Clinical trial NCT02669849
Conditions: Cervical Spinal Cord Injury
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2016-07-01; Completion date: 2018-11-01
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the efficacy and safety of VX-210 in subjects with Acute Traumatic Cervical Spinal Cord Injury. Secondary objectives include the specific evaluation of the effects of VX-210 on neurological recovery and daily function after spinal cord injury.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: VX-210 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Page 1 of 74 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 2b/3, Double-blind, Randomized, 
Placebo-controlled, Multicenter Study to Assess the 
Efficacy and Safety of VX-210 in Subjects With Acute 
Traumatic Cervical Spinal Cord Injury 
Vertex Study Number: VX15-210-101 
 
Date of Protocol: 14 April 2017 (Version 2.0) 
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210, 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. 








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2 
PROTOCOL SYNOPSIS 
Title A Phase 2b/3, Double-blind, Randomized, Placebo-controlled, Multicenter Study 
to Assess the Efficacy and Safety of VX-210 in Subjects With Acute Traumatic 
Cervical Spinal Cord Injury 
  
Clinical Phase and 
Clinical Study Type  
Phase 2b/3, efficacy and safety  
  
Objectives Primary Objectives: 
Evaluation of the efficacy and safety of VX-210 treatment  
Secondary Objectives: 
 Neurological recovery: examination of the effects of VX-210 on the recovery 
of sensation and motor activity  
 Daily function: analysis of the impact of VX-210 on activities of daily living 
and requirements for attendant care 
  
Endpoints Primary Endpoint:  
Change from baseline in upper extremity motor score (UEMS) at 6 months after 
treatment 
Secondary Endpoints:  
 Spinal Cord Independence Measure (SCIM) III Self-Care subscore at 
6 months after treatment 
 Capabilities of Upper Extremity Test (CUE-T) score at 6 months after 
treatment 
 Graded Redefined Assessment of Strength, Sensibility and Prehension 
(GRASSP) Quantitative Prehension score at 6 months after treatment 
 American Spinal Injury Association Impairment Scale (AIS) grade 
conversion from baseline to 6 months after treatment 
 Motor level change from baseline to 6 months after treatment 
 Pharmacokinetic (PK) parameters of VX-210 
  
Number of Subjects Approximately 100 subjects: approximately 50 subjects per arm (9-mg VX-210 
and placebo) 
  
Study Population  Male and female subjects 14 through 75 years of age with acute traumatic 
cervical spinal cord injury 
 Motor level C4, C5, C6, or C7 (subset) on each side 
 Scheduled and planned to undergo a spinal decompression/stabilization 


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surgery that commences within 72 hours after the initial injury 
 AIS grade A or AIS grade B 
  
Investigational Drug Active substance: VX-210 
 Activity: inhibition of Rho GTPase 
 Strengths and route of administration:  
 9 mg and placebo 
 One-time, direct, extradural administration on dura mater of the spinal cord 
during decompression/stabilization surgery 
  
Study Duration For an individual subject, the study will last approximately 12 months. 
  
Study Design In this multicenter, double-blind, placebo-controlled, Phase 2b/3 study, subjects 
will be randomized to receive a single 9-mg dose of VX-210 in fibrin sealant or a 
placebo (buffer solution) in fibrin sealant. The 1-time treatment (or placebo) will 
be administered by a surgeon directly to the dura mater of the spinal cord at the 
site of injury during decompression/stabilization surgery that commences within 
72 hours after the initial injury. Follow-up assessments of recovery in VX-210-
treated versus placebo-treated subjects will be conducted at 6 weeks, 3 months, 
6 months, and 12 months after treatment. 
  
Assessments Safety:  
Adverse events, vital signs, electrocardiograms, clinical laboratory tests (serum 
chemistry, hematology, coagulation, and urinalysis), physical examinations, 
surgical site examinations, and immunogenicity measures  
Efficacy:  
International Standards for the Neurological Classification of Spinal Cord Injury 
examination, SCIM III, CUE-T, GRASSP Quantitative Prehension test, 
, hospitalizations, 
 
PK: Serum concentrations of VX-210 
  
Statistical Analyses Randomization: Subjects will be randomized to the 2 study arms at a 1:1 ratio.  
Stratification: Subjects will be stratified by age (<30 versus ≥30 years of age) and 
AIS grade (A versus B with sacral pinprick preservation versus B without sacral 
pinprick preservation) when they are randomized to the 2 study arms. 
Null Hypotheses: The mean change from baseline in UEMS at 6 months after 
treatment is the same for 9-mg dose of VX-210 and placebo. 
Sample Size Considerations: If 9-mg 
dose group improves in UEMS by 4 points 
over placebo, a total of approximately 100 subjects (approximately 50/arm) will 
provide approximately 82.1% power to detect a statistically significant treatment 
effect for 9-mg dose group compared to placebo, considering the interim futility 
analysis.
  
Primary Analyses: The study will have an overall 2-sided type I error rate 
controlled at ≤0.05. The primary efficacy endpoint will be analyzed using a 
mixed-effects model for repeated measures. The model will include the change 
from baseline in UEMS as the dependent variable; treatment, visit, and treatment-
by-visit interaction as fixed effects; and subject as a random effect, with 
adjustment for age and AIS grade (A versus B with sacral pinprick preservation 


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versus B without sacral pinprick preservation) at baseline. The primary result 
obtained from the model will be the treatment effect at 6 months after treatment. 
Statistical significance for the primary efficacy endpoint will be tested between 9-
mg dose group and the placebo group at significance level α = 0.05. 
Secondary Analyses: To control the type I error rate, a hierarchical testing 
procedure will be used for the important efficacy endpoints. At each step, the test 
for treatment effect will be considered statistically significant if the test meets the 
criteria for significance and all previous tests are also statistically significant. The 
first endpoint in the testing hierarchy will be the primary endpoint (change from 
baseline in UEMS at 6 months after treatment). The second endpoint in the testing 
hierarchy will be the SCIM III Self-Care subscore at 6 months after treatment. 
  
IDMC Reviews Safety and tolerability data will be reviewed by an independent data monitoring 
committee to ensure the safety of the subjects in the study. 
Results of an interim analysis for futility will be reviewed by the IDMC. 
  
3 
SCHEDULE OF ASSESSMENTS 
The Schedule of Assessments is shown in Table 3-1. 


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Table 3-1 
Study VX15-210-101 Schedule of Assessments 
Event/Assessment 
Screeninga Surgeryb 
Post-
Surgeryc 
6-Week 
Follow-up 
(± 7 Days)
d 
3-Month 
Follow-up 
(± 7 Days)
d 
6-Month 
Follow-up 
(± 7 Days)
d 
12-Month 
Follow-up 
(± 7 Days)
d 
Early 
Terminationd 
Safety Follow-up 
28 (± 3) Days 
After 
Treatment
d,e 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Review of spine imaging 
X 
 
 
 
 
 
 
 
 
Serum β-HCG (all female 
subjects) 
X 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal 
female subjects <60 years only) 
Xf 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
 
 
 
 
 
 
 
 
Enrollment and randomization 
X 
 
 
 
 
 
 
 
 
 
a  Results of assessments performed as part of standard of care (with the exception of the ISNCSCI examination) within 72 hours after the initial injury and 
before signing of informed consent form may be carried forward as screening results.  
b  ‘Surgery’ in this table refers to the spinal decompression/stabilization surgery that commences within 72 hours after the initial injury during which the study 
drug (VX-210 or placebo) is administered in fibrin sealant. 
c  The Post-Surgery assessments will be performed within the time period following the completion of surgery and 7 days after surgery as specified in the 
footnotes for each individual assessment. 
d  Transportation to follow-up assessments will be available if required. Follow-up assessments of recovery will be conducted at 6 weeks, 3 months, 6 months, 
and 12 months after treatment. 
e  The Safety Follow-up Visit will be required in addition to the Early Termination Visit only for subjects who prematurely terminate from the study prior to 
Day 28 after treatment. Subjects who prematurely terminate from the study subsequent to Day 28 after treatment will only be required to complete the Early 
Termination Visit. 
f  Serum FSH assessment is only required when a waiver to contraception is sought. Only 1 serum FSH assessment is required, at Screening, Surgery, or Post-
Surgery. 






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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...................................................................................................................... 15
 
List of Figures 
.................................................................................................................... 15 
5 Introduction.................................................................................................................... 16 
5.1 Introduction .............................................................................................................. 16 
5.1.1 Overview of SCI 
............................................................................................... 16 
5.1.2 Lack of Available Treatments for SCI ............................................................. 16 
5.1.3 Scientific Rationale for VX-210 Development 
................................................ 16 
6 Study Objectives ............................................................................................................ 17 
6.1 Primary Objectives 
................................................................................................... 17 
6.2 Secondary Objectives 
............................................................................................... 17 
7 Study Endpoints 
............................................................................................................. 17 
7.1 Primary Endpoint 
...................................................................................................... 17 
7.2 Secondary Endpoints 
................................................................................................ 17 
7.2.1 Secondary Endpoints 
........................................................................................ 17 
8 Study Design 
................................................................................................................... 18 
8.1 Overview of Study Design ....................................................................................... 18 
8.1.1 Screening Assessments 
..................................................................................... 19 
8.1.2 Surgery and Post-Surgery 
................................................................................. 19 
8.1.3 Follow-up.......................................................................................................... 19 
8.1.4 Early Discontinuation 
....................................................................................... 20 
8.1.5 Independent Data Monitoring Committee 
........................................................ 20 
8.2 Rationale for Study Design and Study Drug Regimens 
........................................... 20 
8.2.1 Rationale for Study Design............................................................................... 20 
8.2.2 Rationale for Study Drug Dose and Duration .................................................. 20 
8.2.3 Rationale for Study Assessments ..................................................................... 21 
8.2.3.1 Primary Endpoint 
....................................................................................... 21 
8.2.3.2 Secondary 
 
................................................................. 21
 
9 Study Population 
............................................................................................................ 24 
9.1 Inclusion Criteria 
...................................................................................................... 24 
9.2 Exclusion Criteria 
..................................................................................................... 24 
9.3 Prior and Concomitant Medications 
......................................................................... 25 
9.4 Removal of Subjects 
................................................................................................. 25 
9.5 Replacement of Subjects .......................................................................................... 26 
10 Study Drug Administration and Management 
........................................................... 26 
10.1 Preparation and Dispensing 
...................................................................................... 26 
10.2 Administration 
.......................................................................................................... 26 
10.3 Method of Assigning Subjects to Treatment Groups 
............................................... 26
 


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10.4 Dose Modification for Toxicity 
................................................................................ 26 
10.5 Packaging and Labeling ........................................................................................... 27 
10.6 Study Drug Supply, Storage, and Handling ............................................................. 27 
10.7 Drug Accountability 
................................................................................................. 27 
10.8 Disposal, Return, or Retention of Unused Drug 
....................................................... 27 
10.9 Compliance 
............................................................................................................... 28 
10.10 Blinding and Unblinding 
.......................................................................................... 28 
10.10.1 Blinding 
............................................................................................................ 28 
10.10.2 Unblinding 
........................................................................................................ 28 
11 Assessments 
.................................................................................................................... 29 
11.1 Timing of Assessments 
............................................................................................. 29 
11.2 Subject and Disease Characteristics 
......................................................................... 29 
11.3 Pharmacokinetics 
...................................................................................................... 29 
11.3.1 Serum Sampling ............................................................................................... 29 
11.3.2 Processing and Handling of Pharmacokinetic Samples ................................... 29 
11.3.3 Bioanalysis........................................................................................................ 29 
 
11.5 Efficacy 
..................................................................................................................... 30 
11.5.1 ISNCSCI Examination ..................................................................................... 30 
11.5.2 The Spinal Cord Independence Measure III 
..................................................... 30
 
11.5.3 Capabilities of Upper Extremity Test 
............................................................... 30 
11.5.4 GRASSP Quantitative Prehension Test 
............................................................ 31 
11.5.7 Hospitalizations 
................................................................................................ 31 
11.6 Safety 
........................................................................................................................ 32 
11.6.1 Adverse Events 
................................................................................................. 32 
11.6.2 Clinical Laboratory Assessments 
..................................................................... 32 
11.6.3 Vital Signs and Surgical Site and Physical Examinations 
................................ 33 
11.6.4 Electrocardiograms 
........................................................................................... 33 
11.6.5 Contraception and Pregnancy 
........................................................................... 34 
11.6.5.1 Contraception 
............................................................................................. 34 
11.6.5.2 Pregnancy 
................................................................................................... 35 
11.6.6 Immunogenicity Measures ............................................................................... 36 
11.6.6.1 Serum Sampling 
......................................................................................... 36 
11.6.6.2 Processing and Handling of Immunogenicity Samples ............................. 36 
11.6.6.3 Bioanalysis 
................................................................................................. 36 
12 Statistical and Analytical Plans 
.................................................................................... 36 
12.1 Sample Size and Power 
............................................................................................ 36 
12.2 Analysis Sets ............................................................................................................ 37 
12.3 Statistical Analysis ................................................................................................... 37 
12.3.1 General Considerations 
..................................................................................... 38 
12.3.2 Background Characteristics 
.............................................................................. 38 
12.3.2.1 Subject Disposition 
.................................................................................... 38 


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12.3.2.2 Demographics and Baseline Characteristics 
.............................................. 39 
12.3.2.3 Prior and Concomitant Medications........................................................... 39 
12.3.2.4 Study Drug Exposure and Compliance 
...................................................... 39 
12.3.3 Efficacy Analysis 
.............................................................................................. 39 
12.3.3.1 Analysis of Primary Efficacy Variables 
..................................................... 39 
12.3.3.2 Analysis of Secondary Efficacy Variables 
................................................. 40 
12.3.3.4 Adjustment for Multiple Comparisons ...................................................... 41 
12.3.4 Safety Analysis 
................................................................................................. 42 
12.3.4.1 Adverse Events........................................................................................... 42 
12.3.4.2 Clinical Laboratory Assessments 
............................................................... 43 
12.3.4.3 Electrocardiograms .................................................................................... 43 
12.3.4.4 Vital Signs 
.................................................................................................. 43 
12.3.4.5 Physical Examinations 
............................................................................... 43 
12.3.4.6 Other Safety Analysis ................................................................................ 44 
12.3.5 Interim and IDMC Analyses 
............................................................................. 44 
12.3.5.1 Interim Analyses 
........................................................................................ 44 
12.3.5.2 IDMC Analyses 
.......................................................................................... 44 
12.4 Clinical Pharmacology Analysis 
.............................................................................. 44 
12.4.1 Pharmacokinetic Analysis 
................................................................................ 44 
13 Procedural, Ethical, Regulatory, and Administrative Considerations 
..................... 45 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting 
.................................................................................................................. 45 
13.1.1 Adverse Events 
................................................................................................. 45 
13.1.1.1 Definition of an Adverse Event.................................................................. 45 
13.1.1.2 Clinically Significant Assessments 
............................................................ 45 
13.1.1.3 Documentation of Adverse Events............................................................. 45 
13.1.1.4 Adverse Event Severity 
.............................................................................. 46 
13.1.1.5 Adverse Event Causality 
............................................................................ 47 
13.1.1.6 Study Drug Action Taken 
.......................................................................... 47 
13.1.1.7 Adverse Event Outcome ............................................................................ 47 
13.1.1.8 Treatment Given......................................................................................... 48 
13.1.2 Serious Adverse Events 
.................................................................................... 48 
13.1.2.1 Definition of a Serious Adverse Event....................................................... 48 
13.1.2.2 Documentation of Serious Adverse Events................................................ 49 
13.1.2.3 Reporting Serious Adverse Events............................................................. 49 
13.1.2.4 Expedited Reporting and Investigator Safety Letters 
................................ 49 
13.2 Administrative Requirements 
................................................................................... 50 
13.2.1 Ethical Considerations 
...................................................................................... 50 
13.2.2 Subject Information and Informed Consent 
..................................................... 50 
13.2.3 Investigator Compliance 
................................................................................... 50 
13.2.4 Access to Records 
............................................................................................. 50 
13.2.5 Subject Privacy 
................................................................................................. 51 
13.2.6 Record Retention 
.............................................................................................. 51 


