A Double-Blind, Controlled Phase 2 Study of the Safety and Efficacy of Modified Stem Cells (SB623) in Patients With Chronic Motor Deficit From Traumatic Brain Injury (TBI)
Phase: PHASE2
Conditions: Traumatic Brain Injury
Sponsor: SanBio, Inc.

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Protocol TBI-01 Version 5, May 17, 2018
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SANBIO INCORPORATED
CLINICAL PROTOCOL
TITLE: A Double-Blind, Controlled Phase 2 Study of the Safety and Efficacy of Modified Stem 
Cells (SB623) in Patients with Chronic Motor Deficit from Traumatic Brain Injury (TBI) 
PROTOCOL #: 
TBI-01 
Version: 
Version 5 
Date: 
May 17, 2018 
SPONSOR:
SanBio, Incorporated 
231 S. Whisman Road 
Mountain View, CA  94041 USA
Phone: +1 650-625-8965 
Fax: +1 650-625-8969 
SITE OF INVESTIGATION:
Multi-Center
PRINCIPAL MONITOR:
Damien Bates, M.D., Ph.D., FRACS (SanBio) 
MEDICAL MONITORS
UNBLINDED:
Carin Verduyn, MD (Biorasi) 
BLINDED:
Ken Carlson, MD (Biorasi) 
SAFETY MONITOR:
ProPharma Group/PROSAR 
CLINICAL LABORATORY:
Clinical laboratory testing will be performed centrally. 
Principal Monitor 
Principal Investigator
Damien Bates, M.D., Ph.D., FRACS 
SanBio
Investigator Name (Printed) 
Signature 
Date
Signature 
Date
Investigator Statement
I have read the protocol, including all appendices, and I agree it contains all of the necessary 
information for me and my staff to conduct this study as described. I will conduct the study as 
outlined herein, in accordance with the regulations stated in the Federal Code of Regulations for Good 
Clinical Practice and International Conference on Harmonization guidelines, and will make a 
reasonable effort to complete the study within the time designated. I also understand that these 
materials contain confidential information belonging to SanBio, Inc.  Except as may be otherwise
agreed to in writing, I agree to hold such information in confidence and not to disclose it to others
(except where required by applicable law) nor use it for unauthorized purposes. In the event of actual 
or suspected breach of this obligation, SanBio, Inc. should be promptly notified. 
SanBio 

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TABLE OF CONTENTS
1.0
PROTOCOL SYNOPSIS ................................................................................................... 6
2.0
BACKGROUND ............................................................................................................... 17
2.1
MEDICAL NEED ............................................................................................................................ 17 
2.2
DUAL ROLE OF INFLAMMATION IN TRAUMATIC BRAIN INJURY.................................................. 17 
2.3
TREATMENT OF TBI...................................................................................................................... 18 
2.3.1 
Current Therapies ................................................................................................................. 18
2.3.2 
Experimental Cellular Therapies .......................................................................................... 18
2.3.3 
Stereotactic Surgery .............................................................................................................. 19
2.4
RATIONALE FOR USE OF SB623 CELLS IN TBI ............................................................................ 20 
2.4.1 
Summary of SB623 Cells Properties ..................................................................................... 20
2.4.2 
Summary of Notch-1 Gene Properties .................................................................................. 20
3.0
OVERALL EXPERIENCE WITH INVESTIGATIONAL PRODUCT ..................... 20
3.1
STUDY AGENT .............................................................................................................................. 20 
3.2
PRECLINICAL PHARMACOLOGY.................................................................................................... 20 
3.3
CLINICAL EXPERIENCE................................................................................................................. 21 
3.4
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS.................................................... 23 
4.0
DESCRIPTION AND JUSTIFICATION OF TREATMENT REGIMEN ................. 23
4.1
DOSAGES ...................................................................................................................................... 23 
4.2
JUSTIFICATION.............................................................................................................................. 24 
5.0
STUDY PARAMETERS AND OBJECTIVES .............................................................. 25
5.1
OBJECTIVES .................................................................................................................................. 25 
5.1.1 
Primary Objective ................................................................................................................. 25
5.1.2 
Secondary Objectives ............................................................................................................ 25
5.2
PARAMETERS................................................................................................................................ 25 
5.2.1 
Efficacy Endpoints ................................................................................................................ 25
5.2.2 
Safety Endpoints.................................................................................................................... 25
5.2.3 
Exploratory Endpoints & Analyses ....................................................................................... 26
6.0
SURGICAL AND IMPLANTATION PROCEDURES ................................................ 27
7.0
PATIENT SELECTION .................................................................................................. 28
7.1
INCLUSION CRITERIA.................................................................................................................... 28 
7.2
EXCLUSION CRITERIA................................................................................................................... 28 
8.0
INVESTIGATIONAL PLAN .......................................................................................... 30
8.1
OVERALL STUDY DESIGN............................................................................................................. 30 
8.2
DURATION OF PATIENT PARTICIPATION....................................................................................... 31 
9.0
STUDY ASSESSMENTS ................................................................................................. 31
9.1
SCHEDULE OF STUDY ACTIVITIES ................................................................................................ 31 
9.2
PRE-STUDY SCREENING AND BASELINE....................................................................................... 35 
9.2.1 
Visit 1: Screening, (Day -84 to -15)....................................................................................... 35
9.3
BASELINE AND CONFIRMATION OF ELIGIBILITY .......................................................................... 35 
9.3.1 
Visit 2: Baseline (Day -14 to -1) ........................................................................................... 35
9.3.2 
Eligibility Confirmation/Randomization ............................................................................... 36
9.4
CELL ADMINISTRATION OR SHAM SURGERY (VISIT 3: DAY 1) .................................................... 36 
9.5
VISIT 4: FOLLOW-UP PERIOD (STUDY DAY 2) ............................................................................. 37 
9.6
VISIT 5: FOLLOW-UP PERIOD (WEEK 1, STUDY DAY 8 ± 1) ......................................................... 37 
9.7
VISIT 6: FOLLOW-UP PERIOD (WEEK 4, STUDY DAY 28 ± 7) ...................................................... 37 

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9.8
VISIT 7: FOLLOW-UP PERIOD (WEEK 12, STUDY DAY 84 ± 7) .................................................... 38 
9.9
VISIT 8: FOLLOW-UP PERIOD (WEEK 24, STUDY DAY 168 ± 7) .................................................. 38 
9.10 
VISIT 9: FOLLOW-UP PERIOD (WEEK 36, STUDY DAY 252 ± 14)................................................ 39 
9.11 
VISIT 10: FOLLOW-UP PERIOD (WEEK 48, STUDY DAY 336 ± 14).............................................. 39 
10.0
DESCRIPTION OF STUDY TREATMENT.............................................................. 40
10.1 
STUDY PRODUCT DESCRIPTION................................................................................................ 40 
10.2 
STUDY PRODUCT PACKAGING .................................................................................................. 40 
10.3 
STUDY PRODUCT SHIPMENT AND STORAGE............................................................................. 40 
10.4 
PREPARATION AND ADMINISTRATION...................................................................................... 40 
10.5 
STUDY PRODUCT ACCOUNTABILITY PROCEDURES.................................................................. 40 
11.0
TREATMENT ASSIGNMENT AND BLINDING..................................................... 41
11.1 
EMERGENCY UNBLINDING PROCEDURES ................................................................................. 42 
12.0
CONCOMITANT MEDICATIONS............................................................................ 42
13.0
TERMINATION, DISCONTINUATION & LOSS TO FOLLOW UP ................... 42
13.1 
STUDY TERMINATION ............................................................................................................... 42 
13.2 
SITE TERMINATION ................................................................................................................... 42 
13.3 
PATIENT DISCONTINUATION..................................................................................................... 42 
13.4 
PATIENTS LOST TO FOLLOW UP................................................................................................ 42 
14.0
STOPPING RULES ...................................................................................................... 43
15.0
CLINICAL AND LABORATORY EVALUATIONS AND PROCEDURES ......... 43
15.1 
MEDICAL HISTORY ................................................................................................................... 43 
15.2 
PHYSICAL EXAMINATION AND VITAL SIGNS............................................................................ 43 
15.3 
SAFETY LABORATORY.............................................................................................................. 43 
15.4 
PREGNANCY TEST: SERUM OR URINE -HCG ........................................................................... 43 
15.5 
HLA TYPING AND APOE4 AND BDNF VAL66MET GENOTYPING............................................ 43 
15.6 
SERUM ANTI-HLA ANTIBODIES ............................................................................................... 44 
15.7 
PBMC SAMPLES ....................................................................................................................... 44 
15.8 
CLINICAL TBI EVALUATIONS ................................................................................................... 44 
15.8.1 
Screening............................................................................................................................... 44
15.8.1.1 
Glasgow Outcome Scale-Extended (GOS-E) ................................................................ 44
15.8.1.2 
Motricity Index .............................................................................................................. 44
15.8.2 
Study Endpoints..................................................................................................................... 44
15.8.2.1 
Fugl-Meyer Motor Scale (FMMS) Score ...................................................................... 44
15.8.2.2 
Disability Rating Scale (DRS) Score............................................................................. 44
15.8.2.3 
Action Research Arm Test (ARAT) Total Score ............................................................ 44
15.8.2.4 
Gait Velocity.................................................................................................................. 44
15.8.2.5 
NeuroQOL ..................................................................................................................... 45
15.8.2.6 
Global Rating of Perceived Change from Baseline ...................................................... 45
15.9 
PHYSIOTHERAPY....................................................................................................................... 45 
15.10 
LEG ACTIVITY MONITORING .................................................................................................... 45 
15.11 
IMAGING (MRI), CHEST X-RAY, CT, AND ECG ....................................................................... 45 
15.11.1 
MRI .................................................................................................................................... 45
15.11.2 
Chest X-ray ........................................................................................................................ 46
15.11.3 
CT Scans ............................................................................................................................ 46
15.11.4 
Electrocardiograms ........................................................................................................... 46
15.12 
CENTRAL IMAGING CORE LABORATORY.................................................................................. 46 
16.0
ADVERSE EVENTS ..................................................................................................... 46

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16.1 
GENERAL INFORMATION........................................................................................................... 46 
16.2 
ADVERSE EVENT REPORTING PERIOD ...................................................................................... 47 
16.3 
RECORDING OF AES.................................................................................................................. 48 
16.4 
ASSESSING RELATIONSHIP OF AE TO STUDY PRODUCT OR SURGICAL PROCEDURE................ 48 
16.5 
REPORTING SERIOUS ADVERSE EVENTS AND PRODUCT TECHNICAL COMPLIANCES.............49
16.6 
FOLLOW-UP OF ADVERSE EVENTS............................................................................................ 49 
17.0
EXTERNAL DATA SAFETY MONITORING BOARD .......................................... 49
18.0
STATISTICAL METHODS ......................................................................................... 50
18.1 
ANALYSIS POPULATIONS .......................................................................................................... 50 
18.1.1 
Modified Intent-to-Treat Population .................................................................................... 50
18.1.2 
Per Protocol Population ....................................................................................................... 50
18.1.3 
Safety Population .................................................................................................................. 50
18.2 
STATISTICAL ANALYSIS............................................................................................................ 50 
18.2.1 
Demographic and Baseline Characteristics.......................................................................... 50
18.2.2 
Analysis of Efficacy ............................................................................................................... 50
18.2.2.1 
Primary Efficacy Endpoint Analysis ............................................................................. 50
18.2.2.2 
Secondary Efficacy Endpoint Analyses ......................................................................... 51
18.2.2.3 
Exploratory Efficacy Analyses ...................................................................................... 51
18.2.2.4 
Subgroup Analysis......................................................................................................... 51
18.3 
ANALYSIS OF SAFETY ............................................................................................................... 51 
18.4 
MULTIPLICITY CONSIDERATIONS ............................................................................................. 52 
18.5 
MISSING DATA.......................................................................................................................... 52 
18.6 
DETERMINATION OF SAMPLE SIZE............................................................................................ 52 
18.7 
INTERIM ANALYSIS ................................................................................................................... 53 
18.8 
DEVIATIONS FROM THE PROTOCOL ANALYSIS PLAN ............................................................... 53 
19.0
ADMINISTRATION OF THE STUDY ...................................................................... 53
19.1 
REGULATORY CONSIDERATIONS .............................................................................................. 53 
19.2 
INDEPENDENT ETHICS COMMITTEE (EC)/INSTITUTIONAL REVIEW BOARD (IRB)
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC)……………………....................................... 53 
19.3 
PATIENT INFORMATION AND INFORMED CONSENT.................................................................. 54 
19.4 
ADHERENCE TO THE PROTOCOL ............................................................................................... 54 
19.5 
PROTOCOL MODIFICATIONS ..................................................................................................... 54 
19.6 
DATA COLLECTION................................................................................................................... 54 
19.7 
MAINTAINING RECORDS ........................................................................................................... 55 
19.8 
MONITORING, AUDITING, INSPECTING ..................................................................................... 55 
19.9 
CONFIDENTIALITY .................................................................................................................... 56 
19.10 
PUBLICATION POLICY ............................................................................................................... 56 
20.0
APPENDIX A: JUSTIFICATION FOR STUDY ENDPOINTS............................... 57
20.1 
JUSTIFICATION FOR USE OF THE FUGL-MEYER MOTOR SCALE AS PRIMARY ENDPOINT .......... 57 
20.2 
JUSTIFICATION FOR THE USE OF THE DISABILITY RATING SCALE (DRS) ................................. 58 
20.3 
RATIONALE FOR NARROW DOMAIN OUTCOME MEASURES IN CHRONIC TBI PATIENTS WITH
MOTOR DEFICIT....................................................................................................................................... 58 
20.3.1 
Justification for use of the Action Research Arm Test (ARAT) as a secondary endpoint ..... 59
20.3.2 
Justification for use of Gait Velocity as a secondary endpoint ............................................. 59
20.3.3 
Justification for use of NeuroQOL as a secondary endpoint ................................................ 59
20.3.3.1 Justification for choice of NeuroQOL Domains ................................................................ 60
20.4 
REFERENCES ............................................................................................................................. 60 
21.0
APPENDIX B: WHO STANDARD TOXICITY CRITERIA ................................... 64 
22.0
APPENDIX C: ANTICOAGULANT GUIDELINES ……………………………… 71 
23.0
REFERENCES .............................................................................................................. 72

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LIST OF TABLES
Table 1 
Summary of SAEs from SB-STR01 Study............................................................................ 23
Table 2 
Dosages, Volumes and Cell Concentrations ......................................................................... 24
Table 3 
Study Procedures Flow Chart ............................................................................................... 32
Table 4 
Relationship of Adverse Event to the Administration of the Study Product or Surgery . 48
Table 5 
WHO (World Health Organization) Toxicity Criteria by Grade....................................... 65
LIST OF FIGURES
Figure 1 
European Stroke Scale (ESS) ............................................................................................. 21
Figure 2 
National Institute of Health Stroke Scale (NIHSS) .......................................................... 22
Figure 3 
Fugl-Meyer Scale................................................................................................................. 22
Figure 4 
Study Schematic .................................................................................................................. 30

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1.0  PROTOCOL SYNOPSIS
Protocol #:
TBI-01
Title:
A Double-Blind, Controlled Phase 2 Study of the Safety and Efficacy of
Modified Stem Cells (SB623) in Patients with Chronic Motor Deficit from
Traumatic Brain Injury (TBI)
Study
Objectives:
Primary: To evaluate the clinical efficacy of intracranial administration of
SB623 cells. 
Secondary: 
•
To evaluate the effect of intracranial administration of SB623 cells on
disability parameters.
•
To evaluate the safety and tolerability of intracranial administration of 
SB623 cells.
Background and
Rationale
SB623 cells are adult bone-marrow-derived cells that have been transiently
transfected with a plasmid construct encoding the intracellular domain of 
human Notch-1.  SB623 cells secrete trophic factors that protect neurons in 
models of ischemic insult.  In addition, beneficial matrix protein is also 
secreted.  In a rat contusion model of TBI, implantation of SB623 around
the area of the injury resulted in significant improvement of motor 
function. 
The safety of implanted SB623 cells has been evaluated in a 6-month 
primate study and in 2 nude rat studies (4 mos. and 12 mos.).  The primates
were immunosuppressed with cyclosporine and the nude rats further
immunosuppressed with an anti-NK cell antibody. There were no SB623- 
related clinical, laboratory, or histological abnormalities found. 
The stereotactic surgical delivery of cells to patients with stroke has been
shown to have an acceptable safety profile in two prior clinical studies with 
another product. In addition, a retrospective study of over 2,650 patients 
undergoing stereotactic surgery during a 28-year period at one major clinic 
has shown a high degree of safety with the procedure.
A 2-year Phase 1/2a dose escalation study (NCT01287936) of SB623 
stereotactically implanted into the brains of patients with chronic motor 
deficits due to ischemic stroke has been completed. The 6-month interim 
study report has shown statistically-significant improvements in motor 
function in each of three scales: the European Stroke Scale (ESS), the 
National Institute of Health Stroke Scale (NIHSS) and the Fugl-Meyer 
scale. The study showed no serious adverse events likely attributed to 
SB623, and only minor adverse events mostly grade 1 or 2 (with one grade 
3) that were unrelated, unlikely related, or possibly related to SB623. No 
dose-limiting toxicities were observed. 
Given that the cells, dosage and route of administration in this Phase 2 TBI 
study will be the same as those used in the Phase 1/2a Chronic Stroke study 
for which no safety concerns with SB623 were seen, we propose 

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initiating a double-blind, controlled study design. The primary efficacy
endpoint will be the Fugl-Meyer Motor Scale score, with the following as
secondary endpoints: 
•
Disability Rating Scale score 
• Action Research Arm Test score 
• Gait Velocity 
• NeuroQOL (Upper Extremity Function and Lower Extremity Function) 
•
Global Perception of Change: 
o
By Subject (may be completed by Caregiver) 
o
By Clinician 

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Study Design
This is a double-blind, sham-surgery controlled study of stereotactic,
intracranial injection of SB623 cells in patients with fixed motor deficits 
from TBI. The study will be conducted at approximately 30 sites in North 
America (i.e., US), Eastern Europe (i.e., Russia and Ukraine), and Asia 
Pacific (i.e., Japan). 
Patients will have moderate or severe TBI with Glasgow Outcome Scale-
Extended (GOS-E) scores of 3-6 and stable motor deficits (defined as at 
least 12 months post-TBI) to be eligible for study participation. Motor 
deficits are defined as a Motricity Index Upper Extremity score of 10-81, 
at least two scores less than 33 with one of these less than 25, and at least 
one score greater than 0 (Upper Extremity [UE] Scale), and/or a Lower 
Extremity score of 10-78, at least two scores less than 33 with one of these 
less than 25, and at least one score greater than 0 (Lower Extremity [LE] 
Scale).
Two groups, Group 1 and Group 2, will receive either SB623 or sham
surgery in a 3:1 randomization scheme. Group 1 will be further
randomized in a 1:1:1 ratio to receive either 2.5, 5 million or 10 million 
SB623 cells. Randomization will be performed via an interactive web 
response system (IWRS). For subjects enrolled outside of Japan, the 
randomization will be stratified by Glasgow Outcome Scale-Extended 
(GOS-E) score (i.e. scores 3, 4, 5 or 6); for subjects in Japan, the 
randomization will not be stratified.
The surgical procedure is a modification of one used earlier with another
cell product (Kondziolka D, Steinberg GK, Wechsler L, et al. 
Neurotransplantation for Patients with Subcortical Motor Stroke: A Phase
2 Randomized Trial. J Neurosurg. 2005; 103:38-45), and which has been
shown to have a high degree of safety in a retrospective study of over 
2,600 patients undergoing stereotactic surgery over the course of 28 years
at one major clinic (Lunsford LD, Niranjan A, Khan AA, Kondziolka D). 
EUgibil'ty 
,3,:1 
-random1,zation 8 ---
6, months to, primary endpoint 
16 month followup 

