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

SanBio 
SANBIOINCORPORATED 
CLINICAL PROTOCOL 
TITLE: A Double-Blind, Controlled Phase 2b Study of the Safety and Efficacy of Modified 
Stem Cells (SB623) in Patients with Chronic Motor Deficit from Ischemic Stroke 
PROTOCOL#: 
Version: 
5 
SPONSOR: 
SITE OF INVESTIGATION: 
PRINCIPAL MONITOR: 
UNBLINDED MEDICAL MONITOR: 
BLINDED MEDICAL MONITOR: 
SAFETY MONITOR: 
CLINICAL LABORATORY: 
SB-STR02 
Date: 05 January 2017 
SanBio, Incorporated 
231 S. Whisman Road 
Mountain View, CA 94041 USA 
Phone: + 1 650-625-8965 
Fax: + 1 650-625-8969 
Multi-Center 
Damien Bates, MD, PhD, FRACS (SanBio) 
Cindy Saacks, MD (INC Research) 
Alexander Shalaurov, MD (INC Research) 
Tim Smith, PharmD, BSN (ProPharma 
Group/PROSAR) 
Clinical laboratory testing will be performed 
centrally 
Principal Monitor 
Principal Investigator 
Damien Bates, MD, PhD, FRACS 
SanBio 
• 
Digitally signed by Damien 
Darnlen Bates Bates 
Date: 2017.01.0816:14:02 -08'00' 
Signature 
Date 
Investigator Name (Printed) 
Signature 
Date 
Investigator Statement 
I agree to abide by all the provisions set forth in the attached protocol. 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. 

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TABLE OF CONTENTS 
1.0 
PROTOCOL SYNOPSIS ................................................................................................... 6 
2.0 
BACKGROUND ............................................................................................................... 14 
2.1 
MEDICAL NEED ............................................................................................................................ 14 
2.2 
TREATMENT OF ISCHEMIC STROKE .............................................................................................. 14 
2.2.1 
Current Therapies ................................................................................................................. 14 
2.2.2 
Time Course for Stable Stroke .............................................................................................. 14 
2.2.3 
Experimental Cellular Therapies .......................................................................................... 14 
2.2.4 
Stereotactic Surgery .............................................................................................................. 15 
2.3 
PROPERTIES OF SB623 .................................................................................................................. 15 
2.3.1 
Summary of SB623 Cells Properties ..................................................................................... 15 
2.3.2 
Summary of Notch-1 Gene Properties .................................................................................. 16 
2.3.3 
Preclinical Pharmacology Studies ........................................................................................ 16 
3.0 
OVERALL EXPERIENCE WITH INVESTIGATIONAL PRODUCT ..................... 17 
3.1 
STUDY AGENT .............................................................................................................................. 17 
3.2 
PRECLINICAL PHARMACOLOGY .................................................................................................... 17 
3.2.1 
In Vitro .................................................................................................................................. 17 
3.3 
CLINICAL EXPERIENCE ................................................................................................................. 17 
3.4 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS .................................................... 19 
4.0 
DESCRIPTION AND JUSTIFICATION OF TREATMENT REGIMEN ................. 21 
4.1 
DOSAGES ...................................................................................................................................... 21 
4.2 
JUSTIFICATION .............................................................................................................................. 21 
5.0 
STUDY PARAMETERS AND OBJECTIVES .............................................................. 22 
5.1 
PARAMETERS ................................................................................................................................ 22 
5.1.1 
Primary Efficacy Endpoint: .................................................................................................. 22 
5.1.2 
Secondary Efficacy Endpoints: ............................................................................................. 22 
5.1.3 
Safety Endpoints .................................................................................................................... 22 
5.1.4 
Exploratory Endpoints .......................................................................................................... 22 
5.2 
OBJECTIVES .................................................................................................................................. 23 
5.2.1 
Primary Objective ................................................................................................................. 23 
5.2.2 
Secondary Objectives ............................................................................................................ 23 
6.0 
SURGICAL AND IMPLANTATION PROCEDURES ................................................ 24 
7.0 
PATIENT SELECTION .................................................................................................. 26 
7.1 
INCLUSION CRITERIA .................................................................................................................... 26 
7.2 
EXCLUSION CRITERIA ................................................................................................................... 26 
8.0 
INVESTIGATIONAL PLAN .......................................................................................... 28 
8.1 
OVERALL STUDY DESIGN ............................................................................................................. 28 
8.2 
DURATION OF PATIENT PARTICIPATION ....................................................................................... 29 
9.0 
STUDY ASSESSMENTS ................................................................................................. 30 
9.1 
SCHEDULE OF STUDY ACTIVITIES ................................................................................................ 30 
9.2 
PRE-STUDY EVALUATION AND BASELINE .................................................................................... 36 
9.2.1 
Visit 1: Screening, (Day -84 to -22; Assessment Site) ........................................................... 36 
9.3 
BASELINE AND CONFIRMATION OF ELIGIBILITY .......................................................................... 36 
9.3.1 
Visit 2: Baseline (Day -21 to -2; Assessment Site) ................................................................ 36 
9.3.2 
Eligibility Confirmation ........................................................................................................ 37 
9.4 
SURGICAL ADMISSION (VISIT 3A: DAY -1; SURGICAL SITE) ....................................................... 37 

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9.5 
RANDOMIZATION AND CELL ADMINISTRATION OR SHAM SURGERY (VISIT 3B: DAY 1; 
SURGICAL SITE) ....................................................................................................................................... 38 
9.6 
VISIT 4: FOLLOW-UP PERIOD (STUDY DAY 2; SURGICAL SITE) ................................................... 38 
9.7 
VISIT 5: FOLLOW-UP PERIOD (WEEK 1, STUDY DAY 8 ± 1; ASSESSMENT SITE).......................... 39 
9.8 
VISIT 6: FOLLOW-UP PERIOD (MONTH 1, STUDY DAY 28 ± 7; ASSESSMENT SITE) ..................... 39 
9.9 
VISIT 7: FOLLOW-UP PERIOD (MONTH 3, STUDY DAY 84 ± 7; ASSESSMENT SITE) ..................... 40 
9.10 
VISIT 8: FOLLOW-UP PERIOD (MONTH 6, STUDY DAY 168 ± 7; ASSESSMENT SITE) ............... 40 
9.11 
VISIT 9: FOLLOW-UP PERIOD (MONTH 9, STUDY DAY 252 ± 14; ASSESSMENT SITE) ............. 41 
9.12 
VISIT 10/EARLY TERMINATION: FOLLOW-UP PERIOD (MONTH 12, STUDY DAY 336 ± 14; 
ASSESSMENT SITE) .................................................................................................................................. 41 
10.0 
DESCRIPTION OF STUDY TREATMENT.............................................................. 43 
10.1 
STUDY PRODUCT DESCRIPTION ................................................................................................ 43 
10.2 
STUDY PRODUCT PACKAGING AND LABELING ......................................................................... 43 
10.3 
STUDY PRODUCT SHIPMENT AND STORAGE ............................................................................. 43 
10.4 
PREPARATION AND ADMINISTRATION ...................................................................................... 43 
10.5 
STUDY PRODUCT ACCOUNTABILITY PROCEDURES .................................................................. 44 
11.0 
TREATMENT ASSIGNMENT AND BLINDING ..................................................... 45 
11.1 
EMERGENCY UNBLINDING PROCEDURES ................................................................................. 46 
12.0 
CONCOMITANT MEDICATIONS ............................................................................ 47 
13.0 
STUDY WITHDRAWAL/TERMINATION .............................................................. 48 
13.1 
STUDY TERMINATION ............................................................................................................... 48 
13.2 
SITE TERMINATION ................................................................................................................... 48 
13.3 
PATIENT DISCONTINUATION ..................................................................................................... 48 
13.4 
PATIENTS LOST TO FOLLOW UP ................................................................................................ 48 
14.0 
STOPPING RULES ...................................................................................................... 49 
15.0 
CLINICAL AND LABORATORY EVALUATIONS AND PROCEDURES ......... 50 
15.1 
MEDICAL HISTORY (INCLUDING STROKE HISTORY) ................................................................ 50 
15.2 
PHYSICAL EXAMINATION AND VITAL SIGNS ............................................................................ 50 
15.3 
SAFETY LABORATORY .............................................................................................................. 50 
15.4 
PREGNANCY TEST: SERUM OR URINE β-HCG ........................................................................... 50 
15.5 
HLA TYPING AND APOE4 AND BDNF VAL66MET GENOTYPING ............................................ 50 
15.6 
SERUM ANTI-HLA ANTIBODIES ............................................................................................... 51 
15.7 
PBMC SAMPLES ....................................................................................................................... 51 
15.8 
OCCULT MALIGNANCY ............................................................................................................. 51 
15.9 
CESD-R .................................................................................................................................... 51 
15.10 
CLINICAL STROKE EVALUATIONS ............................................................................................ 51 
15.11 
PHYSIOTHERAPY ....................................................................................................................... 53 
15.12 
LEG ACTIVITY MONITORING .................................................................................................... 53 
15.13 
IMAGING (MRI), CHEST X-RAY, CT, AND ECG ....................................................................... 53 
16.0 
ADVERSE EVENTS ..................................................................................................... 55 
16.1 
GENERAL INFORMATION ........................................................................................................... 55 
16.2 
ADVERSE EVENT REPORTING PERIOD ...................................................................................... 56 
16.3 
RECORDING OF AES .................................................................................................................. 56 
16.4 
ASSESSING RELATIONSHIP OF AE TO STUDY PRODUCT ........................................................... 56 
16.5 
REPORTING SERIOUS ADVERSE EVENTS ................................................................................... 57 
16.6 
FOLLOW-UP OF ADVERSE EVENTS ............................................................................................ 57 
17.0 
EXTERNAL DATA SAFETY MONITORING BOARD .......................................... 58 

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18.0 
STATISTICAL METHODS ......................................................................................... 59 
18.1 
ANALYSIS POPULATIONS .......................................................................................................... 59 
18.1.1 
Efficacy Population ............................................................................................................... 59 
18.1.2 
Safety Population .................................................................................................................. 59 
18.2 
STATISTICAL ANALYSIS ............................................................................................................ 59 
18.2.1 
Analysis of Efficacy ............................................................................................................... 59 
18.2.1.1 Primary Efficacy Analysis .................................................................................. 59 
18.2.1.2 Secondary Efficacy Analyses .............................................................................. 59 
18.2.1.3 Exploratory Efficacy Analyses ........................................................................... 60 
18.2.1.4 Subgroup Analysis .............................................................................................. 61 
18.3 
ANALYSIS OF SAFETY ............................................................................................................... 61 
18.4 
MULTIPLICITY CONSIDERATIONS ............................................................................................. 61 
18.5 
MISSING DATA .......................................................................................................................... 61 
18.6 
POOLING STRATEGY FOR SURGICAL SITES ............................................................................... 61 
18.7 
DETERMINATION OF SAMPLE SIZE ............................................................................................ 61 
18.8 
DEVIATIONS FROM THE PROTOCOL ANALYSIS PLAN ............................................................... 62 
19.0 
ADMINISTRATION OF THE STUDY ...................................................................... 63 
19.1 
REGULATORY CONSIDERATIONS .............................................................................................. 63 
19.2 
INDEPENDENT ETHICS COMMITTEE (EC)/INSTITUTIONAL REVIEW BOARD (IRB) .................. 63 
19.3 
PATIENT INFORMATION AND INFORMED CONSENT .................................................................. 63 
19.4 
ADHERENCE TO THE PROTOCOL ............................................................................................... 64 
19.5 
PROTOCOL MODIFICATIONS ..................................................................................................... 64 
19.6 
DATA COLLECTION ................................................................................................................... 64 
19.7 
COMPUTERIZED SYSTEMS USED FOR SOURCE DATA ............................................................... 65 
19.8 
MAINTAINING RECORDS ........................................................................................................... 67 
19.9 
MONITORING, AUDITING, INSPECTING ..................................................................................... 67 
19.10 
CONFIDENTIALITY .................................................................................................................... 67 
19.11 
PUBLICATION POLICY ............................................................................................................... 68 
20.0 
APPENDIX A: JUSTIFICATION FOR STUDY ENDPOINTS ............................... 69 
20.1 
JUSTIFICATION FOR USE OF THE FUGL-MEYER MOTOR SCALE AS PRIMARY ENDPOINT .......... 69 
20.2 
RATIONALE FOR NARROW DOMAIN OUTCOME MEASURES IN CHRONIC STROKE PATIENTS 
WITH MOTOR DEFICIT ............................................................................................................................. 70 
20.3 
JUSTIFICATION FOR USE OF THE ACTION RESEARCH ARM TEST (ARAT) AS A SECONDARY 
ENDPOINT................................................................................................................................................. 70 
20.4 
JUSTIFICATION FOR USE OF GAIT VELOCITY AS A SECONDARY ENDPOINT .............................. 71 
20.5 
JUSTIFICATION FOR USE OF NEUROQOL AS A SECONDARY ENDPOINT .................................... 71 
20.6 
JUSTIFICATION FOR CHOICE OF NEUROQOL DOMAINS ............................................................ 72 
21.0 
APPENDIX B: WHO STANDARD TOXICITY CRITERIA ................................... 76 
22.0 
APPENDIX C: ANTICOAGULANT GUIDELINES ................................................ 84 
23.0 
REFERENCES .............................................................................................................. 85 
 