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13.2.7 Study Termination 
............................................................................................ 51 
13.3 Data Quality Assurance 
............................................................................................ 52 
13.4 Monitoring 
................................................................................................................ 52 
13.5 Electronic Data Capture ........................................................................................... 52 
13.6 Publications and Clinical Study Report 
.................................................................... 53 
13.6.2 Clinical Study Report 
....................................................................................... 53 
14 References 
....................................................................................................................... 54 
16 Protocol Signature Pages .............................................................................................. 73 
16.1 Sponsor Signature Page 
............................................................................................ 73 
16.2 Investigator Signature Page 
...................................................................................... 74 
 


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List of Tables 
Table 3-1 
Study VX15-210-101 Schedule of Assessments 
.............................................. 8 
Table 8-1 
Summary of Efficacy Endpoints and Assessments 
......................................... 23 
Table 10-1 Study Drug 
...................................................................................................... 27 
Table 11-1 Safety Laboratory Test Panels 
........................................................................ 32 
Table 12-1 Power Estimates Under a Variety of Treatment Differences, Given 
45 Randomized Subjects With Follow-up Assessments in Each Treatment 
Group .............................................................................................................. 37
 
Table 13-1 Grading of AE Severity .................................................................................. 46 
Table 13-2 Classifications for AE Causality 
..................................................................... 47
 
Table 13-3 Classifications for Study Drug Action Taken With Regard to an AE 
............ 47
 
Table 13-4 Classifications for Outcome of an AE 
............................................................ 47 
List of Figures 
Figure 8-1 
Schematic of Study Design 
............................................................................. 19 
 


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5 
INTRODUCTION 
5.1 
Introduction 
5.1.1 
Overview of SCI 
A traumatic lesion to the spinal cord results in paralysis below the level of the injury. More 
than 17,000 individuals in the US per year suffer spinal cord injuries (SCIs) from motor 
vehicle accidents (38%), falls (30.5%), violence (13.5%), sports (9%), medical or surgical 
accidents (5%), or other causes (4%).
1 Approximately half of SCIs in the US are cervical
1,2,
 
and complete cervical SCI leads to lifelong quadriplegia. Individuals with complete cervical 
SCI are therefore often unable to independently conduct activities of daily living (ADLs), 
and may require up to 24-hour attendant care.
3,4 Individuals with SCI also face serious 
comorbidities, including autonomic dysreflexia
5, bladder dysfunction
6, osteoporosis
7, 
pressure sores8, reduced immune function
9, chronic lifelong pain
10, and cardiovascular 
complications.
11 Based on these comorbidities and post-SCI paralysis, the lifespan of 
individuals with cervical SCI is substantially shorter than the lifespan for those without SCI.
1 
5.1.2 
Lack of Available Treatments for SCI 
There are no approved treatments to restore motor function after SCI. Currently, 
decompression/stabilization surgery is widely recognized as standard of care in the 
management of acute traumatic SCI to alleviate pressure within the spinal cord and prevent 
further lesion-induced nervous tissue damage.
12 Individuals with SCI are also commonly 
given methylprednisolone, although the impact of this drug on recovery from paralysis is 
controversial.
13 Spinal cord injuries, therefore, represent a high unmet medical need where 
small improvements in function can have a large impact on well-being.  
5.1.3 
Scientific Rationale for VX-210 Development 
The inability of patients to recover motor function after SCI stems, in part, from the failure of 
neurons in the central nervous system (CNS) to regrow their axons after injury. Axon 
regeneration is impeded by a number of growth-inhibiting factors.
14,15 These factors stimulate 
an intracellular master enzyme, Rho
16,17, which leads to a cascade of events culminating in 
collapse of the neuronal growth cone
18 and a failure of injured axons to regenerate.
14,15 
Inhibition of Rho activity represents a potential treatment for CNS injuries such as SCI. 
VX-210 is a protein derivative of C3 transferase that inhibits Rho 
 
 In rodent models of SCI, this stimulates axon regeneration and plasticity,20,21
 and 
decreases secondary tissue damage and glial scarring at the injury site.
20,22,23,24 These 
neuroregenerative and neuroprotective effects combine to promote functional recovery after 
SCI in rodents.
20,22,25 Therefore, in humans with acute SCI, the expected effect of VX-210 is 
the recovery of motor function. 


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6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
The evaluations of the efficacy and safety of VX-210 treatment are the primary objectives of 
the study. 
6.2 
Secondary Objectives 
 Neurological recovery: examination of the effects of VX-210 on the recovery of 
sensation and motor activity  
 Daily function: analysis of the impact of VX-210 on ADLs and requirements for 
attendant care 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
Change from baseline in upper extremity motor score (UEMS) at 6 months after treatment is 
the primary endpoint of the study. 
7.2 
Secondary Endpoints 
7.2.1 
Secondary Endpoints  
 Spinal Cord Independence Measure (SCIM) III Self-Care subscore at 6 months after 
treatment 
 Capabilities of Upper Extremity Test (CUE-T) score at 6 months after treatment 
 Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) 
Quantitative Prehension score at 6 months after treatment 
 American Spinal Injury Association Impairment Scale (AIS) grade conversion from 
baseline to 6 months after treatment 
 Motor level change from baseline to 6 months after treatment 
 Pharmacokinetic (PK) parameters of VX-210 


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8 
STUDY DESIGN 
8.1 
Overview of Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled study to examine the 
efficacy and safety of VX-210 treatment. The study will be conducted at approximately 
45 sites in the United States and Canada and will enroll approximately 100 male or female 
subjects 14 to 75 years of age (inclusive) with acute traumatic SCI, C4 to C7 (motor level) on 
each side, and AIS grade A or AIS grade B. Subjects will be randomized to receive a single 
9-mg dose of VX-210 in fibrin sealant or a placebo (buffer solution) in fibrin sealant at a 1:1 
ratio until approximately 100 subjects are enrolled (approximately 50 subjects in each 
treatment arm: 9-mg VX-210 and placebo). Subjects will be stratified by age (<30 versus ≥30 
years of age) and AIS grade (A versus B with sacral pinprick preservation versus B without 
sacral pinprick preservation) when they are randomized to the 2 study arms. The 1-time dose 
of VX-210 or placebo will be administered by a surgeon directly to the dura mater of the 
spinal cord at the site of injury during decompression/stabilization surgery that commences 
within 72 hours after the initial injury. 
For an individual subject, the study will last approximately 12 months. Follow-up 
appointments after the initial hospital stay will be at 6 weeks, 3 months, 6 months, and 
12 months after treatment. At specified time points during the study, subjects will be 
evaluated for medical, neurological, and functional changes, and serum will be collected for 
PK and immunological analyses (Table 3-1).  


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A schematic of the study design is provided in Figure 8-1. 
Figure 8-1  Schematic of Study Design  
 
8.1.1 
Screening Assessments 
Screening assessments are listed in Table 3-1. 
The investigator (or an appropriate authorized designee at the study site) will obtain informed 
consent from each subject or legally authorized representative. 
Results of assessments performed as part of standard of care (with the exception of the 
ISNCSCI examination) within 72 hours after the initial injury and before signing of informed 
consent form may be carried forward as screening.  
8.1.2 
Surgery and Post-Surgery 
Surgery and post-surgery assessments are listed in Table 3-1. 
VX-210 or placebo will be administered by a surgeon as a 1-time, topical dose to the dura 
mater of the spinal cord at the site of injury during the subject’s decompression/stabilization 
surgery. A fibrin sealant vehicle will be used for delivery. For details on administration see 
Section 10.2. 
8.1.3 
Follow-up 
Follow-up assessments and timepoints are listed in Table 3-1. Transportation for subjects to 
the site for follow-up assessments will be available if required. 


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8.1.4 
Early Discontinuation 
Early Termination Visit will be conducted when a subject withdraws or is withdrawn from 
the study (Section 9.4), or 1 or multiple study sites are closed (Section 13.2.7). Assessments 
at the Early Termination Visit are listed in Table 3-1. The Safety Follow-up Visit will be 
required in addition to the Early Termination Visit only for subjects who prematurely 
terminate from the study prior to Day 28 after treatment. Subjects who prematurely terminate 
from the study subsequent to Day 28 after treatment will only be required to complete the 
Early Termination Visit. 
8.1.5 
Independent Data Monitoring Committee 
Safety and tolerability data will be reviewed by an independent data monitoring committee 
(IDMC) to ensure the safety of the subjects in the study (Section 12.3.5.2). Results of an 
interim analysis for futility (Section 12.3.5.1) will be reviewed by the IDMC. Procedural 
details of the IDMC
's structure and function, frequency of meetings, and data planned for 
review will be included in the IDMC charter. The IDMC charter will be finalized before the 
first subject is screened in the study.  
8.2 
Rationale for Study Design and Study Drug Regimens 
8.2.1 
Rationale for Study Design 
The design for this study was developed using guidelines from the International Campaign 
for Cures of Spinal Cord Injury Paralysis
3,26,27,28, as well as more recent examinations of 
functionally meaningful efficacy endpoints for SCI clinical studies.
4,29,30 
The rationale for study drug dose and duration are described in Section 8.2.2.  
The primary and secondary endpoints will provide evidence of whether VX-210 offers a 
meaningful benefit compared to placebo. The rationale and background for the primary and 
secondary efficacy assessments are provided in Section 8.2.3.  
8.2.2 
Rationale for Study Drug Dose and Duration 
VX-210 is administered as a 1-time, topical dose to the dura mater of the spinal cord, as an 
adjunct to decompression/stabilization surgery.
31 For delivery, VX-210 is reconstituted in a 
fibrin sealant 
. After administration, the VX-210 sealant solution 
polymerizes into a fibrin gel, from which VX-210 is expected to be released into the 
surrounding tissues over the next several hours. This non-invasive, 1-time administration 
requires no additional surgery or hospitalization and eliminates the risk of further spinal cord 
damage from needle insertion. 
An open-label, dose-escalation Phase 1/2a study (Protocol Number: BA-210-101) to evaluate 
the safety and tolerability of VX-210 as a treatment for SCI was conducted at 9 sites in the 
United States and Canada.
7,31 The study enrolled 48 men and women, ages 16 to 70 years 
inclusive, with acute AIS A cervical SCIs (n = 16) or acute AIS A thoracic SCIs (n = 32). 
Five doses of VX-210 were tested (0.3, 1, 3, 6, and 9 mg). VX-210 doses were reconstituted 
in a fibrin sealant and administered to the dura mater of the spinal cord in a single, extradural 
dose, as an adjunct to decompression/stabilization surgery. No study serious adverse events 
(SAEs) were assessed as related to VX-210, and preliminary efficacy analyses showed a 


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trend toward a reduction in paralysis in cervical subjects in comparison with historical 
controls.
7,31  
The 9-mg dose was selected to maximize target engagement. Details of relevant clinical and 
nonclinical studies are provided in the Investigator’s Brochure. 
8.2.3 
Rationale for Study Assessments 
The safety and PK assessments are standard parameters for clinical studies in drug 
development. The scope of the assessments is considered appropriate for safety monitoring in 
the context of this study. Immunogenicity testing will enable evaluation of the immune 
response to VX-210. 
Vertex has carefully selected the following efficacy assessments based on guidance from 
international panels 
4,27, input from key opinion leaders, and the recent review of SCI 
Common Data Elements by the National Institute of Neurological Disorders and Stroke. 
The efficacy endpoints and associated assessments are summarized in Table 8-1. 
8.2.3.1 
Primary Endpoint 
Upper Extremity Motor Score  
UEMS is a subset of the ISNCSCI examination, an assessment developed by the American 
Spinal Injury Association (ASIA) that is widely used for evaluating efficacy in SCI clinical 
trials.
27  
The upper extremity motor score focuses selectively on the hand and arm control most 
relevant to individuals with a cervical spinal cord injury.
32 Muscle contraction strength is 
graded in 5 key arm and hand muscle groups on each side of the body from 0 (total paralysis) 
to 5 ([normal] active movement), for a total possible UEMS score of 50. Importantly, UEMS 
has been shown to measure neurological recovery in a manner that correlates with 
improvement on functional tests.
30,33,34,35,36 As each of the muscles measured in the UEMS 
assessment is critical for daily function, small increases in UEMS can correspond to a 
significant improvement in functional recovery.
30,37 The ISNCSCI scoresheet is provided in 
Section 15.1. 
8.2.3.2 
Secondary 
 
The Spinal Cord Independence Measure III 
The SCIM III38,39,40 is an SCI-specific disability scale viewed as the most sensitive, reliable, 
and relevant test for assessing function after SCI.
12,41 The Self-Care section of the SCIM III 
is a 20-point subscale that specifically examines a subject’s ability to feed, dress, groom, and 
bathe themselves on a daily basis. This subscale is often evaluated as a measure of the ability 
to perform ADLs dependent on the changes in hand and arm control most relevant to the 
cervical SCI population. The SCIM III Self-Care subscore will be a secondary endpoint.  


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Capabilities of Upper Extremity Test 
The CUE-T42 is a functional test 
35,42 that measures a subject’s ability to perform specific 
functional movements/tasks with the arms and hands (e.g., grasping a pencil, pushing or 
lifting a weight). The total possible score is 128 (after proper score conversion of all 32 items 
to a 0 to 4 scale). The CUE-T scoresheet is provided in the study reference manual.   
GRASSP Quantitative Prehension Test 
GRASSP Quantitative Prehension Test 43 is a functional test 
34,43,44,45,46 that ranks a subject’s 
ability to perform specific functional tasks with the arms, hands, and fingers (e.g., turning a 
key in a lock, pouring water in a cup). The total possible score is 60. The GRASSP 
Prehension scoresheet is provided in Section 15.3. 
Other Common Derivatives of the ISNCSCI Assessment  
The ASIA Impairment Scale (AIS) ranks impairment according to body-wide motor/sensory 
results (see ISNCSCI Scoresheet in Section 15.1 for additional details):  
 AIS A; Complete: No sensory or motor function is preserved in the sacral segments 
S4 to 5.  
 AIS B; Sensory Incomplete: Sensory but not motor function is preserved below the 
neurological level and includes the sacral segments S4 to 5 (light touch or pin prick at 
S4 to 5 or deep anal pressure) AND no motor function is preserved more than 3 levels 
below the motor level on either side of the body. 
 AIS C; Motor Incomplete: Motor function is preserved at the most caudal sacral 
segments for voluntary anal contraction OR the patient meets the criteria for sensory 
incomplete status (sensory function preserved at the most caudal sacral segments (S4 
to S5) by light touch, pin prick, or deep anal pressure) and has some sparing of motor 
function more than 3 levels below the ipsilateral motor level on either side of the 
body (This includes key or non-key muscle functions to determine motor incomplete 
status). For AIS C – less than half of key muscle functions below the single 
neurological level of injury have a muscle grade ≥3.   
 AIS D; Motor Incomplete: Motor incomplete status as defined above, with at least 
half (half or more) of key muscle functions below the single neurological level of 
injury having a muscle grade ≥3.   
 AIS E; Normal: If sensation and motor function as tested with the ISNCSCI are 
graded as normal in all segments, and the patient has prior deficits, then the AIS 
grade is E. Someone without an SCI does not receive an AIS grade. 
Using “Not Determined” (ND): To document the ASIA Impairment Scale grade 
when it is unable to be determined based on the examination results. 
Conversion of 2 or more AIS grades has been used previously as a clinical assessment of 
significant neurologic recovery.
47,48 
The motor level for the right or left side is defined by the lowest key muscle function that has 
a grade of at least 3 (on supine testing), provided the key muscle functions represented by 




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9 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
9.1 
Inclusion Criteria 
Subjects who meet all of the following inclusion criteria will be eligible. 
1. Subject (or a witness, or his or her legally appointed and authorized representative) will 
sign and date an informed consent form (ICF).  
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, 
contraceptive guidelines, and other study procedures. 
3. Subjects are male or female between 14 and 75 years of age, inclusive. 
4. Acute traumatic cervical SCI, motor level of C4, C5, C6, or C7 on each side:  
 Screening UEMS score must be ≤16 points on each side. 
 AIS A subjects with a C4 motor level on both sides must have at least 1 point of 
motor activity between C5 and T1 on at least 1 side. 
 AIS B subjects with a C4 motor level on both sides must have at least 1 point of 
motor activity between C5 and C7 on at least 1 side. 
5. AIS grade A or AIS grade B. 
6. Scheduled and planned to undergo a spinal decompression/stabilization surgery that 
commences within 72 hours after the initial injury.  
7. Computed tomography (CT) scan or magnetic resonance imaging (MRI) is consistent 
with the subject’s neurological deficit. 
9.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible. 
1. Participation in any other clinical study for acute SCI without approval by the sponsor 
(Vertex). 
2. Inability to undergo decompression/stabilization surgery that commences within 72 hours 
after injury.  