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Establishing a Benchmark for Complications Using Frame-Based 
Stereotactic Surgery. Stereotact Funct Neurosurg. 2008; 86:278-287). This 
procedure was also used in the ongoing clinical trial SB-STR01. On the 
morning of surgery, either a head CT scan overlaid on the Baseline MRI or
a head MRI scan alone is to be performed for stereotactic targeting. The 
MRI scans are to use at least 1.5 tesla. A safe trajectory is to be defined to 
enter a cortical gyrus, sparing a sulcus. Implant sites are to be determined 
in the cortical or cerebral motor sites adjacent to the injured area. Three 
needle tracks are to be determined with trajectories to surround the 
damaged area, so that cell deposit targets are spaced 5-6 mm apart. Either 
frameless or frame stereotaxy procedures may be used. 
Group 1 
One burr-hole craniostomy (1-1.5 cm) is to be fashioned under local
anesthesia and sedation. The aim of the sedation is two-fold: to minimize
subject discomfort and to prevent any subject recall or awareness of the
procedure to preserve subject blinding. The dura is to be opened and a
stabilizing cannula (size dependent on the use of a frame or frameless
procedure) containing a removable solid stylet is to be inserted to a point 
just proximal to the damaged area. The solid stylet is then to be removed, 
followed by insertion into the stabilizing cannula of an implantation needle 
with back-loaded Hamilton syringe (previously qualified for product
stability and delivery and provided by the Sponsor, as needed) down to the 
deepest target point for the first implantation. Five 20- L volumes of cells 
are to be injected slowly (approximately 10 L/min.) into 5 implantation 
sites, slowly withdrawing the needle to produce equally spaced implants 
(intervals of 5-6 mm) within the cerebral motor sites adjacent to the injured
region. The target locations will be selected by the site neurosurgeon to be 
closest to the motor pathway based on the patient’s own neuroanatomy. 
This procedure is to be repeated with 2 other needle tracks with different 
trajectories, inserted through the same burr-hole craniostomy. 
Group 2 
Group 2 will receive sham surgery (sedation, stereotactic planning
procedure, partial-thickness skull outer table burr hole, scalp suture, but no 
penetration of inner table or dura mater). This will be done under sedation 
and local anesthetic. Again the purpose of the sedation is two-fold: to 
minimize subject discomfort and to prevent any subject recall or awareness
of the procedure to preserve subject blinding. The sham surgery procedure
will be scripted to mimic as closely as possible the procedure undertaken
by Group 1. Subjects in Group 2 will remain in the Operating Room (OR)
for the same duration as Group 1. 
Post-Surgical
After completion of the procedure, both groups will receive a CT scan and 
be admitted to a neurosurgical patient ward for 24-hour observation. 
µ 
µ 

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The patient will be discharged on the first post-operative day unless
complications require a longer stay. An MRI is to be done on the first post-
operative day (Day 2) to ensure there are no significant bleeding risks.
The neurological assessment team evaluating Fugl-Meyer and other
efficacy endpoints will be blinded, with the subjects also blinded. The 
surgical team will remain unblinded, any communication between the 
surgical and neurological team (including the investigator) will be blinded
regarding surgical treatment.
Safety will be monitored by the Investigator, Principal Monitor, Medical
Monitor (Unblinded and Blinded), and an external Data Safety Monitoring
Board including clinical symptoms, laboratory findings, and head MRI. 
Two or more serious adverse events potentially attributed to SB623 as
assessed by the Investigator will trigger a review by the DSMB before 
continuing enrollment. In addition, the DSMB will review the study at 25%,
50%, 75% and 100% enrollment. The DSMB shall be the final arbitrator for
attributions. Efficacy will be determined based on changes in the clinical
measures of TBI through standardized assessments (Fugl-Meyer Motor 
Scale (FMMS), Disability Rating Scale (DRS), Action Research Arm Test 
(ARAT), Gait Velocity, two Domains of the NeuroQOL and the Global
Perception of Change (subject and clinician). MRI of the brain will be
performed at scheduled time points (pre- and post-contrast T1 weighted, 
dual echo, and FLAIR sequences). MRIs will be analyzed by a central 
reader and post-surgery blinded reports will be sent back to the assessment 
site staff (excluding the assessment site efficacy assessor) without any 
accompanying images. Exploratory imaging (e.g. diffusion tensor imaging 
[DTI] and dynamic susceptibility contrast [DSC] MRI for perfusion
imaging) will also be performed. Note that in this document DSC and 
Perfusion Imaging are used interchangeably. Primary and secondary efficacy 
assessments will be completed solely by blinded study personnel (i.e. 
assessment site efficacy assessor) that do not have access to patient study 
safety information (this include adverse events, concomitant medications, 
progress notes, MRI reports, etc.).
Stopping Rules: 
If the DSMB determines that continuation of enrollment in the trial provides
an unreasonable risk to the patients, it may recommend study termination. 
All SAEs, regardless of attribution shall be reviewed by the DSMB.
In addition, adverse events attributable to the surgical procedure, such as
intracranial infection, intracranial bleeding and seizures, shall be subject to 
review by the DSMB. 
The DSMB shall be the final arbitrator for attributions.

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Patient
Population
Adult male or female patients with stable, chronic motor deficits secondary
to focal traumatic brain injury.  Stable TBI will be defined as at least 12 
months post TBI. This requirement is based on a number of studies that
have shown that the majority of TBI patients are stable by 6-12 months post-
TBI. 
Statistical
Considerations
For a two-sample t-test to show superiority of SB623 over sham control,
assuming 80% power, alpha of 0.05, a two-tailed test, and 3:1 
randomization, a sample size of 48 (36 subjects in the treatment group and 
12 subjects in the control group) is required.  This assumes the mean
change from baseline to 6 months in the FM-Motor Scale score is 10.0 for 
the treatment group (pooling all SB623 doses) and 3.0 for the control 
group, with an assumed standard deviation of 7.25 in each group. Based on 
an 8% upward adjustment to compensate for dropout patients, a total of 
approximately 52 subjects will be required. Since the analysis of efficacy is 
to be based on the modified ITT population, subjects will continue to be 
enrolled in the study until there are a total of approximately 52 subjects in 
the mITT population. The vast majority of subjects will be from outside of 
Japan; however, a sufficient number of Japanese patients are to be enrolled 
in order to address Japanese regulatory requirements.
For efficacy analyses, comparing treatment to control, all three dose groups 
will be combined.  In addition, a possible SB623 dose-response will be 
evaluated. 
No. of Patients
Approximately 52 subjects
No. of Study Sites
Approximately 30 sites

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Inclusion
Criteria
1. Age 18-75 years 
2. Documented history of TBI, with correlated MRI or CT 
3. At least 12 months post-TBI 
4. Focal cerebral injury able to be identified on MRI (+/– concomitant 
diffuse axonal injury) 
5. Neurological motor deficit substantially due to focal cerebral
injury observed on MRI 
6. GOS-E score of 3-6 (i.e. moderate or severe disability) 
7. Require Motricity Index UE Scale of 10-81, at least two scores less 
than 33 with one of these less than 25, and at least one score greater 
than 0, and/or a LE Scale of 10-78, at least two scores less than 33 
with one of these less than 25, and at least one score greater than 0. 
8. Able and willing to undergo computed tomography (CT) and 
magnetic resonance imaging (MRI) 
9. Must agree to use of antiplatelet, anticoagulant, or non-steroidal anti-
inflammatory drugs to be in accordance with the Anticoagulant 
Guidelines described in Appendix C.
10. Subjects must be willing to participate in study related exercises to 
the extent possible 
11. Must be willing to discontinue herbal or non-traditional medicines
for 1 week before and 1 week after the surgical procedure 
12. Able to undergo all planned neurological assessments 
13. Ability of patient to understand and sign an Informed Consent
Exclusion 
Criteria
1. History or presence of any other major neurological 
disease
2. Any seizures in the prior 3 months 
3. The presence of contracture at any joints that would 
interfere with interpretation of any of the neurological 
assessments (e.g., contracture preventing the detection of 
any increase in the range of motion or ability to perform a 
task)
4. Other neurologic, neuromuscular or orthopedic disease that
limits motor function
5. Clinically significant finding on MRI of brain not related 
to TBI 
6. Known presence of any malignancy except squamous or 
basal cell carcinoma of the skin 
7. History of CNS malignancy 
8. Positive findings on tests for occult malignancy, unless a
non- malignant etiology is confirmed 
9. Uncontrolled systemic illness, including, but not limited to: 
hypertension (systolic >150 mm Hg or diastolic >95 mm
Hg); diabetes; renal, hepatic, or cardiac failure 
10. Uncontrolled major psychiatric illness, including 
depression symptoms (CESD-R Scale of 
11. Total bilirubin >1.9 mg/dL 
12. Serum creatinine >1.5 mg/dL
~16) 

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13. Hemoglobin <10.0 g/dL
14. Absolute neutrophil count <2000/mm3
15. Absolute lymphocytes <800/mm3
16. Platelet count <100,000/mm3
17. Liver disease documented by AST (SGOT) or ALT 
(SGPT)
institutional upper limit of normal 
18. Serum calcium >11.5 mg/dL
19. Unexplained abnormal preoperative test values (blood 
tests, electrocardiogram [ECG], chest X-ray); x-ray 
evidence of infection; uncontrolled atrial fibrillation or 
uncontrolled congestive heart failure 
20. Presence of craniectomy (without bone flap replacement)
or other contraindication to stereotactic surgery 
21. Participation in any other investigational trial within 4 
weeks of initial screening or within 7 weeks of study entry 
22. Botulinum toxin injection, phenol injection, intrathecal 
baclofen, or any other interventional treatments for 
spasticity (except bracing and splinting) within 16 weeks of 
the Baseline visit. (interventional treatment refers to 
treatment done with special equipment which is typically 
performed in a surgical or procedural type facility - this does 
not apply to oral medications such as oral baclofen)
23. Ongoing use of herbal or other non-traditional drugs 
24. Substance use disorder (per DSM-V criteria, including 
drug or alcohol) 
25. Contraindications to head CT or MRI 
26. Pregnant or lactating
27. Female patients of childbearing potential unwilling to use an 
adequate birth control method during the 12 months of the study 
28. Any other condition or situation that the investigator believes may
interfere with the safety of the subject or the intent and conduct of 
the study 
29. Patients with allergic reactions to the ingredients of SB623, the 
drugs used when administering SB623 or the drugs used in testing 
(applicable for Japan only) 
~2.5 X 

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Dosage, Mode of
Administration, 
and Treatment
Duration 
SB623 cells are provided as a 1-mL sterile cell suspension, containing
X 106 cells/mL, cryopreserved in CryoStor™ freezing media. Cells are
provided in individual 2-mL Nalgene™ cryovials with screw caps. 
Cells to be administered stereotactically only once through one burr-hole
craniostomy within and adjacent to the injured area using 3 needle tracks 
and 5 cell deposits per track at varying depths (20 L per deposit):
2.5 X 106 SB623 Cells (8.3 X 106 cells/mL)
5.0 X 106 SB623 Cells (17 X 106 cells/mL)
10.0 X 106 SB623 Cells (33 X 106 cells/mL)
Details for preparation of the cell suspension for administration and for 
loading the syringe in the OR will be provided by the Sponsor in a 
separate document. Clinical sites will be provided necessary materials for 
reconstitution of the cells and will be trained by the Sponsor. The 
cryopreserved cells will be thawed, washed, centrifuged, and re-
suspended in Plasma-Lyte A at varying concentrations for administration 
to the patient within approximately 3 hours of dose release. Prior to 
administration, a gram stain and a test for endotoxin will be done and a 
sterility test initiated on the last cell wash to ensure continued sterility. If
the endotoxin level is > 5 EU/mL or the gram stain is positive, 
implantation will not occur. If the sterility test is positive, an 
investigation will be conducted to determine the source of the 
contamination by the sponsor. In addition, identification of the pathogen 
and sensitivity will be done and the patient treated with an appropriate
antibiotic. In this event, the patient will be followed closely for adverse
events associated with a possible infection and response to antimicrobial
therapy, including frequent clinic visits until any infection is cleared.
SB623 cells will be kept frozen in vapor phase liquid nitrogen or in 
storage equipment maintaining the same temperature as vapor phase 
liquid nitrogen, at study sites, either within the shipping or other 
acceptable storage container approved by the Sponsor until ready for use. 
SB623 cells will then be thawed, washed, and re-suspended in Plasma-
Lyte A® at the concentration summarized above. 
Sites will be trained in proper cell handling procedures and these
will be documented.
Duration of
Patient Study
Participation 
Twelve months post-randomization (except if there is an unresolved
adverse event, in which case the patient will be followed until the adverse 
event has resolved or a stable clinical endpoint has been reached). 
2:8 
µ 
• 
• 
• 

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Efficacy
Parameters
•
Primary Efficacy Endpoint:
• Change from baseline in Fugl-Meyer Motor Scale (FMMS) 
score at Week 24 among all patients
• Secondary Efficacy Endpoints: 
• Change from baseline in Disability Rating Scale (DRS) 
score at Week 24 among all patients
• Change from baseline in Action Research Arm Test
(ARAT) total score at Week 24 among upper extremity 
deficit patients
• 
Change from baseline in Gait Velocity at Week 24 among 
lower extremity deficit patients
• Change from baseline in T scores at Week 24 of NeuroQOL
Domains: 
o Upper Extremity Function (Fine motor ADL) among 
upper extremity deficit patients
o Lower Extremity Function (Mobility) among lower 
extremity deficit patients
•
Global Rating of Perceived Change scores at Week 24 (from 
baseline) among all patients: assessed by the subject (may be 
completed by caregiver) and by the clinician
For the mITT Population, patients with a Motricity Index UE Scale 
score at Screening of 10-81 will be considered to have an upper 
extremity deficit, and patients with a LE Scale score at Screening of 10-
78 will be considered to have a lower extremity deficit. For the Per 
Protocol Population, patients with a Motricity Index UE Scale score at 
Screening of 10-81, at least two scores less than 33 with one of these less 
than 25, and at least one score greater than 0, will be considered to have 
an upper extremity deficit, and patients with a LE Scale score of 10-78, 
at least two scores less than 33 with one of these less than 25, and at least 
one score greater than 0, will be considered to have a lower extremity 
deficit.
Safety
Parameters
•
All adverse events whether or not related to SB623 or the surgical 
procedure using WHO toxicity criteria
•
Adverse changes imaged by head MRI 
• Serious adverse events (SAEs) using WHO toxicity criteria
• Serum chemistry, hematology, vital signs, physical examinations 
•
Changes in serum antibodies to SB623 over time

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Exploratory
Endpoints &
Analyses
•
Change from baseline in Fugl-Meyer Motor Scale (FMMS) score at
Week 24 among patients with both upper and lower extremity deficits
• Change from baseline in Fugl-Meyer Motor upper-extremity subscale
(UE-FM) score at Week 24 among upper extremity deficit patients
• Change from baseline in Fugl-Meyer Motor lower-extremity subscale
(LE-FM) score at Week 24 among lower extremity deficit patients
• Improvement by 
at Week 24 from Baseline in UE-FM score
among upper extremity deficit patients
• Improvement by 3 points at Week 24 from Baseline in LE-FM score 
among lower extremity deficit patients
• Improvement by 
at Week 24 from Baseline in Fugl-Meyer 
Motor Scale (FMMS) score among patients with both upper and lower 
extremity deficits
• Improvement by 
at Week 24 from Baseline in Action Research
Arm Test (ARAT) score among upper extremity deficit patients
• Improvement of at least one functional level [e.g., from <0.4 m/s to 0.4-
0.8 m/s or from 0.4 - 0.8 m/s to >0.8 m/s] at Week 24 from Baseline in
Gait Velocity on standard 10 m walk among lower extremity deficit 
patients
•
Pre- and post-contrast standard T1 and T2 weighted, dual echo, and 
FLAIR-MRI among all patients
•
Perfusion MRI among all patients
•
Diffusion tensor imaging (DTI) with tractography among all patients
• Lower limb motion as measured by leg activity monitor among lower 
extremity patients (applicable for US and Japan only) 
•
Outcome analysis among all patients based on genotyping of 
polymorphisms at 3 specific loci: HLA; BDNFVal66Met; and ApoE 
Interim Analysis
The primary efficacy end point is at 24 weeks. Therefore an interim analysis 
is planned after all randomized subjects who have not dropped out of the 
study have completed their 24 weeks visit, to facilitate strategic discussion 
with regulatory agencies for future plans of the program. 
2:6 points 
> 
2:10 points 
2:6 points 

