Clinical trial NCT04977336
Conditions: Acute Pain
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2021-07-19; Completion date: 2022-03-04
Enrollment: 274 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 a bunionectomy.

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 milligrams (mg)/ APAP 325 mg every 6 hours (q6h) for 2 days. arm 3: Participants received VX-548 20 mg as first dose, followed by VX-548 10 mg tablet every 12 hours (q12h) for 2 days. arm 4: Participants received VX-548 60 mg as first dose, followed by VX-548 30 mg q12h for 2 days. arm 5: 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: 


Protocol VX21-548-101, Version 5.0 
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Summary of Changes to the Protocol  
The previous version of this protocol (Version 4.0, 22 November 2021) was amended to create 
the current version (Version 5.0, 21 January 2022). The protocol history is below. 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 27 April 2021 
Original version 
Version 2.0, 26 July 2021 
To ensure subject safety and assess wound healing, the Safety Follow-up 
was changed from an interview to an outpatient visit. In addition, 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 
• 
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 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, 22 November 2021 
• 
Updated the sample size (approximately 202 subjects) and power 
calculations to support the clinical development plan. 
• 
Added the option for the Screening Visit to occur as a home health 
visit. This also includes: 
o 
Added the option to obtain informed consent remotely if 
permitted by local regulations. 
o 
Clarified that Screening Visit assessments may be performed on 
different days within the screening period (e.g., informed 
consent may be obtained before the home health visit, if 
applicable). 
o 
For subjects who are screened via home health: Modified the 
physical examination (PE) assessment such that an abbreviated 
PE will be performed during the Screening Visit and a complete 
PE will be performed before surgery on Day -1. 
• 
Added hormonal contraceptives as an acceptable method of 
contraception for female subjects based on results from the 
drug-drug interaction study of VX 548 with oral contraceptives 
(Study VX21-548-004). 
• 
Added that a limited Vertex team not directly involved in the 
conduct of the study may have access to NPRS data (in addition to 
PK, PK/PD, and/or safety data) for continuous monitoring purposes. 
Version 5.0, 21 January 2022 
Current version 
 
Key changes in the current version of the protocol are summarized below.  
Change and Rationale 
Affected Sections  
Updated the sample size (approximately 243 subjects) and power calculations to 
support the clinical development plan. 
Sections 2, 9.1, 9.2, and 
12.1 


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Change and Rationale 
Affected Sections  
Added the option for home health nurse visits and telemedicine to be used during 
the Safety Follow-up Visit. 
Table 3-3 and 
Sections 9.1.4, 11.7.3, and 
11.7.4 
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. 


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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 2, Randomized, Double-blind, Placebo-controlled, Dose-ranging, Study Evaluating 
the Efficacy and Safety of VX-548 for Acute Pain After a Bunionectomy 
 
 
Brief Title 
A Study Evaluating Efficacy and Safety of VX-548 for Acute Pain After a Bunionectomy 
 
 
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 a bunionectomy 
Secondary Objectives 
• 
To evaluate the safety and tolerability of VX-548 
• 
To evaluate the pharmacokinetics (PK) of VX-548 and its metabolite, 
 
Other Objective 
• 
To evaluate the dose-response and exposure-response relationship  
 
 
Endpoints 
Primary Endpoint 
• 
Time-weighted sum of the pain intensity difference (SPID) as recorded on a Numeric 
Pain Rating Scale (NPRS) 0 to 48 hours (SPID48) after the first dose of study drug 
Secondary Endpoints 
• 
Time-weighted SPID as recorded on an NPRS 0 to 24 hours (SPID24) after the first 
dose of study drug 
• 
Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at 48 hours 
after the first dose of study drug 
• 
PK parameter estimates of VX-548 and its metabolite, 
 
• 
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 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 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 
 
 
Number of 
Subjects 
Approximately 243 subjects  


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Study 
Population 
Male or female subjects, 18 through 75 years of age (inclusive), with pain that is ≥4 on the 
NPRS and moderate or severe on a Verbal Categorical Rating Scale (VRS) after a 
bunionectomy 
 
 
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 4 days (from 
Day -1 to Day 3) 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, dose-ranging, 5-arm, 
parallel study design evaluating the efficacy and safety of VX-548 doses in treating acute 
pain after a bunionectomy (Figure 2-1). 
On Day -1, subjects will undergo a primary unilateral bunionectomy with distal first 
metatarsal osteotomy (i.e., Austin procedure) and internal fixation under regional anesthesia 
(Mayo and popliteal sciatic block). A continuous popliteal sciatic block infusion 
(0.2% ropivacaine) will be started after surgery and remain in place until approximately 
3AM, but no later than 5AM, on Day 1. After removal of the popliteal sciatic block, a 
subject will be randomized to 1 of 5 treatment groups if (1) the subject requests the first dose 
of study drug for pain relief, (2) the subject’s pain is moderate or severe on the VRS, and (3) 
the subject’s pain is ≥4 on the NPRS. If a subject does not meet the VRS and NPRS criteria 
within 9 hours of removal of the popliteal sciatic block, the subject will not be eligible for 
this study. 
Approximately 243 subjects will be randomized 2:2:1:2:2 to 5 treatment groups: VX-548 
(high dose); VX-548 (mid dose); VX-548 (low dose); HB/APAP (opioid reference); or 
placebo (Table 2-1). Randomization will be stratified by site and baseline NPRS (<8 versus 
≥8). To maintain the blind, all subjects will receive the same number of tablets and/or 
capsules every 6 hours (q6h) in a double-dummy design. 


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Figure 2-1 
VX21-548-101 Study Design 
CRU: clinical research unit; HB/APAP: hydrocodone bitartrate/acetaminophen; NPRS: Numeric 
Pain Rating Scale; VRS: Verbal Categorical Rating Scale 
Notes: After removal of the popliteal sciatic block, a subject will be randomized to 1 of 5 treatment 
groups if (1) the subject requests the first dose of study drug for pain relief, (2) the subject’s 
pain is moderate or severe on the VRS, and (3) the subject’s pain is ≥4 on the NPRS. If a 
subject does not meet the VRS and NPRS criteria within 9 hours of removal of the popliteal 
sciatic block, the subject will not be eligible for this study. 
 
Table 2-1 
VX21-548-101 Treatment Groups 
Treatment 
Active Dose 
Number of Subjects 
VX-548 (high dose) 
100 mg first dose, then 50 mg q12h 
54 
VX-548 (mid dose) 
60 mg first dose, then 30 mg q12h 
54 
VX-548 (low dose) 
20 mg first dose, then 10 mg q12h 
27 
HB/APAP 
5 mg/325 mg q6h 
54 
Placebo 
 
54 
HB/APAP: hydrocodone bitartrate/acetaminophen; q6h: every 6 hours; q12h: every 12 hours 
Notes: To maintain the blind, all subjects will receive the same number of tablets and/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 each scheduled time point through 
48 hours after the first dose of study drug. In addition, pain intensity will be recorded on the 
NPRS immediately before each administration of rescue medication. 
Ibuprofen (400 mg orally q6h as needed) is permitted as a rescue medication for pain relief 
upon the subject’s request starting any time after the first dose of study drug through 
48 hours after the first dose of study drug. Subjects are encouraged to wait 90 minutes after 
the first dose of study drug to request rescue medication, and subjects should generally not 
receive rescue medication unless their NPRS score is ≥4. 
 
 
Assessments 
Efficacy: NPRS, double-stopwatch assessment, and use of rescue medications 
Safety: 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, PGA of study drug, and DNA blood sample (optional) 
 
 


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Statistical 
Analyses 
The sample size calculation is based on the comparison between VX-548 and placebo. The 
primary efficacy endpoint is the time-weighted SPID48 after the first dose. Assuming a 
standardized effect size of 0.8 for VX-548 (high or mid dose) compared to placebo as well 
as a 2-sided significance level of 0.05, 48 evaluable subjects per group would provide at 
least 90% power. This sample size would allow a minimal detectable standardized effect size 
of 0.4 to achieve statistical significance between VX-548 (high or mid dose) and placebo. 
Assuming an observed standardized effect size of 0.8, this sample size would provide 
sufficient precision, with 90% probability for the true standardized effect size greater than 
0.53. To allow for withdrawal of up to 10% of randomized subjects over 48 hours of 
treatment, the study will enroll and randomize approximately 243 subjects in total. 
The primary efficacy analysis will be based on an analysis of covariance (ANCOVA) model. 
The model will include SPID48 as the dependent variable and treatment as a fixed effect, 
with adjustment for stratification factors (i.e., site and baseline NPRS). If the 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 between VX-548 
versus placebo. The estimated mean treatment effect, a 95% CI, and a 2-sided P value will 
be provided. 


