those 
samples can be identified as his/her samples. 
9.9 
Replacement of Subjects 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug Treatment 
Period may be replaced at Vertex’s discretion. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects.  
Study drug will be dispensed at the CRU 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 10-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 at 
United States Pharmacopeia controlled room temperature 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 10-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 


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10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information about the dates and 
amounts of (1) study drug received and (2) study drug dispensed to the subjects. These materials 
will be retained at the site according to instructions provided by Vertex or its designee. The study 
monitor will review study drug records and inventory throughout the study. If a site uses a 
site-specific drug accountability system and/or process, including processes associated with the 
destruction of returned materials, the process must be documented and approved by Vertex. The 
study monitor must review the drug accountability documentation on a regular basis. The study 
monitor will promptly communicate to Vertex any discrepancies he/she is unable to resolve with 
the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials until the study monitor has 
performed drug accountability. The investigator will ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any special 
instructions provided by Vertex. Destruction will be adequately documented. 
The principal investigator, study site staff, including pharmacy personnel will assist Vertex with 
any recall activities (as applicable) and place impacted investigational medicinal product (IMP) 
in quarantine when requested. 
10.6 
Compliance  
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 in the CRU to 
ensure 100% study treatment compliance. 
10.7 
Blinding and Unblinding 
This is a double-blind study. 
10.7.1 
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 
• The unblinded site monitor and unblinded trip report reviewer 
• 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 


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• 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 SET (the Vertex 
bioanalytical SET member will continue to be blinded) 
Vertex medical monitor may, for matters relating to safety, unblind individual subjects at any 
time.  
A limited Vertex team not directly involved in the conduct of the study may be unblinded to 
individual subject treatment assignments and have access to PK, efficacy, and/or safety data 
(e.g., AEs, clinical laboratory assessments) for continuous monitoring purposes. These 
individuals will not be a member of the study team and will not interact with the CRU or study 
personnel. No unblinded data or results of unblinded analyses will be shared with the CRU or 
with blinded Vertex personnel. Masked identifications will be used for PK and efficacy analyses. 
All instances of unblinding by Vertex personnel will be documented. 
10.7.2 
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.  


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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, height, and weight.  
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 its metabolite, 
. 
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. Samples collected outside of 
these acceptable windows will be considered protocol deviations. 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 each dose. 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Sampling Time 
Time From Scheduled Sampling Allowed 
Predose  
Any time on Day 1 after completion of eligibility 
assessments and before surgery 
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. 


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11.3 
Other Assessments 
11.3.1 
Verbal Categorical Rating Scale 
In the postoperative period before randomization, VRS at rest will be completed upon request for 
the first dose of study drug for pain relief. Pain intensity will be recorded after a ≥3-minute rest 
in bed in either the supine or up to approximately 15-degree head-up position. 
If a subject does not meet the VRS and NPRS criteria (Section 8.1) within 4 hours after surgery 
completion, the subject will not be eligible for this study. 
11.3.2 
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. 
11.3.3 
Exploratory Assessments: Pharmacogenomics 
A blood sample (optional DNA sample) will be collected for potential exploratory evaluation of 
associations between DNA markers and health and disease, especially 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.  
11.4 
Efficacy 
11.4.1 
Placebo and Pain Assessment Video Training 
All subjects will complete placebo and pain assessment video training at the Screening Visit and 
on Day 1 prior to the surgical procedure.  
11.4.2 
Numeric Pain Rating Scale 
NPRS will be completed at rest and during movement as follows: 
• NPRS at rest: Pain intensity will be recorded after a ≥3-minute rest in bed in either the 
supine or up to approximately 15-degree head-up position. 
• NPRS during movement: Perform immediately after completion of NPRS at rest. Pain 
intensity will be recorded after the subject sits up in bed, unassisted, at an angle of 
approximately 45 degrees or more. 
In the postoperative period before randomization, NPRS at rest will be completed after VRS at 
rest if the subject’s pain is rated moderate or severe on the VRS at rest. If a subject does not meet 
the VRS and NPRS criteria (Section 8.1) within 4 hours after surgery completion, the subject 
will not be eligible for this study. 
During the Treatment Period, subjects will report their pain intensity on the NPRS at rest at each 
scheduled time point through 48 hours after the first dose of study drug. Starting 8 hours after the 
first dose of study drug, subjects will also report their pain intensity on the NPRS during 
movement. In addition, pain intensity will be recorded on the NPRS at rest immediately before 
each administration of rescue medication (Section 9.4.1.2). 


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11.4.3 
Double-stopwatch Assessment 
At the time of first dose, 2 stopwatches will be started by the appropriate study site staff: 
1 labeled “first perceptible pain relief” and the other labeled “meaningful pain relief”. Both 
stopwatches will be given to the subject at the same time. The subject will stop the “first 
perceptible pain relief” stopwatch when/if they first feel any pain relief and stop the “meaningful 
pain relief” stopwatch when/if they first feel relief that is “meaningful” to them. If the subject 
does not stop both stopwatches by 6 hours after the first dose, or receives rescue medication, the 
stopwatches will be stopped. 
11.4.4 
Use of Rescue Medications 
Guidelines on administration of ibuprofen as rescue medication are included in Section 9.4.1.2. 
Rescue medication is permitted for pain relief upon subject’s request. A record will be kept of all 
rescue medication use, and an unscheduled NPRS at rest will be completed immediately before 
each administration of rescue medication. 
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.  
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 Tests at Screening: The following additional tests will be performed during screening 
to assess eligibility: 
• Serology: hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), and 
antibodies against human immunodeficiency viruses 1 and 2 (HIV-1/HIV-2 Abs) 
• Serum Follicle-stimulating Hormone (FSH): Serum FSH will be tested at the Screening Visit 
for female subjects who are suspected to be postmenopausal. For a subject to be considered 
of non-childbearing potential, the serum FSH levels will be within the laboratory’s range for 
postmenopausal females. 
• Pregnancy Testing: All female subjects will have a serum β-human chorionic gonadotropin 
(β-hCG) test during the Screening Visit. Female subjects of childbearing potential (as defined 
in Section 11.5.5.1), will also have a urine β-hCG test on Day 1 before admission. Both the 
serum and urine β-hCG test must be negative to receive study drug. 
• Drug and Alcohol Screening: Drug screening for opioids, methadone, cannabinoids, cocaine, 
amphetamines/methamphetamines, barbiturates, and benzodiazepines will be assessed by a 
urine test. Alcohol screening will be assessed 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 


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drug. A positive drug screen for a known prescribed concomitant medication that is not 
otherwise exclusionary (e.g., benzodiazepines) will not disqualify subjects; however, 
marijuana (or any cannabis derivative) will not be allowed. 
Additional evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used, 
with the following exceptions: 
• Day 1 (pre-procedure) drug and alcohol (breath) 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 (pre-procedure) if there is clear evidence of laboratory error (Section 9.1.1.1) in the 
central laboratory assessment. 
• Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the 
investigator becomes aware of the abnormal result. If it is not possible to send a timely 
specimen to the central laboratory (e.g., the subject was hospitalized elsewhere), the 
investigator may base the assessment of an AE on the local laboratory value. 
11.5.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits. At other visits, symptom-directed PEs and symptom-directed vital signs assessments 
can be performed at the discretion of the investigator or healthcare provider. 
A PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, nose, and 
throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs. 
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 for at least 5 minutes before vital 
signs are assessed.  
11.5.4 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines: 
• The ECG will be done before any other procedures that may affect heart rate, such as blood 
draws. 
• The subject will be instructed to rest for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position 


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A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. Clinically significant ECG abnormalities occurring during the study 
through the Safety Follow-up Visit will be recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. A subject with a 
QTcF value above the threshold value will discontinue dosing. 
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. 
11.5.5.1 
Contraception 
Study participation requires a commitment from subjects and their partners to use methods of 
contraception, as outlined in Table 11-3, from the Screening Visit through 30 days after the last 
dose of study drug. 