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2.0  BACKGROUND
2.1
Medical Need
Traumatic brain injury (TBI) results from a sudden and external physical impact to the head, and 
often leads to motor (e.g., loss of ambulation, balance, coordination, fine motor skills, strength, and 
endurance) and cognitive (e.g., loss of communication, information processing, memory, and 
perceptual skills) impairment.  Annually, there are 1.4 million new cases of TBI in the United
States alone, resulting in over 50,000 deaths and 80,000 disabilities.1, 2 There are over 5 million
Americans (approximately 2% of the population of the United States) currently living with a long- 
term disability caused by TBI.2   The economic impact, costing approximately $60 billion (in 
medical and loss of productivity costs) per year3, as well as the health and sociological implications 
prompt the demand for clinically effective treatments. 
The physical impact to the brain tissue initially causes necrotic cell death in the underlying tissue,
followed by apoptotic cell death in surrounding tissue due to multiple subsequent events such as
edema, ischemia, excitotoxicity, increase in free radicals, and altered gene expression.4, 5 Both 
primary and secondary insults initiate a glial response, which acutely acts to sequester and clean 
debris at the injury site.  Cellular components of the glial scar include reactive astrocytes, which 
help buffer excess glutamate and secrete neurotrophic factors, and activated microglia, which along 
with monocyte-derived macrophages, clear out dead tissue.
However, extracellular components 
of the glial scar that forms adjacent to the injury site have been found to inhibit neurite extension
(e.g., chondroitin sulphate proteoglycans (CSPGs), Nogo protein), thus limiting regeneration.6    It 
has also been appreciated recently that the brain may be attempting to repair through 
developmental-like processes, as evidenced by the increases in neurogenesis and angiogenesis that
occur following TBI.7, 8, 9
2.2    Dual Role of Inflammation in Traumatic Brain Injury
While the brain is considered immune-privileged (due to the tight regulation of the central nervous 
system microenvironment which largely excludes blood leukocytes from entering), immune 
responses occur during pathological conditions.10  In TBI, the initial release of cell contents from 
the primary necrosis initiates an inflammatory reaction. While inflammation occurring in the brain 
is associated with deleterious events, the beneficial role of inflammation in TBI has gained 
appreciation.11, 12, 13 The major events of inflammation following TBI are summarized here with an 
emphasis on the dual nature of this endogenous immune response. 
The three major classes of protein mediators of inflammation are cytokines, chemokines, and 
complement proteins.    Pro-inflammatory cytokines (e.g., tumor necrosis factor (TNF),
interleukins-1 and -6) are released within minutes following TBI.13 Studies with specific cytokine 
knockout mice, as well as in vitro studies indicate that these cytokines may have acute deleterious 
effects (e.g., blood-brain barrier [BBB] dysfunction, promotion of neuronal death), but are
beneficial at later time points (e.g., induce synthesis of anti-inflammatory cytokines, induce
neurotrophic factors, promote proliferation of oligodendrocyte precursor cells which may help in 
remyelination.13 Neurons and glial cells (astrocytes, microglia, and oligodendrocytes) can produce
both chemokines (e.g., TN
, interferon-  and complement proteins (e.g., C3, C5), and have 
receptors for these proteins.  In a similar dual role, chemokines and complement proteins are 
involved in acute BBB dysfunction and edema, while these proteins eventually lead to increased 
Fa 
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nerve growth factor production in astrocytes and microglia.  Furthermore, complement proteins 
have been found to protect neurons from excitotoxicity-induced apoptosis and promote 
opsonization.14
With respect to the cellular aspect of the inflammatory response, microglia (resident brain immune 
cells) are the first to respond (minutes to hours) by proliferating, and becoming activated microglia 
which migrate to the area of injury, where they essentially function as macrophages.15, 16 In a
traumatic injury, which is associated with increased BBB permeability, leukocytes from the blood 
can pass through the endothelium at the site of injury; and this process is mediated by cytokines, 
chemokines, and complement proteins.14 Neutrophils are the first to infiltrate (hours to days),
followed by monocytes (days).15 Again, there are both beneficial and deleterious roles for these
immune cells. The oxidative burst of neutrophils and macrophages is harmful because of the 
release of oxygen free radicals and neurotoxic enzymes14, however, both activated microglia and 
monocyte-derived macrophages aid in clearing debris from dead/damaged cells via phagocytosis.17  
Because of the dual nature of the inflammatory response, treatments for TBI that target specific 
cells or proteins involved in the inflammation response may not be ideal.4
2.3    Treatment of TBI
2.3.1    Current Therapies
Current treatment methods in clinical practice primarily aim to reduce intracranial pressure in an 
effort to minimize brain damage caused by swelling. Examples include moderate hypocapnia and 
mannitol (first line measures), followed by barbiturates, moderate hypothermia, or a decompressive
craniectomy (second line measures) if early attempts fail.18   However, these therapies have a 
modest effect on acute brain damage or subsequent cell death pathways, which lead to functional 
impairment.19 Furthermore, these treatments do not provide sustained efforts to promote repair or 
regeneration.  Since many TBI patients are young adults, there is a demand for chronic treatments 
that would prevent further brain damage and help repair or compensate for damage that has already 
occurred.  Treatment approaches under investigation for TBI in the past several years aim to target 
one or more of the pathological events following TBI in an effort to rescue cells or promote repair
and regeneration.  While many prospective treatments seemed promising in animal models, results
in clinical trials have been mixed at best.  For example, excitotoxicity results from excess glutamate
released from necrotic cells over-stimulating neurons (primarily through NMDA receptors), causing 
increased intracellular calcium levels and ultimately cell death; and targeting excitotoxicity showed 
therapeutic potential in animal models.  However, various treatments that mediate along this path, 
such as glutamate antagonists, were not found to be effective for humans with TBI.20, 21 Similar 
results occurred with other investigational drugs including free radical scavengers and steroids. 22   
These treatments may have failed in the clinic because they target pathways that are both 
deleterious and beneficial, thus the dosage and time of treatment are critical to not interfere with
normal homeostasis or reparative mechanisms in the brain.  Furthermore, these treatments targeted 
single mechanisms, which may not be enough in light of the multi-faceted pathology. 
2.3.2    Experimental Cellular Therapies
The complex pathology that occurs after TBI requires a multi-faceted treatment paradigm.  Cell
transplantation is a promising treatment strategy due in part to the ability to target a variety of 
mechanisms in a sustained manner with just a single therapeutic dose.
There are numerous 
investigations into cell transplantation paradigms for TBI with differing cell types and delivery
times / locations with varying responses of donor cell function and effects on host recovery.23 Cell 
transplantation has already shown promise in the clinic for treating severe TBI24, and it is important

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to move cell transplantation research towards providing effective clinical therapies.
Stem cells are receiving attention as attractive candidate cells for transplantation, due largely to 
the proliferative and pluri-/multipotent nature of these cells. The fate of these cells is dictated by
both in vitro preparation and the host environment.  This is important because multipotent stem
cells can adapt to the “needs” of the host tissue.25 Neural stem cells are multipotent stem cells 
that have the capacity to differentiate into the major cells in the central nervous system: neurons, 
astrocytes, and oligodendrocytes, and have many potential applications in central nervous system
transplantation.  Endogenous neural stem cells persist in the adult brain26, 27 and contribute to 
neurogenesis that occurs throughout adult mammalian life in the olfactory and hippocampal
regions.7,26 Furthermore, the rate of neuro- and gliogenesis increases following injury.7,8,9,26  This 
is thought to be an attempt at self-repair and plasticity, but regeneration in the brain is limited due 
to mechanisms that are not completely understood, but are attributed to an inhibitory environment. 
Transplanting exogenous neural stem cells (as well as other cell types) into the injured brain may
augment the neuro- and gliogenic environment that the brain inherently attempts to create 
following injury.  Moreover, neural stem cells are an attractive candidate for cell transplantation 
because they could potentially replace cells lost to injury, and they secrete many neurotrophic
factors that could help repair and regenerate injured brain tissue.28  Transplantation of primary
neural stem  cells  has  been  shown  to  improve  functional  recovery following  experimental
TBI.29, 30, 31
Adult bone marrow-derived mesenchymal stem cells are another promising stem cell for treatment 
following TBI. Mesenchymal stem cells from the bone marrow are multipotent stem cells that can
differentiate into cells in mesodermal tissues (e.g., bone, cartilage, adipose, muscle). 32 There is 
also evidence that these cells can trans-differentiate into neural cells (including neurons, astrocytes
and neural stem cells) in the proper in vitro33, 34 or in vivo35, 36environments. Mesenchymal stem cells
are also known to produce a variety of trophic factors that may be beneficial to the injured and 
regenerating brain.37, 38 Transplantation of mesenchymal stem cells has been shown to improve 
functional recovery following experimental TBI.39
2.3.3    Stereotactic Surgery
A retrospective study of over 2,650 patients who received stereotactic surgery over a 28-year
period at one major clinic found an incidence of surgery-related complications to be <1%,
establishing the high degree of safety for this procedure.  Complications reported included a need
for a craniotomy for hematoma evacuation (0.36%), perioperative seizures (0.36%), burr hole 
infections (0.08%), and death (0.08%).40

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2.4
Rationale for Use of SB623 cells in TBI
2.4.1    Summary of SB623 Cells Properties
SB623 cells are human bone marrow-derived cells and are being developed as an allogeneic cell
therapy for chronic neurological deficits, such as stroke, TBI and other neurodegenerative 
conditions. SB623 cells are generated under GMP conditions by the transient transfection of bone 
marrow stromal cells (MASC) with a plasmid encoding the human Notch-1 intracellular domain.41
This transfection is considered transient because the plasmid rapidly disappears with further 
expansion/passaging of the cells. Thus, the gene and its products, which were initially detected at 
very low levels are not expected to be present at all after a short time post-implantation. 
Unlike the MASC cells used to produce SB623 cells, the product has limited potential to 
differentiate into bone, cartilage or adipose cells.
2.4.2    Summary of Notch-1 Gene Properties
Notch-1 is involved in the regulation of the development process in many species, including 
humans.  Notch is a heterodimeric transmembrane receptor.  Its natural ligands (Serrate, Jagged, 
Delta) are also integral membrane proteins, revealing a cell-cell or juxtacrine role for Notch. Once 
stimulated by a ligand, Notch is proteolytically cleaved releasing the Notch IntraCellular Domain 
(NICD) from the plasma membrane.  Once released, the NICD migrates to the nucleus where it 
plays the role of an activating transcription factor for a number of genes.
3.0 Overall Experience with Investigational Product
This section includes a brief summary of preclinical and clinical data available on the Study Agent 
SB623.  More detailed information can be found in the Investigator’s Brochure for SB623 cells.
3.1    Study Agent
SB623 cells are bone-marrow-derived stromal cells that have been transiently transfected with the 
intercellular domain of the human Notch-1 gene. 
3.2    Preclinical Pharmacology
The in vitro characterization of SB623 cells has included 8 basic areas: fate of SB623 cells, 
protection of primary neurons from Oxygen Glucose Deprivation, the secretion of neurotrophic 
factors, Notch-1 signal transduction, epigenetic changes, osteo- and adipogenesis, and anti- 
inflammatory properties of SB623. 
Several studies evaluating the pharmacology and toxicology of SB623 cells (cell dosage, 
pharmacokinetics, formulation, efficacy, safety, biodistribution, tumorigenicity and use with 
cyclosporine) have been conducted. See the Investigator’s Brochure for details on these studies.

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3.3
Clinical Experience
A 2-year Phase 1/2a study (SB-STR01 - NCT01287936) to investigate the safety and efficacy of 
intracranial administration of SB623 cells in chronic stroke patients with motor deficit has been 
completed. This was an open-label study of 18 chronic ischemic stroke patients. The dose levels
used were in a standard dose escalation paradigm: 2.5M, 5.0M, and 10.0M cells administered once 
into the peri-infarct region of the brain. Four stroke measurement scales were used: NIH Stroke 
Scale (NIHSS), European Stroke Scale (ESS), Fugl-Meyer Scale (FMS), and the Modified Rankin 
Scale (mRS). All of these scales, except mRS, showed a statistically-significant average 
improvement over Baseline at 6 months and other time points (see Figures 1-3 below). 
Figure 1 
European Stroke Scale (ESS)
ESS 
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(+SEM)
Change from Baseline (+SEM)
Figure 2 
National Institute of Health Stroke Scale (NIHSS)
NIHSS
P=.03 
P=.004 
P=.0006
Months  Post-treatment 
Figure 3 Fugl-Meyer Scale
Fugl-Meyer
 
 
 
P=.0002 
 
 
P=.0006
P=.000006
Months Post-treatment
The FMS scale is considered sensitive to improvements in motor function.  Page et al. (2012) 
define a clinically important difference to be a 10% or greater improvement over the scale range.42
The average improvement score on the FMS in SB-STR01 was 22.19 points, which is a 10% 
improvement over the 226 point FMS range. Therefore, clinically relevant improvements in 
impairment scores of patients with chronic motor deficit have been demonstrated by 6 months post 
intracranial administration of SB623. 
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3.4
Summary of Known and Potential Risks and Benefits
Based on the available animal data, no risks have been identified, but considerable potential benefit 
in reversing neurological deficits has been observed in a rat model of TBI and stroke.  One Phase
1/2a study (NCT01287936) in chronic stroke patients with motor deficit has been completed. There
was a common theme of headache and local pain post-surgical procedure, but these were mild and 
transient. There were no serious adverse events likely attributable to SB623. All of the SAEs 
observed to date (six months post implant of the last patient) are summarized in Table 1 below.
Table 1 
Summary of SAEs from SB-STR01 Study
Subject
Event
Grade
Attribution 
Cells
Attribution 
Surgery
Reason for 
SAE
01-006 
Seizure Disorder
4
Unrelated
Possibly 
Related
Hospitalization
01-007 
Subacute Subdural 
Hematoma (with 
Hygroma below)
3
Unrelated
Definitely 
Related
Hospitalization
01-007 
Hygroma 
3
Unrelated
Definitely 
Related
Hospitalization
01-012
UTI
4
Unrelated
Unrelated
Hospitalization
02-001
ICA Stenosis
3
Unrelated
Unrelated
Hospitalization
02-003 
Recurrence of 
Stroke Symptoms
1
Unlikely 
Related
Unrelated
Hospitalization
02-006 
Pneumonia 
3
Unrelated
Probably 
Related
Hospitalization
No safety concerns with SB623 have been found.  The Adverse Events attributed to SB623 have been
Grade 3 or less, with attributions no higher than Possibly Related.
4.0  DESCRIPTION AND JUSTIFICATION OF TREATMENT REGIMEN
4.1    Dosages
All dosages of cells are to be administered stereotactically through one burr-hole craniostomy
using 3 needle tracks within and adjacent to the focal area of injured brain tissue using 5 cell
deposits per track at varying depths, with 20 µL per deposit. Concentrations of cell suspensions to
be used will vary depending on the total dosage required per patient.  See Table 2 below.

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Total
SB623
Cells/Pt.
Total SB623
Cells/Deposit
Total SB623
Cells/Track
Concentration 
of SB623
Cells
Total Volume
per Deposit, per 
Track, and 
Total
2.5 X 106
1.7 X 105
8.3 X 105
cells/mL 
20 µL, 100 µL, 
and 300 µL
5.0 X 106
3.3 X 105
16.5 X 105
cells/mL 
20 µL, 100 µL, 
and 300 µL
10 X 106
6.6 X 105
33 X 105
cells/mL 
20 µL, 100 µL, 
and 300 µL
Table 2 
Dosages, Volumes and Cell Concentrations
8.3 X 106
17 X 106
33 X 106
4.2    Justification
A 2-year Phase 1/2a dose escalation study (NCT01287936) of SB623 stereotactically implanted
into the brains of patients with chronic motor deficits due to ischemic stroke has been completed. 
The 6-month interim study report has shown statistically-significant improvements in motor 
function in each of three scales: the ESS, the NIHSS and the FMS. In particular, statistically and 
clinically significant improvements (i.e. greater than 10% improvement over the scale range) in
motor function were noted. The study also showed no serious adverse events likely attributable to
SB623, and only minor adverse events mostly grade 1 or 2 (with one grade 3) that were unrelated, 
unlikely related, or possibly related to SB623. No dose-limiting toxicities or antibody responses
were observed. 
Given that the cells, dosage and route of administration in this Phase 2 TBI study will be the same
as those used in the Phase 1/2a study in chronic stroke for which no safety concerns with SB623 were 
seen, we propose initiating a double-blind, controlled study design. The primary efficacy endpoint 
will be the Fugl-Meyer Motor Score, with the following scales as secondary endpoints: 
•
Disability Rating Scale
•
Action Research Arm Test
•
Gait Velocity 
•
NeuroQOL (Upper Extremity Function and Lower Extremity Function) 
•
Global Perception of Change: 
o
By Subject (may be completed by Caregiver) 
o
By Clinician 
Rationales for selecting study endpoints are provided in Appendix A. 
The patient population of at least 12 months post-TBI was chosen to allow for stabilization of motor 
deficits, particularly after physical therapy, and to allow a sufficient number of patients for 
reasonable accrual.

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5.0 STUDY PARAMETERS AND OBJECTIVES
The overall objective of the study is to evaluate the safety and efficacy of SB623 cells 
stereotactically implanted in the brains of patients with TBI. 
5.1 
Objectives
5.1.1
Primary Objective
To evaluate the clinical efficacy of intracranial administration of SB623 cells
5.1.2 Secondary Objectives
•
To evaluate the effect of intracranial administration of SB623 cells on disability parameters 
•
To evaluate the safety and tolerability of intracranial administration of SB623 cells.
5.2 
Parameters
5.2.1
Efficacy Endpoints
For the mITT Population, patients with a Motricity Index UE Scale score at Screening of 10-81 
will be considered to have an upper extremity deficit, and patients with a LE Scale score at 
Screening of 10-78 will be considered to have a lower extremity deficit. For the Per Protocol 
Population, patients with a Motricity Index UE Scale score at Screening of 10-81, at least two 
scores less than 33 with one of these less than 25, and at least one score greater than 0, will be 
considered to have an upper extremity deficit, and patients with a LE Scale score of 10-78, at least 
two scores less than 33 with one of these less than 25, and at least one score greater than 0, will be 
considered to have a lower extremity deficit.
The primary efficacy endpoint is the change from baseline in the Fugl-Meyer Motor Scale
(FMMS) score at Week 24 among all patients. The secondary efficacy endpoints are as follows: 
• Change from baseline in Disability Rating Scale (DRS) score at Week 24 among all patients
• Change from baseline in Action Research Arm Test (ARAT) total score at Week 24 among 
upper extremity deficit patients
• Change from baseline in Gait Velocity at Week 24 among lower extremity deficit patients
• Change from baseline in T scores at Week 24 of NeuroQOL Domains: 
o
Upper Extremity Function (Fine motor ADL) among upper extremity deficit patients
o
Lower Extremity Function (Mobility) among lower extremity deficit patients
•
Global Rating of Perceived Change scores at Week 24 (from baseline) among all 
patients: assessed by the subject (may be completed by caregiver) and by the clinician
5.2.2 Safety Endpoints
•
All adverse events whether or not related to SB623 or the surgical procedure using WHO
toxicity criteria 
•
Adverse changes imaged by head MRI 
• Serious adverse events (SAEs) using WHO toxicity criteria
• Serum chemistry hematology, vital signs, physical examinations 
• Changes in serum antibodies to SB623 over time

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5.2.3 Exploratory Endpoints
Change from baseline in Fugl-Meyer Motor Scale (FMMS) score at Week 24 among patients 
with both upper and lower extremity deficits 
• Change from baseline in Fugl-Meyer Motor upper-extremity subscale (UE-FM) score at
Week 24 among upper extremity deficit patients
• Change from baseline in Fugl-Meyer Motor lower-extremity subscale (LE-FM) score at 
Week 24 among lower extremity deficit patients
• Improvement by 
at Week 24 from Baseline in UE-FM score among upper 
extremity deficit patients
• Improvement by 3 points at Week 24 from Baseline in LE-FM score among lower extremity 
deficit patients
• Improvement by 
at Week 24 from Baseline in Fugl-Meyer Motor Scale (FMMS) 
score among patients with both upper and lower extremity deficits 
• Improvement by 
at Week 24 from Baseline in Action Research Arm Test (ARAT)
score among upper extremity deficit patients
• Improvement of at least one functional level [e.g., from <0.4 m/s to 0.4-0.8 m/s or from 0.4 - 
0.8 m/s to >0.8 m/s] at Week 24 from Baseline in Gait Velocity on standard 10 m walk
among lower extremity deficit patients
Pre- and post-contrast standard T1 and T2 weighted, dual echo, and FLAIR-MRI among all 
patients
•
Diffusion tensor imaging (DTI) with tractography among all patients
•
Perfusion MRI among all patients
• Lower limb motion as measured by leg activity monitor among lower extremity deficit 
Patients (applicable for US and Japan only) 
•
Outcome analysis among all patients based on genotyping of polymorphisms at 3 specific 
loci:
o
HLA – degree of donor/recipient mismatch
o
BDNFVal66Met mutation present (yes/no)
o
ApoE (i.e., homo and heterozygosity for ApoE2, ApoE3, ApoE4 alleles)
• 
~6 points 
> 
~10 points 
~6 points 