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LIST OF TABLES 
Table 1: Summary of SAEs from SB-STR01 Study............................................................................ 19 
Table 2: Dose, Volume and Cell Concentration .................................................................................. 21 
Table 3: Schedule of Assessments ......................................................................................................... 31 
Table 4: Relationship of Adverse Event to the Administration of the Study Product or Surgery . 56 
Table 5: Computerized Systems Used for Source Data ...................................................................... 66 
Table 6: WHO (World Health Organization) Toxicity Criteria by Grade ....................................... 77 
 
LIST OF FIGURES 
Figure 1: 
ESS ........................................................................................................................................ 18 
Figure 2: 
NIHSS ................................................................................................................................... 18 
Figure 3: 
Fugl-Meyer ........................................................................................................................... 19 
Figure 4: 
Study Schematic .................................................................................................................. 28 

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1.0 
PROTOCOL SYNOPSIS 
Protocol #: 
SB-STR02 
Title: 
A Double-Blind, Controlled Phase 2B Study of the Safety and Efficacy of 
Modified Stem Cells (SB623) in Patients with Chronic Motor Deficit from 
Ischemic Stroke 
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 stem cells that have been transiently 
transfected with a plasmid construct encoding the intracellular domain of human 
Notch-1.  SB623 cells secrete factors that protect neurons in models of ischemic 
insult.  In a rat occlusion model of stroke to the middle cerebral artery region, 
implantation of SB623 into and around the area of the infarct resulted in 
improvement of neurological behavior. 
The safety of implanted SB623 cells was 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.  Results of a six-month interim study 
report of this study have 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 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. 
Based on the Phase 1/2a study, SB-STR01, no safety concerns with SB623 were 
seen, but efficacy was suggested.  Therefore, a double-blind, controlled Phase 2b 
study is justified using patients who are not as disabled (modified Rankin Score 
[mRS 2-4]).  The primary efficacy endpoint will be the Fugl-Meyer Motor Score 
(FMMS), with the following scales as secondary endpoints: 
• 
Modified Rankin Scale 
• 
Action Research Arm Test 
• 
Gait Velocity 
• 
NeuroQOL (Upper Extremity Function and Lower Extremity 
Function) 
• 
Global Rating of Perceived Change: 

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o By Subject (may be completed by Caregiver) 
o By Clinician. 
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 ischemic 
stroke.  The study will be conducted at approximately 65 sites in the United 
States. 
Two cohorts, Group 1 (2.5 and 5 million SB623 cells combined) and Group 2 
(sham placebo), will be included in this study.  Subjects who are randomized into 
this study will receive either approximately 2.5 million SB623 cells, 
approximately 5 million SB623 cells, or sham surgery at a 1:1:1 randomization 
ratio.  Randomization will be performed via an interactive web/voice response 
system (IXRS), stratified by Screening mRS score (recorded in the IXRS at the 
clinical site). 
 
 
Note: Group 1 (Implant) will receive either approximately 2.5 million SB623 cells or 
approximately 5 million SB623 cells. 
Abbreviation: M = million. 
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), 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. Establishing a Benschmark for Complications Using 
Frame-Based Stereotactic Surgery. Sterotact 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 insulated posts, an RIF transmitter head, and at least 1.5 tesla.  Implant sites 
are to be determined in the subcortical peri-infarct tissue to surround the infarct. 
Three needle tracks are to be determined with trajectories to surround the infarct, 
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 

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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 penumbra of the stroke area.  The 
solid stylet is then to be removed, followed by insertion into the stabilizing 
cannula of an implantation cannula (previously qualified for product stability and 
delivery and provided by the Sponsor, as needed) down to the deepest target point 
for the first implantation.  A safe trajectory to enter a 100 µL of cell suspension is 
defined. A volume of 125 µL of cells is backloaded into a 100 µL syringe, 25 µL 
of these cells are injected to clear the implant cannula, thus the final volume in the 
syringe for implant is 100 µL. Detailed information will be provided separately 
from this protocol in an Investigational Product Manual. Five 20-µL volumes of 
cells are to be injected slowly (approximately 10 µL/min.) into 5 implantation 
sites, slowly withdrawing the stabilizing needle probe to produce equally spaced 
implants (intervals of 5-6 mm) within the peri-infarct region extending from 
inferior to the infarct to superior to the infarct.  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 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 require a longer 
stay.  An MRI is to be done on the first post-operative day prior to discharge (Day 
2) to insure 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 treatment assignment. 
Safety will be monitored throughout the study.  In addition an external Data 
Safety Monitoring Board will be utilized to review safety data, including clinical 
symptoms, laboratory findings, and MRI brain imaging.  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 for safety at 25%, 50%, and 75% enrollment.  The 
DSMB shall be the final arbitrator for attributions. 
Efficacy will be determined based on changes in the clinical measures of stroke 
through standardized assessments (Fugl-Meyer Motor Scale (FMMS), Modified 
Rankin Scale (mRS), Action Research Arm Test (ARAT), Gait Velocity and two 
sub-domains of the NeuroQOL scale). MRI of the brain will be performed at 
scheduled time points (pre- and post-contrast T1 weighted, dual echo, and Fluid 
Attenuated Inversion Recovery [FLAIR] sequences). 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 

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accompanying images. Exploratory imaging (e.g. diffusion tensor imaging [DTI] 
and dynamic susceptibility contrast [DSC] MRI for perfusion imaging) will also 
be performed at capable sites.  Primary and secondary efficacy assessments will 
be completed solely by blinded study personnel that do not have access to patient 
study safety information (this includes adverse events, concomitant medications, 
progress notes, and MRI reports). 
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, or seizures, shall be subject to review 
by the DSMB. 
The DSMB shall be the final arbitrator for attributions. 
Patient Population Adult patients with chronic motor deficits secondary to ischemic stroke between 
6 months and 90 months (7.5 years) post stroke.  The interval of 6 months to 
90 months (7.5 years) for this patient population is based on a number of studies 
that have shown that over 90% of ischemic stroke patients are stable by 90 days 
post-stroke.  A Phase 1/2a study (SB-STR01) was conducted to investigate safety 
and efficacy of intracranial administration of SB623 cells in chronic stroke 
patients with motor deficit. 
No. of Patients 
Approximately 156 subjects 
No. of Study Sites 
Approximately 65 sites 
Inclusion Criteria 
1. Age 18-75 years, inclusive 
2. Documented history of completed ischemic stroke in subcortical region of 
MCA or lenticulostriate artery with or without cortical involvement, with 
correlated findings by MRI 
3. Between 6 months and 90 months (7.5 years) post-stroke, and having a 
chronic motor neurological deficit 
4. Neurological motor deficit substantially due to incident stroke (ie, the stroke 
that qualified the patient for the study) 
5. Modified Rankin Score of 2-4 
6. Require Motricity Index 30-75 (UE Scale) or 27-74 (LE Scale) 
7. Able to undergo all planned neurological assessments 
8. Able and willing to undergo magnetic resonance imaging (MRI) with contrast 
and computed tomography (CT) 
9. Agree that use of antiplatelet, anti-coagulant, or non-steroidal anti-
inflammatory drugs be in accordance with the Anticoagulant Guidelines 
described in Appendix C. 
10. Subjects must have had physical therapy prior to entry and be willing to 
continue 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. Ability of patient to understand and sign an Informed Consent 
Exclusion Criteria 
1. 
History or presence of any other major neurological disease other than stroke 
2. 
Cerebral infarct size >150 cm3 measured by MRI 

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3. 
Primary intracerebral hemorrhage 
4. 
Myocardial infarction within prior 6 mos. 
5. 
Malignancy unless in remission >5 yrs. 
6. 
Clinically significant finding on MRI of brain not related to stroke 
7. 
Any seizures in the 3 months prior to Screening 
8. 
More than 5 degrees of contracture at shoulder, elbow, wrist, fingers, hip, 
knee and ankle 
9. 
Other neurologic, neuromuscular or orthopedic disease that limits motor 
function  
10. Uncontrolled systemic illness, including, but not limited to: hypertension; 
diabetes; renal, hepatic, or cardiac failure 
11. Positive findings on tests for occult malignancy, unless a non-malignant 
etiology is confirmed 
12. Uncontrolled major psychiatric illness, including depression symptoms 
(CESD-R Scale of ≥16 is exclusionary) 
13. Total bilirubin >1.9 mg/dL at Screening 
14. Serum creatinine >1.5 mg/dL at Screening 
15. Hemoglobin <10.0 g/dL at Screening 
16. Absolute neutrophil count <2000 /mm3 at Screening 
17. Absolute lymphocytes <800 /mm3 at Screening 
18. Platelet count <100,000 /mm3 at Screening 
19. Liver disease supported by AST (SGOT) or ALT (SGPT) ≥2.5 x upper limit 
of normal at Screening 
20. Serum calcium >11.5 mg/dL at Screening 
21. International Normalized Ratio of Prothrombin Time (INR) >1.2 at 
Screening, if the patient does not take anticoagulants; for patients on 
anticoagulants, INR must be confirmed to be ≤1.2 prior to surgery 
22. Presence of craniectomy (without bone flap replacement) or other 
contraindication to stereotactic surgery  
23. Participation in any other investigational trial within 4 weeks of initial 
screening and within 7 weeks of Baseline visit 
24. Botulinum toxin injection, phenol injection, intrathecal baclofen, or any other 
interventional treatments for spasticity (except bracing and splinting) 
16 weeks prior to the Baseline visit 
25. Substance use disorder (per DSM-V criteria, including drug or alcohol) 
26. Contraindications to head MRI (with contrast) or CT 
27. Pregnant or lactating 
28. Female patients of childbearing potential unwilling to use an adequate birth 
control method during the 12 months of the study 
29. 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 
30. Any prior SB623 cell implantation and/or any prior stem cell treatment for 
stroke or other reason regardless of mode of administration 
31. Subject is taking any prohibited medications (see Section 12.0) 

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Dosage, Mode of 
Administration, 
and Treatment 
Duration 
The investigational product, SB623 cells, are sterile cell suspension in unit 
volume of 1 mL, containing ≥8 X 106 cells/mL, cryopreserved in CryoStore™ 
freezing media in a 2 mL vial. 
Cells to be administered stereotactically only once through one burr-hole 
craniostomy within and adjacent to the infarct using 3 needle tracks and 5 cell 
deposits per track at varying depths (20 µL each): 
• 
Approximately 2.5 X 106 SB623 Cells (8.5 X 106 cells/mL) 
• 
Approximately 5.0 X 106 SB623 Cells (17 X 106 cells/mL) 
Details for preparation of the cell suspension for administration and for loading 
the syringe in the Operation Room will be provided by the Sponsor to the clinical 
site unblinded personnel who will performed the cell target concentration 
preparation, labeling, administration and accountability of investigational product.  
Detailed information will be provided separately from this protocol in a Pharmacy 
Manual.  Clinical sites will be provided with the 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 to achieve target concentrations of approximately 2.5 X 106 cells/ 
0.3 mL and approximately 5 X 106 cells/ 0.3 mL, respectively.  The formulated 
dose for injection is packaged individually in 1.0 mL conical Nalgene™ vials 
with a Teflon seal closure. 
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 insure continued sterility for release 
of target concentrations.  The formulated dose for injection must be administered 
to the patient within 3 hours post release testing. 
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.  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. 
The cryovials containing the frozen cell suspensions are shipped in a dry nitrogen 
shipper and should be stored in the vapor phase (≤ -150 C) within the shipping 
container provided by the Sponsor until transferred at the site to a GMP-compliant 
liquid nitrogen container.  At the clinical site, the investigational product should 
be stored in the vapor phase (≤ -150 C) within the liquid nitrogen container. 
Duration of 
Patient Study 
Participation 
Twelve months post-randomization (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). 