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are in Table 3-1, Table 3-2, and Table 3-3. 
Table 3-1 
Study VX21-548-101: Screening Through Admission 
Event/Assessmenta 
Day -28 to Day -2 
Day -1 
Comments 
Screening Visit 
Pre-procedure 
Outpatient or home health visit 
X 
 
Subjects will have the option to complete this visit 
in the clinic or to have a home health visit. Home 
health visits are only an option if permitted by local 
regulations. Section 9.1.1 
CRU admission 
 
X 
Upon completion of pre-procedure eligibility 
assessments; Section 8. 
Informed consent  
X 
 
Must be obtained before performing any 
study-related procedures. Remote consent may be 
used if permitted by local regulations; Section 13.2.3 
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 11.7.3. 
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 11.7.4. 
Physical Examination 
X 
(X) 
Screening Visit: A complete PE will be performed 
if the visit occurs in clinic. An abbreviated PE will 
be performed if the visit occurs via home health. 
Day -1: A complete PE will be performed only if 
the Screening Visit occurs via home health; 
Section 11.7.3 
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 11.7.2 
Serum β-hCG 
X 
 
All female subjects; Section 11.7.2. 
Serum FSH 
X 
 
Postmenopausal female subjects only; 
Section 11.7.5.1 
Serum chemistry 
X 
 
Section 11.7.2 
Hematology 
X 
 
Section 11.7.2 
Coagulation 
X 
 
Section 11.7.2 
Urinalysis 
X 
 
Section 11.7.2 
Drug test 
X 
X 
Urine; Section 11.7.2. 
Day -1: Testing kit assessed by staff onsite. 
Urine β-hCG 
 
X 
All female subjects of childbearing potential. 
Assessed by staff onsite. Section 11.7.2. 
Alcohol test 
 
X 
Urine, blood, or breath. Breath testing kit assessed 
by staff onsite. Section 11.7.2. 
Placebo and pain assessment 
video training 
X 
X 
Section 11.6.1 
 
 
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 3-1 
Study VX21-548-101: Screening Through Admission 
Event/Assessmenta 
Day -28 to Day -2 
Day -1 
Comments 
Screening Visit 
Pre-procedure 
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 
 
Adverse events 
Continuous from signing of ICF 
through Safety Follow-up 
Section 11.7.1 
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 


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Table 3-2 
Study VX21-548-101: Bunionectomy Procedure Through Randomization 
Event/Assessment 
Day -1 
Day 1 
Comments 
Procedure and 
Post-procedure 
Block Removal Through 
Randomization / Predosea 
Inpatient CRU 
X 
X 
 
Bunionectomy 
X 
 
Section 9.1 
Record supplemental 
analgesia medication 
X 
X 
Record pain medications given postoperatively 
through time of block removal. Type of pain 
medication allowed is based on NPRS. 
Section 9.4.1.1. 
Clear liquid diet 
 
X 
Starting 2 hours before block removal through 4 
hours after the first dose of study drug. 
Section 9.4.2. 
Removal of popliteal 
sciatic block (block 
removal)  
 
X 
Defined as removal of infusion catheter and/or 
completion of ropivacaine infusion. Timing is 
expected between 3AM and 5AM (Day 1) after 
surgical procedure. Section 9.4.1.1 
VRS 
 
X 
Complete after block removal upon request for the 
first dose of study drug for pain relief; 
Section 11.3. 
NPRS 
X 
X 
Before block removal: Complete immediately 
before each dose of supplemental analgesia 
medication (Section 9.4.1.1). 
After block removal: Complete after VRS only if 
pain is rated moderate or severe on the VRS. 
Section 11.6.2 
Vital signs 
 
X 
Complete after a ≥5-minute rest and before blood 
draws or ECG assessments. Section 11.7.3. 
Standard 12-lead ECG 
 
X 
Complete after a ≥5-minute rest in the supine 
position and before blood draws or any procedures 
that may affect heart rate. Section 11.7.4. 
Blood sampling for PK 
 
X 
Collect any time prior to first study drug dose on 
Day 1; Section 11.2.1 
Randomization 
 
X 
Subject must request study drug for relief of pain 
meeting criteria (≥4 on NPRS and moderate or 
severe on VRS) within 9 hours after block removal 
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 the 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 11.7.1 
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 VX21-548-101: 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 or home 
health visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Subjects will have the option to complete this visit in the clinic or to 
have a home health visit. Home health visits are only an option if 
permitted by local regulations. Section 9.1.4 
Telemedicine video 
conference or 
telephone contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
A consultation between the subject and investigator must be performed 
within 2 business days after the home health visit (can be outside the 
visit window) and may also include a separate follow-up with the study 
coordinator. Required only for subjects who have a home health visit; 
not required for subjects who have a clinic visit. Section 9.1.4. 
PGA of study drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Complete before the start of any other assessments scheduled at the 
same time point; Section 11.4 
Vital signs 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Complete after a ≥5-minute rest. Acceptable window is ± 1 hour from 
the scheduled time point.  
Section 11.7.3. 
Standard 12-lead 
ECG 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
28 h 
40 h 
 
 
Complete after a ≥5-minute rest in the supine position. ECGs must be 
performed before blood draws or any procedures that may affect heart 
rate (Section 11.7.4). Acceptable window is ± 1 hour from the 
scheduled time point. 
Complete PE 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
Perform at SFU only if a clinical finding during the Treatment Period 
requires follow up; Section 11.7.3. 
Focused PE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Assess wound healing at the operative site; Section 11.7.3. 
NPRS 
 
X 
X 
X 
X X X X X X 
X 
X 
 
X 
X 
28 h 
32 h 
36 h 
40 h 
44 h 
X 
 
Acceptable window is ± 5 minutes from the scheduled time point; 
Section 11.6.2. 
DNA blood sample 
(optional) 
X 
 
May be collected anytime during CRU confinement after 
randomization; Section 11.5 
Blood sampling for 
PK 
 
 
X 
 
X 
 
X 
 
X X 
X 
 
 
 
X 
25, 26, 
28, 30, 
and 32 h 
36 h 
X 
 
12, 24, and 36 hours after first dose: Collect within 15 minutes 
before the next study drug dose. 
All other time points after first dose: Collect within ± 30 minutes of 
scheduled time point. Section 11.2.1. 
Serum chemistry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 11.7.2 
Hematology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 11.7.2 
Coagulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 11.7.2 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 11.7.2 
 
a 
When assessment time points coincide, assessments will be performed in this order: PGA of study drug, vital signs, 12-lead ECG, PE, NPRS, 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 VX21-548-101: 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 
Clear liquid diet 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Starting 2 hours before block removal through 4 hours after the first 
dose of study drug. Section 9.4.2. 
Fasting period 
 
 
 
 
 
 
 
 
 
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 
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 11.6.3). 
Rescue medication 
use 
Ibuprofen 400 mg orally q6h prn (upon request) after first dose of study drug 
 
Record NPRS immediately before each administration. Record date 
and time of administration. Sections 9.4.1.2 and 11.6.4. 
Adverse events 
Continuous from signing of ICF through Safety Follow-up 
Section 11.7.1 
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; VRS: Verbal Categorical Rating Scale 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
Summary of Changes to the Protocol......................................................................................... 2 
2 
Protocol Synopsis ................................................................................................................... 4 
3 
Schedule of Assessments........................................................................................................ 8 
4 
Table of Contents ................................................................................................................. 13 
List of Tables............................................................................................................................ 16 
List of Figures .......................................................................................................................... 16 
List of Abbreviations................................................................................................................ 17 
Abbreviation of Study Numbers .............................................................................................. 18 
5 
Introduction.......................................................................................................................... 19 
5.1 
Background ..................................................................................................................... 19 
5.2 
Study Rationale .............................................................................................................. 19 
6 
Study Objectives .................................................................................................................. 20 
6.1 
Primary Objective ........................................................................................................... 20 
6.2 
Secondary Objectives ..................................................................................................... 20 
6.3 
Other Objective .............................................................................................................. 20 
7 
Study Endpoints ................................................................................................................... 20 
7.1 
Primary Endpoint ............................................................................................................ 20 
7.2 
Secondary Endpoints ...................................................................................................... 20 
7.3 
Other Endpoints .............................................................................................................. 20 
8 
Study Population .................................................................................................................. 20 
8.1 
Inclusion Criteria ............................................................................................................ 21 
8.2 
Exclusion Criteria ........................................................................................................... 21 
9 
Study Implementation ......................................................................................................... 23 
9.1 
Study Design .................................................................................................................. 23 
9.1.1 
Screening ................................................................................................................ 24 
9.1.1.1 
Repetition of Screening Assessments .............................................................. 24 
9.1.1.2 
Rescreening ...................................................................................................... 24 
9.1.2 
Bunionectomy Procedure to Randomization .......................................................... 25 
9.1.3 
Treatment Period .................................................................................................... 25 
9.1.4 
Follow-up................................................................................................................ 25 
9.1.5 
Early Discontinuation ............................................................................................. 25 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 26 
9.3 
Rationale for Study Elements ......................................................................................... 26 
9.3.1 
Study Design........................................................................................................... 26 
9.3.2 
Study Drug Dose and Duration .............................................................................. 26 
9.3.3 
Rationale for Study Assessments ........................................................................... 27 
9.4 
Study Restrictions ........................................................................................................... 27 
9.4.1 
Analgesic Medications ........................................................................................... 28 
9.4.1.1 
Perioperative Pain Management ...................................................................... 28 
9.4.1.2 
Rescue Medication ........................................................................................... 29 
9.4.2 
Additional Dietary Restrictions .............................................................................. 29 
9.5 
Prior and Concomitant Medications ............................................................................... 29 
9.6 
Administration ................................................................................................................ 30 