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6.0  SURGICAL AND IMPLANTATION PROCEDURES
The surgical procedure is a modification of one used earlier with another cell product,43 and which
has been shown to have a high degree of safety in a retrospective study of over 2,600 patients 
undergoing stereotactic surgery over the course of 28 years at one major clinic.40 The procedure is 
also identical to that being used in the ongoing clinical study in chronic stroke patients. There are
to be two groups randomized in a 3:1 ratio: Group 1 (treatment with SB623) and Group 2 (sham
surgery control). Group 1 will be further randomized in a 1:1:1 ratio of subjects receiving 2.5, 5
or 10 million cells. On the morning of surgery, a standard stereotactic coordinate frame is to be 
applied to the head under local anesthesia and mild sedation.  Either a head CT scan overlaid on 
the Baseline MRI or a head MRI scan alone is to be performed for stereotactic targeting. A safe 
trajectory is to be defined to enter a cortical gyrus, sparing a sulcus. Implant sites are to be 
determined in the cortical or cerebral motor sites adjacent to the injured area. Three needle tracks 
are to be determined with trajectories to surround the damaged area, so that cell deposit targets are 
spaced 5-6 mm apart. Either frameless or frame stereotaxy procedures may be used. 
Group 1 
One burr-hole craniostomy (1-1.5 cm) is to be fashioned under local anesthesia and sedation. The 
aim of the sedation is two-fold: to minimize subject discomfort and to prevent any subject recall 
or awareness of the procedure to preserve subject blinding. The dura is to be opened and a
stabilizing cannula (size dependent on the use of a frame or frameless procedure) containing a 
removable solid stylet is to be inserted to a point just proximal to the damaged area. The solid stylet 
is then to be removed, followed by insertion into the stabilizing cannula of an implantation needle 
with back-loaded Hamilton syringe (previously qualified for product stability and delivery and 
provided by the Sponsor, as needed) down to the deepest target point for the first implantation. Five 
20- L volumes of cells are to be injected slowly (approximately 10
L/min.) into 5 implantation
sites, slowly withdrawing the needle to produce equally spaced implants (intervals of 
5-6 mm) within the cerebral motor sites adjacent to the injured region. The target locations will be 
selected by the site neurosurgeon to be closest to the motor pathway based on the patient’s own 
neuroanatomy. This procedure is to be repeated with 2 other needle tracks with different 
trajectories, inserted through the same burr-hole craniostomy. 
Group 2 
Group 2 will receive sham surgery (sedation, stereotactic planning procedure, partial-thickness 
skull outer table burr hole, scalp suture, but no penetration of inner table or dura mater). This will 
be done under sedation and local anesthetic. Again the purpose of the sedation is two-fold: to 
minimize subject discomfort and to prevent any subject recall or awareness of the procedure to 
preserve subject blinding. The sham surgery procedure will be scripted to mimic as closely as 
possible the procedure undertaken by Group 1. Subjects in Group 2 will remain in the Operating 
Room (OR) for the same duration as Group 1. 
Post-Surgical
After completion of the procedure, both groups will receive a CT scan and be admitted to a
neurosurgical patient ward for 24 hour observation. The patient will be discharged on the first
post-operative day unless complications or local standard medical practice require a longer stay. 
An MRI is to be done on the first post-operative day (Day 2) to ensure there are no significant 
bleeding risks.
µ 
µ 

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7.0  PATIENT SELECTION
7.1 
Inclusion Criteria
1.   Age 18-75 years 
2.   Documented history of TBI, with correlated MRI or CT 
3. At least 12 months post-TBI 
4.   Focal cerebral injury able to be identified on MRI (+/- concomitant diffuse axonal 
injury) 
5.   Neurological motor deficit substantially due to focal cerebral injury observed on MRI 
6.   GOS-E score of 3-6 (i.e. moderate or severe disability) 
7.   Require Motricity Index UE Scale of 10-81, at least two scores less than 33 with one of 
these less than 25, and at least one score greater than 0, and/or a LE Scale of 10-78, at 
least two scores less than 33 with one of these less than 25, and at least one score greater 
than 0. 
8.   Able and willing to undergo computed tomography (CT) and magnetic resonance
imaging (MRI) 
9. Must agree to use of antiplatelet, anticoagulant, or non-steroidal anti-inflammatory 
drugs to be in accordance with the Anticoagulant Guidelines described in Appendix C. 
10. Subjects must be willing to participate in study related exercises to the extent possible 
11. Must be willing to discontinue herbal or non-traditional medicines for 1 week before
and 1 week after the surgical procedure 
12. Able to undergo all planned neurological assessments 
13. Ability of patient to understand and sign an Informed Consent 
7.2 
Exclusion Criteria
1.   History or presence of any other major neurological disease
2.   Any seizures in the prior 3 months 
3. The presence of contracture at any joints that would interfere with interpretation of 
any of the neurological assessments (e.g., contracture preventing the detection of 
any increase in the range of motion or ability to perform a task) 
4.   Other neurologic, neuromuscular or orthopedic disease that limits motor function
5.   Clinically significant finding on MRI of brain not related to TBI 
6.   Known presence of any malignancy except squamous or basal cell carcinoma of the 
skin 
7.   History of CNS malignancy 
8.   Positive findings on tests for occult malignancy, unless a non-malignant etiology is 
confirmed

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9.   Uncontrolled systemic illness, including, but not limited to: hypertension (systolic
>150 mm Hg or diastolic >95 mm Hg); diabetes; renal, hepatic, or cardiac failure 
10.   Uncontrolled major psychiatric illness, including depression symptoms (CESD-R Scale
of 
11. Total bilirubin >1.9 mg/dL 
12. Serum creatinine >1.5 mg/dL 
13. Hemoglobin <10.0 g/dL 
14. Absolute neutrophil count <2000/mm3
15. Absolute lymphocytes <800/mm3
16. Platelet count <100,000/mm3
17. Liver disease documented by AST (SGOT) or ALT (SGPT)
 institutional upper 
limit of normal 
18. Serum calcium >11.5 mg/dl
19. Unexplained abnormal preoperative test values (blood tests, electrocardiogram [ECG],
chest X-ray); x-ray evidence of infection; uncontrolled atrial fibrillation or uncontrolled
congestive heart failure 
20. Presence of craniectomy (without bone flap replacement) or other contraindication to 
stereotactic surgery
21. Participation in any other investigational trial within 4 weeks of initial screening or 
within 7 weeks of study entry 
22. Botulinum toxin injection, phenol injection, intrathecal baclofen, or any other
interventional treatments for spasticity (except bracing and splinting) within 16 
weeks of the Baseline visit. (interventional treatment refers to treatment done 
with special equipment which is typically performed in a surgical or procedural 
type facility - this does not apply to oral medications such as oral baclofen). 
23. Ongoing use of herbal or other non-traditional drugs 
24. Substance use disorder (per DSM-V criteria, including drug or alcohol) 
25. Contraindications to head CT or MRI 
26. Pregnant or lactating
27. Female patients of childbearing potential unwilling to use an adequate birth control 
method during the 12 months of the study 
28. Any other condition or situation that the investigator believes may interfere with the 
safety of the subject or the intent and conduct of the study 
29. Patients with allergic reactions to the ingredients of SB623, the drugs used when 
administering SB623 or the drugs used in testing (applicable to Japan only)
2:16) 
2:2.5 X 

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8.0 INVESTIGATIONAL PLAN
8.1
Overall Study Design
This is a double-blind, sham-surgery controlled study of stereotactic, intracranial injection of 
SB623 cells in patients with fixed motor deficits from TBI. The study will be conducted at
approximately 30 sites in North America (i.e., US), Eastern Europe (i.e., Russia and Ukraine), and 
Asia Pacific (i.e., Japan). 
Two groups, Group 1 and Group 2, will receive SB623 and sham surgery, respectively, in a 3:1 
randomization scheme. Group 1 will be further randomized in a 1:1:1 ratio to receive either 2.5, 5 
million or 10 million SB623 cells. Randomization will be performed via an interactive web
response system (IWRS). For subjects enrolled outside of Japan, the randomization will be
stratified by GOS-E score (i.e. scores 3, 4, 5 or 6); for subjects in Japan, the randomization will not 
be stratified. 
The study schematic is shown in the figure below. 
Figure 4 
Study Schematic
The neurological assessment team evaluating Fugl-Meyer Motor Score and other efficacy
endpoints will be blinded, with the subjects also blinded. The surgical team will remain unblinded,
any communication between the surgical and neurological team (including the investigator) will 
be blinded. 
Safety will be monitored by the Investigator, Principal Monitor, Medical Monitor (Unblinded and 
Blinded), and an external Data Safety Monitoring Board including clinical symptoms, laboratory
findings, and head MRI. Two or more serious adverse events potentially attributed to SB623 as 
assessed by the Investigator will trigger a review by the DSMB before continuing enrollment. In 
addition, the DSMB will review the study at 25%, 50%, 75% and 100% enrollment. The DSMB
shall be the final arbitrator for attributions. Efficacy will be determined based on changes in the 
clinical measures of TBI through standardized assessments (Fugl-Meyer Motor Scale (FMMS), 
Disability Rating Scale (DRS), Action Research Arm Test (ARAT), Gait Velocity, two Domains 
of the NeuroQOL and the Global Perception of Change (subject and clinician). MRI of the brain
Eligibility 
3:1 
randomization 
' 
Sham 
1 
6 months to primary endpoint 6 month followup 

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will be performed at scheduled time points and imaging (pre- and post-contrast T1-weighted, dual 
echo, and FLAIR sequences). MRIs will be analyzed by a central reader and post-surgery blinded 
reports will be sent back to the assessment site staff (excluding the assessment site efficacy 
assessor) without any accompanying images. Exploratory imaging (e.g. diffusion tensor imaging 
[DTI] and dynamic susceptibility contrast [DSC] MRI for perfusion imaging) will also be 
performed. Note that in this document DSC and Perfusion Imaging are used interchangeably.
Primary and secondary efficacy assessments will be completed solely by blinded study personnel 
(i.e. assessment site efficacy assessor) that do not have access to patient study safety information 
(this includes adverse events, concomitant medications, progress notes, MRI reports, etc.).
Stopping Rules:
If the DSMB determines that continuation of enrollment in the trial provides an unreasonable risk 
to the patients, it may recommend study termination. All SAEs, regardless of attribution shall be 
reviewed by the DSMB. 
In addition, adverse events attributable to the surgical procedure, such as intracranial infection, 
intracranial bleeding and seizures, shall be subject to review by the DSMB. 
The DSMB shall be the final arbitrator for attributions. 
8.2    Duration of Patient Participation
Twelve months post-surgery (except if there is an unresolved adverse event of at least Grade 2 and 
at least possibly related to the therapy, in which case the patient will be followed until resolved or 
reduced to Grade 1). 
9.0 STUDY ASSESSMENTS
9.1    Schedule of Study Activities
Table 3 below lists the procedures to be followed throughout the course of the study. 

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Table 3 
Study Procedures Flow Chart
Study Period
Screening
Baseline 1
Sham or
Follow-Up Period
Study Visit
Study Day
-84 to -15
-14 to -1 
(±
28
(± 7)
84
(± 7)
168
(± 7)
Study Week
Study Month
Informed Consent
Demographics
Inclusion/Exclusion
Eligibility Criteria Review3
X
Randomization
Medical History
Physical Therapy Instruction and
Subject Exercise Diary given to subject
Subject Exercise Diary Review
Leg Activity Monitor given to subject1
Leg Activity Monitor data download
Pregnancy
6
Physical Exam
Vital Signs2
Chest X-Ray and ECG
Hematology
Serum Chemistry
INR and APTT
X7
HLA typing of each subject
ApoE4 & BDNF Val66Met genotyping
Occult Malignancy
CESD-R Scale
Head CT
X8
1 All inclusion and exclusion criteria must be verified to confirm that the patient qualifies for the study prior to proceeding to Visit 3. NOTE: Hematology, Serum Chemistry, APTT and INR at Baseline (Day -14 to -1) are to be performed by both the central laboratory (for 
data collection purposes) and the local laboratory (to ensure subject is suitable for surgical procedure), all other on study laboratory assessments to be done by central laboratory only. 
2 Subjects can stay at hospital until Visit 5 (Day 8) for post-surgery observation due to standard local medical practice.
3 Screening eligibility is confirmed at the blinded site, and the surgical safety (i.e. ability to proceed safely with surgery) is confirmed at the unblinded site. 
4 Leg Activity Monitors may be replaced at any Visit if the battery is low. If leg activity monitor is dispensed at baseline visit (can be dispensed at screening or baseline), data download will be done at Follow-Up Visit 5.
5 Only for women of childbearing potential. 
6 Serum -HCG at Screening (Visit 1), Visit 8, and Visit 10; either serum or urine -HCG at Baseline (Visit 2). 
7 Both International Normalized Ratio of Prothrombin Time (INR) and Activated Partial Thromboplastin Time (APTT) shall be performed in the local lab prior to surgery; both results must be normal according to local lab (e.g. INR >1.2 and APTT >38 seconds). 
8 Head CT on Day 1 is post-operative.
1 Mandatory for subjects in US and Japan only
2 Height and weight should be collected
Cell 
1 
2 
3 
4 
5 
6 
7 
8 
8 
1 
22 
1) 
1 
4 
12 
24 
1 
3 
6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4 
X 
X 
X 
X 
X 
Test5• 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
p 
p 

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Study Period
Screening
Baseline 1
Sham or 
Follow-Up Period
Study Visit
Study Day
-84 to -15
-14 to -1 
(± 
28
(± 7)
84
(± 7)
168
(± 7)
Study Week
Study Month
Imaging--Head
9
Imaging – Diffusion Tensor & Dynamic 
Susceptibility Contrast Imaging12
Clinical TBI Evaluations
Global Rating of Perceived Change 
(subject and clinician)
Serum for anti-HLA Antibodies
PBMC Sample16
Adverse Events
Concomitant Medications
Sham Surgery or Cell Administration17
9 Magnetic Resonance Imaging (MRI) of the brain will be obtained using either a 1.5 or 3 Tesla MRI scanner. Each subject should have all scans conducted on
the same scanner if possible (excepting those used for stereotactic planning and post-operative assessments, within 2 weeks of the surgery (implant/sham)). T1
and dual echo and FLAIR MRI will be obtained, and will be recorded in standard digital format for review. 
10 Or CT overlaid with MRI from Baseline.
11 MRI with Gadolinium.
12 Diffusion tensor imaging (DTI) is an MRI technique which characterizes the magnitude, anisotropy and orientation of the diffusion tensor, using the pulsed- 
gradient, spin echo pulse sequence with a single-shot, echo planar imaging readout. Whole brain DTI data will be obtained with at least 30 diffusion encoding 
directions and may be obtained using either a 1.5 or 3 Tesla MRI scanner. Dynamic Susceptibility Contrast (DSC) Imaging is acquired using single shot gradient 
echo planar image covering the whole brain. This allows calculation of perfusion parameters.
13 GOS-E; Motricity Index 
14 Fugl-Meyer Motor Score; Disability Rating Scale, Action Research Arm Test, Gait Velocity, and NeuroQOL (2 Domains). Primary and secondary efficacy 
assessments will be completed solely by blinded study personnel (i.e. assessment site efficacy assessor) that do not have access to patient study safety 
information (this includes adverse events, concomitant medications, progress notes, MRI reports, etc.). 
15 Clinician ideally includes assessment site efficacy assessor who does not have access to patient study safety information because Global Rating of Perceive
Change is a component of secondary endpoint, thereby maintaining the blind of the trial.
16 At each time point that serum antibody samples are collected, an additional sample for PBMC will also be collected and stored at the central laboratory 
17 Subjects can be admitted to the clinical site on Day -1 and undergo study surgical procedure on Day 1 only after all other procedures for this visit have been 
completed. Subjects will be discharged on Day 2 unless complications or local standard medical practice require a longer stay. 
Cell 
Admin 
1 
2 
3 
4 
5 
6 
7 
8 
1 
2 
8 
1) 
1 
4 
12 
24 
1 
3 
6 
MRI 
xn 
xn 
xio 
X 
X" 
X" 
X 
X 
X 
X 
x13 
x14 
x14 
x14 
x14 
xis 
xis 
xis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Schedule of Assessments (Continued)
Study Period
Follow-Up
Study Visit
Study Day
252 (± 14)
336 (± 14)
Study Week
Study Month
Informed Consent
Demographics
Inclusion/Exclusion
Eligibility Criteria Review
Randomization
Medical History
Physical Therapy Instruction and Subject Exercise Diary given to subject
Subject Exercise Diary Review
Leg Activity Monitor data download4
X
Pregnancy Test5,6
Physical Exam.
Vital Signs
Chest X-Ray and ECG
Hematology
Serum Chemistry
INR and APTT
HLA typing of each subject
ApoE4 & BDNF Val66Met genotyping
Occult Malignancy
CESD-R Scale
Head CT
Imaging--Head MRI9
Imaging – Diffusion Tensor & Dynamic Susceptibility Contrast Imaging12
Clinical TBI Evaluations
Global Rating of Perceived Change (subject and clinician)
Serum for anti-HLA Antibodies
PBMC Sample16
Adverse Events
Concomitant Medications
Sham Surgery or Cell Administration17
18 Patients who have withdrawn from the study must return for Visit 10 assessments.
Period 
9 
1018 
36 
48 
9 
12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x11 
X 
X'4 
X'4 
xis 
xis 
X 
X 
X 
X 
X 
X 

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Protocol TBI-01 Version 5, May 17, 2018
9.2 
Pre-study Screening and Baseline
The following will be done prior to performing any study-specific procedures:
Informed Consent Signed: study-related details will be carefully discussed with the patient. 
The patient will sign an Informed Consent Form approved by the local Ethics Committee. 
9.2.1
Visit 1: Screening, (Day -84 to -15)
• Inclusion/Exclusion Criteria
• Demographics 
• Medical History 
• Concomitant Medications
• Pregnancy Test (serum -hCG) for women of childbearing potential only 
• Physical Therapy Instructions and Subject Exercise Diary given to subject
• Leg Activity Monitor Given to Subject (applicable for US and Japan only) 
• Physical Exam
•
Vital Signs Including Weight and Height 
• Chest X-Ray and ECG 
• Hematology 
• Serum Chemistry 
• Determination of occult malignancy by occult blood in stools (hemoccult test), finding on 
chest x-ray, carcinoembryonic antigen, prostate-specific antigen (males only), cancer antigen
125 (females only), -fetoprotein, a
-hCG 
• CESD-R Scale Administration (subject must have score of <16) 
• Imaging (head MRI) if no head MRI available that was performed within the last 3 months 
• Clinical TBI Evaluation (GOS-E and Motricity Index) 
9.3 
Baseline and Confirmation of Eligibility
9.3.1
Visit 2: Baseline (Day -14 to -1)
The following will be performed at Baseline: 
•
Eligibility Criteria Review 
•
Adverse events 
• Concomitant medications 
• Pregnancy Test (serum or urine -hCG) for women of childbearing potential only 
• Physical Exam
• Subject Exercise Diary Review
• Leg Activity Monitor data download (applicable for US and Japan only) 
g 
gpu 
n 
g 

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Protocol TBI-01 Version 5, May 17, 2018
•
Vital Signs 
•
Hematology 
•
Serum Chemistry 
•
INR and APTT 
•
HLA typing (molecular) of each subject
•
ApoE4 & BDNF Val66Met genotyping of each subject
•
Blood draw for Serum anti-HLA Antibodies 
•
Blood draw for PBMC
•
Imaging (head MRI) with Gadolinium 
•   Exploratory Imaging (pre- and post-contrast T1-weighted, dual echo, FLAIR MRI, Diffusion 
tensor imaging (DTI) with tractography and Dynamic Susceptibility Contrast (DSC) MRI for 
perfusion imaging) 
•
Clinical TBI Evaluations (FMMS; DRS; ARAT; Gait Velocity; NeuroQOL (Upper 
Extremity Function and Lower Extremity Function) 
9.3.2    Eligibility Confirmation/Randomization
Confirmation of eligibility can only occur after performing all assessments and verifying that the 
patient meets the inclusion and exclusion criteria for the study. Screening eligibility is confirmed 
at the blinded site, and the surgical safety (i.e. ability to proceed safely with surgery) will be 
confirmed at the unblinded site prior to surgery. 
9.4    Cell Administration or Sham Surgery (Visit 3: Day 1)
Subjects can be admitted to the clinical site on Day -1 and undergo study surgical procedure on 
Day 1. Prior to any procedures, the patient will be queried on the use of any or changes in 
medication or adverse events that have occurred since Baseline.
The patient will be randomized prior to surgery via IWRS. The surgical staff, especially the 
surgeon, should make every effort to remain blinded to the assigned treatment until the start of the 
surgical procedures. The patient’s group allocation will be known by the unblinded laboratory staff 
so that the appropriate SB623 dose can be prepared for the patient (if randomized to Group 1). 
Prior to cell implantation, either a head CT overlaid with the Baseline head MRI or a head MRI 
alone will be done to determine the exact locations for the implants. Both International
Normalized Ratio of Prothrombin Time (INR) and Activated Partial Thromboplastin Time 
(APTT) shall be performed in the local lab prior to surgery, both results must be normal according 
to local lab (e.g. INR >1.2 and APTT >38 seconds). 
Group 1: 
One burr hole will be made in the skull of the patient in a location that will allow ready 
access adjacent to the focal area of injured brain tissue region. Cells will be implanted 
using 3 needle tracks with 5 cell deposits for each track at varying depths.  Cell
implantation will be standardized as to volume (20 µL/deposit) and rate (10 µL /min), 
with spacing between each implant of approximately 5-6 mm.
Group 2: 
Subjects will be given procedures similar to Group 1, except will be given a sham surgery
(light sedation, stereotactic procedure, partial-thickness skull outer table burr hole, scalp 
suture, but no penetration of inner table or dura mater).
After cell implantation or sham surgery, the following will be performed: 
•
Imaging (head CT only) 
•
Adverse Events 
•
Concomitant medications 

