Conditions: Acute Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 243
Healthy volunteers: no

Brief summary:
This is a Phase 2 randomized, double-blind, placebo-controlled, 3-arm, parallel design study to evaluate the efficacy and safety of VX-150 in treating acute pain following bunionectomy.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: VX-150 intervention 2: HB/APAP intervention 3: Placebo
Intervention descriptions: intervention 1: Participants received VX-150 1500 milligram (mg) as first dose, followed by VX-150 750 mg dose every 12 hours (q12h) for 2 days. intervention 2: Participants received HB 5 mg/APAP 325 mg every 6 hours (q6h) for 2 days. intervention 3: Participants received placebo matched to VX-150 and HB/APAP for 2 days.

Protocol document:
Prot_000.pdf: 
Page 1 of 51 
Vertex Pharmaceuticals Incorporated 
 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 2 Randomized, Double-blind, 
Placebo-controlled, 3-arm, Parallel-design Study of 
the Efficacy and Safety of VX-150 for Acute Pain 
Following Bunionectomy 
Vertex Study Number: VX16-150-103 
 
Date of Protocol: 30 August 2017 (Version 3.0) 
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 VX16-150-103, Version 3.0 
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Assessments Efficacy: 11-point NPRS, 4-point VRS, double-stopwatch assessment, and use of 
rescue medications 
Safety: AEs, clinical laboratory assessments, clinical evaluation of vital signs, 
electrocardiograms (ECGs), and physical examinations. 
PK: Plasma PK parameters of VRT-1207355 and the metabolite M5 
 
  
Statistical Analyses Randomization: Subjects will be randomized (1:1:1) to VX-150, placebo, or 
HB/APAP. 
Null hypothesis for the primary endpoint: The mean time-weighted sum of the 
pain intensity difference 0 to 24 hours after the first dose is the same for the VX-150 
and placebo groups. 
Sample-size considerations based on a comparison between VX-150 and 
placebo: Assuming a standard deviation of 20, 64 subjects completing the study per 
treatment group would provide about 80% power to detect a treatment difference of 
10 between VX-150 and placebo (effect size of 0.5) in mean time-weighted sum of 
the pain intensity difference over the first 24 hours after the first dose with a 5% level 
of significance. In order to allow for withdrawal of up to 20% of randomized subjects 
over the first 24 hours after the first dose, the study will enroll and randomize 
approximately 80 subjects per treatment group. 
Primary analyses: The primary efficacy analysis 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 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. The estimated mean treatment effect, a 95% 
confidence interval, and a 2-sided P value will be provided. 
  


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of Assessments are shown in Table 3-1 and Table 3-2. 
Table 3-1 
Study VX15-150-103: Screening Period 
Assessment 
Screening Period 
Day -28 to Day -2 
Outpatient visit 
X 
Informed consent form (ICF) 
X 
Inclusion/exclusion criteria 
X 
Demographics 
X 
Medical history 
X 
History of drug and alcohol use 
X 
Weight, height, and body mass index (BMI)a 
X 
Vital signsb 
X 
Standard 12-lead electrocardiogram (ECG)
c 
X 
Physical examination 
X 
Serum follicle-stimulating hormone (FSH)
d 
X 
Serum β-hCG (all female subjects)e 
X 
Serology (HBsAg, HCV, and HIV 1/HIV 2)f 
X 
Serum chemistryg 
X 
Hematologyg 
X 
Coagulationg 
X 
Urinalysis 
X 
Drug test (urine) 
X 
Medications reviewh 
Continuous from signing of ICF through Safety Follow-up 
Treatments and procedures 
Continuous from signing of ICF through Safety Follow-up 
Adverse events 
Continuous from signing of ICF through Safety Follow-up 
 
 
a Weight and height will be measured with shoes off. 
b Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be collected after the subject has 
been supine for at least 5 minutes and before any ECG or PK blood sampling. 
c ECGs will be performed after subjects have been supine for at least 5 minutes. ECGs will be done after vital 
signs and before any procedures that may affect heart rate (e.g., blood sampling). 
d Serum FSH is required for postmenopausal female subjects only.  
e Serum β-hCG is required of all female subjects, and must be conducted within 7 days before Day 1.  
f Serology includes testing for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (HCV) and 
human immunodeficiency viruses 1 and 2 (HIV 1/HIV 2). 
g Blood samples will be collected for clinical laboratory assessments following a fast of at least 4 hours. 
h  All medications taken within 28 days before screening through the end of the study will be recorded. 


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Table 3-2 
Study VX16-150-103: 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  
Xg 
 
 
 
 
Coagulation 
Xg 
 
 
 
 
 
 
 
 
 
 
PK blood sampleh 
 
X 
X 
X 
 
Drug test (urine) 
X 
 
 
 
 
Alcohol test (breath) 
X 
 
 
 
 
NPRSi 
X 
X 
X 
X 
 
VRSj 
 
X 
 
 
 
 
a  To maintain the blind, all subjects will receive the same number of capsules. The final dose of VX-150 or 
VX-150 placebo will be given 36 hours after the first dose, and the final dose of HB/APAP or HB/APAP 
placebo will be given 42 hours after the first dose. 
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 collected after the subject has been supine for at least 5 minutes 
and before any ECG or PK blood sampling. 
e Standard 12-lead ECGs will be measured before the first dose, and at 4 (± 1) hours after the first dose on Day 1. 
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. 
i  On Day -1, subjects will report their pain on the NPRS scale before administration of preoperative/perioperative 
pain medications. 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. 
j  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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Table 3-2 
Study VX16-150-103: 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 
Double-stopwatch assessment 
 
X 
 
 
 
Record rescue medication use 
 
X 
X 
X 
 
Medications review 
Continuous from signing of ICF through Safety Follow-up 
Treatments and procedures 
Continuous from signing of ICF through Safety Follow-up 
Adverse events 
Continuous from signing of ICF through Safety Follow-up 


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4 
TABLE OF CONTENTS 
1 Title Page 
................................................................................................
................................ 1 
 
2 Protocol Synopsis 
................................................................................................................... 4 
3 Schedule of Assessments........................................................................................................ 7 
4 Table of Contents 
................................................................................................................. 10 
List of Tables............................................................................................................................ 13 
List of Figures 
.......................................................................................................................... 13
 