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9.7 
Dose Modification for Toxicity ...................................................................................... 30 
9.8 
Removal of Subjects ....................................................................................................... 30 
9.9 
Replacement of Subjects ................................................................................................ 31 
10 Study Drug Information and Management ....................................................................... 31 
10.1 Preparation and Dispensing ............................................................................................ 31 
10.2 Packaging and Labeling ................................................................................................. 31 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 31 
10.4 Drug Accountability ....................................................................................................... 31 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 32 
10.6 Compliance ..................................................................................................................... 32 
10.7 Blinding and Unblinding ................................................................................................ 32 
10.7.1 
Blinding .................................................................................................................. 32 
10.7.2 
Unblinding .............................................................................................................. 33 
11 Assessments .......................................................................................................................... 34 
11.1 Subject and Disease Characteristics ............................................................................... 34 
11.2 Pharmacokinetics ............................................................................................................ 34 
11.2.1 
Blood Sampling ...................................................................................................... 34 
11.2.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 34 
11.2.3 
Bioanalysis.............................................................................................................. 34 
11.3 Verbal Categorical Rating Scale .................................................................................... 34 
11.4 Patient Global Assessment of Study Drug ..................................................................... 35 
11.5 Exploratory Assessments: Pharmacogenomics .............................................................. 35 
11.6 Efficacy ........................................................................................................................... 35 
11.6.1 
Placebo and Pain Assessment Video Training ....................................................... 35 
11.6.2 
Numeric Pain Rating Scale ..................................................................................... 35 
11.6.3 
Double-stopwatch Assessment ............................................................................... 35 
11.6.4 
Use of Rescue Medications .................................................................................... 35 
11.7 Safety .............................................................................................................................. 36 
11.7.1 
Adverse Events ....................................................................................................... 36 
11.7.2 
Clinical Laboratory Assessments ........................................................................... 36 
11.7.3 
Physical Examinations and Vital Signs .................................................................. 37 
11.7.4 
Electrocardiograms ................................................................................................. 38 
11.7.5 
Contraception and Pregnancy ................................................................................. 38 
11.7.5.1 Contraception ................................................................................................... 39 
11.7.5.2 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 Endpoints ........................................................................ 42 
12.3.3.2 Analysis of Secondary Endpoints .................................................................... 42 
12.3.3.3 Multiplicity Adjustment ................................................................................... 42 
12.3.3.4 Missing Data Handling .................................................................................... 42 


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12.3.4 
Safety Analysis ....................................................................................................... 43 
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 ........................... 44 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 44 
13.1.1 
Adverse Events ....................................................................................................... 44 
13.1.1.1 Definition of an Adverse Event........................................................................ 44 
13.1.1.2 Clinically Significant Assessments .................................................................. 44 
13.1.1.3 Documentation of Adverse Events................................................................... 44 
13.1.1.4 Adverse Event Severity .................................................................................... 45 
13.1.1.5 Adverse Event Causality .................................................................................. 45 
13.1.1.6 Study Drug Action Taken ................................................................................ 46 
13.1.1.7 Adverse Event Outcome .................................................................................. 46 
13.1.1.8 Treatment Given............................................................................................... 47 
13.1.2 
Serious Adverse Events .......................................................................................... 47 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 47 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 48 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 48 
13.2 Administrative Requirements ......................................................................................... 49 
13.2.1 
Product Complaints ................................................................................................ 49 
13.2.2 
Ethical Considerations ............................................................................................ 49 
13.2.3 
Subject Information and Informed Consent ........................................................... 49 
13.2.4 
Investigator Compliance ......................................................................................... 49 
13.2.5 
Access to Records ................................................................................................... 49 
13.2.6 
Subject Privacy ....................................................................................................... 50 
13.2.7 
Record Retention .................................................................................................... 50 
13.2.8 
Study Termination .................................................................................................. 50 
13.2.9 
End of Study ........................................................................................................... 51 
13.3 Data Quality Assurance .................................................................................................. 51 
13.4 Monitoring ...................................................................................................................... 51 
13.5 Electronic Data Capture ................................................................................................. 51 
13.6 Confidentiality and Disclosure ....................................................................................... 52 
13.7 Publications and Clinical Study Report .......................................................................... 52 
13.7.1 
Publication of Study Results ................................................................................... 52 
13.7.2 
Clinical Study Report ............................................................................................. 53 
14 References ............................................................................................................................. 54 
15 Protocol Signature Pages .................................................................................................... 57 
15.1 Sponsor Signature Page .................................................................................................. 57 
15.2 Investigator Signature Page ............................................................................................ 58 
 


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List of Tables 
Table 2-1 
VX21-548-101 Treatment Groups .......................................................................... 6 
Table 3-1 
Study VX21-548-101: Screening Through Admission........................................... 8 
Table 3-2 
Study VX21-548-101: Bunionectomy Procedure Through Randomization ......... 10 
Table 3-3 
Study VX21-548-101: Treatment Period and Safety Follow-up .......................... 11 
Table 9-1 
VX21-548-101 Treatment Groups ........................................................................ 24 
Table 9-2 
Study Restrictions ................................................................................................. 27 
Table 10-1 
Study Drug ............................................................................................................ 31 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 34 
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 ........................................................................... 46 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 46 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 47 
List of Figures 
Figure 2-1 
VX21-548-101 Study Design ................................................................................. 6 
Figure 9-1 
VX21-548-101 Study Design ............................................................................... 23 
 


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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 
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 
NPRS 
Numeric Pain Rating Scale 


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NSAIDs 
nonsteroidal anti-inflammatory drugs 
P 
probability 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PGA 
Patient Global Assessment 
PK 
pharmacokinetic, pharmacokinetics 
prn 
as needed 
q6h 
every 6 hours 
q12h 
every 12 hours 
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 
SPID24 
sum of the pain intensity difference 0 to 24 hours 
SPID48 
sum of the pain intensity difference 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.2 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.3 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.4, 5 
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 NSAIDs6; only 3 new molecular entity drugs for 
moderate to severe pain have been approved by the FDA since 2008.7-11 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.12, 13 Support 
for this assertion arises from (1) evaluation of the role NaV1.8 plays in normal physiology14-18, 
(2) pathological states arising from mutations in the NaV1.8 gene (SCN10A)19, 20, (3) animal 
models21-24, and (4) pharmacology of known NaV1.8-modulating agents.25-27 In addition, because 
NaV1.8 expression is restricted to peripheral neurons, particularly those that sense pain (e.g., the 
dorsal root ganglia)14, 16, 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.1 
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).1 
This study will evaluate the efficacy and safety of VX-548 doses in treating acute pain after a 
bunionectomy. 


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6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
• To evaluate the efficacy of VX-548 doses in treating acute pain after a bunionectomy 
6.2 
Secondary Objectives 
• To evaluate the safety and tolerability of VX-548 
• To evaluate the pharmacokinetics (PK) of VX-548 and its metabolite, 
 
6.3 
Other Objective 
• To evaluate the dose-response and exposure-response relationship 
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) 0 to 48 hours (SPID48) after the first dose of study drug 
7.2 
Secondary Endpoints 
• Time-weighted SPID as recorded on an NPRS 0 to 24 hours (SPID24) after the first dose of 
study drug 
• Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at 48 hours after the 
first dose of study drug 
• PK parameter estimates of VX-548 and its metabolite, 
  
• 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 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 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 
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 primary unilateral bunionectomy with distal first metatarsal 
osteotomy (i.e., Austin procedure) and internal fixation under regional anesthesia (Mayo and 
popliteal sciatic block). 
After Surgery: 
6. Subject reported pain of ≥4 on the NPRS and moderate or severe pain on the Verbal 
Categorical Rating Scale (VRS) within 9 hours after removal of the popliteal sciatic block on 
Day 1. 
7. Subject is lucid and able to follow commands. 
8. All analgesic guidelines (Section 9.4.1) were followed during and after the bunionectomy. 
8.2 
Exclusion Criteria 
Before Surgery: 
1. Prior history of bunionectomy or other foot surgery on the index foot; or bunionectomy on 
the opposite foot as part of this study. 
2. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study drug to the 
subject. This may include, but is not limited to, history of relevant drug or food allergies; 
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). 
3. 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 
4. Alanine aminotransferase or aspartate aminotransferase values >2.5 × upper limit of normal. 
5. 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. 
6. History of any sensory abnormality that, in the opinion of the investigator, may confound the 
ability of the subject to assess postoperative pain. 
7. Subjects who have a painful physical condition that, in the opinion of the investigator, may 
confound the assessments of postoperative pain. 


