Clinical trial NCT03764072
Conditions: Acute Pain
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2018-12-12; Completion date: 2019-01-25
Enrollment: 250 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the dose-response relationship and safety of VX-150 in treating acute pain following bunionectomy.

Detailed description:

Arms: arm 1: Participants received placebo matched to VX-150 for 2 days. arm 2: Participants received VX-150 1500 milligrams (mg) as first dose, followed by VX-150 750 mg every 12 hours (q12h) for 2 days. arm 3: Participants received VX-150 1000 mg once daily (qd) for 2 days. arm 4: Participants received VX-150 500 mg q12h for 2 days. arm 5: Participants received VX-150 500 mg as first dose, followed by VX-150 250 mg q12h for 2 days. arm 6: Participants received VX-150 250 mg qd for 2 days.
Interventions: intervention 1: VX-150 intervention 2: Placebo
Intervention descriptions: intervention 1: Capsules for oral administration. intervention 2: Capsules for oral administration.

Protocol documents:
Prot_000.pdf: 
Page 1 of 51 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 2B Randomized, Double-blind, 
Placebo-controlled, Dose-ranging, Parallel-design 
Study of the Efficacy and Safety of VX-150 for Acute 
Pain Following Bunionectomy 
Vertex Study Number: VX18‑150‑104 
 
Date of Protocol: 26 September 2018 (Version 2.0). 
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 




Protocol VX18-150-104, Version 2.0 
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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 2B Randomized, Double-blind, Placebo-controlled, Dose-ranging, Parallel-
design Study of the Efficacy and Safety of VX-150 for Acute Pain Following 
Bunionectomy 
  
Brief Title 
A Dose-ranging Study to Evaluate Efficacy and Safety of VX-150 in Subjects With 
Acute Pain Following Bunionectomy 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 2B efficacy and safety 
 
 
Objectives 
Primary Objective 
To evaluate the dose-response relationship of VX-150 in treating acute pain following 
bunionectomy 
Secondary Objectives 
• To evaluate the safety and tolerability of VX-150 
• To evaluate the pharmacokinetics (PK) of VRT-1207355 and the metabolite 
VRT-1268114 (M5) 
 
 
Endpoints  Primary Endpoint 
Time-weighted sum of the pain intensity difference between VX-150 versus placebo 
as recorded on a Numeric Pain Rating Scale (NPRS) 0 to 24 hours (SPID24) after 
the first dose 
Secondary Endpoints 
• Time-weighted sum of the pain intensity difference between VX-150 versus 
placebo as recorded on an NPRS 0 to 48 hours (SPID48) after the first dose 
• Proportions of subjects with at least 30%, 50%, or 70% reduction in NPRS at 24 
hours after the first dose of VX-150 versus placebo 
• Time to onset of “confirmed perceptible pain relief” and “meaningful pain relief” 
after the first dose of VX-150 versus placebo 
• Plasma PK parameters of VRT-1207355 and the metabolite M5 
• Safety and tolerability based on the incidence and type of adverse events (AEs), 
changes from baseline in clinically significant laboratory test results, and vital 
signs at designated visits 
Number of Subjects 
Approximately 242 subjects. 
 
 
Study Population 
Male and female subjects who are between the ages of 18 and 65 years (inclusive) 
with pain that is ≥4 on the NPRS and is moderate or severe on the Verbal Categorical 
Rating Scale (VRS) after bunionectomy 
 
 


Protocol VX18-150-104, Version 2.0 
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Investigational Drug 
Active substance: VX-150 
 
Activity: Voltage-gated sodium channel (Nav) 1.8 inhibitor 
 
Strength and route of administration: 250-mg capsules administered orally 
 
Study Duration 
Excluding the Screening Period, each subject will participate in the study for 11 (± 2) 
days (from Day -1 to the Safety Follow-up Phone Interview). 
 
 
Study Design 
This is a Phase 2B randomized, double-blind, placebo-controlled, dose-ranging, 
6-arm, parallel-design study. Subjects will receive a primary unilateral first metatarsal 
bunionectomy repair on Day -1. A continuous popliteal sciatic block infusion (0.2% 
ropivacaine) will be started after surgery and will be removed between 3AM and 
5AM on Day 1. After removal of the popliteal sciatic block, a subject can be 
randomized once the subject requests the first dose of study drug for pain relief, and 
the subject’s pain is ≥4 on the NPRS and is moderate or severe on the VRS. If a 
subject does not meet the NPRS and VRS criteria within 9 hours of removal of the 
popliteal sciatic block, the subject will not be eligible to enroll in the study. 
A total of approximately 242 subjects will be randomized 2:2:2:2:1:2 to 6 treatment 
arms, evaluating a range of 5 VX-150 dose levels as shown in Table 2-1: 
Table 2-1 
VX-150 Doses by Treatment Arm 
Treatment 
Dose Level 
Dose 
Number of 
Subjects 
VX-150 
1 (highest) 
First dose 1500 mg, then 750 mg 
q12h 
44 
 
2 
1000 mg qd 
44 
 
3 
500 mg q12h 
44 
 
4 
First dose 500 mg, then 250 mg 
q12h 
44 
 
5 (lowest) 
250 mg qd 
22 
Placebo 
 
 
44 
q12h: every 12 hours; qd: daily 
Note: q12h dosing will be through 36 hours after the first dose of study drug 
throughout the protocol. 
Randomization will be stratified by site and sex. To maintain the blind, all subjects 
will receive the same number of capsules in a double-dummy design. 
Subjects will report their pain on the NPRS at scheduled time points 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. 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. However, subjects may receive rescue medication at any time after the 
first dose of study drug per their request. The rescue medication will be ibuprofen 
(400 mg [oral] every 4 hours [q4h] as needed [prn]). 
 
 
Assessments 
Efficacy: 11-point NPRS, 4-point VRS, double-stopwatch assessment, 
 
 
Safety: AEs, clinical laboratory assessments, clinical evaluation of vital signs, ECGs, 
and physical examinations. 
PK: Plasma PK parameters of VRT-1207355 and the metabolite M5 
 


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Statistical Analyses 
The primary efficacy endpoint is the time-weighted sum of the pain intensity 
difference between VX-150 versus placebo as recorded on a NPRS 0 to 24 hours 
(SPID24) after the first dose. 
The primary efficacy analysis will be using the MCP-Mod (multiple comparison 
procedures with modeling techniques) approach to detect the dose-response 
relationship from a candidate set of 4 dose-response models (Linear, Emax, Logistic, 
and Sigmoid Emax). Two-sided P value for each dose-response model will be 
provided. 
Both MCP-Mod approach 
 in SPID24 between VX-150 and 
placebo will be based on an analysis of covariance (ANCOVA) model. The model 
will include the time-weighted sum of the pain intensity difference 0 to 24 hours 
(SPID24) after the first dose as the dependent variable, and treatment as a fixed 
effect, with adjustment for stratification factors, i.e., site and sex, and baseline pain as 
a covariate. 
 
 
 


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are in Table 3-1 and Table 3-2. 
Table 3-1 
Study VX18-150-104: Screening Period Prior to Surgery 
Assessment 
Screening Period Prior to Surgery 
Day -28 to Day -2 
Outpatient visit 
X 
Informed consent form  
X 
Inclusion/exclusion criteria 
X 
Demographics 
X 
Medical history 
X 
History of drug and alcohol use 
X 
Weight, height, and BMIa 
X 
Vital signsb 
X 
Standard 12-lead ECGc 
X 
Physical examination 
X 
Serum FSH (postmenopausal female subjects 
only)  
X 
Serum β-hCG (all female subjects)d 
X 
Serology (HBsAg, HCV, and HIV 1/HIV 2)e 
X 
Serum chemistryf 
X 
Hematologyf 
X 
Coagulationf 
X 
Urinalysis 
X 
Drug test (urine) 
X 
Prior use of opioid medicationsg 
X 
Medications reviewh 
Continuous from signing of ICF through Safety Follow-up 
Treatments and procedures review 
Continuous from signing of ICF through Safety Follow-up 
Adverse events 
Continuous from signing of ICF through Safety Follow-up 
β-hCG: beta-human chorionic gonadotropin; BMI: body mass index; FSH: follicle-stimulating hormone; 
HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV-1 and HIV-2 Abs: antibodies against human 
immunodeficiency viruses 1 and 2; ICF: informed consent form 
 a 
Weight and height will be measured with shoes off. 
b 
Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be assessed in the supine position 
after the subject has been instructed to rest for at least 5 minutes. Vital signs will be performed before blood 
draws or ECG assessments. 
c 
ECGs will be done in the supine position and before any other procedures that may affect heart rate, such as 
blood draws. Subjects will rest for at least 5 minutes before having an ECG. 
d 
Serum β-hCG is required of all female subjects and must be conducted within 7 days before Day 1.  
e 
Serology includes testing for HBsAg and antibodies to HCV and human immunodeficiency viruses 1 and 2 
(HIV 1/HIV 2). 
f 
Blood samples will be collected for clinical laboratory assessments following a fast of at least 4 hours. 
g 
Any opioid medications taken within 12 months of Screening Visit will be recorded. 
h 
All medications taken within 14 days before screening through the end of the study will be recorded. 


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Table 3-2 
Study VX18-150-104: Day -1, Treatment Period and Safety Follow-up 
Event/Assessment 
Day -1 
Day 1 
Day 2 
Day 3 
Safety Follow-up  
7 (± 2) Days After Last 
Dose of Study Drug 
Admission to CRU 
X 
 
 
 
 
Bunionectomy 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
Study drug dosinga 
 
X 
X 
X 
 
Discharge from CRUb 
 
 
 
X 
 
Phone interviewc 
 
 
 
 
X 
Vital signsd 
X 
X 
X 
X 
 
Standard 12-lead ECG 
 
Xe 
 
 
 
Physical examination 
X 
 
 
 
 
β-hCG (urine) 
Xf 
 
 
 
 
Serum chemistry 
Xg 
 
 
 
 
Hematology  
X 
 
 
 
 
Coagulation 
X 
 
 
 
 
PK blood sampleh 
 
X 
X 
X 
 
 a 
To maintain the blind, all subjects will receive the same number of capsules. 
b 
Subjects will be discharged on Day 3 after completion of the Day 3 assessments. 
c 
The Safety Follow-up will consist of a phone interview for the purpose of collecting information on adverse events, medications, and treatments and 
procedures. A visit will only be required if a clinical finding during the Treatment Period requires follow-up. 
d 
On dosing days, vital signs will be collected before the first dose of the day. Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be 
assessed in the supine position after the subject has been instructed to rest for at least 5 minutes. Vital signs will be performed before blood draws or ECG 
assessments. 
e 
Standard 12-lead ECGs will be measured before the first dose, and at 4 (± 1) hours after the first dose on Day 1. ECGs will be done in the supine position 
and before any other procedures that may affect heart rate, such as blood draws. Subjects will rest for at least 5 minutes before having an ECG. 
f 
A β-hCG test on Day -1 is only required for women of childbearing potential. 
g 
If less than 1 week has passed since a subject completed the screening assessments, clinical chemistry, hematology, and coagulation do not need to be 
performed at Day -1.  
h 
PK blood samples will be collected at 0 hour (before dosing) and at 1, 2, 4, 6, 8, and 12 hours after the first and third dose of VX-150 or VX-150 placebo in 
the study. A PK blood sample will also be collected 12 hours after the last dose of VX-150 or VX-150 placebo in the study. Study drug dosing details for 
each treatment arm are described in Section 9.1. When NPRS assessments coincide with collection of PK blood samples, the NPRS assessment will be 
performed first. 