List of Abbreviations................................................................................................................ 14 
5 Introduction.......................................................................................................................... 16 
6 Study Objectives 
.................................................................................................................. 17
 
6.1 Primary Objective 
........................................................................................................... 17
 
6.2 Secondary Objectives 
..................................................................................................... 17
 
 
 
7 Study Endpoints 
................................................................................................................... 17
 
7.1 Primary Endpoint 
............................................................................................................ 17 
7.2 Secondary Endpoints 
...................................................................................................... 17 
 
 
8 Study Population 
.................................................................................................................. 18
 
8.1 Inclusion Criteria 
............................................................................................................ 18
 
8.2 Exclusion Criteria 
........................................................................................................... 19
 
9 Study Implementation 
......................................................................................................... 20
 
9.1 Study Design .................................................................................................................. 20
 
9.1.1 Screening 
................................................................................................................ 21
 
9.1.2 Treatment Period 
.................................................................................................... 21
 
9.1.3 Follow-up................................................................................................................ 21 
9.1.4 Early Discontinuation 
............................................................................................. 22 
9.2 Method of Assigning Subjects to Treatment Groups 
..................................................... 22 
9.3 Rationale for Study Design and Study Drug Regimens 
................................................. 22 
9.3.1 Study Design........................................................................................................... 22 
9.3.2 Study Drug Dose and Duration .............................................................................. 22 
9.3.3 Rationale for Study Assessments ........................................................................... 23
 
9.4 Study Restrictions 
........................................................................................................... 23
 
9.4.1 Analgesic Medications ........................................................................................... 24
 
9.4.2 Additional Dietary Restrictions 
.............................................................................. 25
 
9.5 Prior and Concomitant Medications 
............................................................................... 25 
9.6 Administration 
................................................................................................................ 25
 
9.7 Dose Modification for Toxicity 
...................................................................................... 26 
9.8 Removal of Subjects 
....................................................................................................... 26 
9.9 Replacement of Subjects ................................................................................................ 26
 
10 Study Drug Information and Management 
....................................................................... 26
 
10.1 Preparation and Dispensing 
............................................................................................ 26 
10.2 Packaging and Labeling ................................................................................................. 26
 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 26 
10.4 Drug Accountability 
....................................................................................................... 27 


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10.5 Disposal, Return, or Retention of Unused Drug 
............................................................. 27 
10.6 Compliance 
..................................................................................................................... 27 
10.7 Blinding and Unblinding 
................................................................................................ 27 
10.7.1 Blinding 
.................................................................................................................. 27 
10.7.2 Unblinding 
.............................................................................................................. 28 
11 Assessments 
.......................................................................................................................... 29
 
11.1 Timing of Assessments 
................................................................................................... 29
 
11.2 Subject and Disease Characteristics 
............................................................................... 29
 
11.3 Pharmacokinetics 
............................................................................................................ 29
 
11.3.1 Blood Sampling 
...................................................................................................... 29 
11.3.2 Processing and Handling of Pharmacokinetic Samples ......................................... 30 
11.3.3 Bioanalysis.............................................................................................................. 30 
 
11.5 Efficacy 
........................................................................................................................... 30
 
11.6 Safety 
.............................................................................................................................. 30
 
11.6.1 Adverse Events 
....................................................................................................... 31
 
11.6.2 Clinical Laboratory Assessments 
........................................................................... 31
 
11.6.3 Physical Examinations and Vital Signs 
.................................................................. 32
 
11.6.4 Electrocardiograms 
................................................................................................. 32
 
11.6.5 Contraception and Pregnancy 
................................................................................. 33 
11.6.5.1 Contraception 
................................................................................................... 33 
11.6.5.2 Pregnancy 
......................................................................................................... 34
 
12 Statistical and Analytical Plans 
.......................................................................................... 34 
12.1 Sample Size and Power 
.................................................................................................. 35
 
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 Variables 
......................................................................... 37
 
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 
............................................................................................ 39
 
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 Interim and IDMC Analyses 
................................................................................... 39
 
12.4 Clinical Pharmacology Analysis 
.................................................................................... 39
 
12.4.1 Pharmacokinetic Analysis 
...................................................................................... 39
 


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12.4.2 Pharmacokinetic/Pharmacodynamic Analyses 
....................................................... 40
 
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................................................................... 41 
13.1.1.4 Adverse Event Severity 
.................................................................................... 41
 
13.1.1.5 Adverse Event Causality 
.................................................................................. 42
 
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 Documentation of Serious Adverse Events...................................................... 44 
13.1.2.3 Reporting Serious Adverse Events................................................................... 44 
13.1.2.4 Expedited Reporting and Investigator Safety Letters 
...................................... 44 
13.2 Administrative Requirements 
......................................................................................... 44
 
13.2.1 Ethical Considerations 
............................................................................................ 44 
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
 
13.3 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 3-1
 
Study VX15-150-103: Screening Period 
................................................................ 7
 
Table 3-2
 
Study VX16-150-103: Day -1, Treatment Period, and Safety Follow-up 
.............. 8 
Table 9-1
 
Study Restrictions 
................................................................................................. 23
 
Table 10-1
 Study Drug 
............................................................................................................ 27
 
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 
.................................................................. 42
 
List of Figures 
Figure 9-1
 
VX16-150-103 Study Design ............................................................................... 20 
 
 


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List of Abbreviations  
Abbreviation 
Definition 
AE 
adverse event 
ANCOVA 
analysis of covariance 
AUC 
area under the concentration versus time curve 
AUC0-24  
AUC from the time of dosing to 24 hours 
BMI 
body mass index 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRU 
clinical research unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
EDC 
web-based electronic data capture 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GPS 
Global Patient Safety 
HB/APAP 
hydrocodone bitartrate/acetaminophen 
HIPPA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IRB 
institutional review board 
IV 
intravenous 
IXRS 
interactive web or voice response system 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum value 
NA 
Not applicable 
NaV 
voltage-gated sodium channels 
NPRS 
Numeric Pain Rating Scale 
PE 
physical examination 
PK 
pharmacokinetics 
POC 
proof-of-concept 
prn 
as needed 
q4h 
every 4 hours 
q6h 
every 6 hours 
q12h 
every 12 hours 
qd 
daily 
QTcF 
QT interval corrected by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 