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Table 11-3 
Contraceptive Requirements 
Male subjects and 
their female 
(non-study) partners  
Male subjects must use a condom (with spermicide, if available) from the Screening 
Visit through 30 days after the last dose of study drug. 
 
In addition, at least 1 of the following acceptable methods must be used as a couple:a 
• Male vasectomy 6 months or more previously, with a documented negative 
post-vasectomy semen analysis for sperm 
• 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. 
Female subjects and 
their male 
(non-study) partners 
Male (non-study) partners must use a condom (with spermicide, if available) from the 
Screening Visit through 30 days after the last dose of study drug. 
 
In addition, at least 1 of the following acceptable methods must be used as a couple:a,b 
• Male vasectomy 6 months or more previously, with a documented negative 
post-vasectomy semen analysis for sperm 
• 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. 
a 
Male subjects must use a condom to avoid exposing a potential fetus to study drug via the seminal fluid. 
Female condom is not an acceptable method due to the increased risk of tearing when the female and male 
condoms are used at the same time. 
b 
The effects of VX-548 on the PK of hormonal contraceptives are not known. A female subject of 
childbearing potential using hormonal contraceptives does not need to stop taking hormonal contraceptives; 
however, they are NOT permitted as an approved form of contraception for female subjects. 
Contraception for the couple is waived for the following: 
• True abstinence for the subject, when this is consistent with the preferred and usual lifestyle 
of the subject. True abstinence must be practiced from the Screening Visit through 30 days 
after the last dose of study drug. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception.  
• If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented through 
examination of a semen specimen. 
• If the female is of non-childbearing potential. To be considered of non-childbearing potential, 
the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH 
level within the laboratory's reference range for postmenopausal females 
o Documented bilateral oophorectomy and/or hysterectomy 
• Same biological sex relationships. 


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Additional notes: 
• Male subjects must not donate sperm from the first study drug dose, throughout the study, 
and for 90 days following the last dose of study drug. 
• Male and female subjects who are not sexually active at the time of screening must agree to 
follow the contraceptive requirements of this study if they become sexually active. 
• If applicable, additional contraception requirements may need to be followed according to 
local regulations and/or requirements. 
Unique situations that may not fall within the above specifications may be discussed with the 
Vertex medical monitor or designee on an individual basis. 
11.5.5.2 
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 
The sample size calculation is based on the comparison between VX-548 and placebo on the 
primary endpoint. Assuming a standardized effect size of 0.8 for VX-548 (high or low dose) 
compared to placebo, 54 evaluable subjects per group would provide at least 90% power at a 
2-sided significance level of 0.05. This sample size would allow a minimal detectable 
standardized effect size of 0.38 to achieve statistical significance between VX-548 (high or low 
dose) and placebo. With this sample size, a two-sided 95% CI for the estimated standard effect 
size will extend 0.38 from the observed standardized effect size, assuming the CI is based on the 
large sample z statistic. To allow for withdrawal of up to 15% of randomized subjects over 48 
hours of treatment, the study will enroll and randomize approximately 256 subjects in total. 


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12.2 
Analysis Sets 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), and Safety 
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 disposition 
summary tables, unless otherwise specified. 
The 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, unless otherwise specified. 
12.3 
Statistical Analysis 
The primary objective of this study is to evaluate the efficacy of VX-548 doses in treating acute 
pain after an abdominoplasty. 
This section presents a summary of the planned statistical analyses of efficacy and safety for this 
study. Methodological and related details (e.g., missing data) will be in the SAP. 
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. 
Treatment-emergent (TE) Period will include the time from the first dose of study drug in the 
Treatment Period to either (1) the Safety Follow-up, or (2) the date of the last dose + 16 days for 
subjects who do not have a Safety Follow-up.  
12.3.2 
Background Characteristics 
Subject disposition (e.g., completed treatment, prematurely discontinued the treatment and the 
reason for discontinuation) will be summarized by treatment group. 
Demographics and baseline characteristics (e.g., sex, age, race, ethnicity, weight, height, BMI, 
and pain intensity) will be summarized by treatment group. No statistical tests will be carried out 
to evaluate any baseline imbalance between treatment groups. 
Medications used will be coded using the World Health Organization Drug Dictionary and 
summarized descriptively.  
All data collected during dispensation of study drug (e.g., time of administration and number of 
tablets and capsules) will be presented in data listings only. 


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Additional details will be provided in the SAP. 
12.3.3 
Efficacy Analysis 
Evaluation of the efficacy of VX-548 doses is the primary objective of this study. All efficacy 
endpoints will be analyzed based on the FAS. The analysis of the primary efficacy endpoint and 
secondary endpoints will only be between VX-548 and placebo. All analyses on comparisons 
between HB/APAP versus placebo will be exploratory. 
12.3.3.1 
Analysis of Primary Endpoint 
The primary efficacy endpoint is the time-weighted SPIDr0-48 after the first dose of study drug. 
The primary efficacy analysis will be based on an analysis of covariance (ANCOVA) model. 
The model will include SPIDr0-48 as the dependent variable and treatment as a fixed effect, with 
stratification factors (i.e., site and baseline NPRS at rest) as covariates. If the model estimation 
does not converge, site will be removed from the model. The least squares means of difference 
versus placebo and the corresponding 95% CIs and P values will be presented. 
Details will be provided in the SAP. 
12.3.3.2 
Analysis of Secondary Efficacy Endpoints 
• Time-weighted SPIDr0-24 after the first dose of study drug: analysis of this variable will be 
similar to the primary analysis. 
• Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at rest at 48 hours 
after the first dose of study drug: These variables will be analyzed using the 
Cochran-Mantel-Haenszel test, stratified by baseline NPRS at rest. 
All analyses of primary and secondary variables on comparisons between HB/APAP versus 
placebo will be exploratory, although similar to those between VX-548 versus placebo. 
12.3.3.3 
Multiplicity Adjustment 
There is no multiplicity adjustment for the pairwise comparisons between different doses of 
VX-548 and placebo. 
12.3.3.4 
Missing Data Handling 
For the primary analysis, NPRS at rest that were collected within 6 hours after a dose of rescue 
medication will be taken as missing and will be imputed using the pre-rescue NPRS at rest. 
Missing values due to early withdrawal will be imputed using the last non-missing observation 
carried forward before the calculation of SPIDr0-48 values. Sensitivity analyses for handling 
missing data will be described in the SAP. 
12.3.4 
Safety Analysis 
The overall safety profile of VX-548 will be assessed in terms of the following safety and 
tolerability endpoints: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis) 
• Standard 12-lead ECG outcomes 
• Vital signs 