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Protocol TBI-01 Version 5, May 17, 2018
9.5
Visit 4: Follow-Up Period (Study Day 2)
The following will be performed: 
•
Adverse Events 
• Concomitant Medications
• Head MRI 
• 
Subjects will be discharged on Day 2 unless complications or local standard medical 
practice require a longer stay
9.6
Visit 5: Follow-Up Period (Week 1, Study Day 8 ± 1) 
The following will be performed: 
•
Vital Signs 
• Hematology 
• Serum Chemistry 
• Physical Therapy Instruction and Subject Exercise Diary given to Subject
Leg Activity Monitor data download (applicable for US and Japan only) 
• Blood draw for Serum anti-HLA Antibodies 
• Blood draw for PBMC
• Head MRI with Gadolinium (MRI must be read before re-starting any antiplatelet,
anticoagulant, or non- steroidal anti-inflammatory agents)  
•
Adverse Events 
• Concomitant Medications
9.7
Visit 6: Follow-Up Period (Week 4, Study Day 28 ± 7)
•
Vital Signs 
• Hematology 
• Serum Chemistry 
• Blood draw for Serum anti-HLA Antibodies 
• Blood draw for PBMC
• Subject Exercise Diary Review
• Physical Therapy Instructions and Subject Exercise Diary given to subject
• Leg Activity Monitor data download (applicable for US and Japan only) 
• Imaging (head MRI) with Gadolinium 
• Exploratory Imaging (Pre- and post-contrast T1 weighted, dual echo, FLAIR MRI, 
Diffusion tensor imaging (DTI) with tractography and Dynamic Susceptibility Contrast 
(DSC) MRI for perfusion imaging) 
• Clinical TBI Evaluations (FMMS; DRS; ARAT; Gait Velocity; NeuroQOL (Upper 
Extremity Function and Lower Extremity Function) 
•
Global Rating of Perceived Change: subject and clinician, 7-point Likert scale
•
Adverse Events 
• Concomitant Medications
• 

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Protocol TBI-01 Version 5, May 17, 2018
9.8
Visit 7: Follow-Up Period (Week 12, Study Day 84 ± 7)
•
Vital Signs 
• Hematology 
• Serum Chemistry 
• Blood draw for Serum anti-HLA Antibodies 
• Blood draw for PBMC
• Subject Exercise Diary Review
• Physical Therapy Instructions and Subject Exercise Diary given to subject
•
Leg Activity Monitor data download (applicable for US and Japan only) 
• Clinical TBI Evaluations (FMMS; DRS; ARAT; Gait Velocity; NeuroQOL (Upper 
Extremity Function and Lower Extremity Function) 
•
Global Rating of Perceived Change: subject and clinician, 7-point Likert scale
•
Adverse Events 
• Concomitant Medications
9.9
Visit 8: Follow-Up Period (Week 24, Study Day 168 ± 7)
• Pregnancy test (ser
-hCG) for women of childbearing potential only 
• Physical Exam.
• Subject Exercise Diary Review
• Leg Activity Monitor data download (applicable for US and Japan only) 
•
Vital Signs 
• Chest X-ray and ECG 
• 
Hematology 
• 
Serum Chemistry 
• 
INR and APTT
• Blood draw for Serum anti-HLA Antibodies 
• Blood draw for PBMC
• Imaging (head MRI)
• Exploratory Imaging (Pre- and post-contrast T1-weighted, dual echo, FLAIR MRI, and 
Diffusion tensor imaging (DTI) with tractography and Dynamic Susceptibility Contrast 
(DSC) for perfusion imaging)
• Clinical TBI Evaluations (FMMS; DRS; ARAT; Gait Velocity; NeuroQOL (Upper
Extremity Function and Lower Extremity Function) 
•
Global Rating of Perceived Change: subject and clinician, 7-point Likert scale
•
Adverse Events 
• 
Concomitant Medications
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9.10 Visit 9: Follow-Up Period (Week 36, Study Day 252 ± 14)
•
Vital Signs 
• Hematology 
• Serum Chemistry 
• Leg Activity Monitor data download (applicable for US and Japan only) 
• Clinical TBI Evaluations (FMMS; DRS; ARAT; Gait Velocity; NeuroQOL (Upper 
Extremity Function and Lower Extremity Function) 
•
Global Rating of Perceived Change: subject and clinician, 7-point Likert scale
•
Adverse Events 
• Concomitant Medications
9.11 Visit 10: Follow-Up Period (Week 48, Study Day 336 ± 14) and scheduled early 
withdraw
• Pregnancy test (ser
-hCG) for women of childbearing potential only 
• Physical Exam
•
Vital Signs 
• Chest X-ray and ECG 
• Hematology 
• Serum Chemistry 
• INR and APTT
• Blood draw for Serum anti-HLA Antibodies 
• Blood draw for PBMC
• Imaging (head MRI) with Gadolinium 
• Exploratory Imaging (Pre- and post-contrast T1-weighted, dual echo, FLAIR MRI, 
Diffusion tensor imaging (DTI) with tractography and Dynamic Susceptibility Contrast 
(DSC) for perfusion imaging) 
• Leg Activity Monitor data download (applicable for US and Japan only)
• Clinical TBI Evaluations (FMMS; DRS; ARAT; Gait Velocity; NeuroQOL (Upper
Extremity Function and Lower Extremity Function) 
•
Global Rating of Perceived Change: subject and clinician, 7-point Likert scale
•
Adverse Events 
• Concomitant Medications
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10.0 DESCRIPTION OF STUDY TREATMENT
10.1 Study Product Description
SB623 cells are provided as a 1-mL sterile cell suspension, containing 
 106 cells/mL, 
cryopreserved in CryoStor™ freezing media. 
10.2 Study Product Packaging
Individual 2-mL Nalgene™ cryovial with screw cap 
10.3 Study Product Shipment and Storage
The cryovials containing the frozen cell suspensions are shipped in a dry nitrogen shipper and 
should be stored in the vapor phase within the shipping container provided by the Sponsor, or in 
storage equipment maintaining the same temperature as vapor phase liquid nitrogen until
transferred at the site to a GMP-compliant liquid nitrogen container or other acceptable storage
container approved by the Sponsor. 
The Sponsor will arrange for Study Product to be shipped to the clinical site. 
10.4 Preparation and Administration
Details for preparation of the cell suspension for administration and for loading the syringe in the 
Operating Room (OR) will be provided by the Sponsor. Clinical sites will be provided necessary
materials for reconstitution of the cells and will be trained by the Sponsor.  The cryopreserved 
cells will be thawed, washed, centrifuged, and re-suspended in Plasma-Lyte A at varying
concentrations for administration to the patient within approximately 3 hours of dose release. Prior 
to administration, a gram stain and a test for endotoxin will be done and a sterility test initiated on
the last cell wash to ensure continued sterility.  If the endotoxin level is > 5 EU/mL or the gram
stain is positive, implantation will not occur.  If the sterility test is positive, an investigation will 
be conducted to determine the source of the contamination by the sponsor. In addition, 
identification of the pathogen and sensitivity will be done and the patient treated with an appropriate
antibiotic. In this event, the patient will be followed closely for adverse events associated with a 
possible infection and response to antimicrobial therapy, including frequent clinic visits until any 
infection is cleared.
This Investigational Product may not be used for any purpose other than this clinical study. 
10.5 Study Product Accountability Procedures
The Investigator will be responsible for maintaining inventory and accounting for all Study Product 
received from the Sponsor.  After reconciliation has been completed, all unused Study Product 
vials received by the Investigator will be returned to the Sponsor in a dry nitrogen shipper stored in
the vapor phase.  Any partially used vials are to be destroyed at the site per institutional standard
operating procedure.  Unopened vials will be stored in the vapor phase of liquid nitrogen, or in 
storage equipment maintaining the same temperature as vapor phase liquid nitrogen, or other 
acceptable storage container approved by the Sponsor until returned to the Sponsor. 

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11.0   TREATMENT ASSIGNMENT AND BLINDING
This is a double-blind study. The blind will be maintained by strict role definition and procedures 
described below:
Unblinded personnel: 
Cell preparation staff 
Unblinded study coordinator 
Surgeon and Operating Room staff 
Designated unblinded sponsor & clinical research organization (CRO) personnel 
Data and Safety Monitoring Board (DSMB) members and the supporting statistician and 
programmer involved in regular review and generation of unblinded safety data 
Blinded personnel: 
Assessment site staff
Designated blinded sponsor & CRO personnel 
In order to maintain the blind the following procedures will be implemented:
1) Unblinded cell preparation staff will prepare and perform quality check of the cell suspension 
for each subject. The identity of the treatment will be concealed by the preparation of study
product that is identical in packaging, labeling, schedule of administration, administration, and 
appearance.
2) The neurosurgeon and Operating Room (OR) staff will perform the sham surgery procedure 
using a surgical script that mimics the cell administration procedure as closely as possible (e.g. 
sequence of steps and overall time taken in the OR). 
3) Subjects, assessment site staff, persons performing the assessments, blinded sponsor staff, and 
blinded CRO staff will remain blind to the identity of the treatment from the time of 
randomization until database lock and unblinding, using the following methods: 
a.
Randomization data are kept strictly confidential until the time of unblinding, and will
not be accessible by any of the blinded study personnel in the study, unless subject 
level emergency unblinding is required as noted in section 11.1 Emergency Unblinding 
Procedures.
b. MRIs will be analyzed by a central reader post-surgery and blinded reports will be sent 
back to the assessment site staff (excluding the assessment site efficacy assessor) 
without any accompanying images. Description of the craniotomy skull defect and 
needle tract from the stereotactic surgical procedure are unblinding by definition and 
will therefore be excluded from the blinded head MRI reports. If an unscheduled head 
MRI is to be done, the same process shall be followed as for the scheduled head MRI 
scans to maintain blinding, unless a local read is necessary for clinical care per the 
assessment site investigator’s discretion. These unblinding events (e.g., local head 
imaging reading) will be recorded and reported to the Sponsor. 
c.
To further safeguard maintenance of the blind, primary and secondary efficacy 
assessments are to be completed solely by the efficacy assessors at assessment sites,
who will be segregated from other activities at the assessment site and not have access 
• 
• 
• 
• 
• 
• 
• 

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to any patient study safety information (e.g. adverse events, concomitant medications, 
head imaging reports, medical charts, etc.,). 
d. All sites will be required to document how they will maintain the blind through a 
Maintenance of the Blind Plan that will require approval and sign off by the Sponsor. 
11.1 Emergency Unblinding Procedures
The blinded treatment assignment/dose information is to be broken only in an emergency when 
knowledge of such treatment may have an impact on further treatment decisions or aid in the
emergency treatment of the subject. The Investigator will obtain the treatment assignment for the 
specified subject by accessing the IWRS. Date and reason for unblinding are to be recorded and 
reported to the Sponsor immediately. 
12.0 CONCOMITANT MEDICATIONS
All concomitant medications including prescription and over-the-counter drugs taken during the
14 days prior to initial screening or used anytime during the study through 1 year post Study 
Products will be documented.  Documentation through Week 48 will include changes from the
prior visit, start and stop dates, dose, and reasons for the medication use. 
Investigational drugs or devices for any other indication are not allowed during the study. 
13.0 TERMINATION, DISCONTINUATION & LOST TO FOLLOW UP
13.1  Study Termination
The protocol may be terminated at any time by the Sponsor in the event of significant Study-Drug- 
related adverse effects.
13.2  Site Termination
The study site will be closed if there is evidence of fraud, other unethical conduct, or significant 
non-compliance to the protocol or to Good Clinical Practices (GCPs).  Should patient enrollment 
be unsatisfactory, or data recording be inaccurate and/or incomplete, the Sponsor may terminate
the study site and remove all study materials from the study site. 
13.3  Patient Discontinuation
Patients will be free to discontinue from the study at any time without giving a reason(s). Patients 
will be considered discontinued from the study in the event of any of the following reasons: 
•
Withdrawal of the patient’s consent for any reason 
•
Investigator’s discretion due to patient’s medical condition 
If patient withdrawal occurs during the study period, the Last Evaluation (Visit 10) visit should be 
performed, if possible, at the time of patient withdrawal or as soon as possible thereafter.
13.4  Patients Lost to Follow Up
Patients who cannot be reached after at least three attempts will be categorized as lost to follow up.
The attempts to reach the patients must be documented, with at least one of the attempts written and 
sent to the patient via certified or registered mail. Patients lost to follow up will still be included in
the analysis of the study. For patients lost to follow up, the Investigator may check public records 
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14.0 STOPPING RULES
If the DSMB determines that continuation of enrollment in the trial provides an unreasonable risk 
to the patients, it may recommend study termination.  All SAEs, regardless of attribution shall be 
reviewed by the DSMB. 
In addition, adverse events attributable to the surgical procedure, such as intracranial infection, 
intracranial bleeding and seizures, shall be subject to review by the DSMB. 
The DSMB shall be the final arbitrator for attributions. 
15.0 CLINICAL AND LABORATORY EVALUATIONS AND PROCEDURES
15.1 Medical History
Medical history will include significant medical conditions and surgical history, medications taken 
within 2 weeks prior to signing the Informed Consent. 
15.2  Physical Examination and Vital Signs
A complete physical examination will be performed (including a genital/rectal exam if clinically
indicated). 
Vital signs will include  temperature, blood pressure at rest (while subject is in seated position), heart
rate, and respiratory rate.  Height and weight will be recorded at Visit 1: Screening only.
15.3  Safety Laboratory
All safety laboratory evaluations will be conducted at a central laboratory. At every sampling time 
point, approximately 15 mL of blood will be drawn for each of the hematology and serum 
chemistry panels.
The following laboratory evaluations will be performed: 
• Hematology Panel: hematocrit, hemoglobin, WBC, platelet count, absolute 
lymphocyte count, absolute neutrophil count 
• Serum Chemistry Panel: sodium, chloride, calcium, potassium, magnesium, creatinine, 
BUN, AST, ALT, alkaline phosphatase, and total bilirubin 
• INR and APTT
15.4  Pregnancy Test: Serum or urine -hCG
•
Serum -hCG at Screening (using same blood draw as for serum chemistry), Visit 8, and 
Visit 10
•
Serum -hCG or Urine -hCG at Baseline
15.5  HLA typing and ApoE4 and BDNF Val66Met Genotyping
HLA typing (molecular) of each subject will be performed at baseline to allow exploratory
analysis of degree of mismatch to SB623 with respect to both efficacy and safety. 
Genotyping at the ApoE locus (i.e., to determine if patient is homozygous for ApoE4, E2 or E3, 
or if patient is heterozygous for E2/E3, E3/E4 or E2/E4) will be performed at baseline.
Assessment of whether BDNFVal66Met mutation is present (yes/no) will be performed at 
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A central laboratory will be utilized for sample storage and assay. 
15.6  Serum Anti-HLA Antibodies
Anti-HLA serum antibody measurements will be made to monitor a possible humoral-mediated 
immune response.  Blood samples will be taken at the intervals indicated in the schedule of 
assessments for measurements of serum anti-HLA antibodies using the Luminex assay.  Assays
will be done periodically on pooled samples. A central laboratory will be utilized for sample 
storage and assay. 
15.7  PBMC Samples
At each timepoint that serum antibody samples are collected, an additional sample for PBMC will 
also be collected. A central laboratory will be utilized for sample storage. 
15.8 Clinical TBI Evaluations
15.8.1  Screening
15.8.1.1 Glasgow Outcome Scale-Extended (GOS-E)
Subjects will require a GOS-E score of 3-6 (i.e. moderate or severe disability) at screening. 
Specific information on scoring using the GOS-E can be found in the publication.44
15.8.1.2 Motricity Index
To ensure subjects have a defined motor deficit, an assessment of the subject’s Motricity Index will
be calculated at Screening for study eligibility purposes. Subjects will require both Motricity Index 
UE score of 10-81 (at least two scores less than 33 with one of these less than 25, and at least one 
score greater than 0), and/or a LE score of 10-78 (at least two scores less than 33 with one of these 
less than 25, and at least one score greater than 0). 
15.8.2 Study Endpoints
15.8.2.1 Fugl-Meyer Motor Scale (FMMS) Score
The FMMS score will be calculated at Baseline and Weeks 4, 12, 24 (primary), 36 and 48. 
The treatment group will be compared to the control group based on the mean change from baseline
at each month. 
15.8.2.2 Disability Rating Scale (DRS) Score
The DRS total will be calculated at Baseline and Weeks 4, 12, 24 (secondary), 36 and 48. The
treatment group will be compared to the control group based on the mean change from baseline at
each month.  Specific information on scoring using the DRS can be found in the publication.45
15.8.2.3 Action Research Arm Test (ARAT) Total Score
ARAT scores will be calculated at Baseline and Weeks 4, 12, 24 (secondary), 36 and 48. The 
treatment group will be compared to the control group based on the mean change from baseline at 
each month. 
15.8.2.4 Gait Velocity
Gait Velocity on a standard 10 m walk will be calculated at Baseline and Weeks 4, 12, 24 
(secondary), 36 and 48. The treatment group will be compared to the control group based on the 
mean change from baseline at each month. 