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Efficacy 
Parameters 
Primary Efficacy Endpoint: 
• 
Proportion of subjects whose Fugl-Meyer Motor scale (FMMS) improve 
by ≥10 points at Month 6 from Baseline 
Secondary Efficacy Endpoints: 
• 
Proportion of subjects whose Modified Rankin Scale (mRS) improve 
by ≥1 point at Month 6 from Baseline 
• 
Proportion of subjects whose Action Research Arm Test (ARAT) 
improve by ≥6 points at Month 6 from Baseline 
• 
Proportion of subjects whose Gait Velocity on standard 10 m walk 
improve at least one functional level [eg, 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 Month 6 from Baseline 
• 
Mean change in T scores at Month 6 of NeuroQOL sub-domains: 
o Upper Extremity Function (Fine motor ADL) 
o Lower Extremity Function (Mobility) 
• 
Proportion of subjects scoring 7 (much better) or 6 (a little improved) in 
the Global Rating of Perceived Change scores at Month 6 assessed by 
subject (may be completed by caregiver) and by clinician 
Safety Parameters 
• 
All adverse events whether or not related to SB623 or 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 
Exploratory  
• 
Standard T1- and T2-weighted MRI 
• 
Fluid-attenuated Inversion Recovery (FLAIR) 
• 
Dynamic Susceptibility Contrast (DSC) imaging 
• 
Diffusion tensor imaging (DTI) with tractography and perfusion imaging 
• 
Motion of leg on side affected by stroke as measured by leg activity monitor 

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Statistical 
Methods 
Sample Size:  
The sample size was estimated based on the primary efficacy endpoint, proportion 
of responders, which is defined as ≥10 points on the FMMS, at Month 6 LOCF 
(last observation carried forward).  Based on the results on the Phase 1/2a study it 
was assumed that the responder rate was 33% for the SB623 treatment group.  
Given high surgical placebo response rates (Meissner et al., 2013) it was assumed 
that the responder rate in the surgical sham was 11.7% (i.e. 35% of the treatment 
responder rate).  Assuming a 80% power, alpha level of 0.05 (two-tailed test), and 
2:1 (pooled SB623 treatments:control) ratio of randomization, a sample size of 
138 (92 subjects in treatment group and 46 subjects in control group) is required 
to detect this 21.3% difference in the proportion of responders.  Based on a 
10% upward adjustment to compensate for dropout patients, a total of 
approximately 156 subjects (104 treatment and 52 control) will be required. 
 
Primary Efficacy Analyses: 
The primary analysis will be a comparison of the proportion of SB623 treated 
subjects (two SB623 doses combined) to sham controls that achieve an 
improvement of at least 10 points on the Fugl-Meyer Motor Scale at 6 months 
from Baseline.  A logistic generalized linear mixed model (GLMM) will be used 
for the primary analysis.   
 
Secondary Efficacy Analyses 
The responder analysis in mRS and other disability scales will be assessed 
similarly to the model utilized for the primary analysis. 

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2.0 
BACKGROUND 
2.1 
Medical Need 
Stroke is the third leading cause of death in the United States and a major cause of prolonged 
neurologic disability in adults, with an annual economic burden of over $62 billion in the United 
States.  Of those who experience an ischemic stroke, approximately one quarter will not survive.  
Of the survivors, more than a third will remain functionally dependent due to their physical and 
cognitive limitations.1,2,3,4,5,6,7,8 
Following an ischemic stroke the acute period is generally defined from hours to several days 
following the event.  Longitudinal studies on rates of improvement after ischemic stroke have 
shown that 90% of patients with ischemic stroke achieve no further improvement after about 
90 days with current standard of care.9  This time period was found to be independent of degree 
of initial severity regardless of methods used to assess by most investigators,10,11 while others 
found that severe and very severe cases continued to have slight improvement for 2-3 weeks 
more using a different method of assessment.12 
Approximately 70–85% of first strokes are accompanied by hemiplegia.  Six months after stroke, 
only 60% of people with hemiparesis who need inpatient rehabilitation have achieved functional 
independence in simple activities of daily living such as toileting and walking short distances.  
Studies of patients 6 months after stroke with hemiparesis suggest that only about 1 in 5 patients 
achieve unlimited community ambulation following inpatient rehabilitation.13 
2.2 
Treatment of Ischemic Stroke 
2.2.1 Current Therapies 
For acute ischemic stroke, immediate post-stroke interventions focus on life support through 
respiratory and cardiac control of blood pressure, monitoring oxygen saturation and blood 
glucose level, prevention of metabolic disturbances, maintenance of organ function, and 
management of elevated intracranial pressure.14  The only approved therapies in the U.S. are 
thrombolytic agents, to be given within 3 hrs. of onset of the stroke.  It has been estimated that 
less than 5% of acute ischemic stroke patients receive this therapy, probably due to the stringent 
criteria for thrombolytic intervention, the patient arrival beyond the 3-hour window, and lack of 
adequate facilities at many hospitals.15  As the stroke fully develops, and the patient stabilizes, 
some regimen of physical therapy is almost universally applied. 
2.2.2 Time Course for Stable Stroke 
Acute ischemic stroke is generally accepted to be defined as up to several days, if not hours.  
Longitudinal studies on rates of improvement after ischemic stroke have shown that 90% of 
patients with ischemic stroke achieve no further improvement after about 90 days.16 
2.2.3 Experimental Cellular Therapies 
For the stable stroke patient, no proven therapies exist to reverse the damage and improve overall 
motor or cognitive function.  As reviewed recently, a variety of cellular therapies have been 
examined.17,18,19  Clinical trials with these agents have so far been limited, with only three trials 
conducted and reported to date, with only two having used human cells. 

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Fetal cells from the porcine lateral ganglionic eminence which had been shown to improve 
deficits in an animal model of Huntington’s disease,20,21 and in an animal model of middle-
cerebral artery occlusion22 were studied in a Phase 1 clinical trial.  Five patients with chronic, 
stable, moderate-sized basal ganglia infarcts received intrastriatal implantation of the cells.  One 
of the patients developed a cortical vein occlusion, and the study was terminated by the Food and 
Drug Administration.  Attribution of the adverse event has not been clarified.  None of the 
patients showed improvement on the Modified Rankin Scale.19 
Cultured human neurons derived from an embryonal carcinoma cell line that was isolated from a 
teratocarcinoma (LBS-Neurons) which had been shown to improve deficits in an animal model 
of middle-cerebral artery occlusion23 were studied in an open-label Phase 1 clinical trial.24, 
Initially, 4 patients with stable stroke received stereotactic implants 2 million cells in one needle 
track into the area of infarction, divided into 3 implants with 20 µL per implant.  Subsequently, 
8 additional patients were randomized to receive either single-pass (2 million cells in 3 implants) 
or 3-pass (6 million cells in 9 implants) injections into the area of infarction.  All patients also 
received cyclosporine A orally.  The outcomes were that the procedures and injections were well 
tolerated with a mean improvement in all patients by the European Stroke Score (ESS) that was 
statistically significant, and with an improvement in FDG-PET scans in half of the patients at 
6 months. 
Based on the encouraging results from that Phase 1 study, an open-label, observer-blinded 
Phase 2 study was conducted with LBS-Neurons in 18 patients who were randomized between 
surgery with 5 or 10 million cells implanted (25 implantation sites) plus rehabilitation 
(14 patients), or rehabilitation alone (4 patients), with all surgical patients also receiving 
cyclosporine A orally.25  The patient mix was approximately an equal number with ischemic or 
hemorrhagic stroke.  The outcomes were that both the procedure and the cell implants were again 
well tolerated.  There was no statistically-significant improvement in the ESS between groups, 
although some improvements were found when patients were analyzed as their own controls.  
Some cognitive improvements were also noted.  Finally, there were statistically-significant 
improvements in some of the Fugl-Meyer assessments, but not on overall motor function. 
2.2.4 Stereotactic Surgery 
In addition to the two studies referred to above with LBS Neurons, 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%).26  Further, a Phase 1/2a study with SB623 has been completed with all subjects 
followed through 24 months post-infarct.  During this study there were serious adverse events 
attributed to the surgery, including subdural hematoma, hygroma, seizure disorder, and 
pneumonia. 
2.3 
Properties of SB623 
2.3.1 Summary of SB623 Cells Properties 
SB623 cells are human bone marrow-derived cells and are being developed as an allogeneic cell 
therapy for chronic, stable stroke and other neurodegenerative conditions.  SB623 cells are 
generated under cGMP conditions by the transient transfection of bone marrow stromal cells 

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(MASC) with a plasmid encoding the human Notch-1 intracellular domain.27  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 or adipose cells. 
2.3.2 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. 
2.3.3 Preclinical Pharmacology Studies 
SB623 has been evaluated in a rat model of ischemic stroke in three studies.  Overall, SB623 
showed statistically-significant benefit on several neurological and motor outcomes compared to 
vehicle control. 

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3.0 
Overall Experience with Investigational Product 
This section includes a brief summary of preclinical data available on SB623.  More detailed 
information can be found in the Investigator’s Drug 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 
3.2.1 In Vitro 
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 Drug Brochure for details on these 
studies. 
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 who were 
shown to be stable in the 3 weeks prior to enrollment.  The dose levels used were in a standard 
dose escalation paradigm: approximately 2.5M, 5.0M, and 10.0M cells administered once into 
the peri-infarct region of the brain.  Four stroke measurement scales were used: NIHSS, ESS, 
F-M, and mRS.  All of these scales, except mRS, showed a statistically-significant average 
improvement over Baseline at 6 months and other time points.  For example, the average change 
from Baseline in the F-M scale was found to be 22 at six months (see Figures 1-3 below).  The 
F-M scale is considered sensitive to improvements in motor function in stroke patients.  Page, et 
al. (2012) evaluated the clinically important difference in the Upper Extremity F-M (UE F-M) to 
range from 4.25 to 7.25 points based on a study of 146 patients with chronic stroke.28 The 
average change from Baseline in the UE F-M in SB-STR01 was 5.94 and therefore in the range 
of clinically important difference as defined by Page et al.  Page, et al. also discusses a clinically 
important difference in the context of 10% improvement over the scale range.  The average 
improvement score on the F-M scale in SB-STR01 was 22.19 points which is a 10% 
improvement over the 226 point F-M scale range and a 16% increase over baseline.  Therefore, 
clinically relevant improvements have been demonstrated by 6 months post treatment. 
The mRS scale did not show statistical or clinically meaningful change from baseline.  Two 
subjects had an improvement of 1, and 1 subject had a 1 point worsening.  Others were 
unchanged during the course of the study. 
Both the NIHSS and the ESS were originally developed as predictors of acute stroke 
outcome.29,30  They were both also used in the Phase 1/2a study due to their common use in acute 
stroke in the U.S. and Europe, respectively.  See figures below. 

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Figure 1: 
ESS 
 
 
Figure 2: 
NIHSS 
 
 
ESS
Months Post-treatment
Change from Baseline (+SEM)
P=.003
P=.02
P=.004
Clinical Outcome
NIHSS
Months Post-treatment
Change from Baseline (+SEM)
P=.004
P=.03
P=.0006
Clinical Outcome

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Figure 3: 
Fugl-Meyer 
 
3.4 
Summary of Known and Potential Risks and Benefits 
A 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 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 
 
Fugl-Meyer
Months Post-treatment
Change from Baseline (+SEM)
P=.0002
P=.0006
P=.000006
Clinical Outcome

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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. 

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4.0 
DESCRIPTION AND JUSTIFICATION OF TREATMENT REGIMEN 
4.1 
Dosages 
Cells are to be administered stereotactically through one burr-hole craniostomy using 3 needle 
tracks adjacent to the infarct and 5 cell deposits per track at varying depths, with 20 µL per 
deposit. 
Based on the 6-mo. follow-up data from SB-STR01, there was no apparent dose response in 
either safety or efficacy measures.  Also, all doses were well tolerated.  The dose of 10.0 million 
cells was associated with higher viscosity, making syringe-loading more difficult.  Therefore, the 
two types of doses chosen for this Phase 2b study are approximately 2.5 and approximately 
5.0 million cells.  See Table 2 below. 
Table 2: 
Dose, Volume and Cell Concentration 
Total SB623 
Cells/Pt. 
Total SB623 
Cells/Deposit 
Total SB623 
Cells/Track 
Concentration of 
SB623 Cells per 
Injection 
Total Volume per 
Deposit, per 
Track, and Total 
~2.5 X 106 
1.7 X 105 
8.5 X 105 
8.5 X 106 
cells/mL 
20 µL, 100 µL, and 
300 µL 
~5.0 X 106 
3.3 X 105 
16.5 X 105 
17 X 106 cells/mL 
20 µL, 100 µL, and 
300 µL 
 
4.2 
Justification 
Based on the Phase 1/2a study, SB-STR01, no safety concerns with SB623 were seen, but 
efficacy was suggested.  Therefore, a double-blind, controlled Phase 2b study is justified using 
patients who are not as disabled (mRS 2-4).  The primary efficacy endpoint will be the Fugl-
Meyer Motor Score, with the following scales as secondary endpoints: 
• Modified Rankin Scale 
• Action Research Arm Test 
• Gait Velocity 
• NeuroQOL (Upper Extremity Function and Lower Extremity Function) 
• Global Rating of Perceived Change: 
o By Subject (The subject global rating of perceived change should be completed 
by the subject. In the event the subject is not able to complete the questionnaire, 
the caregiver will be allowed to ask the questions of the subject and complete the 
questionnaire using the subject’s answer(s)) 
o By Clinician 
Rationales for selecting study endpoints are provided in Appendix A. 