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Safety endpoints will be analyzed 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 
Data Monitoring Committee Analysis 
Not applicable 
12.6 
Clinical Pharmacology Analysis 
12.6.1 
Pharmacokinetic Analysis 
The PK of VX-548 and its metabolite, 
, will be determined by noncompartmental 
analysis and 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. 
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 abbreviated modeling and simulation analysis plan (AMSAP). The results of 
the population PK and exposure-response 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, 


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the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the following times: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, withdrawal of 
consent) 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up Visit 
• For enrolled subjects who do not have a Safety Follow-up Visit, 16 days after the last dose of 
study drug. 
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the case report 
form (CRF) and source document. AEs for subjects who are screened but not subsequently 
enrolled will be recorded only in the subject’s source documents. The following data will be 
documented for each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 


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Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
September 2019). 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 adverse event 
Source: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed September 2019) 
ADL: activities of daily living; AE: adverse event 
Note: A semi-colon indicates ‘or’ within the description of the grade. 
a 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the subject’s medical record). 
AE: adverse event 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories in Table 13-3.  


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Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classificationa 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
AE: adverse event  
a 
Refer to Section 9.7 for directions regarding what drug actions are permitted per protocol.  
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow up) 
AE: adverse event 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation and is suspected of being a delayed toxicity due to administration of the study 
drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  


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• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious”, which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent through the Safety Follow-up Visit, 
regardless of causality, will be reported by the investigator to Vertex GPS within 24 hours of 
identification. In addition, all SAEs that occur after the Safety Follow-up Visit and are 
considered related to study drug(s) will be reported to Vertex GPS within 24 hours of 
identification.  
For SAEs that occur after obtaining informed consent through the Safety Follow-up Visit, the 
SAE Form will be completed for new/initial events as well as to report follow-up information on 
previously reported events. Investigators are asked to report follow-up information as soon as it 
becomes available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
 
  
For technical issues related to submitting the form, contact telephone: 
 
SAEs that occur after the Safety Follow-up Visit and are considered related to study drug(s) will 
be recorded on the Vertex Clinical Trial Safety Information Collection Form (hereafter referred 
to as the “SAE Form”) using a recognized medical term or diagnosis that accurately reflects the 
event. SAEs will be assessed by the investigator for relationship to the investigational study 
drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be assessed 


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only as related (includes possibly related) or not related (includes unlikely related), and severity 
assessment will not be required. For the purposes of study analysis, if the event has not resolved 
at the end of the study reporting period, it will be documented as ongoing. For purposes of 
regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report the outcome to Vertex using the SAE Form. 
13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions 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. 
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, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable) before study participation. 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 


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immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
13.2.5 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.6 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers, and access to subject names linked to such 
numbers will be limited to the site and the study physician and will not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE Forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 
For sites participating in the US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will comply with all HIPAA 
requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.7 
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. 


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Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.2.9 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the qualifications 
of each investigator, inspect clinical study site facilities, and inform the investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation per 
current ICH E6 GCP Guidelines. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each subject. Study 
data for each enrolled subject will be entered into a CRF by study site personnel using a secure, 
validated, web-based electronic data capture (EDC) application. Vertex will have read-only 
access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
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 investigation is conducted according to the protocol design and 
regulatory requirements. 
13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
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 


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CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc or other electronic media will be placed in the investigator’s 
study file. 
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 
13.7.1 
Publication of Study Results 
Vertex is committed to reporting the design and results of all clinical studies in a complete, 
accurate, balanced, transparent, and timely manner, consistent with Good Publication Practices 
(GPP3).34  
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 criteria35: 
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;  


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3. Final approval of the version to be published; and 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
All authors must meet conditions 1, 2, 3, and 4. All persons designated as authors should qualify 
for authorship, and all those who qualify should be listed. Contributions such as medical writing, 
enrollment of subjects, acquisition of funding, collection of data, or general supervision of the 
research group, alone, do not justify authorship.  
Contributors: Contributors who meet fewer than all 4 of International Committee of Medical 
Journal Editors 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 
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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: 
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Centers for Disease Control and Prevention. Vital statistics rapid release: Provisional 
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European Monitoring Centre for Drugs and Drug Addiction. European drug report: 
Trends and developments. Lisbon, Portugal: 2020. 
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Taneja A, Della Pasqua O, Danhof M. Challenges in translational drug research in 
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United States Department of Health and Human Services. Food and Drug Administration. 
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valReports/UCM091096.pdf. Accessed 01 March 2019. 
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United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research. 2010. Novel Drug Approvals. Available at: 
https://web.archive.org/web/20120301171618/http:/www.fda.gov/downloads/Drugs/Deve
lopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicAppro
valReports/UCM242677.pdf. Accessed 01 March 2019. 
9 
United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research. 2011-2014. Novel Drug Approvals. Available 
at: https://wayback.archive-
it.org/7993/20170722032043/https:/www.fda.gov/Drugs/DevelopmentApprovalProcess/
DrugInnovation/default.htm. Accessed 01 March 2019. 
10 
United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research. 2015-2019. Novel Drug Approvals. Available 
at: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm629491.h
tm. Accessed 01 March 2019. 
11 
England S. Voltage-gated sodium channels: the search for subtype-selective analgesics. 
Expert Opin Investig Drugs. 2008;17(12):1849-64. 
12 
Krafte D, Bannon A. Sodium channels and nociception: recent concepts and therapeutic 
opportunities. Curr Opin Pharmacol. 2008;8(1):50-6. 
13 
Akopian AN, Sivilotti L, Wood JN. A tetrodotoxin-resistant voltage-gated sodium 
channel expressed by sensory neurons. Nature. 1996;379(6562):257-62. 


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14 
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. 
15 
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. 
16 
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. 
17 
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. 
18 
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. 
19 
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. 
20 
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. 
21 
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. 
22 
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. 
23 
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. 
24 
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. 
25 
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. 
26 
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. 
27 
Vertex Pharmaceuticals Incorporated. VX-548 Investigator's Brochure.  
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. 


