Clinical trial NCT03304522
Conditions: Small Fiber Neuropathy
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2017-09-20; Completion date: 2018-11-08
Enrollment: 89 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluating the efficacy of VX-150 for the treatment of pain caused by small fiber neuropathy.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: VX-150 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants received VX-150 1250 milligrams (mg) once daily (qd) orally for 6 weeks. intervention 2: Participants received placebo matched to VX-150 for 6 weeks.

Protocol documents:
Prot_000.pdf: 
 
Page 1 of 54 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 2, Randomized, Double-blind, 
Placebo-controlled, 6-Week, Parallel-design Study of 
the Efficacy and Safety of VX-150 in Treating 
Subjects With Pain Caused by Small Fiber 
Neuropathy 
Vertex Study Number: VX16-150-102 
 
EudraCT Number: 2017-001042-10  
Date of Protocol: 25 May 2018 (Version 5.0) 
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 VX16-150-102, Version 5.0 
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2 
PROTOCOL SYNOPSIS 
Title A Phase 2, Randomized, Double-blind, Placebo-controlled, 6-Week, Parallel-design 
Study of the Efficacy and Safety of VX-150 in Treating Subjects With Pain Caused 
by Small Fiber Neuropathy 
Brief Title A Study to Evaluate the Efficacy and Safety of VX-150 in Treating Subjects With 
Pain Caused by Small Fiber Neuropathy 
  
Clinical Phase and 
Clinical Study Type  
Phase 2 efficacy and safety 
  
Objectives Primary Objective: 
To evaluate the efficacy of VX-150 for the treatment of pain caused by small fiber 
neuropathy 
Secondary Objectives: 
• 
To evaluate the safety and tolerability of VX-150 
• 
To evaluate the pharmacokinetics (PK) of VRT-1207355 and the metabolite 
VRT-1268114 
  
Endpoints Primary Endpoint: 
Change from baseline in the weekly average of daily pain intensity on the 11-point 
numeric rating scale (NRS), as reported in the daily diary, at Week 6  
Secondary Endpoints: 
• 
Proportion of subjects with ≥30% reduction in the weekly average of daily pain 
intensity on the 11-point NRS, as reported in the daily diary, at Week 6 
• 
Proportion of subjects with ≥50% reduction in the weekly average of daily pain 
intensity on the 11-point NRS, as reported in the daily diary, at Week 6 
• 
Change from baseline in the Daily Sleep Interference Scale (DSIS) at Week 6 
• 
Proportion of subjects categorized as improved at Week 6 on the patient global 
impression of change (PGIC) assessment  
• 
Change from baseline in pain intensity on the 11-point NRS, as reported at study 
visits, at Week 6 
• 
Plasma PK parameters of VRT-1207355 and the metabolite VRT-1268114 
• 
Safety and tolerability based on the Columbia Suicide Severity Rating Scale (C-
SSRS), incidence and type of adverse events (AEs), changes from baseline in 
clinically significant laboratory test results, vital signs, and ECGs at each visit 
Number of Subjects Up to approximately 114 subjects 
  
Study Population Males and females between the ages of 18 and 80 years, inclusive 


Protocol VX16-150-102, Version 5.0 
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Investigational Drug Active substance: VX-150 
 Activity: Nav 1.8 blocker 
 Strength and route of administration: 1250 mg total dose daily, administered as 
250-mg capsules orally 
  
Study Duration From Day -7 to last day of Safety Follow-up Visit, each subject will participate in the 
study for approximately 11 weeks. 
  
Study Design This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study. Up to approximately 114 subjects with small fiber neuropathy will 
be randomized 1:1 to VX-150 or placebo. Randomization will be stratified by sex and 
diagnosis of diabetes. Subjects with diabetes will not exceed approximately 60% of 
the total number of subjects. Subjects with diabetes and HbA1c ≥8% and <11% at 
screening will not exceed approximately 20% of the total number of subjects.  
This study will include: 
• 
A 7-day Run-in Period to establish the baseline NRS pain score 
• 
A 6-week Treatment Period 
• 
A 28-day Safety Follow-up Period 
  
Assessments Efficacy: NRS, DSIS, PGIC, 
 
Safety: AEs, C-SSRS, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, and physical examinations (PEs). 
PK: Plasma PK parameters of VRT-1207355 and VRT-1268114 
 
  
Statistical Analyses The primary efficacy endpoint is the change from baseline in the weekly average of 
daily pain intensity on the 11-point NRS, as reported in the daily diary, at Week 6. 
The primary analysis of the primary endpoint will be a within-group treatment 
comparison in the VX-150 treatment group. The analysis will be conducted using a 
mixed-effects model for repeated measures (MMRM). The  between-group treatment 
comparison will also be generated using the same MMRM.  
The model will include the change from study baseline in the weekly average of daily 
NRS pain score as the dependent variable; treatment, sex, diagnosis of diabetes, 
week, and treatment-by-week interaction as fixed effects; subject as a random effect; 
and baseline pain intensity score as a covariate. In the model, week will be treated as 
a class variable, and an unstructured covariance matrix will be assumed to model the 
within-subject variability.  
The estimated mean and corresponding 95% CI for VX-150 will be provided for the 
within-group change. The CI will first be used to facilitate the comparison with 0; this 
will be followed by a comparison with 0.8. In addition, the estimated mean and 
corresponding 95% CI for the between-group difference 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 VX16-150-102: Screening 
Event/Assessment 
Screeninga 
Day -28 to Day -1 
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)b 
X 
Vital signsc 
X 
Physical examination 
X 
Standard 12-lead electrocardiogram (ECG)d 
X 
Serum β-hCG (all female subjects) 
X 
Serum follicle-stimulating hormone (FSH)e 
X 
Serology (HBsAg, HCV, and HIV 1/HIV 2) 
X 
Serum chemistryf 
X 
Hematologyf 
X 
Coagulationf 
X 
HbA1cg 
X 
Thyroid function test 
X 
Methylmalonic acid 
X 
Vitamin B12 
X 
Urinalysis 
X 
Drug and alcohol testing  
X 
Skin biopsy 
X 
Nerve conduction studies (NCS) 
X 
Education on appropriate expectations for being in a clinical 
study and reporting pain 
X 
11-pt numeric rating scale (NRS) pain score via daily diary 
from Days -7 through -1h 
X 
 a 
Subjects must discontinue all treatment for neuropathic pain (including medications, supplements, and 
non-pharmaceutical therapies) by Day -14 (see Section 9.4.1). 
b 
Weight and height will be measured with shoes off. 
c 
Vital signs (pulse rate, respiratory rate, blood pressure, and temperature) will be collected after the subject has 
been seated or supine for at least 5 minutes and before any 12-lead ECG assessment or blood sampling. 
d 
12-lead ECGs will be performed after subjects have been supine for at least 5 minutes. 12-lead ECGs will be 
done after vital signs and before any procedures that may affect heart rate (e.g., blood sampling). 
e 
Serum FSH is required for suspected postmenopausal female subjects only.  
f 
Blood samples will be collected for clinical laboratory assessments following a fast of at least 4 hours. 
g  
HbA1c will only be assessed for subjects with diabetes. 
h  
Subjects will report their average daily pain during the last 24 hours on the NRS.  


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Table 3-1 
Study VX16-150-102: Screening 
Event/Assessment 
Screeninga 
Day -28 to Day -1 
Prior medications taken for the treatment of   
neuropathic paini 
X 
Prior and concomitant medicationsj 
Continuous from signing of ICF through Safety 
Follow-up Visit 
Treatments and procedures 
Continuous from signing of ICF through Safety 
Follow-up Visit 
Adverse events 
Continuous from signing of ICF through Safety 
Follow-up Visit 
 i  
All medications previously taken for the treatment of neuropathic pain will be recorded. Subjects will also 
indicate whether the medications were discontinued, and if so, the reason for discontinuation. 
j  
All medications taken within 28 days before screening through the Safety Follow-up Visit will be recorded. 


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Table 3-2 
Study VX16-150-102: Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessment 
Day -7 
(During 
Screening) 
Day 1 
Day 7 
(± 1 Day) 
Week 3 
(± 3 Days) 
Week 6 
(± 3 Days) 
ETT 
Visita 
Safety 
Follow-up Visit  
28 (± 7) Days 
After the Last 
Dose of Study 
Drug 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
Study drug dosingb 
 
Day 1 through Week 6 
Weightc 
X 
X 
  
  
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
Standard 12-lead ECGe 
X 
X 
X 
 
 
X 
X 
Physical examinationf 
 
X 
 
 
 
 
 
Neurological examination 
 
 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
 
 
 
X 
X 
Drug and alcohol testing 
X 
 
 
X 
X 
X 
 
Pregnancy testg 
serum 
urine 
urine 
urine 
serum 
serum 
serum 
Coagulation 
 
 
 
  
X 
X 
X 
Hematology 
 
X 
 
X 
X 
 
X 
Serum chemistry 
 
X 
 
X 
X 
 
X 
PK samplingh 
 
 
X 
X 
X 
X 
 
a 
If the subject prematurely discontinues study treatment, an Early Termination of Treatment (ETT) Visit should be scheduled as soon as possible after the subject decides to 
terminate study treatment. Subjects who prematurely discontinue treatment will also be required to complete the Safety Follow-up Visit, approximately 28 (± 7) days after 
their last dose of study drug. If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit will replace the Safety Follow-up Visit, and a 
separate Safety Follow-up Visit will not be required. 
b 
Study drug (VX-150 or placebo) will be administered daily under fasted conditions. The Day 7 dose will be administered at the clinic. 
c 
Weight will be measured with shoes off. 
d 
Vital signs will be collected after the subject has been at rest (seated or supine) for at least 5 minutes. 
e 
Standard 12-lead ECGs will be performed after subjects have been supine for at least 5 minutes. 12-lead ECGs will be done after vital signs and before any procedures that 
may affect heart rate (e.g., blood sampling).  
f 
The neurological component of the Day 1 complete physical examination includes sensory testing conducted with the bedside sensory testing kit (BSTK). Symptom-directed 
physical examinations will occur at any time during the study if triggered by AEs or if deemed necessary by the investigator. 
g 
Pregnancy tests will only be performed for female subjects of childbearing potential. 
h 
With the exception of Day 7, PK samples will be collected at any time during the study visit. On Day 7, 2 PK samples will be collected: 1 sample before the dose of study 
drug, and 1 sample 1 to 4 hours after the dose of study drug.  