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Table 3-2 
Study VX18-150-104: Day -1, Treatment Period and Safety Follow-up 
Event/Assessment 
Day -1 
Day 1 
Day 2 
Day 3 
Safety Follow-up  
7 (± 2) Days After Last 
Dose of Study Drug 
Drug test (urine) 
X 
 
 
 
 
Alcohol test (breath) 
X 
 
 
 
 
NPRSj 
 
X 
X 
X 
 
VRSk 
 
X 
 
 
 
Double-stopwatch assessment 
 
X 
 
 
 
Medications review 
Continuous from signing of ICF through Safety Follow-up 
Treatments and procedures review 
Continuous from signing of ICF through Safety Follow-up 
Adverse events 
Continuous from signing of ICF through Safety Follow-up 
β-hCG: beta-human chorionic gonadotropin; CRU: clinical research unit; NPRS: Numeric Pain Rating Scale; PK: pharmacokinetic; VRS: Verbal Categorical 
Rating Scale 
 
 
Starting on Day 1, subjects will report their pain on the NPRS 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) after 
the first dose of study drug. In addition, pain intensity on the NPRS will be recorded when the subject requests the first dose of study drug for pain relief and 
immediately before each administration of rescue medication. 
k 
On Day 1, subjects will report their pain on the VRS when they request the first dose of study drug for pain relief. 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 6 
4 
Table of Contents ................................................................................................................... 9 
List of Tables............................................................................................................................ 12 
List of Figures .......................................................................................................................... 12 
List of Abbreviations................................................................................................................ 13 
5 
Introduction.......................................................................................................................... 15 
5.1 
Background ..................................................................................................................... 15 
5.2 
Study Rationale .............................................................................................................. 15 
6 
Study Objectives .................................................................................................................. 15 
6.1 
Primary Objective ........................................................................................................... 15 
6.2 
Secondary Objectives ..................................................................................................... 16 
7 
Study Endpoints ................................................................................................................... 16 
7.1 
Primary Endpoint ............................................................................................................ 16 
7.2 
Secondary Endpoints ...................................................................................................... 16 
8 
Study Population .................................................................................................................. 16 
8.1 
Inclusion Criteria ............................................................................................................ 16 
8.2 
Exclusion Criteria ........................................................................................................... 17 
9 
Study Implementation ......................................................................................................... 18 
9.1 
Study Design .................................................................................................................. 18 
9.1.1 
Screening ................................................................................................................ 19 
9.1.1.1 
Repetition of Screening Assessments .............................................................. 19 
9.1.1.2 
Rescreening ...................................................................................................... 20 
9.1.2 
Treatment Period .................................................................................................... 20 
9.1.3 
Follow-up................................................................................................................ 20 
9.1.4 
Early Discontinuation ............................................................................................. 20 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 21 
9.3 
Rationale for Study Elements ......................................................................................... 21 
9.3.1 
Study Design........................................................................................................... 21 
9.3.2 
Study Drug Dose and Duration .............................................................................. 21 
9.3.3 
Rationale for Study Assessments ........................................................................... 21 
9.4 
Study Restrictions ........................................................................................................... 22 
9.4.1 
Analgesic Medications ........................................................................................... 23 
9.4.2 
Additional Dietary Restrictions .............................................................................. 24 
9.5 
Prior and Concomitant Medications ............................................................................... 24 
9.6 
Administration ................................................................................................................ 24 
9.7 
Dose Modification for Toxicity ...................................................................................... 25 
9.8 
Removal of Subjects ....................................................................................................... 25 
9.9 
Replacement of Subjects ................................................................................................ 25 
10 Study Drug Information and Management ....................................................................... 25 
10.1 Preparation and Dispensing ............................................................................................ 25 


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10.2 Packaging and Labeling ................................................................................................. 26 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 26 
10.4 Drug Accountability ....................................................................................................... 26 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 26 
10.6 Compliance ..................................................................................................................... 26 
10.7 Blinding and Unblinding ................................................................................................ 26 
10.7.1 
Blinding .................................................................................................................. 27 
10.7.2 
Unblinding .............................................................................................................. 27 
11 Assessments .......................................................................................................................... 28 
11.1 Subject and Disease Characteristics ............................................................................... 28 
11.2 Pharmacokinetics ............................................................................................................ 28 
11.2.1 
Blood Sampling ...................................................................................................... 28 
11.2.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 29 
11.2.3 
Bioanalysis.............................................................................................................. 29 
11.4 Efficacy ........................................................................................................................... 29 
11.5 Safety .............................................................................................................................. 30 
11.5.1 
Adverse Events ....................................................................................................... 30 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 30 
11.5.3 
Physical Examinations and Vital Signs .................................................................. 32 
11.5.4 
Electrocardiograms ................................................................................................. 32 
11.5.5 
Contraception and Pregnancy ................................................................................. 33 
11.5.5.1 Contraception ................................................................................................... 33 
11.5.5.2 Pregnancy ......................................................................................................... 34 
12 Statistical and Analytical Plans .......................................................................................... 34 
12.1 Sample Size and Power .................................................................................................. 34 
12.2 Analysis Sets .................................................................................................................. 35 
12.3 Statistical Analysis ......................................................................................................... 35 
12.3.1 
General Considerations ........................................................................................... 35 
12.3.2 
Background Characteristics .................................................................................... 36 
12.3.2.1 Subject Disposition .......................................................................................... 36 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 36 
12.3.2.3 Prior and Concomitant Medications................................................................. 36 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 36 
12.3.3 
Efficacy Analysis .................................................................................................... 36 
12.3.3.1 Analysis of Primary Variable ........................................................................... 36 
12.3.3.2 Analysis of Secondary Efficacy Variables ....................................................... 37 
12.3.4 
Safety Analysis ....................................................................................................... 38 
12.3.4.1 Adverse Events................................................................................................. 38 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 38 
12.3.4.3 Electrocardiogram ............................................................................................ 38 
12.3.4.4 Vital Signs ........................................................................................................ 39 
12.3.4.5 Physical Examination ....................................................................................... 39 
12.3.4.6 Other Safety Analysis ...................................................................................... 39 
12.3.5 
Other Analysis ........................................................................................................ 39 


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12.3.6 
Interim and Independent Data Monitoring Committee Analyses ........................... 39 
12.4 Clinical Pharmacology Analysis .................................................................................... 39 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 39 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 39 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 40 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 40 
13.1.1 
Adverse Events ....................................................................................................... 40 
13.1.1.1 Definition of an Adverse Event........................................................................ 40 
13.1.1.2 Clinically Significant Assessments .................................................................. 40 
13.1.1.3 Documentation of Adverse Events................................................................... 40 
13.1.1.4 Adverse Event Severity .................................................................................... 41 
13.1.1.5 Adverse Event Causality .................................................................................. 41 
13.1.1.6 Study Drug Action Taken ................................................................................ 42 
13.1.1.7 Adverse Event Outcome .................................................................................. 42 
13.1.1.8 Treatment Given............................................................................................... 43 
13.1.2 
Serious Adverse Events .......................................................................................... 43 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 43 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 44 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 44 
13.2 Administrative Requirements ......................................................................................... 45 
13.2.1 
Ethical Considerations ............................................................................................ 45 
13.2.2 
Subject Information and Informed Consent ........................................................... 45 
13.2.3 
Investigator Compliance ......................................................................................... 45 
13.2.4 
Access to Records ................................................................................................... 45 
13.2.5 
Subject Privacy ....................................................................................................... 45 
13.2.6 
Record Retention .................................................................................................... 46 
13.2.7 
Study Termination .................................................................................................. 46 
13.2.8 
End of Study ........................................................................................................... 46 
13.3 Data Quality Assurance .................................................................................................. 46 
13.4 Monitoring ...................................................................................................................... 47 
13.5 Electronic Data Capture ................................................................................................. 47 
13.6 Publications and Clinical Study Report .......................................................................... 47 
13.6.2 
Clinical Study Report ............................................................................................. 48 
14 References ............................................................................................................................. 49 
15 Protocol Signature Pages .................................................................................................... 50 
15.1 Sponsor Signature Page .................................................................................................. 50 
15.2 Investigator Signature Page ............................................................................................ 51 
 


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List of Tables 
Table 2-1 
VX-150 Doses by Treatment Arm .......................................................................... 4 
Table 3-1 
Study VX18-150-104: Screening Period Prior to Surgery ..................................... 6 
Table 3-2 
Study VX18-150-104: Day -1, Treatment Period and Safety Follow-up ............... 7 
Table 9-1 
VX-150 Doses by Treatment Arm ........................................................................ 18 
Table 9-2 
Study Restrictions ................................................................................................. 22 
Table 10-1 
Study Drug ............................................................................................................ 26 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 29 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 31 
Table 11-3 
Acceptable Methods of Contraception.................................................................. 34 
Table 13-1 
Grading of AE Severity ........................................................................................ 41 
Table 13-2 
Classifications for AE Causality ........................................................................... 42 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 42 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 43 
List of Figures 
Figure 9-1 
VX18-150-104 Study Design ............................................................................... 19 
 


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List of Abbreviations 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ANCOVA 
analysis of covariance 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
CD 
compact disc 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
Emax 
maximum effect attributable to the drug 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GPS 
Global Patient Safety 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV-1 and HIV-2 Abs 
antibodies against human immunodeficiency viruses 1 and 2 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
 
 
IRB 
institutional review board 
IXRS 
interactive web or voice response system 
max 
maximum value 
MCP-Mod 
multiple comparison procedures with modeling techniques 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum value 
n 
number of subjects 
Nav 
voltage-gated sodium channels 
NPRS 
Numeric Pain Rating Scale 
PC 
publication committee 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PI 
Principal Investigator 
PK 
pharmacokinetic, pharmacokinetics 
POC 
proof-of-concept 


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Abbreviation 
Definition 
prn 
as needed 
PT 
Preferred Term 
q12h 
every 12 hours 
q2h 
every 2 hours 
q4h 
every 4 hours 
qd 
daily 
QTcF 
QT interval corrected by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
steering committee 
SD 
standard deviation 
SE 
standard error 
SET 
Study Execution Team 
SPID24 
sum of the pain intensity difference 0 to 24 hours 
SPID48 
sum of the pain intensity difference 0 to 48 hours 
SUSAR 
suspected, unexpected, serious adverse reaction 
TEAE 
treatment-emergent adverse event 
 
 
ULN 
upper limit of normal 
US 
United States 
VRS 
Verbal Categorical Rating Scale 
WHO-DD 
World Health Organization-Drug Dictionary  
WOMAC 
Western Ontario and McMaster Universities 
 
 


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5 
INTRODUCTION 
5.1 
Background 
Pain is one of the most common symptoms for which patients seek medical attention. It is a 
protective mechanism designed to prevent tissue injury. When pain persists beyond its 
usefulness, it becomes pathological and can prove debilitating. Current pain therapies suffer from 
poor efficacy and a high risk of adverse events (AEs). For example, lidocaine (a nonselective 
sodium channel blocker) may effectively reduce pain, but its utility is limited because of 
prominent side effects when given at dose levels required for pain relief.1 According to 2016 
estimates, more than 42,000 deaths were attributable to opioids in the US, and in Europe, more 
than 80% of fatal drug overdoses involve opioids.2, 3 The limited treatment options for pain, 
combined with a growing awareness of the risks of the current standards of care, underscore the 
need for new pain management therapies. 
Voltage-gated sodium channels (Nav) play a critical role in pain signaling based on both 
nonclinical and clinical evidence. Evaluation of the role these channels play in normal 
physiology and the pathological states arising from mutations in sodium channel genes and 
animal models, as well as the pharmacology of known sodium channel modulating agents, all 
point to the critical role of Navs in pain sensation.4-6 The Nav1.8 channel is primarily restricted to 
peripheral neurons that sense pain (e.g., dorsal root ganglia) and is known to mediate pain 
sensation and chronic pain. For example, Nav1.8 gain-of-function mutations are thought to 
directly cause chronic pain in patients with painful small fiber neuropathy.7-9 This channel has 
been identified as a target for analgesia10 and selective Nav1.8 inhibitors, which have the 
potential to treat pain indications where the primary mechanism for pain is nociceptor 
hyperexcitability.  
VX-150, an orally bioavailable prodrug that rapidly converts in vivo to the active moiety 
VRT-1207355, is being developed for the treatment of pain. VRT-1207355 is a Nav1.8 blocker 
that is highly selective for Nav1.8 relative to the other sodium channel subtypes. In vivo safety 
studies conducted with either VX-150 or VRT-1207355 have not identified target organs of 
toxicity. 
5.2 
Study Rationale 
To date, 5 Phase 1 clinical studies and 2 Phase 2 proof-of-concept (POC) studies have been 
completed with VX-150. This Phase 2 dose-ranging study was designed to help inform dose 
selection for Phase 3 studies in acute pain.  
Data from clinical and nonclinical studies of VX-150 and the current unmet medical need for 
new treatments for acute pain support clinical development of VX-150. Further details of the 
VX-150 development program are available in the VX-150 Investigator’s Brochure.11  
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the dose-response relationship of VX-150 in treating acute pain following 
bunionectomy 


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6.2 
Secondary Objectives 
• To evaluate the safety and tolerability of VX-150 
• To evaluate the pharmacokinetics (PK) of VRT-1207355 and the metabolite VRT-1268114 
(M5) 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Time-weighted sum of the pain intensity difference between VX-150 versus placebo as recorded 
on a Numeric Pain Rating Scale (NPRS) 0 to 24 hours (SPID24) after the first dose 
7.2 
Secondary Endpoints 
• Time-weighted sum of the pain intensity difference between VX-150 versus placebo as 
recorded on an NPRS 0 to 48 hours (SPID48) after the first dose 
• Proportions of subjects with at least 30%, 50%, or 70% reduction in NPRS at 24 hours after 
the first dose of VX-150 versus placebo 
• Time to onset of “confirmed perceptible pain relief” and “meaningful pain relief” after the 
first dose of VX-150 versus placebo 
• Plasma PK parameters of VRT-1207355 and the metabolite M5 
• Safety and tolerability based on the incidence and type of adverse events (AEs), changes 
from baseline in clinically significant laboratory test results, and vital signs at designated 
visits 
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
8.1 
Inclusion Criteria 
Before surgery: 
1. Subject will sign and date an informed consent form (ICF) 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures  
3. Body mass index (BMI) of 18.0 to 38.0 kg/m2, inclusive 