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3. One or more upper extremity muscle groups untestable during screening ISNCSCI 
examination. 
4. Acute SCI from gunshot or penetrating/stab wound; non-traumatic SCI (e.g., transverse 
myelitis, acute disc herniation); brachial plexus injury; complete spinal cord transection; 
or multifocal SCI. 
5. Females who are breastfeeding or have a positive serum pregnancy test.  
6. Body mass index (BMI) of ≥40 kg/m2 at screening.  
7. History of an adverse reaction to a fibrin sealant or its human or bovine components. 
8. Unconsciousness or other mental impairment that precludes reliable ISNCSCI 
examination. 
9. Known immunodeficiency, including human immunodeficiency virus, or use of 
immunosuppressive or cancer chemotherapeutic drugs. 
10. Any significant medical or psychiatric comorbidities (e.g., neurologic, cardiac, 
respiratory, hepatic, bleeding/coagulation disorder, renal, active malignancy) that would 
significantly increase the risk of study enrollment and/or significantly interfere with study 
outcomes or assessments, in the judgment of the investigator. (Note: Subjects with 
chronic medical conditions that are well controlled are eligible for the study: e.g., a 
subject with mild and well-controlled asthma or diabetes would be eligible, whereas a 
subject with severe congestive heart failure limiting activity or severe cardiopulmonary 
disorder limiting exercise would not be eligible.) 
11. 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. 
9.3 
Prior and Concomitant Medications 
Intravenous steroid medications (e.g., methylprednisolone) for the treatment of SCI are 
permitted. At screening, all medications received in the past 30 days will be collected. 
Information regarding all concomitant medications administered from screening through the 
end of study participation will be collected.  
9.4 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from the study 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 the study, the subject should continue to be followed, 
provided the subject has not withdrawn consent.  
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. 
The investigator will inquire about the reason for withdrawal, request that the subject return 
for an Early Termination Visit and/or Safety Follow-up Visit, as applicable (see 
Section 8.1.4), and follow up with the subject regarding any unresolved AEs. 


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If the subject withdraws consent, 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. 
9.5 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study will not be replaced. 
10 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
VX-210 or placebo will be provided to study sites in a blinded fashion. Each individual 2 mL 
glass vial will contain 0.5 mL of blinded clinical study material.  
The fibrin sealant delivery vehicle 
 will be provided as a single-use kit, 
consisting of 4 components packed in separate vials. 
Additional details regarding packaging, labeling, and dispensing for VX-210 will be included 
in the Pharmacy Manual. 
Additional details regarding preparation of VX-210/placebo  
 are provided in the 
Formulation Preparation Instructions. 
10.2 
Administration 
Each subject will receive 1 single dose of VX-210 or placebo in fibrin sealant. The single 
dose of VX-210 or placebo in fibrin sealant will be administered during 
decompression/stabilization surgery that commences within 72 hours after the initial injury.  
VX-210 or placebo in fibrin sealant will be delivered topically to the dural surface of the 
spinal cord at the site of injury (local, extradural administration). The start time of application 
of clinical study material must be collected. Presence of dural tears will be collected. 
Administration details will be provided in the Surgical Guidelines. 
10.3 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized to receive a single 9-mg dose of VX-210 in fibrin sealant, or a 
placebo (buffer solution) in fibrin sealant at a 1:1 ratio. Subjects will be stratified by age (<30 
versus ≥30 years of age) and AIS grade (A versus B with sacral pinprick preservation versus 
B without sacral pinprick preservation) when they are randomized to the 2 study arms. 
An interactive web or voice response system (IXRS) will be used to assign subjects to 
treatment. The randomization code will be produced by Vertex Biostatistics or a qualified 
randomization vendor. The Vertex study biostatistician will review and approve the dummy 
randomization list. The final randomization list will be generated and approved by an 
unblinded biostatistician or designee who is not a member of the study execution team.  
10.4 
Dose Modification for Toxicity 
This is a single-dose study. No dose modifications for toxicity are allowed or required. 


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10.5 
Packaging and Labeling 
Vertex will supply VX-210 or placebo in 2.0 mL glass vials (Table 10-1). Blinded study drug 
labeling will be in compliance with applicable local and national regulations. Additional 
details regarding packaging, labeling, and dispensing for VX-210 will be included in the 
Pharmacy Manual. 
 
10.6 
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 drug accountability forms as instructed by Vertex. 
Table 10-1 Study Drug  
Drug Name 
Formulation/ 
Route 
Dosage Packaging 
Storage 
Condition 
VX-210 
VX-210 drug product in 
5 mM sodium citrate buffer 
to be reconstituted in fibrin 
sealant 
 
before 1-time extradural 
administration 
9-mg  
2.0 mL glass vials 
containing 0.5 mL of 
frozen VX-210 at 
30 mg/mL (15 mg 
VX-210/vial) 
According to the 
container label 
Placebo 
Sodium citrate buffer to be 
reconstituted in fibrin 
sealant 
 
before 1-time extradural 
administration 
-- 
2.0 mL glass vials 
containing 0.5 mL of 
frozen sodium citrate 
buffer 
According to the 
container label 
 
10.7 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates 
and amounts of study drug administered. Study drug 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. 
10.8 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain study drug at the site 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. 


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10.9 
Compliance  
The single study drug dose is administered during the inpatient period of the study by the 
investigator or designee. Guidance on investigator compliance can be found in 
Section 13.2.3. 
10.10 
Blinding and Unblinding 
This will be a randomized, double-blind study. 
10.10.1 
Blinding  
All Vertex study personnel will be blinded to subject treatment assignments, except for the 
following individuals: an external vendor biostatistician preparing the final (production) 
randomization list who is not part of the SET; Bioanalytical CRO analyzing PK samples and 
the Vertex Bioanalytical staff who needs to review the raw data from Bioanalytical CRO 
(excluding Bioanalytical SET member who will continue to be blinded); and Vertex Global 
Patient Safety (GPS) and Regulatory Affairs representatives when required to satisfy 
regulatory reporting requirements.  
10.10.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of the individual subject
's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject
's study treatment 
is necessary for clinical management. In such cases, investigators will use their best 
judgment as to whether to unblind without first attempting to contact the medical monitor to 
discuss and agree to the need for unblinding. If investigators deem it not necessary to unblind 
immediately, they will first attempt to contact the medical monitor to discuss and agree to the 
need for unblinding. If investigators have tried, but are unable to reach the medical monitor, 
they will use their best judgment, based on the nature and urgency of the clinical situation, 
and may proceed with unblinding without having successfully reached and discussed the 
situation with the medical monitor. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center 
 will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If a subject
's treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding 
event. The reason and the date of the unblinding will be documented clearly in the subject
's 
study file. 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), contract research organization (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 


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definitions or criteria for SAEs, and if so, submit an SAE report to Vertex GPS or designee, 
per Section 13.1.2. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, 
unblind individual subjects at any time.  
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments is shown in Table 3-1.  
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 
Serum Sampling 
Serum samples for the determination of the concentrations of VX-210 will be collected at 
visits indicated in Table 3-1 and at the time of any SAE occurring within 3 days after 
treatment. 
The acceptable window for the post-treatment PK sampling time points is ± 30 minutes. 
Samples collected outside this window will be considered a protocol deviation. All efforts 
will be made to obtain the PK samples at the exact nominal time relative to dosing. 
The following will be recorded accurately in the source document: date and time of 
administration of the dose; date and time of each of the PK serum samples.  
11.3.2 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of serum samples and further procedures for 
processing and handling of samples for PK analysis will be provided in the Laboratory 
Manual and/or 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. 


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11.5 
Efficacy 
For all assessments, all efforts will be made to use the same assessor for a given examination 
for a given subject. 
11.5.1 
ISNCSCI Examination 
The ISNCSCI examination will be conducted at time points indicated in Table 3-1 and will 
be conducted by an independent, trained assessor. All efforts will be made to use the same 
assessor for all ISNCSCI examinations for a given subject. All trained assessors must meet 
Vertex requirements provided in the Assessment Handbook and must complete required 
training.  
In addition to providing detailed motor and sensory scores, this assessment will determine the 
right and left motor levels, AIS Grade, neurological level, and complete/incomplete status. 
Specifics on proper ISNCSCI administration will be provided in the Assessment Handbook.  
11.5.2 
The Spinal Cord Independence Measure III 
The SCIM III survey will be administered at the time points indicated in Table 3-1 by an 
independent, trained assessor. All efforts will be made to use the same assessor for all 
SCIM III examinations for a given subject. All trained assessors must meet Vertex 
requirements provided in the Assessment Handbook and must complete required training. 
This functional assessment measures (1) self-care abilities (feeding, dressing, grooming, 
bathing); (2) respiration and sphincter management; and (3) mobility. 
Specifics on proper SCIM III administration will be provided in the Assessment Handbook.  
11.5.3 
Capabilities of Upper Extremity Test 
The CUE-T assessment will be conducted at the time points indicated in Table 3-1 and will 
be conducted by an independent, trained assessor. All trained assessors must meet Vertex 
requirements provided in the Assessment Handbook and must complete required training. 
This test measures reaching capabilities and the ability to perform specific functional tasks 
with the hands and arms (e.g., grasping a pencil, pushing/lifting a weight). 
Specifics on proper CUE-T administration will be provided in the Assessment Handbook.  


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11.5.4 
GRASSP Quantitative Prehension Test 
The GRASSP Quantitative Prehension test will be conducted at the time points indicated in 
Table 3-1 and will be conducted by an independent, trained assessor. All trained assessors 
must meet Vertex requirements provided in the Assessment Handbook and must complete 
required training. 
This test measures a subject’s ability to perform specific functional tasks with the hands/arms 
(e.g., pouring water from bottle, screwing nuts on bolts). 
Specifics on proper GRASSP Quantitative Prehension Test administration will be provided 
in the Assessment Handbook.  
11.5.7 
Hospitalizations 
At visits indicated in Table 3-1, subjects will be queried about hospitalizations. The dates for 
hospitalizations (i.e., dates of admission and discharge) and the reasons will be collected.  


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11.6 
Safety 
Safety evaluations will include AEs, vital signs, electrocardiograms (ECGs), clinical 
laboratory assessments, physical examinations, surgical site examinations, and 
immunogenicity measures. 
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 case report 
form (CRF) completion guidelines for investigators as well as training will be provided. 
11.6.2 
Clinical Laboratory Assessments 
Blood and urine samples for safety assessment will be analyzed at each site
's local 
laboratory. See the following sections for details regarding collection of blood samples for 
immunogenicity (Section 11.6.6), PK (Section 11.3),
  
Blood samples for clinical laboratory assessments will be collected at time points indicated in 
Table 3-1. After screening, 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 
Urinalysis 
Glucose  
Blood urea nitrogen 
Creatinine  
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Inorganic phosphate  
Total bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate aminotransferase (= SGOT)  
Alanine aminotransferase (= SGPT)  
Amylase  
Lipase  
Gamma glutamyl transferase  
Total protein  
Albumin  
Creatine kinase . 
Uric acid  
Cholesterol  
Hemoglobin  
Erythrocytes  
Mean corpuscular hemoglobin  
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelets  
Leukocytes  
Differential (absolute and percent): 
Eosinophils  
Basophils  
Neutrophils  
Lymphocytes  
Monocytes  
Coagulation Studies 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
 
Leukocyte 
esterase 
Nitrite 
Urobilinogen 
Urine protein 
pH 
Urine blood 
Specific gravity 
Urine ketones 
Urine bilirubin 
Urine glucose 


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Table 11-1 Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysis 
Triglycerides 
Low-density lipoprotein  
High-density lipoprotein  
 
Additional tests at screening: The following additional tests will be performed during 
screening to assess eligibility or contraception requirements:  
 Serum beta-human chorionic gonadotropin (ßHCG) for all female subjects  
 Serum follicle-stimulating hormone (FSH) for suspected postmenopausal female subjects 
<60 years of age when a waiver to contraception is sought. Levels will be within the 
laboratory
's range for postmenopausal for subjects to be considered of non-childbearing 
potential. 
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. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
11.6.3 
Vital Signs and Surgical Site and Physical Examinations  
The surgical site will be examined for proper wound healing and lack of infection at time 
points indicated in Table 3-1. 
A physical examination of all body systems and vital signs assessments will be performed at 
the Screening, Early Termination, and Safety Follow-up Visits (see Table 3-1). At other 
visits, symptom-directed physical examinations and symptom-directed vital sign assessments 
can be performed at the discretion of the investigator or healthcare provider
. 
A physical examination should include a review of the following systems: head/neck/thyroid; 
eyes/ears/nose/throat (EENT); respiratory; cardiovascular; abdomen; skin; musculoskeletal; 
and neurological. Breast, anorectal, and genital examinations will be performed when 
medically indicated. After screening, any clinically significant abnormal findings in physical 
examinations will be reported as AEs. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. These will be assessed following a 5-minute rest in the supine position. After 
screening, any clinically significant findings in vital signs will be reported as AEs. 
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). Additional standard 12-lead ECGs will be performed 
at any other time if clinically indicated. The performance of all ECGs will adhere to the 
following guidelines: 


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 The subject will be instructed to rest in the supine position for at least 5 minutes before 
having an ECG performed. 
 The ECG will be performed before any other procedures that may affect heart rate, such 
as blood draws. 
The ECG traces will be manually read at the study site by the PI or designee (e.g., qualified 
cardiologist). A printout of the ECG traces will be made for safety review by the investigator 
and maintained with source documentation. Clinically significant ECG abnormalities 
occurring during the study will be recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site will make 
comparisons to baseline measurements. If the QTcF is increased by >45 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 
(>45 msec from baseline or ≥500 msec), continuous 3- or 5-lead ECG monitoring should be 
performed until QTcF values fall below the threshold value that triggered the repeat 
measurement, followed by a single ECG to confirm. If the subject is no longer on continuous 
monitoring, a single 12-lead ECG will be performed at least every 8 to 12 hours until QTcF 
values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement. If QTcF values do not return to baseline within 72 hours after administration 
of study drug, further monitoring will be done as clinically indicated. 
11.6.5 
Contraception and Pregnancy 
11.6.5.1 
Contraception 
At this stage in the development of VX-210, study participation requires a commitment from 
the subject and his/her partner to use 2 methods of birth control. Acceptable methods of 
contraception for subjects and their partners are listed below.  
Contraception for the couple is waived for the following: 
 True abstinence for the subject, when this is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
 The male subject is infertile (e.g., bilateral vasectomy, as described in "acceptable 
contraceptive methods" below).  
 The female subject is of non-childbearing potential. To be considered of non-childbearing 
potential, the female must meet at least 1 of the following criteria: 
o Postmenopausal: amenorrheic for at least 12 months and have a serum FSH level 
within the laboratory’s reference range for postmenopausal females; the FSH 
requirement is waived for female subjects ≥60 years of age.  
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
All other female subjects (including subjects with bilateral tubal ligations <6 months 
before administration of study drug and subjects who do not have a documented 


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hysterectomy or bilateral oophorectomy/salpingo-oophorectomy) will be considered to be 
of childbearing potential. 
Acceptable Contraceptive Methods: 
Acceptable contraceptive methods for male subjects or male partners of female subjects 
include the following:  
 Documented bilateral vasectomy at least 6 months before administration of study drug, 
with a negative post-vasectomy semen analysis for sperm  
 Barrier contraception (such as diaphragm, cervical cap, or female condom) with 
spermicide (if available). If spermicide is not available then 2 methods of contraception, 
one of which includes a condom, must be used (e.g., condom plus diaphragm, condom 
plus cervical cap). Local regulations may require use of an additional acceptable method 
of contraception. 
Acceptable contraceptive methods for female subjects and female partners of male subjects 
include the following:  
 Documented bilateral tubal ligation performed 6 months or more before administration of 
study drug. 
 Oral, transdermal, injectable, or implantable hormonal birth control method successfully 
used for at least 60 days before administration of study drug.  
 An intrauterine device (nonhormone-releasing) in place for at least 90 days before 
administration of study drug. 
 Barrier contraception (such as diaphragm, cervical cap, or female condom) with 
spermicide (if available). If spermicide is not available then 2 methods of contraception, 
one of which includes a condom, must be used (e.g., condom plus diaphragm, condom 
plus cervical cap.) Local regulations may require use of an additional acceptable method 
of contraception.  
Additional notes: 
 Female condom cannot be used with male condom (as a double method of contraception) 
due to risk of tearing.  
 All contraceptive methods will be used throughout the study. 
 Male subjects will not donate sperm for 90 days after administration of study drug.  
11.6.5.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during the 
study. 
If a subject or the female partner of a male subject becomes pregnant during the study, the 
investigator will notify the medical monitor and Vertex GPS within 24 hours of the site
's 
knowledge of the subject
's (or partner
's) pregnancy using the Pregnancy Information 
Collection Form.  