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SE 
standard error 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States of America 
Vertex 
Vertex Pharmaceuticals Incorporated 
VRS 
Verbal Categorical Rating Scale 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 
 








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8.2 
Exclusion Criteria 
Prior to 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 subjects 
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 
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. Intolerant of or unwilling to receive hydrocodone, acetaminophen, or 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  
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 
11. Participated in another investigational study within 30 days of the first dose of study drug 
12. 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 concomitant medication that is not otherwise 
exclusionary (e.g., benzodiazepines) will not disqualify subjects; however, marijuana will 
not be allowed  
13. 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 
14. Use of restricted medication or food within the specified duration before the first dose of 
study drug, as defined in Table 9-1 


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After surgery: 
15. Subject had a type 3 deformity requiring a base wedge osteotomy or concomitant surgery 
such as hammertoe repair; or experienced 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 2 randomized, double-blind, placebo-controlled, 3-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 remain in place until approximately 3AM, but no later than 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 240 subjects will be randomized 1:1:1 to VX-150, placebo, or 
HB/APAP; randomization will be stratified by site and sex. The first dose of VX-150 will be 
1500 mg, followed by 750 mg every 12 hours (q12h). The dose of HB/APAP will be 5 mg/325 
mg every 6 hours (q6h). 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 (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] q4h as needed [prn]).  
Figure 9-1 VX16-150-103 Study Design 
 
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. To maintain the blind, all subjects will receive the same number of capsules. 


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9.1.1 
Screening 
Screening Visit assessments are listed in Table 3-1. 
Screening will occur within 28 days before administration of study drug. 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). 
Subjects who do not meet the eligibility criteria may not be rescreened, with the following 
exceptions, all of which require medical monitor approval: 
• 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 
• Subjects who met all eligibility criteria but are not randomized for administrative reasons 
(e.g., interactive web or voice response system (IXRS) is temporarily inaccessible or 
nonfunctional, or study drug is not available at the study site) 
Any subject granted approval by the medical monitor for any of the exceptions listed above may 
have the screening window extended by 1 week before needing to undergo any rescreening 
assessments. If more than 35 days have elapsed from screening before first dose of study drug, 
all screening assessments need to be repeated. 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). In all cases, the medical monitor must authorize retesting. 
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 so 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. 




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2 hours of dosing, and maintain concentrations >1.9 µg/mL throughout the 48-hour period in 
which efficacy will be evaluated. This should result in rapid and sustained treatment effect.  
Based on the observed PK of the capsule formulation of VX-150, the mean VRT-1207355 C
max 
and AUC0-24 in this study will not exceed the exposure observed at the highest tested dose in 
human that was found to be safe and well tolerated 
 
  
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.
13 
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.
14, 15 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.” 
Use of rescue medications: The use of rescue medications is an important covariate in pain 
studies that can impact the analysis of other efficacy assessments. The use of rescue medications 
also provides an indirect assessment of study drug efficacy.  
9.4 
Study Restrictions 
Study restrictions are summarized in Table 9-1. 
Table 9-1 
Study Restrictions 
Restricted 
Medication/Food/Activity a 
Timing of Restriction 
From (minimum) 
To 
Other investigational drugs or 
devices 
28 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 such as iron, 
calcium, and 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 






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• 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. If a subject 
has been withdrawn from study drug treatment, the subject will continue to be followed, 
provided the subject has not withdrawn consent.  
If a subject does not return for a scheduled visit/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 the Safety Follow-up Phone Interview, if applicable (see 
Section 9.1.4), and follow up with the subject regarding any unresolved AEs. 
If the subject withdraws consent for the study, no further evaluations will be performed and no 
additional data will be collected. Vertex may retain and continue to use any data collected before 
such withdrawal of consent. 
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 individual dosing containers by 2 operators, and following national and local laws and 
regulations. 
10.2 
Packaging and Labeling 
Vertex will supply the 250-mg VX-150 capsules, 5-mg/325-mg HB/APAP capsules, and 
matching placebos. Study drug labeling will be in compliance with applicable local and national 
regulations. Additional details 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 


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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 
Formulation/ 
Route 
Dosage 
Packaging 
Storage 
Condition 
VX-150  
Capsule/Oral 
1500 mg 
(1
st dose) and 
750 mg q12h 
Supplied as 250-mg 
capsules  
≤25°C with excursions to 30°C 
VX-150 
placebo 
Capsule/Oral 
None 
Supplied as capsule 
≤25°C with excursions to 30°C 
HB/APAP 
Capsule/Oral 
5/325 mg 
Supplied as 
over-encapsulated 
5-mg/325-mg tablets 
20°C to 25°C 
HB/APAP 
placebo 
Capsule/Oral 
None 
Supplied as capsules 
20°C to 25°C 
 
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 until 
inventoried by the study monitor. The study monitor will review study drug records and 
inventory throughout the study. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will be required to retain all unused study drug until 
final drug accountability has been performed, at which point the investigator will be required to 
return all unused study drug to the sponsor, or designee, as instructed by the study monitor. The 
investigator will be required to maintain copies of study drug shipping receipts, drug 
accountability records, and records of return or final disposal of study drug. 
10.6 
Compliance  
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 will be a double-blind study.  
10.7.1 
Blinding  
All study personnel will be blinded to subject treatment assignments except for the following 
individuals:  
• Any site personnel for whom this information is important to ensure the safety of the subject 
in the event of a life-threatening medical emergency 


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• 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 
• An unblinded pharmacist at the CRU for dispensing study drug 
• 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 execution team 
• Vertex IXRS Management for IXRS oversight and system administration 
• Vertex Clinical Supply Chain 
• The bioanalytical laboratory/vendor personnel providing sample testing for the study 
Vertex medical monitor may, for matters relating to safety concerns, unblind individual subjects 
at any time. 
Vertex bioanalytical monitors will be unblinded to allow real time review of bioanalytical data. 
The Vertex bioanalytical monitors will not be members of the study team, and will not interact 
with the CRU or study personnel. 
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. This individual will not be a member of the study team, and will not 
interact with the CRU or study personnel. Masked IDs will be used for these analyses. 
10.7.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
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 
monitor. 
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. 