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Table 3-2 
Study VX16-150-102: Run-in Period, Treatment Period, and Safety Follow-up Visit 
Event/Assessment 
Day -7 
(During 
Screening) 
Day 1 
Day 7 
(± 1 Day) 
Week 3 
(± 3 Days) 
Week 6 
(± 3 Days) 
ETT 
Visita 
Safety 
Follow-up Visit  
28 (± 7) Days 
After the Last 
Dose of Study 
Drug 
11-pt numeric rating scale (NRS) pain score 
via daily diaryi 
Day -7 through Week 6 or ETT Visit via daily diary 
 
 
11-pt NRS pain score at study visitsj 
X 
X 
X 
X 
X 
X 
X 
Daily Sleep Interference Scale (DSIS)k 
Day -7 through Week 6 or ETT Visit via daily diary 
 
 
Patient global impression of change (PGIC) 
 
X 
X 
X 
X 
X 
X 
Columbia Suicide Severity Rating Scale 
(C-SSRS) 
 
X 
X 
X 
X 
X 
X 
Study drug count  
 
 
X 
X 
X 
X 
 
Medications review 
Continuous from signing of the ICF through the Safety Follow-up Visit 
Concomitant treatments and procedures 
Continuous from signing of the ICF through the Safety Follow-up Visit 
Adverse events 
Continuous from signing of the ICF through the Safety Follow-up Visit 
  i 
From Day -7 through Week 6 or ETT Visit, subjects will report their average daily pain during the last 24 hours on the NRS each evening. Subjects will also report their 
current pain immediately before each administration of rescue medication.  
j 
At study visits, subjects will report their average pain during the last 24 hours on the NRS. 
k 
From Day -7 through Week 6 or ETT Visit, subjects will report each morning on the previous night’s sleep using the DSIS. 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Protocol Synopsis ................................................................................................................... 5 
3 
Schedule of Assessments ........................................................................................................ 7 
4 
Table of Contents ................................................................................................................. 11 
List of Tables ........................................................................................................................... 14 
List of Figures .......................................................................................................................... 14 
List of Abbreviations ............................................................................................................... 15 
5 
Introduction .......................................................................................................................... 17 
6 
Study Objectives .................................................................................................................. 18 
6.1 
Primary Objective ........................................................................................................... 18 
6.2 
Secondary Objectives ..................................................................................................... 18 
7 
Study Endpoints ................................................................................................................... 18 
7.1 
Primary Endpoint ............................................................................................................ 18 
7.2 
Secondary Endpoints ...................................................................................................... 18 
 
 
8 
Study Population .................................................................................................................. 19 
8.1 
Inclusion Criteria ............................................................................................................ 19 
8.2 
Exclusion Criteria ........................................................................................................... 19 
9 
Study Implementation ......................................................................................................... 21 
9.1 
Study Design .................................................................................................................. 21 
9.1.1 
Screening ................................................................................................................ 21 
9.1.2 
Run-in Period .......................................................................................................... 22 
9.1.3 
Treatment Period .................................................................................................... 22 
9.1.4 
Follow-up ................................................................................................................ 22 
9.1.5 
Early Termination of Treatment ............................................................................. 23 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 23 
9.3 
Rationale for Study Design and Study Drug Regimens ................................................. 23 
9.3.1 
Study Design ........................................................................................................... 23 
9.3.2 
Study Drug Dose and Duration .............................................................................. 23 
9.3.3 
Rationale for Study Assessments ........................................................................... 24 
9.4 
Study Restrictions ........................................................................................................... 25 
9.4.1 
Treatments for Pain ................................................................................................ 26 
9.4.2 
Additional Dietary Restrictions .............................................................................. 26 
9.5 
Administration ................................................................................................................ 26 
9.6 
Dose Modification for Toxicity ...................................................................................... 27 
9.7 
Removal of Subjects ....................................................................................................... 27 
9.8 
Replacement of Subjects ................................................................................................ 27 
10 Study Drug Information and Management ....................................................................... 28 
10.1 Preparation and Dispensing ............................................................................................ 28 
10.2 Packaging and Labeling ................................................................................................. 28 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 28 
10.4 Drug Accountability ....................................................................................................... 28 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 28 


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10.6 Compliance ..................................................................................................................... 28 
10.7 Blinding and Unblinding ................................................................................................ 29 
10.7.1 
Blinding .................................................................................................................. 29 
10.7.2 
Unblinding .............................................................................................................. 29 
11 Assessments .......................................................................................................................... 30 
11.1 Timing of Assessments ................................................................................................... 30 
11.2 Subject and Disease Characteristics ............................................................................... 30 
11.3 Pharmacokinetics ............................................................................................................ 30 
11.3.1 
Blood Sampling ...................................................................................................... 30 
11.3.2 
Processing and Handling of Pharmacokinetic Samples ......................................... 31 
11.3.3 
Bioanalysis .............................................................................................................. 31 
 
11.5 Efficacy ........................................................................................................................... 31 
11.6 Safety .............................................................................................................................. 31 
11.6.1 
Adverse Events ....................................................................................................... 32 
11.6.2 
Clinical Laboratory Assessments ........................................................................... 32 
11.6.3 
Physical Examinations and Vital Signs .................................................................. 34 
11.6.4 
Electrocardiograms ................................................................................................. 34 
11.6.5 
Columbia Suicide Severity Rating Scale ................................................................ 35 
11.6.6 
Contraception and Pregnancy ................................................................................. 35 
11.6.6.1 Contraception ................................................................................................... 35 
11.6.6.2 Pregnancy ......................................................................................................... 36 
12 Statistical and Analytical Plans .......................................................................................... 36 
12.1 Sample Size and Power .................................................................................................. 37 
12.2 Analysis Sets .................................................................................................................. 37 
12.3 Statistical Analysis ......................................................................................................... 38 
12.3.1 
General Considerations ........................................................................................... 38 
12.3.2 
Background Characteristics .................................................................................... 38 
12.3.2.1 Subject Disposition .......................................................................................... 38 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 38 
12.3.2.3 Prior and Concomitant Medications ................................................................ 38 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 39 
12.3.3 
Efficacy Analysis .................................................................................................... 39 
12.3.3.1 Analysis of Primary Variable ........................................................................... 39 
12.3.3.2 Analysis of Secondary Efficacy Variables ....................................................... 39 
 
12.3.4 
Safety Analysis ....................................................................................................... 40 
12.3.4.1 Adverse Events ................................................................................................ 40 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 41 
12.3.4.3 Electrocardiogram ............................................................................................ 41 
12.3.4.4 Vital Signs ........................................................................................................ 41 
12.3.4.5 Physical Examination ....................................................................................... 41 
12.3.4.6 Other Safety Analysis ...................................................................................... 41 
12.3.5 
Interim and IDMC Analyses ................................................................................... 42 
12.4 Clinical Pharmacology Analysis .................................................................................... 42 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 42 


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12.4.2 
Pharmacodynamic Analysis ................................................................................... 42 
12.4.3 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 42 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 42 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 42 
13.1.1 
Adverse Events ....................................................................................................... 42 
13.1.1.1 Definition of an Adverse Event........................................................................ 42 
13.1.1.2 Clinically Significant Assessments .................................................................. 42 
13.1.1.3 Documentation of Adverse Events................................................................... 43 
13.1.1.4 Adverse Event Severity .................................................................................... 43 
13.1.1.5 Adverse Event Causality .................................................................................. 44 
13.1.1.6 Study Drug Action Taken ................................................................................ 44 
13.1.1.7 Adverse Event Outcome .................................................................................. 45 
13.1.1.8 Treatment Given............................................................................................... 45 
13.1.2 
Serious Adverse Events .......................................................................................... 45 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 45 
13.1.2.2 Documentation of Serious Adverse Events ...................................................... 46 
13.1.2.3 Reporting Serious Adverse Events .................................................................. 46 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 46 
13.2 Administrative Requirements ......................................................................................... 47 
13.2.1 
Ethical Considerations ............................................................................................ 47 
13.2.2 
Subject Information and Informed Consent ........................................................... 47 
13.2.3 
Investigator Compliance ......................................................................................... 47 
13.2.4 
Access to Records ................................................................................................... 47 
13.2.5 
Subject Privacy ....................................................................................................... 47 
13.2.6 
Record Retention .................................................................................................... 48 
13.2.7 
Study Termination .................................................................................................. 48 
13.3 Data Quality Assurance .................................................................................................. 49 
13.4 Monitoring ...................................................................................................................... 49 
13.5 Electronic Data Capture ................................................................................................. 49 
13.6 Publications and Clinical Study Report .......................................................................... 50 
 
 
13.6.2 
Clinical Study Report ............................................................................................. 50 
14 References ............................................................................................................................. 51 
15 Protocol Signature Pages .................................................................................................... 53 
15.1 Sponsor Signature Page .................................................................................................. 53 
15.2 Investigator Signature Page ............................................................................................ 54 


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List of Tables 
Table 3-1 
Study VX16-150-102: Screening ............................................................................ 7 
Table 3-2 
Study VX16-150-102: Run-in Period, Treatment Period, and Safety Follow-up 
Visit ......................................................................................................................... 9 
Table 9-1 
Study Restrictions ................................................................................................. 25 
Table 10-1 
Study Drug ............................................................................................................ 28 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 32 
Table 11-2 
Acceptable Methods of Contraception .................................................................. 36 
Table 12-1 
Power for the 95% CIs for Within- and Between-group Changes ........................ 37 
Table 13-1 
Grading of AE Severity ........................................................................................ 44 
Table 13-2 
Classifications for AE Causality ........................................................................... 44 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 44 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 45 
List of Figures 
Figure 9-1 
Schematic of Study Design ................................................................................... 21 
 


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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 
area under the concentration versus time curve from the time of dosing to 24 hours 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
BSTK 
bedside sensory testing kit 
Cmax 
maximum observed concentration 
CI 
confidence interval 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
CSR 
clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDI 
drug-drug interaction 
DSIS 
Daily Sleep Interference Scale 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ETT 
Early Termination of Treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GPS 
Global Patient Safety 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
independent ethics committee 
IRB 
institutional review board 
IXRS 
interactive response system in which X represents voice or web, such as IWRS 
max 
maximum value 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
MRC 
Medical Research Council 
n 
number of subjects 


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Abbreviation 
Definition 
Nav 
voltage-gated sodium channels 
NCS 
nerve conduction studies 
 
 
NRS 
numeric rating scale 
PCS 
potentially clinically significant 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
PGIC 
patient global impression of change 
PK 
pharmacokinetic, pharmacokinetics 
PR 
PR interval, segment 
prn 
as needed 
qd 
daily 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QT 
QT interval 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SET 
study execution team 
 
 
 
 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SI 
SI units (International System of Units) 
TEAE 
treatment-emergent adverse event 
US 
United States 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 
 


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5 
INTRODUCTION 
Pain is the most common symptom for which patients seek medical attention. It is a protective 
mechanism designed to prevent tissue injury. When pain persists beyond its usefulness, it 
becomes pathological and can prove debilitating. Current pain therapies suffer from poor 
efficacy and have a high risk of adverse events (AEs). For example, lidocaine (a nonselective 
sodium channel blocker) may effectively reduce pain, but its utility is limited because of 
prominent side effects when given at dose levels required for pain relief.1 Opioid pain 
medications have a high abuse liability with approximately 16,000 annual deaths in the US and 
between 10,000 and 20,000 annual deaths in Europe due to overdose.2, 3 In addition, opioid-
induced hyperalgesia also limits the long-term use of opioids. While the incidence of opioid-
induced hyperalgesia is not known, it is encountered regularly in clinical practice and creates 
significant challenges in pain management.4 The limited treatment options for pain, particularly 
chronic pain indications, combined with a growing awareness of the risks of the current 
standards of care underscore the need for new pain management therapies.  
Voltage-gated sodium channels (Nav) play a critical role in pain signaling based on both 
nonclinical and clinical evidence. Evaluation of the role these channels play in normal 
physiology and the pathological states arising from mutations in sodium channel genes and 
animal models, as well as the pharmacology of known sodium channel modulating agents, all 
point to the critical role of Navs in pain sensation.5-7 The Nav1.8 channel is primarily restricted to 
peripheral neurons that sense pain (e.g., dorsal root ganglia) and is known to mediate pain 
sensation and chronic pain. For example, Nav1.8 gain-of-function mutations are thought to 
directly cause chronic pain in some patients with painful small fiber neuropathy.8-10 This channel 
has been identified as a target for analgesia11 and selective Nav1.8 blockers, which have the 
potential to treat pain indications where the primary mechanism for pain is nociceptor 
hyperexcitability. 
VX-150, an orally bioavailable prodrug that rapidly converts in vivo to the active moiety 
VRT-1207355, is being developed for the treatment of pain. VRT-1207355 is a Nav1.8 blocker 
that is highly selective for Nav1.8 relative to the other sodium channel subtypes. 
To date, 4 Phase 1 clinical studies have been completed with VX-150.
 