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If confirmed to have been treated with active drug, the subject or partner will be followed 
until the end of the pregnancy and 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. 
11.6.6 
Immunogenicity Measures 
11.6.6.1 
Serum Sampling 
Serum samples will be collected at visits indicated in Table 3-1 and will also be collected at 
the time of any SAE occurring within 3 days after treatment. 
The following will be recorded accurately in the source document: date and time of 
administration of the dose; date and time of each of the immunogenicity serum samples. 
11.6.6.2 
Processing and Handling of Immunogenicity Samples 
Detailed procedures for the collection of serum samples and further procedures for 
processing and handling of samples for immunogenicity analysis will be provided in the 
Laboratory Manual and Sample Handling Guidelines. The shipment address and assay 
laboratory contact information will be provided to the investigational site before initiation of 
the study. 
11.6.6.3 
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. 
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. 
12.1 
Sample Size and Power 
The primary efficacy endpoint is the change from baseline in UEMS at 6 months after 
treatment.  
The null hypothesis to be tested is that the mean change from baseline in UEMS at 6 months 
after treatment is the same for 9-mg dose of VX-210 and placebo. This null hypothesis will 
be tested at 2-sided significance level α = 0.05. 
The sample size was calculated using a projected standard deviation (SD) of 6.0, based on 
the variability of improvement in UEMS scores of cervical subjects in the historical Sygen 
database. Anticipated withdrawal of 10% of subjects before the first follow-up assessment 
was also included in the sample size calculation.  
If 9-mg dose group improves in UEMS by 4 points over placebo (a clinically meaningful 
increase), a total of approximately 100 subjects (approximately 50 per arm) will have 


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approximately 82.1% power to detect a statistically significant treatment effect for 9-mg dose 
group compared to placebo, considering the interim futility analysis.  
Based on the review of data from Anderson et al.,
38 the SD was projected to be 3.8 for 
SCIM III Self-Care subscore. Table 12-1 presents the estimated power for detecting different 
treatment differences between an active treatment group and the placebo group in SCIM III 
Self-Care subscore, assuming 45 randomized subjects with follow-up assessment in each 
treatment group without considering the possible power loss from the interim futility 
analysis.  
Table 12-1 Power Estimates Under a Variety of Treatment Differences, Given 
45 Randomized Subjects With Follow-up Assessments in Each Treatment 
Group 
Mean Difference in SCIM III Self-Care Subscore 
Power (%) 
1 
23 
2 
69 
3 
95 
Power estimates are based on 2-sided t-test with α = 0.05. 
12.2 
Analysis Sets 
Assignment of subjects to analysis sets will be performed before the clinical data lock for the 
study and treatment unblinding.  
The All Subjects Set is defined as all subjects who have been randomized or have received 
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 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 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. 
12.3 
Statistical Analysis 
The primary objectives of this study are to evaluate the efficacy and safety of VX-210 
treatment in subjects with acute traumatic cervical SCI. The primary analyses will be based 
on the 6 month data. 
 
 
This section presents a summary of the planned statistical analyses of efficacy and safety for 
this study. The Vertex Biometrics department or a designated CRO will analyze the data 
derived from this study. Statistical Analysis System Version 9.2 or higher will be used to 
generate all statistical outputs (tables, figures, listings, and data sets). 
Statistical analysis and presentation details will be provided in the SAP for the study. 


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12.3.1 
General Considerations 
All individual subject data for all individual subjects randomized or received study drug will 
be presented in data listings.  
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, standard error (SE), median, minimum value (min), 
and maximum value (max). The precision of the measurement for each continuous variable 
will be used to determine the number of decimal places to present in tables, figures, and 
derived listings. Unless otherwise specified, min and max values will be reported with the 
same precision as the units of measure; the mean, median, SD, and SE will be reported to 
1 greater decimal place. Any values that require transformation to standard units (metric or 
International System [SI]) will be converted with the appropriate corresponding precision. 
Details will be provided in the SAP. 
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline value, unless otherwise specified, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before administration of study drug. 
Change (absolute change) from baseline will be calculated as postbaseline value - baseline 
value. 
The treatment-emergent (TE) period will include the time from dosing with study drug to the 
Safety Follow-up Visit or 28 days after treatment for subjects who do not have a Safety 
Follow-up Visit. 
12.3.2 
Background Characteristics 
Subject disposition, demographic and baseline characteristics, prior and concomitant 
medications, and other background characteristics will be summarized. Additionally, all 
subject data will be presented in subject data listings. All summaries will be based on the 
FAS, unless otherwise specified in the SAP for the study. No statistical hypothesis testing 
will be performed on background characteristics. 
12.3.2.1 
Subject Disposition 
Number and percentage of subjects in the following categories will be summarized as 
appropriate: 
 Randomized or dosed (All Subjects Set) 
 Randomized 
 Dosed (Safety Set) 
 Randomized and dosed (FAS) 
 Completed 6-Month Follow-up Visit 
 Completed study 
 Prematurely discontinued the study and the reasons for discontinuation 


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Subject disposition summary will be presented based on the All Subjects Set. 
12.3.2.2 
Demographics and Baseline Characteristics 
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized. Protocol deviations/violations will be provided in a subject data listing only.  
The following demographics and baseline characteristics will be summarized by treatment 
group for the FAS: sex, race, ethnicity, age, weight, height, BMI, country, AIS (A or B with 
or B without sacral pinprick preservation), and baseline UEMS score. 
12.3.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by the World Health Organization Drug 
Dictionary Enhanced (WHO-DDE) and will be categorized as follows:  
 Prior medication: any medication that started prior to dosing with study drug, 
regardless of when it ended. 
 Concomitant medication: medication continued or newly received at or after dosing 
of study drug through the end of the TE period.  
 Post-treatment medication: medication continued or newly received after the TE 
period. 
A given medication can be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; 
or prior, concomitant, and post-treatment. If a medication has a missing or partial missing 
start/end date or time and cannot be determined whether it was received prior to dosing with 
study drug, concomitantly, or beyond the TE period, it will be considered as prior, 
concomitant, and post-treatment. 
Prior medications and concomitant medications will be summarized descriptively based on 
the FAS. Post-treatment medications will be listed for each subject. 
12.3.2.4 
Study Drug Exposure and Compliance 
Study drug exposure will be presented in an individual data listing to indicate whether the 
study drug was administered. 
12.3.3 
Efficacy Analysis 
Assessment of efficacy of VX-210 treatment is 1 of the primary objectives of this pivotal 
study. A hierarchical testing strategy will be used to preserve the overall 2-sided type I error 
rate at the 0.05 level. All efficacy endpoints will be analyzed based on the FAS. 
12.3.3.1 
Analysis of Primary Efficacy Variables 
The primary efficacy endpoint is the change from baseline in UEMS at 6 months after 
treatment. The null hypothesis to be tested is that the mean change from baseline in UEMS at 
6 months after treatment is the same for 9-mg dose of VX-210 and placebo.  
The primary analysis will be based on a mixed-effects model for repeated measures 
(MMRM). The model will include the change from baseline in UEMS as the dependent 
variable; treatment, visit, and treatment-by-visit interaction as fixed effects; and subject as a 


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random effect, with adjustment for age and AIS grade (A versus B with sacral pinprick 
preservation versus B without sacral pinprick preservation) at baseline. In the model, visit 
will be treated as a class variable, and an unstructured covariance matrix will be assumed to 
model the within-subject variability. This model imposes no assumptions on the correlation 
structure and is considered robust. Denominator degrees of freedom for the F-test for fixed 
effects will be estimated using the Kenward-Roger approximation.
52 With a mixed-effects 
model based on restricted maximum likelihood estimation as the primary analysis and 
assuming that, conditional on fixed and random effects, data are missing at random, no 
imputation of missing data will be performed. 
The primary result obtained from the model will be the estimated mean treatment effect at 
6 months after treatment. The estimated mean treatment effect, a 95% CI, and a 2-sided 
P value will be provided. Furthermore, the treatment effect at each postbaseline visit, 
obtained from the model, will also be provided. 
If there is a convergence problem due to the use of an unstructured covariance matrix, the 
unstructured covariance matrix will be replaced by a compound symmetric covariance matrix 
to model the within-subject errors. 
 
 
12.3.3.2 
Analysis of Secondary Efficacy Variables 
For all secondary efficacy variables, the primary analysis will focus on the treatment effects 
at 6 months after treatment. 
 SCIM III Self-Care subscore at 6 months after treatment: The analysis of this variable 
will be based on an analysis of covariance (ANCOVA) model, which will include the 
SCIM III Self-Care subscore at 6 months after treatment as the dependent variable, 
and treatment as a fixed effect, with adjustment for age and AIS grade (A versus B 
with sacral pinprick preservation versus B without sacral pinprick preservation) at 
baseline. If the SCIM III Self-Care subscore at 6 months after treatment is missing, 
the score at the Early Termination Visit will be carried forward for the analysis. 
 CUE-T score at 6 months after treatment: The analysis of this variable will be similar 
to the analysis of the SCIM III Self-Care subscore. 
 GRASSP Quantitative Prehension score at 6 months after treatment: The analysis of 
this variable will be similar to the analysis of the SCIM III Self-Care subscore. 
 AIS grade conversion from baseline to 6 months after treatment: The response 
variable will be analyzed using the 2-sided Cochran-Mantel-Haenszel (CMH) test 
stratified by age (<30 versus ≥30 years of age) and AIS grade (A versus B with sacral 
pinprick preservation versus B without sacral pinprick preservation).  
 Motor level change from baseline to 6 months after treatment: The analysis of this 
response variable will be similar to the analysis of the AIS grade conversion from 
baseline to 6 months after treatment. 


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12.3.3.4 
Adjustment for Multiple Comparisons 
The multiplicity adjustment will control the overall 2-sided type I error rate at 0.05 for testing 
9-mg of VX-210 versus placebo for multiple endpoints. 
The following multiplicity adjustment approach will be used to strongly control the overall 
2-sided type I error rate at 0.05 for the primary endpoint and key secondary endpoints. 
A hierarchical testing procedure will be used for the multiple endpoints at the 2-sided 
significance level α = 0.05 as follows: 
Step 1: The primary efficacy endpoint will be tested at significance level α = 0.05. 
Step 2: If VX-210 is statistically significant at α = 0.05 from Step 1, the first key secondary 
efficacy endpoint will be tested at α = 0.05. 
At each step, the test for treatment effect will be considered statistically significant if the test 
meets the criteria for significance and all previous tests are also statistically significant. The 
first 2 layers of the testing hierarchy are as follows: 
1. Change from baseline in UEMS at 6 months after treatment 
2. SCIM III Self-Care subscore at 6 months after treatment 
After the primary (change in UEMS) and first key secondary endpoint (SCIM III Self-Care) 
have met the level of significance for VX-210 compared to placebo, additional functional 
tests will be added to this hierarchy, with a test for treatment effect at each step that will be 
considered statistically significant only if the test is statistically significant and all previous 


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tests are also statistically significant. The hierarchy of endpoints after change in UEMS and 
SCIM III Self-Care subscore will be described in the SAP.  
Note that the comparisons that cannot be performed formally due to hierarchical testing 
strategy will still be performed, and the corresponding P values will be considered 
descriptive. 
12.3.4 
Safety Analysis 
All safety summaries will be based on the set of data associated with the TE period for 
subjects in the Safety Set. 
The overall safety profile of VX-210 will be assessed in terms of the following safety and 
tolerability endpoints: 
 Incidence of treatment-emergent adverse events (TEAEs) 
 Clinical laboratory values (i.e., hematology, serum chemistry, coagulation studies, 
and urinalysis) 
 ECGs 
 Vital signs 
All safety data will be presented in individual subject data listings. 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
 Pretreatment AE: Any AE that started prior to dosing with study drug. 
 TEAE: Any AE that developed or worsened at or after dosing of study drug through 
the end of the TE period. 
 Post-treatment AE: Any AE that developed or worsened beyond the TE period. 
For AEs with missing or partial missing start dates, if there is no clear evidence that the AEs 
started before or after study treatment, then the AEs will be classified as TEAEs. 
AE summary tables will be presented for TEAEs only and will include the following: 
 All TEAEs  
 TEAEs by relationship  
 TEAEs by maximal severity 
 Serious TEAEs 
 TEAEs leading to death 
Summaries will be presented by MedDRA system organ class and preferred term using 
frequency counts and percentages (i.e., number and percentage of subjects with an event as 
well as total number of events). When summarizing the number and percentage of subjects 
with an event, subjects with multiple occurrences of the same AE or a continuing AE will be 


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counted once, only the maximum severity level will be presented in the severity summaries, 
and the worst/highest relationship level in the relationship summaries. An AE overview table 
will be provided. A separate table will summarize all TEAEs when each of them is 
considered unique, hereafter referred to as an AE count table. In addition, a listing containing 
individual subject AE data for all deaths and other serious and significant AEs will be 
provided separately. All AEs, including pre- and post-treatment AEs, will be presented in 
individual subject data listings.  
12.3.4.2 
Clinical Laboratory Assessments 
The raw values and change from baseline values of the continuous laboratory parameters will 
be summarized in SI units by treatment group at each scheduled time point during the TE 
period. 
The number and percentage of subjects with at least 1 potentially clinically significant (PCS) 
event during the TE period will be summarized by treatment group. The PCS criteria for 
clinical laboratory data will be provided in the SAP. 
Immunogenicity results will be summarized in tables and listings. 
Results of urinalysis and the serum pregnancy test will be listed in individual subject data 
listings only. In addition, a listing containing individual subject laboratory assessment values 
outside the reference ranges will be provided. Individual subject data listings will include 
data from scheduled and unscheduled time points.  
12.3.4.3 
Electrocardiograms 
A summary of raw values and change from baseline values will be provided by treatment 
group at each scheduled time point during the TE period for the following standard 12-lead 
ECG measurements: PR, QT, QTc for heart rate (HR) interval (QTcF), QRS duration, and 
HR. In addition, the mean value at each visit will be plotted by treatment group for QTcF. 
The number and percentage of subjects with at least 1 PCS event during the TE period will 
be summarized by treatment group. The PCS criteria for ECG data will be provided in the 
SAP. 
12.3.4.4 
Vital Signs 
The raw values and change from baseline values during the TE period will be summarized by 
treatment group at each scheduled time point: systolic and diastolic blood pressure (mm Hg), 
body temperature (C), HR (beats per minute [bpm]), and respiratory rate (breaths per 
minute).  
The number and percentage of subjects with at least 1 PCS event during the TE period will 
be summarized by treatment group. The PCS criteria for vital signs data will be provided in 
the SAP. 
12.3.4.5 
Physical Examinations 
Physical examination, including surgical site examination, results will be presented in 
individual subject data listings only. After screening, any clinically significant abnormal 
findings in physical examinations will be reported as AEs.  