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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 stable ischemic stroke. 
5.1 
Parameters 
5.1.1 Primary Efficacy Endpoint: 
• Proportion of subjects whose Fugl-Meyer Motor scale (FMMS) improve by 
≥10 points at Month 6 from Baseline  
5.1.2 Secondary Efficacy Endpoints: 
• Proportion of subjects whose Modified Rankin Scale (mRS) improve by ≥1 point at 
Month 6 from Baseline  
• Proportion of subjects whose Action Research Arm Test (ARAT) improve by 
≥6 points at Month 6 from Baseline  
• Proportion of subjects whose Gait Velocity on standard 10 m walk improve at least 
one functional level [eg, 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 Month 6 from Baseline  
• Mean change in T scores at Month 6 of NeuroQOL sub-domains 
o Upper Extremity Function (Fine motor ADL) 
o Lower Extremity Function (Mobility) 
• Proportion of subjects scoring 7 (much better) or 6 (a little improved) in the Global 
Rating of Perceived Change scores at Month 6 assessed by subject (may be 
completed by caregiver) and by clinician 
5.1.3 Safety Endpoints 
• All adverse events whether or not related to SB623 or 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 
5.1.4 Exploratory Endpoints 
• Standard T1- and T2-weighted MRI 
• Fluid-attenuated Inversion Recovery (FLAIR) 
• Dynamic Susceptibility Contrast (DSC) imaging 
• Diffusion tensor imaging (DTI) with tractography and perfusion imaging 
• Motion of leg on side affected by stroke as measured by leg activity monitor 

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5.2 
Objectives 
5.2.1 Primary Objective 
• To evaluate the clinical efficacy of intracranial administration of SB623 cells 
5.2.2 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 

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6.0 
SURGICAL AND IMPLANTATION PROCEDURES 
The surgical procedure is a modification of one used earlier with another cell product,25 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.26  
This procedure was also used in the ongoing clinical trial SB-STR01.  Two cohorts, Group 1 (2.5 
and 5 million SB623 cells combined) and Group 2 (sham placebo), will be included in this study.  
Subjects who are randomized into this study will receive either approximately 2.5 million SB623 
cells, approximately 5 million SB623 cells or sham surgery at a 1:1:1 randomization ratio.  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 insulated posts, an 
RIF transmitter head, and at least 1.5 tesla.  Implant sites are to be determined in the subcortical 
peri-infarct tissue to surround the infarct.  Three needle tracks are to be determined with 
trajectories to surround the infarct, 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 penumbra of the stroke 
area.  The solid stylet is then to be removed, followed by insertion into the stabilizing cannula of 
an implantation cannula (previously qualified for product stability and delivery and provided by 
the Sponsor, as needed) down to the deepest target point for the first implantation.  A safe 
trajectory to enter a 100 µL of cell suspension is defined. A volume of 125 µL of cells is 
backloaded into a 100 µL syringe, 25 µL of these cells are injected to clear the implant cannula, 
thus the final volume in the syringe for implant is 100 µL. Detailed information will be provided 
separately from this protocol in an Investigational Product Manual.  Five 20-µL volumes of cells 
are to be injected slowly (approximately 10 µL/min.) into 5 implantation sites, slowly 
withdrawing the stabilizing needle probe to produce equally spaced implants (intervals of 
5-6 mm) within the peri-infarct region extending from inferior to the infarct to superior to the 
infarct.  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 for the same duration as Group 1. 

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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 require a longer stay.  An MRI is to be done on the first 
post-operative day prior to discharge (ie, Day 2) to insure there are no significant bleeding risks. 

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7.0 
PATIENT SELECTION 
7.1 
Inclusion Criteria 
1. Age 18-75 years, inclusive 
2. Documented history of completed ischemic stroke in subcortical region of MCA or 
lenticulostriate artery with or without cortical involvement, with correlated findings by 
MRI 
3. Between 6 months and 90 months (7.5 years) post-stroke, and having a chronic motor 
neurological deficit 
4. Neurological motor deficit substantially due to incident stroke (i.e. the stroke that 
qualified the patient for the study) 
5. Modified Rankin Score of 2-4 
6. Require Motricity Index 30-75 (UE Scale) or 27-74 (LE Scale) 
7. Able to undergo all planned neurological assessments 
8. Able and willing to undergo magnetic resonance imaging (MRI) with contrast and 
computed tomography (CT) 
9. Agree that use of antiplatelet, anti-coagulant, or non-steroidal anti-inflammatory drugs be 
in accordance with the Anticoagulant Guidelines described in Appendix C 
10. Subjects must have had physical therapy prior to entry (and be willing to continue 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. Ability of patient to understand and sign an Informed Consent 
7.2 
Exclusion Criteria 
1. 
History or presence of any other major neurological disease other than stroke 
2. 
Cerebral infarct size >150 cm3 measured by MRI 
3. 
Primary intracerebral hemorrhage 
4. 
Myocardial infarction within prior 6 mos. 
5. 
Malignancy unless in remission >5 yrs. 
6. 
Clinically significant finding on MRI of brain not related to stroke 
7. 
Any seizures in the 3 months prior to Screening 
8. 
More than 5 degrees of contracture at shoulder, elbow, wrist, fingers, hip, knee and 
ankle 
9. 
Other neurologic, neuromuscular or orthopedic disease that limits motor function  
10. Uncontrolled systemic illness, including, but not limited to: hypertension; diabetes; 
renal, hepatic, or cardiac failure 
11. Positive findings on tests for occult malignancy, unless a non-malignant etiology is 
confirmed 
12. Uncontrolled major psychiatric illness, including depression symptoms (CESD-R Scale 
of ≥16 is exclusionary) 
13. Total bilirubin >1.9 mg/dL at Screening 

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14. Serum creatinine >1.5 mg/dL at Screening 
15. Hemoglobin <10.0 g/dL at Screening 
16. Absolute neutrophil count <2000 /mm3 at Screening 
17. Absolute lymphocytes <800 /mm3 at Screening 
18. Platelet count <100,000 /mm3 at Screening 
19. Liver disease supported by AST (SGOT) or ALT (SGPT) ≥2.5 x upper limit of normal 
at Screening 
20. Serum calcium >11.5 mg/dL at Screening 
21. International Normalized Ratio of Prothrombin Time (INR) >1.2 at Screening, if the 
patient does not take anticoagulants; for patients on anticoagulants, INR must be 
confirmed to be ≤1.2 prior to surgery 
22. Presence of craniectomy (without bone flap replacement) or other contraindication to 
stereotactic surgery  
23. Participation in any other investigational trial within 4 weeks of initial screening and 
within 7 weeks of Baseline visit 
24. 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. 
25. Substance use disorder (per DSM-V criteria, including drug or alcohol) 
26. Contraindications to head MRI (with contrast) or CT 
27. Pregnant or lactating 
28. Female patients of childbearing potential unwilling to use an adequate birth control 
method during the 12 months of the study 
29. 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 
30. Any prior SB623 cell implantation and/or any prior stem cell treatment for stroke or 
other reason regardless of mode of administration 
31. Subject is taking any prohibited medications (see Section 12.0) 

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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 ischemic stroke.  The study will be 
conducted at approximately 65 sites in the United States. 
Two cohorts, Group 1 (approximately 2.5 and approximately 5 million SB623 cells combined) 
and Group 2 (sham placebo), will be included in this study.  Subjects who are randomized into 
this study will receive either approximately 2.5 million SB623 cells, approximately 5 million 
SB623 cells or sham surgery at a 1:1:1 randomization ratio.  Randomization will be performed 
via an interactive web/voice response system (IXRS), stratified by Screening mRS score 
(recorded in the IXRS at the clinical site). 
The study schematic is shown in the following figure. 
 
Figure 4: 
Study Schematic 
 
Note: Group 1 (Implant) will receive either approximately 2.5 million SB623 cells or approximately 5 million 
SB623 cells.  
Abbreviation: M = million. 
 
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. 
Safety will be monitored throughout the study.  In addition, an external Data Safety Monitoring 
Board will be utilized to review safety data, including clinical symptoms, laboratory findings, 
and MRI brain imaging.  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 for safety at 25%, 50%, and 75% enrollment.  The 
DSMB shall be the final arbitrator for attributions.   

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Efficacy will be determined based on changes in the clinical measures of stroke through 
standardized assessments (Fugl-Meyer Motor Scale (FMMS), Modified Rankin Scale (mRS), 
Action Research Arm Test (ARAT), Gait Velocity and two sub-domains of the NeuroQOL 
scale).  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 post-
surgery and 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 at capable sites.   
The primary and secondary efficacy assessments will be completed solely by blinded study 
personnel that do not have access to patient study safety information (this includes adverse 
events, concomitant medications, progress notes, and MRI reports). 
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, or 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). 

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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: 
Schedule of Assessments 
Study Period 
Screening 
Baseline 
Sham or Cell 
Admin 
Follow-Up Period 
Study Visit Type 
Assessment 
Assessment 
Surgical 
Assessment 
Study Visit 
1 
2 
3A1 
3B 
4 
5 
6 
7 
8 
Study Day 
-84 to -22 
-21 to -2 
-1 
1 
2 
8 
(± 1) 
28 
(± 7) 
84 
(± 7) 
168 
(± 7) 
Study Week 
 
 
 
 
 
1 
4 
12 
24 
Study Month 
 
 
 
 
 
 
1 
3 
6 
Informed Consent 
X 
 
X2 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
Eligibility Criteria Review3 
 
X 
X 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
Medical History (including stroke history) 
X 
 
 
 
 
 
 
 
 
Physical Therapy Instruction and  
Subject Exercise Diary given to subject 
X 
 
 
 
 
X 
X 
X 
X 
Subject Exercise Diary Review 
 
X 
 
 
 
 
X 
X 
X 
Leg Activity Monitor given to subject 
X 
X 
 
 
 
X 
X 
X 
X 
Collect Leg Activity Monitor 
 
X 
 
 
 
X 
X 
X 
X 
Pregnancy Test4 
X 
X 
X 
 
 
 
 
 
X 
Physical Exam 
X 
X 
X 
 
 
 
 
 
X 
Vital Signs (weight and height recorded at 
Screening only) 
X 
X 
X 
X 
 
X 
X 
X 
X 
Chest X-Ray and ECG 
X 
 
X 
 
 
 
 
 
X 
Hematology 
X 
 
X3 
 
 
X 
X 
X 
X 
Serum Chemistry 
X 
 
X3 
 
 
X 
X 
X 
X 
INR 
X 
 
X3 
 
 
 
 
 
X 
HLA typing of each subject 
 
X 
 
 
 
 
 
 
 
ApoE4 & BDNF Val66Met genotyping 
 
X 
 
 
 
 
 
 
 
Serum for anti-HLA Antibodies5 
 
X 
 
 
 
X 
X 
X 
X 
PBMC Sample5 
 
X 
 
 
 
X 
X 
X 
X 
Occult Malignancy 
X 
 
 
 
 
 
 
 
 
CESD-R Scale 
X 
 
 
 
 
 
 
 
 
Head CT 
 
 
 
X6 
 
 
 
 
 
Imaging--Head MRI7 
X 
X 
 
X8 
X 
X 
X 
 
X 
Motricity Index 
X 
 
 
 
 
 
 
 
 

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Study Period 
Screening 
Baseline 
Sham or Cell 
Admin 
Follow-Up Period 
Study Visit Type 
Assessment 
Assessment 
Surgical 
Assessment 
Study Visit 
1 
2 
3A1 
3B 
4 
5 
6 
7 
8 
Study Day 
-84 to -22 
-21 to -2 
-1 
1 
2 
8 
(± 1) 
28 
(± 7) 
84 
(± 7) 
168 
(± 7) 
Study Week 
 
 
 
 
 
1 
4 
12 
24 
Study Month 
 
 
 
 
 
 
1 
3 
6 
Imaging – Diffusion Tensor Imaging9 
 
X 
 
 
 
 
X 
 
X 
Modified Rankin Score (mRS)10 
X11 
X 
 
 
 
 
X 
X 
X 
Fugl-Meyer Motor Score (FMMS)10 
 
X 
 
 
 
 
X 
X 
X 
Action Research Arm Test (ARAT)10 
 
X 
 
 
 
 
X 
X 
X 
Gait Velocity10 
 
X 
 
 
 
 
X 
X 
X 
NeuroQOL (2 subdomains)10 
 
X 
 
 
 
 
X 
X 
X 
Global Rating of Perceived Change 
(subject and clinician) – 7-point Likert 
Scale10, 12 
 
 
 
 
 
 
X 
X 
X 
Admission1 
 
 
X 
 
 
 
 
 
 
Sham Surgery or Cell Administration13 
 
 
 
X 
 
 
 
 
 
Discharge14 
 
 
 