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29 
Breivik H, Borchgrevink PC, Allen SM, Rosseland LA, Romundstad L, Hals EK, et al. 
Assessment of pain. Br J Anaesth. 2008;101(1):17-24. 
30 
Cooper SA, Desjardins PJ, Turk DC, Dworkin RH, Katz NP, Kehlet H, et al. Research 
design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT 
recommendations. Pain. 2016;157(2):288-301. 
31 
Srikandarajah S, Gilron I. Systematic review of movement-evoked pain versus pain at 
rest in postsurgical clinical trials and meta-analyses: a fundamental distinction requiring 
standardized measurement. Pain. 2011;152(8):1734-39. 
32 
Gilron I, Orr E, Tu D, O'Neill JP, Zamora JE, Bell AC. A placebo-controlled randomized 
clinical trial of perioperative administration of gabapentin, rofecoxib and their 
combination for spontaneous and movement-evoked pain after abdominal hysterectomy. 
Pain. 2005;113(1-2):191-200. 
33 
Mehlisch DR, Ardia A, Pallotta T. A controlled comparative study of ibuprofen arginate 
versus conventional ibuprofen in the treatment of postoperative dental pain. J Clin 
Pharmacol. 2002;42(8):904-11. 
34 
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. 
35 
International Committee of Medical Journal Editors (ICMJE). December 2017. 
Recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals. Available at: http://www.icmje.org/recommendations/. Accessed 03 
August 2018. 
 


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15
PROTOCOL SIGNATURE PAGES
15.1
Sponsor Signature Page
Protocol #:
VX21—548-102
Version #:
4.0
Version Date:
21 January 2022
Study Title: A Phase 2, Randomized, Double-blind, Placebo-controlled, Multi-dose Study
Evaluating the Efficacy and Safety ofVX-548 for Acute Pain After an Abdominoplasty
This clinical study protocol has been reviewed and approved by the sponsor.
Vertex Phannaceuticals Incorporated
Condential Information


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15.2 
Investigator Signature Page 
Protocol #:  VX21-548-102 
Version #: 
4.0 
Version Date: 
21 January 2022 
Study Title: A Phase 2, Randomized, Double-blind, Placebo-controlled, Multi-dose Study 
Evaluating the Efficacy and Safety of VX‑548 for Acute Pain After an Abdominoplasty 
I have read Protocol VX21-548-102, 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 27 
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1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX21-548-102 Version 3.0 
(Final Analysis) 
 
A Phase 2, Randomized, Double-blind, Placebo-controlled, Multi-
dose Study Evaluating the Efficacy and Safety of VX‑548 for Acute 
Pain After an Abdominoplasty 
Author of SAP: 
 
 
Version: 1.0 
Version Date of SAP: 20 December 2021   
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


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 Objective ................................................................................................... 5 
5.3 
Other Objectives ......................................................................................................... 5 
6 
Study Endpoints ............................................................................................................... 5 
6.1 
Primary Endpoint ........................................................................................................ 5 
6.2 
Secondary Endpoints .................................................................................................. 5 
6.3 
Other Endpoints .......................................................................................................... 6 
7 
Overall Design .................................................................................................................. 6 
7.1 
Sample Size and Power .............................................................................................. 7 
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 ................................................................................................ 10 
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 .......................................................................... 11 
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 
Primary Analysis ........................................................................................ 12 
9.3.1.3 
Additional Analyses ................................................................................... 13 
9.3.1.4 
Sensitivity Analyses ................................................................................... 13 
9.3.1.5 
Subgroup Analysis ..................................................................................... 13 
9.3.2 
Analysis of Secondary Efficacy Variables ....................................................... 13 
9.3.2.1 
Definition of Secondary Efficacy Variables .............................................. 13 
9.3.2.2 
Secondary Analyses ................................................................................... 14 
9.3.3 
Analysis of Other Efficacy Variables ............................................................... 14 


Statistical Analysis Plan (Methods)  
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9.3.3.1 
Definition of Other Efficacy Variables ...................................................... 14 
9.3.3.2 
Other Analyses ........................................................................................... 15 
9.4 
Safety Analysis ......................................................................................................... 17 
9.4.1 
Adverse Events ................................................................................................. 17 
9.4.2 
Clinical Laboratory Assessments ..................................................................... 18 
9.4.3 
Electrocardiogram ............................................................................................ 19 
9.4.4 
Vital Signs ........................................................................................................ 19 
9.4.5 
Physical Examination ....................................................................................... 19 
10 Summary of Interim and IDMC Analyses .................................................................. 19 
11 References ....................................................................................................................... 19 
12 List of Appendices .......................................................................................................... 20 
Appendix A 
: Analysis Visit Windows for Safety and Efficacy Assessments ............... 20 
Appendix B 
: Imputation Rules for Missing Prior/Concomitant Medication Dates ...... 22 
Appendix C 
: Imputation Rules for Missing AE Dates and Times ................................ 23 
Appendix D 
: Threshold Value Criteria .......................................................................... 24 
 


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 VX21-
548-102 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 database 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 database lock will be documented in the clinical study report for this study. 
The analysis addressing the pharmacokinetic (PK) objective of the study will be described in 
the Clinical Pharmacology Analysis Plan (CPAP) which will be developed separately by the 
Clinical Pharmacology department at Vertex Pharmaceuticals Incorporated (Vertex). 
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
• To evaluate the efficacy of VX-548 doses in treating acute pain after an abdominoplasty 
5.2 
Secondary Objective 
• To evaluate the safety and tolerability of VX-548 
5.3 
Other Objectives  
• To evaluate the pharmacokinetics (PK) 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 a Numeric 
Pain Rating Scale (NPRS) at rest 0 to 48 hours (SPIDr0-48) after the first dose of study 
drug 
6.2 
Secondary Endpoints 
• Time-weighted SPID as recorded on an NPRS at rest 0 to 24 hours (SPIDr0-24) after the 
first dose of study drug 
• Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at rest at 48 
hours after the first dose of study drug 


Statistical Analysis Plan (Methods)  
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• 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 an NPRS during movement 8 to 24 hours (SPIDm8-
24) and 8 to 48 hours (SPIDm8-48) after the first dose of study drug 
• Time to onset of “confirmed perceptible pain relief” and “meaningful pain relief” after 
the first dose of study drug 
• Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at rest at 
24 hours after the first dose of study drug 
• Patient Global Assessment (PGA) of study drug at 48 hours after the first dose of study 
drug 
• Percentage of subjects using rescue medication, and total rescue medication usage, 0 to 
48 hours after the first dose of study drug 
• PK parameter estimates of VX-548 and its metabolite, 
 
7 
OVERALL DESIGN  
This is a Phase 2, randomized, double-blind, placebo-controlled, 4-arm, parallel study design 
evaluating the efficacy and safety of VX-548 doses in treating acute pain after an 
abdominoplasty (Figure 7-1).  
On Day 1, subjects will undergo a standard (“full”) abdominoplasty procedure. After surgery 
completion, a subject will be randomized to 1 of 4 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 at rest, and (3) the subject’s pain is ≥4 on the NPRS at rest. If a subject does not meet 
the VRS and NPRS criteria within 4 hours of surgery completion, the subject will not be 
eligible for this study. 
Approximately 256 subjects will be randomized 1:1:1:1 to 4 treatment groups: high-dose 
VX-548 (100 mg/50 mg every 12 hours [q12h]); low-dose VX-548 (60 mg/30 mg q12h); 
hydrocodone bitartrate/acetaminophen (HB/APAP; opioid reference); or placebo (Table 7-1). 
Randomization will be stratified by site and baseline NPRS at rest (<8 versus ≥8). To 
maintain the blind, all subjects will receive the same number of tablets and/or capsules every 
6 hours (q6h) in a double-dummy design. 