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8. A known or clinically suspected infection with human immunodeficiency virus or hepatitis B 
or C viruses. 
9. Any prior surgery within 1 month before the first study drug dose unless approved by the 
medical monitor. 
10. American Society of Anesthesiologists physical status classification of ≥3. 
11. 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. 
12. Subjects who have started new medications that have not been at a stable dose for at least 
14 days prior to the scheduled bunionectomy procedure and before dosing with 
investigational product. 
13. Subjects unwilling to receive any protocol-related medicine (e.g., ibuprofen, acetaminophen, 
fentanyl, hydrocodone). 
14. 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. 
15. Subjects with sleep apnea and/or on a home continuous positive airway pressure machine. 
16. 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. 
17. 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. 
18. Participation in a previous study investigating VX-548. 
19. Participated in another investigational study within 30 days of the first dose of study drug. 
20. 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 11.7.2. 
o A positive drug screen for a known prescribed concomitant medication that is not 
otherwise exclusionary (e.g., benzodiazepines) will not disqualify subjects; however, 
a positive drug screen for marijuana (or any cannabis derivative) will not be allowed. 
21. Use of the substances, activities, or devices, as defined in Section 9.4, during the specified 
times. 
22. 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: 
23. Subject had a Type 3 deformity requiring a base wedge osteotomy or concomitant surgery 
such as hammertoe repair, or had medical complications during the bunionectomy that, in the 
opinion of the investigator, should preclude randomization. 


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9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-ranging, 5-arm, parallel 
study design evaluating the efficacy and safety of VX-548 doses in treating acute pain after a 
bunionectomy (Figure 9-1). 
On Day -1, subjects will undergo a primary unilateral bunionectomy with distal first metatarsal 
osteotomy (i.e., Austin procedure) and internal fixation under regional anesthesia (Mayo and 
popliteal sciatic block). A continuous popliteal sciatic block infusion (0.2% ropivacaine) will be 
started after surgery and remain in place until approximately 3AM, but no later than 5AM, on 
Day 1. After removal of the popliteal sciatic block, a subject will be randomized to 1 of 5 
treatment groups if (1) the subject requests the first dose of study drug for pain relief, (2) the 
subject’s pain is moderate or severe on the VRS, and (3) the subject’s pain is ≥4 on the NPRS. If 
a subject does not meet the VRS and NPRS criteria within 9 hours of removal of the popliteal 
sciatic block, the subject will not be eligible for this study. 
Approximately 243 subjects will be randomized 2:2:1:2:2 to 5 treatment groups: VX-548 (high 
dose); VX-548 (mid dose); VX-548 (low dose); hydrocodone bitartrate/acetaminophen 
(HB/APAP) (opioid reference); or placebo (Table 9-1). Randomization will be stratified by site 
and baseline NPRS (<8 versus ≥8). To maintain the blind, all subjects will receive the same 
number of tablets and/or capsules every 6 hours (q6h) in a double-dummy design.  
Figure 9-1 
VX21-548-101 Study Design 
 
CRU: clinical research unit; HB/APAP: hydrocodone bitartrate/acetaminophen; NPRS: Numeric Pain Rating 
Scale; VRS: Verbal Categorical Rating Scale 
Notes: After removal of the popliteal sciatic block, a subject will be randomized to 1 of 5 treatment groups if (1) 
the subject requests the first dose of study drug for pain relief, (2) the subject’s pain is moderate or severe on 
the VRS, and (3) the subject’s pain is ≥4 on the NPRS. If a subject does not meet the VRS and NPRS criteria 
within 9 hours of removal of the popliteal sciatic block, the subject will not be eligible for this study. 
 


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Table 9-1 
VX21-548-101 Treatment Groups 
Treatment 
Active Dose 
Number of Subjects 
VX-548 (high dose) 
100 mg first dose, then 50 mg q12h 
54 
VX-548 (mid dose) 
60 mg first dose, then 30 mg q12h 
54 
VX-548 (low dose) 
20 mg first dose, then 10 mg q12h 
27 
HB/APAP 
5 mg/325 mg q6h 
54 
Placebo 
 
54 
HB/APAP: hydrocodone bitartrate/acetaminophen; q6h: every 6 hours; q12h: every 12 hours 
Notes: To maintain the blind, all subjects will receive the same number of tablets and/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 each scheduled time point through 
48 hours after the first dose of study drug. In addition, pain intensity will be recorded on the 
NPRS immediately before each administration of rescue medication (Section 9.4.1.2). 
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 score is ≥4. 
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 27 days before the scheduled bunionectomy procedure and 
may occur in the clinic or as a home health visit with a qualified visiting nurse if permitted by 
local regulations. The investigator (or an appropriate authorized designee at the study site) will 
obtain informed consent from each subject in person or remotely (Section 13.2.3) before 
performing any study-related procedure. If needed, Screening Visit assessments may be 
performed on different days within the screening period (e.g., informed consent may be obtained 
before the home health visit, if applicable). 
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 


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• 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 
Bunionectomy Procedure to Randomization 
Assessments to be completed after the bunionectomy procedure through randomization are listed 
in Table 3-2. 
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 9 hours after removal of the popliteal sciatic block, 
the subject will not be eligible for this study. 
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 a Safety Follow-up Visit 14 (± 2) days after the last dose of study drug. This 
visit may occur in the clinic or as a home health visit with a qualified visiting nurse if permitted 
by local regulations. Safety Follow-up Visits occurring via home health must have a consultation 
between the subject and investigator (i.e., telemedicine video conference or telephone contact) 
within 2 business days after the home health visit in order to check-in and collect AEs and may 
also include a separate follow up with the study coordinator. 
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 


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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 243 subjects will be randomized 2:2:1:2:2 to 5 treatment groups: VX-548 (high 
dose); VX-548 (mid dose); VX-548 (low dose); HB/APAP (opioid reference); or placebo. The 
randomization ratio of 2:2:1:2:2 will be controlled for the overall study, and the details of the 
randomization implementation will be specified in separate documents. 
Each randomized subject will be assigned a unique subject number. Randomization will be 
stratified by site and baseline NPRS (<8 versus ≥8). 
An interactive web or voice response system (IXRS) will be used to assign subjects to treatment. 
The randomization code will be produced by Vertex Biostatistics or a qualified randomization 
vendor. The Vertex study biostatistician will review and approve the production of the final 
randomization list, which will be reviewed and approved by a designated unblinded 
biostatistician who is not a member of the Study Execution Team (SET).  
9.3 
Rationale for Study Elements 
9.3.1 
Study Design 
Bunionectomy is a well-established, multi-dose, surgical, acute pain model. A randomized, 
double-blind study design was selected to avoid observer bias and reduce symptoms or outcomes 
arising from the subjects’ knowledge of treatment. A parallel design is considered most 
appropriate given the acute nature of bunionectomy surgery. 
A range of 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 removal of the popliteal 
sciatic block and after the subject’s pain meets the pain threshold criteria. The pain threshold 
criteria are designed to ensure subjects have sufficient pain to determine if the drug is effective. 
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 (Table 9-1) 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.1 The selected 
VX-548 doses are predicted to achieve concentrations that are able to produce 74% (low dose) to 
91% (high dose) NaV1.8 inhibition in the in vitro human DRG assay. 


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Based on population PK modeling, the mean exposures (AUC0-24 and Cmax) for VX-548 and its 
major metabolite, 
, at the highest dose in this study (100 mg/50 mg every 12 hours 
[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:1  
• 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 bunionectomy studies and is recognized by the FDA as a 
valid pain intensity measure.28 Pain rated ≥4 on an 11-point (0 to 10) NPRS at baseline ensures 
subjects have sufficient pain to determine if the study drug is effective. 
Double-stopwatch assessment: The double-stopwatch assessment is a standardized assessment 
for determining the onset of pain relief.29, 30 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. 
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 


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Table 9-2 
Study Restrictions 
Restricted 
Medication/Food/Activity a 
Timing of Restriction 
Start 
Stop 
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, opioids and/or NSAIDs are not allowed for 
5 half-lives or 2 days (whichever is longer) before admission through discharge from CRU. 
9.4.1.1 
Perioperative Pain Management 
Perioperative pain management will follow the standard-of-care, becoming progressively more 
conservative before removal of the popliteal sciatic block. 
Pre- and perioperative: 
• Intravenous (IV) midazolam and/or fentanyl will be administered, followed by IV propofol, a 
popliteal sciatic block (≤0.5% ropivacaine), and a Mayo block (2% lidocaine without 
epinephrine). NSAIDs may not be administered. 
Postoperative: 
• A continuous popliteal sciatic block infusion (0.2% ropivacaine) will be started after surgery 
and will be removed after approximately 3AM, but no later than 5AM on Day 1. Block 
removal is defined as removal of the infusion catheter and/or completion of the ropivacaine 
infusion. 