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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), 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 
11.1 
Timing of Assessments 
The timing of assessments is shown in Table 3-1 and Table 3-2.  
11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 
11.3 
Pharmacokinetics 
11.3.1 
Blood Sampling 
For the evaluation of plasma concentrations of VRT-1207355 and VRT-1268114, blood samples 
will be collected as shown in Table 11-1.  
These samples may also be used for evaluations of VX-150, metabolites of VRT-1207355, for 
further evaluation of the bioanalytical method, and for analyses that provide information on the 
metabolic pathways used by or affected by VX-150 and VRT-1207355. 
Plasma concentration samples collected from subjects treated with placebo study drug will not be 
routinely analyzed.  
All efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
Acceptable windows for sampling times are shown in Table 11-1. Samples collected outside of 
these acceptable windows will be considered protocol deviations. The following 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. 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Sampling Time 
Time From Scheduled Sampling Allowed 
Predose on Day 1 
Any time prior to 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 
 




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11.6.1 
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. 
11.6.2 
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. 
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. 


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Serum follicle-stimulating hormone (Screening Visit): 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 11.6.5.1), 
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 
for a subject to receive study drug. A positive drug screen for a known 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. 
11.6.3 
Physical Examinations and Vital Signs 
A PE of all body systems and vital signs assessment will be performed at Screening and select 
study visits (see Table 3-1 and Table 3-2). At other visits, symptom-directed PEs and symptom-
directed vital sign assessments can be performed at the discretion of the investigator or 
healthcare provider. 
A PE includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/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 (oral), pulse rate, and 
respiration rate. These will be assessed following at least a 5-minute rest in the supine position. 
11.6.4 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Schedule of Assessments (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: 


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• The subject will be instructed to rest in the supine position for at least 5 minutes before 
having an ECG performed. 
• The ECG will be performed before any other procedures that may affect heart rate, such as 
blood draws. 
The ECG traces will be manually read at the study site at the Screening Visit. 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 will be 
recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. A subject with a 
QTcF value above the threshold value will discontinue dosing. 
11.6.5 
Contraception and Pregnancy 
11.6.5.1 
Contraception 
At this stage in the development of VX-150, study participation requires a commitment from the 
male subject that he and his partner use 1 highly effective method of birth control (those, alone 
or in combination, which result in a low failure rate, i.e., less than 1% per year, when used 
consistently and correctly) 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. 


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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. 
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. 
11.6.5.2 
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 
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the Statistical Analysis Plan (SAP), and clinical pharmacologic 
analysis details will be provided in the Clinical Pharmacology Analysis Plan (CPAP), both of 
which will be finalized before the clinical data lock for the study and treatment unblinding. 


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12.1 
Sample Size and Power 
The sample size calculation is based on the primary efficacy analysis, i.e., the comparison 
between VX-150 and placebo. 
The primary efficacy endpoint is the time-weighted sum of the pain intensity difference 0 to 
24 hours after the first dose. The null hypothesis to be tested is that the mean time-weighted sum 
of the pain intensity difference 0 to 24 hours after the first dose is the same for VX-150 and 
placebo treatment groups. 
Assuming a standard deviation of 20, 64 subjects completing the study per treatment group 
would provide about 80% power to detect a treatment difference of 10 between VX-150 and 
placebo (effect size of 0.5) in mean time-weighted sum of the pain intensity difference over the 
first 24 hours after the first dose with a 5% level of significance. In order to allow for withdrawal 
of up to 20% of randomized subjects over the first 24 hours after the first dose, the study will 
enroll and randomize approximately 80 subjects per treatment group. 
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 efficacy 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 9.2 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 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, standard deviation (SD), standard error 


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(SE), median, minimum value (min), and maximum value (max). Categorical data will be 
summarized using counts and percentages. 
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 (i.e., completed Safety Follow-up Phone 
Interview), 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 will be 
summarized by Preferred Name using the World Health Organization-Drug Dictionary Enhanced 
(WHO-DDE) 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. 
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 8 time points during a period 
of 42 hours. 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 
Assessment of efficacy of VX-150 is the primary objective of this study. All efficacy endpoints 
will be analyzed based on the FAS. 






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A listing containing individual subject hematology and clinical chemistry measurements 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. The threshold value criteria for clinical 
laboratory data will be provided in the SAP. Urinalysis results will be listed only in individual 
subject data listings. These results will not be summarized. 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 visit for the following ECG measurements: PR, QT, QRS, and QTcF 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 ≤0 msec, >0 and ≤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 time point: 
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 time point will be provided. For each subject in the listing, measurements at all 
time points 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 
Interim and IDMC 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 provided in the CPAP. 


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


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13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF is signed until the following time points: 
• 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. 
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 in the study 
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 August 
2015). 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  
 


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13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories presented in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, such 
as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study 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 shown 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 shown in Table 13-4. 
Table 13-4  Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/Resolved With 
Sequelae 
Resolution of an AE with residual signs or symptoms 


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Table 13-4  Classifications for Outcome of an AE 
Classification 
Definition 
Not Recovered/Not 
Resolved (Continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
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, hospitalization, 
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 in the study 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. 
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 


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“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 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent through the Safety Follow-up Phone 
Interview, regardless of causality, will be reported by the investigator to Vertex GPS. 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. 
SAEs will be recorded on the Vertex Clinical Trial Safety Information Collection Form 
(hereafter referred to as the “SAE Form”) using a recognized medical term or diagnosis that 
accurately reflects the event. SAEs will be assessed by the investigator for relationship to the 
investigational study drug(s) and possible etiologies. On the SAE Form, relationship to study 
drug(s) will be assessed only as related (includes possibly related) or not related (includes 
unlikely related), and severity assessment will not be required. For the purposes of study 
analysis, if the event has not resolved at the end of the study reporting period, it will be 
documented as ongoing. For purposes of regulatory safety monitoring, the investigator is 
required to follow the event to resolution and report to Vertex the outcome of the event using the 
SAE Form. 
13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. 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: 
  
Contact Telephone: 
 
13.1.2.4 
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 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/local IEC 
of all unexpected serious adverse drug reactions involving risk to human subjects. 
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 


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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 only 
be conducted 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 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 shall be limited to the site and the study physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex and/or its representatives access to all pertinent 
medical records to allow for the verification of data gathered in the CRFs/SAE Forms and the 
review of the data collection process. The FDA and regulatory authorities in other jurisdictions, 
including the IRB/IEC, may also request access to all study records, including source 
documentation, for inspection. 