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4. Subjects (male and female) will be between the ages of 18 and 65 years, inclusive 
5. Be scheduled to undergo a primary unilateral first metatarsal bunionectomy repair, without 
collateral procedures, under regional anesthesia (Mayo and popliteal sciatic block) not to 
include base wedge procedure 
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. History in the past 10 years of malignancy, 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) 
2. 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 
3. History of abnormal laboratory results ≥2.5 × upper limit of normal (ULN) indicative of any 
significant medical disease that in the opinion of the investigator would preclude the 
subject’s participation in the study 
4. History of peripheral neuropathy 
5. A known or clinically suspected infection with human immunodeficiency virus or hepatitis B 
or C viruses 
6. Prior medical history of bunionectomy or other foot surgery on the index foot; or 
bunionectomy on the opposite foot as part of this study 
7. Any prior surgery within 1 month before the first dose of study drug unless approved by the 
medical monitor 
8. Other serious, acute, or chronic medical or psychiatric illness that, in the judgment of the 
investigator, could compromise subject safety, limit the subject’s ability to complete the 
study, and/or compromise the objectives of the study (e.g., peripheral arterial insufficiency, 
peripheral edema) 
9. History of peptic ulcer disease, or intolerance or unwillingness to receive ibuprofen 
10. For female subjects: Pregnant, nursing, or planning to become pregnant during the study or 
within 90 days after the last study drug dose  
11. For male subjects: Male subjects with a female partner who is pregnant, nursing, or planning 
to become pregnant during the study or within 90 days after the last study drug dose 
12. Participated in another investigational study within 30 days of the first dose of study drug 


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13. History of drug or alcohol dependence in the past 3 years, or a positive test for drugs of abuse 
• A positive drug screen for a known prescribed concomitant medication that is not 
otherwise exclusionary (e.g., benzodiazepines) will not disqualify subjects; however, 
marijuana will not be allowed.  
14. Subject, or close relative of the subject, is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study at that site 
15. Use of restricted medication or food within the specified duration before the first dose of 
study drug, as defined in Section 9.4 
16. Participation in a previous study investigating VX-150 
After surgery: 
17.  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 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 2B randomized, double-blind, placebo-controlled, dose ranging, 6-arm, 
parallel-design study. Subjects will receive a primary unilateral first metatarsal bunionectomy 
repair on Day -1 (Figure 9-1). A continuous popliteal sciatic block infusion (0.2% ropivacaine) 
will be started after surgery and will be removed between 3AM and 5AM on Day 1. After 
removal of the popliteal sciatic block, a subject can be randomized once the subject requests the 
first dose of study drug for pain relief, and the subject’s pain is ≥4 on the NPRS and is moderate 
or severe on the VRS. If a subject does not meet the NPRS and VRS criteria within 9 hours of 
removal of the popliteal sciatic block, the subject will not be eligible to enroll in the study. 
A total of approximately 242 subjects will be randomized 2:2:2:2:1:2 to 6 treatment arms, 
evaluating a range of 5 VX-150 dose levels as shown in Table 9-1. 
Table 9-1 
VX-150 Doses by Treatment Arm 
Treatment 
Dose Level 
Dose 
Number of Subjects 
VX-150 
1 (highest) 
First dose 1500 mg, then 750 mg q12h 
44 
 
2 
1000 mg qd 
44 
 
3 
500 mg q12h 
44 
 
4 
First dose 500 mg, then 250 mg q12h 
44 
 
5 (lowest) 
250 mg qd 
22 
Placebo 
 
 
44 
q12h: every 12 hours; qd: daily 
Note: q12h dosing will be through 36 hours after the first dose of study drug throughout the protocol. 
Randomization will be stratified by site and sex. To maintain the blind, all subjects will receive 
the same number of capsules in a double-dummy design. 


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Subjects will report their pain on the NPRS at scheduled time points (Table 3-2) 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. 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. However, subjects may 
receive rescue medication at any time after the first dose of study drug per their request. The 
rescue medication will be ibuprofen (400 mg [oral] every 4 hours [q4h] as needed [prn]).  
Figure 9-1 
VX18-150-104 Study Design 
 
CRU: clinical research unit; NPRS: Numeric Pain Rating Scale; VRS: Verbal Categorical Rating Scale 
Notes: After removal of the popliteal sciatic block, a subject can be randomized once the subject requests the first 
dose of study drug for pain relief, and the subject’s pain is ≥4 on the NPRS and is moderate or severe on the 
VRS. VX-150 dose levels (Dose Levels 1 [highest], 2, 3, 4, and 5 [lowest]) are shown in Table 9-1. To maintain 
the blind, all subjects will receive the same number of capsules. 
 
9.1.1 
Screening 
Screening Visit assessments required before the day of surgery are listed in Table 3-1. 
Screening will occur within 28 days before administration of study drug; this includes the 
screening period before surgery and the day of surgery (Day -1). The investigator (or an 
appropriate authorized designee at the study site) will obtain informed consent from each subject.  
To prepare for study participation, subjects will be instructed on the study restrictions 
(Section 9.4). 
9.1.1.1 
Repetition of Screening Assessments 
Repetition of any screening assessment that did not meet eligibility criteria is not permitted, 
unless there is clear evidence of a laboratory error (e.g., hemolysis of sample). 


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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 study drug dose that was properly 
evaluated and which resolved fully 
• Subjects who met all eligibility criteria but were not able to obtain required documentation 
within the allotted screening window 
• Subjects who met all eligibility criteria but transiently (for personal reasons) are unable to 
commit to all study procedures 
Any subject who is rescreened for any of the exceptions listed above may have the screening 
window extended by 2 weeks before needing to undergo any rescreening assessments. If more 
than 35 days have elapsed from screening before first dose of study drug, all screening 
assessments need to be repeated. 
9.1.2 
Treatment Period 
Treatment Period assessments are listed in Table 3-2. The study will be conducted as described 
in Section 9.1. Dosing details are given 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. 
9.1.3 
Follow-up 
Subjects will have a Safety Follow-up Phone Interview 7 (± 2) days after the last study drug dose 
for the purpose of collecting information on AEs, medications, and treatments and procedures. A 
visit will only be required if a clinical finding during the Treatment Period requires follow-up. 
9.1.4 
Early Discontinuation 
Subjects who prematurely discontinue study drug dosing will remain under observation for at 
least 12 hours after the last dose of study drug, after which point they can be discharged from the 
CRU. If a subject has any clinically significant, study-related abnormalities, the medical monitor 
(or authorized designee) will be notified, and the subject will be asked to remain in the CRU 
until such abnormalities resolve. If the subject is unable or unwilling to remain in the CRU, the 
medical monitor (or authorized designee) will be notified, and the investigator will make every 
effort to arrange follow-up evaluations at appropriate intervals to document the course of the 
abnormalities. See Section 9.8 for additional details on removal of subjects. 
Subjects who prematurely discontinue study drug dosing will complete the Safety Follow-up 
Phone Interview 7 (± 2) days after the last study drug dose for the purpose of collecting 
information on AEs, medications, and treatments and procedures. A visit will only be required if 
a clinical finding during the Treatment Period requires follow-up. 


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9.2 
Method of Assigning Subjects to Treatment Groups 
An interactive 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.  
9.3 
Rationale for Study Elements 
9.3.1 
Study Design 
This is a Phase 2B randomized, double-blind, placebo-controlled, dose-ranging, parallel-group 
study to evaluate the effect of VX-150 on acute surgical pain. 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 range of VX-150 doses will be evaluated to help inform 
dose selection for Phase 3 studies. A parallel design is considered most appropriate given the 
acute nature of bunionectomy surgery.  
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 
Five dose levels of VX-150 (Dose Levels 1 [highest], 2, 3, 4, and 5 [lowest]) will be evaluated as 
shown in Table 9-1. The highest dose level (Dose Level 1 [first dose 1500 mg, then 750 mg 
every 12 hours (q12h)]) will not exceed a maximum dose of 2250 mg per day. The maximum 
dose has been selected on the basis of favorable safety and VRT-1207355 PK results after oral 
dosing with VX-150 in 
 
VX16-150-103 (Study 103). Multiple oral doses up to 1750 mg qd VX-150 for 14 days have 
been evaluated and found to be safe and well tolerated. Additionally, the treatment duration is 
the same as in Study 103. 
The highest dose level (Dose Level 1) to be tested (2250 mg per day; first dose 1500 mg 
followed by doses of 750 mg q12h) was evaluated in Study 103 in subjects with acute pain 
following bunionectomy. After administration of the first dose of VX-150 on Day 1 and Day 2, 
the mean VRT-1207355 maximum observed concentration (Cmax) of 4.95 µg/mL (Day 1) and 
4.92 µg/mL (Day 2) exceeded the concentration resulting in 50% of the maximum inhibition 
(IC50) for inhibition of Nav1.8. The maximum concentrations for VRT-1207355 were reached 
approximately 5.58 hours after the first dose on Day 1 and 4.03 hours after the first dose on 
Day 2. A statistically significant treatment effect was observed at 24 hours following the first and 
second doses, favoring VX-150 compared to placebo. VX-150 was generally well tolerated in 
these subjects without any significant safety concerns. 
9.3.3 
Rationale for Study Assessments 
11-point (0 to 10) Numeric Pain Rating Scale: NPRSs are frequently used in bunionectomy 
studies and are recognized by the FDA as a valid pain intensity measure.12 


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4-point Verbal Categorical Rating Scale: A VRS (none, mild, moderate, or severe) is included 
as part of the pain threshold inclusion criterion to ensure that all subjects are experiencing 
moderate or severe pain at baseline. Moderate or severe pain at baseline ensures subjects have 
sufficient pain to determine if the drug is effective. 
Double-stopwatch assessment: The double-stopwatch assessment is a standardized assessment 
for determining the onset of pain relief.13, 14 The stopwatches are started at the time of the first 
dose. Subjects are told to stop the first watch when they first feel “perceptible pain relief,” and to 
stop the second watch when they first feel “meaningful pain relief.” 
9.4 
Study Restrictions 
Study restrictions are summarized in Table 9-2. 
 
 
 
 Study 
restrictions related to analgesic medications are described in Section 9.4.1. 
A non-exhaustive list of study restrictions will be provided in the Study Reference Manual. 
Table 9-2 
Study Restrictions 
Restricted 
Medication/Food/Activitya 
Timing of Restriction 
From (Minimum) 
To 
Other investigational drugs or 
devices 
30 days before first study drug dose, 
5 half-lives before first study drug 
dose, or time determined by local 
requirements; whichever is longer 
Completion of Safety Follow-up  
Analgesic medications 
Starting 2 days before admission to 
the CRU, analgesic medication use 
will follow the guidelines outlined in 
Section 9.4.1 
Until discharge from CRU 
Dietary supplements 
 
 vitamin E 
supplements 
24 hours before first study drug dose 
Until discharge from CRU 
Grapefruit or grapefruit juice, 
pomelos, star fruit; Seville 
oranges 
7 days before first study drug dose 
Until last PK sample is taken 
Apple or orange juice, vegetables 
from the mustard green family 
(e.g., kale, broccoli, watercress, 
collard greens, kohlrabi, Brussels 
sprouts, mustard), and charbroiled 
meats 
24 hours before first study drug dose 
Until last PK sample is taken 


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Table 9-2 
Study Restrictions 
Restricted 
Medication/Food/Activitya 
Timing of Restriction 
From (Minimum) 
To 
Alcohol 
24 hours before admission to the CRU 
Until discharge from CRU 
Strenuous exercise (e.g., heavy 
lifting, weight training, and 
aerobics) 
48 hours before first clinical 
laboratory testing  
Completion of Safety Follow-up  
CRU: clinical research unit; PK: pharmacokinetics 
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 are not allowed from 2 days before 
admission on Day -1 through discharge on Day 3. 
• Perioperative pain management will follow the standard of care, becoming progressively 
more conservative before removal of the popliteal sciatic block: 
o Preoperatively, 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). 
o A continuous popliteal sciatic block infusion (0.2% ropivacaine) will be started after 
surgery and will be removed between 3AM and 5AM on Day 1. 
o After surgery and before removal of the popliteal sciatic block: 
− The use of ice packs is required until removal of the popliteal sciatic block. 
− IV ketorolac can be administered q6h as needed until 6 hours before removal 
of the popliteal sciatic block for subjects with NPRS score of 4 through 6 after 
surgery. 
− Morphine sulfate 2- to 4-mg IV dose can be administered every 2 hours (q2h) 
as needed until 1.5 hours before removal of the popliteal sciatic block for 
subjects with NPRS score of 7 or above after surgery. 
− Bolus ropivacaine can be used prn until removal of the popliteal sciatic block. 
• No pain treatments are allowed between removal of the popliteal sciatic block and the first 
dose of study drug 
• Rescue medication: 
o 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 