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• The following supplemental analgesia medications are permitted postoperatively through 
time of popliteal block removal: 
o Acetaminophen (975 to 1000 mg) can be administered q6h prn until 6 hours before 
removal of the popliteal block for subjects with NPRS score of 4 through 6 after 
surgery. 
o Fentanyl citrate (12.5 to 25 µg IV) can be administered every 2 hours (q2h) prn until 
1.5 hours before removal of the popliteal block for subjects with NPRS score of 7 or 
above after surgery. 
o Ropivacaine boluses and/or infusion rate changes can be used prn prior to removal of 
the popliteal block; boluses should not be used at the time of block removal. 
o The use of ice packs is not permitted. 
• A record (date and time of administration) will be kept of all standard-of-care pain 
medication use prior to removal of the popliteal block, and an unscheduled NPRS will be 
completed immediately before each administration of supplemental analgesia medication. 
• No pain treatments are allowed between removal of the popliteal block and the first dose of 
study drug. 
9.4.1.2 
Rescue Medication 
• Ibuprofen (400 mg orally q6h prn) is permitted as a rescue medication for pain relief upon 
the subject’s request starting any time after the first dose of study drug through 48 hours after 
the first dose of study drug. 
• Subjects are encouraged to wait 90 minutes after the first dose of study drug to request rescue 
medication, and subjects should generally not receive rescue medication unless their NPRS 
score is ≥4. 
• A record (date and time of administration) will be kept of all rescue medication use. 
• An unscheduled NPRS will be completed immediately before each administration of rescue 
medication. 
9.4.2 
Additional Dietary Restrictions 
• Subjects will be on a clear liquid diet (≤8 fluid ounces per hour) starting 2 hours before block 
removal through 4 hours after the first dose of study drug (Table 3-2 and Table 3-3). Refer to 
the Study Reference Manual for a list of permitted liquids. 
• Subjects will abstain from all food and drink (except ≤8 fluid ounces per hour of water) 
during the fasting periods indicated in 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. 
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. 
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 


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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 
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 


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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 
• The bioanalytical laboratory/vendor personnel responsible for the sample testing (Vertex or 
external) 


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• 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 may have access to NPRS, PK, 
PK/pharmacodynamic (PD), 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 IDs will be used 
for NPRS, PK, and PK/PD 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 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 prior to first study drug dose on Day 1 
At 12, 24, and 36 hours after the first dose of study drug 
Within 15 minutes before the next study drug dose 
At all other time points after the first dose of study drug 
Within ± 30 minutes of scheduled time point 
Note: Refer to Table 3-2 and Table 3-3 for pharmacokinetic sampling time points. 
11.2.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be in the Laboratory Manual. 
11.2.3 
Bioanalysis 
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee standard operating procedures. A description of the assay and validation data will be 
provided in separate reports. 
11.3 
Verbal Categorical Rating Scale 
VRS will be completed upon request for the first dose of study drug for pain relief after removal 
of the popliteal sciatic block. 


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If a subject does not meet the VRS and NPRS criteria (Section 8.1) within 9 hours after removal 
of the popliteal sciatic block, the subject will not be eligible for this study. 
11.4 
Patient Global Assessment of Study Drug 
The PGA of study drug must be completed before the start of any other assessments scheduled at 
the same time point. Detailed procedures for the administration of the PGA of study drug will be 
provided in a separate document. 
11.5 
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.  
11.6 
Efficacy 
11.6.1 
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.  
11.6.2 
Numeric Pain Rating Scale 
Before removal of the popliteal sciatic block, an unscheduled NPRS will be completed 
immediately before each administration of supplemental analgesia medication. The type of 
supplemental analgesia allowed is based on the NPRS score (Section 9.4.1.1). 
After removal of the popliteal sciatic block, NPRS will be completed after VRS if the subject’s 
pain is rated moderate or severe on the VRS. If a subject does not meet the VRS and NPRS 
criteria (Section 8.1) within 9 hours after removal of the popliteal sciatic block, the subject will 
not be eligible for this study. 
During the Treatment Period, subjects will report their pain intensity on the NPRS at each 
scheduled time point through 48 hours after the first dose of study drug. In addition, pain 
intensity will be recorded on the NPRS immediately before each administration of rescue 
medication (Section 9.4.1.2). 
11.6.3 
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. 
11.6.4 
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 


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rescue medication use, and an unscheduled NPRS will be completed immediately before each 
administration of rescue medication. 
11.7 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, standard 12-lead ECGs, and physical examinations (PEs). 
11.7.1 
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. 
11.7.2 
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 11.7.1). 
The safety laboratory test panels are shown in Table 11-2. 
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. 


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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 11.7.5.1), will also have a urine β-hCG test on Day -1. 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 
drug. A positive drug screen for a known prescribed concomitant medication that is not 
otherwise exclusionary (e.g., benzodiazepines) will not disqualify subjects; however, a 
positive drug screen for 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 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 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. 
11.7.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits. Screening visits that occur using a home health nurse will have an abbreviated PE. 


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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 complete PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, 
nose, and throat; respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs. 
The abbreviated PE will include an assessment of the following body systems: general; 
cardiovascular system; respiratory system; skin; and abdomen. 
A focused PE of the operative site 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. 
If there is an abnormal clinical assessment during a home visit, depending on its severity and at 
investigator discretion, the subject may be instructed to have a PE or other evaluation in the 
clinic. 
11.7.4 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout. Additional standard 
12-lead ECGs will be performed at any other time if clinically indicated. The performance of all 
ECGs will adhere to the following guidelines: 
• The ECG will be done before any other procedures that may affect heart rate, such as blood 
draws. 
• The subject will be instructed to rest for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position 
A printout of the ECG traces will be made for safety review by the investigator and maintained 
with source documentation. Clinically significant ECG abnormalities occurring during the study 
through the Safety Follow-up Visit will be recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site or an approved home 
nurse at the home health visit 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. 
11.7.5 
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. 


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11.7.5.1 
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. 
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 
• Male vasectomy 6 months or more previously, with a documented negative 
post-vasectomy semen analysis for spermb 
• Female bilateral tubal ligation performed at least 6 months previously 
• Female continuous use of an intrauterine device for at least 90 days before the first 
dose of study drug, throughout study drug treatment, and until 30 days after the last 
dose of study drug. 
• Female hormonal contraceptives, if successfully used for at least 60 days before the 
first dose of study drug, throughout study drug treatment, and until 30 days after the 
last dose of study drug. 
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 
Medical record documentation of contraception for non-study partners is not required. The subject must 
confirm that their partner has documented proof, and the subject’s confirmation should be documented. 
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. The subject must confirm that they will practice true abstinence 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: 


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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. 
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. 
• Medical record documentation of contraception for non-study partners is not required. 
• If applicable, additional contraception requirements may need to be followed according to 
local regulations and/or requirements. 
Unique situations that may not fall within the above specifications may be discussed with the 
Vertex medical monitor or designee on an individual basis. 
11.7.5.2 
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. The 
primary efficacy endpoint is the time-weighted SPID48 after the first dose. Assuming a 
standardized effect size of 0.8 for VX-548 (high or mid dose) compared to placebo as well as a 


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2-sided significance level of 0.05, 48 evaluable subjects per group would provide at least 90% 
power. This sample size would allow a minimal detectable standardized effect size of 0.4 to 
achieve statistical significance between VX-548 (high or mid dose) and placebo. Assuming an 
observed standardized effect size of 0.8, this sample size would provide sufficient precision, with 
90% probability for the true standardized effect size greater than 0.53. To allow for withdrawal 
of up to 10% of randomized subjects over 48 hours of treatment, the study will enroll and 
randomize approximately 243 subjects in total. 
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 a bunionectomy. 
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. 


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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. 
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 Endpoints 
The primary efficacy endpoint is the time-weighted SPID48 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 SPID48 as the dependent variable and treatment as a fixed effect, with 
adjustment for stratification factors (i.e., site and baseline NPRS). If the 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 between VX-548 versus placebo. The 
estimated mean treatment effect, a 95% CI, and a 2-sided P value will be provided. 
In addition, an exploratory dose-response analysis will be conducted. 
Details will be provided in the SAP. 
12.3.3.2 
Analysis of Secondary Endpoints 
• Time-weighted SPID as recorded on an NPRS 0 to 24 hours (SPID24) 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 48 hours after the 
first dose of study drug: This variable will be analyzed using the Cochran-Mantel-Haenszel 
test, stratified by baseline NPRS. 
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 of the primary efficacy endpoint, NPRS 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. Missing values due to early withdrawal will be imputed using the last 


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non-missing observation carried forward before the calculation of SPID48 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 
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 PK/PD analysis (if done) will be reported in a separate document. 


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


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1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled will be 
recorded only in the subject’s source documents. The following data will be documented for 
each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
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. 


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Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the subject’s medical record). 
AE: adverse event 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classificationa 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
AE: adverse event  
a 
Refer to Section 9.7 for directions regarding what drug actions are permitted per protocol.  
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4. 


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


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Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious”, which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent through the Safety Follow-up Visit, 
regardless of causality, will be reported by the investigator to Vertex GPS within 24 hours of 
identification. In addition, all SAEs that occur after the Safety Follow-up Visit and are 
considered related to study drug(s) will be reported to Vertex GPS within 24 hours of 
identification.  
For SAEs that occur after obtaining informed consent through the Safety Follow-up Visit, the 
SAE Form will be completed for new/initial events as well as to report follow-up information on 
previously reported events. Investigators are asked to report follow-up information as soon as it 
becomes available to ensure timely reporting to health authorities.  
Please send completed SAE Forms to Vertex GPS via: 
 
  
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 
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. 