 
X 
 
 
 
 
Adverse Events15 
X 
X 
X 
X16 
X 
X 
X 
X 
X 
Concomitant Medications 
X17 
X 
X 
X16 
X 
X 
X 
X 
X 
1 
Pre-operative procedures may be performed within 14 days of the surgery day and admission may occur on the day of surgery (Day 1) to accommodate 
scheduling. 
2  
Confirmation of appropriate Informed consent. 
3 
The assessment of a subject’s suitability for surgery will be performed at Visit 3A (Day -1) according to clinical site standard practice and Investigator 
judgement.  
NOTE: Hematology, Serum Chemistry, and INR at admission (Visit 3A) 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. 
NOTE: Post-operative visits may be conducted according to the surgical site’s standard of care. 
4 
Only for women of childbearing potential.  Serum β-HCG at Screening (Visit 1), Visit 8, and Visit 10; either serum or urine β-HCG at Baseline (Visit 2) 
and Admission (Visit 3A). 
5 
At each timepoint that serum antibody samples are collected an additional sample for PBMC will also be collected and stored at the central laboratory. 
6 
Head CT on Day 1 is post-operative. 
7 
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).  Standard T1 and T2 sequences and FLAIR will be obtained, and will be recorded in standard digital format for review.  Contrast is to be 
utilized for MRI procedures at Baseline (Visit 2), Day of surgery (Visit 3B), Day 8 (Visit 5), Month 1 (Visit 6), and Month 12 (Visit 10); at these visits 

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Dynamic Susceptibility Contrast (DSC) imaging will also be performed. All other scheduled MRI to be performed without contrast.  MRI within 3 months 
of Visit 1 is acceptable for Screening MRI. 
8 
Or CT overlaid with MRI from Baseline.  Contrast is not to be utilized for CT procedures. 
9 
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.  DTI data will be obtained using whole brain coverage, a 
maximum of 2.5 mm isotropic resolution and at least 30 diffusion encoding directions and may be obtained using either a 1.5 or 3 Tesla MRI scanner. DTI 
is required for subjects at assessment sites with DTI capability. DTI is optional for sites without access to DTI-compatible scanners. Perfusion imaging is 
also required for subjects at assessments sites when the MRI has the capacity. 
10 
All efficacy assessments will be completed solely by blinded study personnel that do not have access to patient study safety information (this includes 
adverse events, concomitant medications, progress notes, and MRI reports). 
11 
The mRS Screening value is to be recorded by the clinical site utilizing the IXRS.  
12 
The subject global rating of perceived change should be completed by the subject. In the event the subject is not able to complete the questionnaire, the 
caregiver will be allowed to ask the questions of the subject and complete the questionnaire using the subject’s answer(s). 
13 
Subjects will undergo study surgical procedure on Day 1 only after all other procedures for this visit have been completed. 
14 
Subjects will be discharged on Day 2 unless complications require a longer stay. 
15 
Adverse event collection begins from the time Informed Consent is provided. 
16 
During the surgical visit, adverse events and concomitant medications will be recorded pre- and post-surgery. 
17 
Including prior and concomitant medications at Screening. 

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Table 3: 
Schedule of Assessments (Continued) 
Study Period 
Follow-up 
Study Visit Type 
Assessment 
Study Visit 
9 
10/ 
Early Termination 
Study Day 
252 
(± 14) 
336 
(± 14) 
Study Week 
36 
48 
Study Month 
9 
12 
Pregnancy Test1 
 
X 
Physical Exam 
 
X 
Physical Therapy Instruction and 
Subject Exercise Diary given to subject 
X 
 
Subject Exercise Diary Review 
X 
X 
Leg Activity Monitor Given to Subject 
X 
 
Leg Activity Monitor Collected from Subject 
X 
X 
Vital Signs 
X 
X 
Chest X-Ray and ECG 
 
X 
Hematology 
X 
X 
Serum Chemistry 
X 
X 
INR 
 
X 
Serum for anti-HLA Antibodies2 
 
X 
PBMC2 
 
X 
Imaging--Head MRI3 
 
X 
Imaging – Diffusion Tensor Imaging4 
 
X 
Modified Rankin Score (mRS)5 
X 
X 
Fugl-Meyer Motor Score (FMMS)5 
X 
X 
Action Research Arm Test (ARAT)5 
X 
X 
Gait Velocity5 
X 
X 
NeuroQOL (2 subdomains)5 
X 
X 
Global Rating of Perceived Change (subject and 
clinician) – 7-point Likert Scale5, 6 
X 
X 
Adverse Events 
X 
X 
Concomitant Medications 
X 
X 
1 
Only for women of childbearing potential, Serum β-HCG. 
2 
At each timepoint that serum antibody samples are collected, an additional sample for PBMC will also be collected and stored at the central laboratory. 

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3 
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).  Standard T1 and T2 sequences and FLAIR will be obtained, and will be recorded in standard digital format for review.  Contrast is to be 
utilized for MRI procedures at Baseline (Visit 2), Day of surgery (Visit 3B), Day 8 (Visit 5), Month 1 (Visit 6), and Month 12 (Visit 10); at these visits, 
Dynamic Susceptibility Contrast (DSC) imaging will also be performed.  All other scheduled MRI to be performed without contrast. 
4 
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.  DTI data will be obtained using whole brain coverage, a 
maximum of 2.5 mm isotropic resolution and at least 30 diffusion encoding directions and may be obtained using either a 1.5 or 3 Tesla MRI scanner. DTI 
is required for subjects at assessment sites with DTI capability. DTI is optional for sites without access to DTI-compatible scanners. Perfusion imaging is 
also required for subjects at assessments sites when the MRI has the capacity. 
5 
All efficacy assessments will be completed solely by blinded study personnel that do not have access to patient study safety information (this includes 
adverse events, concomitant medications, progress notes, and MRI reports). 
6 
The subject global rating of perceived change should be completed by the subject. In the event the subject is not able to complete the questionnaire, the 
caregiver will be allowed to ask the questions of the subject and complete the questionnaire using the subject’s answer(s). 

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9.2 
Pre-study Evaluation 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 -22; Assessment Site) 
The Medical Monitor will be consulted if any screening procedures may be conducted outside 
the specified Screening visit window (eg, due to operating room scheduling delay). 
• Inclusion/Exclusion Criteria (refer to Appendix C for anticoagulant guidelines) 
• Demographics 
• Medical History (including stroke history) 
• Prior and concomitant Medications 
• Pregnancy Test (serum β-hCG) for women of childbearing  potential only 
• Physical Therapy Instructions and Subject Exercise Diary given to subject 
• Leg Activity Monitor Given to Subject 
• Physical Exam 
• Vital Signs Including Weight and Height 
• Chest X-Ray 
• 12-lead ECG 
• Hematology  
• Serum Chemistry  
• INR 
• Determination of occult malignancy  
• CESD-R Scale Administration (subject must have score of <16) 
• Imaging (head MRI).  NOTE: MRI within 3 months of Visit 1 is acceptable for 
Screening MRI as long as meets criteria (does not require DTI or perfusion imaging) 
• Clinical Stroke Evaluation (Modified Rankin and Motricity Index) 
• Adverse events 
Subjects may be re-screened with the approval of the medical monitor. If during the screening or 
re-screening period, there is a change in medical condition, additional, repeat, or unscheduled 
procedures may be performed at the Investigator’s discretion. 
9.3 
Baseline and Confirmation of Eligibility 
9.3.1 Visit 2: Baseline (Day -21 to -2; Assessment Site) 
The following will be performed at Baseline: 

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• Eligibility Criteria Review 
• Adverse events 
• Concomitant medications 
• Pregnancy Test (serum or urine β-hCG) for women of childbearing  potential only 
• Physical Exam 
• Subject Exercise Diary Review 
• Collect Leg Activity Monitor  
• Re-issue Leg Activity Monitor 
• Vital Signs 
• 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) 
• Exploratory Imaging (Standard T1- and T2-weighted MRI, and FLAIR), and at sites 
with capability Diffusion tensor imaging (DTI) with tractography and perfusion 
imaging (including DSC) 
• Clinical Stroke Evaluations (FMMS; mRS; ARAT; Gait Velocity; NeuroQOL (Upper 
Extremity Function and Lower Extremity Function) 
9.3.2 Eligibility Confirmation 
Confirmation of eligibility can only occur after performing all assessments and verifying that the 
patient meets the inclusion and exclusion criteria for the study. 
9.4 
Surgical Admission (Visit 3A: Day -1; Surgical Site) 
Pre-operative procedures may be performed within 14 days of the surgery day and admission 
may occur on the day of surgery (D1) to accommodate scheduling. 
• Admission 
• Confirm Informed Consent 
• Review Eligibility Criteria to determine suitability for surgery (according to clinical 
site standard practice and Investigator judgment) 
• Adverse events 
• Concomitant medications 
• Pregnancy Test (serum or urine β-hCG) for women of childbearing  potential only 
• Physical Exam 

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• Vital Signs 
• Chest X-ray 
• 12-lead ECG 
• Hematology 
• Serum Chemistry  
• INR 
9.5 
Randomization and Cell Administration or Sham Surgery (Visit 3B: Day 1; Surgical 
Site) 
Prior to any procedures, the patient will be queried on the use of any or changes in medication 
since Baseline. 
• Adverse events 
• Concomitant medications 
• Vital Signs 
• Imaging (head MRI or CT with MRI overlay) 
• Randomization 
 
Prior to cell implantation, either a head CT or a head MRI alone will be done to determine the 
exact locations for the implants. 
Group 1: 
One burr hole will be made in the skull of the patient in a location that will allow ready 
access to the infarct 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 
9.6 
Visit 4: Follow-Up Period (Study Day 2; Surgical Site)  
The following will be performed at the surgical site: 

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• Adverse Events 
• Concomitant Medications 
• Head MRI 
• Discharge 
NOTE: If additional days are required in the clinic, adverse events and concomitant 
medications will be monitored and recorded. Post-operative visits may be scheduled as 
required by the site’s standard of care. 
9.7 
Visit 5: Follow-Up Period (Week 1, Study Day 8 ± 1; Assessment Site) 
The following will be performed: 
• Adverse Events 
• Concomitant Medications  
• Vital Signs 
• Hematology  
• Serum Chemistry  
• Physical Therapy Instructions and Subject Exercise Diary given to subject 
• Collect Leg Activity Monitor  
• Re-issue Leg Activity Monitor 
• Blood draw for Serum anti-HLA Antibodies  
• Blood draw for PBMC 
• Head MRI (MRI must be read before re-starting any antiplatelet, anticoagulant, or 
non-steroidal anti-inflammatory agents) 
9.8 
Visit 6: Follow-Up Period (Month 1, Study Day 28 ± 7; Assessment Site) 
• Adverse Events 
• Concomitant Medications  
• 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 
• Collect Leg Activity Monitor  

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• Re-issue Leg Activity Monitor 
• Imaging (head MRI) 
• Exploratory Imaging (Standard T1- and T2-weighted MRI, and FLAIR), and at sites 
with capability Diffusion tensor imaging (DTI) with tractography and perfusion 
imaging (including DSC) 
• Clinical Stroke Evaluations (FMMS; mRS; ARAT; Gait Velocity; NeuroQOL (Upper 
Extremity Function and Lower Extremity Function) 
• Global Rating of Perceived Change: subject and clinician, 7-point Likert scale 
9.9 
Visit 7: Follow-Up Period (Month 3, Study Day 84 ± 7; Assessment Site) 
• Adverse Events 
• Concomitant Medications  
• 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 
• Collect Leg Activity Monitor 
• Re-issue Leg Activity Monitor 
• Clinical Stroke Evaluations (FMMS; mRS; ARAT; Gait Velocity; NeuroQOL (Upper 
Extremity Function and Lower Extremity Function) 
• Global Rating of Perceived Change: subject and clinician, 7-point Likert scale  
9.10 Visit 8: Follow-Up Period (Month 6, Study Day 168 ± 7; Assessment Site) 
• Adverse Events 
• Concomitant Medications  
• Pregnancy test (serum β-hCG) for women of childbearing potential only 
• Physical Exam 
• Subject Exercise Diary Review 
• Physical Therapy Instructions and Subject Exercise Diary given to subject 
• Collect Leg Activity Monitor  
• Re-issue Leg Activity Monitor 
• Vital Signs 