 
 
  
One Phase 2a study has completed dosing; Study VX15-150-101 (Study 101) is a proof of 
concept study to evaluate efficacy in patients with osteoarthritis pain. Overall, VX-150 has been 
well tolerated without any safety concerns. Additional details of the VX-150 development 
program are available in the VX-150 Investigator’s Brochure.12 
Small fiber neuropathy is a distinct clinical condition caused by diseases affecting peripheral 
small nerve fibers (Aδ- and C-fibers). Common symptoms include burning pain in the feet and 


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evoked pain (e.g., pressure and touch allodynia). Diagnosis is defined as possible, probable, and 
definite based on the combination of symptoms, signs, evidence of large sensory nerve fiber 
function integrity by nerve conduction studies (NCS) and abnormal skin biopsy or quantitative 
sensory testing.13, 14 By inhibiting NaV1.8 in the peripheral nerve fibers, VX-150 has the potential 
to treat pain caused by hyperexcitability of the damaged or diseased nerves. 
Study VX16-150-102 is a proof of concept study that will evaluate the efficacy, safety, 
tolerability, and pharmacokinetics (PK) of VX-150 in the treatment of neuropathic pain in 
subjects with small fiber neuropathy. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the efficacy of VX-150 for the treatment of pain caused by small fiber neuropathy 
6.2 
Secondary Objectives 
• To evaluate the safety and tolerability of VX-150 
• To evaluate the PK of VRT-1207355 and the metabolite VRT-1268114 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Change from baseline in the weekly average of daily pain intensity on the 11-point numeric 
rating scale (NRS), as reported in the daily diary, at Week 6 
7.2 
Secondary Endpoints 
• Proportion of subjects with ≥30% reduction in the weekly average of daily pain intensity 
on the 11-point NRS, as reported in the daily diary, at Week 6 
• Proportion of subjects with ≥50% reduction in the weekly average of daily pain intensity 
on the 11-point NRS, as reported in the daily diary, at Week 6 
• Change from baseline in the Daily Sleep Interference Scale (DSIS) at Week 6 
• Proportion of subjects categorized as improved at Week 6 on the patient global 
impression of change (PGIC) assessment  
• Change from baseline in pain intensity on the 11-point NRS, as reported at study visits, at 
Week 6  
• Plasma PK parameters of VRT-1207355 and the metabolite VRT-1268114 
• Safety and tolerability based on the Columbia Suicide Severity Rating Scale (C-SSRS), 
incidence and type of AEs, changes from baseline in clinically significant laboratory test 
results, vital signs, and ECGs at each visit 


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8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible 
for the study. 
8.1 
Inclusion Criteria 
1. Subject will sign and date an informed consent form (ICF) 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures 
3. Subjects (male and female) will be between the ages of 18 and 80 years, inclusive.  
4. Body mass index (BMI) of ≥18.0 kg/m2 
5. Diagnosis of small fiber neuropathy, as per European Federation Neurological Societies 
(EFNS)/American Academy of Neurology (AAN) guidelines, with pain for at least 3 months 
prior to screening  
6. Reduction below the 5th percentile of sex and age-adjusted normal values in epidermal nerve 
fiber density on punch skin biopsy at the distal site of the leg performed at screening  
7. Presence of sural nerve responses 
8. Average NRS score between ≥4 and ≤9 reported in the daily diary on Days -7 through -1  
8.2 
Exclusion Criteria 
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. Exposure to neurotoxic drugs (i.e., chemotherapy) since diagnosis of small fiber neuropathy. 
Untreated or uncontrolled connective tissue disorders, sarcoidosis, Sjögren’s syndrome, 
amyloidosis, Fabry’s disease, celiac disease, Lyme disease, autoimmune disorders (i.e., as 
assessed by anti-nuclear antibodies, rheumatoid factor, sedimentation rate, and/or lupus anti-
coagulant) including myasthenia gravis and Guillain-Barre syndrome, which in the opinion 
of the investigator makes the subject unsuitable for inclusion in this study. 
3. A known or clinically suspected infection with human immunodeficiency virus or hepatitis B 
or C viruses 


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4. Current clinically significant liver or kidney dysfunction 
5. Current uncontrolled thyroid dysfunction 
6. Subjects with a diagnosis of diabetes who have any 1 of the following criteria: 
• HbA1c ≥11% at screening 
• are not stabilized on oral hypoglycemics and/or subcutaneous insulin or diet, in the 
opinion of the investigator 
• evidence of ulcers or severe nephropathy resulting from their diabetes 
• advanced retinopathy, defined as greater than State 3 (moderate non-proliferative diabetic 
retinopathy)15 
• history of a clinical atherosclerotic event, such as myocardial infarction or stroke  
7. History of cardiac dysrhythmias requiring anti-arrhythmia treatment(s); or history or 
evidence of abnormal ECGs that in the opinion of the investigator or medical monitor would 
preclude the subject's participation in the study 
8. Standard 12-lead ECG demonstrating QTc >450 msec at screening. If QTc exceeds 
450 msec, the ECG will be repeated 2 more times, and the average of the 3 QTc values will 
be used to determine the subject’s eligibility. 
9. Concomitant severe pain conditions (i.e., low back pain, radiculopathy, severe bone and 
musculoskeletal disorders) which may impair self-assessment of pain due to small fiber 
neuropathy 
10. Abnormal laboratory results indicative of any significant medical disease that, in the opinion 
of the investigator, would preclude the subject's participation in the study 
11. 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  
12. Female subjects who are pregnant, nursing, or planning to become pregnant during the study 
or within 90 days after the last study drug dose 
13. 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 
14. Use of restricted medication or food within the specified duration before the first dose of 
study drug, as defined in Table 9-1 
15. Alcohol, analgesic/opioid, and/or illicit drug abuse as defined by the American Psychiatric 
Association Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, in the last 
12 months before screening, or a positive test for drugs of abuse at screening  
• A positive drug screen for a known concomitant medication that is not otherwise 
exclusionary (e.g., benzodiazepines) will not disqualify subjects; however, marijuana and 
marijuana derivatives will not be allowed  


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16. 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 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter 
study (Figure 9-1). Up to approximately 114 subjects with small fiber neuropathy will be 
randomized 1:1 to VX-150 or placebo. Randomization will be stratified by sex and diagnosis of 
diabetes. Subjects with diabetes will not exceed approximately 60% of the total number of 
subjects. Subjects with diabetes and HbA1c ≥8% and <11% at screening will not exceed 
approximately 20% of the total number of subjects.  
This study will include: 
• A 7-day Run-in Period to establish the baseline NRS pain score 
• A 6-week Treatment Period 
• A 28-day Safety Follow-up Period 
Figure 9-1 
Schematic of Study Design 
 
D: Day; qd: daily; W: Week 
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 Screening Visit can 
occur between Days -28 and -8. 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). During screening, subjects will discontinue their current pain treatments as 
outlined in Section 9.4.1. Subjects will be permitted to take acetaminophen as needed (prn), 
following the guidelines in Section 9.4.1. 
Subjects will be instructed during screening on appropriate expectations around their 
participation in a clinical study and the importance of consistently and accurately reporting their 
pain throughout the study (e.g., “Participating in a Research Study” and “Reporting Your Pain”, 
Analgesic Solutions, Natick, MA). Review of these educational materials may be repeated for 


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some or all subjects depending on findings of an ongoing blinded data review (e.g., if pain score 
variability is increased on a subject or site level). 
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, except skin biopsy and NCS, 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 
Run-in Period 
Run-in Period assessments are listed in Table 3-2 and will occur from Day -7 through Day -1 
during screening. During the Run-in Period, subjects will report their average pain as described 
in Section 11.5 to establish the baseline NRS pain score. Subjects will follow the pain treatment 
restrictions outlined in Section 9.4.1. Subjects will be permitted to take acetaminophen prn, 
following the guidelines in Section 9.4.1, as a rescue medication for intermittent pain. 
9.1.3 
Treatment Period 
Treatment Period assessments are listed in Table 3-2. 
All study periods will be conducted as described previously in Section 9.1. Dosing details are 
given in Section 9.3.2. During the Treatment Period, subjects will follow the pain treatment 
restrictions outlined in Section 9.4.1. Subjects will be permitted to take acetaminophen prn, 
following the guidelines in Section 9.4.1, as a rescue medication for intermittent pain. 
Subjects who prematurely discontinue study drug treatment will remain in the study from the 
time of discontinuation of study drug treatment through the last scheduled study visit, and 
complete assessments for all study visits, as described in Section 9.1.5. 
9.1.4 
Follow-up 
Subjects will have a Safety Follow-up Visit 28 (± 7) days after the last study drug dose. Safety 
Follow-up Visit assessments are listed in Table 3-2. 


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9.1.5 
Early Termination of Treatment 
If the subject prematurely discontinues study drug treatment, an Early Termination of Treatment 
(ETT) Visit should be scheduled as soon as possible after the subject decides to terminate study 
drug treatment. 
Subjects who prematurely discontinue treatment will also be required to complete the Safety 
Follow-up Visit, approximately 28 days (± 7) days after their last dose of study drug. The 
assessments performed at the Safety Follow-up Visit are listed in Table 3-2. If the ETT Visit 
occurs 3 weeks or later following the last dose of study drug, then the ETT Visit will replace the 
Safety Follow-up Visit, and a separate Safety Follow-up Visit will not be required.  
If the subject withdraws consent for the study, no further evaluations should be performed, and 
no additional data should be collected. Vertex Pharmaceuticals Incorporated may retain and 
continue to use any data collected before such withdrawal of consent. 
9.2 
Method of Assigning Subjects to Treatment Groups 
An interactive web response system (IWRS) will be used to assign subjects to treatment. The 
randomization code will be produced by Vertex Biostatistics or a qualified randomization 
vendor. The Vertex study biostatistician will review and approve the production of the final 
randomization list, which will be reviewed and approved by a designated unblinded 
biostatistician who is not a member of the study execution team (SET). 
9.3 
Rationale for Study Design and Study Drug Regimens 
9.3.1 
Study Design 
This study is designed to evaluate the efficacy of VX-150 for treatment of pain in subjects with 
small fiber neuropathy. The randomized, double-blind study design will limit observer bias, 
minimize carryover effect and reduce the possibility for unblinding. The potential for a carryover 
effect is due either to the potential subjective nature of pain measurements and/or the effect of 
treatment with VX-150. For the primary endpoint, daily NRS pain scores will be averaged over a 
weekly period to reduce the impact on the analyses of individual high or low pain scores. 
9.3.2 
Study Drug Dose and Duration 
The VX-150 dose selected for this study will be 1250 mg qd administered under fasting 
conditions using a capsule formulation.
 
  
 
 
 
  
 
 
 
 
 
 


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9.3.3 
Rationale for Study Assessments 
11-point NRS: Pain intensity is the FDA-recommended efficacy endpoint for studies of pain 
drugs.16, 17 This evaluation is a standard pain assessment scale used in many pain registration 
studies. The 11-point scale ranges from 0 (no pain) to 10 (worst imaginable pain).  
The minimum clinically important difference for an individual is considered to be a 1-point 
change from baseline, approximately equivalent to 15% to 20% improvement. Changes of 
2 points are considered equivalent to approximately 30% to 36% improvement (i.e., meaningful 
improvement); and changes of ≥4 points are considered equivalent to ≥50% improvement 
(i.e., substantial improvement).17, 18  
DSIS: Pain frequently interferes with sleep and sleep is important to quality of life. The FDA 
recommends evaluating the effect of analgesics on sleep.16, 17 DSIS is commonly used in 
neuropathic pain studies and is assessed on an 11-point NRS. The 11-point scale ranges from 0 
(none) to 10 (severe).  
PGIC: The PGIC is commonly used in neuropathic pain studies, and the IMMPACT group 
recommends it as a core outcome measure for chronic pain studies.17 There is some evidence that 
PGIC may be more sensitive in neuropathic pain studies than pain intensity assessments because 
it may assess additional quality of life measures.18 The assessment consists of a single item on a 
7-point scale from 1 (very much improved) to 7 (very much worse). 
C-SSRS: The FDA recommends the evaluation of suicidality in clinical studies. The C-SSRS 
evaluates this through a series of questions about suicidal thoughts and behaviors. 