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For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act and associated regulations (“HIPAA”), an executed HIPAA 
authorization shall be obtained by the site from each subject (or the legal representative of the 
subject) before research activities may begin. Each HIPAA authorization shall 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. 
13.3 
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. 
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 study 
participant. 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.  






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14 
REFERENCES 
1  
Petersen KL, Rowbotham MC. Will ion-channel blockers be useful for management of 
nonneuropathic pain? J Pain. 2000;1(3 Suppl):26-34. 
2  
Centers for Disease Control and Prevention. Prescription Drug Overdose in the United 
States. Available at: http://www.cdc.gov/drugoverdose/data/index.html. Accessed 19 
June 2015. 
3  
European Monitoring Centre for Drugs and Drug Addiction. European Drug Report 
2014: Trends and Developments. Spain: 2014. 
4  
Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of 
opioid-induced hyperalgesia. Pain Physician. 2011;14(2):145-61. 
5 
Rush AM, Cummins TR. Painful Research: Identification of a Small-Molecule Inhibitor 
that Selectively Targets Nav1.8 Sodium Channels. Molecular Interventions. 
2007;7(4):192-95. 
6  
England S. Voltage-gated sodium channels: the search for subtype-selective analgesics. 
Expert Opinion on Investigational Drugs. 2008;17(12):1849-64. 
7  
Krafte D, Bannon A. Sodium channels and nociception: recent concepts and therapeutic 
opportunities. Current Opinion in Pharmacology. 2008;8(1):50-56. 
8 
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. 
9  
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. 
10  
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. 
11  
Akopian AN, Sivilotti L, Wood JN. A tetrodotoxin-resistant voltage-gated sodium 
channel expressed by sensory neurons. Nature. 1996;379(6562):257-62. 
12 
Vertex Pharmaceuticals Incorporated. Report VX-150 Investigator
's Brochure, Version 
3.0. Report date: 09 December 2016. 
13  
U.S. Food and Drug Administration. Guidance for Industry: Analgesic Indications: 
Developing Drug and Biological Products. 2014. 
14  
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. 
15  
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. 




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15.2 
Investigator Signature Page 
Protocol #:  VX16-150-103 Version #: 3.0 
Version Date: 
30 August 2017 
Study Title: A Phase 2 Randomized, Double-blind, Placebo-controlled, 3-arm, Parallel-design 
Study of the Efficacy and Safety of VX-150 for Acute Pain Following Bunionectomy 
 
 
I have read Protocol VX16-150-103, Version 3.0, 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: 
 
 
 
Vertex Pharmaceuticals Incorporated 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan (Final Analysis): 
Methods 
Protocol Number VX16-150-103 
(Final Analysis) 
 
A Phase 2 Randomized, Double-blind, Placebo controlled, 3-arm, 
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: 15 Dec 2017 
 
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 3 of 33 
Protocol Number: VX16-150-103 
Final Analysis 
Vertex Pharmaceuticals Incorporated 
 
8.3.2 Analysis of Secondary Efficacy Variables 
....................................................... 16 
8.3.2.1 Definition of Secondary Efficacy Variables 
.............................................. 16 
8.3.2.2 Secondary Analyses 
................................................................................... 17 
 
 
8.4 Safety Analysis 
......................................................................................................... 18 
8.4.1 Adverse Events 
................................................................................................. 18 
8.4.2 Clinical Laboratory Assessments 
..................................................................... 19 
8.4.3 Electrocardiogram ............................................................................................ 19 
8.4.4 Vital Signs 
........................................................................................................ 19 
8.4.5 Physical Examination 
....................................................................................... 19 
8.4.6 Other Safety Analysis 
....................................................................................... 20 
9 Summary of Interim and IDMC Analyses 
.................................................................. 20 
10 References 
....................................................................................................................... 21 
11 List of Appendices.......................................................................................................... 22 
Appendix A: Schedule of Assessments.............................................................................. 22 
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments ................... 25 
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates 
........... 27 
Appendix D: Imputation Rules for Missing AE dates 
....................................................... 28 
Appendix E: Threshold Value Criteria .............................................................................. 29 
 
Appendix G: Important Protocol Deviation Categories 
..................................................... 33 
 








Statistical Analysis Plan (Methods)  
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Final Analysis 
Vertex Pharmaceuticals Incorporated 
 
5.2 
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 
6 
STUDY DESIGN  
6.1 
Overall Design  
This is a Phase 2 randomized, double-blind, placebo-controlled, 3-arm, parallel-design study. 
Subjects will receive a primary unilateral first metatarsal bunionectomy repair on Day -1 
(Figure 6-1). A continuous popliteal sciatic block infusion (0.2% ropivacaine) will be started 
after surgery, and remain in place until approximately 3AM 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 Verbal Categorical Rating Scale (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. 
Subjects will report their pain on the NPRS at scheduled time points (Table 11-2) 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] q4h as needed [prn]).  
 
Figure 6-1  VX16-150-103 Study Design 
 
 
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. To maintain the blind, all subjects will receive the same number of capsules. 


Statistical Analysis Plan (Methods)  
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Final Analysis 
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6.2 
Sample Size and Power 
The sample size calculation is based on the primary efficacy analysis, i.e., the comparison 
between VX-150 and placebo. 
The primary efficacy endpoint is the time-weighted sum of the pain intensity difference 0 to 
24 hours after the first dose. The null hypothesis to be tested is that the mean time-weighted 
sum of the pain intensity difference 0 to 24 hours after the first dose is the same for VX-150 
and placebo treatment groups. 
Assuming a standard deviation of 20, 64 subjects completing the study per treatment group 
would provide about 80% power to detect a treatment difference of 10 between VX-150 and 
placebo (effect size of 0.5) in mean time-weighted sum of the pain intensity difference over 
the first 24 hours after the first dose with a 5% level of significance. In order to allow for 
withdrawal of up to 20% of randomized subjects over the first 24 hours after the first dose, 
the study will enroll and randomize approximately 80 subjects per treatment group. 
6.3 
Randomization 
A total of approximately 240 subjects will be randomized 1:1:1 to VX-150, placebo, or 
HB/APAP; randomization will be stratified by site and sex. The first dose of VX-150 will be 
1500 mg, followed by 750 mg every 12 hours (q12h). The dose of HB/APAP will be 
5 mg/325 mg every 6 hours (q6h). To maintain the blind, all subjects will receive the same 
number of capsules in a double-dummy design. 
An interactive web or voice response system (IXRS) will be used to assign subjects to 
treatment. The randomization code will be produced by 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.  
6.4 
Blinding and Unblinding 
This will be a double-blind study.  
6.4.1 
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 
 An unblinded pharmacist at the Clinical research Unit (CRU) for dispensing study drug 
 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 execution team 