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12.3.4.6 
Other Safety Analysis 
Not applicable. 
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analyses 
An interim analysis will be conducted when 33% of enrolled patients have completed the 6-
Month Follow-up Visit. Based on the results of this interim analysis, the study may continue 
or stop for futility. The IDMC will conduct review of this interim analysis and make 
recommendation to the sponsor. If the study is considered unsuccessful at the time of the 
interim analysis, the study is to be terminated, study enrollment is to be stopped, and subjects 
are to be followed for safety reasons only. 
Vertex will conduct the primary analysis for the study that includes safety, efficacy, and PK 
after all subjects receiving study drug have completed the 6-Month Follow-up Visit, or Early 
Termination Visit/Safety Follow-up Visit for subjects who prematurely terminate from the 
study before the 6-Month Follow-up Visit, and all data from these visits have been entered 
into the clinical study database, and the data have been cleaned and locked. If the study is 
considered unsuccessful at this primary analysis, the study is to be terminated and subjects 
are to be followed for safety reasons only. If the study is considered successful at this 
analysis, an updated analysis will be conducted by Vertex after all subjects receiving study 
drug have completed the 12-Month Follow-up Visit, or Early Termination Visit/Safety 
Follow-up Visit for subjects who prematurely terminate from the study before the 12-Month 
Follow-up Visit, and all data from these visits have been entered into the clinical study 
database, and the data have been cleaned and locked. 
12.3.5.2 
IDMC Analyses 
An IDMC will be formed before study initiation. The IDMC’s objectives and operational 
details will be defined in a separate document (IDMC charter), which will be finalized before 
the first subject is screened in the study. The IDMC will conduct regular planned safety 
reviews of study data as outlined in the IDMC Charter. 
12.4 
Clinical Pharmacology Analysis 
12.4.1 
Pharmacokinetic Analysis 
The PK parameters of VX-210 will be determined using standard non-compartmental 
analysis and 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. Unblinded 
PK analyses will be conducted after the database is cleaned and locked for the 6-month 
analysis. 
If warranted, a population PK analysis of plasma concentration versus time data of VX-210 
will be performed using the nonlinear mixed-effects modeling approach. Data permitting, the 
effect of demographic variables on PK parameters will be determined. The results from the 
population PK analysis will be included in a separate report. 


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13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, 
Severity Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the 
event does not necessarily have a causal relationship with the treatment. This includes any 
newly occurring event or worsening of a preexisting 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, physical examinations, and vital signs, 
will be assessed and those deemed a clinically significant worsening from baseline will be 
documented as an AE. When possible, a clinical diagnosis for the study assessment will be 
provided, rather than the abnormal test result alone (e.g., urinary tract infection, anemia). In 
the absence of a diagnosis, the abnormal study assessment itself will be listed as the AE (e.g., 
bacteria in urine or decreased hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more 
of the following: 
 Concomitant signs or symptoms related to the abnormal study assessment 
 Further diagnostic testing or medical/surgical intervention 
 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 clinical status of the subject 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) 


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 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 latest of: 
o 28 days after study drug treatment, or 
o The last study visit. 
All subjects will be queried, using non-leading 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 non-serious 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 
April 2017). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” The 
severity of an AE that does not appear in the CTCAE will be determined according to the 
definitions in Table 13-1.  
Table 13-1 Grading of AE Severity 
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening 
(Grade 4) 
Any adverse drug experience that places the subject, in the view of the 
investigator, at immediate risk of death  
 


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13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to 
the study drug(s). Causality will be classified using the categories presented in Table 13-2. 
Table 13-2 Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled 
out, and/or the event re-appeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to 
be related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject
's medical record). 
 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action 
taken will be classified according to the categories shown in Table 13-3.  
Table 13-3 Classifications for Study Drug Action Taken With Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
 
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4. 
Table 13-4 Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/Resolved 
With Sequelae 
Resolution of an AE with residual signs or symptoms 


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


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Clarification will be made between the terms “serious” and "severe,” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may 
be of relatively minor medical significance, such as a severe headache. This is not the same 
as “serious,” which is based on subject/event outcome or action described above, and is 
usually associated with events that pose a threat to a subject
's life or functioning. 
Seriousness, not severity, serves as a guide for defining expedited regulatory reporting 
obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through 
follow-up visits, regardless of causality, will be reported by the investigator to Vertex GPS. 
In addition, all SAEs that occur after the study has concluded and are considered related to 
study drug(s) will be reported to Vertex GPS within 24 hours. 
SAEs will be recorded on the Vertex Organized Safety Information Collection Form 
(hereafter referred to as the “SAE Form”) using a recognized medical term or diagnosis that 
accurately reflects the event. SAEs will be assessed by the investigator for relationship to the 
investigational study drug(s) and possible etiologies. On the Clinical Trials 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 Vertex Clinical Trials 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 Vertex 
Clinical Trial 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 Global Patient Safety via 
Email: 
 (Preferred Choice) 
Or via Fax: 
 
Contact Telephone: 
 
13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities and participating 
investigators in accordance with ICH Guidelines and/or local regulatory requirements, as 
applicable. In addition, Vertex, or authorized designee, will be responsible for the submission 
of safety letters to central independent ethics committees (IECs).  


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It is the responsibility of the investigator or designee to promptly notify the local institutional 
review board (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 or legal representative or guardian (if applicable) 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 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.  


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13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and 
privacy laws and regulations, all CRFs, study reports, and communications relating to the 
study will identify subjects by assigned subject numbers and access to subject names linked 
to such numbers shall be limited to the site and the study doctor 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/EC, 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 
Study 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 


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Written notification that includes the reason for the clinical study termination is required. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit to verify the 
qualifications of each investigator, inspect clinical study site facilities, and inform the 
investigator of responsibilities and procedures for ensuring adequate and correct study 
documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled subject will be entered into a CRF by study site 
personnel using a secure, validated web-based electronic data capture (EDC) application. 
Vertex will have read-only access to site-entered clinical data in the EDC application.  
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.  


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Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival 
CRF in the form of a compact disc or other electronic media will be placed in the 
investigator
's study file. 
13.6 
Publications and Clinical Study Report 
13.6.2 
Clinical Study Report  
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted 
in accordance with local regulations.  


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14 
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NSCISC. Spinal Cord Injury. Facts and Figures at a Glance. National Spinal Cord 
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Accessed 20 
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2   
Grossman RG, Frankowski RF, Burau KD, Toups EG, Crommett JW, Johnson MM, 
et al. Incidence and severity of acute complications after spinal cord injury. J 
Neurosurg Spine. 2012;17(1 Suppl):119-28. 
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Fawcett JW, Curt A, Steeves JD, Coleman WP, Tuszynski MH, Lammertse D, et al. 
Guidelines for the conduct of clinical trials for spinal cord injury as developed by the 
ICCP panel: spontaneous recovery after spinal cord injury and statistical power 
needed for therapeutic clinical trials. Spinal Cord. 2007 Mar;45(3):190-205.  
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Steeves JD, Lammertse DP, Kramer JL, Kleitman N, Kalsi-Ryan S, Jones L, et al. 
Outcome measures for acute/subacute cervical sensorimotor complete (AIS-A) spinal 
cord injury during a Phase 2 clinical trial. Top Spinal Cord Inj Rehabil. 2012 
Winter;18(1):1-14. 
5   
Krassioukov AV, Furlan JC, Fehlings MG. Autonomic dysreflexia in acute spinal 
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6   
Cameron AP, Wallner LP, Tate DG, Sarma AV, Rodriguez GM, Clemens JQ. 
Bladder management after spinal cord injury in the United States 1972 to 2005. J 
Urol. 2010;184(1):213-7. 
7   
McKerracher L, Anderson KD. Analysis of recruitment and outcomes in the Phase 
I/IIa Cethrin clinical study for acute spinal cord injury. J Neurotrauma. 
2013;30(21):1795-804. 
8   
Ackery A, Tator C, Krassioukov A. A global perspective on spinal cord injury 
epidemiology. J Neurotrauma. 2004;21(10):1355-70. 
9   
Cruse JM, Lewis RE, Dilioglou S, Roe DL, Wallace WF, Chen RS. Review of 
immune function, healing of pressure ulcers, and nutritional status in patients with 
spinal cord injury. J Spinal Cord Med. 2000;23(2):129-35. 
10   Cruz-Almeida Y, Martinez-Arizala A, Widerström-Noga EG. Chronicity of pain 
associated with spinal cord injury: a longitudinal analysis. J Rehabil Res Dev. 
2005;42(5):585-94. 
11   Krassioukov AV, Furlan JC, Fehlings MG. Medical co-morbidities, secondary 
complications, and mortality in elderly with acute spinal cord injury. J Neurotrauma. 
2003;20(4):391-9. 
 


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12   Furlan JC, Noonan V, Cadotte DW, Fehlings MG. Timing of decompressive surgery 
of spinal cord after traumatic spinal cord injury: an evidence-based examination of 
pre-clinical and clinical studies. J Neurotrauma. 2011;28(8):1371-99. 
13  
Walters BC, Hadley MN, Hurlbert RJ, Aarabi B, Dhall SS, Gelb DE, et al.; American 
Association of Neurological Surgeons; Congress of Neurological Surgeons. 
Guidelines for the management of acute cervical spine and spinal cord injuries: 2013 
update. Neurosurgery. 2013 Aug;60Suppl 1:82-91. 
14   Schwab ME. Nogo and axon regeneration. Curr Opin Neurobiol. 2004 
Feb;14(1):118-24. 
15   
McKerracher L, David S. Easing the brakes on spinal cord repair. Nat Med. 2004 
Oct;10(10):1052-3. 
16   Dubreuil CI, Winton MJ, McKerracher L. Rho activation patterns after spinal cord 
injury and the role of activated Rho in apoptosis in the central nervous system. J Cell 
Biol. 2003 Jul 21;162(2):233-43. 
17   
Madura T, Yamashita T, Kubo T, Fujitani M, Hosokawa K, Tohyama M. Activation 
of Rho in the injured axons following spinal cord injury. EMBO Rep. 2004 
Apr;5(4):412-7. 
18   Shibata A, Wright MV, David S, McKerracher L, Braun PE, Kater SB. Unique 
responses of differentiating neuronal growth cones to inhibitory cues presented by 
oligodendrocytes. J Cell Biol. 1998 Jul 13;142(1):191-202. 
20   Lord-Fontaine S, Yang F, Diep Q, Dergham P, Munzer S, Tremblay P, et al. Local 
inhibition of Rho signaling by cell-permeable recombinant protein BA-210 prevents 
secondary damage and promotes functional recovery following acute spinal cord 
injury. J Neurotrauma. 2008 Nov;25(11):1309-22. 
21   Dergham P, Ellezam B, Essagian C, Avedissian H, Lubell WD, McKerracher L. Rho 
signaling pathway targeted to promote spinal cord repair. J Neurosci. 
2002;1;22(15):6570-7. 
23   Fournier AE, Takizawa BT, Strittmatter SM. Rho kinase inhibition enhances axonal 
regeneration in the injured CNS. J Neurosci. 2003;15;23(4):1416-23. 
 


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24   Shearer MC, Niclou SP, Brown D, Asher RA, Holtmaat AJ, Levine JM, et al. The 
astrocyte/meningeal cell interface is a barrier to neurite outgrowth which can be 
overcome by manipulation of inhibitory molecules or axonal signaling pathways. Mol 
Cell Neurosci. 2003;24(4):913-25. 
26   Lammertse D, Tuszynski MH, Steeves JD, Curt A, Fawcett JW, Rask C, et al. 
International Campaign for Cures of Spinal Cord Injury Paralysis. Guidelines for the 
conduct of clinical trials for spinal cord injury as developed by the ICCP panel: 
clinical trial design. Spinal Cord. 2007 Mar;45(3):232-42. 
27   Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH, Ditunno JF, et al. 
International Campaign for Cures of Spinal Cord Injury Paralysis. Guidelines for the 
conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: 
clinical trial outcome measures. Spinal Cord. 2007 Mar;45(3):206-21. 
28   Tuszynski MH, Steeves JD, Fawcett JW, Lammertse D, Kalichman M, Rask C, et al. 
International Campaign for Cures of Spinal Cord Injury Paralysis. Guidelines for the 
conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: 
clinical trial inclusion/exclusion criteria and ethics. Spinal Cord. 2007 Mar;45(3):222-
31. 
29   
Marino RJ, Burns S, Graves DE, Leiby BE, Kirshblum S, Lammertse DP. Upper- and 
lower-extremity motor recovery after traumatic cervical spinal cord injury: an update 
from the national spinal cord injury database. Arch Phys Med Rehabil. 2011 
Mar;92(3):369-75. 
30   Kramer JL, Lammertse DP, Schubert M, Curt A, Steeves JD. Relationship between 
motor recovery and independence after sensorimotor-complete cervical spinal cord 
injury. Neurorehabil Neural Repair. 2012 Nov-Dec;26(9):1064-71. 
31   Fehlings MG, Theodore N, Harrop J, Maurais G, Kuntz C, Shaffrey CI, et al. A Phase 
I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. 
J Neurotrauma. 2011;28(5):787-96. 
32   Anderson KD. Targeting recovery: priorities of the spinal cord-injured population. 
J Neurotrauma. 2004 Oct;21(10):1371-83. 
33   Rudhe C, van Hedel HJ. Upper extremity function in persons with tetraplegia: 
relationships between strength, capacity, and the spinal cord independence measure. 
Neurorehabil Neural Repair. 2009 Jun;23(5):413-21. 
34   Velstra IM, Curt A, Frotzler A, Abel R, Kalsi-Ryan S, Rietman JS, et al. Changes in 
strength, sensation, and prehension in acute cervical spinal cord injury: European 
multicenter responsiveness study of the GRASSP. Neurorehabil Neural Repair. 2015 
Jan 7. 
 


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35   
Marino RJ, Kern SB, Leiby B, Schmidt-Read M, Mulcahey MJ. Reliability and 
validity of the capabilities of upper extremity test (CUE-T) in subjects with chronic 
spinal cord injury. J Spinal Cord Med. 2014 Oct 9. 
36   
Marino RJ, Graves DE. Metric properties of the ASIA motor score: subscales 
improve correlation with functional activities. Arch Phys Med Rehabil. 2004 
Nov;85(11):1804-10. 
37   
Marino RJ, Jones L, Kirshblum S, Tal J, Dasgupta A. Reliability and repeatability of 
the motor and sensory examination of the international standards for neurological 
classification of spinal cord injury. J Spinal Cord Med. 2008;31(2):166-70. 
38   Anderson KD, Acuff ME, Arp BG, Backus D, Chun S, Fisher K, et al. United States 
(US) multi-center study to assess the validity and reliability of the Spinal Cord 
Independence Measure (SCIM III). Spinal Cord. 2011 Aug;49(8):880-5. 
39   Itzkovich M, Gelernter I, Biering-Sorensen F, Weeks C, Laramee MT, Craven BC, 
et al. The Spinal Cord Independence Measure (SCIM) version III: reliability and 
validity in a multi-center international study. Disabil Rehabil. 2007 
Dec 30;29(24):1926-33. 
40   Bluvshtein V, Front L, Itzkovich M, Aidinoff E, Gelernter I, Hart J, et al. SCIM III is 
reliable and valid in a separate analysis for traumatic spinal cord lesions. Spinal Cord. 
2011 Feb;49(2):292-6. 
41   Anderson K, Aito S, Atkins M, Biering-Sørensen F, Charlifue S, Curt A, et al. 
Functional Recovery Outcome Measures Work Group. Functional recovery measures 
for spinal cord injury: an evidence-based review for clinical practice and research. 
J Spinal Cord Med. 2008;31(2):133-44. 
42   
Marino RJ, Patrick M, Albright W, Leiby BE, Mulcahey M, Schmidt-Read M, et al. 
Development of an objective test of upper-limb function in tetraplegia: the 
capabilities of upper extremity test. Am J Phys Med Rehabil. 2012 Jun;91(6):478-86. 
43   Kalsi-Ryan S, Curt A, Fehlings MG, Verrier MC. Assessment of the hand in 
tetraplegia using the Graded Redefined Assessment of Strength, Sensibility and 
Prehension (GRASSP): impairment versus Function. Top Spinal Cord Inj Rehabil. 
(2009);14(4):34-46. 
44   Velstra IM, Bolliger M, Tanadini LG, Baumberger M, Abel R, Rietman JS, et al. 
Prediction and stratification of upper limb function and self-care in acute cervical 
spinal cord injury with the graded redefined assessment of strength, sensibility, and 
prehension (GRASSP). Neurorehabil Neural Repair. 2014 Sep;28(7):632-42. 
45   Kalsi-Ryan S, Curt A, Verrier MC, Fehlings MG. Development of the Graded 
Redefined Assessment of Strength, Sensibility and Prehension (GRASSP): reviewing 
measurement specific to the upper limb in tetraplegia. J Neurosurg Spine. 2012 
Sep;17(1 Suppl):65-76. 
 