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NCS: NCS are a standard assessment for the diagnosis of small fiber neuropathy. Normal NCS 
are part of the diagnostic criteria for small fiber neuropathy. NCS will be performed to rule out 
large nerve fiber involvement. 
Skin biopsy: Punch skin biopsy will be performed at screening to confirm the diagnosis of small 
fiber neuropathy based on the epidermal nerve fiber density. Skin biopsy is considered the gold 
standard for diagnosis of small fiber neuropathy.  
9.4 
Study Restrictions 
Study restrictions are summarized in Table 9-1. 
Table 9-1 
Study Restrictions 
Restricted 
Medication/Food/Activitya 
Timing of Restriction 
From (minimum) 
To 
Other investigational drugs or 
devices 
1 month before first study drug dose, 
or time determined by local 
requirements; whichever is longest 
Completion of Safety Follow-up Visit 
assessments 
Sensitive CYP3A substrates 
7 days before first study drug dose  
Completion of Safety Follow-up Visit 
assessments 
Medications with potential effects 
on sodium channel function, 
including lamotrigine, 
carbamazepine, oxcarbazepine, 
mexiletine, amitriptyline, and 
topical agents 
14 days before first study drug dose  
Completion of Week 6 or ETT Visit 
assessments 
Any use of marijuana or 
marijuana derivatives 
14 days before first study drug dose 
Completion of Week 6 or ETT Visit 
assessments 
Capsaicin patch 
90 days before first study drug dose 
Completion of Week 6 or ETT Visit 
assessments 
Gabapentin and pregabalin 
14 days before first study drug dose 
Completion of Week 6 or ETT Visit 
assessments 
All treatments for pain  
(as outlined in Section 9.4.1) 
14 days before first study drug dose 
Completion of Week 6 or ETT Visit 
assessments 
Vitamin E supplements 
7 days before first study drug dose 
Completion of Safety Follow-up Visit 
assessments 


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Table 9-1 
Study Restrictions 
Restricted 
Medication/Food/Activitya 
Timing of Restriction 
From (minimum) 
To 
Grapefruit/grapefruit juice, 
pomelos, star fruit, Seville 
oranges, marmalade 
7 days before first study drug dose 
Completion of Week 6 or ETT Visit 
assessments 
a 
Refer to the Study Reference Manual for a more complete list of prohibited/restricted medications. 
All medications taken from 28 days before screening through the Safety Follow-up Visit will be 
recorded with indication, route of administration, and start and stop dates of administration. All 
subjects will be questioned about medications at each study visit. 
9.4.1 
Treatments for Pain 
• Subjects will abstain from all treatment for neuropathic pain (including medications, 
supplements, and non-pharmaceutical therapies) from 14 days before the first dose of 
study drug through the Week 6 Visit (or ETT Visit, if applicable). Subjects taking aspirin 
for cardiovascular health may remain on their stable dose throughout the study. 
• Acetaminophen will be permitted as a pain rescue medication prn throughout the study. 
Subjects will be permitted to take 500 mg every 4 to 6 hours prn, up to a maximum of 
2500 mg in any 24-hour period prn. Subjects will record rescue medication use, and their 
current pain on the NRS immediately before each administration of rescue medication. 
• There are no restrictions on pain treatments between the completion of the Week 6 Visit 
(or ETT Visit, if applicable) and the Safety Follow-up Visit. 
9.4.2 
Additional Dietary Restrictions 
Subjects will abstain from all food and drink (except water) at least 4 hours before the Screening 
Visit safety laboratory evaluations. 
Subjects will abstain from all food and drink (except water, black coffee, or tea) at least 2 hours 
prior to dosing and for 2 hours after dosing.
 
 
9.5 
Administration 
VX-150 will be administered 1250 mg qd orally.  
• Subjects will abstain from all food and drink (except water, black coffee, or tea) at least 
2 hours prior to dosing and for 2 hours after dosing. 
 
 
• Subjects will take study drug at approximately the same time each day and will be 
administered orally with approximately 240 mL (8 fluid ounces) of water. 


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• Subjects will swallow the study drug whole, and will not chew the drug before 
swallowing. 
• If a subject forgets to take a dose and remembers within 12 hours (before the halfway 
point of the dosing interval), they will take the dose at that time and resume their normal 
schedule for the following dose. 
• If a subject forgets to take a dose and remembers more than 12 hours after the missed 
dose, they will skip that dose and resume their normal schedule for the following dose. 
• On days of the study visits where a PK sample is collected, the following will be 
recorded for each of the 2 doses taken before the visit: 
o date and time the dose was taken 
o amount taken 
o whether the dose was taken with or without food 
• The Day 7 dose will be administered at the clinic. At the Day 7 clinic visit, 1 PK sample 
will be collected before the dose of study drug, and 1 PK sample will be collected 1 to 
4 hours after the dose of study drug. 
9.6 
Dose Modification for Toxicity 
If any unacceptable toxicity arises, individual subjects will discontinue dosing (Section 9.1.5). 
9.7 
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.  
Subjects who discontinue study treatment early should continue to return for safety assessments, 
as noted in Section 9.1.5.  
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a Safety Follow-up Visit, if 
applicable (see Section 9.1.5), 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. 
9.8 
Replacement of Subjects 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period may be replaced at Vertex's discretion. 


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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. 
10.2 
Packaging and Labeling 
Vertex will supply the 250-mg VX-150 and placebo capsules. 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. 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 
VX-150  
Capsule/Oral 
1250 mg, qd 
Supplied as 250-mg capsules  
VX-150 placebo 
Capsule/Oral 
None 
Supplied as capsules 
 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. Subjects will be instructed to return all unused materials associated with 
the study drug to the site. 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 retain all materials returned by the subjects until 
the study monitor has performed drug accountability. At the end of the study, the study monitor 
will provide instructions as to the disposition of any unused investigational product. If the study 
monitor authorizes destruction at the study site, the investigator will ensure that the materials are 
destroyed in compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Vertex. Destruction will be adequately documented. 
10.6 
Compliance  
Drug accountability will be assessed at each clinic visit by counting returned dosage units. 
Discrepancies will be discussed with the subject and recorded in the source documents. If 
subjects demonstrate continued noncompliance of study drug dosing despite educational efforts, 


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the investigator will contact the medical monitor to discuss discontinuing the subject from the 
study.  
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 
• Any site personnel for whom this information is important to ensure the safety of the 
subject (or female partner of the male subject) and the fetus in the event of a pregnancy 
• An unblinded pharmacist at the contract research organization (CRO) 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 team 
• Vertex IXRS Management for IXRS oversight and system administration 
• Vertex Clinical Supply Chain 
• The bioanalytical laboratory/vendor personnel managed by Vertex Bioanalysis 
Vertex medical monitor may, for matters relating to safety concerns, unblind individual subjects 
at any time 
A Vertex Bioanalysis Representative will be unblinded to allow real time review of bioanalytical 
data. This individual, however, will not be a member of the SET, and will not interact with the 
clinical research unit (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 data set is being provided for 
preliminary analysis. This individual, however, will not be a member of the SET, 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. 


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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. 
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 
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 from all subjects according to the Schedule of Assessments (Table 3-2). 
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.  
Blood samples collected from subjects administered placebo will not be routinely analyzed.  
The following will be recorded before PK sample collection: date and time the dose was taken, 
amount taken, time since they last ate, and a description of the contents of their meal. 


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11.3.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be provided in the PK sample handling guidelines. 
The shipment address and assay laboratory contact information will be provided to the 
investigational site before initiation of the study. 
11.3.3 
Bioanalysis 
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee standard operating procedures. A description of the assay and validation data will be 
provided in separate reports. 
11.5 
Efficacy 
11-point NRS: Pain intensity will be evaluated using the 11-point NRS. From Day -7 through 
Week 6, subjects will report their average daily pain during the last 24 hours on the NRS via 
electronic diary. 
 
 At study visits, subjects will also report their average pain during the last 24 hours 
on the NRS. The NRS scores from the daily diary will be used in the primary endpoint analysis, 
and the proportion of subjects with ≥30% and ≥50% reduction in weekly average scores as 
reported in the daily diary and at study visits will be used in the secondary endpoint analyses. 
DSIS: The DSIS will be completed each morning in an electronic diary to describe how pain 
interfered with the subject’s sleep. 
PGIC: The PGIC will be completed at study visits to quantify the change in subjects’ overall 
status. 
11.6 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, ECGs, physical examinations (PEs), and the C-SSRS. 


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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. At other time points, fasting is only required with respect to dosing (see 
Section 9.4.2 and Section 9.5). On Day 1, blood samples will be collected before the first dose of 
study drug. At all other scheduled visits, these samples will be collected at any time during the 
clinic visit. 
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 11-1. 
Table 11-1 
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 transaminase (=SGOT)  
Alanine transaminase (=SGPT)  
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Thyrotropin 
Cholesterol  
Triglycerides 
Low-density lipoprotein-direct  
High-density lipoprotein  
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  
Leukocyte esterase  
Nitrite  
Urine protein  
pH 
Urine blood  
Specific gravity  
Urine glucose  
Note: Screening Visit blood draws will be done after a minimum 4-hour fast.  
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be performed and results provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
b 
If blood urea nitrogen cannot be collected, urea may be substituted. 


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Additional tests at screening: The following additional tests will be performed during screening 
to assess eligibility: 
• Serum beta-human chorionic gonadotropin (β-hCG) for all female subjects 
• Serum follicle-stimulating hormone (FSH) for suspected postmenopausal female subjects 
only. Levels will be within the laboratory’s range for postmenopausal levels for subjects 
to be considered of non-childbearing potential. 
• 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). 
• HbA1c (for subjects with diabetes only) 
• Thyroid function test 
• Methylmalonic acid 
• Vitamin B12 
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. 
Pregnancy testing for female subjects of childbearing potential (as defined in Section 11.6.6.1): 
Pregnancy test results must be negative for female subjects of childbearing potential to receive 
study drug. 
During treatment, if a urine or serum pregnancy test is positive, all study drug dosing will stop 
and the pregnancy will be confirmed with a serum β-hCG test. If confirmed, the pregnancy will 
be reported and the subject will be permanently withdrawn from study drug dosing as discussed 
in Section 11.6.6.2. If a pregnancy test is positive, the procedures outlined in Section 11.6.6.2 
will be followed. 
Drug and alcohol testing: Opiates, methadone, amphetamines/methamphetamines, cannabinoids, 
cocaine, barbiturates, and benzodiazepines will be assessed by a urine test. Alcohol will be 
assessed by a blood, urine, or breath test. Subjects may undergo random drug and alcohol testing 
if deemed appropriate by the investigator. Drug and alcohol test results must be negative for all 
subjects to receive study drug. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
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. 


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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 (Table 3-1 and Table 3-2). At other visits, symptom-directed PEs will occur at any 
time during the study if triggered by AEs or if deemed necessary by the investigator. 
A PE includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/throat; 
respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and neurological. 
Breast, anorectal, and genital examinations will be performed when medically indicated. After 
screening, any clinically significant abnormal findings in PEs will be reported as AEs. 
The neurological component of the Day 1 complete PE includes the bedside sensory testing kit 
(BSTK) for the purpose of standardized assessment and phenotyping of subjects’ pain, using the 
usual components of the neurological examination. Included in the BSTK are standard tools used 
in assessment of the neurological system, including a turning fork, foam brushes, von Frey fiber, 
and safety pins.  
A focused neurological examination will be performed at all other visits after the Day 1 Visit. 
The focused neurological examination includes: testing of strength via the Medical Research 
Council (MRC) rating scale, reflexes, sensation to light touch, and pin prick. 
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 seated or 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: 
• 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 procedures that may affect heart rate, such as 
blood sampling. 
The ECG traces will be manually read at the study site at the Screening Visit and Safety 
Follow-up 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 through the Safety Follow-up Visit will be recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF is increased by >60 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If either of the QTcF 
values from these repeated ECGs remains above the threshold value (>60 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. A subject with a 
QTcF value above the threshold value will discontinue dosing. 