Statistical Analysis Plan (Methods)  
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Figure 7-1 
VX21-548-102 Study Design 
 
CRU: clinical research unit; HB/APAP: hydrocodone bitartrate/acetaminophen; NPRS: Numeric Pain Rating Scale; 
q6h: every 6 hours; VRS: Verbal Categorical Rating Scale 
Notes: After surgery completion, a subject will be randomized to 1 of 4 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 at rest, and (3) the subject’s 
pain is ≥4 on the NPRS at rest. If a subject does not meet the VRS and NPRS criteria within 4 hours of surgery 
completion, the subject will not be eligible for this study. 
 
Table 7-1 
VX21-548-102 Treatment Groups 
Treatment 
Active Dose 
Number of Subjects 
VX-548 (high dose) 
100 mg first dose, then 50 mg q12h 
64 
VX-548 (low dose) 
60 mg first dose, then 30 mg q12h 
64 
HB/APAP 
5 mg/325 mg q6h 
64 
Placebo 
 
64 
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/or capsules q6h in a double-dummy 
design. VX-548 active and/or VX-548 placebo 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. HB/APAP active or HB/APAP placebo 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. 
Subjects will report their pain intensity on the NPRS at rest at each scheduled time point 
through 48 hours after the first dose of study drug. Starting 8 hours after the first dose of 
study drug, subjects will also report their pain intensity on the NPRS during movement. In 
addition, pain intensity will be recorded on the NPRS at rest 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 at rest score is ≥4. 
7.1 
Sample Size and Power 
The sample size calculation is based on the comparison between VX-548 and placebo on the 
primary endpoint. Assuming a standardized effect size of 0.8 for VX-548 (high or low dose) 


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compared to placebo, 54 evaluable subjects per group would provide at least 90% power at a 
2-sided significance level of 0.05. This sample size would allow a minimal detectable 
standardized effect size of 0.38 to achieve statistical significance between VX-548 (high or 
low dose) and placebo. With this sample size, a two-sided 95% CI for the estimated standard 
effect size will extend 0.38 from the observed standardized effect size, assuming the CI is 
based on the large sample z statistic. To allow for withdrawal of up to 15% of randomized 
subjects over 48 hours of treatment, the study will enroll and randomize approximately 256 
subjects in total. 
7.2 
Randomization 
Refer to Section 9.2 of the CSP for details. 
7.3 
Blinding and Unblinding 
Refer to Section 10.7 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 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 will be used to summarize subject demographics, 
baseline characteristics, and for all efficacy analyses in which subjects will be analyzed 
according to their randomized treatment group, unless otherwise specified. 
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 will be used for all safety analyses in which subjects will be analyzed according to 
the treatment they received, unless otherwise specified. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of the CSP. The precision standards 
for reporting variables are provided in an internal Biometrics document that specifies the 
programming rules including the precision for derived variables. 
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, standard deviation (SD), median, minimum value 
(min), and maximum value (max), unless otherwise specified.  


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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.  
Change (absolute change) from baseline will be calculated as post-baseline value – 
baseline value.  
Treatment-emergent (TE) Period will include the time from the first dose of study drug in 
the Treatment Period to either (1) the Safety Follow-up, or (2) the date of the last dose +16 
days for subjects who do not have a Safety Follow-up.  
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
• In scheduled visit windows per specified visit windowing rules 
• In the derivation of baseline 
• 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, unless otherwise specified. 
Multiplicity: No multiplicity adjustment will be performed for hypothesis testing. All P 
values are nominal. 
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
The disposition summary will be provided by treatment and overall. 
The number of subjects in the following categories will be summarized:  
• All Subjects Set 
• Randomized 
• Full Analysis Set (FAS) 
• Safety Set 
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 


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• Completed study 
• Prematurely discontinued the study and the reason for discontinuation from study 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. A randomization listing of subjects will also 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 (in years) 
• 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) 
• BMI category (<18.5, ≥18.5 – <25, ≥25 – <30, ≥30 kg/m2) 
• Site (016, 017, 018, 057, 058, 062, 063) 
• NPRS at rest 
• NPRS category at rest (<8, ≥8) 
• VRS (moderate, severe) 
In addition, data listings will also be provided for: 
• Informed consent 
• Inclusion/exclusion criteria violations for subjects with any such violations 
9.2.3 
Medical History 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). Medical history will be summarized descriptively based on the FAS by 
MedDRA system organ class (SOC) and preferred term (PT). This summary will be provided 
by treatment group and overall. The corresponding data listing will also be provided. 


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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 on or after the date of 
the first dose of study drug through the end of the TE Period 
A given medication may be classified as a prior medication, a concomitant medication, or 
both a prior and a concomitant medication.  
If a medication start date is on or after the first dose date of study drug, then the medication 
will be classified as a concomitant medication regardless of whether the medication end date 
is missing or not. If a medication end date is before the first dose date of study drug, then the 
medication will be classified as a prior medication regardless of whether the medication start 
date is missing or not.  
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/end date 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/stop 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. Supplemental 
analgesic medications administered after surgery and before randomization will be included 
in the summary of prior medications but will be listed separately. Rescue medication will 
also be included in the summary of concomitant medications but 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 
exposure to study drug or compliance are not needed. All data collected during dispensation 
of study drug (i.e., time of administration and number of capsules taken) will be presented in 
an individual data listing only.  
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.  