Statistical Analysis Plan (Methods)  
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Final Analysis 
Vertex Pharmaceuticals Incorporated 
 
 Vertex IXRS Management for IXRS oversight and system administration 
 Vertex Clinical Supply Chain 
 The bioanalytical laboratory/vendor personnel providing sample testing for the study 
Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time. 
Vertex bioanalytical monitors will be unblinded to allow real time review of bioanalytical 
data. The Vertex bioanalytical monitors will not be members of the study team, and will not 
interact with the CRU or study personnel. 
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. This individual will not be a member of the study team, 
and will not interact with the CRU or study personnel. Masked IDs will be used for these 
analyses. 
6.4.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
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 monitor. 
7 
ANALYSIS SETS 
Assignment of subjects to analysis sets will be performed before the clinical data lock for the 
study.  
7.1 
All Subjects Set 
The All Subjects Set is defined as all subjects who have been randomized or have received at 
least 1 dose of study drug. This analysis set will be used in subject listings and disposition 
summary table, unless otherwise specified. 
7.2 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all randomized subjects who have received at least 
1 dose of study drug. The FAS is to be used in efficacy analyses in which subjects will be 
analyzed according to their randomized treatment group and not to the treatment they 
actually received. 


Statistical Analysis Plan (Methods)  
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Final Analysis 
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7.3 
Safety Set 
The Safety Set is defined as all subjects who have received at least 1 dose of study drug. The 
Safety Set is to be used for all safety analyses in which subjects will be analyzed according to 
the treatment they received and not according to their randomized treatment group. 
7.4 
Screen Failure Analysis Set 
The Screen Failure Analysis Set is defined as all subjects who completed the surgery but 
were not randomized and did not receive any study drug. This analysis set will be used to 
present a limited amount of data in tables and/or listings. 
 
8 
STATISTICAL ANALYSIS 
8.1 
General Considerations 
The Schedule of Assessments is provided in Appendix A. 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. 
All individual subject data, including those derived, for subjects who were randomized or 
received at least 1 dose of study drug, i.e. All Subjects Set, will be presented in individual 
subject data listings. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (SD), standard error (SE), 
median, minimum value (min), and maximum value (max). 
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 it will be 
defined as the most recent non-missing measurement (scheduled or unscheduled) collected 
before the initial administration 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.  
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/minimum on-treatment values and maximum/minimum 
change from baseline values for safety analyses. 
 In individual subject data listings as appropriate. 


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Visit windowing rules: The analysis visit windows for protocol-defined visits are provided 
in Appendix B.  
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 specified otherwise. 
Multiplicity: No multiplicity adjustment will be performed for hypothesis testing. 
8.2 
Background Characteristics  
8.2.1 
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 
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 treatment 
 Prematurely discontinued the treatment and the reason for discontinuation  
 Completed study (i.e., completed Safety Follow-up Phone Interview or Visit) 
 Prematurely discontinued the study and the reason for discontinuation  
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation. A randomization listing of subjects will be provided. 
No statistical tests will be carried out to evaluate any baseline imbalance between treatment 
groups. 
8.2.2 
Demographics and Baseline Characteristics 
Demographics, medical history 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 (female and male) 


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 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 on Day -1 as recorded on the NPRS 
 Pain intensity at baseline as recorded on the NPRS 
 Pain intensity at baseline as recorded on the VRS 
Medical history will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term (PT). 
8.2.3 
Prior and Concomitant Medications 
Medications taken 14 days before the Screening Visit and up to the Safety Follow-up will be 
summarized by Preferred Name using the World Health Organization-Drug Dictionary 
Enhanced (WHO-DDE, March 1, 2017) 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 a completely missing or partially missing start/stop date and it cannot be 
determined whether it was taken before the first dose date or concomitantly, it will be 
classified as prior and concomitant.
 
Details for imputing missing or partial start and/or stop dates of medication are described in 
Appendix C. 
8.2.4 
Study Drug Exposure and Study Drug Compliance 
All study drugs will be given to the subjects by site personnel at eight different times during 
a period of 42 hours. Therefore, it is not needed to perform a calculation of exposure to study 


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drug or a calculation of compliance. 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.  
8.2.5 
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 G.  
All IPDs will be summarized descriptively by treatment group and/or presented in an 
individual subject data listing. 
8.2.6 
Data for Screen Failures  
The following data will be summarized overall based on the Screen Failure Set 
 Age (in years) 
 Sex (female and male) 
 Inclusion criteria not met 
 Exclusion criteria met 
 Site 
 Pain intensity on Day -1 as recorded on the NPRS 
 Pain intensity on Day 1 as recorded on the NPRS 
 Pain intensity on Day 1 as recorded on the VRS 
If there are multiple measurements collected for NPRS and VRS on Day 1, select the most 
recent non-missing measurement. The same data will also be presented in individual subject 
data listings. 
 
8.3 
Efficacy Analysis 
The primary efficacy analysis in this study aims an effectiveness estimand that would assess 
effectiveness at planned endpoint using the time-weighted sum of the pain intensity 
difference (SPID), focusing on the causal effects attributable to the initially randomized 
treatments without the effects of possible rescue medication usage.  
Such an estimand hypothetically aims the treatment effects of the initial randomization only 
rather than any other treatment regimen including (inevitable) rescue medication usage after 
randomization. With such an estimand, all subjects in FAS with their primary efficacy 
endpoint data up to the planned time point would have been used even with possible rescue 
periods and discontinuation of initial randomized treatments. Due to the expectation of free 
confounding effects from rescues, pain intensity scores that were collected during certain 