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medication unless their NPRS is ≥4. However, subjects may receive rescue 
medication at any time after the first dose of study drug per their request.  
o The rescue medication will be ibuprofen (400 mg [oral] q4h prn).  
o A record will be kept of all rescue medication use, and an unscheduled NPRS 
assessment will be completed immediately before each administration of rescue 
medication. 
9.4.2 
Additional Dietary Restrictions 
• Subjects will abstain from all food and drink (except water) at least 4 hours before the 
screening serum chemistry assessment.  
• On Day 1, subjects will be on a clear liquid diet until 11 hours after removal of the popliteal 
sciatic block (i.e., 2 hours after the end of the randomization window). Doses administered 
after the end of the clear liquid diet period can be administered without regard to meal 
timings. 
9.5 
Prior and Concomitant Medications 
• Subjects will abstain from all concomitant medications as described in Exclusion 
Criterion 14 and Table 9-2. 
• All opioid medications taken within 12 months of Screening Visit will be recorded with 
indication, route of administration, and start and stop dates of administration. 
• 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. 
• A female subject of childbearing potential using hormonal contraceptives does not need to 
stop taking hormonal contraceptives; however, they are not considered an approved form of 
contraception (Section 11.5.5.1). 
9.6 
Administration 
Study drug will be administered as follows: 
• Doses for the 5 VX-150 treatment arms are shown in Table 9-1. The total maximum daily 
dose will not exceed 2250 mg (1500 mg loading dose followed by doses of 750 mg q12h). 
• VX-150 arms will receive a combination of VX-150 and VX-150 placebo capsules. 
• Placebo arm will receive only VX-150 placebo.  
• To maintain the blind, all subjects will receive the same number of capsules. All subjects will 
receive 6 capsules for the first dose and 4 capsules for the remainder of the dosing period. 
Additional details on dispensing will be included in the Pharmacy Manual. 


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• Study drug will be administered as described above, with the final dose of VX-150 or 
VX-150 placebo given 36 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 the drug before swallowing. 
• Study drug must be administered following the food restrictions outlined in Section 9.4.2. 
9.7 
Dose Modification for Toxicity 
If any unacceptable toxicity arises, individual subjects will discontinue dosing (Section 9.1.4). 
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 or participate in a scheduled phone call, 
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 Phone Interview, if 
applicable (see Section 9.1.4), and follow up with the subject regarding any unresolved AEs. 
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study, the study data and samples collected will remain part of the study. A subject will 
not be able to request the withdrawal of his/her information from the study data. A subject may 
request destruction of the samples collected from him/her during the study as long as those 
samples can be identified as his/her samples. 
9.9 
Replacement of Subjects 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period(s) may be replaced at Vertex’s discretion. 
10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
Capsules 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. 


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10.2 
Packaging and Labeling 
Vertex will supply the 250-mg VX-150 capsules and matching placebos. Study drug labeling 
will be in compliance with applicable local and national regulations. Additional details regarding 
packaging, labeling, and dispensing for VX-150 will be included 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. 
Table 10-1 lists the storage conditions for the capsules. 
Table 10-1 
Study Drug 
Drug Name 
Dosing Form/Route 
Dosage 
How Supplied 
VX-150  
Capsule/Oral 
≤2250 mg per day 
Supplied as 250-mg capsules  
VX-150 placebo 
Capsule/Oral 
None 
Supplied as capsule 
 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received and (2) study drug dispensed to the subjects. These materials 
will be retained at the site according to instructions provided by Vertex or its designee. The study 
monitor will review study drug records and inventory throughout the study. If a site uses a 
site-specific Drug Accountability System and/or process, including processes associated with the 
destruction of returned materials, the process must be documented and approved by Vertex. The 
study monitor must review the drug accountability documentation on a regular basis. The study 
monitor will promptly communicate to Vertex any discrepancies he/she is unable to resolve with 
the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials until the study monitor has 
performed drug accountability. The investigator will ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any special 
instructions provided by Vertex. Destruction will be adequately documented. 
10.6 
Compliance 
For study drug doses administered during the inpatient periods, 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. 


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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 the subject 
in the event of a life-threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of the subject 
and the fetus in the event of a pregnancy 
• Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy serious 
adverse event (SAE) processing and reporting regulations 
• External vendor (unblinded) statistician preparing the final (production) randomization list 
who is not part of the study team 
• Vertex IXRS Management for IXRS oversight and system administration 
• Vertex Clinical Supply Chain 
• The bioanalytical contract research organization (CRO) laboratory/vendor personnel 
managed by Vertex Bioanalysis 
• The Vertex bioanalytical personnel responsible for reviewing raw data from the bioanalytical 
CRO, who is not a member of the Study Execution Team (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 Vertex Modeling & Simulations and Biomarker scientist may be unblinded to individual 
subject PK data for conducting PK/pharmacodynamic (PD) analyses. In addition, a Vertex 
clinical pharmacologist will be partially unblinded to help in management of the PK workspace 
and ensure that only the blinded PK dataset is being provided for preliminary analysis. 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 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 a 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 and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for 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 without having successfully reached and discussed the situation with the medical 


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monitor. In case of emergency, the investigator will have the final decision and unilateral right 
for unblinding. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center 
 will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
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 the sponsor (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 concerns, unblind 
individual subjects at any time.  
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1 and Table 3-2. 
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 
For the evaluation of plasma concentrations of VRT-1207355 and VRT-1268114, blood samples 
will be collected as shown in Table 3-2. 
These samples may also be used for evaluations of rescue medication, VX-150, metabolites of 
VRT-1207355, analyses that provide information on the metabolic pathways used by or affected 
by VX-150 and VRT-1207355, and further evaluation of the bioanalytical method. 
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 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 the taking of each PK blood sample; and date and 
time of the last meal taken before each dose. 


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Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Sampling Time 
Time From Scheduled Sampling Allowed 
Predose on Day 1 
Any time before first study drug dose on Day 1 
Predose on Day 2 
-15 minutes 
From 1 up to 12 hours after study drug dosing 
±30 minutes 
 
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 provided in the PK Sample Handling 
Guidelines. The shipment address and assay laboratory contact information will be provided to 
the investigational site before initiation of the study. 
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. 
11.4 
Efficacy 
Pain scales: After removal of the popliteal sciatic block, a subject can be randomized once the 
subject requests the first dose of study drug for pain relief, and the subject’s pain is ≥4 on the 
NPRS and is moderate or severe on the VRS. If a subject does not meet the NPRS and VRS 
criteria within 9 hours of removal of the popliteal sciatic block, the subject will not be eligible 
for the study. 
Subjects will report their pain on the NPRS at scheduled time points (Table 3-2) through 
48 hours after the first dose of study drug. In addition, pain intensity will be recorded on the 
NPRS scale immediately before each administration of rescue medication. 
When NPRS assessments coincide with collection of PK blood samples, the NPRS assessment 
will be performed first. 


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Double-stopwatch assessment: At the time of first dose, 2 stopwatches will be started: 1 labeled 
“perceptible pain relief” and the other labeled “meaningful pain relief.” Subjects will stop the 
“perceptible pain relief” stopwatch when/if they feel any pain relief at all and stop the 
“meaningful pain relief” stopwatch when/if they 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.  
11.5 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, and physical examinations (PEs). 
11.5.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP Guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF completion 
guidelines for investigators as well as training will be provided. 
11.5.2 
Clinical Laboratory Assessments 
At the Screening Visit, blood specimens will be collected for safety laboratory tests following at 
least a 4-hour fast. Fasting is not required at other time points.  
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table 3-1 and Table 3-2. Laboratory test results that are abnormal and considered clinically 
significant will be reported as AEs (see Section 13.1). 
The safety laboratory test panels are shown in Table 11-2. 


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Table 11-2 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate aminotransferase 
(=SGOT)  
Alanine aminotransferase (=SGPT)  
Amylase  
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Urate  
Hemoglobin  
Erythrocytes 
Mean corpuscular volume 
Platelets  
Leukocytes  
Differential (absolute and percent): 
Eosinophils 
Basophils  
Neutrophils 
Lymphocytes 
Monocytes  
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
Urobilinogen  
Urine protein  
pH 
Urine blood  
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine glucose  
Note: Screening Visit blood draws will be done after a minimum 4-hour fast. All subsequent blood draws do not 
require fasting.  
a 
If urinalysis results are positive for protein or blood, microscopic examination of urine will be performed and 
results provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
b 
If blood urea nitrogen cannot be collected, urea may be substituted. 
Clinical laboratory assessments from screening will 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: 
Serum follicle-stimulating hormone: Serum follicle-stimulating hormone will be tested at 
screening for female subjects who are suspected to be postmenopausal. For a subject to be 
considered of non-childbearing potential, the serum follicle-stimulating hormone levels will be 
within the laboratories’ range for postmenopausal females. 
Pregnancy testing: All female subjects must have a Screening serum pregnancy test within 
7 days before Day 1. Female subjects of childbearing potential (as defined in Section 11.5.5.1), 
must also have a Day -1 urine pregnancy test. Both the pregnancy test at Screening and Day -1 
must be negative to receive study drug.  
Drug and alcohol screening (Screening Visit and Day -1): Opiates, methadone, cannabinoids, 
cocaine, amphetamines/methamphetamines, barbiturates, and benzodiazepines will be assessed 
by a urine test. Subjects may also undergo random urine drug screening and alcohol testing if 
deemed appropriate by the investigator. The drug test at Screening and Day -1 must be negative 


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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, marijuana will not be allowed. 
Additional evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
With the exception of the Day -1 drug and alcohol tests and the pregnancy tests, only laboratory 
tests done in the central laboratory may be used. Local laboratories may be used at the discretion 
of the local investigator for management of urgent medical issues. If a local laboratory test value 
is found to be abnormal and clinically significant, it will be verified by the central laboratory as 
soon as possible after the investigator becomes aware of the abnormal result. If it is not possible 
to send a timely specimen to the central laboratory (e.g., the subject was hospitalized elsewhere), 
the investigator may base the assessment of an AE on the local laboratory value. 
11.5.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at screening and select 
study visits (Table 3-1 and Table 3-2). At other visits, symptom-directed PEs and 
symptom-directed vital signs assessments can be performed at the discretion of the investigator 
or healthcare provider. 
A PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, nose, and 
throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in PEs will be reported as 
AEs. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. Vital signs will be assessed in the supine position after the subject has been 
instructed to rest for at least 5 minutes. Vital signs will be performed before blood draws or ECG 
assessments. 
11.5.4 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout (Table 3-1 and 
Table 3-2). 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 Phone Interview will be recorded as AEs. 
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 


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values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. A subject with a 
QTcF value above the threshold value will discontinue dosing. 
11.5.5 
Contraception and Pregnancy 
11.5.5.1 
Contraception 
At this stage in the development of VX-150, study participation requires a commitment from the 
subject that he/she and subject's respective partner use 1 acceptable method of birth control 
listed in Table 11-3 from the Screening Visit through 90 days after the last dose of study drug. 
Male subjects must also not donate sperm from the time of first study drug dose through 90 days 
after the last dose of study drug. Additional contraception requirements may need to be followed 
according to local regulations and/or requirements. 
The contraception requirement for the couple is waived for the following: 
• True abstinence for the subject, when this is consistent with the preferred and usual lifestyle 
of the subject. True abstinence must be practiced from the Screening Visit through 90 days 
after the last dose of study drug. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception.  
• If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented through 
examination of a semen specimen. 
• If the female is of non-childbearing potential. To be considered of non-childbearing potential, 
the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 2 years and a serum follicle-stimulating 
hormone level within the laboratory's reference range for postmenopausal females 
o Documented bilateral oophorectomy and/or hysterectomy 
• Same sex relationships. 
Unique situations that may not fall within the above specifications may be discussed with the 
sponsor’s medical monitor or designee on an individual basis. 