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15.8.2.5 NeuroQOL
Two Domains of the NeuroQOL will be assessed at Baseline and Weeks 4, 12, 24 (secondary), 
36 and 48 using the Short Forms. The 2 subdomains are the Upper Extremity Function (Fine motor 
ADL) and Lower Extremity Function (Mobility). The treatment group will be compared to the 
control group based on the mean change from baseline in T Scores at each month. 
15.8.2.6 Global Rating of Perceived Change from Baseline
This assessment will be performed at Weeks 4, 12, 24 (secondary), 36 and 48. It will be 
performed by both the subject (may be completed by caregiver) and a blinded efficacy assessment 
clinician (ideally the “assessment site efficacy assessor”) who does not have access to patient 
study safety information, thereby maintaining the blind of the trial. Subjects and clinicians will be
asked about perceived changes in the subject’s motor function by comparing “how well they are 
doing compared to before the surgical procedure”. The following 7-point Likert scale will be 
used:
•
Score 7 = Much better
•
Score 6 = A little better, meaningful 
•
Score 5 = A little better, not meaningful 
•
Score 4 = About the same
•
Score 3 = A little worse, not meaningful 
•
Score 2 = A little worse, meaningful 
•
Score 1 = Much worse
15.9  Physiotherapy
Subjects will be instructed on of a set of exercises (cylinder grasp, thumb raise, stand and squat, 
walk) to be carried out at home every morning and afternoon and to indicate their performance in 
a patient diary during Screening and Weeks 4, 12, and 26. The patient’s diary will be reviewed at the 
clinical site to ensure completeness.
15.10 Leg Activity Monitoring
Leg Activity Monitoring is mandatory in the US and Japan only. Bilateral ankle sensors will be 
worn by subjects throughout the study. The leg activity monitors will be dispensed at either the 
Screening or Baseline visit, and at least 2 weeks of baseline data will be required. Activity data will 
be downloaded at the clinical site and changes from Baseline in activity parameters will be 
calculated at Months 1, 3, 6, 9 and 12.
15.11 Imaging (MRI), Chest X-Ray, CT, and ECG
15.11.1 MRI
Magnetic Resonance Imaging (MRI) of the brain will be obtained using either a 1.5 or 3 Tesla MRI
scanner. Each subject should have all scans conducted on the same scanner if possible (excepting 
those used for stereotactic planning and post-operative assessments, within 2 weeks of the surgery 
(implant/sham)). All MRI scans will include T1-weighted, dual echo, and FLAIR MRI. These 
images will be recorded in standard digital format (DICOM) for review.
On visits 2, 5, 6, and 10 post-contrast MRI will also be acquired. The post-contrast images will be 
acquired 5 minutes after the administration of the contrast agent. During this waiting period,
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additional acquisition does not increase the scan time. 
Diffusion tensor imaging (DTI) is an MRI technique which characterizes the magnitude, anisotropy
and orientation of the diffusion tensor, using the pulsed-gradient, spin echo pulse sequence with a 
single-shot, echo planar imaging (EPI) readout. DTI data will be obtained from the whole brain, 
at least 30 diffusion encoding directions and may be obtained using either a 1.5 or 3 Tesla MRI 
scanner.
15.11.2 Chest X-ray
Standard chest x-ray techniques will be performed according to the schedule described above. 
15.11.3 CT Scans
Standard CT techniques will be performed according to the schedule described above. 
15.11.4 Electrocardiograms
All ECGs will be obtained in the supine position, after the subject has been resting supine for at
least 10 minutes. ECGs will be 12 lead with a 10 second rhythm strip. ECGs should be obtained
prior to drawing blood samples. All attempts should be made to use the same ECG recorder for all
visits within individual subjects. ECGs will be centrally read at a core lab according to established 
quality assurance procedures for inter/intra reader variability. ECGs will be reviewed, signed and 
dated by the Investigator listed on the Form FDA 1572 (MD or DO) after each ECG collection. 
The same Investigator should review all ECG reports for a given subject whenever possible. 
15.12 Central Imaging Core Laboratory
A centralized imaging core laboratory will be used to review lesion at study entry, develop 
imaging acquisition protocols, and conduct imaging processing and analyses.
16.0 ADVERSE EVENTS
16.1  General Information
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject enrolled in the study and that does not necessarily have a causal relationship with the study 
product or surgical procedure.  An AE can therefore be any unfavorable and unintended sign,
symptom, or disease temporally associated with the use of the study product or surgical procedure, 
whether or not considered related to the study product or surgical procedure.  This includes any
side effects, injury, toxicity, or sensitivity reaction, and may include a single symptom or sign, 
a set of related symptoms or signs, or a disease. An adverse event is also any laboratory 
abnormality judged to be clinically significant by the Investigator or Sub-investigator(s) that
worsened compared to baseline. 
Throughout the course of the study, every effort should be made to remain alert to possible adverse 
experiences. Patients should be encouraged to report adverse events spontaneously or in response 
to general, non-directed questioning. 
With the occurrence of an adverse event, the primary concern is the safety of the patient.   If
necessary, appropriate medical intervention should be provided. 
An AE does not include: 
•
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure is an adverse event 

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•
Pre-existing diseases or conditions present or detected at the start of the study that do not 
worsen in severity or frequency 
•
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions)
•
Overdose of concomitant medication without any signs or symptoms
A Serious Adverse Event (SAE) is any adverse event that results in any of the following: 
•
death, 
•
life-threatening event, 
•
inpatient hospitalization or prolongation of hospitalization, 
•
a persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions, 
•
congenital anomaly/birth defect, or 
•
an event that may require intervention to prevent any one of the other outcomes listed 
above (based on medical judgment) 
If the subject develops an adverse event during the post-surgical hospitalization, the adverse 
event should be assessed as non-serious UNLESS the adverse event prolonged the hospital 
stay [beyond Visit 5], or resulted in one of the other serious outcomes (e.g., life-threatening; 
required intervention to prevent permanent impairment or damage; other serious (medically 
important event). 
A Product Technical Compliance (PTC) includes a failure or malfunction and any adverse 
reaction and/or any responses in recipients of manufacturers of human cells, tissues, and 
cellular and tissue-based products, regardless of manufactures, distribution, storage, or 
use/application. 
An Unexpected Adverse Event is any AE that is not identified in nature, severity, or frequency
in the current Investigator’s Brochure or product information. Adverse events assessed as related 
to surgical procedure, and Clavien-Dindo Classification 
(http://www.surgicalcomplication.info/index-2.html) Grade II or higher would be considered 
unexpected or unanticipated, unless such event has been previously reported and documented in 
the IB.
A Suspected Adverse Reaction is an AE for which there is a reasonable possibility that the study 
product or surgical procedure caused the AE. A reasonable possibility means there is evidence to 
suggest a causal relationship between the study product or surgical procedure and the AE.
A Serious and Unexpected Suspected Adverse Reaction (SUSAR) is any suspected adverse 
reaction to the study product or surgical procedure that is both serious and unexpected. 
All SUSARs will be submitted as expedited reports to the applicable regulatory authorities/federal 
agencies. For this study, serious and unexpected AEs involving neurological deterioration, 
procedural complications, seizures, benign and malignant tumors and pregnancy will also be 
submitted as expedited reports, regardless of attribution. 
16.2  Adverse Event Reporting Period
The adverse event reporting period for this trial begins upon Enrollment and ends 12 months after
the administration of SB623.

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All AEs (both serious and non-serious) and PTCs must be followed until resolution or until a stable 
clinical endpoint is reached.  All measures required for AE management and the ultimate outcome 
of the AE must be recorded in the source document and reported to the Sponsor. 
16.3  Recording of AEs
All AEs, regardless of severity, seriousness, or presumed relationship to the study product or 
surgical procedure, must be recorded using medical terminology in the source document and on 
the CRF.
Events will be recorded at all study sites using standard terminology provided by the
Sponsor or designate (e.g., CRO), such as MedDRA terminology. 
The WHO (World Health Organization) Standard Toxicity Criteria (STC) will be used to assist in 
categorizing and grading adverse events.  A copy of the WHO STC will be provided in the study
documents. Whenever possible, a diagnosis should be given when signs and symptoms are due to 
common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as “upper respiratory infection”). 
16.4 Assessing Relationship of AE to Study Product or Surgical Procedure
The Investigator must record his/her opinion concerning the relationship of the AE to the study 
product and the surgical procedure on the Adverse Event CRF.  Table 4 below provides guidance 
for assigning relationship to study product or surgical procedure. 
Table 4           Relationship of Adverse Event to Administration of the Study Product or
Surgical Procedure
Unrelated
No temporal relationship to study product or surgical procedure, or the 
presence of a reasonable causal relationship to another drug, concurrent 
disease, or circumstance and the adverse event (AE). 
Unlikely
A temporal relationship to study product or surgical procedure, but no reasonable
causal relationship between study product or surgical procedure and the AE.
Possibly
A reasonable causal relationship between the study product or surgical procedure
and the AE. Information related to withdrawal of cell treatment/procedure was
lacking or unclear. 
Probably
A reasonable causal relationship between the study product or surgical procedure 
and the AE. The event responded to withdrawal of cell treatment/procedure. Re- 
challenge was not required. 
Definitely
A reasonable causal relationship between the study product or surgical procedure
and the AE. The event responded to withdrawal of the cell treatment/procedure,
and recurred with re-challenge, when clinically feasible.

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16.5  Reporting Serious Adverse Events and Product Technical Compliances
Any Serious Adverse Event or PTC, including death, that occurs during this study, whether or not 
the event is considered to be related to the study product or surgical procedure, must be reported 
within 24 hours after the site becomes aware of the event to the Safety Monitor (ProPharma 
Group/PROSAR or designee). 
The contact information for reporting SAEs is as follows for the US and Ukraine: 
ProPharma/Group PROSAR 
Email: clinicalsafety@propharmagroup.com
FAX: 866-681-1063 
The contact information for reporting SAEs is as follows for Japan: 
TBI-01safety@crodot.ip 
The Investigator is encouraged to discuss with the Unblinded Medical Monitor any adverse 
experiences for which the issue of reportability is unclear or questioned. 
A verbal SAE notification must be followed by a completed Serious Adverse Event Report form
signed by the Investigator within 24 hours. The report should be as complete as possible without 
delaying ProPharma Group/PROSAR notification.
Any SAE follow-up information requested by ProPharma Group/PROSAR or designate should be
provided in a timely manner. 
Upon receipt of notification of any Serious Adverse Event, ProPharma Group/PROSAR, 
the Unblinded Medical Monitor and the Sponsor will immediately conduct an evaluation of the 
event and take action indicated by the results of the evaluation.  This may include notification of 
applicable regulatory authorities/federal agencies, other Investigators, IRBs, IBCs and/or the 
suspension or termination of the study.  The Sponsor will remain blinded during this process.
The Investigator is required to report all IND Safety Reports to the local Ethics Committee (EC) 
or Institutional Review Board (IRB) and Institutional Biosafety Committee (IBC) in accordance 
with the EC/IRB/IBC by laws. 
All additional follow-up evaluations of the SAE must be reported to ProPharma Group/PROSAR or 
designee as soon as they are available.
16.6  Follow-up of Adverse Events
All AEs (both serious and non-serious) should be followed until resolution or until a stable clinical
endpoint is reached.  All measures required for AE management and the ultimate outcome of the 
AE must be recorded in the source document. 
17.0  EXTERNAL DATA SAFETY MONITORING BOARD
An External Data Safety Monitoring Board (DSMB) will evaluate efficacy and toxicity and 
mortality rates, and recommend appropriate actions, according to the DSMB Charter. The 
DSMB will review ongoing study data within one month of the enrollment of subjects at the
25%, 50%, 75% and 100% of the total population. 

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18.0 STATISTICAL METHODS
18.1  Analysis Populations
18.1.1  Modified Intent-to-Treat Population
The Intent-to-Treat (ITT) population will include all randomized patients. All efficacy analyses
will be conducted on modified ITT (mITT) population, which is defined as all randomized patients 
who complete the surgical procedure. In analyses based on the mITT population, subjects will be 
analyzed according to their randomized treatment assignment. Analyses based on the mITT
population will be considered the primary analyses of efficacy. 
18.1.2  Per Protocol Population
The Per Protocol (PP) population will include all randomized patients who have no major protocol 
violations. Major protocol violations will be identified based on blinded data after the study is 
completed, but before database lock and the unblinding of the treatment group assignments. All 
efficacy analyses will be repeated on this population. In analyses based on the PP population, 
subjects will be analyzed according to their randomized treatment assignment. Analyses based on 
the PP population will be considered secondary analyses of efficacy. 
18.1.3  Safety Population
The safety population will include all study patients who undergo surgery (implant or sham). All 
safety analyses will utilize this population. In analyses based on the safety population, subjects 
will be analyzed according to the actual treatment received. 
18.2  Statistical Analysis
The Statistical Analysis Plan (SAP) will provide details on the statistical methods planned for this 
study, and it will be finalized prior to the clinical study database being locked and the treatment 
being unblinded. 
In general, continuous variables will be summarized by the following descriptive statistics: sample 
size, mean, median, standard deviation, minimum, and maximum. Categorical variables will be 
summarized by frequencies and percentages (contingency tables). The three SB623 dose groups 
will be pooled for all analyses, except where noted otherwise. 
18.2.1  Demographic and Baseline Characteristics
Demographics and baseline characteristics will be summarized by treatment group using 
descriptive statistics for continuous variables and frequencies and percentages for categorical 
variables.
18.2.2  Analysis of Efficacy
All efficacy analyses will be performed on the mITT and PP populations. The efficacy endpoints 
are to be analyzed per the SAP. 
18.2.2.1 Primary Efficacy Endpoint Analysis
The primary analysis will be a comparison of the mean change from baseline in the Fugl-Meyer 
Motor Scale score of SB623 treated subjects (pooling all SB623 doses) to sham surgical controls at 
24 weeks. A mixed model repeated measures (MMRM) analysis will be performed with terms for 
treatment, visit, the baseline Fugl-Meyer Motor Scale score, the GOS-E score at screening, and the
treatment-by-visit interaction. The Restricted Maximum Likelihood Estimation procedure will be
employed using an unstructured covariance matrix.  Missing observations will not be imputed. 

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18.2.2.2 Secondary Efficacy Endpoint Analyses
Secondary analyses will evaluate a number of outcomes:
A. 
Comparison of the mean change from baseline in the Disability Rating Scale (DRS) score
of SB623 treated subjects (pooling all SB623 doses) to sham surgical controls at 24 weeks
will be performed in a manner analogous to that for the primary efficacy endpoint. 
B. 
Comparison of the mean change from baseline in the Action Research Arm Test (ARAT) 
total score of SB623 treated subjects (pooling all SB623 doses) to sham surgical controls 
at 24 weeks will be performed in a manner analogous to that for the primary efficacy
endpoint. This analysis will be based on upper extremity deficit patients only. 
C. 
Comparison of the mean change from baseline in Gait Velocity of SB623 treated subjects 
(pooling all SB623 doses) to sham surgical controls at 24 weeks will be performed in a
manner analogous to that for the primary efficacy endpoint. This analysis will be based on 
lower extremity deficit patients only.
D. 
Comparison of the mean change from baseline in the two NeuroQOL subdomain T scores
of SB623 treated subjects (pooling all SB623 doses) to sham surgical controls at 24 weeks
will be performed in a manner analogous to that for the primary efficacy endpoint. The two 
subdomains include: 
a.   Upper Extremity Function (Fine Motor ADL) 
b.   Lower Extremity Function (Mobility) 
The analysis of the Upper Extremity Function domain will be based on upper extremity 
deficit patients only, and the analysis of the Lower Extremity Function domain will be 
based on lower extremity deficit patients only.
E.
The proportion of SB623 treated subjects (pooling all SB623 doses) scoring either 7 (much 
better) or 6 (a little better, meaningful) on the Global Rating of Perceived Change by both 
Subject and Clinician will be compared to sham-surgery controls at 24 weeks (from 
Baseline) using a logistic regression model with treatment (SB623 vs. sham placebo), the 
baseline Fugl-Meyer Motor Scale score, and the GOS-E score at screening as terms in the 
model.  The outcome variable of this analysis is a dichotomized variable based on of the 
Global Rating of Perceived Change score (
 <6). 
In addition, each efficacy endpoint mentioned above will be analyzed to examine dose response.
Similar statistical methodologies to those used to evaluate SB623 combined doses versus the 
surgical sham control will be used for each efficacy endpoint, except that dose will be included as
a term in the model instead of treatment. Dose will be a continuous variable with the control 
treatment assigned a value of 0. 
18.2.2.3 Exploratory Efficacy Analyses
The analyses of exploratory efficacy endpoints will be detailed in the SAP. 
18.2.2.4 Subgroup Analysis
Inferential analyses will be performed on some subgroups of interest.  Details of the subgroup 
analyses will be included in the SAP. 
18.3  Analysis of Safety
All safety analyses will be performed on the safety population. 
Adverse events (AEs) will be summarized by presenting, for each treatment group, the number
and percentage of patients having any adverse events, having an adverse event that led to 
2':6 vs. 

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discontinuation from the study, having an adverse event in each System Organ Class (SOC) and 
having each individual type of adverse event (Preferred Term).  These analyses will also be 
performed for serious adverse events (SAEs). Adverse events will also be summarized at the event 
level by severity, by relationship to study product or surgery, and by action taken.
Other 
information collected will be listed. The summary of AEs will be limited to treatment emergent 
AEs (TEAEs), which are defined as any adverse event with onset on or after the initiation of 
treatment or any adverse event already present that worsens in intensity following exposure to 
study treatment. 
For each treatment group, descriptive statistics will be presented by visit for the actual values and
the changes from baseline for each quantitative laboratory test. The difference between treatment 
groups in the mean change from baseline will also be presented. For each laboratory test and each 
treatment group, the one- sample t-test will be used to test whether the mean change from baseline 
equals 0 for each post-baseline time point. The two-sample t-test will be used to test whether the 
mean changes from baseline are equal for the two treatments. A shift table will summarize changes
in status (normal, abnormal) from baseline to each post-baseline time point for each laboratory test, 
and abnormal lab values will be flagged in the data listings.
For each treatment group, descriptive statistics will be presented by visit for the actual values and 
the changes from baseline for each vital sign. The difference between treatment groups in the mean 
change from baseline will also be presented. For each vital sign and each treatment group, the one- 
sample t-test will be used to test whether the mean change from baseline equals 0 for each post- 
baseline time point. The two-sample t-test will be used to test whether the mean changes from 
baseline are equal for the two treatments. A shift table will summarize changes in status (normal, 
abnormal) from baseline to each post-baseline time point for each vital sign, and abnormal values 
will be flagged in the data listings.
18.4  Multiplicity Considerations
Multiplicity considerations will not be taken into consideration in the analyses for this Phase 2 
study.
18.5  Missing Data
Every effort will be made to reduce the number of dropouts and to document reasons for 
dropping out. Missing data will be discussed in the Statistical Analysis Plan (SAP).
18.6  Determination of Sample Size
For a two-sample t-test to show superiority of SB623 over sham control, assuming 80% power,
alpha of 0.05, a two-tailed test, and 3:1 randomization, a sample size of 48 (36 subjects in the 
treatment group and 12 subjects in the control group) is required.  This assumes that the mean change 
from baseline to 24 weeks in the FM-Motor Scale score is 10.0 for the treatment group (pooling all 
SB623 doses) and 3.0 for the control group, with an assumed standard deviation of 7.25 in each
group.  Based on an 8% upward adjustment to compensate for dropout patients, a total of 
approximately 52 subjects will be required. Since the analysis of efficacy is to be based on the 
modified ITT population, subjects will continue to be enrolled in the study until there are a total of
approximately 52 subjects in the mITT population. The vast majority of subjects will be from 
outside of Japan; however, a sufficient number of Japanese patients are to be enrolled in order to 
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18.7  Interim Analysis
The primary efficacy end point is at 24 weeks. Therefore an interim analysis is planned after all
randomized subjects who have not dropped out of the study have completed their 24 weeks visit to 
facilitate strategic discussion with regulatory agencies for future plans of the program. 
18.8  Deviations from the Protocol Analysis Plan
Any deviations from the original planned analysis as described in the protocol will be detailed in 
the clinical study report.
19.0 ADMINISTRATION OF THE STUDY
19.1  Regulatory Considerations
This study will be conducted in compliance with the protocol, ICH Good Clinical Practice
Guidelines (GCPs), and the applicable local regulatory requirements. This study will be conducted
in accordance with the ethical principles that originate in the Declaration of Helsinki and ICH
Guidelines for Good Clinical Practices (GCPs). 
Study protocols and Informed Consent Forms will be approved by the appropriate Ethics
Committee or Institutional Review Board (and governmental authorities, as needed) prior to 
initiation of the study at a particular site.  All patients will sign an Informed Consent Form prior 
to any study-specific procedures.  Performance during the study will be routinely monitored by a 
study monitor selected by the Sponsor. 
19.2  Independent Ethics Committee (EC)/Institutional Review Board 
(IRB)/Institutional Biosafety Committee (IBC)
The Investigator must submit the final protocol and proposed informed consent document to an
Independent Ethics Committee (EC) or Institutional Review Board (IRB) and Institutional 
Biosafety Committee (IBC), where applicable, that complies with the ICH Guideline for Good 
Clinical Practice. The EC/IRB/IBC will provide the Investigator with a written decision regarding 
the conduct of the study at that site and a copy of the document will be forwarded to the Project 
Manager. The study will not be initiated and patients will not be enrolled until the appropriate
documentation of EC/IRB/IBC approval of the study protocol and the informed consent has been 
received. 
Substantive modifications to the protocol will be submitted to the EC/IRB/IBC for approval. 
These modifications may be implemented only after EC/IRB/IBC written approval has been 
received and forwarded to the Project Manager.  Administrative changes to the protocol such as a 
change that has no effect on the conduct of the study or risk to the patient should be submitted to
the EC/IRB/IBC for review, but formal approval is not required. 
The Investigator must also submit any other written information that will be given to the study
patients as well as any advertisements for patient recruitment, if used, to the EC/IRB/IBC for 
approval prior to implementing these documents. 
The Investigator will make appropriate and timely reports to the EC/IRB/IBC as required by 
applicable government regulations and EC/IRB/IBC policy. In addition to progress reports, all
known information regarding serious adverse events, whether observed at their clinical site or at 
another site participating in a clinical investigation with the Study Product, will be reported to the 
EC/IRB/IBC.  It is the Sponsor and/or its designee’s responsibility to inform the Investigator of 
serious adverse events observed at other investigational sites.