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46   Kalsi-Ryan S, Beaton D, Curt A, Popovic MR, Verrier MC, Fehlings MG. Outcome 
of the upper limb in cervical spinal cord injury: Profiles of recovery and insights for 
clinical studies. J Spinal Cord Med. 2014 Sep;37(5):503-10. 
47   Fehlings MG, Vaccaro A, Wilson JR, Singh A, W Cadotte D, Harrop JS, et al. Early 
versus delayed decompression for traumatic cervical spinal cord injury: results of the 
Surgical Timing in Acute Spinal Cord Injury Study (STASCIS). PLoS One. 
2012;7(2):e32037. 
48   Geisler FH, Coleman WP, Grieco G, Poonian D; Sygen Study Group. The Sygen 
multicenter acute spinal cord injury study. Spine (Phila Pa 1976). 2001 
Dec 15;26(24 Suppl):S87-98. 
52   Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics. 1997 Sep;53(3):983-97. 
































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16.2 
Investigator Signature Page 
Protocol #: VX15-210-101 Version #: 2.0 
Version Date: 
14 April 2017 
Study Title: Phase 2b/3, Double-blind, Randomized, Placebo-controlled, Multicenter Study 
to Assess the Efficacy and Safety of VX-210 in Subjects With Acute Traumatic Cervical 
Spinal Cord Injury 
I have read Protocol VX15-210-101, Version 2.0 and agree to conduct the study according to 
its terms. I understand that all information concerning VX-210 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 2 of 38 
Protocol Number: VX15-210-101 
Vertex Pharmaceuticals Incorporated 
 
2 
TABLE OF CONTENTS 
1 Title Page 
.......................................................................................................................... 1 
2 Table of Contents 
............................................................................................................. 2 
4 Introduction...................................................................................................................... 6 
5 Study Objectives 
.............................................................................................................. 6
 
5.1 Primary Objective 
....................................................................................................... 6
 
5.2 Secondary Objectives 
................................................................................................. 6
 
6 Study Endpoints 
............................................................................................................... 7
 
6.1 Primary Endpoint 
........................................................................................................ 7 
6.2 Secondary Endpoints 
.................................................................................................. 7 
7 Study Design 
..................................................................................................................... 7
 
7.1 Overall Design 
............................................................................................................ 7
 
7.2 Sample Size and Power 
.............................................................................................. 8
 
7.3 Randomization 
............................................................................................................ 9 
7.4 Blinding and Unblinding 
............................................................................................ 9 
7.4.1 Blinding 
.............................................................................................................. 9 
7.4.2 Unblinding 
.......................................................................................................... 9 
8 Analysis Sets 
................................................................................................................... 10 
8.1 All Subjects Set ........................................................................................................ 10
 
8.2 Full Analysis Set 
....................................................................................................... 10
 
8.3 Safety Set 
.................................................................................................................. 10
 
9 Statistical Analysis 
......................................................................................................... 11
 
9.1 General Considerations ............................................................................................ 11 
9.2 Background Characteristics 
...................................................................................... 12
 
9.2.1 Subject Disposition 
........................................................................................... 12
 
9.2.2 Demographics and Baseline Characteristics 
..................................................... 12
 
9.2.3 Prior and Concomitant Medications 
................................................................. 13
 
9.2.4 Study Drug Exposure........................................................................................ 14 
9.2.5 Study Drug Compliance 
................................................................................... 14 
9.2.6 Important Protocol Deviations 
.......................................................................... 14 
9.3 Efficacy Analysis 
...................................................................................................... 14
 
9.3.1 Analysis of Primary Efficacy Variable(s) ........................................................ 15
 
9.3.1.1 Definition of Variable 
................................................................................ 15 
9.3.1.2 Primary Analysis 
........................................................................................ 15
 
9.3.2 Analysis of Secondary Efficacy Variables 
....................................................... 16
 
9.3.2.1 Secondary Analyses 
................................................................................... 16
 


Statistical Analysis Plan (Methods) 
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9.3.4 Multiplicity Adjustment ................................................................................... 18
 
9.4 Safety Analysis 
......................................................................................................... 18
 
9.4.1 Adverse Events 
................................................................................................. 18
 
9.4.2 Clinical Laboratory 
........................................................................................... 19
 
9.4.3 Electrocardiogram ............................................................................................ 19
 
9.4.4 Vital Signs 
........................................................................................................ 20
 
9.4.5 Physical Examination 
....................................................................................... 20
 
9.4.6 Other Safety Analysis 
....................................................................................... 20
 
10 Summary of Interim and IDMC Analyses 
.................................................................. 20 
10.1 Interim Analysis ....................................................................................................... 20
 
10.1.1 Interim Background Characteristics 
................................................................. 21
 
10.1.2 Interim Efficacy Analysis 
................................................................................. 22
 
10.1.3 Interim Safety Analysis 
.................................................................................... 24
 
10.2 IDMC Safety Review Analyses 
................................................................................ 25
 
11 References 
....................................................................................................................... 26
 
12 List of Appendices.......................................................................................................... 27 
Appendix A: Schedule of Assessments.............................................................................. 27 
Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments ................... 31 
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates 
........... 32 
Appendix D: Imputation Rules for Missing AE dates 
....................................................... 33 
Appendix E: Criteria for Potentially Clinically Significant Events 
................................... 34
 
Appendix F: Details of Statistical Methodology 
................................................................ 37
 
 






Statistical Analysis Plan (Methods) 
Page 6 of 38 
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4 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis and interim analysis (IA) of study 
VX15-210-101 and is based on the  
• approved clinical study protocol, 14 April 2017, Version 2.0   
• approved eCRF, dated May 24 2018, Version 4.0 
VX15-210-101  is  a  Phase  2b/3,  double-blind,  randomized,  placebo-controlled  multicenter 
study.  This  study  will  assess  the  efficacy  and  safety  of  VX-210  in  subjects  with  acute 
traumatic cervical spinal cord injury. 
This  SAP  
(Methods)  documents  
the  
interim  and  
final  efficacy  and  safety  analysis  and  data 
presentation for VX15-210-101.  
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) Version  1.0 was  finalized  and  approved  before  the  data  cut  for  the 
interim  analysis.  The  interim  analysis  methods  specified  in  Section  10.1  of  the  SAP 
(Methods) Version 1.0 were implemented during the interim analysis. Any  
revisions to the 
approved  SAP  (Methods) Version  1.0 will  be  documented  and  approved  prior  
to  
the  final 
clinical database lock and treatment unblinding for the study. 
Any  changes  made  
to  
the  SAP  
(Methods)  after  
the  clinical  data  
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).  The 
independent  data  monitoring  committee  (IDMC)  analyses  are  also  described  in  a  separate 
SAP. 
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
Evaluation of the efficacy and safety of VX-210 treatment is the primary objective of the 
study. 
5.2 
Secondary Objectives  
• Neurological recovery: examination of the effects of VX-210 on the recovery of 
sensation and motor activity  
• Daily function: analysis of the impact of VX-210 on activities of daily living (ADLs) 
and requirements for attendant care 


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6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
Change from baseline in upper extremity motor score (UEMS) at 6 months after treatment 
6.2 
Secondary Endpoints 
• Spinal Cord Independence Measure (SCIM) III Self-Care subscore at 6 months after 
treatment 
• Capabilities of Upper Extremity Test (CUE-T) score at 6 months after treatment 
• Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) 
Quantitative Prehension score at 6 months after treatment 
• American Spinal Injury Association Impairment Scale (AIS) grade conversion from 
baseline to 6 months after treatment 
• Motor level change from baseline to 6 months after treatment 
• Pharmacokinetic (PK) parameters of VX-210 
7 
STUDY DESIGN  
7.1 
Overall Design  
This  is  a  multicenter,  randomized,  double-blind,  placebo-controlled  study  to  examine  the 
efficacy  and  safety  of  VX-210  treatment.  The  study  will  be  conducted  at  approximately 
45 sites in the United States and Canada and will enroll approximately 100 male or female 
subjects 14 to 75 years of age (inclusive) with acute traumatic SCI, C4 to C7 (motor level) on 
each side, and AIS grade A or AIS grade B. Subjects will be randomized to receive a single 
9-mg dose of VX-210 in fibrin sealant or a placebo (buffer solution) in fibrin sealant at a 1:1 
ratio  until  approximately  100  subjects  are  enrolled  (approximately  50  subjects  in  each 
treatment arm: 9-mg VX-210 and placebo). Subjects will be stratified by age (<30 versus ≥30 
years of age) and AIS grade (A versus B with sacral pinprick preservation versus B without 
sacral pinprick preservation) when they are randomized to the 2 study arms. The 1-time dose 
of  VX-210  or  placebo  will  be  administered by  a  surgeon  directly  
to  
the  dura  mater  of  
the 
spinal cord at the site of injury during decompression/stabilization surgery that commences 
within 72 hours after the initial injury. 
For  an  individual  subject,  the  study  will  last  approximately  12  months.  Follow-up 
appointments  after  the  initial  hospital  stay  will  be  at  6  weeks,  3  months,  6  months,  and 


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12 months  after  treatment.  At  specified  time  points  during  the  study,  subjects  will  be 
evaluated for medical, neurological, and functional changes, and serum will be collected for 
PK and immunological analyses. 
A schematic of the study design is provided in Figure 7-1. 
Figure 7-1 
Schematic of Study Design  
 
7.2 
Sample Size and Power 
The  primary  efficacy  endpoint  is  the  change  from  baseline  in  UEMS  at  6  months  after 
treatment.  
The null hypothesis to be tested is that the mean change from baseline in UEMS at 6 months 
after treatment is the same for 9-mg dose of VX-210 and placebo. This null hypothesis will 
be tested at 2-sided significance level α = 0.05. 
The sample size was  calculated using  a projected  
standard deviation (SD) of 6.0, based on 
the variability of improvement in UEMS scores of cervical subjects in the historical Sygen 
database.  Anticipated  withdrawal  of  10%  of  subjects  before  
the  
first  
follow-up  assessment 
was also included in the sample size calculation.  
If  9-mg  dose  group  
improves  
in  UEMS  by  4  points  over  placebo  (a  clinically  meaningful 
increase),  a  total  of  approximately  100  subjects  (approximately  50  per  arm)  will  have 
approximately 82.1% power to detect a statistically significant treatment effect for 9-mg dose 
group compared to placebo, considering the interim futility analysis.  
Based  on  the  review  of  data  from  Anderson  et  al.,  the  SD  was  projected  to  be  3.8  for 
SCIM III  Self-Care  subscore. Table  7-1 presents  
the  estimated  power  
for  detecting  various 


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treatment differences between an active treatment group and the placebo group in SCIM III 
Self-Care  subscore,  assuming  45  randomized  subjects  with  follow-up  assessment  in  each 
treatment  group  without  considering  the  possible  power  loss  from  the  interim  futility 
analysis. 
Table 7-1 
Power Estimates Under a Variety of Treatment Differences, Given 45 Randomized 
Subjects With Follow-up Assessments in Each Treatment Group 
Mean Difference in SCIM III Self-Care Subscore 
Power (%) 
1 
23 
2 
69 
3 
95 
Power estimates are based on 2-sided t-test with α = 0.05. 
7.3 
Randomization 
Subjects will be randomized to receive a single 9-mg dose of VX-210 in fibrin sealant, or a 
placebo (buffer solution) in fibrin sealant at a 1:1 ratio. Subjects will be stratified by age (<30 
versus ≥30 years of age) and AIS grade (A versus B with sacral pinprick preservation versus 
B without sacral pinprick preservation) when they are randomized to the 2 study arms. 
An  interactive  web  or  voice  response  system  (IXRS)  will  be  used  to  assign  subjects  to 
treatment.  The  
randomization  code  will  be  produced  by  Vertex  Biostatistics  or  a  qualified 
randomization vendor. The Vertex study biostatistician will review and approve the dummy 
randomization  list.  The  final  randomization  list  will  be  generated  and  approved  by  an 
unblinded biostatistician or designee who is not a member of the study execution team.  
7.4 
Blinding and Unblinding 
This will be a randomized double-blind study. 
7.4.1 Blinding 
All Vertex study personnel will be blinded to subject treatment assignments, except for the 
following  individuals:  an  external  vendor  biostatistician  preparing  the  final  (production) 
randomization list who is not part of the Study  Execution Team (SET); Bioanalytical CRO 
analyzing PK samples and the Vertex Bioanalytical staff who needs to review the raw data 
from  Bioanalytical  CRO  (excluding  Bioanalytical  SET  member  who  will  continue  to  be 
blinded);  and  Vertex  Global  Patient  Safety  (GPS)  and  Regulatory  Affairs  representatives 
when required to satisfy regulatory reporting requirements.  
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 


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is  necessary  for  clinical  management.  In  such  cases,  investigators  will  use  their  best 
judgment as to whether to unblind without first attempting to contact the medical monitor to 
discuss and agree to the need for unblinding. If investigators deem it not necessary to unblind 
immediately, they will first attempt to contact the medical monitor to discuss and agree to the 
need for unblinding. If investigators have tried, but are unable to reach the medical monitor, 
they will use their best judgment, based on the nature and urgency of the clinical situation, 
and  may  proceed  with  unblinding  without  having  successfully  reached  and  discussed  the 
situation with the medical monitor. 
Contact  
information  
for  
the  medical  monitor  
(or  appropriate  backup)  will  be  provided  
in  a 
separate document. 
In  addition,  
the  Vertex  Medical  Information  Call  Center 
  will  answer  calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If  a  subject
's  
treatment  assignment  has  been  unblinded  
for  a  medical  emergency  or  urgent 
clinical  situation,  the  medical  monitor  will  be  notified  within  24 hours  of  the  unblinding 
event. The reason and the date of the unblinding will be documented clearly in the subject
's 
study file. 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), contract research organization (CRO), or any site personnel (other than the 
physician treating the subject). In addition, the investigator will consider whether the clinical 
event  that  prompted  unblinding  will be  considered  an  SAE,  according  to  the  regulatory 
definitions or criteria for SAEs, and if so, submit an SAE report to Vertex GPS or designee, 
per Section 13.1.2 of the protocol. 
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.  
8 
ANALYSIS SETS 
8.1 
All Subjects Set 
The All Subjects Set is defined as all subjects who have been randomized or have received 
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 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 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. 