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subjects, time to onset will be considered censored at the time the stopwatch is stopped 
plus 4 hours or at 6 hours, whichever happened earlier. If a subject discontinues from the 
study after the first six hours after the first dose of study medication, time to onset will be 
considered censored at 6 hours. If it can’t determined that whether a subject discontinues 
from the study within 6 hours after the first dose of study medication, time to onset will 
be considered censored at 6 hours.   
 Time to first rescue medication is the time elapsed from first dose of VX-150 or placebo 
until the subject receives the first dose of rescue medication. If the subject does not 
receive any rescue medication during the 48 hour treatment period, time to first dose will 
be considered censored at 48 hours. 
 The proportion of subjects with any use of rescue medication (Yes/No) within 24 hours 
after first dose of VX-150 or placebo will be evaluated in a categorical analysis. 
 Total use of rescue medication during the period 0 to 24 hours will be calculated as the 
sum of number of capsules*strength at each dosing occasion.  
 The proportion of subjects with any use of rescue medication (Yes/No) 24 to 48 hours 
after the first dose of VX-150 or placebo will be evaluated in a categorical analysis. 
 Total use of rescue medication during the period >24 to 48 hours will be calculated as the 
sum of number of capsules*strength at each dosing occasion.  
8.3.2.2 
Secondary Analyses  
 SPID22 and SPID48 will be analyzed in the same way as described for SPID24 after the 
same imputation strategies are applied as in Section 8.3.1.  
 Time to onset of “perceptible pain relief” will be analyzed using Cox regression model. 
The model will include treatment, site and sex as covariates. Additionally, the Kaplan-
Meier method will be used to estimate time to onset rates by treatment group and the 
associated plot will also be provided. 
Note: If in either treatment group fewer than 5 subjects experience “perceptible pain 
relief”, the Cox regression will not be performed and analysis of time-to-first event will 
be restricted to the Kaplan-Meier estimates 
 Time to onset of “meaningful pain relief” will be analyzed in the same way as described 
for time to onset of “perceptible pain relief”.  
 Time to first intake of rescue medication will be analyzed in the same way as described 
for time to onset of “perceptible pain relief”. 
 The proportion of subjects with any use of rescue medication during the period 0 – 2 
hours, 0 – 24 hours as well as >24 – 48 hours after first dose of VX-150 or placebo will 
be analyzed using the Cochran-Mantel-Haenszel test, stratified by site and sex. 
 Total rescue medication use 0 – 2 hours, 0 – 24 hours as well as >24 – 48 hours after the 
first dose of VX-150 or placebo will be analyzed using the Wilcoxon rank-sum test, 
stratified by site and sex. 
 




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SAEs, AEs leading to death, and AEs leading to study drug discontinuation will be listed 
separately. All AEs through Safety Follow-up will be listed in an individual subject data 
listing, including pretreatment AEs.  
8.4.2 
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 laboratory tests are provided in Appendix E. 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.  
8.4.3 
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, QTc for HR interval (QTcF [QTcF = QT/RR0.33]), QRS duration, 
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 as ≤30 msec, >30 and ≤60 msec, and >60 msec, will be 
provided. 
The threshold value criteria for ECG data are provided in Appendix E. A listing containing 
individual subject measurements meeting the threshold value criteria at any visit 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 Visit will be recorded as AEs.  
8.4.4 
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), HR (beats per minute), and respiratory rate (breaths per minute).  
The threshold value criteria for vital signs data are provided in Appendix E. A listing 
containing individual subject measurements meeting the threshold value criteria at any visit 
will be provided. For each subject in the listing, ECG measurements at all time points will be 
included. Clinically significant abnormal findings in vital signs will be reported as AEs.  
8.4.5 
Physical Examination  
PE results will be presented in individual subject data listings only. Clinically relevant results 
identified after screening will be reported as AEs. 


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8.4.6 
Other Safety Analysis 
Not applicable. 
9 
SUMMARY OF INTERIM AND IDMC ANALYSES 
Not applicable. 


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10 
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. 
 
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. 


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11 
LIST OF APPENDICES 
Appendix A: Schedule of Assessments 
Schedules of Assessments are shown in Table 11-1 and Table 11-2. 
Table 11-1 Study VX15-150-103: Screening Period 
Assessment 
Screening Period 
Day -28 to Day -2 
Outpatient visit 
X 
Informed consent form (ICF) 
X 
Inclusion/exclusion criteria 
X 
Demographics 
X 
Medical history 
X 
History of drug and alcohol use 
X 
Weight, height, and body mass index (BMI)a 
X 
Vital signsb 
X 
Standard 12-lead electrocardiogram (ECG)
c 
X 
Physical examination 
X 
Serum follicle-stimulating hormone (FSH)
d 
X 
Serum β-hCG (all female subjects)e 
X 
Serology (HBsAg, HCV, and HIV 1/HIV 2)f 
X 
Serum chemistryg 
X 
Hematologyg 
X 
Coagulationg 
X 
Urinalysis 
X 
Drug test (urine) 
X 
Medications reviewh 
Continuous from signing of ICF through Safety Follow-up 
Treatments and procedures 
Continuous from signing of ICF through Safety Follow-up 
Adverse events 
Continuous from signing of ICF through Safety Follow-up 
 
                                                 
a  Weight and height will be measured with shoes off. 
b  Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be collected after the subject has 
been supine for at least 5 minutes and before any ECG or PK blood sampling. 
c  ECGs will be performed after subjects have been supine for at least 5 minutes. ECGs will be done after vital 
signs and before any procedures that may affect heart rate (e.g., blood sampling). 
d  Serum FSH is required for postmenopausal female subjects only.  
e Serum β-hCG is required of all female subjects, and must be conducted within 7 days before Day 1.  
f  Serology includes testing for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (HCV) and 
human immunodeficiency viruses 1 and 2 (HIV 1/HIV 2). 
g  Blood samples will be collected for clinical laboratory assessments following a fast of at least 4 hours. 
h  All medications taken within 28 days before screening through the end of the study will be recorded. 