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11.6.5 
Columbia Suicide Severity Rating Scale 
The C-SSRS will be performed according to the Schedule of Assessments (Table 3-2). 
11.6.6 
Contraception and Pregnancy 
11.6.6.1 
Contraception 
Following the recommendations outlined by the Heads of Medicines Agencies Clinical Trial 
Facilitation Group, study participation requires a commitment from the subject that he/she and 
his/her partner use 1 acceptable method of contraception that is listed in Table 11-2 from the 
Screening Visit through 90 days after the last dose of study drug. Male subjects must also not 
donate sperm from the first study drug dose through 90 days after the last dose of study drug. 
Additional contraception requirements may need to be followed according to local regulations 
and/or requirements. 
The contraception requirement for the couple is waived for the following: 
• True abstinence for the subject, when this is consistent with the preferred and usual 
lifestyle of the subject. True abstinence must be practiced from the Screening Visit 
through 90 days after the last dose of study drug. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable 
methods of contraception.  
• If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented 
through examination of a semen specimen. 
• If the female is of non-childbearing potential. To be considered of non-childbearing 
potential, the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 2 years and a serum follicle-stimulating 
hormone level within the laboratory's reference range for postmenopausal females 
o Documented bilateral oophorectomy and/or hysterectomy 
• Same sex relationships 
Unique situations that may not fall within the above specifications may be discussed with the 
sponsor’s medical monitor or designee on an individual basis. 


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Table 11-2 
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 
first dose of study drug  
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) 
used alone or in combination with cap, 
diaphragm, or sponge with spermicide 
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 (non-hormone releasing) for at 
least 90 days before the first dose of 
study drug 
Yes 
Yes 
Hormonal contraceptives, if 
successfully used for at least 60 days 
before the first dose of study drug 
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 acceptable form of contraception due to the potential for 
drug-drug interactions between hormonal contraceptives and VX-150 resulting in reduced exposure and 
contraception failure. 
11.6.6.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a subject or the female partner of a male subject becomes pregnant while participating in the 
study, 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 Safety 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 primary efficacy endpoint is the change from baseline in the weekly average of daily pain 
intensity on the 11-point NRS, as reported in the daily diary, at Week 6. The primary analysis of 
the primary efficacy endpoint will be a within-group treatment comparison in the VX-150 
treatment group. The 95% CI for the within-group change will be used to evaluate if there is any 
significant change from baseline (within-group change against 0). Additional analyses will 
include an evaluation of this within-group change against 0.8, an expected change from the 
placebo group, and a 95% CI for the between-group comparison of change from baseline. 
Assuming a within-group change of 0.8 for placebo and a between-group treatment difference of 
1.2522-24, the expected within-group change for VX-150 is 2.05. With an SD of 2.08, the power 
for the 95% CI for the within-group change to rule out 0 or 0.8 is summarized in Table 12-1 for 
25, 35, or 45 evaluable subjects per group. The power for the 95% CI for the between-group 
treatment difference to rule out 0 is also provided. In order to allow for withdrawal of up to 20% 
of randomized subjects over 6 weeks of treatment, the study will enroll and randomize a 
minimum of approximately 62 subjects (25 evaluable subjects per group) and up to 
approximately 114 subjects (45 evaluable subjects per group) in total.  
Table 12-1 
Power for the 95% CIs for Within- and Between-group Changes 
Number of  Evaluable 
Subjects Per Group 
Power for the 95% CI 
for the Within-group 
Change to Rule Out 0 
Power for the 95% CI 
for the Within-group 
Change to Rule Out 0.8 
Power for the 95% CI for 
the Between-group 
Treatment Difference to 
Rule Out 0 
25 
>99% 
82% 
55% 
35 
>99% 
93% 
70% 
45 
>99% 
98% 
81% 
CI: confidence interval 
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 is considered to be sufficient and interpretable. 


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12.3 
Statistical Analysis 
The primary objective of this study is to evaluate the efficacy of VX-150 in treating pain caused 
by small fiber neuropathy.  
This section presents a summary of the planned statistical analyses of efficacy and safety. The 
Vertex Biometrics department 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. 
12.3.1 
General Considerations 
All individual subject data for all individual subjects randomized or exposed to study drug will 
be presented in data listings. Continuous data will be summarized using the following descriptive 
summary statistics: the number of subjects (n), mean, SD, SE, median, minimum value (min), 
and maximum value (max). Categorical data will be summarized using counts and percentages. 
Baseline value for the NRS daily diary scores and the DSIS will be defined as the average score 
from Day -7 to Day -1. For all other variables baseline will be defined as the most recent 
non-missing measurement 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 Visit), 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, diagnosis of diabetes, and pain 
in the Run-in Period. 
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 28 days before the Screening Visit and up to the Safety Follow-up Visit 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. 


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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 
Exposure to study drug (i.e., duration of treatment) will be summarized for the FAS in terms of 
duration of treatment a subject received (in days), defined as the last day minus the first day of 
study drug plus 1. 
Dosing compliance will be summarized for the FAS, and is calculated as the actual number of 
dosing occasions at which study drug was administered, as a percentage of the planned number 
of dosing occasions. 
Duration of treatment and dosing compliance will be summarized by means of descriptive 
summary statistics. 
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. 
12.3.3.1 
Analysis of Primary Variable 
The primary efficacy endpoint is the change from baseline in the weekly average of daily pain 
intensity on the 11-point NRS, as reported in the daily diary, at Week 6. 
The primary analysis of the primary endpoint will be a within-group treatment comparison in the 
VX-150 treatment group. The analysis will be conducted using a mixed-effects model for 
repeated measures (MMRM). The between-group treatment comparison will also be generated 
using the same MMRM. The model will include the change from study baseline in the weekly 
average of daily pain intensity score as the dependent variable; treatment, sex, diagnosis of 
diabetes, week, and treatment-by-week interaction as fixed effects; subject as a random effect; 
and baseline pain intensity score as a covariate. In the model, week will be treated as a class 
variable, and an unstructured covariance matrix will be assumed to model the within-subject 
variability. The denominator degrees of freedom for the F-test for fixed effects will be estimated 
using the Kenward-Roger approximation. 
The estimated mean and corresponding 95% CI for VX-150 will be provided for the within-
group change. The CI will first be used to facilitate the comparison with 0; this will be followed 
by a comparison with 0.8. In addition, the estimated mean and corresponding 95% CI for the 
between-group difference will be provided.  
12.3.3.2 
Analysis of Secondary Efficacy Variables 
Secondary endpoints are:  
• Proportion of subjects with ≥30% reduction in the weekly average of daily pain intensity 
on the 11-point NRS, as reported in the daily diary, at Week 6. This endpoint will be 
evaluated using descriptive statistics. 


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• Proportion of subjects with ≥50% reduction in the weekly average of daily pain intensity 
on the 11-point NRS, as reported in the daily diary, at Week 6. This endpoint will be 
evaluated using descriptive statistics. 
• Change from baseline in the DSIS at Week 6. The analysis of this endpoint will be 
similar to the primary analysis. 
• Proportion of subjects categorized as improved at Week 6 on the PGIC assessment. This 
endpoint will be evaluated using descriptive statistics. 
• Change from baseline in pain intensity on the 11-point NRS, as reported at study visits, at 
Week 6. The analysis of this endpoint will be similar to the primary analysis. 
12.3.4 
Safety Analysis 
The overall safety profile of VX-150 will be assessed in terms of the following safety and 
tolerability endpoints:  
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (including coagulation studies) 
• ECG outcomes 
• Vital signs 
• C-SSRS 
Safety analyses will be based on the Safety Set. 
All safety data will be presented in individual subject data listings. 
12.3.4.1 
Adverse Events 
AEs will be coded according to MedDRA. The number and percentage of subjects experiencing 
an AE will be summarized by the MedDRA System Organ Class and Preferred Term, as well as 
by treatment group. AEs will be classified as pretreatment or treatment-emergent as follows: 
Pretreatment AEs are defined as AEs that were reported or worsened after signing the ICF up 
to the start of study drug dosing. 


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Treatment-emergent AEs are defined as AEs that were reported or worsened on or after the 
start of study drug dosing through the Safety Follow-up Visit. 
Only TEAEs will be summarized in tables. All summaries of TEAEs will be presented by the 
severity of the AE and relationship to the study drug. Some rules that will apply to the 
summarization of AEs are (1) a subject with multiple occurrences of the same AE or a 
continuing AE will only be counted once; (2) only the maximum severity level will be presented 
in the severity summary; and (3) only the worst relationship level will be presented in the 
relationship summary. 
AEs leading to death, SAEs, AEs leading to dose discontinuation, and study discontinuation will 
be listed separately. All AEs through the Safety Follow-up Visit will be listed in an individual 
subject data listing, including pretreatment AEs.  
12.3.4.2 
Clinical Laboratory Assessments 
All statistical analyses of laboratory values will be performed using SI units. Hematology 
(including coagulation) and clinical chemistry results will be summarized by treatment group at 
each scheduled time point. The number and percentage of subjects with at least 1 potentially 
clinically significant (PCS) event will be summarized by treatment group at each scheduled time 
point. A listing containing individual subject laboratory measurements meeting the PCS criteria 
will be provided. For each subject in the listing, laboratory measurements at all time points will 
be included. The PCS 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. 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). 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 
Responses to the C-SSRS will be tabulated by treatment group. 


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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 the metabolite VRT-1268114 will be described using 
summary statistics. Preliminary review and analyses of the drug concentrations may be done 
before database lock under the conditions of masked identifications of the subject concentrations. 
Details of the analyses will be provided in the CPAP. 
12.4.2 
Pharmacodynamic Analysis 
12.4.3 
Pharmacokinetic/Pharmacodynamic Analyses 
A population PK analysis of plasma concentration versus time data of VRT-1207355 and 
VRT-1268114 may be performed using a 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 will be presented 
in the Population PK/PD Analysis Plan. The results of the population PK and PK/PD analysis (if 
done) will be reported in a separate document. 
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 


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• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time 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 Visit: through the Safety Follow-up 
Visit 
• For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of 
o 35 days after the last dose of study drug, or 
o the ETT Visit, if that visit is 3 weeks or later following the last dose of study drug 
(see Section 9.1.5) 
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 


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an AE that does not appear in the CTCAE will be determined according to the definitions in 
Table 13-1.  
Table 13-1 
Grading of AE Severity  
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug event that places the subject, in the view of the investigator, at 
immediate risk of death  
 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories 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. 
 


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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 
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 


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indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject's life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Safety Follow-up Visit, regardless of causality, will be reported by the investigator to Vertex 
GPS. In addition, all SAEs that occur after the Safety Follow-up Visit and are considered related 
to study drug(s) will be reported to Vertex GPS within 24 hours. 
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 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 


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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 
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 assent (if applicable) and the contents of the consent will comply with ICH GCP and 
all applicable laws and regulations and will be subject to approval by Vertex or its designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 


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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. 
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. 


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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.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex will be followed to 
comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, or designee (study site monitor), who will review the 
CRFs/SAE Forms and source documents. The study site monitor will ensure that the 
investigation is conducted according to the protocol design and regulatory requirements. 
13.5 
Electronic Data Capture  
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator's responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject's 
CRF. Source documentation supporting the CRF data will indicate the subject's participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user's identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a CD or other electronic media will be placed in the investigator's study file. 


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13.6 
Publications and Clinical Study Report 
13.6.2 
Clinical Study Report  
A CSR, written in accordance with the ICH E3 Guideline, will be submitted in accordance with 
local regulations. 


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14 
REFERENCES 
1 
Petersen KL, Rowbotham MC. Will ion-channel blockers be useful for management of 
nonneuropathic pain? 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-
5. 
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):50-6. 
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. VX-150 Investigator's Brochure, Version 3.0. 
Report date: 09 December 2016. 
13 
Chan AC, Wilder-Smith EP. Small fiber neuropathy: getting bigger! Muscle Nerve. 
2016;53(5):671-82. 
14 
Hoeijmakers JG, Faber CG, Lauria G, Merkies IS, Waxman SG. Small-fibre 
neuropathies--advances in diagnosis, pathophysiology and management. Nat Rev Neurol. 
2012;8(7):369-79. 
15 
DCCT EDIC Research Group, Nathan DM, Bebu I, Hainsworth D, Klein R, Tamborlane 
W, et al. Frequency of Evidence-Based Screening for Retinopathy in Type 1 Diabetes. N 
Engl J Med. 2017;376(16):1507-16. 
16 
United States Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research. Draft guidance for industry: analgesic 
indications: developing drug and biological products. Rockville, MD: February 2014. 