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Table 11-3 
Acceptable Methods of Contraception 
Contraceptive Method 
Male Subjects and  
Their Female Partners 
Female Subjects and  
Their Male Partners 
Documented vasectomy (with a 
negative sperm postvasectomy 
semen analysis) at least 6 months 
before the study drug dose  
Yes 
Yes 
Condom with spermicide (either as a 
single product if commercially 
available and/or allowed according 
to local regulations; otherwise 
condom and spermicide as separate 
products). 
Yesa 
Yesa 
Documented bilateral tubal ligation 
performed at least 6 months before 
the first dose of study drug 
Yes 
Yes 
Continuous use of an intrauterine 
device (nonhormone-releasing) for 
at least 90 days 
Yes 
Yes 
Hormonal contraceptives, if 
successfully used for at least 60 days 
Yes 
Nob 
a 
Female condom cannot be used with male condom due to risk of tearing. 
b 
A female subject of childbearing potential using hormonal contraceptives does not need to stop taking 
hormonal contraceptives; however, they are not considered an approved form of contraception. 
11.5.5.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and up to 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, study drug will be permanently discontinued immediately. The investigator will notify the 
medical monitor and Vertex GPS within 24 hours of the site's knowledge of the subject's (or 
partner's) pregnancy using the Pregnancy Information Collection Form. 
If confirmed to be on active drug, the subject or partner will be followed for safety (adverse 
events) until the end of the pregnancy and similarly, the infant will be followed for 1 year after 
the birth, provided informed consent is obtained. A separate ICF will be provided to explain 
these follow-up activities. Pregnancy itself does not constitute an AE. 
12 
STATISTICAL AND ANALYTICAL PLANS 
12.1 
Sample Size and Power 
The sample size calculation is based on the primary analysis of the primary efficacy endpoint. 
The primary efficacy endpoint is the time-weighted sum of the pain intensity difference 0 to 
24 hours after the first dose (SPID24). The primary analysis of this endpoint is to detect if there 
is a significant dose-response relationship across VX-150 dose groups and placebo using the 
MCP-Mod (multiple comparison procedures with modeling techniques). Under MCP-Mod, a 


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pre-specified candidate set of 4 dose-response models (Linear, Emax, Logistic, and Sigmoid Emax) 
is proposed. 
Assuming the maximum effect size compared to placebo is 0.7, 40 evaluable subjects in the 
placebo, VX-150 Dose Level 1 (highest), 2, 3, and 4 groups, and 20 evaluable subjects in 
VX-150 Dose Level 5 (lowest) group would provide approximately at least 88% power to detect 
a dose-response relationship from the candidate set with a 5% level of significance. In addition, 
40 evaluable subjects per treatment group can provide at least 85% power to detect an effect size 
of 0.7 compared to placebo. In order to allow for withdrawal of up to 10% of randomized 
subjects, the study will enroll and randomize approximately 242 subjects in total. 
12.2 
Analysis Sets 
Assignment of subjects to analysis sets will be performed before the clinical data lock for the 
study. 
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. 
The Full Analysis Set (FAS) is defined as all randomized subjects who have received at least 
1 dose of study drug. The FAS is to be used in efficacy analyses in which subjects will be 
analyzed according to their randomized treatment group and not to the treatment they actually 
received. 
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 and not according to their randomized treatment group. 
The PK Set is defined as all subjects who have received at least 1 dose of study drug and for 
whom the primary PK data are considered to be sufficient and interpretable. 
12.3 
Statistical Analysis 
The primary objective of this study is to evaluate the dose-response relationship of VX-150 in 
treating acute pain following bunionectomy. 
This section presents a summary of the planned statistical analyses of efficacy and safety for this 
study. The Vertex Biometrics department or a designated CRO will analyze the data derived 
from this study. Statistical Analysis System Version 9.4 or higher and R Version 3.5.0 or higher 
will be used to generate all statistical outputs (tables, figures, listings, and data sets). 
Statistical analysis and presentation details will be provided in the Statistical Analysis Plan 
(SAP) for the study. 
12.3.1 
General Considerations 
All individual subject data for all individual subjects randomized or exposed to study drug will 
be presented in data listings. Continuous data 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 data will be summarized using counts and percentages. 


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Baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the initial administration of study 
drug. 
12.3.2 
Background Characteristics 
12.3.2.1 
Subject Disposition 
The disposition summary will be based on the All Subjects Set. 
The number and percentage of subjects in each of the following disposition categories will be 
summarized based on the FAS: completed treatment, prematurely discontinued the treatment and 
the reason for discontinuation, completed study, and prematurely discontinued study, with a 
breakdown of the reasons for discontinuation. 
12.3.2.2 
Demographics and Baseline Characteristics 
The following demographics and baseline characteristics will be summarized by treatment group 
based on the FAS: sex, age, race, ethnicity, weight, height, BMI, and pain intensity. 
No statistical tests will be carried out to evaluate any baseline imbalance between treatment 
groups. 
12.3.2.3 
Prior and Concomitant Medications 
Medications taken 14 days before the Screening Visit and up to the Safety Follow-up Phone 
Interview will be summarized by Preferred Name using the World Health Organization-Drug 
Dictionary (WHO-DD) for the FAS as frequency tables in 2 parts: 
Prior medication: Medication that started before the first dose of study drug, regardless of when 
dosing of the medication ended. 
Concomitant medication: Medication received at or after the first dose of study drug, 
medication that was received before initial dosing and continued after initial dosing of study 
drug, or medication with missing stop date. 
Medication that started before the first dose of study drug and continued after the first dose of 
study drug will be summarized as prior medication and separately as concomitant medication. 
Medications with a missing start date will be considered to have a start date before the first dose 
of study drug. 
12.3.2.4 
Study Drug Exposure and Compliance 
Study drug will be administered to the subjects by site personnel at time points specified in 
Table 3-2 and as described in Section 9.6. All data collected during dispensation of study drug 
(i.e., time of intake and number of capsules taken) will be presented in data listings only. 
12.3.3 
Efficacy Analysis 
Evaluation of the dose-response of the efficacy of VX-150 is the primary objective of this study. 
All efficacy endpoints will be analyzed based on the FAS. 
12.3.3.1 
Analysis of Primary Variable 
The primary efficacy endpoint is the time-weighted sum of the pain intensity difference between 
VX-150 versus placebo as recorded on a Numeric Pain Rating Scale (NPRS) 0 to 24 hours 
(SPID24) after the first dose. The primary efficacy analysis will be using the MCP-Mod 


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approach to detect the dose-response relationship from a candidate set of 4 dose-response models 
(Linear, Emax, Logistic, and Sigmoid Emax). Two-sided P value for each dose-response model will 
be provided.  
Both MCP-Mod approach 
 in SPID24 between VX-150 and placebo 
will be based on an analysis of covariance (ANCOVA) model. The model will include the time-
weighted sum of the pain intensity difference 0 to 24 hours (SPID24) after the first dose as the 
dependent variable, and treatment as a fixed effect, with adjustment for stratification factors, i.e., 
site and sex, and baseline pain as a covariate. 
 
Pain intensity scores that were collected within 4 hours after a dose of rescue medication will be 
taken as missing and will be imputed using the pre-rescue numerical pain rating scale. Missing 
values due to early withdrawal will be imputed using the last non-missing observation carried 
forward before the calculation of SPID24 values.
 
 
12.3.3.2 
Analysis of Secondary Efficacy Variables 
• Time-weighted sum of the pain intensity difference between VX-150 versus placebo as 
recorded on a NPRS 0 to 48 hours (SPID48) after the first dose: analysis of this variable will 
be similar to the primary analysis. 
• Proportions of subjects with at least 30%, 50%, or 70% reduction in NPRS at 24 hours after 
the first dose of VX-150 versus placebo: This variable will be analyzed using the 
Cochran-Mantel-Haenszel test, stratified by site and sex. 
• Time to onset of “confirmed perceptible pain relief” after the first dose of VX-150 versus 
placebo: This variable will be analyzed using Cox regression model. The model will include 
a covariate for treatment and adjustment for site and sex. Additionally, the Kaplan-Meier 
method will be used to produce graphical presentation of the survival curves by treatment 
group and to estimate survival rates by treatment group. 
• Time to onset of “meaningful pain relief” after the first dose of VX-150 versus placebo: The 
analysis of this variable will be similar to the analyses of time to onset of “perceptible pain 
relief.” 


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12.3.4 
Safety Analysis 
The overall safety profile of VX-150 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 
Safety endpoints will be analyzed based on the Safety Set. 
All safety data will be presented in individual subject data listings. 
12.3.4.1 
Adverse Events 
AEs will be coded according to MedDRA. The number and percentage of subjects experiencing 
an AE will be summarized by the MedDRA System Organ Class and Preferred Term (PT), as 
well as by treatment group. AEs will be classified as pretreatment or treatment-emergent as 
follows:  
Pretreatment AEs are defined as AEs that occurred or worsened after signing the ICF up to the 
start of study dosing. 
Treatment-emergent AEs are defined as AEs that occurred or worsened on or after the start of 
drug dosing through the Safety Follow-up. Only TEAEs will be summarized in tables. All 
summaries of TEAEs will be presented by severity of the AE and the relationship to the study 
drug. Some rules that will apply to the summarization of AEs are (1) a subject with multiple 
occurrences of the same AE or a continuing AE will only be counted once; (2) only the 
maximum severity level will be presented in the severity summary; and (3) only the worst 
relationship level will be presented in the relationship summary. 
SAEs and AEs leading to death, dose interruption, and permanent discontinuation will be listed 
separately. All AEs through Safety Follow-up will be listed in an individual subject data listing, 
including pretreatment AEs.  
12.3.4.2 
Clinical Laboratory Assessments 
All statistical analyses of laboratory values will be performed using the International System of 
Units. Hematology and clinical chemistry results at baseline will be summarized by treatment 
group. Other assessments will be collected as needed (i.e., at unscheduled visits). 
A listing containing individual subject hematology and clinical chemistry measurements outside 
the threshold value criteria at any visit will be provided. For each subject in the listing, 
measurements at all visits will be included. The threshold value criteria for clinical laboratory 
data will be provided in the SAP. Results of coagulation, urinalysis, and the urine/serum 
pregnancy test will be presented in individual subject data listings only. Clinically significant 
abnormal laboratory findings will be reported as AEs. 
12.3.4.3 
Electrocardiogram 
A summary of raw values and change from baseline values will be provided by treatment group 
at each scheduled time point for the following ECG measurements: PR, QT, QRS, and QTcF 


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intervals and heart rate. In addition, the number and percentage of subjects by maximum 
on-treatment 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 on-treatment change from 
baseline value of QT/QTcF intervals, categorized as ≤30 msec, >30 and ≤60 msec, and 
>60 msec, will be provided. 
A listing containing individual ECG measurements that are outside the threshold value criteria at 
any time point will be provided. For each subject in the listing, measurements at all time points 
will be included. Clinically significant abnormal findings will be reported as AEs. 
12.3.4.4 
Vital Signs 
The following vital signs will be summarized by treatment group at each scheduled visit: systolic 
and diastolic blood pressure (mm Hg), body temperature (°C), pulse rate (beats per minute), and 
respiratory rate (breaths per minute). 
A listing containing individual vital signs measurements that are outside the threshold values 
criteria at any visit will be provided. For each subject in the listing, measurements at all visits 
will be included. Clinically significant abnormal findings in vital signs will be reported as AEs. 
12.3.4.5 
Physical Examination 
PE results will be presented in individual subject data listings only. Clinically relevant results 
identified after screening will be reported as AEs. 
12.3.4.6 
Other Safety Analysis 
Not applicable. 
12.3.5 
Other Analysis 
Not applicable. 
12.3.6 
Interim and Independent Data Monitoring Committee Analyses 
Not applicable. 
12.4 
Clinical Pharmacology Analysis 
12.4.1 
Pharmacokinetic Analysis 
The PK parameters of VRT-1207355 and VRT-1268114 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 clinical pharmacology analysis plan (CPAP). 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses 
A population PK analysis of plasma concentration versus time data of VRT-1207355 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 
Population PK/PD Analysis Plan. 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 Phone Interview: through the Safety 
Follow-up Phone Interview 
• For enrolled subjects who do not have a Safety Follow-up Phone Interview, 9 days after the 
last dose of study drug. 


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All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled will be 
recorded only in the subject’s source documents. The following data will be documented for 
each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
November 2017). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” The 
severity of an AE 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 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
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). 
 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4. 


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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 followup) 
 
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 and assent (where applicable) through the 
Safety Follow-up Phone Interview, 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 Phone Interview and are considered related to study drug(s) will be reported to Vertex 
GPS within 24 hours of identification.  
For SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Phone Interview, the SAE Form will be completed for new/initial events as 
well as to report follow-up information on previously reported events. Investigators are asked to 
report follow-up information as soon as it becomes available to ensure timely reporting to health 
authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email:
 (preferred choice) 
Fax: 
  
For questions, contact telephone:
 
SAEs that occur after the Safety Follow-up Phone Interview and are considered related to study 
drug(s) will be recorded on the Vertex Organized Safety Information Collection Form (hereafter 
referred to as the “SAE Form”) using a recognized medical term or diagnosis that accurately 
reflects the event. SAEs will be assessed by the investigator for relationship to the investigational 
study drug(s) and possible etiologies. On the SAE Form, relationship to study drug(s) will be 
assessed only as related (includes possibly related) or not related (includes unlikely related), and 
severity assessment will not be required. For the purposes of study analysis, if the event has not 
resolved at the end of the study reporting period, it will be documented as ongoing. For purposes 
of regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report the outcome to Vertex using the SAE Form. 
13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IECs, and 
participating investigators in accordance with ICH Guidelines and/or local regulatory 
requirements, as applicable. In addition, Vertex, or authorized designee, will be responsible for 
the submission of safety letters to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/IEC of all 
unexpected serious adverse drug reactions involving risk to human subjects. 