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Table 11-2 Study VX16-150-103: 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 dosing9 
 
X 
X 
X 
 
Discharge from CRU10 
 
 
 
X 
 
Phone interview11 
 
 
 
 
X 
Vital signs12 
X 
X 
X 
X 
 
Standard 12-lead ECG 
 
X13 
 
 
 
Physical examination 
X 
 
 
 
 
β-hCG (urine) 
X14 
 
 
 
 
Serum chemistry 
X15 
 
 
 
 
Hematology  
X15 
 
 
 
 
Coagulation 
X15 
 
 
 
 
PK blood sample  
 
X 
X 
X 
 
                                                 
9  To maintain the blind, all subjects will receive the same number of capsules. The final dose of VX-150 or VX-150 placebo will be given 36 hours after 
the first dose, and the final dose of HB/APAP or HB/APAP placebo will be given 42 hours after the first dose. 
10 Subjects will be discharged on Day 3 after completion of the Day 3 assessments. 
11  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. 
12 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 collected after the subject has been supine for at least 5 minutes and before any ECG or PK blood sampling. 
13 Standard 12-lead ECGs will be measured before the first dose, and at 4 (± 1) hours after the first dose on Day 1. 
14  A β-hCG test on Day -1 is only required for women of childbearing potential. 
15 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.  
16 PK blood samples will be collected on Days 1 and 2 before the first dose of VX-150 or VX-150 placebo for the day and at 1, 2, 4, 6, 8, and 12 hours 
after the first dose of VX-150 or VX-150 placebo for the day. On Day 2, a PK blood sample will also be collected 12 hours after the second dose of VX-
150 or VX-150 placebo for the day. 


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Table 11-2 Study VX16-150-103: 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 
 
 
 
 
NPRS17 
X 
X 
X 
X 
 
VRS18 
 
X 
 
 
 
Double-stopwatch assessment 
 
X 
 
 
 
Record rescue medication use 
 
X 
X 
X 
 
Medications review 
Continuous from signing of ICF through Safety Follow-up 
Treatments and procedures 
Continuous from signing of ICF through Safety Follow-up 
Adverse events 
Continuous from signing of ICF through Safety Follow-up 
 
 
 
                                                 
17  On Day -1, subjects will report their pain on the NPRS scale before administration of preoperative/perioperative pain medications. 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. 
18  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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Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 11-3 Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit 
Target Study Day per 
the protocol 
Analysis Visit Window 
(in study days) 
Safety Assessment 
Hematology 
Serum Chemistry 
Coagulation 
Baseline 
 
Day -1 
 
Before first dose of study 
drug 
 
 
 
 
 
 
Standard 12-Lead ECG 
 
Baseline 
Day 1 
Before first dose of study 
drug 
Day 1  
 
4 hrs. after first dose of 
study drug at Day 1 
3 – 5 hours after first dose of 
study drug  
 
Vital Signs 
 
Baseline 
Day 1 
 
Day 2  
 
Day 2 
 
Day 3  
 
Day 3 
 
Efficacy Assessment 
NPRS 
 
Day -1 
 
 
Day -1 
 
 
Before administration of 
preoperative/perioperative 
pain medications 
Baseline  
Day 1, 0 hrs. 
After removal of the 
popliteal sciatic block and 
before first dose of study 
drug 
Day 1 - Day 3 
0.5, 1, 1.5, 2, 3, 4, 5, 
6, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, and 
48 hrs. after first dose 
of study drug at Day 1 
± 5 minutes at each timepoint 
VRS 
 
Baseline 
 
 
Day 1 
 
 
After removal of the 
popliteal sciatic block and 
before first dose of study 
drug  
 
Rescue Medication 
Day 1, Day 2 and Day 3 Any time 
After first dose of study drug  
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. 


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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 will be used; or  
ii. If there are multiple measurements within the same distance from the target day, 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 will be used; or  
ii. If there are multiple measurements within the same distance from the target day, the latest 
measurement will be used. 
 
c. When define efficacy and safety at baseline, refer to the generic baseline definition on Section 8.1.  
For vital sign, there is no time collected and Day 1 will be baseline.  
 
 


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Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month.  
b. If DAY and Month are both missing, use the first day of the year.  
c. 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. 
In summary, the prior and/or concomitant categorization of a medication is described below. 
Table 11-4 Prior and/orConcomitant Categorization of a Medication 
Medication Start Date 
Medication Stop Date 
< First Dose Date of 
Study Drug 
≥ First Dose Date and ≤ End Date of TE 
Period 
< First dose date of study drug 
P 
PC 
≥ First dose date and  
≤ End date of TE period 
- 
C 
C: Concomitant; P: Prior 
 
 


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Appendix D: Imputation Rules for Missing AE dates 
Imputation rules for missing or partial AE start date are defined below: 
If only Day of AE start date is missing:  
If the AE start year and month are the same as that for the first dose date, then: 
 If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start day as the day of first dose date; otherwise, impute 
the AE start day as 1. 
 Otherwise, 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 AE start year is the same as first dose year, then: 
 If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start Month and Day as the Month and Day of first dose 
date; otherwise, impute the AE start Month as January and the Day as 1. 
 Otherwise, impute the AE start MONTH as January and the DAY as 1. 
Compare the imputed AE start date with TE period to determine whether the AE is 
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. 


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Appendix E: Threshold Value Criteria 
 
Table 11-5 Threshold Value Criteria for Laboratory Tests 
Parameter 
 
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 
 


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Table 11-5 Threshold Value Criteria for Laboratory Tests 
Parameter 
 
Comments 
Sodium 
≤129 mmol/L 
≥150 mmol/L 
 
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. 
 
 
 


Protocol VX16-150-103, Version 1.0 
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Table 11-6 Threshold Value Criteria for ECGs 
Parameter 
 
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 
Borderline 
Prolonged* 
Additional 
 
Absolute values (ms) 
Borderline: 431-450 ms (Male); 451-470 ms 
(Female) 
Prolonged: >450 ms (Male); >470 ms (Female) 
≥500 ms 
 
Increase from baseline 
Borderline: Increase from baseline 30-60 ms 
Prolonged: Increase from baseline >60 ms 
To be applied to any kind of QT correction 
formula.  
 
 
 
 
Note: Based on CPMP 1997 guideline. 
 
Table 11-7 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. 
Orthostatic 
Hypotension 
Orthostatic SBP 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA criteria Feb 2007. 
 
 
 
 




Protocol VX16-150-103, Version 1.0 
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Vertex Pharmaceuticals Incorporated 
 
Appendix G: Important Protocol Deviation Categories 
 Date Informed Consent Signed 
 Inclusion/Exclusion Criteria Eligibility 
 Randomization / Enrollment 
 Missing/Out of Window Study Assessment 
 Timing of Assessments 
 Study Restrictions/ Withdrawal Criteria 
 Dose Administration 
 Sample Collection 
 Safety Assessments