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13.2 
Administrative Requirements 
13.2.1 
Product Complaints 
A product complaint is defined as any verbal or written communication addressed to Vertex, or 
designee, of inquiry or dissatisfaction with the identity, strength, quality, or purity of a released 
drug product, IMP, or medical device. In addition, suspected counterfeit/falsified product is 
considered a product complaint.   
Product complaints are to be reported to Vertex. 
13.2.2 
Ethical Considerations 
The study will be conducted in accordance with the current ICH E6 GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will be 
conducted only at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.3 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable) before study participation and before 
performing any study-related procedures. Remote consent may be used. Remote consent would 
include a phone call or telemedicine visit between the site and subject for the consent discussion. 
The method of obtaining and documenting the informed consent and the contents of the consent 
will comply with current ICH E6 GCP Guidelines and all applicable laws and regulations and 
will be subject to approval by Vertex or its designee. 
13.2.4 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
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 


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(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. 
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 


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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 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  


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Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc 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).31  
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 criteria32: 
1. Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data;  
2. Drafting of the article or revising it critically for important intellectual content;  
3. Final approval of the version to be published; and 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
All authors must meet conditions 1, 2, 3, and 4. All persons designated as authors should qualify 
for authorship, and all those who qualify should be listed. Contributions such as medical writing, 
enrollment of subjects, acquisition of funding, collection of data, or general supervision of the 
research group, alone, do not justify authorship.  


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Contributors: Contributors who meet fewer than all 4 of International Committee of Medical 
Journal Editors 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 
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1 
Vertex Pharmaceuticals Incorporated. VX-548 Investigator's Brochure.  
2 
Payne R. Limitations of NSAIDs for pain management: toxicity or lack of efficacy? J 
Pain. 2000;1(3 Suppl):14-8. 
3 
Centers for Disease Control and Prevention, Hedegaard H, Minino AM, Warner M. Drug 
overdose deaths in the United States, 1999-2018. NCHS Data Brief. 2020;No. 356:1-8. 
4 
Centers for Disease Control and Prevention. Vital statistics rapid release: Provisional 
Drug Overdose Death Counts Available at: https://www.cdc.gov/nchs/nvss/vsrr/drug-
overdose-data.htm#ref7. Accessed 24 June 2021. 
5 
European Monitoring Centre for Drugs and Drug Addiction. European drug report: 
Trends and developments. Lisbon, Portugal: 2020. 
6 
Taneja A, Della Pasqua O, Danhof M. Challenges in translational drug research in 
neuropathic and inflammatory pain: the prerequisites for a new paradigm. Eur J Clin 
Pharmacol. 2017;73(10):1219-36. 
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United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research. 2008. Novel Drug Approvals. Available at: 
https://web.archive.org/web/20110507202042/http:/www.fda.gov/downloads/Drugs/Deve
lopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicAppro
valReports/UCM081805.pdf. Accessed 01 March 2019. 
8 
United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research. 2009. Novel Drug Approvals Available at: 
https://web.archive.org/web/20110507202020/http:/www.fda.gov/downloads/Drugs/Deve
lopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicAppro
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. 
10 
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. 
11 
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. 
12 
England S. Voltage-gated sodium channels: the search for subtype-selective analgesics. 
Expert Opin Investig Drugs. 2008;17(12):1849-64. 
13 
Krafte D, Bannon A. Sodium channels and nociception: recent concepts and therapeutic 
opportunities. Curr Opin Pharmacol. 2008;8(1):50-6. 
14 
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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15 
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. 
16 
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. 
17 
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. 
18 
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. 
19 
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. 
20 
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. 
21 
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. 
22 
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. 
23 
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. 
24 
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. 
25 
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. 
26 
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. 
27 
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. 
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 
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. 
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 
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. 
32 
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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15.2 
Investigator Signature Page 
Protocol #:  VX21-548-101 
Version #: 
5.0 
Version Date: 
 21 January 2022 
Study Title: A Phase 2, Randomized, Double-blind, Placebo-controlled, Dose-ranging Study 
Evaluating the Efficacy and Safety of VX-548 for Acute Pain After a Bunionectomy 
 
 
I have read Protocol VX21-548-101, Version 5.0, 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 26 
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1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX21-548-101 Version 5.0 
(Final Analysis) 
 
A Phase 2, Randomized, Dose-ranging, Double-blind, Placebo-
controlled Study Evaluating the Efficacy and Safety of VX-548 for 
Acute Pain After a Bunionectomy 
Author of SAP: 
 
 
Version: 1.0 
Version Date of SAP: 03 March 2022   
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods)  
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2 
TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
2 
Table of Contents ............................................................................................................. 2 
3 
Modifications .................................................................................................................... 4 
3.1 
Modifications to the Approved Clinical Study Protocol ............................................ 4 
3.2 
Modifications to the Approved Statistical Analysis Plan ........................................... 4 
4 
Introduction ...................................................................................................................... 5 
5 
Study Objectives .............................................................................................................. 5 
5.1 
Primary Objective ....................................................................................................... 5 
5.2 
Secondary Objectives ................................................................................................. 5 
5.3 
Other Objectives ......................................................................................................... 5 
6 
Study Endpoints ............................................................................................................... 5 
6.1 
Primary Endpoint ........................................................................................................ 5 
6.1.1 
Secondary Endpoints .......................................................................................... 5 
6.1.2 
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 
Supportive Analyses .................................................................................. 13 
9.3.1.4 
Additional Analyses ................................................................................... 13 
9.3.1.5 
Sensitivity Analyses ................................................................................... 13 
9.3.1.6 
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 


Statistical Analysis Plan (Methods)  
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9.3.3 
Analysis of Other Efficacy Variables ............................................................... 14 
9.3.3.1 
Definition of Other Efficacy Variables ...................................................... 14 
9.3.3.2 
Other Analyses ........................................................................................... 15 
9.4 
Safety Analysis ......................................................................................................... 16 
9.4.1 
Adverse Events ................................................................................................. 16 
9.4.2 
Clinical Laboratory Assessments ..................................................................... 17 
9.4.3 
Electrocardiogram ............................................................................................ 17 
9.4.4 
Vital Signs ........................................................................................................ 18 
9.4.5 
Physical Examination ....................................................................................... 18 
10  Summary of Interim and IDMC Analyses .................................................................. 18 
11  References ....................................................................................................................... 18 
12  List of Appendices .......................................................................................................... 19 
Appendix A 
: Analysis Visit Windows for Safety and Efficacy Assessments ............... 19 
Appendix B 
: Imputation Rules for Missing Prior/Concomitant Medication Date ........ 21 
Appendix C 
: Imputation Rules for Missing AE Date and Time ................................... 22 
Appendix D 
: Threshold Value Criteria .......................................................................... 23 
 


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-
548-101 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 a bunionectomy 
5.2 
Secondary Objectives  
 To evaluate the safety and tolerability of VX-548 
 To evaluate the pharmacokinetics (PK) of VX-548 and its metabolite, 
 
5.3 
Other Objectives  
 To evaluate the dose-response and exposure-response relationship 
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) 0 to 48 hours (SPID48) after the first dose of study drug 
6.1.1 
Secondary Endpoints 
 Time-weighted SPID as recorded on an NPRS 0 to 24 hours (SPID24) after the first dose 
of study drug 
 Proportions of subjects with ≥30%, ≥50%, and  ≥70% reduction in NPRS at 48 hours 
after the first dose of study drug 
 PK parameter estimates of VX-548 and its metabolite, 
 


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 
6.1.2 
Other Endpoints 
 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 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 
7 
OVERALL DESIGN  
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-ranging, 5-arm, 
parallel study design evaluating the efficacy and safety of VX-548 doses in treating acute 
pain after a bunionectomy (Figure 7-1).  
On Day -1, subjects will undergo a primary unilateral bunionectomy with distal first 
metatarsal osteotomy (i.e., Austin procedure) and internal fixation under regional anesthesia 
(Mayo and popliteal sciatic block). A continuous popliteal sciatic block infusion (0.2% 
ropivacaine) will be started after surgery and remain in place until approximately 3AM, but 
no later than 5AM, on Day 1. After removal of the popliteal sciatic block, a subject will be 
randomized to 1 of 5 treatment groups if (1) the subject requests the first dose of study drug 
for pain relief, (2) the subject’s pain is moderate or severe on the VRS, and (3) the subject’s 
pain is ≥4 on the NPRS. If a subject does not meet the VRS and NPRS criteria within 9 hours 
of removal of the popliteal sciatic block, the subject will not be eligible for this study.  
Approximately 202 subjects will be randomized 2:2:1:2:2 to 5 treatment groups: VX-548 
(high dose); VX-548 (mid dose); VX-548 (low dose); HB/APAP (opioid reference); or 
placebo (Table 7-1). Randomization will be stratified by site and baseline NPRS (<8 versus 
≥8). To maintain the blind, all subjects will receive the same number of tablets and/or 
capsules every 6 hours (q6h) in a double-dummy design. 