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It is the Investigator's obligation to provide the Sponsor and/or its designees with copies of all 
study-related correspondence with the EC/IRB/IBC in a timely fashion and to retain originals in a
file. This EC/IRB/IBC correspondence file will be made available as requested to appropriate
designees for monitoring or quality assurance review and to governmental regulatory 
representatives during site audits. 
19.3  Patient Information and Informed Consent
Written informed consent must be obtained from each patient after the nature of the study has been 
fully explained in accordance with the ICH Guideline for Good Clinical Practice.  Informed 
consent must be obtained prior to performing any study-specific procedures.  The consent form
that is used must be approved by both the reviewing EC/IRB and by the Sponsor. 
The patient and the individual explaining the study will sign the current EC/IRB- approved version 
of the consent form.  A copy of the signed consent form will be given to the patient.  The date
that consent was obtained will be recorded on the case report form as well as in the patient's chart.
A copy of the EC/IRB-approved version of the consent form will be provided to the Sponsor.
Original signed consent form must be maintained at the site and be made available for inspection, 
as appropriate.
19.4  Adherence to the Protocol
The study shall be conducted as described in this protocol except for an emergency situation in 
which proper care of the patient requires immediate alternative intervention.  This protocol refers
to the protocol as provided by the Sponsor and approved by both the IRB and the FDA. All of 
these versions of the protocol must be the same. While FDA regulations permit the protocol to be 
amended, this must be done in accordance with the provisions agreed upon on Section 19.5.  Any
deviation from the design of the study as set forth in this document must be recorded as a protocol 
deviation and be explained in detail as it occurs and/or is detected. 
19.5  Protocol Modifications
Neither the Investigators nor the Sponsor will modify this protocol without obtaining the 
concurrence of the other.  All protocol amendments will be issued by the Sponsor, and must be
signed and dated by the Investigator prior to implementation of the amendment. The Sponsor will 
submit protocol modifications to Regulatory Agencies as required. The Investigator is responsible 
for notifying the EC/IRB/IBC of changes.  Substantive changes will require EC/IRB/IBC approval, 
such as changes in experimental procedures that affect patient safety, changes in dosage or study 
treatment, changes in assessment parameters, or changes in patient eligibility criteria.
The
EC/IRB/IBC may require the Informed Consent Form to be altered in the event of protocol changes 
or new safety information. 
In situations requiring a departure from the protocol, the Investigator or other physician in 
attendance will contact the Sponsor or designee by fax or telephone.  If possible, this contact will
occur before implementing any departure from protocol.  In all cases, contact with the Sponsor or 
designee must be made as soon as possible in order to discuss the situation and agree on an
appropriate course of action.  The CRF and source document must describe any departure from 
the protocol and the circumstances.
19.6 Data Collection
Patient screening/enrollment will be documented in a study-specific log at the study site. This log
may capture the following information: patient number, initials, date of screen/enrollment, reason
for not enrolling (if applicable), and any comments.
The results from Screening and data collected during the study (except clinical laboratory test 

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results) will be recorded in the subject’s electronic CRF. The study sites will use an EDC system 
that is compliant with relevant FDA regulatory requirements per 21 CFR Part 11. Password
protected access to the EDC system will be via a secure website. Data queries and data corrections 
will be handled through the same system. All transactions within the EDC system are fully
documented within an electronic audit trail. Each set of completed CRFs must be reviewed and
electronically signed and dated by the Investigator. 
In compliance with remote data retention requirements, the study sites will be provided with a CD-
ROM containing the CRFs and the complete audit trail in portable document format (PDF),
subsequent to database lock. 
Upon further data processing, queries may be generated and sent to the Investigator for 
clarification or correction.  The Investigator will address any queries and forward resolutions as
directed by the site monitor. 
19.7  Maintaining Records
A study binder must be maintained at the investigative site for study documents, including a signed 
Investigator Agreement.  The Sponsor, or its designee, will provide a Study Binder to the site. 
According to U.S. Federal Regulations (21 CFR 312), all records related to this clinical trial must
be retained by the Investigator for at least 15 years after the last approval of a marketing application 
and until there are no pending or contemplated marketing applications or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational product or 
for the length of time required by the relevant national or local health authorities.  No records may 
be disposed without the written approval of the Sponsor. Written notification should be provided 
to the Sponsor prior to transferring any records to another party or moving them to another location. 
The study site must make available any records for inspection by applicable health authorities.
Study records that must be retained include, but are not necessarily limited to: patient charts, case 
report forms, product disposition records, essential documents, and study reports.
The samples will be stored for at least 15 years to allow for post marketing analysis.
19.8  Monitoring, Auditing, Inspecting
The Sponsor or designee (e.g., clinical research organization [CRO]) will assure the accuracy of 
data, the selection of qualified Investigators, appropriate study centers and review protocol 
procedures with the Investigators and associated personnel prior to the study and during periodic 
monitoring visits. The Sponsor or a designee will review CRFs for accuracy and completeness 
during on-site monitoring visits and via access to the secure website.  Discrepancies will be
resolved with the Investigator as appropriate. 
The Sponsor or its designees will monitor the study using the following methods: 
•
telephone contacts
•
periodic site visits
•
review of original patient records, case report forms, drug accountability and storage, and 
general study documentation
So that the study may be adequately monitored, the Investigator will cooperate in providing the 
Sponsor’s designees with all study documents (e.g., patient charts and study files) and responding 
to inquiries that may arise as a result of the document review.
Review of these documents will usually occur during a routine monitoring visit, but may also be 
required during a visit by a quality assurance auditor. The Investigator will also provide access to 

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these records to regulatory representatives if and when requested.  The Sponsor reserves the right 
to terminate the study site if access to source documentation of work performed in this study is 
denied to the Sponsor or regulatory representatives.
19.9 Confidentiality
The anonymity of patients participating in this study must be maintained.
Patients will be 
identified by their assigned patient number and their initials in all written communications between
the Investigator and Sponsor.  Documents that are not submitted to the Sponsor and that identify
the patient (e.g., signed informed consent; source documents/charts) will be made available to the 
Sponsor or regulatory authorities for inspections, but will be maintained in confidence.
All study related information provided by the Sponsor to the Investigator and not previously
published, including but not limited to the active study agent identity, the investigator's brochure, 
the study protocol, verbal and written communication, case report forms, assay methods and 
scientific data, will be considered confidential.  In addition, all information developed during the 
conduct of the clinical investigation of the study agent is also considered confidential. Neither the 
Investigator nor any of his/her employees or agents shall disclose or use this information for any
purpose other than the performance of the clinical study.  Such information shall remain the 
confidential and proprietary property of the Sponsor, and disclosure to others will be limited to 
other physicians who are conducting studies with the same active study agent, the Ethics
Committee/IRB/IBC and the applicable regulatory authorities except by prior written permission of 
the Sponsor or its agents.  At such time that information becomes widely and publicly available 
through no fault of the Investigator, the obligation of nondisclosure toward that particular 
information will cease. 
19.10 Publication Policy
Publication of the results of this study may be appropriate.  At least 30 days prior to expected
submission to the intended publisher or meeting committee, the Investigator must submit a copy of
the desired presentation (oral or written) or publication manuscript to the Sponsor. This review
period may be shortened upon mutual consent where circumstances require expeditious review.
The Sponsor reserves the right to suggest modification of any publication, presentation or use by
the Investigator if such activity may jeopardize a patent application, an existing patent, or other
proprietary rights. Individual investigators will not publish details of specific subjects separately
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20.0 APPENDIX A: JUSTIFICATION FOR STUDY ENDPOINTS
To overcome the perceived limitations of composite scales or global measures of disability, several
narrow domain outcome measures have been devised, validated and applied to the assessment of
clinical recovery following neurological injury. While many of these measures have been applied 
to patients recovering from stroke they are also used in the context of traumatic brain injury (TBI).1-
4 These narrow domain outcome measures fall along a continuum of measurement moving from 
measurements at the level of body function or structure to those focused on participation and life 
satisfaction. Consistent with the WHO ICF conceptual framework, we propose using narrow 
domain outcome measures that address the three primary levels of human functioning – the body
or body part, the whole person and the whole person in relation to his/her social context.5  Given
that the focus of SB623 is to treat chronic TBI patients with persistent deficits in the motor domain 
of neurological function, the outcome measures we propose to use in our Phase 2 study include 
the following in addition to the global functional Disability Rating Scale which has been used 
extensively in the assessment of recovery from TBI6-10: 
•
Impairment (or Body Function/ Structure): Fugl-Meyer Motor Scale (Primary Endpoint) 
•
Disability (or Activity): 
o
Upper Extremity Motor – Action Research Arm Test (Secondary Endpoint) 
o
Lower Extremity Motor – Gait Velocity (Secondary Endpoint)
•
Handicap (Participation/ Life Satisfaction): NeuroQOL Domains (Secondary Endpoints) - 
o
Upper Extremity Function
o
Lower Extremity Function
20.1  Justification for use of the Fugl-Meyer Motor Scale as primary endpoint
The Fugl-Meyer (F-M) scale was developed specifically because prior scales focused on Activities
of Daily Living (ADLs) and measures of global function and not on specific improvements in the 
neuromuscular function of the affected limb. The need that gave rise to the F-M scale was for a
specific and quantitative method for measuring recovery from hemiplegia.11 The F-M scale is now 
one of the most widely recognized and clinically relevant measures of body function impairment.12
The motor component of the F-M scale in particular has well-established reliability and validity
across different recovery time points.11, 13
The F-M scale assesses several dimensions of impairment, including range of motion, pain, 
sensation, upper extremity, lower extremity, and balance.14 The items of the F-M are mainly scored
on a 3-point Likert-type ordinal scale, from 0 to 2 applied to each item, and the items are summed 
to provide a maximum score of 226. The motor domain includes items measuring movement, 
coordination, and reflex action about the upper extremity joints (shoulder, elbow, forearm, wrist,
hand) and lower extremity joints (hip, knee, and ankle). The motor score ranges from 0 
(hemiplegia) to a maximum of 100 points (normal motor performance).11 The F-M motor 
component consists of the 33-item upper-extremity subscale (UE- FM) and the 17-item lower-
extremity subscale (LE-FM).14 The UE-FM ranges from 0 to 6615 and the LE-FM from 0-34. The 
use of these subscales can be used alone to lessen the patient burden of the full questionnaire. 

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The F-M scale assesses several impairment dimensions and has been extensively used in studies 
with chronic motor deficit following neurological injury. In fact, in a systematic review of RCTs 
examining robot assisted therapy, 60% of the RCTs included in analysis used the F-M scale as the 
primary outcome parameter.16 More recent RCTs investigating the use of patients continue to use 
the F-M motor scale as the primary outcome measure.17-20 Other studies include constraint induced
therapy trials21, 22, brain-machine interface23, transcutaneous electrical nerve stimulation (primary
outcome measure)24, 25 and mirror therapy (primary outcome measure in this 33 patient RCT).26
20.2  Justification for the use of the Disability Rating Scale (DRS)
The DRS has been commonly used to track recovery of an individual from coma to community
and to measure general functional changes over the course of recovery for individuals with 
moderate to severe TBI.27 It is a sensitive, functional, reliable, and quantitative means of monitoring 
patients with traumatic head injury during the course of their recovery.6 It is an observer rated, 30 
point continuous scale that evaluates eight areas of functioning in four categories:
(1) Consciousness (eye opening, verbal response, motor response)
(2) Cognitive ability (feeding, toileting, grooming) 
(3) Dependence on others 
(4) Employability 
Each area of functioning is rated on a scale of 0 to either 3 or 5. The maximum score is 29 (extreme 
vegetative state) and the minimum score is 0 (person without disability). 
Ceiling effects at discharge and at 1 year post injury are lower for the DRS than the Functional
Independence Measure (FIM).7, 27  DRS is also more sensitive to changes during a shorter time 
period than FIM and seems to be more appropriate for detecting long-term deficits.10 However, it 
has also been noted that this instrument which measures global function may not be ideal at
detecting meaningful changes year to year after TBI in contrast to narrow domain measures of 
disability.10
20.3 Rationale for Narrow Domain Outcome Measures in Chronic TBI Patients with
Motor Deficit
The neurological deficit associated with TBI depends on the location, extent and pattern of 
resolution of the injury. Deficits can involve different neurological domains such as: motor, 
sensory, cognitive, attention, language, visual, coordination and gait. These domain specific deficits 
can occur alone or in combination. 
Several narrow domain outcome measures have been devised, validated and applied to the 
assessment of clinical recovery following neurological injury. These narrow domain outcome
measures fall along a continuum of measurement moving from measurements at the level of body
function or structure to those focused on participation and life satisfaction.5
Justification for the specific choice of the Action Research Arm Test (ARAT) and Gait Velocity as 
narrow domain outcome measures that assess changes in the level of disability in the upper and
lower extremity respectively of chronic TBI patients with motor deficits is provided below.

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20.3.1  Justification for use of the Action Research Arm Test (ARAT) as a secondary endpoint
The ARAT is an observer-rated, performance-based assessment of upper extremity function and 
dexterity among individuals who sustained cortical damage resulting in hemiplegia.3, 28, 29 It has
been used extensively to measure changes in upper extremity disability following a variety of 
therapeutic interventions (e.g. mirror therapy, somatosensory stimulation, robot training,
transcranial magnetic stimulation and constraint induced therapy).30-35 This outcome measure
specifically assesses a subject’s ability to handle objects differing in size, weight and shape and 
therefore can be considered to be an arm-specific measure of activity limitation.36 The ARAT 
consists of 19 items grouped into four hierarchical subscales: grasp, grip, pinch, and gross 
movement.37 Summation of a 0-3 score in each item yields a total score between 0 and 57. 
20.3.2  Justification for use of Gait Velocity as a secondary endpoint
Gait is commonly affected in TBI1, 2, 4, 38 and Gait Velocity is a useful outcome measure of lower 
extremity function as walking speed predicts the level of disability39, 40 as improvements are
correlated with better quality of life.41 Furthermore, Gait Velocity measures are objective and have 
well defined thresholds. 
20.3.3  Justification for use of NeuroQOL as a secondary endpoint
Justification for choosing two specific NeuroQOL Domains as narrow domain outcome measures
that assess changes in the level of Quality of Life, Satisfaction and Participation secondary to 
improvements in upper and lower extremity motor function are provided below.
To address existing limitations of Quality of Life (QOL) scales in neurology such as questionable 
validity, poor interpretability and disease specific applicability, the National Institute of 
Neurological Disorders and Stroke devised the NeuroQOL.  NeuroQOL is a set of self-report
measures that assesses the health-related quality of life (HRQOL) of adults and children with 
neurological disorders.42 As outlined in the NeuroQOL User Manual, NeuroQOL is comprised of 
item banks and scales that evaluate symptoms, concerns, and issues that have been validated for a
variety of neurological diseases. The domains included in NeuroQOL were identified through 
several sources, including an extensive literature review, an on-line Request for Information (RFI), 
two phases of in-depth expert interviews (n=44 and n=89, respectively), patient and caregiver focus 
groups (N = 11 groups) and individual interviews with patients and proxies (N = 63). On the basis
of this input, 17 Health-Related QOL domains and sub-domains were chosen for adults. Items
were selected for inclusion in each domain through a multi-step, iterative process whereby
candidate items were reviewed to ensure relevance, translatability, clarity and comprehensive 
content coverage. The resultant sets of items (item pools) underwent calibration using Item
Response Theory (IRT) analyses to form the final item banks and scales. The scales and short
forms (8-10 items) from each bank were subsequently validated in adult and pediatric clinical
samples.43 In short, the validity of the NeuroQOL measures for adults with neurological
impairment is supported with satisfactory internal consistency, test-retest reliability and significant 
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20.3.3.1 Justification for choice of NeuroQOL Domains
Neuro-QOL instruments were developed to be appropriate for a range of neurological conditions. 
They are not disease-specific measures. Consequently, researchers will need to consider what 
domains of self-reported health are worth assessing within a given disease and within a given study
methodology.42 Given this study’s focus on improvements in motor function the following QOL
Domains were chosen: 
•
The Upper Extremity Domain of NeuroQOL measures one's ability to carry out various 
activities involving digital, manual and reach-related functions, ranging from fine motor to 
self-care (activities of daily living). 
•
The Lower Extremity Domain of NeuroQOL measures one's ability to carry out various 
activities involving the trunk region and increasing degrees of bodily movement, ambulation, 
balance or endurance.
20.4  References
1.
Esquenazi A, Lee S, Packel AT, Braitman L. A randomized comparative study of 
manually assisted versus robotic-assisted body weight supported treadmill training in 
persons with a traumatic brain injury. PM & R : the journal of injury, function, and 
rehabilitation. 2013;5:280-290 
2.
Hirsch MA, Williams K, Norton HJ, Hammond F. Reliability of the timed 10-metre walk 
test during inpatient rehabilitation in ambulatory adults with traumatic brain injury. Brain 
injury. 2014;28:1115-1120 
3.
Huijgen BC, Vollenbroek-Hutten MM, Zampolini M, Opisso E, Bernabeu M, Van 
Nieuwenhoven J, et al. Feasibility of a home-based telerehabilitation system compared to 
usual care: Arm/hand function in patients with stroke, traumatic brain injury and multiple 
sclerosis. Journal of telemedicine and telecare. 2008;14:249-256 
4. 
Williams G, Banky M, Olver J. Distribution of lower limb spasticity does not influence
mobility outcome following traumatic brain injury: An observational study. The Journal
of head trauma rehabilitation. 2014 
5. 
Salter K, Campbell N, Richardson M, Mehta S, Jutai J, Moses M, et al. Outcome 
measures in stroke rehabilitation. Evidence-Based Review of Stroke Rehabilitation. 
2013;2014 
6. 
Hall K, Cope DN, Rappaport M. Glasgow outcome scale and disability rating scale:
Comparative usefulness in following recovery in traumatic head injury. Archives of
physical medicine and rehabilitation. 1985;66:35-37 
7. 
Hall KM, Bushnik T, Lakisic-Kazazic B, Wright J, Cantagallo A. Assessing traumatic 
brain injury outcome measures for long-term follow-up of community-based individuals. 
Archives of physical medicine and rehabilitation. 2001;82:367-374 
8. 
Rappaport M, Hall KM, Hopkins K, Belleza T, Cope DN. Disability rating scale for 
severe head trauma: Coma to community. Archives of physical medicine and 
rehabilitation. 1982;63:118-123 