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17 
Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. 
Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: 
IMMPACT recommendations. J Pain. 2008;9(2):105-21. 
18 
Attal N. Assessment of neuropathic pain in the setting of intervention trials. Clinical 
Investigation. 2011;1(4):501-07. 
22 
Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful 
diabetic neuropathy: a randomized controlled trial. Neurology. 2004;63(11):2104-10. 
23 
Richter R, Portenoy R, Sharma U, Lamoreaux L, Bockbrader H, Knapp L. Relief of 
painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled 
trial. The Journal of Pain. 2005;6(4):253-60. 
24 
Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of 
painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 
2004;110(3):628-38. 
 




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15.2 
Investigator Signature Page 
Protocol #:  
VX16-150-102 
Version #: 
5.0 
Version Date: 
25 May 2018 
Study Title: A Phase 2, Randomized, Double-blind, Placebo-controlled, 6-Week, Parallel-design 
Study of the Efficacy and Safety of VX-150 in Treating Subjects With Pain Caused by Small 
Fiber Neuropathy 
 
 
I have read Protocol VX16-150-102, Version 5.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-150 and this protocol supplied to me by 
Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods)  
Page 1 of 30 
Protocol Number: VX16-150-102  
Vertex Pharmaceuticals Incorporated 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX16-150-102  
(Final Analysis) 
 
A Phase 2 Randomized, Double-blind, Placebo controlled, 6-Week, 
Parallel-design Study of the Efficacy and Safety of VX-150 in Treating 
Subjects With Pain Caused by Small Fiber Neuropathy 
 
Author of SAP: 
 
 
Version: 1.0 
Version Date of SAP: 06 NOV 2018 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods)  
Page 2 of 30 
Protocol Number: VX16-150-102 
Vertex Pharmaceuticals Incorporated 
 
2 
TABLE OF CONTENTS 
1 
Title Page .......................................................................................................................... 1 
2 
Table of Contents ............................................................................................................. 2 
4 
Introduction ...................................................................................................................... 5 
5 
Study Objectives .............................................................................................................. 5 
5.1 
Primary Objective ....................................................................................................... 5 
5.2 
Secondary Objectives ................................................................................................. 5 
6 
Study Endpoints ............................................................................................................... 6 
6.1 
Efficacy Endpoints ..................................................................................................... 6 
6.1.1 
Primary Efficacy Endpoint ................................................................................. 6 
6.1.2 
Secondary Efficacy Endpoints ............................................................................ 6 
 
 
6.2 
Safety Endpoints ......................................................................................................... 6 
7 
Study Design ..................................................................................................................... 6 
7.1 
Overall Design ............................................................................................................ 6 
7.2 
Sample Size and Power .............................................................................................. 7 
7.3 
Randomization ............................................................................................................ 8 
7.4 
Blinding and Unblinding ............................................................................................ 8 
7.4.1 
Blinding .............................................................................................................. 8 
7.4.2 
Unblinding .......................................................................................................... 9 
8 
Analysis Sets ..................................................................................................................... 9 
8.1 
All Subjects Set .......................................................................................................... 9 
8.2 
Full Analysis Set ......................................................................................................... 9 
8.3 
Safety Set .................................................................................................................... 9 
9 
Statistical Analysis ........................................................................................................... 9 
9.1 
General Considerations .............................................................................................. 9 
9.2 
Background Characteristics ...................................................................................... 11 
9.2.1 
Subject Disposition ........................................................................................... 11 
9.2.2 
Demographics and Baseline Characteristics ..................................................... 11 
9.2.3 
Prior and Concomitant Medications ................................................................. 12 
9.2.4 
Study Drug Exposure and Study Drug Compliance ......................................... 12 
9.2.5 
Important Protocol Deviations .......................................................................... 13 
9.3 
Efficacy Analysis ...................................................................................................... 13 
9.3.1 
Analysis of Primary Efficacy Variable ............................................................. 13 
9.3.1.1 
Definition of Primary Efficacy Variable .................................................... 13 
9.3.1.2 
Primary Analysis ........................................................................................ 13 
9.3.2 
Analysis of Secondary Efficacy Variables ....................................................... 14 
9.3.2.1 
Definition of Secondary Efficacy Variables .............................................. 14 
9.3.2.2 
Secondary Analyses ................................................................................... 14 
 
 


Statistical Analysis Plan (Methods)  
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9.4 
Safety Analysis ......................................................................................................... 16 
9.4.1 
Adverse Events ................................................................................................. 17 
9.4.2 
Clinical Laboratory Assessments ..................................................................... 17 
9.4.3 
Electrocardiogram ............................................................................................ 18 
9.4.4 
Vital Signs ........................................................................................................ 18 
9.4.5 
C-SSRS ............................................................................................................. 18 
9.4.6 
Physical Examination ....................................................................................... 19 
9.4.7 
Neurological Examination ................................................................................ 19 
9.4.8 
Bedside Sensory Testing Kit ............................................................................ 19 
10 Summary of Interim and IDMC Analyses .................................................................. 19 
11 References ....................................................................................................................... 20 
12 List of Appendices .......................................................................................................... 21 
Appendix A 
: Analysis Visit Windows for Safety and Efficacy Assessments ............... 21 
Appendix B 
: Imputation Rules for Missing Prior/Concomitant Medication Dates ...... 24 
Appendix C 
: Imputation Rules for Missing AE dates ................................................... 25 
Appendix D 
: Threshold Value Criteria .......................................................................... 26 
Appendix E 
: Important Protocol Deviation Categories ................................................ 29 
 
 
 




Statistical Analysis Plan (Methods)  
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Vertex Pharmaceuticals Incorporated 
 
4 
INTRODUCTION 
This statistical analysis plan (SAP) for the final analysis is based on the approved clinical 
study protocol (CSP), dated 25 MAY 2018 for Version 5.0, 25 MAY 2018 for Version 5.1 
NL, 25 MAY 2018 for Version 5.2 IT, 25 MAY 2018 for Version 5.3 DE, final electronic 
case report form (eCRF) completion guidelines, Version 2.0, dated 29 OCT 2018, and 
approved eCRF, Version 5.0, dated 19 OCT 2018. 
Small fiber neuropathy is a distinct clinical condition caused by diseases affecting peripheral 
small nerve fibers (Aδ- and C-fibers). Common symptoms include burning pain in the feet 
and evoked pain (e.g., pressure and touch allodynia). Diagnosis is defined as possible, 
probable, and definite based on the combination of symptoms, signs, evidence of large 
sensory nerve fiber function integrity by nerve conduction studies (NCS) and abnormal skin 
biopsy or quantitative sensory testing. By inhibiting Nav1.8 in the peripheral nerve fibers, 
VX-150 has the potential to treat pain caused by hyperexcitability of the damaged or diseased 
nerves. 
Study VX16-150-102 is a proof-of-concept study that will evaluate the efficacy, tolerability, 
PK and safety of VX-150 in the treatment of neuropathic pain in subjects with small fiber 
neuropathy.  
This SAP (Methods) documents the planned final statistical analysis of efficacy and safety 
endpoints defined in the study protocol of VX16-150-102 and provide additional details and 
clarifications.  
The Vertex Biometrics Department will perform the final statistical analysis of the efficacy 
and safety data; SAS® Version 9.4 Software (SAS Institute, Cary, North Carolina, USA) or 
higher will be used to generate all statistical outputs (tables, figures, listings and datasets).   
The SAP (Methods) for the final analysis will be finalized and approved before the database 
lock for the final analysis. Any changes made to the SAP after the clinical database lock has 
occurred will be documented in the clinical study report for this study. 
The analysis addressing the pharmacokinetic (PK) objective of the study will be described in 
the Clinical Pharmacology Analysis Plan (CPAP) which will be developed separately by the 
Clinical Pharmacology department at Vertex Pharmaceuticals Incorporated (Vertex). 
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
To evaluate the efficacy of VX-150 for the treatment of pain caused by small fiber 
neuropathy 
5.2 
Secondary Objectives  
• To evaluate the safety and tolerability of VX-150  
• To evaluate the pharmacokinetics (PK) of VRT-1207355 and the metabolite 
VRT-1268114 


Statistical Analysis Plan (Methods)  
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Vertex Pharmaceuticals Incorporated 
 
6 
STUDY ENDPOINTS 
6.1 
Efficacy Endpoints 
6.1.1 
Primary Efficacy Endpoint 
Change from baseline in the weekly average of daily pain intensity on the 11-point numeric 
rating scale (NRS), as reported in the daily diary, at Week 6 
6.1.2 
Secondary Efficacy Endpoints 
• Proportion of subjects with ≥30% reduction in the weekly average of daily pain intensity 
on the 11-point NRS, as reported in the daily diary, at Week 6  
• Proportion of subjects with ≥50% reduction in the weekly average of daily pain intensity 
on the 11-point NRS, as reported in the daily diary, at Week 6  
• Change from baseline in the Daily Sleep Interference Scale (DSIS) at Week 6 
• Proportion of subjects categorized as improved at Week 6 on the patient global 
impression of change (PGIC) assessment 
• Change from baseline in pain intensity on the 11-point NRS, as reported at study visits, at 
Week 6 
6.2 
Safety Endpoints 
• Safety and tolerability based on the Columbia Suicide Severity Rating Scale (C-SSRS), 
incidence and type of AEs, changes from baseline in clinically significant laboratory test 
results, vital signs, and ECGs at each visit  
7 
STUDY DESIGN  
7.1 
Overall Design  
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter 
study (Figure 7-1). Up to approximately 114 subjects with small fiber neuropathy will be 
randomized 1:1 to VX-150 or placebo.  
This study will include: 
• A 7-day Run-in Period to establish the baseline NRS pain score 
• A 6-week Treatment Period 


Statistical Analysis Plan (Methods)  
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• A 28-day Safety Follow-up 
Figure 7-1 
VX16-150-102 Study Design 
 
D: Day; qd: daily; W: Week 
7.2 
Sample Size and Power 
The primary efficacy endpoint is the change from baseline in the weekly average of daily 
pain intensity on the 11-point NRS, as reported in the daily diary, at Week 6. The primary 
analysis of the primary efficacy endpoint will be a within-group treatment comparison in the 
VX-150 treatment group. The 95% CI for the within-group change will be used to evaluate if 
there is any significant change from baseline (within-group change against 0). Additional 
analyses will include an evaluation of this within-group change against 0.8, an expected 
change from the placebo group, and a 95% CI for the between-group comparison of change 
from baseline. 
Assuming a within-group change of 0.8 for placebo and a between-group treatment 
difference of 1.25, the expected within-group change for VX-150 is 2.05. With an SD of 
2.08, the power for the 95% CI for the within-group change to rule out 0 or 0.8 is 
summarized in for 25, 35, or 45 evaluable subjects per group. The power for the 95% CI for 
the between-group treatment difference to rule out 0 is also provided. In order to allow for 
withdrawal of up to 20% of randomized subjects over 6 weeks of treatment, the study will 
enroll and randomize a minimum of approximately 62 subjects (25 evaluable subjects per 
group) and up to approximately 114 subjects (45 evaluable subjects per group) in total. 
Table 7-2 
Power for the 95% Confidence Intervals for Within- and Between-
group Changes 
Number of  
Evaluable Subjects 
Per Group 
Power for the 95% CI 
for the Within-group 
Change to Rule out 0 
Power for the 95% CI 
for the Within-group 
Change to Rule Out 
0.8 
Power for the 95% CI for 
the Between-group 
Treatment Difference to 
Rule Out 0 
25 
> 99% 
82% 
55% 
35 
> 99% 
93% 
70% 
45 
> 99% 
98% 
81% 
 
 