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13.2 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will be 
conducted only at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Vertex, as allowable by local 
applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject before study participation. The method of obtaining and documenting the informed 
consent and assent (if applicable) and the contents of the consent will comply with ICH GCP and 
all applicable laws and regulations and will be subject to approval by Vertex or its designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers, and access to subject names linked to such 
numbers will be limited to the site and the study physician and will not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE Forms and the 


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review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 
For sites participating in the US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will comply with all HIPAA 
requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP Guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Vertex 
will be notified. 
13.2.7 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.2.8 
End of Study 
The end of study is defined as the last scheduled visit (or 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. 


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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 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP Guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc (CD) or other electronic media will be placed in the investigator’s 
study file. 
13.6 
Publications and Clinical Study Report 


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13.6.2 
Clinical Study Report  
A CSR, written in accordance with the ICH E3 Guideline, will be submitted in accordance with 
local regulations. 


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14 
REFERENCES 
1 
Petersen KL, Rowbotham MC. Will ion-channel blockers be useful for management of 
nonneuropathic pain? The Journal of Pain. 2000;1(3):26-34. 
2 
Centers for Disease Control and Prevention. 2017. Opioid Overdose Available at: 
https://www.cdc.gov/drugoverdose/. Accessed 16 August 2018. 
3 
European Monitoring Centre for Drugs and Drug Addiction. European Drug Report 
2016: Trends and Developments. Lisbon, Portugal: 2016. 
4 
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. 
5 
England S. Voltage-gated sodium channels: the search for subtype-selective analgesics. 
Expert Opinion on Investigational Drugs. 2008;17(12):1849-64. 
6 
Krafte D, Bannon A. Sodium channels and nociception: recent concepts and therapeutic 
opportunities. Current Opinion in Pharmacology. 2008;8(1):50-6. 
7 
Huang J, Yang Y, Zhao P, Gerrits MM, Hoeijmakers JGJ, Bekelaar K, et al. Small-fiber 
neuropathy Nav1.8 mutation shifts activation to hyperpolarized potentials and increases 
excitability of dorsal root ganglion neurons. Journal of Neuroscience. 
2013;33(35):14087-97. 
8 
Faber CG, Lauria G, Merkies ISJ, Cheng X, Han C, Ahn HS, et al. Gain-of-function 
Nav1.8 mutations in painful neuropathy. Proceedings of the National Academy of 
Sciences. 2012;109(47):19444-49. 
9 
Han C, Vasylyev D, Macala LJ, Gerrits MM, Hoeijmakers JGJ, Bekelaar KJ, et al. The 
G1662S NaV1.8 mutation in small fibre neuropathy: impaired inactivation underlying 
DRG neuron hyperexcitability. Journal of Neurology, Neurosurgery & Psychiatry. 
2013;85(5):499-505. 
10 
Akopian AN, Sivilotti L, Wood JN. A tetrodotoxin-resistant voltage-gated sodium 
channel expressed by sensory neurons. Nature. 1996;379(6562):257-62. 
11 
Vertex Pharmaceuticals Incorporated. VX-150 Investigator’s Brochure.  
12 
United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research. Draft guidance for industry: analgesic 
indications: developing drug and biological products. Rockville, MD: February 2014. 
13 
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. 
14 
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. 
15 
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. 
16 
International Committee of Medical Journal Editors (ICMJE). 2017. Recommendations 
for conduct, reporting, editing, and publication of scholarly work in medical journals. 
Available at: http://www.icmje.org/recommendations/. Accessed 09 April 2018. 
 


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15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol#: 
VX18-150-104 I Version#: 
2.0 
I Version Date: 
26 September 2018 
Study Title: A Phase 2B Randomized, Double-blind, Placebo-controlled, Dose-ranging, 
Parallel-design Study of the Efficacy and Safety ofVX-150 for Acute Pain Following 
Bunionectomy 
Vertex Pharmaceuticals Incorporated 
 


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Vertex Pharmaceuticals Incorporated 
 
15.2 
Investigator Signature Page 
Protocol #:  
VX18‑150‑104 
Version #: 2.0 
Version Date: 
26 September 2018 
Study Title: A Phase 2B Randomized, Double-blind, Placebo-controlled, Dose-ranging, 
Parallel-design Study of the Efficacy and Safety of VX-150 for Acute Pain Following 
Bunionectomy 
 
 
I have read Protocol VX18‑150‑104, Version 2.0, and agree to conduct the study according to 
its terms. I understand that all information concerning VX-150 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 29 
Protocol Number: VX18-150-104  
Vertex Pharmaceuticals Incorporated 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX18-150-104  
(Final Analysis) 
 
A Phase 2B Randomized, Double-blind, Placebo-controlled, Dose-
ranging, Parallel-design Study of the Efficacy and Safety of VX-150 
for Acute Pain Following Bunionectomy 
Author of SAP: 
 
 
Version: 1.0  
Version Date of SAP: 05 MAR 2019   
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods)  
Page 2 of 29 
Protocol Number: VX18-150-104 
Vertex Pharmaceuticals Incorporated 
 
2 
TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
2 
Table of Contents ............................................................................................................. 2 
4 
Introduction ...................................................................................................................... 5 
5 
Study Objectives .............................................................................................................. 5 
5.1 
Primary Objective ....................................................................................................... 5 
5.2 
Secondary Objectives ................................................................................................. 5 
6 
Study Endpoints ............................................................................................................... 5 
6.1 
Efficacy Endpoints ..................................................................................................... 5 
6.1.1 
Primary Efficacy Endpoint ................................................................................. 5 
6.1.2 
Secondary Efficacy Endpoints ............................................................................ 5 
6.2 
Safety Endpoints ......................................................................................................... 6 
7 
Study Design ..................................................................................................................... 6 
7.1 
Overall Design ............................................................................................................ 6 
7.2 
Sample Size and Power .............................................................................................. 7 
7.3 
Randomization ............................................................................................................ 8 
7.4 
Blinding and Unblinding ............................................................................................ 8 
8 
Analysis Sets ..................................................................................................................... 8 
8.1 
All Subjects Set .......................................................................................................... 8 
8.2 
Full Analysis Set ......................................................................................................... 8 
8.3 
Safety Set .................................................................................................................... 8 
9 
Statistical Analysis ........................................................................................................... 8 
9.1 
General Considerations .............................................................................................. 8 
9.2 
Background Characteristics ........................................................................................ 9 
9.2.1 
Subject Disposition ............................................................................................. 9 
9.2.2 
Demographics and Baseline Characteristics ..................................................... 10 
9.2.3 
Medical History ................................................................................................ 11 
9.2.4 
Prior and Concomitant Medications ................................................................. 11 
9.2.5 
Study Drug Exposure and Study Drug Compliance ......................................... 11 
9.2.6 
Important Protocol Deviations .......................................................................... 11 
9.3 
Efficacy Analysis ...................................................................................................... 12 
9.3.1 
Analysis of Primary Efficacy Variable ............................................................. 12 
9.3.1.1 
Definition of Primary Efficacy Variable .................................................... 12 
9.3.1.2 
Primary Analysis ........................................................................................ 13 
 
 
9.3.2 
Analysis of Secondary Efficacy Variables ....................................................... 14 
9.3.2.1 
Definition of Secondary Efficacy Variables .............................................. 14 
9.3.2.2 
Secondary Analyses ................................................................................... 15 


Statistical Analysis Plan (Methods)  
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9.4 
Safety Analysis ......................................................................................................... 17 
9.4.1 
Adverse Events ................................................................................................. 17 
9.4.2 
Clinical Laboratory Assessments ..................................................................... 18 
9.4.3 
Electrocardiogram ............................................................................................ 18 
9.4.4 
Vital Signs ........................................................................................................ 18 
9.4.5 
Physical Examination ....................................................................................... 18 
10 Summary of Interim and IDMC Analyses .................................................................. 18 
11 References ....................................................................................................................... 19 
12 List of Appendices .......................................................................................................... 20 
Appendix A 
: Analysis Visit Windows for Safety and Efficacy Assessments ............... 20 
Appendix B 
: Imputation Rules for Missing Prior/Concomitant Medication Date ........ 22 
Appendix C 
: Imputation Rules for Missing AE Date and Time ................................... 23 
Appendix D 
: Threshold Value Criteria .......................................................................... 24 
Appendix E 
: Important Protocol Deviation Categories ................................................ 27 
 
 
 




Statistical Analysis Plan (Methods)  
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Vertex Pharmaceuticals Incorporated 
 
4 
INTRODUCTION 
This statistical analysis plan (SAP) for the final analysis is based on the approved clinical 
study protocol (CSP), dated 26 September 2018 for Version 2.0, approved eCRF, 
Version 3.0, dated 31 January and final electronic case report form (eCRF) completion 
guidelines, Version 2.0, dated 11 February.  
Study VX18-150-104 is a Phase 2 dose-ranging study which was designed to help inform 
dose selection for Phase 3 studies in acute pain. This SAP (Methods) documents the planned 
final statistical analysis of efficacy and safety endpoints defined in the study protocol of 
VX18-150-104 and provide 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 and R Version 3.5.0 or higher will be used to generate all statistical outputs (tables, 
figures, listings and datasets).   
The SAP (Methods) for the final analysis will be finalized and approved before the database 
lock for the final analysis. Any changes made to the SAP after the clinical database lock has 
occurred 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 dose-response relationship of VX-150 in treating acute pain following 
bunionectomy 
5.2 
Secondary Objectives  
• To evaluate the safety and tolerability of VX-150  
• To evaluate the pharmacokinetics (PK) of VRT-1207355 and the metabolite 
VRT-1268114 (M5) 
6 
STUDY ENDPOINTS 
6.1 
Efficacy Endpoints 
6.1.1 
Primary Efficacy Endpoint 
Time-weighted sum of the pain intensity difference between VX-150 versus placebo as 
recorded on a Numeric Pain Rating Scale (NPRS) 0 to 24 hours (SPID24) after the first dose 
6.1.2 
Secondary Efficacy Endpoints 
• Time-weighted sum of the pain intensity difference between VX-150 versus placebo as 
recorded on an NPRS 0 to 48 hours (SPID48) after the first dose 


Statistical Analysis Plan (Methods)  
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Protocol Number: VX18-150-104 
Vertex Pharmaceuticals Incorporated 
 
• Proportions of subjects with at least 30%, 50%, or 70% reduction in NPRS at 24 hours 
after the first dose of VX-150 versus placebo 
• Time to onset of “confirmed perceptible pain relief” and “meaningful pain relief” after 
the first dose of VX-150 versus placebo 
6.2 
Safety Endpoints 
• Safety and tolerability based on the incidence and type of adverse events (AEs), changes 
from baseline in clinically significant laboratory test results, and vital signs at designated 
visits 
7 
STUDY DESIGN  
7.1 
Overall Design  
This is a Phase 2B randomized, double-blind, placebo-controlled, dose ranging, 6-arm, 
parallel-design study. Subjects will receive a primary unilateral first metatarsal 
bunionectomy repair on Day -1 (Figure 7-1). A continuous popliteal sciatic block infusion 
(0.2% ropivacaine) will be started after surgery and will be removed between 3AM and 5AM 
on Day 1. After removal of the popliteal sciatic block, a subject can be randomized once the 
subject requests the first dose of study drug for pain relief, and the subject’s pain is ≥4 on the 
NPRS and is moderate or severe on the VRS (Verbal Categorical Rating Scale). If a subject 
does not meet the NPRS and VRS criteria within 9 hours of removal of the popliteal sciatic 
block, the subject will not be eligible to enroll in the study.  
A total of approximately 242 subjects will be randomized 2:2:2:2:1:2 to 6 treatment arms, 
evaluating a range of 5 VX-150 dose levels as shown in Table 7-1. 
Table 7-1          VX-150 Doses by Treatment Arm 
Treatment 
Dose Level 
Dose 
Number of Subjects 
VX-150 
1 (highest) 
First dose 1500 mg, then 750 mg q12h 
44 
 
2 
1000 mg qd 
44 
 
3 
500 mg q12h 
44 
 
4 
First dose 500 mg, then 250 mg q12h 
44 
 
5 (lowest) 
250 mg qd 
22 
Placebo 
 
 
44 
q12h: every 12 hours; qd: daily 
Note: q12h dosing will be through 36 hours after the first dose of study drug throughout the protocol. 
Subjects will report their pain on the NPRS at scheduled time points (See Table 3-2 in CSP) 
through 48 hours after the first dose of study drug. In addition, pain intensity will be recorded 


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on the NPRS immediately before each administration of rescue medication. 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. 
However, subjects may receive rescue medication at any time after the first dose of study 
drug per their request. The rescue medication will be ibuprofen (400 mg [oral] every 4 hours 
[q4h] as needed [prn]). 
Figure 7-1 
VX18-150-104 Study Design 
 
CRU: clinical research unit; NPRS: Numeric Pain Rating Scale; VRS: Verbal Categorical Rating Scale 
Notes: After removal of the popliteal sciatic block, a subject can be randomized once the subject requests the 
first dose of study drug for pain relief, and the subject’s pain is ≥4 on the NPRS and is moderate or severe on 
the VRS. VX-150 dose levels (Dose Levels 1 [highest], 2, 3, 4, and 5 [lowest]) are shown in Table 7-1. To 
maintain the blind, all subjects will receive the same number of capsules. 
7.2 
Sample Size and Power 
The sample size calculation is based on the primary analysis of the primary efficacy 
endpoint. The primary efficacy endpoint is the time-weighted sum of the pain intensity 
difference 0 to 24 hours after the first dose (SPID24). The primary analysis of this endpoint 
is to detect if there is a significant dose-response relationship across VX-150 dose groups and 
placebo using the MCP-Mod (multiple comparison procedures with modeling techniques). 
Under MCP-Mod, a pre-specified candidate set of 4 dose-response models (Linear, Emax, 
Logistic, and Sigmoid Emax) is proposed. 
Assuming the maximum effect size compared to placebo is 0.7, 40 evaluable subjects in the 
placebo, VX-150 Dose Level 1 (highest), 2, 3, and 4 groups, and 20 evaluable subjects in 
VX-150 Dose Level 5 (lowest) group would provide approximately at least 88% power to 
detect a dose-response relationship from the candidate set with a 5% level of significance. In 
addition, 40 evaluable subjects per treatment group can provide at least 85% power to detect 
an effect size of 0.7 compared to placebo. In order to allow for withdrawal of up to 10% of 
randomized subjects, the study will enroll and randomize approximately 242 subjects in total. 