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IPDs will be summarized descriptively by treatment group and overall. 
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. All 
treatment groups will be included in the statistical models described in this section. 
9.3.1 
Analysis of Primary Endpoint 
9.3.1.1 
Definition of Primary Endpoint 
The primary endpoint is the time-weighted SPID48 at rest (SPIDr0-48) after the first dose of 
study drug. In general, SPIDr is calculated as: ∑∆timei x PIDri where:  
• ∆timei = time (in hours) elapsed since previous measurement 
• PIDri = pain intensity (NPRS) at rest at baseline - pain intensity (NPRS) at rest at 
hour i 
Hence: 
• SPIDr0-48 = 0.5 × PIDr0.5 + 0.5 × PIDr1 + 0.5 × PIDr1.5 + 0.5 × PIDr2 + PIDr3 + PIDr4 
+ PIDr5 + PIDr6 + 2 × PIDr8 + 4 × PIDr12 + 4 × PIDr16 + 4 × PIDr20 + 4 × PIDr24 + 4 
× PIDr28 + 4 × PIDr32 + 4 × PIDr36 + 4 × PIDr40 + 4 × PIDr44 + 4 × PIDr48  
9.3.1.2 
Primary Analysis  
The primary efficacy analysis will be based on an analysis of covariance (ANCOVA) model. 
The model will include the SPIDr0-48 as the dependent variable and treatment as a fixed 
effect, with site and baseline NPRS at rest as covariates. Data from all treatment groups will 
be included in the model. If model estimation does not converge, then site will be removed 
from the model. The primary results obtained from the model will be the estimated mean 
treatment effect for VX-548 versus placebo. The Least Squares (LS) mean difference for 
each dose group of VX-548 versus placebo will be provided along with the 95% CI and 2-
sided P value. In addition, the LS mean with 95% confidence interval (CI) will be provided 
for each treatment group. 
The following imputation scheme will be applied for the primary analysis: 
1) NPRS at rest during the rescue period (within 6 hours after rescue medication) will be 
replaced by the pre-rescue NPRS at rest.  
• The pre-rescue NPRS at rest will be the NPRS at rest collected immediately 
before the administration of rescue medication, or the last observed NPRS at 
rest if that score is missing. The last observed NPRS at rest can be a score 
from a regularly scheduled measurement at rest or the previous pre-rescue 
NPRS at rest but cannot be any observed scores during the previous rescue 
period. 
• If there are multiple administrations of rescue medication within the same 6-
hour period, a local highest NPRS at rest will be used for the imputation 
during the second 6-hour rescue period. The local highest NPRS at rest is the 


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highest value among the first pre-rescue, the second pre-rescue, and the actual 
observed (if any) in the overlapping period. 
2) Missing NPRS at rest following treatment discontinuation will be imputed with the 
last observed or previously imputed NPRS at rest prior to discontinuation. 
3) Missing NPRS at rest for subjects who completed the treatment but with missing data 
from certain time point to 48 hours will be imputed with the last observed or 
previously imputed NPRS at rest.  
4) Intermittently missing NPRS at rest will be imputed using linear interpolation. 
9.3.1.3 
Additional Analyses 
This additional analysis will be performed by modifying the primary analysis in such a way 
that NPRS at rest during the rescue period (within 6 hours after rescue medication) will not 
be replaced by the pre-rescue NPRS at rest. The observed NPRS at rest will be used instead. 
The same ANCOVA model as described in Section 9.3.1.2 will be performed. 
9.3.1.4 
Sensitivity Analyses 
This sensitivity analysis will be performed by modifying the primary analysis in such a way 
that missing NPRS at rest following treatment discontinuation due to an AE will be imputed 
using the baseline NPRS at rest, while missing NPRS at rest following treatment 
discontinuation due to other reasons will be imputed by the last observed or previously 
imputed NPRS at rest prior to discontinuation. The same ANCOVA model as described in 
Section 9.3.1.2 will be performed.  
9.3.1.5 
Subgroup Analysis 
No subgroup analyses for the primary efficacy variable are planned. 
For the primary analysis, additional analysis, and sensitivity analysis, SPIDr0-48 will also be 
summarized descriptively, including standard error (SE), by treatment. In addition, NPRS 
measurements at rest will be summarized descriptively, including SE, by treatment at each 
scheduled time point and the mean values over time by treatment will be presented in a 
figure. 
9.3.2 
Analysis of Secondary Efficacy Variables 
9.3.2.1 
Definition of Secondary Efficacy Variables 
Time-weighted SPIDr0-24 after the first dose of study drug: SPIDr0-24 is calculated using the 
following formula: 
• SPIDr0-24 = 0.5 × PIDr0.5 + 0.5 × PIDr1 + 0.5 × PIDr1.5 + 0.5 × PIDr2 + PIDr3 + PIDr4 
+ PIDr5 + PIDr6 + 2 × PIDr8 + 4 × PIDr12 + 4 × PIDr16 + 4 × PIDr20 + 4 × PIDr24 
Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at rest at 48 hours 
after the first dose of study drug: Subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS 
at rest at 48 hours after the first dose of study drug will be defined as “responders”. The 
percentage reduction in the NPRS will be calculated as following: 


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• 100% × (NPRS at rest at baseline − NPRS at rest at 48 hours) / NPRS at rest at 
baseline 
The same imputation strategies as described in Section 9.3.1.2 will be applied. However, 
subjects who discontinue study drug treatment for any reason prior to 48 hours will be 
defined as “non-responders” for all 3 criteria.   
9.3.2.2 
Secondary Analyses  
Time-weighted SPIDr0-24 after the first dose of study drug: SPIDr0-24 will be analyzed in the 
same way as described in Section 9.3.1.2. SPIDr0-24 will also be analyzed in the same way as 
described for SPIDr0-48 in Sections 9.3.1.4 and 9.3.1.5. 
Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at rest at 48 hours 
after the first dose of study drug: The responder rates at 48 hours will be presented 
descriptively. The Cochran-Mantel-Haenszel test, stratified by the baseline NPRS category at 
rest (<8, ≥8), will be used to compare responder rates at 48 hours between each dose of VX-
548 and placebo.  
9.3.3 
Analysis of Other Efficacy Variables 
9.3.3.1 
Definition of Other Efficacy Variables 
Time-weighted SPIDm8-24 after the first dose of study drug: For the endpoints based on 
NPRS during movement, SPIDm is calculated as ∑∆timei x PIDmi where:  
• ∆timei = time (in hours) elapsed since previous measurement 
• PIDmi = pain intensity (NPRS) at rest at baseline - pain intensity (NPRS) during 
movement at hour i 
(Note: NPRS at rest at baseline is used because NPRS during movement is not collected at 
baseline.) SPIDm8-24 is calculated using the following formula: 
• SPIDm8-24 = 4 × PIDm12 + 4 × PIDm16 + 4 × PIDm20 + 4 × PIDm24 
Time-weighted SPIDm8-48 after the first dose of study drug: SPIDm8-48 is calculated using the 
following formula: 
• SPIDm8-48 = 4 × PIDm12 + 4 × PIDm16 + 4 × PIDm20 + 4 × PIDm24 + 4 × PIDm28 + 4 
× PIDm32 + 4 × PIDm36 + 4 × PIDm40 + 4 × PIDm44 + 4 × PIDm48 
Time to onset of “confirmed perceptible pain relief” and “meaningful pain relief” after the 
first dose of study drug: The time to the onset of “first perceptible pain relief” is the time 
elapsed from the first dose of study drug until the subject stops the “first perceptible pain 
relief” stopwatch. The time to the onset of “meaningful pain relief” is the time elapsed from 
the first dose of study drug until the subject stops the “meaningful pain relief” stopwatch. 
The time to the onset of “confirmed perceptible pain relief” will be defined as the time to the 
onset of “first perceptible pain relief” for those subjects who achieved “meaningful pain 
relief”.  
If the subject has not stopped the stopwatch by 6 hours after the first dose of the study drug 
or the subject receives rescue medication during the first 6 hours, the stopwatch will be 