Statistical Analysis Plan (Methods)  
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Figure 7-1 
VX21-548-101 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 removal of the popliteal sciatic block, a subject will be randomized to 1 of 5 treatment groups if (1) the subject 
requests the first dose of study drug for pain relief, (2) the subject’s pain is moderate or severe on the VRS, and (3) the 
subject’s pain is ≥4 on the NPRS. If a subject does not meet the VRS and NPRS criteria within 9 hours of removal of 
the popliteal sciatic block, the subject will not be eligible for this study. 
Table 7-1          VX21-548-101 Treatment Groups 
Treatment 
Active Dose 
Number of Subjects 
VX-548 (high dose) 
100 mg first dose, then 50 mg q12h 
54 
VX-548 (mid dose) 
60 mg first dose, then 30 mg q12h 
54 
VX-548 (low dose) 
20 mg first dose, then 10 mg q12h 
27 
HB/APAP 
5 mg/325 mg q6h 
54 
Placebo 
 
54 
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 on the NPRS at each scheduled time point through 48 hours 
after the first dose of study drug. In addition, pain intensity will be recorded on the NPRS 
immediately before each administration of rescue medication.  
Ibuprofen (400 mg orally q6h as needed) will be 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 receive rescue medication, and subjects should generally not 
receive rescue medication unless their NPRS is ≥4. 
7.1 
Sample Size and Power 
The sample size calculation is based on the comparison between VX-548 and placebo. The 
primary efficacy endpoint is the time-weighted SPID48 after the first dose. Assuming a 
standardized effect size of 0.8 for VX-548 (high or mid-dose) compared to placebo as well as 
a 2-sided significance level of 0.05, 48 evaluable subjects per group would provide at least 
90% power. This sample size would allow a minimal detectable standardized effect size of 
0.4 to achieve statistical significance between VX-548 (high or mid-dose) and placebo. 


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Assuming an observed standardized effect size of 0.8, this sample size would provide 
sufficient precision, with 90% probability for the true standardized effect size greater than 
0.53. To allow for withdrawal of up to 10% of randomized subjects over 48 hours of 
treatment, the study will enroll and randomize approximately 243 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 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.  
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.  


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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 TE period, and maximum and 
minimum change from baseline values during 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: For NPRS measurements, missing data will be imputed by 
applying linear interpolation to the valid observations immediately before and after the 
missing observation(s). If there are no valid observations after the missing observation(s), the 
last observation carried forward (LOCF) principle will be applied as a primary approach. 
Additional details on how to handle missing data is 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 for pairwise comparisons in primary efficacy variable, secondary analyses, and other 
analyses 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 FAS) of subjects in each of the following disposition 
categories will be summarized: 
 Completed treatment 


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 Prematurely discontinued treatment and the reason for discontinuation from treatment 
 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 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 (005, 016, 017, 018, 057, 058, 062, 063) 
 NPRS 
 NPRS category (<8, ≥8) 
 VRS (moderate, severe) 
In addition, data listings will also be provided for: 
 Informed consent 
 Inclusion/exclusion criteria violation for subjects with any such violations 
9.2.3 
Medical History 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). Medical history will be summarized descriptively based on the FAS by 
MedDRA system organ class (SOC) and preferred term (PT). This summary will be provided 
by 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 purpose of analysis: 
Prior medication: Medication that started before the first dose of study drug, regardless of 
when dosing of the medication ended 
Concomitant medication: Medication continued or newly received on or after the date of 
the first dose of study through the end of the TE Period 
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 removal of the 
popliteal sciatic block will be included in the Prior medications summary but will be listed 
separately. Rescue medication will also be included in the summary of Prior medications but 
will be listed separately.   
Prior and concomitant non-pharmacological treatments or procedures will 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, it is not needed 
to perform a calculation of exposure to study drug or a calculation of compliance. 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 


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database lock. IPDs will be identified by the PD review team according to the protocol 
deviation plan.  
IPDs will be summarized descriptively by treatment group and overall. 
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. 
Although the results from the efficacy analyses will be presented as separate pairwise 
comparisons (i.e. VX-548 versus placebo and HB/APAP versus placebo), 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 after the first dose of study drug. 
In general, SPID is calculated as: ∑ ∆timei x PIDi where:  
 ∆timei  =  time (in hours) elapsed since previous measurements 
 PIDi  = pain intensity (NPRS) at baseline - pain intensity (NPRS) at hour i 
Hence: 
 SPID48 = 0.5 × PID0.5 + 0.5 × PID1 + 0.5 × PID1.5 + 0.5 × PID2 + PID3 + PID4 + PID5 
+ PID6 + 2 × PID8 + 4 × PID12 + 4 × PID16 + 4 × PID20 + 4 × PID24 + 4 × PID28 + 4 × 
PID32 + 4 × PID36 + 4 × PID40 + 4 × PID44 + 4 × PID48 
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 SPID48 as the dependent variable and treatment as a fixed effect, 
with site and baseline NPRS as covariates. Data from all treatment groups will be included in 
the model. If the 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 between VX-548 versus placebo. The Least Squares (LS) mean of the treatment 
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 scores during the rescue period (within 6 hours after rescue medication) will be 
replaced by the pre-rescue NPRS.  
 The pre-rescue NPRS will be the NPRS collected immediately before the 
administration of rescue medication, or the last observed NPRS if that score is 
missing. The last observed NPRS can be a score from a regularly scheduled 
measurement or the previous pre-rescue NPRS but cannot be any observed 
scores during the previous rescue period. 


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 If there are multiple administrations of rescue medication within the same 6-
hour period, a local highest NPRS will be used for the imputation during the 
second 6-hour rescue period. The local highest NPRS is the highest value 
among the first pre-rescue, the second pre-rescue, and the actual observed (if 
any) in the overlapping period. 
2) Missing NPRS scores following treatment discontinuation will be imputed with the 
last observed or previously imputed NPRS score prior to discontinuation. 
3) Missing NPRS scores 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 score.  
4) Intermittently missing NPRS scores will be imputed using linear interpolation. 
9.3.1.3 
Supportive Analyses 
A supportive analysis based on the Linear trend test will be performed to assess the dose-
response relationship. The linear trend test will be based on the LS means obtained from the 
ANCOVA model from the primary analysis. The 2-sided P value will be provided.  
9.3.1.4 
Additional Analyses 
This additional analysis will be performed by modifying the primary analysis in such a way 
that NPRS scores during the rescue period (within 6 hours after rescue medication) will not 
be replaced by the pre-rescue NPRS score. The observed NPRS scores will be used instead. 
The same ANCOVA model as described in Section 9.3.1.2 will be performed. 
9.3.1.5 
Sensitivity Analyses 
This sensitivity analysis will be performed by modifying the primary analysis in such a way 
that missing NPRS scores following treatment discontinuation due to AE will be imputed 
with the baseline NPRS while the NPRS following treatment discontinuation due to other 
reasons will be imputed by the last observed or previously imputed NPRS score prior to 
discontinuation. The same ANCOVA model as described in Section 9.3.1.2 will be 
performed.  
9.3.1.6 
Subgroup Analysis 
No subgroup analysis for the primary efficacy variable is planned. 
For the primary analysis, additional analysis, and sensitivity analysis, SPID48 will also be 
summarized descriptively, including standard error (SE), by treatment. In addition, NPRS 
measurements 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 SPID24 after the first dose of study drug: In general, SPID24 is calculated 
using the following formula: 


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 SPID24 = 0.5 × PID0.5 + 0.5 × PID1 + 0.5 × PID1.5 + 0.5 × PID2 + PID3 + PID4 + PID5 
+ PID6 + 2 × PID8 + 4 × PID12 + 4 × PID16 + 4 × PID20 + 4 × PID24 
Proportions of subjects with ≥30%, ≥50%, and  ≥70% reduction in NPRS at 48 hours after 
the first dose of study drug: Subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS 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: 
 100% × (NPRS at baseline  ̶ NPRS at 48 hours) / NPRS 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 any of the 3 criteria.   
9.3.2.2 
Secondary Analyses  
Time-weighted SPID24 after the first dose of study drug: SPID24 will be analyzed in the 
same way as described in Section 9.3.1.2. SPID24 will also be analyzed in the same way as 
described for SPID48 in Sections 9.3.1.4 and 9.3.1.5. 
Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at 48 hours after the 
first dose of study drug: Analysis of responder rates at 48 hours between VX-548 and 
placebo will be conducted using Cochran-Mantel-Haenszel test, stratified by baseline NPRS 
(<8, ≥8).  
9.3.3 
Analysis of Other Efficacy Variables 
9.3.3.1 
Definition of Other Efficacy Variables 
Time to onset of “confirmed perceptible pain relief” and “meaningful pain relief” after the 
first dose of study drug: Time to onset of “first perceptible pain relief” is the time elapsed 
from first dose of study drug until the subject stops the “first perceptible pain relief” 
stopwatch. Time to onset of “meaningful pain relief” is the time elapsed from first dose of 
study drug until the subject stops the “meaningful pain relief” stopwatch. Time to onset of 
“confirmed perceptible pain relief” will be defined as the time to 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 or the subject 
receives rescue medication during the first 6 hours, the stopwatch will be stopped and time to 
onset will be considered censored at 6 hours. If the “first perceptible pain relief” is obtained 
without subsequent “meaningful pain relief”, time to 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 24 hours after the 
first dose of study drug: Subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS 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 baseline  ̶ NPRS at 24 hours) / NPRS at baseline 


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The same imputation strategies as described in Section 9.3.1.2 will be applied. However, 
Subjects who discontinue the study drug treatment for any reason prior to 24 hours will be 
“non-responders” for any of the three 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 to onset of “confirmed perceptible pain relief” and “meaningful pain relief” after the 
first dose of study drug: Time to onset of “confirmed perceptible pain relief” will be analyzed 
using Cox regression model. The model will include treatment as a fixed effect and baseline 
NPRS as a covariate. Pairwise comparison between VX-548 and placebo will be conducted 
under the 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, 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 VX-548 and placebo.  
Time to onset of “meaningful pain relief” and time to onset of “first perceptible pain relief” 
will be analyzed in the same way as described for time to onset of “confirmed perceptible 
pain relief”.  
Proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS 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. Cochran-Mantel-Haenszel test, stratified by 
baseline NPRS (<8, ≥8), will be conducted to compare VX-548 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 Cochran-Mantel-Haenszel test, stratified by 
baseline NPRS (<8, ≥8), to compare VX-548 and placebo. Total rescue medication usage 
from 0 to 48 hours will be summarized descriptively and Wilcoxon rank-sum test, stratified 
by baseline NPRS (<8, ≥8), will be conducted to compare VX-548 and placebo. 
All analyses described in Sections 9.3.1, 9.3.2 and 9.3.3 on comparisons between VX-548 
and placebo will be repeated based on a comparison between HB/APAP and placebo. 