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7.3 
Randomization 
A total of approximately 242 subjects will be randomized 2:2:2:2:1:2 to 6 treatment arms. 
Randomization will be stratified by site and sex. To maintain the blind, all subjects will 
receive the same number of capsules in a double-dummy design. 
An interactive web response system (IWRS) 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).  
7.4 
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 will be 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) will be 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.  
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. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of CSP. The precision standards for 
reporting safety and efficacy variables are provided in an internal Biometrics document that 
specifies the programming rules including the precision for derived variables. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, 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 for NPRS will be defined as the most recent non-missing measurement 
collected on Day 1 before the first dose of study drug. For all other variables, unless 


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otherwise specified, baseline value will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug.  
Change (absolute change) from baseline will be calculated as post-baseline value – 
baseline value unless otherwise specified.  
Treatment-emergent (TE) Period will be defined as the time from first dose of study drug 
through the Safety Follow-up (for enrolled subjects who do not have a Safety Follow-up 
Phone Interview: it will be defined as the time from first dose of study drug through 9 days 
after the last dose of study drug)  
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/last on-treatment measurements. 
• 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 will be imputed for NPRS 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 or remedy the presence 
of statistical outliers, unless otherwise specified. 
Multiplicity: No multiplicity adjustment will be performed for hypothesis testing except for 
MCP-Mod procedure in Section 9.3.1.2 and 9.3.1.3.
 
 
 
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized overall and by 
treatment group:  
• All Subjects Set 
• Randomized 
• Full Analysis Set (FAS) 
• Safety Set 


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The number and percentage (based on FAS) of subjects in each of the following disposition 
categories will be summarized overall and by treatment group: 
• Completed study drug treatment 
• Prematurely discontinued the study drug treatment and the reason for discontinuation  
• Completed study (i.e., completed Safety Follow-up Phone Interview) 
• Prematurely discontinued the study and the reason for discontinuation  
A listing will be provided for subjects who discontinued study drug 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 overall and by treatment 
group based on the FAS. 
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 more than 2 races reported from a subject]) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
 
 
Disease characteristics will include the following: 
• Pain intensity at baseline as recorded on the NPRS 
• VRS at baseline 
In addition, data listings will also be provided for: 
• Inclusion/Exclusion criteria violation for subjects with any such violations 
• Supplemental analgesic medications administered after surgery and before removal of the 
popliteal sciatic block 


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9.2.3 
Medical History 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). For the FAS, medical history will be summarized descriptively by system organ 
class (SOC) and preferred term (PT). The corresponding data listing will also be provided. 
9.2.4 
Prior and Concomitant Medications 
Medications taken 14 days before the Screening Visit and up to the Safety Follow-up will be 
coded and summarized by Preferred Name using the World Health Organization-Drug 
Dictionary (WHO-DD) for the FAS as frequency tables in 2 parts:  
1. Prior medication: Medication that started before the first dose of study drug, regardless of 
when dosing of the medication ended. 
2. Concomitant medication: Medication received at or after the first dose of study drug, 
medication that was received before initial dosing and continued after initial dosing of 
study drug, or medication with missing stop date. 
Medication that started before the first dose of study drug and continued after the first dose of 
study drug will be summarized as prior medication and separately as concomitant 
medication.  
If a medication has completely missing or partially missing start/stop dates and it cannot be 
determined whether it was taken before the first dose or concomitantly, it will be classified as 
prior and concomitant. 
Details for imputing missing or partial start/stop date and time of medication are described in 
Appendix B. 
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 
Table 3-2 and as described in Section 9.6 of CSP during a period of 36 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  
Important protocol deviation (IPD) is a subset of protocol deviations (any change, 
divergence, or departure from the study design or procedures defined in the protocol) that 
may significantly impact the completeness, accuracy, and/or reliability of the study data or 
that may significantly affect a subjects’ rights, safety or well-being. IPDs will be identified 
from the clinical database and/or site deviation log.  
A list of categories of IPDs identified for this study is presented in Appendix E.  
All IPDs will be summarized descriptively by treatment group and presented in an individual 
subject data listing. 


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9.3 
Efficacy Analysis 
Unless otherwise defined, all efficacy analyses described in this section will be based on the 
FAS. Subjects will be analyzed according to their randomized treatment assignment. 
9.3.1 
Analysis of Primary Efficacy Variable 
9.3.1.1 
Definition of Primary Efficacy Variable 
The primary efficacy endpoint is the time-weighted sum of the pain intensity difference 0 to 
24 hours (SPID24) after the first dose of VX-150 or placebo. 
In general SPID is calculated as: ∑ ∆timei x PIDi  
Where:  
• ∆timei  =  time (in hours) elapsed since previous measurements 
• PIDi  = pain intensity at baseline when the subject requests the first dose of study 
medication  - pain intensity at hour i 
Hence: 
• 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 
As stated in Section 9.1, intermittent missing data will be imputed for NPRS by applying 
linear interpolation to the valid observations immediately before and after the missing 
observation(s) during 0 to 48 hours. Such intermittent missing data are assumed to be 
missing completely at random. 
Pain intensity scores that were collected within 4 hours after a dose of rescue medication 
(rescue period) will not be used in the analysis. Instead, these observations will be imputed 
with the pain assessment completed immediately before the administration of rescue 
medication. If that pain assessment is missing, the last non-missing regular pain intensity 
score will be applied (the LOCF principle). This approach assumes that the effect of the 
study drug on pain intensity score remains the same as the pre-rescue measurement during 
the first 4 hours after administration of rescue medication. 
If there are multiple administrations of rescue medication within the same 4 hour period, a 
local highest pain intensity score will be used for the imputation during the second 4 hours 
rescue period. The local highest pain intensity score is the highest values among the first pre-
rescue, the second pre-rescue and the actual observed (if any) in the overlapping period.  
If a subject discontinues the study drug treatment prior to 24 hours, the LOCF principle will 
be used to impute all pain intensity scores up to 24 hours, irrespective of reason for study 
drug treatment discontinuation so that SPID24 can be calculated accordingly. Even if a 
subject completes the study, but has missing data from a certain time point to hour 24, the 
LOCF principle will be used to impute all pain intensity scores up to 24 hours. The last 
observed pain intensity score should be from a regularly scheduled measurement including a 
previous pre-rescue assessment, but cannot be any actual measurements taken during a 
previous rescue period. The LOCF principle assumes that the last observed pain intensity 
score represents the effects of study drug in the remaining of study period towards the 


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planned endpoint, regardless of reason for discontinuation and if the subject completes the 
study or not.  
The imputation order will be: (1) intermittent missing data (2) 4 hours after administration of 
rescue medication and (3) missing data from a certain time point towards the planned 
endpoint including after early discontinuation from study drug treatment.  
9.3.1.2 
Primary Analysis  
The primary efficacy analysis will be using the MCP-Mod approach to detect the dose-
response relationship from a candidate set of 4 dose-response models (Linear, Emax, 
Logistic, and Sigmoid Emax). Dose level 2 and Dose level 3 of VX-150 group will be 
combined into one treatment group in the MCP-Mod procedure. Total dose on Day 1 for each 
treatment group will be used in the MCP-Mod procedure as shown in Table 9-1. 
Table 9-1  VX-150 Doses by Treatment in Primary Analysis 
 
Treatment 
Dose Level 
Dose 
Total Dose on Day 1 
Analysis Treatment Group 
VX-150 
1 (highest) 
First dose 1500 mg, then 
750 mg q12h 
2250 mg 
VX-150 Dose Level 1 
 
2 
1000 mg qd 
1000 mg 
VX-150 Dose Level 2/3  
 
3 
500 mg q12h 
 
4 
First dose 500 mg, then 250 
mg q12h 
750 mg 
VX-150 Dose Level 4 
 
5 (lowest) 
250 mg qd 
250 mg 
VX-150 Dose Level 5 
Placebo 
 
 
0 mg 
Placebo 
 
 
 
 
 
MCP-Mod approach will be based on an analysis of covariance (ANCOVA) model. The 
model will include SPID24 after the first dose as the dependent variable, treatment as a fixed 
effect, with site, sex, and baseline pain intensity score as covariates. The Least Squares (LS) 
means (SE) and 95% confidence interval (CI) will be provided for each treatment group. 
From the MCP-Mod procedure, the 2-sided P value will be provided for each dose-response 
model in the candidate set. If at least one dose-response model in the candidate set is 
statistically significant, a dose-response model will be selected based on the maximum test 
statistic criterion. The selected dose-response model will be estimated and presented in a 
figure.  
Pain intensity scores used for the primary analysis 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. SPID24 used for the primary analysis will also be 
summarized descriptively including SE by treatment.  


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9.3.2 
Analysis of Secondary Efficacy Variables 
9.3.2.1 
Definition of Secondary Efficacy Variables 
Time-weighted sum of the pain intensity difference between VX-150 versus placebo as 
recorded on a NPRS 0 to 48 hours (SPID48) after the first dose: SPID48 will be calculated 
using the following formula: 
• 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 


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Proportions of subjects with at least 30%, 50%, or 70% reduction in NPRS at 24 hours after 
the first dose of VX-150 versus placebo: A subject with at least 30%, 50%, or 70% reduction 
in NPRS at 24 hours after the first dose of study drug will be defined as a “responder”. The 
percentage reduction in the NPRS will be calculated as following: 
• 100 × (NPRS at baseline  ̶ NPRS at 24 hours) / NPRS at baseline 
If a subject discontinues the study drug treatment for any reason prior to 24 hours, this 
subject will not be a “responder” for any of the three criteria. If a subject has missing NPRS 
at 24 hours without discontinuing the study drug treatment prior to 24 hours, the LOCF 
principle will be used to impute pain intensity score at 24 hours. The last observed pain 
intensity score should be from a regularly scheduled measurement including a previous pre-
rescue assessment, but cannot be any actual measurements taken during a previous rescue 
period. 
Time to onset of “confirmed perceptible pain relief” and “meaningful pain relief” after the 
first dose of VX-150 versus placebo: Time to onset of “perceptible pain relief” is the time 
elapsed from first dose of VX-150 or placebo until the subject stops the “perceptible pain 
relief” stopwatch. Time to onset of “meaningful pain relief” is the time elapsed from first 
dose of VX-150 or placebo 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 
perceptible pain relief for those subjects who had meaningful pain relief.  
If the subject has not stopped the stopwatch by 6 hours after the first dose, the stopwatch will 
be stopped and time to onset will be considered censored at 6 hours. If the subject receives 
rescue medication during the first 6 hours, the stopwatch will be stopped immediately before 
administration of rescue medication and time to onset will be considered censored at the time 
of rescue medication plus 4 hours or at 6 hours, whichever happened earlier. If perceptible 
pain relief is obtained without associated meaningful pain relief, time to onset of “confirmed 
perceptible pain relief” will also be considered censored at 6 hours.  
9.3.2.2 
Secondary Analyses  
Time-weighted sum of the pain intensity difference between VX-150 versus placebo as 
recorded on a NPRS 0 to 48 hours (SPID48) after the first dose: Same imputation strategies 
as described for SPID24 in Section 9.3.1.1 will be applied to SPID48.
 