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• Chest X-ray 
• 12-lead ECG 
• Hematology  
• Serum Chemistry  
• INR 
• Blood draw for Serum anti-HLA Antibodies  
• Blood draw for PBMC 
• Imaging (head MRI) 
• Exploratory Imaging (Standard T1- and T2-weighted MRI, and FLAIR), and at sites 
with capability Diffusion tensor imaging (DTI) with tractography and perfusion 
imaging (including DSC) 
• Clinical Stroke Evaluations (FMMS; mRS; ARAT; Gait Velocity; NeuroQOL (Upper 
Extremity Function and Lower Extremity Function) 
• Global Rating of Perceived Change: subject and clinician, 7-point Likert scale 
9.11 Visit 9: Follow-Up Period (Month 9, Study Day 252 ± 14; Assessment Site) 
• Adverse Events 
• Concomitant Medications  
• Vital Signs 
• Hematology 
• Serum Chemistry  
• Subject Exercise Diary Review 
• Physical Therapy Instructions and Subject Exercise Diary given to subject 
• Collect Leg Activity Monitor  
• Re-issue Leg Activity Monitor 
• Clinical Stroke Evaluations (FMMS; mRS; ARAT; Gait Velocity; NeuroQOL (Upper 
Extremity Function and Lower Extremity Function) 
• Global Rating of Perceived Change: subject and clinician, 7-point Likert scale 
9.12 Visit 10/Early Termination: Follow-Up Period (Month 12, Study Day 336 ± 14; 
Assessment Site) 
• Adverse Events 
• Concomitant Medications  
• Pregnancy test (serum β-hCG) for women of childbearing potential only 
• Serum Chemistry  

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• Subject Exercise Diary Review 
• Collect Leg Activity Monitor  
• Vital Signs 
• Chest X-ray 
• 12-lead ECG 
• Hematology  
• Serum Chemistry  
• INR 
• Blood draw for Serum anti-HLA Antibodies  
• Blood draw for PBMC 
• Imaging (head MRI) 
• Exploratory Imaging (Standard T1- and T2-weighted MRI, and FLAIR), and at sites 
with capability Diffusion tensor imaging (DTI) with tractography and perfusion 
imaging (including DSC) 
• Clinical Stroke Evaluations (FMMS; mRS; ARAT; Gait Velocity; NeuroQOL (Upper 
Extremity Function and Lower Extremity Function) 
• Global Rating of Perceived Change: subject and clinician, 7-point Likert scale  

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10.0 DESCRIPTION OF STUDY TREATMENT 
10.1 Study Product Description 
The investigational product, SB623 cells, are sterile cell suspension in unit volume of 1 mL, 
containing ≥8 X 106 cells/mL, cryopreserved in CryoStore™ freezing media in a 2 mL vial. 
10.2 Study Product Packaging and Labeling 
The investigational product, SB623 cells, are provided to clinical sites in unit volume of 1 mL 
suspension,  packaged and cryopreserved in CryoStore™ freezing media in a 2 mL Nalgene™ 
cryovials with a Teflon® seal closure.  The vials are labeled at minimum with the following 
information: 
• Product Name (SB623) 
• Manufacture Lot. Number 
• Vial number 
• Sponsor Name and Address 
• Manufacturer Name and Address 
• Storage Conditions 
• Investigational Drug Statement in accordance with 21CFR312.6 
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 (≤ -150 oC) within the shipping container provided by the 
Sponsor until transferred at the site to a GMP-compliant liquid nitrogen container.  At the 
clinical site, the investigational product should be stored in the vapor phase (≤ -150 oC) within 
the liquid nitrogen container. 
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 
Operation Room will be provided by the Sponsor to the clinical site unblinded personnel who 
will performed the cell target concentration preparation, labeling, administration and 
accountability of investigational product.  Detailed information will be provided separately from 
this protocol in an Investigational Product Manual.  Clinical sites will be provided with the 
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 to achieve target concentrations of approximately 2.5 X 106 cells/ 0.3 mL and approximately 
5 X 106 cells/ 0.3 mL, respectively.  The formulated dose for injection is packaged individually 
in 1.0 mL conical Nalgene ™ vials with a Teflon seal closure. 
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 insure continued sterility for release of target concentrations.  

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The formulated dose for injection must be administered to the patient within 3 hours post release 
testing.   
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.  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. 
10.5 Study Product Accountability Procedures 
The Investigator will be responsible for maintaining inventory and accounting for all Study 
Product received from the Sponsor.  The investigator will be responsible for the accountability of 
target concentrations prepared and actually used for dosing for a subject.  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.  All vials (used or unused [ie, 
resuspended cells]) are to be returned to the cell laboratory for reconciliation destruction. 

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11.0 TREATMENT ASSIGNMENT AND BLINDING 
This is a double-blind study.  Subjects will be randomized in a 1:1:1 ratio via an IXRS, stratified 
by Screening mRS score.  Each subject will be randomized at a surgical site prior to the surgical 
procedure after study eligibility is confirmed.  The randomization will be balanced, in terms of 
numbers of subjects between the treatment groups, within each surgical site. 
The blind will be maintained by 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 a 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 assessment site investigator’s discretion.  These 
unblinding events will be recorded and reported to the Sponsor.  

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c. 
To further safeguard maintenance of the blind, all 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 to any 
patient study safety information (e.g. adverse events, concomitant medications, 
head imaging reports, and medical charts etc.). 
d. 
All sites will be trained on Maintenance of the blind procedures and the training 
will be documented prior to site activation. 
The following are the exceptions to those staff required to remain blinded: Data and Safety 
Monitoring Board (DSMB) members involved in regular review of safety data, unblinded cell 
preparation staff, unblinded neurosurgeon and OR surgical staff, unblinded study monitor. 
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 IXRS.  Date and reason for unblinding are to be promptly 
communicated via telephone and in writing to the Medical Monitor and documented in the CRF. 
Any subject for whom the treatment assignment/dose information was unblinded should continue 
to follow study procedures. 

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12.0 CONCOMITANT MEDICATIONS 
The following medications should not be used during participation in the study:  
• Bupropion (Wellbutrin®, Zyban®, others) 
• Tricyclic Antidepressants (includes amitryptilene, nortryptilene, clomipramine, others) 
• Clozapine (Clozaril®) 
• Tramadol (Ultram®, Ultracet®) 
• Meperidine (Demerol®) 
• Theophylline (Theolair®, Slo-Bid®, Aminophylline, others)  
• Cyclosporin 
 
All concomitant medications including prescription and over-the-counter drugs taken during the 
14 days prior to enrollment or used anytime during the study through 12 months post-Study 
Product (ie, End of Study) or Early Termination will be documented.  Documentation 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. 
Refer to Appendix C for anticoagulant guidelines. 

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13.0 STUDY WITHDRAWAL/TERMINATION 
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 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 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 should be 
performed, whenever possible, at the time of patient withdrawal or as soon as possible.  If 
possible, the Investigator should attempt to evaluate the medical condition for 12 months 
post-surgery for any patient who has withdrawn (provided the patient consents to such 
follow-up). 
In the event a patient withdraws from the study for any reason, the Investigator must 
notify the Principal Monitor by telephone within 24 hours of withdrawal. 
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 will be 
asked to check public records for survival status at 12 months when possible. 

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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, or seizures, shall be subject to review by the DSMB. 
The DSMB shall be the final arbitrator for attributions. 

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15.0 CLINICAL AND LABORATORY EVALUATIONS AND PROCEDURES 
15.1 Medical History (Including Stroke History) 
Medical history (including stroke 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 oral temperature, blood pressure at rest (while subject is in seated 
position), heart rate, and respiratory rate. Weight and height will be recorded at screening only. 
15.3 Safety Laboratory 
All safety laboratory evaluations will be conducted at a central laboratory (except at surgical 
visit).  At every sampling time point, approximately 15 mL of blood will be drawn for each of 
the hematology and serum chemistry panels.  Detailed information regarding collection of blood 
samples for clinical safety laboratory evaluations will be provided separately from this protocol. 
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 
15.4 Pregnancy Test: Serum or urine β-hCG 
• Serum β-hCG at Screening (using same blood draw as for serum chemistry), Visit 8, 
and Visit 10 
• Serum β-hCG or Urine β-hCG at Baseline and Admission (Visit 3A) 
Detailed information regarding collection of samples for pregnancy testing will be provided 
separately from this protocol. 
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 (ie, 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 
baseline. 
A central laboratory will be utilized for sample storage and assay.  Detailed information 
regarding collection of samples will be provided separately from this protocol. 
The samples will be stored for at least 15 years to allow for post marketing analysis. 

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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 and for 
storage.  Assays will be done periodically on pooled samples.  A central laboratory will be 
utilized for sample storage and assay.  Detailed information regarding collection of samples will 
be provided separately from this protocol. 
The samples will be stored for at least 15 years to allow for post marketing analysis. 
 
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.  Detailed 
information regarding collection of samples will be provided separately from this protocol. 
The samples will be stored for at least 15 years to allow for post marketing analysis. 
 
15.8 Occult Malignancy 
Occult Malignancy will be determined by occult blood in stools (hemocult test), finding on chest 
x-ray, carcinoembryonic antigen, prostate-specific antigen (males only), cancer antigen 125 
(females only), α-fetoprotein, and β-hCG. 
15.9 CESD-R 
The Center for Epidemiologic Studies Depression Scale Revised will be used for screening for 
depression and depressive disorder. 
15.10 Clinical Stroke Evaluations 
Detailed information regarding clinical stroke evaluations (including sample forms and 
instructions for conducting the evaluations) will be provided separately from this protocol. 
 
Fugl-Meyer Motor Score (FMMS) 
FMMS will be calculated as change from baseline for Months 1, 3, 6 (primary), 9 and 12.  The 
treatment group will be compared to the control group based on the relative proportion of 
subjects who improve at least 10 points. 
 
Modified Rankin Scale (mRS) 
The mRS will be calculated to determine eligibility (mRS 2-4) at screening and again at 
Baseline, Months 1, 3, 6 (secondary), 9 and 12 months.  The treatment group will be compared to 
the control group based on based on the relative proportion of subjects who improve at least 

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1 point.  The mRS for all assessments except the Screening assessment will be recorded on video 
and reviewed in a blinded fashion by a central external rater. 
 
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 either 
Motricity Index 30-75 (Upper Extremity Scale) OR 27-74 (Lower Extremity Scale).  
 
Action Research Arm Test (ARAT) 
ARAT scores will be calculated at Baseline and Months 1, 3, 6 (secondary), 9 and 12.  The 
treatment group will be compared to the control group based on the relative proportion of 
subjects who improve at least 6 points. 
 
Gait Velocity 
Gait Velocity on a standard 10 m walk will be calculated at Baseline and Months 1, 3, 6 
(secondary), 9 and 12.  The treatment group will be compared to the control group based on the 
relative proportion of subjects who improve 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). 
 
NeuroQOL  
Two subdomains of the NeuroQOL will be assessed at Baseline and Months 1, 3, 6 (secondary), 
9 and 12 using the Short Forms.  The 2 subdomains include: 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 in T Scores from baseline.  
 
Global Rating of Perceived change from Baseline 
This assessment will be performed at Months 1, 3, 6 (secondary), 9 and 12.  It will be performed 
by both subject (may be completed by caregiver) and clinician.  Subjects and clinicians will be 
asked about perceived changes in their motor function by comparing “how well they are doing 
compared to before the surgical procedure”.  The subject global rating of perceived change 
should be completed by the subject. In the event the subject is not able to complete the 
questionnaire, the caregiver will be allowed to ask the questions of the subject and complete the 
questionnaire using the subject’s answer(s). 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 

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• Score 1 = Much worse 
15.11 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 while in the study.  Subjects will be 
asked to keep a daily diary of their performance of the exercises. 
Physical therapy treatment during the study will be recorded in the CRF. 
15.12 Leg Activity Monitoring 
Bilateral ankle sensors will be worn by subjects for 2 week intervals at Screening (Day -14), 
Baseline (Day -1) and Months 1, 3, 6, and 9.  Data will be provided to a centralized reviewer for 
analysis.  Detailed information regarding leg activity monitoring will be provided separately 
from this protocol. 
15.13 Imaging (MRI), Chest X-Ray, CT, and ECG 
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).  Standard T1 and T2 sequences and FLAIR will be obtained, and 
will be recorded in standard digital format for review.  Contrast is to be utilized for MRI 
procedures at Baseline (Visit 2), Day of surgery (Visit 3B), Day 8 (Visit 5), Month 1 (Visit 6), 
and Month 12 (Visit 10); all other scheduled MRI to be performed without contrast. 
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.  DTI data will be obtained using 
whole brain coverage, a maximum of 2.5 mm isotropic resolution and at least 30 diffusion 
encoding directions and may be obtained using either a 1.5 or 3 Tesla MRI scanner. DTI is 
required for subjects at assessment sites with DTI capability. DTI is optional for sites without 
access to DTI-compatible scanners. Perfusion imaging, including DSC, is also required for 
subjects at assessment sites when the MRI has the capacity. 
A centralized imaging core laboratory will be used to confirm lesion size for analysis purposes, 
develop imaging acquisition protocols, and conduct imaging processing and analyses.   
Detailed information regarding MRI procedures will be provided separately from this protocol. 
Chest X-ray 
Standard chest x-ray techniques will be performed according to the schedule described above. 
 