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9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Appendix A.  
The precision standards for reporting safety and efficacy variables are provided in an internal 
Biometrics  document  that  specifies  the  programming  rules,  including  the  precision  for 
derived variables. 
All individual subject data for subjects who were randomized or received study drug will be 
presented in individual subject data listings. 
Continuous  variables will  be  summarized  using  the  following  descriptive  summary 
statistics: the number of subjects (n), mean, SD, standard error (SE), median, minimum value 
(min), and maximum value (max).  
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place unless otherwise specified. 
Baseline  value, unless otherwise specified, will  be defined  as  
the most recent non-missing 
measurement (scheduled or unscheduled) collected before administration of study drug. 
Change (absolute change) from baseline will be calculated as:  
Post baseline value - baseline value. 
The treatment-emergent (TE) period will include the time from dosing with study drug to 
the Safety Follow-up Visit or 28 days after treatment / the last available visit (whichever is 
later) for subjects who do not have a Safety Follow-up Visit. 
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 measurements 
• In the derivation of maximum/minimum values and maximum/minimum changes 
from baseline values. 
• In individual subject data listings as appropriate. 
Visit window rules:  The analysis visit windows for protocol-defined visits are provided in 
Appendix B. 
Repeated observations within the same visit window: 
• For all efficacy parameters, if there are multiple measurements within a visit window, 
the record at the scheduled visit will be used. If there are no measurements at the 
scheduled visit, then 1) the record closest to the target day will be used; or 2) if there 
are multiple records with the same distance to the target day, the latest record will be 
used.   
• For all safety parameters, if there are multiple measurements within a visit window, 
then 1) the record closest to the target day will be used; or 2) if there are multiple 
records with the same distance to the target day, the latest record will be used. 




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• Sex (female and male) 
• Age at baseline (in years) 
• Age group (<30 versus ≥30 years of age) 
• 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, and 
Other) 
• Country 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• AIS Grade (A or B with or B without sacral pinprick preservation) 
• Baseline UEMS score (total, left and right) 
All  medical  history  will  be  coded  using  the  latest  version  of  Medical  Dictionary  for 
Regulatory  Activities  (MedDRA).  Medical  history  will  be  summarized  using  descriptive 
statistics  by  MedDRA  system  organ  class  
(SOC)  and  preferred  
term  
(PT).  Medical  history 
will also be displayed in a subject listing. 
9.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced (WHODDE) and categorized as follows: 
Prior medication: any medication that started before the dose date of study drug, regardless 
of when the medication ended. 
Concomitant medication: medication continued or newly received on or after the dose date 
of study drug through the end of the TE period. 
Post-treatment medication: medication continued or newly received after the TE period. 
A given medication may be classified as follows: prior, concomitant, post-treatment, both 
prior and concomitant, both concomitant and post-treatment, or prior, concomitant, and 
post-treatment.  
If a medication has a completely missing or partially missing start/stop date and it cannot be 
determined whether it was taken before the dose date, concomitantly, or after the TE period, 
it will be classified as prior, concomitant, and post-treatment. Imputation rules for missing or 
partial medication start/stop dates are defined in Appendix C. 


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Prior medications and concomitant medications will be summarized descriptively by (1) 
preferred names; (2) anatomic class (ATC) level 1, ATC level 2, and preferred names based 
on the Full Analysis Set. 
Summaries of medications will be based on the Full Analysis Set.  
Post-treatment medications will be listed by subject. 
9.2.4 
Study Drug Exposure  
Study drug exposure will be presented in an individual data listing to indicate whether the 
study drug was administered. 
9.2.5 
Study Drug Compliance  
Not applicable. 
9.2.6 
Important Protocol Deviations  
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a 
subject’s rights, safety, or well-being. IPDs will be identified from the clinical database 
and/or site deviation log, and finalized prior to the database lock. 
The protocol deviations that should be considered as potential IPDs may fall in, but are not 
limited to, the following categories:  
• Safety 
• Informed consent 
• Eligibility and entry criteria 
• Randomization 
• Investigational medicinal product 
• Study procedures and laboratory assessments 
The protocol deviations that fall in these categories are categorized as IPDs only if they have 
the potential to significantly affect the completeness, accuracy, or reliability of the study data 
or to significantly affect a subject’s rights, safety, or well-being. 
IPDs will be provided in an individual subject data listing. 
9.3 
Efficacy Analysis  
Assessment of efficacy of VX-210 treatment is one of the primary objectives of this pivotal 
study. All efficacy  endpoints will be analyzed based  on the FAS. All Efficacy data will be 
presented in listings based on the All Subjects Set. 
The primary efficacy analysis in this study targets an estimand that would assess efficacy by 
using the change from baseline in the UEMS score at 6 months after treatment, focusing on 
the effect attributable to the initially randomized treatment.  
Such  an  estimand  targets  the  effect  of  the  initially  randomized  treatment  regimen,  with 
consideration for the fact that enrolled subjects will also receive standard of care. With such 




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Kenward-Roger approximation. If change from baseline in the UEMS score is missing after 
the  visit  windows  
rules  have  been  applied,  
the  missing  value  will  be  assumed  
to  be  MAR 
conditional  on  the  observed  data.  With  an  MMRM  model  based  on  restricted  maximum 
likelihood  estimation  as  
the  primary efficacy  analysis  and  under  
the  MAR  assumption,  no 
imputation of missing data will be performed. 
The  primary  
result  obtained  
from  
the  primary  efficacy  analysis  will  be  
the  estimated  mean 
treatment  effect  (Least  Squares  [LS]  means  difference)  at  6  months  after  treatment.  The 
estimated mean treatment effect at 6 months after treatment, a 95% confidence interval (CI), 
and  a  2-sided P value  will  be  provided.  Furthermore,  
the  estimated  mean  
treatment  effects 
(with 95% CI) at 6 weeks, 3 months, and 12 months after treatment, obtained from the model 
established, will also be provided. 
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. 
All UEMS data will be presented in a subject listing. 
9.3.2 
Analysis of Secondary Efficacy Variables 
9.3.2.1 
Secondary Analyses  
Secondary  efficacy  endpoints  will  be  summarized  using  descriptive  summary  statistics  by 
treatment group and all post-baseline follow-up visits (AIS grade and motor level will also be 
summarized descriptively at baseline).  
• SCIM III Self-Care subscore at 6 months after treatment: The range of the SCIM III 
Self-Care subscore is 0-20. The score collected in the CRF will be directly used in the 
analysis. The SCIM III Self-Care subscore at 6 weeks, 3 months, 6 months, and 12 
months after treatment will be summarized descriptively by treatment group.  
• CUE-T score at 6 months after treatment: The range of the CUE-T score is 0-128. 
The score collected in the CRF will be directly used in the analysis. The CUE-T score 
at 6 months after treatment will be summarized descriptively by treatment group.  


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• GRASSP  Quantitative  Prehension  score  at  6  months  after  
treatment:  The  GRASSP 
Quantitative Prehension score will be derived as described in Appendix F. The range 
of  
the  score  
is  0-60.  The  GRASSP  Quantitative  Prehension  score  at  6  months  after 
treatment will be summarized descriptively by treatment group.  
• AIS grade conversion from baseline at 6 months after treatment: An AIS responder is 
defined as a subject with improvement by ≥ 2 AIS grades (i.e., baseline AIS grade A 
changed to  grade C, D,  or E; baseline  AIS  grade B changed to D or E  at 6 months 
after  
treatment). The AIS  grade  at  baseline,  6  weeks,  3  months,  6  months,  and  12 
months after treatment will be summarized descriptively by treatment group. The AIS 
responder,  defined  as  aforementioned,  at  6  weeks,  3  months,  6  months,  and  12 
months after treatment will also be summarized descriptively by treatment group. 
• Motor  level  change  from  baseline  at  6  months  after  treatment: A  motor  level 
responder is defined as a subject with improvement by ≥ 2 motor levels on either side 
of the body (i.e., baseline level C4 changed to C6, C7, C8 on the left; or baseline level 
C5  changed  to  C7,  C8…  on  the  right  and  so  on). A  subject  with  a  missing/not 
determined motor level on one side of the body for a given visit and an improvement 
of ≥ 2 motor levels on the other side of the body at that visit will be classified as a 
responder  for  that  visit;  for  all  other  cases  in  which  one  or  both  motor  levels  are 
missing/not determined at a given visit, the responder result at that visit will be noted 
as  ‘missing’.  The  motor  level  at  baseline,  6  weeks,  3  months,  6  months,  and  12 
months  after  treatment  will  be  summarized  descriptively  by  treatment  group.  The 
motor level  
responder, defined  as  aforementioned, at 6 weeks, 3  months, 6 months, 
and  12  months  after  treatment  will  also  be  summarized  descriptively  by  treatment 
group. 


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9.3.4 
Multiplicity Adjustment 
Not applicable. 
9.4 
Safety Analysis 
All safety summaries will be based on the set of data associated with the TE period for 
subjects in the Safety Set. 
The overall safety profile of VX-210 will be assessed in terms of the following safety and 
tolerability endpoints: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation studies, 
and urinalysis) 
• ECGs 
• Vital signs 
All safety data will be presented in individual subject data listings. 
9.4.1 
Adverse Events  
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs, defined as follows:  
• Pretreatment AE: Any AE that started prior to dosing with study drug. 
• TEAE: Any AE that developed or worsened at or after dosing of study drug through 
the end of the TE period. 
• Post-treatment AE: Any AE that developed or worsened beyond the TE period. 
For AEs with missing or partial missing start dates, if there is no clear evidence that the AEs 
started before or after study treatment, then the AEs will be classified as pre-treatment 
AEs/TEAEs/post-treatment AEs. Imputation rules for missing or partial AE start date are 
defined in the Appendix D. 
AE summary tables will be presented for TEAEs only, overall and by treatment group, and 
will include the following: 
• All TEAEs  
• TEAEs by relationship  
• TEAEs by maximal severity 
• Serious TEAEs 


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• TEAEs leading to death 
Summaries  will  be  presented  by  MedDRA  system  organ  class  and  preferred  term  using 
frequency counts and percentages (i.e., number and percentage of subjects with an event as 
well as total number of events). When summarizing the number and percentage of subjects 
with an event, subjects with multiple occurrences of the same AE or a continuing AE will be 
counted once, only the maximum severity level will be presented in the severity summaries, 
and the worst/highest relationship level in the relationship summaries.  
An AE overview table will be provided. 
A listing containing individual subject AE data for all deaths and other serious  AEs will be 
provided  separately.  All  AEs,  
including  pre- and  post-treatment  AEs,  will  be  presented  
in 
individual subject data listings. 
9.4.2 
Clinical Laboratory 
The raw values and change from baseline values of the continuous hematology, chemistry, 
and coagulation parameters will be summarized in SI units by treatment group at each 
scheduled time point during the TE period. 
The number and percentage of subjects with at least 1 potentially clinically significant (PCS) 
event  during  
the  TE  period  will  be  summarized  overall  and  by  
treatment  group.  The  PCS 
criteria are provided in Appendix E. 
Immunogenicity analysis is out of the scope of this SAP. 
Results  of  urinalysis  and  
the  serum  pregnancy  
test  will  be  
listed  
in  
individual  subject  data 
listings only. 
A  
listing  of  subjects  with  elevated  
liver  function  results  (defined  as  any  of  
the  following: 
AST ≥ 3 × ULN, ALT ≥ 3 × ULN, ALP ≥ 1.5 × ULN, or total bilirubin ≥ 2 × ULN) during 
the TE period will be presented. For each subject in the listing, LFT assessments at all visits 
will be included. 
In  addition,  
listings  containing  
individual  subject  
laboratory  assessment  values  outside  
the 
reference  ranges  will  be  provided.  Individual  subject  data  listings  will  include  data  from 
scheduled and unscheduled time points. 
9.4.3 
Electrocardiogram 
A summary of raw values and changes from baseline will be provided by treatment group at 
each scheduled  time  point  during  the  TE  period  for  the  following  standard  12-lead  ECG 
measurements: PR, QT, QTc for heart rate (HR) interval (QTcF), QRS duration, and HR. 
The number and percentage of subjects with at least 1 PCS event during the TE period will 
be summarized overall and by treatment group. The PCS criteria for ECG data are provided 
in Appendix E.  
A listing containing individual subject ECG assessments will also be provided. 


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9.4.4 
Vital Signs 
The raw values and change from baseline values during the TE period will be summarized by 
treatment group at each scheduled time point: systolic and diastolic blood pressure (mm Hg), 
body  temperature  (oC),  HR  (beats  per  minute  [bpm]),  and  respiratory  rate  (breaths  per 
minute).  
The number and percentage of subjects with at least 1 PCS event during the TE period will 
be  summarized  overall  and  by  treatment  group.  The  PCS  criteria  for  vital  signs  data  are 
provided in Appendix E.  
A listing containing individual subject vital signs assessments will also be provided. 
9.4.5 
Physical Examination  
Physical  examination,  including  surgical  site  examination,  results  will  be  presented  in 
individual subject data listings only.  
After screening, any clinically significant abnormal findings in physical examinations will be 
reported as AEs. 
9.4.6 
Other Safety Analysis 
Not applicable 
10 
SUMMARY OF INTERIM AND IDMC ANALYSES 
10.1 
Interim Analysis 
An interim analysis will be conducted when approximately 33% of enrolled subjects have 
completed the 6-month follow-up visit. Based on the results of this interim analysis, the study 
may continue or stop for futility. The IDMC will conduct review of this interim analysis and 
make recommendation to the sponsor. If the study is considered unsuccessful at the time of 
the interim analysis, the study is to be terminated, study enrollment is to be stopped, and 
subjects are to be followed for safety reasons only. 
Based on the review of the data provided at the interim analysis meeting, the IDMC will 
make a recommendation regarding whether the study should continue or should stop for 
futility. The guideline for futility stopping will be that the 9-mg dose group improves in 
UEMS by less than approximately 1.19 points over placebo for the approximately 33% of 
subjects analyzed, under the assumed standard deviation (SD) of 6. 
The IDMC will review the observed SD at the time of the interim analysis. If the SD deviates 
from  
the  assumption,  
the  
futility  guide  
is  adjusted  
to  be  
that  
the  study  will  be  stopped  
for 
futility  if conditional  power  (under  observed  primary  endpoint  treatment  effect  size)  is 
<10.6% or the observed primary endpoint treatment effect size is <1.19. The following table 
presents  examples  of  the  futility  boundary  with  respect  to  different  sizes  of  SD.  The  last 
column  refers  to  the  minimum  observed  primary  endpoint  effect  size  that  is  required  to 
achieve statistical significance under the given size of SD at the final analysis.  
Table 10-1 Guidelines for Futility Stopping 
Standard Deviation Futility Boundary Conditional Power (Under Minimum Required Observed 


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Observed Effect Size) 
Effect Size at Final Analysis 
4 
1.19 
25.1% 
1.7 
6 
1.19 
10.6% 
2.5 
8 
1.59 
10.6% 
3.3 
10 
1.98 
10.6% 
4.1 
In all analyses supporting this interim analysis, only the first 43 randomized subjects will be 
used unless otherwise specified; this sub-population includes approximately 33% of enrolled 
subjects who are dosed with placebo or 9-mg of VX-210 and who will have completed the 6-
month follow-up visit at the time of the interim analysis data cut.  
10.1.1 
Interim Background Characteristics 
• Subject disposition: 
The number of subjects in the following categories will be summarized overall and by 
treatment group based on the All Subjects Set: 
o 
Randomized or dosed (All Subjects Set) 
o 
Randomized 
o 
Dosed (Safety Set) 
o 
Full Analysis Set 
The number and percentage (based on the Full Analysis Set) of subjects in each of the 
following disposition categories will be summarized overall and by treatment group: 
o 
6-Month Follow-up Visit Occurred 
o 
Completed study 
o 
Prematurely discontinued the study and the reasons for discontinuation 
A listing will be provided for disposition, including the subjects who discontinued 
study with reasons for discontinuation. 
• Demographics and baseline characteristics: 
Demographics and baseline characteristics will be summarized overall and by 
treatment group based on the Full Analysis Set. 
Demographic data will include the following: 
o 
Sex (female and male) 
o 
Age (in years) 
o 
Age group (<30 versus ≥30 years of age) 