 
   
Proportions of subjects with at least 30%, 50%, or 70% reduction in NPRS at 24 hours after 
the first dose of VX-150 versus placebo: Analysis of responder rates between each individual 
dose level of VX-150 and placebo will be conducted using Cochran-Mantel-Haenszel test, 
stratified by site and sex.  
Time to onset of “confirmed perceptible pain relief” and “meaningful pain relief” after the 
first dose of VX-150 versus placebo: Time to onset of “confirmed perceptible pain relief” 
will be analyzed using Cox regression model. The model will include treatment, site and sex 
as covariates. Pairwise comparison between each individual dose level of VX-150 and 
placebo will be conducted under the model. 


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Note: If placebo group has fewer than 5 subjects experience “confirmed perceptible pain 
relief”, the Cox regression will not be performed. If any dose level of VX-150 group has 
fewer than 5 subjects experience “confirmed perceptible pain relief”, the particular dose level 
group will not be included in the Cox regression model. 
Additionally, the Kaplan-Meier method will be used to produce graphical presentation of the 
survival curves by treatment group. 
Time to onset of “meaningful pain relief” and time to onset of “perceptible pain relief” will 
be analyzed in the same way as described for time to onset of “confirmed perceptible pain 
relief”.  


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9.4 
Safety Analysis 
The overall safety profile of VX-150 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 
Safety analyses will be based on the Safety Set. 
Safety analyses will be based on the Safety Set and subjects will be analyzed according to the 
treatment they actually received. 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, if the subject receives more than one dose level of 
VX-150, the actual treatment is defined as the highest dose level among all received VX-150 
treatment, regardless of the randomized treatment assignment. For any dosed subjects, the 
actual treatment is defined as placebo only if the subject receives placebo at all visits in the 
study. 
9.4.1 
Adverse Events  
AEs will be coded according to MedDRA. The number and percentage of subjects 
experiencing an AE will be summarized by the MedDRA System Organ Class and preferred 
term, as well as by treatment group. AEs will be classified as pretreatment or 
treatment-emergent as follows: 
Pretreatment AEs are defined as AEs that were reported or worsened after signing the ICF 
up to the start of study drug dosing. 
Treatment-emergent AEs are defined as AEs that were reported or worsened on or after the 
first dose of study drug through the end of the TE period. 
Details for imputing missing or partial start date and time of adverse events are described in 
Appendix C. 
Only TEAEs will be summarized in tables. All summaries of TEAEs will be presented by the 
severity of the AE and relationship to the study drug. Some rules that will apply to the 
summarization of AEs are (1) a subject with multiple occurrences of the same AE or a 
continuing AE will only be counted once; (2) only the maximum severity level will be 
presented in the severity summary; and (3) only the strongest relationship level will be 
presented in the relationship summary. An AE with relationship missing is counted as related 
AE. 
SAEs, AEs leading to death, and AEs leading to study drug interruption and study drug 
treatment discontinuation will be listed separately. All AEs through Safety Follow-up will be 
listed in an individual subject data listing, including pretreatment AEs.  


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9.4.2 
Clinical Laboratory Assessments 
All statistical analyses of laboratory values will be performed using International System of 
Units. Hematology and clinical chemistry results at baseline will be summarized by treatment 
group. Other assessments will be collected as needed, i.e. at unscheduled visits. The 
threshold value criteria for hematology and clinical chemistry laboratory tests are provided in 
Appendix D. A listing containing individual subject hematology and clinical chemistry 
measurements meeting the threshold value criteria at any visit will be provided. For each 
subject in the listing, measurements at all visits will be included. Results of coagulation, 
urinalysis and the urine/serum pregnancy test will be presented in individual subject data 
listings only.  
Clinically significant abnormal laboratory findings will be reported as AEs.  
9.4.3 
Electrocardiogram 
A summary of raw values and change from baseline values will be provided by treatment at 
each scheduled time point during the TE period for the following standard 12-lead ECG 
measurements: PR, QT, QRS, QTcF [QTcF = QT/RR0.33], and HR. In addition, the number 
and percentage of subjects by maximum on-treatment 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 on-treatment change from baseline value of QT/QTcF 
intervals, categorized ≤30 msec, >30 and ≤60 msec, and >60 msec, will be provided. 
The threshold value criteria for ECG data are provided in Appendix D. A listing containing 
individual subject measurements meeting the threshold value criteria at any time point will 
be provided. For each subject in the listing, ECG measurements at all time points will be 
included.  
Clinically significant ECG abnormalities occurring during the study through the Safety 
Follow-up will be recorded as AEs.  
9.4.4 
Vital Signs 
The raw values and change from baseline values during the TE period will be summarized by 
treatment at each scheduled visit: systolic and diastolic blood pressure (mm Hg), body 
temperature (°C), pulse rate (beats per minute), and respiratory rate (breaths per minute).  
The threshold value criteria for vital signs data are provided in Appendix D. A listing 
containing individual subject measurements meeting the threshold value criteria at any visit 
will be provided. For each subject in the listing, vital signs at all visits will be included. 
Clinically significant abnormal findings in vital signs will be reported as AEs. 
9.4.5 
Physical Examination  
PE results will be presented in individual subject data listings only. Clinically relevant results 
identified after screening will be reported as AEs. 
10 
SUMMARY OF INTERIM AND IDMC ANALYSES 
Not applicable. 


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11 
REFERENCES 
Guidance for Industry Analgesic Indications: Developing Drug and Biological Products, 
FDA DRAFT GUIDANCE, 2014. 
 
Preventing and Treating Missing Data in Longitudinal Clinical Trials: A Practical Guide. 
Craig H. Mallinckrodt, Cambridge University Press, 2013. 
 
SAS Institute Inc. 2014. Base SAS® 9.4 Procedures Guide: Statistical Procedures, Third 
Edition. Cary, NC: SAS Institute Inc. 
 
The Prevention and Treatment of Missing Data in Clinical Trials. Panel on handling Missing 
Data in Clinical Trials. Committee on National Statistics, Division of Behavioral and Social 
Sciences and Education. Washington, DC: The national Academies. National Research 
Council. 2010. 
 
Xun X, Bretz F. “The MCP-Mod Methodology: Practical Considerations and the 
DoseFinding R Package”, Chapter 12 in Handbook of Methods for Designing, Monitoring, 
and Analyzing Dose-Finding Trials, eds. O’Quigley J, Iasonos A, Bornkamp B., CRC Press, 
2017. 
 
 


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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) 
Safety Assessment 
Hematology 
Serum Chemistry 
Coagulation 
Baseline 
 
-1 
 
[Screening visit, Pre-dose Day 
1] 
Standard 12-Lead ECG 
 
Baseline 
1 
[Screening visit, Pre-dose Day 
1] 
Day 1, 4 hours  
4 hours after the 
first dose of study 
drug 
3 – 5 hours after the first dose 
of study drug on Day 1 
Vital Sign 
Baseline 
1 
[Screening visit, Day 1] 
Day 2 
2 
2 
Day 3 
3 
3 
Efficacy Assessment 
NPRS 
Baseline  
1 
[After removal of the popliteal 
sciatic block, Pre-dose Day 1] 
At 0.5, 1, 1.5, 2, 3, 4, 5, 6, 
8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, and 48 hours  
1 - 3  
± 5 minutes for 0.5 to 12 hours 
± 10 minutes for 16 to 48 hours 
VRS 
Baseline  
1 
[After removal of the popliteal 
sciatic block, Pre-dose Day 1] 
1 Visit/Time point name for analysis purpose is used to report data in tables and figures. 
 
Notes:  
The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
1. If no numerical measurement is available within a visit window, the measurement will be considered 
missing for the visit.  
2. If there is more than 1 numerical measurement available within the same visit window, use the 
following rules:  
a. 
a. For efficacy assessments: if there are multiple measurements within a visit window,   
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. 
b. For safety assessments: if there are multiple measurements within a visit window,   
i. The measurement closest to the target day/time point will be used; or  


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ii. If there are multiple measurements within the same distance from the target day/time point, 
the latest measurement will be used. 
3. When define efficacy and safety at baseline, refer to the generic baseline definition in Section 9.1. If 
hour and/or minute of first dose time are missing, baseline will be defined as the most recent non-
missing measurement collected before the date of first dose of study drug.  
4. For vital sign, if scheduled and unscheduled measurements at the same date, the scheduled 
measurement will be used. 
5. Age (in years) at first dose date (for demographics, listing): 
Obtain the age at screening visit (in days) in “yy, mm” format (e.g., 24 years, 6 months) from the Vital 
Signs (VS) page at the Screening Visit, and add 0.5 month to convert to days. 
Obtain the screening visit date. 
Then age (in years) at first dose = [(first dose date– screening visit date) in days + age at screening visit 
(in days)]/365.25. 
 
 


Statistical Analysis Plan (Methods)  
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Vertex Pharmaceuticals Incorporated 
 
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.  
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 
 
 


Statistical Analysis Plan (Methods)  
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Protocol Number: VX18-150-104 
Vertex Pharmaceuticals Incorporated 
 
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. 


Statistical Analysis Plan (Methods)  
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Protocol Number: VX18-150-104 
Vertex Pharmaceuticals Incorporated 
 
Appendix D : Threshold Value Criteria 
Table 12-3 
 Threshold Value Criteria for Laboratory Tests 
Parameter 
Thresholds 
Comments 
Clinical Chemistry 
ALT 
≤3xULN*(Not a PCS criterion) 
>3x to ≤ 5xULN 
>5x to ≤ 8xULN 
>3xULN 
>5xULN 
>8xULN 
FDA DILI Guidance Jul 2009.  
AST 
≤3xULN*(Not a PCS criterion) 
>3x to  ≤ 5xULN 
>5x to ≤ 8xULN 
>3xULN 
>5xULN 
>8xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
ALT>3xULN or AST>3xULN 
Vertex LFT working group 2014. 
To be counted within the same treatment 
period. 
Alkaline 
Phosphatase 
>1.5xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>1.5x to ≤2xULN 
>2xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total 
Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
To be counted within a same treatment 
period. 
AST and Total 
Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
To be counted within a same treatment 
period. 
(ALT or AST) and 
Total Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
Vertex LFT working group 2014. 
To be counted within the same treatment 
period. 
CPK 
>3x to ≤ 10xULN 
>10xULN 
FDA criteria Feb 2005. 
Am J Cardiol April 2006. 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Blood Urea 
Nitrogen 
≥17 mmol/L 
 
Chloride 
<85 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥150 mmol/L 
 


Statistical Analysis Plan (Methods)  
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Protocol Number: VX18-150-104 
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Table 12-3 
 Threshold Value Criteria for Laboratory Tests 
Parameter 
Thresholds 
Comments 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
Albumin 
≤25 g/L 
 
Amylase 
>2.0 to 5.0 x ULN   
>5.0 x ULN 
  
Criteria based upon CTCAE 
Lipase 
>2.0 to 5.0 x ULN   
>5.0 x ULN 
  
Criteria based upon CTCAE 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count 
available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) International Consensus meeting on drug-
induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline 
are more relevant than based on absolute 
value. Other categories for decrease from 
baseline can be used (≥30 g/L, ≥40 g/L, 
≥50 g/L). 
RBC 
≥6 Tera/L 
 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 
 
 
 
 


Statistical Analysis Plan (Methods)  
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Protocol Number: VX18-150-104 
Vertex Pharmaceuticals Incorporated 
 
Table 12-4 
Threshold Value Criteria for ECGs 
Parameter 
Thresholds  
Comments 
HR 
≤50 bpm and decrease from baseline ≥10 bpm 
≥120 bpm and increase from baseline ≥10 bpm 
 
PR 
≥220 ms and increase from baseline ≥20 ms 
 
QRS 
≥120 ms 
 
QTc 
 
Absolute values (ms) 
Borderline prolonged: 431-450 ms (Male); 451-470 ms (Female) 
Prolonged : >450 ms (Male); >470 ms (Female) 
 
Increase from baseline 
Borderline prolonged: Increase from baseline 30-60 ms 
Prolonged: Increase from baseline >60 ms 
To be applied to any 
kind of QT correction 
formula.  
 
 
 
 
 
 
Table 12-5 
Threshold Value Criteria for Vital Signs 
Parameter 
PCS 
Comments 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including 
missing) except STANDING. 
SBP 
≤90 mmHg and decrease from baseline 
≥20mmHg 
≥160 mmHg and increase from baseline ≥20 
mmHg 
To be applied for all positions (including 
missing) except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 
mmHg 
≥110 mmHg and increase from baseline ≥10 
mmHg 
To be applied for all positions (including 
missing) except STANDING. 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA criteria Feb 2007. 
 
 
 
 


Statistical Analysis Plan (Methods)  
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Protocol Number: VX18-150-104 
Vertex Pharmaceuticals Incorporated 
 
Appendix E : Important Protocol Deviation Categories 
• Investigational Product  
• Informed Consent  
• Study Conduct/Procedures  
• Other