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7.3 
Randomization 
Up to approximately 114 subjects with small fiber neuropathy will be randomized 1:1 to VX-
150 or placebo. Randomization will be stratified by sex and diagnosis of diabetes. Subjects 
with diabetes will not exceed approximately 60% of the total number of subjects. Subjects 
with diabetes and HbA1c ≥8% and <11% at screening will not exceed approximately 20% of 
the total number of subjects. 
An interactive web response system (IWRS) will be used to assign subjects to treatment. The 
randomization code will be produced by Vertex Biostatistics or a qualified randomization 
vendor. The Vertex study biostatistician will review and approve the production of the final 
randomization list, which will be reviewed and approved by a designated unblinded 
biostatistician who is not a member of the study execution team (SET).  
7.4 
Blinding and Unblinding 
This will be a double-blind study.  
7.4.1 
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 contract research organization (CRO) 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 team 
• Vertex IXRS Management for IXRS oversight and system administration 
• Vertex Clinical Supply Chain 
• The bioanalytical laboratory/vendor personnel managed by Vertex Bioanalysis 
Vertex medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time. 
A Vertex Bioanalysis Representative will be unblinded to allow real time review of 
bioanalytical data. This individual, however, will not be a member of the SET, and will not 
interact with the clinical research unit (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 data set is being 
provided for preliminary analysis. This individual, however, will not be a member of the 


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SET, and will not interact with the CRU or study personnel. Masked IDs will be used for 
these analyses. 
7.4.2 
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. 
8 
ANALYSIS SETS 
Assignment of subjects to analysis sets will be performed before the clinical data lock for the 
study.  
8.1 
All Subjects Set 
The All Subjects Set is defined as all subjects who have been randomized or have received at 
least 1 dose of study drug. This analysis set will be used in subject listings and disposition 
summary table, unless otherwise specified. 
8.2 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all randomized subjects who have received at least 
1 dose of study drug. The FAS 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. 
8.3 
Safety Set 
The Safety Set is defined as all subjects who have received at least 1 dose of study drug. The 
Safety Set is to be used for all safety analyses in which subjects will be analyzed according to 
the treatment they received and not according to their randomized treatment group. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of CSP. The precision standards for 
reporting safety and efficacy variables are provided in an internal Biometrics document that 
specifies the programming rules including the precision for derived variables. 


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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 as described. 
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 the NRS via daily diary and the DSIS will be defined as the average score 
of at least 4 nonmissing scores from Day -7 to Day -1. For all other variables baseline will be 
defined as the most recent nonmissing measurement collected before the initial 
administration of study drug unless specified otherwise.  
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 dosing with study drug 
until the following time point: 
• For enrolled subjects who have a Safety Follow-up Visit: through the Safety Follow-up 
Visit 
• For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of  
 35 days after the last dose of study drug, or 
 the ETT Visit if that visit is 3 weeks or later following the last dose of study drug (see 
Section 9.1.5 of CSP) 
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. 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided 
in Appendix A.  
Incomplete/missing data will not be imputed, unless otherwise specified.  
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. 


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9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
The number of subjects in the following categories will be summarized overall and by 
treatment group:  
• All Subjects Set 
• Randomized 
• Full Analysis Set (FAS) 
• Safety Set 
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 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. 
9.2.2 
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 (male, female) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, not collected per local regulations, Other and 
Multiracial (if more than 2 races reported from a subject)) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 


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• Diagnosis of diabetes (Yes, No) 
Disease characteristics will include the following: 
• Pain intensity at baseline as recorded on the NRS 
• Daily sleep interference at baseline as recorded on the DSIS 
Small fiber neuropathy history will include the following: 
• Distribution of the symptoms (stocking/glove distribution, non-length dependent) 
• The small fiber neuropathy symptoms have been present for >= 3 months (Yes, No) 
• Quality of the small fiber neuropathy symptoms (burning, sharp stabbing, throbbing, cold 
sensation, itch, loss of sensation and other) 
• Autonomic features associated with the small fiber neuropathy (Yes, No)  
Medical history will be summarized by MedDRA system organ class (SOC) and preferred 
term (PT). 
9.2.3 
Prior and Concomitant Medications 
Medications taken 28 days before the Screening Visit and up to the Safety Follow-up will 
coded and summarized by Preferred Name using the World Health Organization-Drug 
Dictionary (WHO-DD) for the FAS as frequency tables in 2 parts:  
1. Prior medication: Medication that started before the first dose of study drug, regardless of 
when dosing of the medication ended. 
2. Concomitant medication: Medication received at or after the first dose of study drug, 
medication that was received before initial dosing and continued after initial dosing of 
study drug, or medication with missing stop date. 
Medication that started before the first dose of study drug and continued after the first dose of 
study drug will be summarized as prior medication and separately as concomitant 
medication.  
If a medication has 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 B. 
9.2.4 
Study Drug Exposure and Study Drug Compliance 
Study drug exposure and study drug compliance summaries will be based on the FAS.  
Duration of study drug exposure is defined as follows: last dose date – first dose date + 1 
day, regardless of any interruption in dosing between the first and the last dose. Duration of 
study drug exposure expressed in weeks will be summarized by means of descriptive 
summary statistics and also into the following categories: ≤1 weeks, >1 and ≤3 weeks, >3 
and ≤6.5 weeks, and >6.5 weeks.  


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Dosing compliance rate will be calculated as following: 
100× [(total number of tablets dispensed) – (total number of tablets returned)] / (total number 
of tablets planned to be taken per day × duration of study drug exposure in days).  
The dosing compliance rate will be summarized descriptively and into the categories of 
<80%, and  ≥80%. 
9.2.5 
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 E.  
All IPDs will be summarized descriptively by treatment group and presented in an individual 
subject data listing. 
9.3 
Efficacy Analysis 
Unless otherwise defined, all efficacy analyses described in this section will be based on the 
FAS. Subjects will be analyzed according to their randomized treatment assignment. 
9.3.1 
Analysis of Primary Efficacy Variable 
9.3.1.1 
Definition of Primary Efficacy Variable 
The primary efficacy endpoint is the change from baseline in the weekly average of daily 
pain intensity on the 11-point NRS, as reported in the daily diary, at Week 6. The weekly 
average of daily pain intensity will be calculated by averaging the nonmissing daily pain 
intensity scores in each week. If the count of nonmissing daily pain intensity scores is less 
than 4 within a week, the weekly average of daily pain intensity will be set to missing.  
9.3.1.2 
Primary Analysis  
The primary analysis of the primary endpoint will be a within-group treatment comparison in 
the VX-150 treatment group. The analysis will be conducted using a mixed-effects model for 
repeated measures (MMRM). The between-group treatment comparison will also be 
generated using the same MMRM.  
The model will include the change from study baseline at each week in the weekly average of 
daily pain intensity score as the dependent variable; treatment, sex, diagnosis of diabetes, 
week, and treatment-by-week interaction as fixed effects and baseline pain intensity score as 
a covariate. The model will be estimated using restricted maximum likelihood. The 
denominator degrees of freedom for the F-test for fixed effects will be estimated using the 
Kenward-Roger approximation. In the model, an unstructured covariance matrix will be 
assumed to model the within-subject variability. If there is a convergence problem due to use 
of an unstructured covariance matrix, the unstructured covariance matrix will be replaced by 
a compound symmetric covariance matrix to model the within-subject variability. 


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Conditional on the observed data and covariates, missing data will be assumed to be missing 
at random; consequently, no imputation of missing data will be performed. 
The post-baseline raw values and the change from baseline at each week will be summarized 
descriptively (n, mean, SD, SE, median, minimum, and maximum). 
The adjusted mean (SE), corresponding 95% 2-sided confidence interval (CI) and 2-sided P 
value for VX-150 treatment group in change from study baseline in weekly average of daily 
NRS at Week 6 will be provided. The CI will first be used to facilitate the comparison with 
0; this will be followed by a comparison with 0.8. Furthermore, the adjusted mean (SE) and 
corresponding 95% CI for the treatment difference between VX-150 and placebo at Week 6 
will be provided. 
In addition, adjusted means (SE) and 95% CIs for all within-group treatment and between-
group treatment comparisons at other weeks will also be provided.  
9.3.2 
Analysis of Secondary Efficacy Variables 
9.3.2.1 
Definition of Secondary Efficacy Variables 
Proportion of subjects with ≥30%, ≥50% reduction in the weekly average of daily pain 
intensity on the 11-point NRS, as reported in the daily diary, at Week 6: The percentage 
reduction in the weekly average of daily pain intensity will be calculated as following: 
100 × (daily pain intensity score at baseline  ̶ the weekly average of daily pain intensity score 
at Week 6) / daily pain intensity  score at baseline. 
Change from baseline in the DSIS at Week 6: The change from baseline in the DSIS at Week 
6 is the change from baseline in the weekly average of daily sleep interference score on the 
DSIS, as reported in the daily diary at Week 6. The weekly average of DSIS will be 
calculated by averaging the nonmissing daily sleep interference scores in each week. If the 
count of nonmissing daily sleep interference scores is less than 4 in a week, the weekly 
average of daily sleep interference on the DSIS will be set to missing. 
Proportion of subjects categorized as improved at Week 6 on the PGIC assessment: The 
assessment consists of a single item on a 7-point scale from 1 (very much improved) to 7 
(very much worse). Subjects will be categorized as following: 
• 1 - 2 reported on the PGIC assessment will be categorized as “improved”; 
• 3 - 4 reported on the PGIC assessment will be categorized as “no change”; 
• 5 - 7 reported on the PGIC assessment will be categorized as “worse”. 
Change from baseline in pain intensity on the 11-point NRS, as reported at study visits, at 
Week 6: Change from baseline in pain intensity will be calculated at each post-baseline visit 
(Day 7, Week 3 and Week 6) following the general definition of the baseline and change 
from baseline in Section 9.1.  
9.3.2.2 
Secondary Analyses  
Proportion of subjects with ≥30% reduction in the weekly average of daily pain intensity on 
the 11-point NRS, as reported in the daily diary, at Week 6: This variable will be evaluated 
using descriptive statistics by treatment group.  


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Proportion of subjects with ≥50% reduction in the weekly average of daily pain intensity on 
the 11-point NRS, as reported in the daily diary, at Week 6: Analysis of this variable will be 
the same as described for proportion of subjects with ≥30% reduction.  
In addition, the proportion of subjects with ≥70% reduction in the weekly average of daily 
pain intensity at Week 6 will also be analyzed in the same way as described for the 
proportion of subjects with ≥30% reduction.  
Change from baseline in the DSIS at Week 6: Analysis of this variable will be based on an 
MMRM similar to the analysis of the primary efficacy variable. Weekly average of daily 
DSIS score at each week will be included in the model as the dependent variable.  
Proportion of subjects categorized as improved at Week 6 on the PGIC assessment: This 
variable will be evaluated using descriptive statistics by treatment group.  
Change from baseline in pain intensity on the 11-point NRS, as reported at study visits, at 
Week 6: Analysis of this variable will be based on an MMRM similar to the analysis of the 
primary efficacy variable. The change from baseline in NRS at each post-baseline visit (Day 
7, Week 3 and Week 6) will be included in the model as the dependent variable.  