CT Scans 
Standard CT techniques will be performed according to the schedule described above.  CT is to 
be conducted without contrast. 
 

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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.  With the exception of Visit 3 ECG, 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. 

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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 this 
treatment.  An AE can therefore be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of an investigational product, whether or not considered 
related to the investigational product.  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 
• 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, 
• hospitalization or prolongation of hospitalization, 
• a persistent or significant disability/incapacity, 
• 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) 
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. 

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A Serious and Unexpected Suspected Adverse Reaction (SUSAR) is an adverse reaction to study 
product or surgical procedure that is both serious and unexpected and for which there is a 
reasonable possibility that the study product or surgical procedure caused the adverse event. 
All SUSARs will be submitted as expedited reports to the FDA.  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 informed consent and ends 
12 months after the administration of SB623, or at Early Termination. 
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. 
16.3 Recording of AEs 
All AEs, regardless of severity, seriousness, or presumed relationship to Study Product, 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 
The Investigator must record his/her opinion concerning the relationship of the AE to study 
therapy on the Adverse Event CRF.  Table 4 below provides guidance for assigning relationship 
to Study Product. 
Table 4: 
Relationship of Adverse Event to the Administration of the Study Product or 
Surgery 
Not related 
No temporal relationship to cell treatment/procedure, or the presence of a reasonable 
causal relationship between another drug, concurrent disease, or circumstance and the 
adverse event (AE). 
Unlikely 
related 
A temporal relationship to cell treatment/procedure, but no reasonable causal 
relationship between cell treatment/procedure and the AE. 
Possibly 
related 
A reasonable causal relationship between the cell treatment/procedure and the AE.  
Information related to withdrawal of cell treatment/procedure was lacking or unclear. 
Probably 
related 
A reasonable causal relationship between the cell treatment/procedure and the AE.  The 
event responded to withdrawal of cell treatment/procedure.   
Definitely 
related 
A reasonable causal relationship between the cell treatment/procedure and the AE.  The 
event responded to withdrawal of the cell treatment/procedure. 

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16.5 Reporting Serious Adverse Events 
Any Serious Adverse Event, 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 
immediately (within 24 hours after the site becomes aware of the event) to the Safety Monitor 
(ProPharma Group/PROSAR). 
 
The contact information for reporting SAEs is as follows: 
Safety Monitor:  Tim Smith, PharmD, BSN (ProPharma Group/PROSAR) 
Email: drugsafety@prosarcorp.com 
FAX: 866-681-1063 
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 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 to 
applicable regulatory authorities/federal agencies, other Investigators, IRBs 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)/Institutional Biosafety Committee (IBC) in accordance with 
the EC/IRB bylaws. 
All additional follow-up evaluations of the SAE must be reported to ProPharma 
Group/PROSAR.  These data should be sent by email as scanned copy or faxed to the Safety 
Monitor at 866-681-1063 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. 

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17.0 EXTERNAL DATA SAFETY MONITORING BOARD 
An External Data Safety Monitoring Board (DSMB) will evaluate safety 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%, and 75% of the total population.  In addition, 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. 

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18.0 STATISTICAL METHODS  
18.1 Analysis Populations 
18.1.1 Efficacy Population 
The intent-to-treat (ITT) population will include all randomized patients.  All efficacy analyses 
will utilize this population. 
18.1.2 Safety Population 
The safety population will include all randomized patients that undergo surgery.  All safety 
analyses will utilize this population. 
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 is locked and the treatment 
is unblinded. 
In general, demographics and baseline characteristics will be presented by treatment group.  
Continuous variables will be summarized by the following descriptive statistics: sample size, 
mean, median, standard deviation, minimum, and maximum.  Discrete variables will be 
summarized by frequencies and percentages (contingency tables). 
18.2.1 Analysis of Efficacy 
All efficacy analyses will be performed on the modified intention to treat (mITT) population, 
which is defined as all randomized patients who complete the surgery treatment procedure (or 
sham). 
18.2.1.1 Primary Efficacy Analysis 
The primary analysis will be a comparison of the proportion of SB623 treated subjects (pooling 
both SB623 doses) to sham surgical controls that achieve an improvement of at least 10 points on 
the Fugl-Meyer Motor Scale at 6 months from Baseline.  A generalized linear mixed model 
(GLMM) will be utilized using the mITT population.  The GLMM model will have the outcome 
variable, responder of FMMS (either ≥ or <10 points improvement in FMMS at Month 6), and 
independent variables of treatment (SB623 combined doses vs. sham surgical control), FMMS 
baseline score and pooled surgical site as fixed effects. 
Hypothesis 
Let PSB623_ combined doses and PPlacebo represent the proportions of responders who have an 
improvement of at least 10 points on the Fugl-Meyer Motor Scale at 6 months from Baseline in 
SB623 combined doses and placebo, respectively.  The primary analysis will test the following 
hypothesis 
H0: PSB623_ combined doses = PPlacebo versus the alternate H1: PSB623_ combined doses ≠  PPlacebo 
18.2.1.2 Secondary Efficacy Analyses 
Secondary analyses will evaluate a number of endpoints: 
• The proportion of SB623 treated subjects (pooling both SB623 doses) that improve at 
least 1 point on the Modified Rankin Scale (mRS) will be analyzed at 6 months (from 

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Baseline) using a similar GLMM model to the primary efficacy analysis.  The 
GLMM model will include treatment (SB623 combined doses vs. sham surgical 
control), mRS baseline score and pooled surgical site as fixed effects. 
• The proportion of SB623 treated subjects (pooling both SB623 doses) that improve at 
least 6 points on the Action Research Arm Test will be compared to sham-surgery 
controls at 6 months (from Baseline) using a similar GLMM model to the primary 
efficacy analysis.  The GLMM model will include treatment (SB623 combined doses 
vs. sham surgical control), ARAT baseline score and pooled surgical site as fixed 
effects. 
• The proportion of SB623 treated subjects (pooling both SB623 doses) that improve at 
least 1 functional level on Gait Velocity will be compared to sham-surgery controls at 
6 months (from Baseline) using a similar GLMM model to the primary efficacy 
analysis.  The GLMM model will include treatment (SB623 combined doses vs. sham 
surgical control), Gait Velocity baseline score and pooled surgical site as fixed 
effects. 
• The mean change in the two of the four NeuroQOL subdomain T scores of SB623 
treated subjects (pooling both SB623 doses) will be compared to sham-surgery 
controls at 6 months (from Baseline) using a mixed model repeated measures model 
(MMRM).  The two subdomains include: 
o Upper Extremity Function (Fine Motor ADL) 
o Lower Extremity Function (Mobility) 
The MMRM model will include treatment, visit, pooled site, corresponding baseline 
subdomain T score, and the treatment-by-visit interactions.  Restricted Maximum 
Likelihood Estimation procedure will be employed using an unstructured covariance 
matrix.  Missing observations will not be imputed for this analysis. 
• The proportion of SB623 treated subjects (pooling both 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 
6 months (from Baseline) using a logistic regression model with treatment (SB623 vs. 
sham placebo) and pooled center as the covariates.  The outcome variable of this 
analysis is a dichotomized variable based on of the Global Rating of Perceived 
Change score (≥6 vs. <6). 
• All efficacy endpoints mentioned above will be analyzed to assess the treatment 
difference between SB623 2.5-million and 5-million cells groups.  The same 
statistical methodologies to evaluate SB623 combined doses vs. surgical sham control 
for each efficacy endpoint will be used. 
18.2.1.3 Exploratory Efficacy Analyses 
The analyses of exploratory efficacy endpoints will be detailed in the SAP. 

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18.2.1.4 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), discontinuation due to AEs, and serious adverse events (SAEs) will be 
summarized by presenting, for each treatment group, the number and percentage of patients 
having any adverse event, having an adverse event in each system organ class and having each 
individual adverse event.  Adverse events will further be categorized for each individual AE by 
severity, relationship to study drug, and action taken.  Other information collected will be listed 
as appropriate.  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. 
Summary statistics for vital signs and laboratory values will be provided.  Vital signs and 
laboratory data will be summarized by presenting shift tables, by presenting summary statistics 
of raw data and change from baseline values (means, standard deviations, medians, ranges) and 
by the flagging of abnormal values in data listings. 
18.4 Multiplicity Considerations 
There are no multiplicity considerations for this study. 
18.5 Missing Data 
Every effort will be made to reduce the number of dropouts and to document reasons for 
dropping out. 
18.6 Pooling Strategy for Surgical Sites 
Some surgical sites may not have sufficient number of subjects for the efficacy analyses.  Small 
surgical sites will be pooled by size within geographic region if necessary.  Details of the pooling 
will be described in the study statistical analysis plan (SAP). 
18.7 Determination of Sample Size 
The sample size was estimated based on the primary efficacy endpoint, proportion of responders, 
which is defined as ≥10 points on the FMMS, at Month 6 LOCF (last observation carried 
forward).  Based on the results on the Phase 1/2a study it was assumed that the responder rate 
was 33% for the SB623 treatment group.  Given high surgical placebo response rates (Meissner 
et al., 2013) it was assumed that the responder rate in the surgical sham was 11.7% (i.e. 35% of 
the treatment responder rate).  Assuming a 80% power, alpha level of 0.05 (two-tailed test), and 
2:1 (pooled SB623 treatments: sham control) ratio of randomization, a sample size of 
138 (92 subjects in treatment group and 46 subjects in control group) is required to detect this 
21.3% difference in the proportion of FMMS responders.  Based on a 10% upward adjustment to 
compensate for dropout patients, a total of approximately 156 subjects (104 treatment and 
52 control) will be required.  

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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 final integrated clinical report with an explanation of the alternative methods employed. 

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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) 
The Investigator must submit the final protocol and proposed informed consent document to an 
Independent Ethics Committee (EC) or Institutional Review Board (IRB) that complies with the 
ICH Guideline for Good Clinical Practice.  The EC/IRB 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 approval of the study protocol and the 
informed consent has been received. 
Substantive modifications to the protocol will be submitted to the EC/IRB for approval.  These 
modifications may be implemented only after EC/IRB 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 
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 for 
approval prior to implementing these documents. 
The Investigator will make appropriate and timely reports to the EC/IRB as required by 
applicable government regulations and EC/IRB 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.  It is the Sponsor and/or its designee’s responsibility to inform the Investigator of 
serious adverse events observed at other investigational sites. 
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 in a timely fashion and to retain originals in a file.  
This EC/IRB 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 

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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 noted in the Protocol 
Modifications section below.  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 of changes.  Substantive changes will require EC/IRB 
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 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 will capture the following information: patient number, initials, patient personal 
identification number or medical record number, date of screen/enrollment, reason for not 
enrolling (if applicable), and any comments. 
The results from Screening and data collected during the study (except data that are 
electronically transferred) will be recorded in the subject’s electronic CRF.  The study sites will 
use an EDC system (Medidata RAVE) that is compliant with relevant FDA regulatory 

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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. 
 
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 Computerized Systems Used for Source Data 
A list of the computerized systems that will be used to create, modify, maintain, archive, retrieve, 
or transmit source data are presented below, pursuant to the Guidance for Industry Computerized 
Systems Used in Clinical Investigations, May 2007. 

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Table 5: 
Computerized Systems Used for Source Data 
Protocol Step  
Computerized System Type or 
Description 
Informed Consent 
A 
Demographics 
A 
Inclusion/Exclusion Review 
A 
Eligibility Criteria Review 
A 
Randomization 
C 
Medical History (including stroke history) 
A 
Subject Exercise Diary 
A 
Leg Activity Monitor 
D 
Urine Pregnancy Test 
A 
Serum Pregnancy Test 
B 
Physical Examination 
A 
Vital Sign Measurements 
A 
Chest X-ray 
A 
12-lead ECG 
D 
Clinical Laboratory Evaluation (Hematology and Serum 
Chemistry) 
B 
INR 
B 
HLA Typing of each Subject 
B 
ApoE4 & BDNF Val66Met genotyping 
B 
Occult Malignancy 
B 
CESD-R Scale 
A 
Head CT 
A 
Imaging – Head MRI 
D 
Imaging – Diffusion Tensor Imaging 
D 
Modified Rankin Score 
A 
Motricity Index 
A 
Fugel-Meyer Motor Score 
A 
ARAT 
A 
Gait Velocity 
A 
NeuroQoL (2 subdomains) 
A 
Global Rating of Perceived Change (subject and 
clinician) 
A 
Adverse Events 
A 
Serum for anti-HLA Antibodies 
B 
PBMC Sample 
B 
Concomitant Medications 
A 
Sham Surgery or Cell Administration 
A 
Statistical Analysis 
SAS®, version 9.4 or higher 
A = EDC (Medidata RAVE); B = LIMS; C = IVRS; D = Core Laboratory Overread. 

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19.8 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.  The Sponsor will inform the Investigator as to when these documents no 
longer need to be retained.  These documents must be stored in a safe location and be available 
in the event of a regulatory audit. 
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. 
19.9 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 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. 
19.10 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. 