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o 
Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
o 
Race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander, not collected per local 
regulations, and Other) 
o 
Country 
Baseline characteristics will include the following: 
o 
Weight (kg) 
o 
Height (cm) 
o 
BMI (kg/m2) 
o 
AIS Grade (A or B with or B without sacral pinprick preservation) 
o 
Baseline UEMS score (total, left and right) 
• Prior and concomitant medications: 
Medications used will be coded as described in section 9.2.3. 
A given medication may be classified as follows: prior, concomitant, post-treatment, 
both prior and concomitant, both concomitant and post-treatment, or prior, 
concomitant, and post-treatment. 
If a medication has a completely missing or partially missing start/stop date and it 
cannot be determined whether it was taken before the dose date, concomitantly, or 
after the TE period, it will be classified as prior, concomitant, and post-treatment. No 
imputation rules for missing or partial medication start/stop dates are applied. 
Prior medications and concomitant medications will be summarized descriptively 
using frequency tables by (1) by preferred names; (2) anatomic class (ATC) level 1, 
ATC level 2, and preferred names. 
Summaries of medications will be based on the Full Analysis Set. 
Post-treatment medications will be listed by subject. 
10.1.2 
Interim Efficacy Analysis 
For the interim futility analysis data review meeting, the IDMC will be provided with 
statistical analyses of the following primary and secondary study endpoints and supportive 
data listings as appropriate. For all the interim efficacy analyses, no P value will be provided. 
All the efficacy endpoints aforementioned will be analyzed based on the FAS. 
• Change from baseline in the UEMS score at 6 months after treatment: The UEMS 
score will be summarized at baseline, 6 weeks, 3 months, 6 months, and 12 months 
after treatment using the descriptive summary statistics by treatment group. The 
change from baseline in the UEMS score at 6 weeks, 3 months, 6 months, and 12 
months after treatment will also be summarized descriptively by treatment group. The 
MMRM analysis of the change from baseline in the UEMS score at 6 months after 


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treatment in the interim analysis is similar to the MMRM analysis of the same 
variable in the primary analysis (see section 9.3.1.2) except for that no P value will be 
provided. 
• SCIM III Self-Care subscore at 6 months after treatment: The SCIM III Self-Care 
subscore at 6 weeks, 3 months, 6 months, and 12 months after treatment will be 
summarized descriptively by treatment group. The analysis of the SCIM III self-care 
subscore at 6 months after treatment will be based on an ANCOVA model, which 
will include the SCIM III self-care subscore at 6 months after treatment as the 
dependent variable, and treatment as a fixed effect, with adjustment for age and AIS 
grade (only including A versus B with sacral pinprick preservation versus B without 
sacral pinprick preservation) at baseline. If the SCIM III self-care subscore at 6 
months after treatment is missing after the visit windows rules have been applied, the 
score at the early termination visit will be carried forward for the analysis. The 
estimated mean treatment effect (LS means difference) at 6 months after treatment 
and a 95% CI will be provided.  No P value will be provided. 
• CUE-T score at 6 months after treatment: The CUE-T score at 6 months after 
treatment will be summarized descriptively by treatment group. The ANCOVA 
analysis of the CUE-T score at 6 months after treatment is similar to the ANCOVA 
analysis of the SCIM III Self-Care subscore at 6 months after treatment in the interim 
analysis except for that the relevant endpoint here is the CUE-T score at 6 months 
after treatment. 
• GRASSP Quantitative Prehension score at 6 months after treatment: The GRASSP 
Quantitative Prehension score at 6 months after treatment will be summarized 
descriptively by treatment group. The ANCOVA analysis of the GRASSP 
Quantitative Prehension score at 6 months after treatment is similar to the ANCOVA 
analysis of the SCIM III self-care subscore at 6 months after treatment in the interim 
analysis except for that the relevant endpoint here is the GRASSP Quantitative 
Prehension score at 6 months after treatment. 
• AIS grade conversion from baseline at 6 months after treatment: The definition of an 
AIS responder is same as that in the primary analysis (see section 9.3.2.1). The AIS 
grade at baseline, 6 weeks, 3 months, 6 months, and 12 months after treatment will be 
summarized descriptively by treatment group. The AIS responder at 6 weeks, 3 
months, 6 months, and 12 months after treatment will also be summarized 
descriptively by treatment group. 
• Motor level change from baseline at 6 months after treatment: The definition of a 
motor level is same as that in the primary analysis (see section 9.3.2.1). The motor 
level at baseline, 6 weeks, 3 months, 6 months, and 12 months after treatment will be 
summarized descriptively by treatment group. The motor level responder at 6 weeks, 
3 months, 6 months, and 12 months after treatment will also be summarized 
descriptively by treatment group. 


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10.1.3 
Interim Safety Analysis 
For reference, the following safety and supporting data will also be presented to the IDMC as 
unblinded tables and supportive data listings as appropriate. Analysis of safety/supporting 
data for the interim futility review meeting will be conducted in accordance with analyses for 
IDMC safety review meetings, and based on the Safety Set. The same general statistical 
consideration as described in section 9.1 of this SAP will be applied except for that no visit 
windows rules will be applied for the interim analysis.  
• Adverse events and/or serious adverse events (as available for all treatment 
arms):  
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-
treatment AEs, defined as described in section 9.4.1. 
For AEs with completely missing or partially missing start dates, if there is no clear 
evidence that the AEs started before or after study treatment, the AEs will be 
classified as pre-treatment AEs / TEAEs / post-treatment AEs. No imputation rules 
for missing or partial AE start date are applied. 
AE summary tables will be presented for TEAEs only, overall and by treatment 
group, and will include the following: 
o 
All TEAEs 
o 
TEAEs by relationship 
o 
TEAEs by maximal severity 
o 
Serious TEAEs 
o 
TEAEs leading to death 
Summaries will be presented by MedDRA system organ class and preferred term 
using frequency counts and percentages (i.e., number and percentage of subjects with 
an event as well as total number of events). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same 
AE or a continuing AE will be counted once, only the maximum severity level will be 
presented in the severity summaries, and the strongest relationship level in the 
relationship summaries. An AE overview table will be provided. 
In addition, a listing containing individual subject AE data for all deaths and other 
serious AEs will be provided separately. All AEs, including pre- and post-treatment 
AEs, will be presented in individual subject data listings. 
• Clinical laboratory values:  
The raw values and change from baseline values of the continuous hematology, 
chemistry, and coagulation parameters will be summarized in SI units by treatment 
group at each scheduled time point during the TE period. 
The number and percentage of subjects with at least 1 potentially clinically significant 
(PCS) event during the TE period will be summarized overall and by treatment group. 
The PCS criteria are provided in Appendix E. 


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Results of urinalysis and the serum pregnancy test will be listed in individual subject 
data listings only. 
In addition, listings containing individual subject laboratory assessment values 
outside the reference ranges will be provided. Individual subject data listings will 
include data from scheduled and unscheduled time points. 
• Electrocardiogram outcomes:  
A summary of raw values and change from baseline values will be provided by 
treatment group at each scheduled time point during the TE period for the following 
standard 12-lead ECG measurements: PR, QT, QTc for heart rate (HR) interval 
(QTcF), QRS duration, and HR. 
The number and percentage of subjects with at least 1 PCS event during the TE 
period will be summarized overall and by treatment group. The PCS criteria are 
provided in Appendix E. 
A listing containing individual subject ECG assessments will also be provided. 
• Vital signs:  
The raw values and change from baseline values during the TE period will be 
summarized by treatment group at each scheduled time point: systolic and diastolic 
blood pressure (mm Hg), body temperature (oC), HR (beats per minute [bpm]), and 
respiratory rate (breaths per minute). 
The number and percentage of subjects with at least 1 PCS event during the TE 
period will be summarized overall and by treatment group. The PCS criteria are 
provided in Appendix E. 
A listing containing individual subject vital signs assessments will also be provided. 
• Physical examination results:  
Physical examination, including surgical site examination, results will be presented in 
individual subject data listings only. 
After screening, any clinically significant abnormal findings in physical examinations 
will be reported as AEs. 
• Other Safety Analysis:  
Not Applicable. 
10.2 
IDMC Safety Review Analyses 
The Analyses for IDMC Safety Review meetings are described in the VX15-210-101 DMC 
Statistical Analysis Plan 


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11 
REFERENCES 
Not applicable. 


Vertex Pharmaceuticals Incorporated
 
 
12 
LIST OF APPENDICES 
Appendix A: Schedule of Assessments 
The Schedule of Assessments is shown in Table 12-1. 
 


Vertex Pharmaceuticals Incorporated
 
 
Table 12-1 Study VX15-210-101 Schedule of Assessments 
Event/Assessment 
Screeninga Surgeryb 
Post-
Surgeryc 
6-Week 
Follow-up 
(± 7 Days)
d 
3-Month 
Follow-up 
(± 7 Days)
d 
6-Month 
Follow-up 
(± 7 Days)
d 
12-Month 
Follow-up 
(± 7 Days)
d 
Early 
Terminationd 
Safety 
Follow-up 
28 (± 3) Days 
After 
Treatment
d,e 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Review of spine imaging 
X 
 
 
 
 
 
 
 
 
Serum β-HCG (all female 
subjects) 
X 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal 
female subjects <60 years 
only) 
Xf 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
 
 
 
 
 
 
 
 
Enrollment and randomization 
X 
 
 
 
 
 
 
 
 
                                                 
a Results of assessments performed as part of standard of care (with the exception of the ISNCSCI examination) within 72 hours after the initial injury 
and before signing of informed consent form may be carried forward as screening results.  
b ‘Surgery’ in this table refers to the spinal decompression/stabilization surgery that commences within 72 hours after the initial injury during which the 
study drug (VX-210 or placebo) is administered in fibrin sealant. 
c The Post-Surgery assessments will be performed within the time period following the completion of surgery and 7 days after surgery as specified in the 
footnotes for each individual assessment. 
d Transportation to follow-up assessments will be available if required. Follow-up assessments of recovery will be conducted at 6 weeks, 3 months, 
6 months, and 12 months after treatment. 
e The Safety Follow-up Visit will be required in addition to the Early Termination Visit only for subjects who prematurely terminate from the study prior 
to Day 28 after treatment. Subjects who prematurely terminate from the study subsequent to Day 28 after treatment will only be required to complete the 
Early Termination Visit. 
f Serum FSH assessment is only required when a waiver to contraception is sought. Only 1 serum FSH assessment is required, at Screening, Surgery, or 
Post-Surgery. 




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Event/Assessment 
Screeninga Surgeryb 
Post-
Surgeryc 
6-Week 
Follow-up 
(± 7 Days)
d 
3-Month 
Follow-up 
(± 7 Days)
d 
6-Month 
Follow-up 
(± 7 Days)
d 
12-Month 
Follow-up 
(± 7 Days)
d 
Early 
Terminationd 
Safety 
Follow-up 
28 (± 3) Days 
After 
Treatment
d,e 
Adverse events and  
prior and concomitant 
medications and procedures 
Continuous from signing of ICF through the last study visit 
Efficacy Assessments 
ISNCSCI examination
o 
X 
 
 
X 
X 
X 
X 
X 
X 
SCIM III
o 
 
 
 
X 
X 
X 
X 
X 
X 
GRASSP Quantitative 
Prehensiono 
 
 
 
 
 
X 
 
X 
X 
CUE-To 
 
 
 
 
 
X 
 
X 
X 
Hospitalizations 
Continuous from signing of ICF through the last study visit 
Study Drug Administration 
VX-210 or placebo  
 
X 
 
 
 
 
 
 
 
Pharmacokinetic Assessments 
Serum samples for PK  
Xq 
Xq 
Xq 
 
 
 
 
 
 
                                                 
o Conducted by an independent, trained assessor (e.g., physiatrist/occupational therapist/physical therapist). 
q Serum samples for PK analyses will be collected at ≤72 hours (before surgery) and at 3, 6, 12, 24, and 48 hours after treatment and at the time of any 
SAE occurring within 3 days after treatment. The acceptable window for the post-treatment PK sampling time points is ± 30 minutes. 


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Appendix B: Analysis Visit Windows for Safety and Efficacy Assessments 
Table 12-2  Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit 
Target Study Day per 
the protocol 
Analysis Visit Window 
(in study days) 
Safety Assessment 
Hematology 
Serum Chemistry 
6 Week Follow-Up 
43 
[8,67] 
3 Month Follow-Up 
91 
[68,365] 
Efficacy Assessment 
ISNCSCI and SCIM III 
6 Week Follow-Up 
43 
[8,67] 
3 Month Follow-Up 
91 
[68,136] 
6 Month Follow-Up 
182 
[137,273] 
12 Month Follow-Up 
365 
[274,450] 
CUE-T and GRASSP 
Quantitative Prehension 
6 Month Follow-Up 
182 
[8,365] 
Special handling for Safety Follow-up, Surgery and Post-Surgery Visit: 
Surgery,  Post-Surgery  and  Safety  Follow-up  will  use  
the  nominal  visit  and  will  not  
follow 
the visit window rule. 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month.  
b. If DAY and Month are both missing, use the first day of the year.  
c. If DAY, Month and Year are all missing, use a date before the first dose date. 
2. Missing or partial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month and year are all missing, assign ‘continuing’ status to stop 
date. 
In summary, the prior, concomitant or post categorization of a medication is described below. 
Table 12-3  Prior, Concomitant, and Post 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 
> End Date of TE 
Period 
< First dose date of study drug 
P 
PC 
PCA 
≥ First dose date and  
≤ End date of TE period 
- 
C 
CA 
> End date of TE period 
- 
- 
A 
A: Post; C: Concomitant; P: Prior 


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Appendix D: Imputation Rules for Missing AE dates 
Imputation rules for missing or partial AE start date are defined below: 
If only Day of AE start date is missing:  
If the AE start year and month are the same as that for the first dose date, then: 
• If the full (or  partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start day as the day of first dose date; otherwise, impute 
the AE start day as 1. 
• Otherwise, impute the AE start day as 1. 
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
If Day and Month of AE start date are missing: 
If AE start year = 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, TEAE or post-treatment AE. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site with 
no imputation. Also compare the full (or partial) AE end date to the first dose date. If the AE 
end date is before the first dose date then the AE should be considered as a pretreatment AE. 
Otherwise, the AE will be considered as TEAE. 
 


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Appendix E: Criteria for Potentially Clinically Significant Events 
Table 12-4 
Criteria for Potentially Clinically Significant Laboratory Tests 
Parameter 
PCS 
Comments 
Clinical Chemistry 
ALT 
≤3xULN*(Not a PCS criterion) 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>3xULN 
>5xULN 
>8xULN 
FDA DILI Guidance Jul 2009.  
AST 
≤3xULN*(Not a PCS criterion) 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>3xULN 
>5xULN 
>8xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
ALT>3xULN or AST>3xULN 
Vertex LFT working group 2014 
Alkaline 
Phosphatase 
>1.5xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>1.5x - ≤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 phase, 
whatever the interval between measurements. 
AST and Total 
Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
To be counted within a same treatment phase, 
whatever the interval between measurements. 
(ALT or AST) and 
Total Bilirubin 
(ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
Vertex LFT working group 2014 
CPK 
>3x - ≤ 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. 
 
Uric Acid 
Hypouricemia 
Hyperuricemia  
 
<120 μmol/L 
 >408 μmol/L 
Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Blood Urea 
Nitrogen 
≥17 mmol/L 
 
Chloride 
<85 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥150 mmol/L 
 


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Table 12-4 
Criteria for Potentially Clinically Significant Laboratory Tests 
Parameter 
PCS 
Comments 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol ≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
Albumin 
≤25 g/L 
 
Amylase 
>2.0 - 5.0 x ULN   
>5.0 x ULN 
Criteria based upon CTCAE 
Lipase 
>2.0 - 5.0 x ULN   
>5.0 x ULN 
Criteria based upon CTCAE 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count 
available. 
Lymphocytes 
<1.0 Giga/L 
>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. 
 
 
 
 
 


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Table 12-5 
Criteria for Potentially Clinically Significant ECGs 
Parameter 
PCS 
Comments 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 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.  
 
 
 
 
Coagulation 
aPPT                    ≥65 seconds 
PT                       ≥17 seconds 
INR                     ≥1.7 
Note: Based on CPMP 1997 guideline. 
 
Table 12-6 
Criteria for Potentially Clinically Significant 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 
≤95 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. 
 


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Appendix F: Details of Statistical Methodology 
GRASSP Prehension Test scoring algorithm: 
The total GRASSP score will be derived as the sum of the right total score and left total score 
collected in the CRF