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stopped and the time to onset will be considered censored at 6 hours. If a time to “first 
perceptible pain relief” is obtained without subsequent “meaningful pain relief”, the time to 
the onset of “confirmed perceptible pain relief” will also be considered censored at 6 hours.  
Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at rest at 24 hours 
after the first dose of study drug: Subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS 
at rest at 24 hours after the first dose of study drug will be defined as “responders”. The 
percentage reduction in the NPRS will be calculated as following: 
• 100% × (NPRS at rest at baseline − NPRS at rest at 24 hours) / NPRS at rest at 
baseline 
The same imputation strategies as described in Section 9.3.1.1 will be applied. However, 
subjects who discontinue study drug treatment for any reason prior to 24 hours will be 
defined as “non-responders” for all 3 criteria.  
Patient Global Assessment (PGA) of study drug at 48 hours after the first dose of study drug: 
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 with missing PGA at 48 hours will be analyzed as part of a “missing” 
category. 
9.3.3.2 
Other Analyses  
Time-weighted SPIDm8-24 after the first dose of study drug and time-weighted SPIDm8-48 
after the first dose of study drug: SPIDm8-24 and SPIDm8-48 will be analyzed using the same 
model as described in Section 9.3.1.2, but applying the following imputation strategies. Note: 
all imputation of NPRS at rest will be performed before any imputation of NPRS during 
movement.  
1) At each administration of rescue medication, a predicted pre-rescue NPRS during 
movement will be imputed based on the pre-rescue NPRS at rest. 
• The predicted pre-rescue NPRS during movement will be equal to the pre-
rescue NPRS at rest (as defined in Section 9.3.1.2) added to Δ𝑘𝑘, a treatment-
arm specific adjustment factor. Δ𝑘𝑘 is defined as the mean difference between 
the NPRS during movement and the NPRS at rest among all subjects assigned 
to treatment arm 𝑘𝑘, averaged across all timepoints (1) where both NPRS 
during movement and NPRS at rest are collected, and (2) that are not during 
any rescue period (within 6 hours after rescue medication). 
2) NPRS during movement during the rescue period (within 6 hours after rescue 
medication) will be replaced by the predicted pre-rescue NPRS during movement 
defined in Step 1.  
• If there are multiple administrations of rescue medication within the same 6-
hour period, a local highest NPRS during movement will be used for the 
imputation during the second 6-hour rescue period. The local highest NPRS 
during movement is the highest value among the first predicted pre-rescue 
NPRS during movement, the second predicted pre-rescue NPRS during 


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movement, and the actual observed NPRS during movement (if any) in the 
overlapping period. 
3) Missing NPRS during movement at the 8-hour timepoint (i.e., the first scheduled 
collection of NPRS during movement) will be imputed with a predicted NPRS during 
movement, calculated by adding Δ𝑘𝑘 to the observed or previously imputed NPRS at 
rest at the 8-hour timepoint, only if no NPRS during movement is available prior to 
the nominal 8-hour timepoint. 
4) Missing NPRS during movement following treatment discontinuation will be imputed 
with the last observed or previously imputed NPRS during movement prior to 
discontinuation. 
5) Missing NPRS during movement for subjects who completed the treatment but with 
missing data from a certain time point to 48 hours will be imputed with the last 
observed or previously imputed NPRS during movement.  
6) Intermittently missing NPRS during movement will be imputed using linear 
interpolation based on observed or previously imputed NPRS during movement.  
SPIDm8-24 and SPIDm8-48 will also be summarized descriptively, including standard error 
(SE), by treatment. In addition, NPRS measurements during movement will be summarized 
descriptively, including SE, by treatment at each scheduled time point and the mean values 
over time by treatment will be presented in a figure. 
Time to onset of “confirmed perceptible pain relief” and “meaningful pain relief” after the 
first dose of study drug: The time to the onset of “confirmed perceptible pain relief” will be 
analyzed using a Cox regression model. The model will include treatment as a fixed effect 
and baseline NPRS at rest as a covariate. Pairwise comparisons between each dose of VX-
548 and placebo will be conducted based on this model. 
Note: If the placebo group has fewer than 5 subjects experience “confirmed perceptible pain 
relief”, the Cox regression will not be performed. If any other dose group has fewer than 5 
subjects experience “confirmed perceptible pain relief”, the particular dose group will not be 
included in the Cox regression model. 
Additionally, the Kaplan-Meier method will be used to estimate the median time to onset of 
“confirmed perceptible pain relief” and the survival curve for each treatment group.  Log-
rank test will be used to compare curves between the VX-548 dose groups and placebo.  
The time to onset of “meaningful pain relief” and the time to the onset of “first perceptible 
pain relief” will be analyzed in the same way as described for the time to the onset of 
“confirmed perceptible pain relief”.  
Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at rest at 24 hours 
after the first dose of study drug: This variable will be analyzed in the same way as described 
in Section 9.3.2.2 for NPRS responder rates at 48 hours.  
Patient Global Assessment (PGA) of study drug at 48 hours after the first dose of study drug: 
This variable will be summarized descriptively. The Cochran-Mantel-Haenszel test, stratified 


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by the baseline NPRS category at rest (<8, ≥8), will be also conducted to compare each VX-
548 dose group and placebo.  
Percentage of subjects using rescue medication, and total rescue medication usage, 0 to 48 
hours after the first dose of study drug: The percentage of subjects using rescue medication 
during 0-48 hours will be analyzed using the Cochran-Mantel-Haenszel test, stratified by the 
baseline NPRS category at rest (<8, ≥8), to compare each VX-548 dose group and placebo. 
The total rescue medication usage from 0 to 48 hours will be summarized descriptively, and 
the Wilcoxon rank-sum test, stratified by the baseline NPRS category at rest (<8, ≥8), will be 
conducted to compare each VX-548 dose group and placebo. 
All analyses described in Sections 9.3.1, 9.3.2 and 9.3.3 for comparisons between VX-548 
and placebo will be repeated for comparisons between HB/APAP and placebo. 
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 may receive more than one treatment in the study, the 
following algorithm will be used to define the actual treatment: regardless of the subject’s 
randomized treatment assignment, if the subject received any VX-548 treatment, the actual 
treatment is defined as the highest dose level among all received VX-548 treatment; if the 
subject did not receive any VX-548 treatment but did receive HB/APAP during at least one 
visit, the actual treatment is defined as HB/APAP; the actual treatment is defined as placebo 
only if the subject received placebo at all visits in the study. 
Only descriptive analyses of safety will be performed, and no statistical hypothesis testing 
will be performed. 
9.4.1 
Adverse Events  
AEs will be coded according to MedDRA. For analysis purposes, AEs will be classified as 
pretreatment AEs and TEAEs as follows: 
Pretreatment AEs: AEs that occurred before the first dose of study drug 
Treatment-emergent AEs: AEs that worsened or started on or after the first dose date of 
study drug through the end of the TE Period 
For AEs with completely missing or partial start dates, if there is no clear evidence that the 
AEs started before or after the first dose of study drug, the AEs will be classified as TEAEs. 
Imputation rules for missing or partial AE start dates are defined in Appendix C. 