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9.4 
Safety Analysis 
The overall safety profile of VX-150 will be assessed in terms of the following safety and 
tolerability endpoints:  
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values  
• ECG outcomes 


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• Vital signs 
• C-SSRS 
Safety analyses will be based on the Safety Set. 
All safety data will be presented in individual subject data listings. 
Safety analyses will be based on the Safety Set and subjects will be analyzed according to the 
treatment they actually received. In an unexpected scenario that a subject may receive more 
than one treatment in the study, the following algorithm will be used to define subject’s 
actual treatment: for any dosed subjects, the actual treatment is defined as VX-150 if the 
subject received any VX-150 treatment, regardless of the randomized treatment assignment. 
Otherwise, the actual treatment is defined as placebo only if the subject receives placebo at 
all visits in the study. 
9.4.1 
Adverse Events  
AEs will be coded according to MedDRA. The number and percentage of subjects 
experiencing an AE will be summarized by the MedDRA System Organ Class and preferred 
term, as well as by treatment group. AEs will be classified as pretreatment or 
treatment-emergent as follows: 
Pretreatment AEs are defined as AEs that were reported or worsened after signing the ICF 
up to the start of study drug dosing. 
Treatment-emergent AEs are defined as AEs that were reported or worsened on or after the 
first dose date of study drug through the end of the TE period. 
Details for imputing missing or partial start dates of adverse events are described in 
Appendix C. 
Only TEAEs will be summarized in tables. All summaries of TEAEs will be presented by the 
severity of the AE and relationship to the study drug. Some rules that will apply to the 
summarization of AEs are (1) a subject with multiple occurrences of the same AE or a 
continuing AE will only be counted once; (2) only the maximum severity level will be 
presented in the severity summary; and (3) only the strongest relationship level will be 
presented in the relationship summary. An AE with relationship missing is counted as related 
AE. 
SAEs, AEs leading to death, and AEs leading to study drug interruption, study drug 
discontinuation, and study discontinuation will be listed separately. All AEs through Safety 
Follow-up will be listed in an individual subject data listing, including pretreatment AEs.  
9.4.2 
Clinical Laboratory Assessments 
All statistical analyses of laboratory values will be performed using International System of 
Units. The raw values and change from baseline values for the continuous hematology, 
clinical chemistry will be summarized by treatment group at each scheduled visit. The 
threshold value criteria for hematology and clinical chemistry laboratory tests are provided in 
Appendix D. The number and percentage of subjects with at least 1 hematology and clinical 
chemistry laboratory measurement meeting the threshold value criteria will be summarized 


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by treatment group at each scheduled visit. Coagulation results will be summarized by 
treatment group at each scheduled visit. The number and percentage of subjects with 
abnormal coagulation values at each scheduled time point will be summarized.  
A listing containing individual subject hematology and clinical chemistry laboratory 
measurements meeting the threshold value criteria at any visit will be provided. For each 
subject in the listing, laboratory measurements at all visits will be included. This listing will 
include data from scheduled and unscheduled time points. Abnormal coagulation and 
urinalysis results also will be listed separately. For each subject in the listing, coagulation and 
urinalysis results at all visits will be included.  Results of the urine/serum pregnancy test will 
be presented in individual subject data listings only. 
Clinically significant abnormal laboratory findings will be reported as AEs.  
9.4.3 
Electrocardiogram 
A summary of raw values and change from baseline values will be provided by treatment at 
each scheduled visit during the TE period for the following standard 12-lead ECG 
measurements: PR, QT, QRS, QTcF [QTcF = QT/RR0.33], and HR. In addition, the number 
and percentage of subjects by maximum on-treatment value of QT/QTcF intervals, 
categorized as ≤450 msec, >450 msec and ≤480 msec, >480 msec and ≤500 msec, and 
>500 msec, as well as maximum on-treatment change from baseline value of QT/QTcF 
intervals, categorized as ≤0 msec, >0 and ≤30 msec, >30 and ≤60 msec, and >60 msec, will be 
provided. 
The threshold value criteria for ECG data are provided in Appendix D. A listing containing 
individual subject measurements meeting the threshold value criteria at any visit will be 
provided. For each subject in the listing, ECG measurements at all visits will be included.  
Clinically significant ECG abnormalities occurring during the study through the Safety 
Follow-up Visit will be recorded as AEs.  
9.4.4 
Vital Signs 
The raw values and change from baseline values during the TE period will be summarized by 
treatment at each scheduled visit: systolic and diastolic blood pressure (mm Hg), body 
temperature (C), pulse rate (beats per minute), and respiratory rate (breaths per minute).  
The threshold value criteria for vital signs data are provided in Appendix D. A listing 
containing individual subject measurements meeting the threshold value criteria at any visit 
will be provided. For each subject in the listing, vital signs at all visits will be included. 
Clinically significant abnormal findings in vital signs will be reported as AEs. 
9.4.5 
C-SSRS 
The responses to the first two questions in the C-SSRS will be summarized by treatment at 
baseline and at each scheduled visit: 
• Wish to be dead 
• Non-specific active suicidal thoughts 


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Subjects with “yes” response to either of the first two questions at baseline and at any 
scheduled visit will be listed separately. For each subject in the listing, responses to all 
questions in the C-SSRS at all visits will be included.  
9.4.6 
Physical Examination  
PE results will be presented in individual subject data listings only. Clinically relevant results 
identified after screening will be reported as AEs. 
9.4.7 
Neurological Examination 
Neurological Examination results will be presented in a data listing only. 
9.4.8 
Bedside Sensory Testing Kit 
Bedside Sensory Testing Kit results will be presented in a data listing only. 
10 
SUMMARY OF INTERIM AND IDMC ANALYSES 
Not applicable. 


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11 
REFERENCES 
Guidance for Industry Analgesic Indications: Developing Drug and Biological Products, 
FDA DRAFT GUIDANCE, 2014. 
 
Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful 
diabetic neuropathy: a randomized controlled trial. Neurology. 2004; 63(11):2104-10. 
 
Preventing and Treating Missing Data in Longitudinal Clinical Trials: A Practical Guide. 
Craig H. Mallinckrodt, Cambridge University Press, 2013. 
 
Richter R, Portenoy R, Sharma U, Lamoreaux L, Bockbrader H, Knapp L. Relief of painful 
diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. The 
Journal of Pain. 2005; 6(4):253-60. 
 
Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful 
diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 2004; 
110(3):628-38. 
 
SAS Institute Inc. 2014. Base SAS® 9.4 Procedures Guide: Statistical Procedures, Third 
Edition. Cary, NC: SAS Institute Inc. 
 
The Prevention and Treatment of Missing Data in Clinical Trials. Panel on handling Missing 
Data in Clinical Trials. Committee on National Statistics, Division of Behavioral and Social 
Sciences and Education. Washington, DC: The national Academies. National Research 
Council. 2010. 


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12 
LIST OF APPENDICES 
Appendix A : Analysis Visit Windows for Safety and Efficacy Assessments 
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
per the protocol 
Analysis Visit Window 
(in study days) 
Safety Assessment 
Hematology 
Serum Chemistry 
Baseline 
 
1 
 
[Screening visit, Pre-dose 
Day 1] 
Week 3  
22 
[1*, 32] 
Week 6 
43 
[33, 57] 
 
Safety Follow-up Visit 
N/A 
Nominal  
Coagulation  
Baseline  
N/A 
[Screening visit, Pre-dose 
Day 1] 
 
Week 6 
43 
[1*, 57] 
 
Safety Follow-up Visit 
N/A 
Nominal  
Standard 12-Lead ECG 
 
Baseline 
1 
[Screening visit, Pre-dose 
Day 1] 
Day 7 
7 
[1*, 57] 
 
Safety Follow-up Visit 
N/A 
Nominal  
Vital Sign 
Baseline 
1 
1 
Day 7  
7 
[2, 14] 
Week 3  
22 
[15, 32] 
 
Week 6 
43 
[33, 57] 
 
Safety Follow-up Visit 
N/A 
Nominal 
C-SSRS 
Baseline 
1 
[-1, 1] 
 
Day 7  
7 
[2, 14] 
 
Week 3  
22 
[15, 32] 
 
Week 6 
43 
[33, 57] 
 
Safety Follow-up Visit 
N/A 
Nominal 


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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day 
per the protocol 
Analysis Visit Window 
(in study days) 
Efficacy Assessment 
NRS via daily diary  
DSIS via daily diary 
Baseline  
N/A 
[-7,  -1]2 
 
Week 1 
N/A 
[1*, 7] 
 
Week 2 
N/A 
[8, 14] 
 
Week 3 
N/A 
[15, 21] 
 
Week 4 
N/A 
[22, 28] 
 
Week 5 
N/A 
[29, 35] 
 
Week 6 
N/A 
[36,  42] 
NRS reported at study visits 
PGIC 
 
Baseline   
1 
Before first dose of study 
drug 
 
Day 7  
7 
[1*, 14] 
 
Week 3  
22 
[15, 32] 
 
Week 6 
43 
[33, 57] 
 
Safety Follow-up Visit 
N/A 
Follow the individual visit 
window to be mapped to 
individual visits if measured 
before / on Day 57 or remain 
as SFU if otherwise.  
 
1* only include day 1 post-dose measurements.  
1 Visit name for analysis purpose is used to report data in tables and figures. 
2 Only include 7 day measurements before the randomization day.  


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Notes:  
The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
1. If no numerical measurement is available within a visit window, the measurement will be considered 
missing for the visit. 
 
2. If there is more than 1 numerical measurement available within the same visit window, use the 
following rules:  
a. 
a. For efficacy assessments: if there are multiple measurements within a visit window,   
i. The measurement closest to the target day 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. 
 
3. When define efficacy and safety at baseline, refer to the generic baseline definition in Section 9.1. If 
the first dose time is missing, baseline will be defined as the most recent nonmissing measurement 
collected before the date of the first dose of study drug. For vital sign, there is no time collected and 
Day 1 will be baseline. For CSSR-S, baseline will be defined as the most recent nonmissing 
measurement collected before/on Day 1.  
 
4. If the first dose time is missing, use the first dose date to determine post-dose measurements. 
 
 


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Appendix B : 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 12-2 
 Prior and/or Concomitant Categorization of a Medication 
Medication Start Date 
Medication Stop Date 
< First Dose Date of 
Study Drug 
≥ First Dose Date and ≤ End Date of TE 
Period 
< First dose date of study drug 
P 
PC 
≥ First dose date and  
≤ End date of TE period 
- 
C 
C: Concomitant; P: Prior 
 
 


Statistical Analysis Plan (Methods)  
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Appendix C : 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. 


Statistical Analysis Plan (Methods)  
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Appendix D : Threshold Value Criteria 
Table 12-3 
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. 
CK 
>3x to ≤ 10xULN 
>10xULN 
FDA criteria Feb 2005. 
Am J Cardiol April 2006. 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Blood Urea Nitrogen ≥17 mmol/L 
 
Chloride 
<85 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥150 mmol/L 
 


Statistical Analysis Plan (Methods)  
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Protocol Number: VX16-150-102 
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Table 12-3 
Threshold Value Criteria for Laboratory Tests 
Parameter 
 
Comments 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
<2.2 mmol/L  
>13.9 mmol/L (fasted) 
 
CTCAE criteria. 
CTCAE criteria. 
Albumin 
≤25 g/L 
 
Thyrotropin 
< LLN 
> ULN 
 
Cholesterol 
≥20% increase from baseline  
D. M. Hegsted and Robert J. Nicolos, 1987 
Demacker PN et al., 1982.  
Triglycerides 
≥20% absolute change from baseline  
D. M. Hegsted and Robert J. Nicolos, 1987 
Demacker PN et al., 1982. 
Low-density 
lipoprotein-direct 
≥20% increase from baseline  
D. M. Hegsted and Robert J. Nicolos, 1987 
Demacker PN et al., 1982. 
High-density 
lipoprotein 
≥ 20% decrease from baseline   
D. M. Hegsted and Robert J. Nicolos, 1987 
Demacker PN et al., 1982. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential 
count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) International Consensus meeting on drug-
induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline 
are more relevant than based on absolute 
value. Other categories for decrease from 
baseline can be used (≥30 g/L, ≥40 g/L, 
≥50 g/L). 
RBC 
≥6 Tera/L 
 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 
 
 


Statistical Analysis Plan (Methods)  
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Table 12-4 
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 12-5 
Threshold Value Criteria for Vital Signs 
Parameter 
PCS 
Comments 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including 
missing) except STANDING. 
SBP 
≤90 mmHg and decrease from baseline 
≥20mmHg 
≥160 mmHg and increase from baseline ≥20 
mmHg 
To be applied for all positions (including 
missing) except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 
mmHg 
≥110 mmHg and increase from baseline ≥10 
mmHg 
To be applied for all positions (including 
missing) except STANDING. 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA criteria Feb 2007. 
 
 
 
 


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Appendix E : Important Protocol Deviation Categories 
• Informed Consent  
• Study Conduct/ Procedures  
• Investigational Product  
• Safety 
• Other