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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 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. 
19.11 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 from the results of the entire trial. 

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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 in the chronic stroke setting.  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.1  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.1  Given that the focus of SB623 
is to treat chronic stroke patients with persistent deficits in the motor domain of neurological 
function, the outcome measures we propose to use in our P2b study include: 
 
• 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 subdomains (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 F-M scale was developed specifically because prior scales focused on 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.2  The F-M scale is now one of the most widely 
recognized and clinically relevant measures of body function impairment after stroke.3 The 
motor component of the F-M scale in particular has well-established reliability and validity 
across different stroke recovery time points including chronic stroke.2, 4 
The F-M scale assesses several dimensions of impairment, including range of motion, pain, 
sensation, upper extremity, lower extremity, and balance.5  The specific items in the upper-
extremity subsections were derived from the Brunnstrom’s stages of post-stroke motor recovery.6 
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 shoulder, 
elbow, forearm, wrist, hand, hip, knee, and ankle.  The motor score ranges from 0 (hemiplegia) 
to a maximum of 100 points (normal motor performance).2  The F-M motor component consists 
of the 33-item upper-extremity subscale (UE-FM) and the 17-item lower-extremity subscale 
(LE-FM).5  The UE-FM ranges from 0 to 667 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.  For example, 

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many of the chronic stroke studies described below use the UE-FM alone to evaluate the specific 
effects of therapeutic intervention on upper limb motor function. 
The F-M scale assesses several impairment dimensions and has been extensively used in studies 
with chronic stroke patients.  In fact, in a systematic review of RCTs examining robot assisted 
therapy in chronic stroke, 60% of the RCTs included in analysis used the F-M scale as the 
primary outcome parameter.8  More recent RCTs investigating the use of patients continue to use 
the F-M motor scale as the primary outcome measure.9-12  Other studies include constraint 
induced therapy trials13, 14, brain-machine interface15, transcutaneous electrical nerve stimulation 
(primary outcome measure)16, 17 and mirror therapy (primary outcome measure in this 33 patient 
RCT).18 
20.2 Rationale for Narrow Domain Outcome Measures in Chronic Stroke Patients with 
Motor Deficit 
The neurological deficit associated with stroke depends on the location, extent and pattern of 
resolution of the infarction.  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.  Each of these domains can dominate the clinical 
presentation of stroke to a greater or lesser extent and may demonstrate different patterns of 
recovery.19 
In contrast to acute stroke, the chronic phase of stroke recovery is associated with incremental 
improvements in neurological function that typically occur asymmetrically in time and extent 
across these different domains.  Often the magnitude of clinical improvement seen in chronic 
stroke patients is less than in the acute stroke phase and therefore require the use of outcome 
measures specific to the neurological domain of interest in order to detect clinically meaningful 
change. 
Several narrow domain outcome measures have been devised, validated and applied to the 
assessment of clinical recovery in the chronic stroke setting.  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.1 
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 stroke patients with motor deficits is provided 
below. 
20.3 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.20, 21  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) in chronic stroke patients.22-27  
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.28  The ARAT consists of 19 items grouped into four hierarchical subscales: grasp, 

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grip, pinch, and gross movement.29 Summation of a 0-3 score in each item yields a total score 
between 0 and 57.1 
The ARAT provides a specific assessment of arm function, including proximal control and 
dexterity and may be predictive of improvement in ADL outcomes.1  The ARAT appears to be 
reliable (r = 0.98), valid (rho = 0.92) and responsive with adequate floor and ceiling effects (only 
12.5 to 17% of patients scoring the lowest or highest scores) in subjects with stroke .29 
The magnitude of change in the ARAT that is considered to be clinically meaningful differs 
according to the time post stroke.  According to Lang et al. patient expectations in the acute 
stroke setting are higher than in the chronic phase where patients may have a greater awareness 
of how smaller changes may be functionally beneficial and may have lower expectations for full 
recovery.30  In chronic stroke patients, a change of at least 6 points on the ARAT has been 
selected as a clinically meaningful threshold.24, 31, 32  For example, Murphy et al. found that a 
decrease in movement time by 5 seconds during the drinking task is associated with 6 points 
improvement in ARAT score.33  This is consistent with the fact that change scores of 5–10% of 
the scale range have been found to be clinically meaningful on a number of health related quality 
of life measures in a variety of patient populations.30 
20.4 Justification for use of Gait Velocity as a secondary endpoint 
Gait is commonly affected by stroke and Gait Velocity is a useful outcome measure of lower 
extremity function as walking speed predicts the level of disability.34, 35  as improvements are 
correlated with better quality of life.36 Furthermore, Gait Velocity measures are objective and 
have well defined thresholds.  For example, in the context of chronic stroke, a gait velocity that 
is greater than 0.8 m/s is associated with full community mobility; 0.4 to 0.8 m/s is associated 
with short walks in the community; and gait velocity less than 0.4 m/s with mobility limited to 
the home.36 In the chronic stroke setting, improvements in gait velocity are known to be related 
to the baseline level of immobility.  Given this fact, the LEAPS trial measured the proportion of 
subjects that moved at least one functional level of walking.34, 37  A 20% difference between 
treatment groups was considered to be clinically meaningful.35  These transitions from one level 
to another are associated with improvements in home or community ambulation, functional 
status, and quality of life.34  The minimal clinically important difference for improvement in gait 
velocity for subjects with subacute stroke is 0.16 m/s and based on the results of the LEAPS 
study there was no significant difference in improvement seen at 6 versus 12 months post 
intervention.38 
20.5 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 that includes stroke.39  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 stroke and other neurological diseases.  The domains 

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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.40  In short, the 
validity of the NeuroQOL measures for adults with stroke is supported with satisfactory internal 
consistency, test-retest reliability and significant correlations with many external validity 
measures. 
20.6 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.39  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. 
 
References Supporting Justification of Endpoints: 
 
1. 
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 
2. 
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 
3. 
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 
4. 
Duncan PW, Propst M, Nelson SG. Reliability of the fugl-meyer assessment of 
sensorimotor recovery following cerebrovascular accident. Physical therapy. 
1983;63:1606-1610 

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5. 
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 
6. 
Brunnstrom S. Motor testing procedures in hemiplegia: Based on sequential recovery 
stages. Physical therapy. 1966;46:357-375 
7. 
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 
8. 
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 
9. 
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 
10. 
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 
11. 
Lo Surdo JL, Millis BA, Bauer SR. Automated microscopy as a quantitative method to 
measure differences in adipogenic differentiation in preparations of human mesenchymal 
stromal cells. Cytotherapy. 2013;15:1527-1540 
12. 
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 
13. 
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 
14. 
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 
15. 
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 
16. 
Lindenberg R, Renga V, Zhu LL, Nair D, Schlaug G. Bihemispheric brain stimulation 
facilitates motor recovery in chronic stroke patients. Neurology. 2010;75:2176-2184 
17. 
Kim TH, In TS, Cho HY. Task-related training combined with transcutaneous electrical 
nerve stimulation promotes upper limb functions in patients with chronic stroke. The 
Tohoku journal of experimental medicine. 2013;231:93-100 
18. 
Wu CY, Huang PC, Chen YT, Lin KC, Yang HW. Effects of mirror therapy on motor 
and sensory recovery in chronic stroke: A randomized controlled trial. Archives of 
physical medicine and rehabilitation. 2013;94:1023-1030 
19. 
Cramer SC, Koroshetz WJ, Finklestein SP. The case for modality-specific outcome 
measures in clinical trials of stroke recovery-promoting agents. Stroke; a journal of 
cerebral circulation. 2007;38:1393-1395 
20. 
Lyle RC. A performance test for assessment of upper limb function in physical 
rehabilitation treatment and research. International journal of rehabilitation research. 

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Internationale Zeitschrift fur Rehabilitationsforschung. Revue internationale de 
recherches de readaptation. 1981;4:483-492 
21. 
Hsueh IP, Hsieh CL. Responsiveness of two upper extremity function instruments for 
stroke inpatients receiving rehabilitation. Clinical rehabilitation. 2002;16:617-624 
22. 
Etoh S, Noma T, Ikeda K, Jonoshita Y, Ogata A, Matsumoto S, et al. Effects of repetitive 
trascranial magnetic stimulation on repetitive facilitation exercises of the hemiplegic 
hand in chronic stroke patients. Journal of rehabilitation medicine. 2013;45:843-847 
23. 
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 
24. 
Kitago T, Liang J, Huang VS, Hayes S, Simon P, Tenteromano L, et al. Improvement 
after constraint-induced movement therapy: Recovery of normal motor control or task-
specific compensation? Neurorehabil Neural Repair. 2013;27:99-109 
25. 
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 
yi zhi. 2014;113:422-428 
26. 
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 
27. 
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 
28. 
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 
29. 
Zipp GPS, J. E. Strokedge taskforce. 2011:1-278 
30. 
Lang CE, Edwards DF, Birkenmeier RL, Dromerick AW. Estimating minimal clinically 
important differences of upper-extremity measures early after stroke. Archives of physical 
medicine and rehabilitation. 2008;89:1693-1700 
31. 
van der Lee JH, Wagenaar RC, Lankhorst GJ, Vogelaar TW, Deville WL, Bouter LM. 
Forced use of the upper extremity in chronic stroke patients: Results from a single-blind 
randomized clinical trial. Stroke; a journal of cerebral circulation. 1999;30:2369-2375 
32. 
van der Lee JH, Beckerman H, Lankhorst GJ, Bouter LM. The responsiveness of the 
action research arm test and the fugl-meyer assessment scale in chronic stroke patients. 
Journal of rehabilitation medicine. 2001;33:110-113 
33. 
Alt Murphy M, Willen C, Sunnerhagen KS. Responsiveness of upper extremity kinematic 
measures and clinical improvement during the first three months after stroke. 
Neurorehabil Neural Repair. 2013;27:844-853 
34. 
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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35. 
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 
36. 
Cramer SC. Improving outcomes after stroke by leaps (locomotor experience applied 
post-stroke) and bounds. Stroke; a journal of cerebral circulation. 2011;42:3659-3660 
37. 
Nadeau SE, Wu SS, Dobkin BH, Azen SP, Rose DK, Tilson JK, et al. Effects of task-
specific and impairment-based training compared with usual care on functional walking 
ability after inpatient stroke rehabilitation: Leaps trial. Neurorehabil Neural Repair. 
2013;27:370-380 
38. 
Tilson JK, Sullivan KJ, Cen SY, Rose DK, Koradia CH, Azen SP, et al. Meaningful gait 
speed improvement during the first 60 days poststroke: Minimal clinically important 
difference. Physical therapy. 2010;90:196-208 
39. 
(NINDS). NIoNDaS. User manual for the quality of life in neurological disorders (neuro-
qol) measures. 2010 
40. 
Cella D, Lai JS, Nowinski CJ, Victorson D, Peterman A, Miller D, et al. Neuro-qol: Brief 
measures of health-related quality of life for clinical research in neurology. Neurology. 
2012;78:1860-1867 
 

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21.0 APPENDIX B: WHO STANDARD TOXICITY CRITERIA 
The WHO Standard Toxicity Criteria is tabulated below in Table 6. 
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 6: 
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  

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Table 6: 
WHO (World Health Organization) Toxicity Criteria by Grade (Continued) 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Metabolic  
Hypocalcaemia 
(mg/dl)  
> 8.4  
8.4 - 7.8  
7.7 - 7.0  
6.9 - 6.1  
6  
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  

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Table 6: 
WHO (World Health Organization) Toxicity Criteria by Grade (Continued) 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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%  
-----  
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  
 
 

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Table 6: 
WHO (World Health Organization) Toxicity Criteria by Grade (Continued) 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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  
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  
 

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Table 6: 
WHO (World Health Organization) Toxicity Criteria by Grade (Continued) 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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  
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  
 

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Table 6: 
WHO (World Health Organization) Toxicity Criteria by Grade (Continued) 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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  
Fever of 
unknown origin  
Fever of unknown 
origin  
none  
37.1 - 38.0o C 98.7o - 
100.4o F  
38.1 - 40.0o C 100.5o - 
104o F  
> 40.0o C > 104.0o 
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  
   
   
   
   

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Table 6: 
WHO (World Health Organization) Toxicity Criteria by Grade (Continued) 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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, anti-coagulant, or non-steroidal anti-inflammatory drugs during the 
conduct of this study will be in accordance with the ACCP 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 the surgery visit. These patients should re-start Warfarin after surgery 
as appropriate. 
• 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 anti-platelet drugs (including NSAIDs) 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 (e.g. Lovenox).  
• Anticoagulants (including antiplatelet or non-steroidal anti-inflammatory drugs 
(NSAIDs) 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.  
• Other than patients at high risk of VTE, no antiplatelet, anti-coagulant, 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 
 
 

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23.0 REFERENCES 
                                                 
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