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9. 
Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, et al.
Protect: A randomized clinical trial of progesterone for acute traumatic brain injury. 
Annals of emergency medicine. 2007;49:391-402, 402.e391-392 
10. 
Hammond FM, Grattan KD, Sasser H, Corrigan JD, Bushnik T, Zafonte RD. Long-term
recovery course after traumatic brain injury: A comparison of the functional
independence measure and disability rating scale. The Journal of head trauma 
rehabilitation. 2001;16:318-329 
11.
Gladstone DJ, Danells CJ, Black SE. The fugl-meyer assessment of motor recovery after 
stroke: A critical review of its measurement properties. Neurorehabilitation and Neural
Repair. 2002;16:232-240 
12. 
Sullivan KJ, Tilson JK, Cen SY, Rose DK, Hershberg J, Correa A, et al. Fugl-meyer
assessment of sensorimotor function after stroke: Standardized training procedure for 
clinical practice and clinical trials. Stroke; a journal of cerebral circulation. 2011;42:427- 
432
13.
Duncan PW, Propst M, Nelson SG. Reliability of the fugl-meyer assessment of 
sensorimotor recovery following cerebrovascular accident. Physical therapy. 
1983;63:1606-1610 
14. 
Fugl-Meyer AR, Jaasko L, Leyman I, Olsson S, Steglind S. The post-stroke hemiplegic 
patient. 1. A method for evaluation of physical performance. Scandinavian journal of 
rehabilitation medicine. 1975;7:13-31 
15. 
Lin JH, Hsu MJ, Sheu CF, Wu TS, Lin RT, Chen CH, et al. Psychometric comparisons of 
4 measures for assessing upper-extremity function in people with stroke. Physical
therapy. 2009;89:840-850 
16.
Kwakkel G, Kollen BJ, Krebs HI. Effects of robot-assisted therapy on upper limb 
recovery after stroke: A systematic review. Neurorehabil Neural Repair. 2008;22:111- 
121
17. 
Lo AC, Guarino P, Krebs HI, Volpe BT, Bever CT, Duncan PW, et al. Multicenter
randomized trial of robot-assisted rehabilitation for chronic stroke: Methods and entry
characteristics for va robotics. Neurorehabil Neural Repair. 2009;23:775-783 
18. 
Conroy SS, Whitall J, Dipietro L, Jones-Lush LM, Zhan M, Finley MA, et al. Effect of 
gravity on robot-assisted motor training after chronic stroke: A randomized trial. 
Archives of physical medicine and rehabilitation. 2011;92:1754-1761 
19. 
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measure differences in adipogenic differentiation in preparations of human mesenchymal
stromal cells. Cytotherapy. 2013;15:1527-1540 
20. 
Wu CY, Yang CL, Chuang LL, Lin KC, Chen HC, Chen MD, et al. Effect of therapist- 
based versus robot-assisted bilateral arm training on motor control, functional
performance, and quality of life after chronic stroke: A clinical trial. Physical therapy. 
2012;92:1006-1016 
21. 
Page SJ, Sisto SA, Levine P. Modified constraint-induced therapy in chronic stroke. 
American journal of physical medicine & rehabilitation / Association of Academic
Physiatrists. 2002;81:870-875 
22. 
Page SJ, Sisto SA, Levine P, Johnston MV, Hughes M. Modified constraint induced
therapy: A randomized feasibility and efficacy study. Journal of rehabilitation research 
and development. 2001;38:583-590 

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Ramos-Murguialday A, Broetz D, Rea M, Laer L, Yilmaz O, Brasil FL, et al. Brain- 
machine interface in chronic stroke rehabilitation: A controlled study. Annals of 
neurology. 2013;74:100-108 
24. 
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facilitates motor recovery in chronic stroke patients. Neurology. 2010;75:2176-2184 
25.
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nerve stimulation promotes upper limb functions in patients with chronic stroke. The 
Tohoku journal of experimental medicine. 2013;231:93-100 
26. 
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and sensory recovery in chronic stroke: A randomized controlled trial. Archives of 
physical medicine and rehabilitation. 2013;94:1023-1030 
27. 
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28. 
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recherches de readaptation. 1981;4:483-492 
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stroke inpatients receiving rehabilitation. Clinical rehabilitation. 2002;16:617-624 
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trascranial magnetic stimulation on repetitive facilitation exercises of the hemiplegic
hand in chronic stroke patients. Journal of rehabilitation medicine. 2013;45:843-847 
31. 
Fleming MK, Sorinola IO, Roberts-Lewis SF, Wolfe CD, Wellwood I, Newham DJ. The 
effect of combined somatosensory stimulation and task-specific training on upper limb 
function in chronic stroke: A double-blind randomized controlled trial. Neurorehabil 
Neural Repair. 2014 
32.
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after constraint-induced movement therapy: Recovery of normal motor control or task- 
specific compensation? Neurorehabil Neural Repair. 2013;27:99-109 
33. 
Lin KC, Chen YT, Huang PC, Wu CY, Huang WL, Yang HW, et al. Effect of mirror 
therapy combined with somatosensory stimulation on motor recovery and daily function 
in stroke patients: A pilot study. Journal of the Formosan Medical Association = Taiwan 
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34.
Timmermans AA, Lemmens RJ, Monfrance M, Geers RP, Bakx W, Smeets RJ, et al.
Effects of task-oriented robot training on arm function, activity, and quality of life in 
chronic stroke patients: A randomized controlled trial. Journal of neuroengineering and 
rehabilitation. 2014;11:45 
35. 
Page SJ, Levine P, Leonard A, Szaflarski JP, Kissela BM. Modified constraint-induced
therapy in chronic stroke: Results of a single-blinded randomized controlled trial. 
Physical therapy. 2008;88:333-340 
36. 
Platz T, Pinkowski C, van Wijck F, Kim IH, di Bella P, Johnson G. Reliability and 
validity of arm function assessment with standardized guidelines for the fugl-meyer test, 
action research arm test and box and block test: A multicentre study. Clinical
rehabilitation. 2005;19:404-411 
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38. 
Walker WC, Pickett TC. Motor impairment after severe traumatic brain injury: A
longitudinal multicenter study. Journal of rehabilitation research and development. 
2007;44:975-982 
39.
Duncan PW, Sullivan KJ, Behrman AL, Azen SP, Wu SS, Nadeau SE, et al. Body- 
weight-supported treadmill rehabilitation after stroke. The New England journal of 
medicine. 2011;364:2026-2036 
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Duncan PW, Sullivan KJ, Behrman AL, Azen SP, Wu SS, Nadeau SE, et al. Protocol for 
the locomotor experience applied post-stroke (leaps) trial: A randomized controlled trial. 
BMC neurology. 2007;7:39 
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post-stroke) and bounds. Stroke; a journal of cerebral circulation. 2011;42:3659-3660 
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(NINDS). NIoNDaS. User manual for the quality of life in neurological disorders (neuro- 
qol) measures. 2010 
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measures of health-related quality of life for clinical research in neurology. Neurology. 
2012;78:1860-1867 

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Protocol TBI-01 Version 5, May 17, 2018
21.0 APPENDIX B: WHO STANDARD TOXICITY CRITERIA
The WHO Standard Toxicity Criteria is tabulated below in Table 5. 
Copies of this document will also be provided to each site as part of the study documents. 
For abnormalities not found elsewhere in the WHO table, use the following scale to assign grade
or severity: 
Grade 1
Mild
Transient of mild discomfort; no limitation in
activity; no medical intervention/therapy required. 
Grade 2
Moderate
Mild-to-moderate limitation in activity; some
assistance may be need.  No or minimal medial
intervention/therapy required.
Grade 3
Severe
Marked limitation in activity, some assistance 
usually required; medical intervention/therapy
required; hospitalization or prolongation of current
hospitalization possible. 
Grade 4
Life-threatening
Extreme limitation in activity, significant assistance
required; significant medial intervention/therapy 
required; hospitalization or prolongation of current 
hospitalization or hospice care probable.

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Table 5 
WHO (World Health Organization) Toxicity Criteria by Grade
Category
Toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Haematology
WBC (x103/l)
4
3.0 - 3.9
2.0 - 2.9
1.0 - 1.9
< 1.0
Haematology
Platelets (x103/l)
WNL
75.0 - normal
50.0 - 74.9
25.0 - 49.9
< 25.0
Haematology 
Haemoglobin
(g/dl)
WNL 
10.0 - normal 
8.0 - 9.9 
6.5 - 7.9 
< 6.5 
Haematology 
Granulocytes/ 
Bands (x103/l)
2
1.5 - 1.9 
1.0 - 1.4 
0.5 - 0.9 
< 0.5 
Haematology 
Lymphocytes
(x103/l)
2
1.5 - 1.9 
1.0 - 1.4 
0.5 - 0.9 
< 0.5 
Haematology 
Haemorrhage 
none
mild, no
gross, 1 - 2 units 
transfusion per
episode 
gross, 3 - 4 units 
transfusion per
episode 
massive, > 4 units 
transfusion per episode 
Coagulation
Fibrinogen
WNL
0.99 - 0.75 x N
0.74 - 0.50 x N
0.49 - 0.25 x N
< 0.25 x N
Coagulation
Prothrombin 
time(Quick) 
WNL 
1.01 - 1.25 x N 
1.26 - 1.50 x N 
1.51 - 2.00 x N 
> 2.00 x N 
Coagulation
Partial
thromboplastin 
time
WNL 
1.01 - 1.66 x N 
1.67 - 2.33 x N 
2.34 - 3.00 x N 
> 3.00 x N 
Metabolic 
Hyperglycaemia
(mg/dl)
< 116 
116 - 160 
161 - 250 
251 - 500 
> 500 or ketoacidosis 
Metabolic 
Hypoglycaemia
(mg/dl)
> 64 
55 - 64 
40 - 54 
30 - 39 
< 30 
Metabolic
Amylase
WNL
< 1.5 x N
1.5 - 2.0 x N
2.1 - 5.0 N
> 5.0 x N
Metabolic 
Hypercalcaemia
(mg/dl)
< 10.6 
10.6 - 11.5 
11.6 - 12.5 
12.6 - 13.4 
13.5
Metabolic 
Hypocalcaemia
(mg/dl)
> 8.4 
8.4 - 7.8 
7.7 - 7.0 
6.9 - 6.1 
6

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Category
Toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Metabolic 
Hypomagnesaemia
(mg/dl)
> 1.4 
1.4 - 1.2 
1.1 - 0.9 
0.8 - 0.6 
0.5
Gastrointestinal Nausea
none
able to eat 
reasonable intake 
intake significantly
decreased but can eat
no significant 
intake 
Gastrointestinal Vomiting
none
1 episode in 24 hrs 2 - 5 episodes in 24 
hrs
6 - 10 episodes in
24 hrs 
> 10 episodes in 24 hrs
or requiring parenteral
support 
Gastrointestinal Diarrhoea 
none
increase of 2 - 3
stools / day over
pre-Rx
increase of 4 - 6
stools / day, or 
nocturnal stools, or 
moderate cramping 
increase of 7 - 9
stools / day, or 
incontinence, or 
severe cramping 
increase of > 10 stools / 
day or grossly bloody
diarrhoea, or need for 
parenteral support 
Gastrointestinal Stomatitis
none
painless ulcers, 
erythema, or mild 
soreness
painful erythema, 
oedema, or ulcers but 
can eat solids
painful erythema,
oedema, or ulcers
and cannot eat
solids 
requires parenteral or 
enteral support for
alimentation
Liver 
Bilirubin (N = 17
µmol/L) 
WNL 
----- 
< 1.5 x N 
1.5 - 3.0 x N 
> 3.0 x N 
Liver 
Transaminase
(SGOT, SGPT)
WNL 
2.5 x N 
2.6 - 5.0 x N 
5.1 - 20.0 x N 
> 20.0 x N 
Liver 
Alk Phos or 5
nucleotidase
WNL 
< 2.5 x N 
2.6 - 5.0 x N 
5.1 - 20.0 x N 
> 20.0 x N 
Liver 
Liver- clinical 
No change
from baseline ----- 
----- 
precoma 
hepatic coma 
Kidney, bladder Creatinine
WNL
< 1.5 x N
1.5 - 3.0 x N
3.1 - 6.0 x N
> 6.0 x N
Kidney, bladder Proteinuria
No change 
1 (+) or < 0.3 g% or
3 g/L 
2 - 3 (+) or 0.3 - 1.0
g% or 3 - 10 g/L
4 (+) or > 1.0 g%
or > 10g/L 
nephrotic syndrome 
Kidney, bladder Haematuria
Negative
microscopic only 
gross, no clots no Rx
needed
gross and clots 
bladder irrigation
requires transfusion or 
cystectomy 
Kidney, bladder Weight gain/ loss
< 5.0 %
5.0 - 9.9 %
10.0 - 19.9 %
20.00%
-----
I 

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Category
Toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Pulmonary 
Pulmonary 
none or no 
change 
asymptomatic, with 
abnormality in
PFTs
dyspnoea on 
significant exertion
dyspnoea at
normal level of 
activity 
dyspnoea at rest
Cardiac
Cardiac
arrhythmias 
none
asymptomatic, 
transient, requiring
no therapy 
recurrent or 
persistent, no therapy
required
requires treatment
requires monitoring; or 
hypotension, or 
ventricular tachycardia 
or fibrillation
Cardiac
Cardiac function
none
asymptomatic,
decline of resting 
ejection fraction by
less than 20 % of 
baseline value 
asymptomatic,
decline of resting 
ejection fraction by
more than 20 % of 
baseline value 
mild CHF, 
responsive to 
therapy 
severe of refractory 
CHF
Cardiac
Cardiac ischaemia none
non-specific T- 
wave flattening 
asymptomatic, ST
and T wave changes 
suggesting ischaemia
angina without 
evidence of
infraction
acute myocardial 
infarction
Cardiac
Cardiac- 
pericardial
none
asymptomatic 
effusion, no 
intervention 
required
pericarditis (rub, 
chest pain, ECG
changes)
symptomatic 
effusion; drainage 
required
tamponade; drainage 
urgently required
Cardiac
Hypertension 
none or no 
change 
asymptomatic,
transient increase 
by greater than 20 
mm Hg (D) or to > 
150 / 100 if 
previously WNL. 
No treatment 
required.
recurrent or 
persistent increase by
greater than 20 mm 
HG (D) or to > 150 / 
100 if previously 
WNL. No treatment 
required.
requires therapy hypertensive crisis

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Category
Toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac
Hypotension 
none or no 
change 
changes requiring
no therapy
(including transient 
orthostatic hypo- 
tension) 
requires fluid 
replacement or other 
therapy but not 
hospitalisation
requires therapy
and 
hospitalisation; 
resolves within
48 hours of 
stopping the 
agent 
requires therapy and
hospitalisation for > 48 
hrs after stopping the 
agent 
Neurologic
Neuro: sensory 
none or no 
change 
mild paraesthesias; 
loss of deep tendon 
reflexes
mild or moderate 
objective sensory
loss moderate 
paraesthesias
severe objective 
sensory loss or 
paraesthesias that 
interfere with 
function
----- 
Neurologic
Neuro: motor 
none or no 
change 
subjective 
weakness; no 
objective findings 
mild objective 
weakness without 
significant 
impairment of 
function
objective 
weakness with 
impairment of 
function
paralysis
Neurologic
Neuro: cortical 
none
mild somnolence or 
agitation
moderate 
somnolence or 
agitation
severe
somnolence, (>50
% waking hours),
agitation, 
confusion, 
disorientation or 
hallucinations 
coma, seizures, toxic 
psychosis 
Neurologic
Neuro: cerebellar
none
slight 
incoordination, 
dysdiadochokinesia
intention tremor,
dysmetria, slurred
speech, nystagmus 
locomotor ataxia cerebellar necrosis
Neurologic
Neuro: mood 
no change 
mild anxiety or 
depression
moderate anxiety or
depression
severe anxiety or 
depression
suicidal ideation

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Category
Toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Neurologic
Neuro: headache 
none
mild
moderate or severe
but transient 
unrelenting and
severe 
----- 
Neurologic
Neuro:
constipation
none or no
change 
mild
moderate
severe 
ileus > 96 hrs 
Neurologic
Neuro: hearing 
none or no 
change 
asymptomatic, 
hearing loss on 
audiometry only 
tinnitus
hearing loss 
interfering with 
function but 
correctable with 
hearing aid
deafness not correctable
Neurologic
Neuro: vision 
none or no 
change 
----- 
----- 
symptomatic 
subtotal loss of 
vision 
blindness
Pain
Pain
none
mild
moderate
severe
reg. narcotics
Skin 
Skin 
none or no 
change 
scattered macular 
or papular eruption 
or erythema that is 
asymptomatic
scattered macular or
papular eruption or 
erythema with 
pruritus or other
associated symptoms
generalised 
symptomatic 
macular, papular 
or vesicular 
eruption 
exfoliative dermatitis or 
ulcerating dermatitis
Alopecia
Alopecia
no loss
mild hair loss 
pronounced or total
hair loss 
----- 
----- 
Allergy 
Allergy 
none
transient rash, drug
fever < 38o C
(100.4o F) 
urticaria, drug fever
38o C (100.4o F),
mild bronchospasm
serum sickness, 
bronchospasm 
requiring
parenteral 
medication
anaphylaxis
Local 
Local 
none
pain
pain and swelling 
with inflammation or 
phlebitis
ulceration
plastic surgery
indicated

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Category
Toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Fever of 
unknown origin
Fever of unknown 
origin
None
37.1° - 38.0° C 
98.7° - 100.4° F 
38.1° - 40.0o C  
100.5o - 104o F 
>40.0o C
(>104o F) for 
less than 24 hrs 
>40.0o C (>104o F) for 
more than 24 hrs or 
accompanied by
hypotension
Infection
Infection
None
mild
moderate
severe
life-threatening
Additional
events 
Asthenia 
Analogous to 
Karnofsky
index (WHO
grading)
Additional
events 
Chills
Analogous to 
fever
Additional
events 
Peripheral oedema analogous to 
weight gain
Additional
events 
Anorexia
analogous to 
weight loss 

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22.0 APPENDIX C: ANTICOAGULANT GUIDELINES
The use of antiplatelet, anticoagulant, or non-steroidal anti-inflammatory drugs during the conduct 
of this study will be in accordance with the American College of Chest Physicians 2012 guideline 
“Perioperative Management of Antithrombotic Therapy: Antithrombotic Therapy and Prevention 
of Thrombosis, 9th Edition: American College of Chest Physicians Evidence-Based Clinical 
Practice Guidelines”. In summary the following should apply: 
Prospective patients that are taking Warfarin regularly should stop taking Warfarin 5 days 
before surgery
INR will need to be repeated prior to surgery to confirm patient is off Warfarin (likely 
performed at the hospital where the surgery is being performed) 
All other antiplatelet drugs (including non-steroidal anti-inflammatory drugs) should be 
stopped 7 days prior to surgery 
Patients at high risk for Venous Thromboembolism (VTE) should be covered with prophylactic 
Low Molecular Weight Heparin (LMWH) (e.g., Lovenox).
Anticoagulants (including antiplatelet or non-steroidal anti-inflammatory drugs) should not be 
recommenced until Day 8 per the protocol unless the patient is at high risk for VTE in which 
use of LMWH only on postop Day 2 is acceptable.3
Other than patients at high risk of VTE, no antiplatelet, anticoagulant, or non-steroidal anti-
inflammatory drugs are to be restarted post-surgery until after the Day 8 MRI is read and are 
determined to be safe to re-start.
 
3 The decision to use bridging anticoagulation (e.g., LMWH) should only be made by the attending surgeon where it is 
believed that the risks of VTE outweigh the risk of postoperative bleeding complications.
• 
• 
• 
• 
• 
• 

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23.0 REFERENCES
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