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AE summary tables will be presented only for TEAEs by treatment, 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. Only the maximum severity level will be 
presented in the severity summaries, and the strongest relationship level in the relationship 
summaries.  
All AEs, including pretreatment AEs and TEAEs will be presented in an individual subject 
data listing based on the All Subjects Set. In addition, a listing containing individual subject 
adverse event data for TEAEs leading to treatment discontinuation, TEAEs leading to 
treatment interruption, SAEs and all deaths will be provided separately. 
9.4.2 
Clinical Laboratory Assessments 
All statistical analyses of laboratory values will be performed using SI units. For treatment-
emergent laboratory measurements, the observed values and change from baseline values of 
the continuous hematology, chemistry, and coagulation results will be summarized at each 
visit. 
The number and percentage of subjects with selected test values meeting threshold analysis 
criteria during the TE period will be summarized. The threshold analysis criterion shift from 
baseline will also be summarized for chemistry measurements. The threshold analysis criteria 
are provided in Appendix D.  
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. 
Results of urinalysis and urine/serum pregnancy tests will be in individual subject data 
listings only. 


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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 interval corrected for 
HR intervals (QTcF [msec]). In addition, the number and percentage of subjects by 
maximum treatment-emergent value of QT/QTcF intervals, categorized as ≤450 msec, 
>450 msec and ≤480 msec, >480 msec and ≤500 msec, and >500 msec, as well as maximum 
treatment-emergent change from baseline value of QT/QTcF intervals, categorized ≤0 msec, 
and >0 and ≤30 msec, >30 and ≤60 msec, and >60 msec, will be provided. 
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. 
9.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each visit. The following vital signs parameters will be 
summarized: systolic and diastolic blood pressure (mm Hg), pulse rate (beats per minute), 
body temperature (°C), respiratory rate (breaths per minute), and oxygen saturation (%).  
The number and percentage of subjects meeting threshold analysis criteria during the TE 
Period will be summarized. The threshold analysis criteria are provided in Appendix D.  
In addition, a listing containing individual subject vital signs values will be provided. This 
listing will include data from both scheduled and unscheduled visits. 
9.4.5 
Physical Examination  
Physical examination (PE) results will be presented in an individual subject data listing only. 
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/Timepoint1 
Target Study Day 
/Timepoint per the 
protocol 
Analysis Visit Window 
(in study days/ timepoints) 2, 
3, 4, 5 
Safety Assessment 
Hematology 
Serum Chemistry 
Coagulation 
Baseline 
Day 1 (Procedure 
through 
randomization/ 
predose) 
≤ Day 1 predose 
48 hours 
48 hours 
Nominal visit 
Standard 12-Lead ECG 
 
Baseline 
Day 1 (Procedure 
through 
randomization/ 
predose) 
≤ Day 1 predose 
4 hours 
4 hours  
Nominal visit for all visits 
16 hours 
16 hours 
 
28 hours 
28 hours 
 
40 hours 
40 hours 
 
Vital Signs 
Baseline 
Day 1 (Procedure 
through 
randomization/ 
predose) 
≤ 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 at rest 
Baseline  
Day 1 (Procedure 
through 
randomization/ 
predose)  
≤ 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 
± 5 minutes for 0.5 to 48 hours 
NPRS during movement 
At 8, 12, 16, 20, 24, 28, 
32, 36, 40, 44, and 48 
hours 
At 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 
and 48 hours 
± 5 minutes for 8 to 48 hours 


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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit/Timepoint1 
Target Study Day 
/Timepoint per the 
protocol 
Analysis Visit Window 
(in study days/ timepoints) 2, 
3, 4, 5 
VRS 
Baseline  
Day 1 (Procedure 
through 
randomization/ 
predose) 
≤ Day 1 (Procedure through 
randomization/predose) 
Rescue Medication 
N/A 
N/A 
[Day 1 post-dose, 48 hours 
post-dose]  
 
Notes:  
1 Visit/Timepoint name for analysis purposes is used to report data in tables and figures. 
2The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered 
missing for the visit.  
b. If there is more than 1 numerical measurement available within the same visit window, use the 
following rules:  
i. 
The measurement closest to the target day/time point will be used. 
ii. 
If there are multiple measurements within the same distance from the target day/time point, 
the latest measurement will be used. 
iii. 
If a scheduled and an unscheduled measurement have the same date/time, the unscheduled 
measurement will be used. 
3For measurements collected on the date of first dose of study drug in Treatment Period, if it cannot be 
determined whether the measurement is before or after the first dose: 
a. 
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 Prior/Concomitant Medication Dates 
Missing or partial dates will be imputed for medications. 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: 
a. If day is missing, use the last day of the month. 
b. If day and month are both missing, use the last day of the year. 
c. If day, month and year are all missing, assign ‘continuing’ status to stop date. 
With missing or partial medication start times, only use the imputed start date to categorize 
as prior and/or concomitant medication as described in Table 12-2. If hour and/or minute of 
first dose time are missing, only use the first dose date to categorize as prior and/or 
concomitant medication. Imputation of missing and/or partial dates for non-pharmacological 
treatments/procedures will follow the same imputation rules.  
Table 12-2 
Prior and/or Concomitant Categorization of a Medication 
Medication Start Date 
Medication Stop Date 
< First Dose Date of Study 
Drug 
≥ First Dose Date and ≤ 
End Date of TE Period 
< First dose date of study drug 
P 
PC 
≥ First dose date 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 12-1 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry 
ALT 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤ 3xULN) or (AST>ULN - 
≤3xULN) 
(ALT>3x - ≤5xULN) or  (AST>3x - 
≤5xULN) 
(ALT>5x - ≤8xULN) or  (AST>5x - 
≤8xULN) 
(ALT>8x - ≤20xULN) or (AST>8x - 
≤20xULN) 
ALT>20xULN or AST>20xULN 
FDA DILI Guidance Jul 2009. 
Alkaline Phosphatase 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5 - ≤5.0xULN 
>5.0 - ≤20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤1.5xULN 
>1.5 - ≤2xULN 
>2 - ≤3xULN  
>3 - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤1.5xULN 
>1.5 - ≤2xULN 
>2 - ≤3xULN  
>3 - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and Total Bilirubin (ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 


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Table 12-1 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
GGT 
>ULN - ≤2.5xULN 
>2.5 - ≤5.0xULN 
>5.0 - ≤20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Albumin 
<LLN - ≥30 g/L 
<30 - ≥20 g/L 
<20 g/L 
CTCAE grade 1-3 
Creatinine 
>ULN - ≤1.5xULN 
>1.5 - ≤3.0xULN 
>3.0 - ≤6.0xULN 
>6.0xULN 
CTCAE grades 1-4 
Lipase 
>ULN - ≤1.5xULN 
>1.5 - ≤2xULN 
>2 - ≤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 12-1 
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 
>2.5xULN 
CTCAE grade 1-3 
 
Table 12-2 
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 12-3   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