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9.4 
Safety Analysis 
The overall safety profile of VX-548 will be assessed in terms of the following safety and 
tolerability endpoints:  
 Incidence of treatment-emergent adverse events (TEAEs) 
 Clinical laboratory values (hematology, serum chemistry, coagulation studies, and 
urinalysis) 
 ECG outcomes 
 Vital signs 
All safety analyses will be performed based on the Safety Set by treatment. Only descriptive 
analyses of safety will be performed, and no statistical hypothesis testing will be performed. 
In an unexpected scenario that a subject may receive more than one treatment in the study, 
the following algorithm will be used to define subject’s actual treatment: for any dosed 
subjects, the actual treatment is defined as the highest dose level among all received VX-548 
treatment if the subject received any VX-548 treatment, regardless of the randomized 
treatment assignment; the actual treatment is defined as HB/APAP if the subject did not 
receive any VX-548 treatment but did receive any HB/APAP; the actual treatment is defined 
as placebo only if the subject received placebo at all visits in the study. 
9.4.1 
Adverse Events  
AEs will be coded according to MedDRA. For analysis purposes, AEs will be classified as 
pretreatment AEs and TEAEs as follows: 
Pretreatment AEs: AEs that occurred before the first dose of study drug 
Treatment-emergent AEs: AEs that worsened or started on or after the first dose date of 
study drug through the end of the TE Period 
For AEs with completely missing or partial start dates, if there is no clear evidence that the 
AEs started before or after the first dose of study drug, the AEs will be classified as TEAEs. 
Imputation rules for missing or partial AE start date are defined as Appendix C. 
AE summary tables will be presented only for TEAEs, and will include the following: 
 All TEAEs 
 TEAEs by strongest relationship 
 TEAEs by maximum severity 
 TEAEs leading to treatment discontinuation 
 TEAEs leading to treatment interruption 
 Related TEAEs 
 Serious TEAEs 
 Related serious TEAEs 


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 TEAEs leading to death 
Summaries will be presented by MedDRA SOC and PT using frequency counts and 
percentages (i.e., number and percentage of subjects with an event). When summarizing the 
number and percentage of subjects with an event, subjects with multiple occurrences of the 
same AE or a continuing AE will be counted once, and only the maximum severity level will 
be presented in the severity summaries, and the strongest relationship level in the relationship 
summaries.  
All AEs, including pretreatment AEs and TEAEs will be presented in an individual subject 
data listing based on the All Subjects Set. In addition, a listing containing individual subject 
adverse event data for TEAEs leading to treatment discontinuation, TEAEs leading to 
treatment interruption, SAEs and all deaths will be provided separately. 
9.4.2 
Clinical Laboratory 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 
criterion event 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.  
Results of urinalysis and the urine/serum pregnancy test will be in individual subject data 
listings only. 
In addition, a listing of individual subject hematology, chemistry, and coagulation values 
outside the normal reference ranges will be provided. This listing will include data from both 
scheduled and unscheduled visits. 
9.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change 
from baseline values will be provided at each visit and time point, as applicable, for the 
following ECG measurements (in msec): heart rate (HR; beats per minute [bpm]), PR 
interval (msec), RR interval (msec), QRS duration (msec), QT interval (msec), and QT 
corrected for HR intervals (QTcF [msec]). 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 criterion during the TE 
period will be summarized. The threshold analysis criteria are provided 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. 


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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), oxygen saturation (%).  
The number and percentage of subjects meeting threshold analysis criterion during the TE 
Period will be summarized. The threshold analysis criteria are provided in Appendix D.  
In addition, a listing containing individual subject vital signs values will be provided. This 
listing will include data from both scheduled and unscheduled visits. 
9.4.5 
Physical Examination  
Physical examination (PE) results will be presented in individual subject data listings only. 
10 
SUMMARY OF INTERIM AND IDMC ANALYSES 
Not applicable. 
11 
REFERENCES 
Not applicable. 


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12 
LIST OF APPENDICES 
Appendix A : Analysis Visit Windows for Safety and Efficacy Assessments  
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit/Time Point1 
Target Study Day 
/Time Point per 
the protocol 
Analysis Visit Window 
(in study days/ time points) 
2, 3, 4, 5 
Safety Assessment 
Hematology 
Serum Chemistry 
Coagulation 
Baseline 
Day 1 
≤ Day 1 Pre-dose 
48 hours 
48 hours 
Nominal Visit  
Standard 12-Lead ECG 
 
Baseline 
Day 1 
≤ Day 1 Pre-dose 
4 hours 
4 hours  
Nominal visit for all visits 
16 hours 
16 hours 
 
28 hours 
28 hours 
 
40 hours 
40 hours 
 
Vital Sign 
Baseline 
Day 1 
≤ Day 1 Pre-dose 
2 hours 
2 hours  
Nominal visit for all visits 
4 hours 
4 hours 
 
24 hours 
24 hours 
 
48 hours 
48 hours 
 
Safety Follow-up 
Not applicable 
 
Efficacy Assessment 
NPRS 
Baseline  
Day 1 
≤ Day 1 Pre-dose 
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 
 
VRS 
Baseline  
Day 1  
≤ Day 1 Pre-dose 
Rescue Medication 
N/A 
N/A 
[Day 1 post-dose, 48 hours 
post-dose]  
 
Notes:  
1 Visit/Time point name for analysis purpose is used to report data in tables and figures. 
2The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered 
missing for the visit.  
b. If there is more than 1 numerical measurement available within the same visit window, use the 
following rules:  


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i. 
The measurement closest to the target day/time point will be used; or  
ii. 
If there are multiple measurements within the same distance from the target day/time point, 
the latest measurement will be used. 
iii. 
If a scheduled and 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 measurement will be treated as post-dose observation. 
4When define 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 Date 
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 only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month and year are all missing, assign ‘continuing’ status to stop 
date. 
With missing or partial medication start time, only use the imputed start date to categorize 
the prior and/or concomitant medication as described in Table 12-2. If hour and/or minute of 
first dose time are missing, only use the first dose date to categorize the prior and/or 
concomitant medication. Imputation of missing and/or partial dates for non-pharmacological 
treatments/procedures will follow the same imputation rule.  
Table 12-2 
Prior and/or Concomitant Categorization of a Medication 
Medication Start Date 
Medication Stop Date 
< First Dose Date 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 Date and Time 
Imputation rules for missing or partial AE start date and time 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 
pretreatment AE. 
 If the AE start date is on or after the first dose date, the AE will be classified as 
TEAE. 
If Day of AE start date is missing:  
 If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then  
o if the AE start year and month are equal to the month and year of first dose 
date, then impute the AE start day as the day of first dose date;  
o else impute the AE start day as 1. 
 Else impute the AE start day as 1. 
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, or TEAE. 
If Day and Month of AE start date are missing: 
 If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing,  
o if AE start year is equal to the year of the first dose date, then impute the AE 
start month and day as the month and day of first dose date.  
o else impute the AE start Month as January and the Day as 1. 
 Else 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 
pretreatment AE, or TEAE. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site with 
no imputation. Also 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 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 
pretreatment AE. 
 If the AE start date is on or after the first dose date, the AE will be classified as 
TEAE. 


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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 
>1.5x - ≤2xULN 
>2x - ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine kinase 
>ULN - ≤2.5xULN 
>2.5 - ≤5xULN 
>5 - ≤10xULN  
>10xULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥100 g/L 
<100 - ≥80 g/L  
<80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤20 g/L above ULN 
>20 g/L above ULN - ≤40 g/L above 
ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥75.0 x 10e9 /L 
<75.0 - ≥50.0 x 10e9 /L  
<50.0 - ≥25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 
Coagulation 
 
 
Activated partial thromboplastin 
time (PTT)  
 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5xULN 
CTCAE grade 1-3 


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Table 12-1 
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 
>2.5 x ULN 
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