Study of Modified Stem Cells (SB623) in Patients With Chronic Motor Deficit From Ischemic Stroke

Study Overview
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Brief Summary
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Controlled study of stereotactic, intracranial injection of SB623 cells in patients with fixed motor deficits from ischemic stroke

Detailed Description
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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 2.5 million SB623 cells, 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).

Official Title
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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

Conditions
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Chronic Ischemic Stroke

Intervention / Treatment
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* Biological: SB623 Implant (2.5M)
* Biological: SB623 Implant (5.0M)
* Procedure: Sham surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75 years, inclusive Documented history of completed ischemic stroke in subcortical region of MCA or lenticulostriate artery with or without cortical involvement, with correlated findings by MRI Between 6 and 90 months (7.5 years) post-stroke, and having a chronic motor neurological deficit Neurological motor deficit substantially due to incident stroke Modified Rankin Score of 2-4 Require Motricity Index 30-75 (UE Scale) or 27-74 (LE Scale) Able to undergo all planned neurological assessments Able and willing to undergo magneti resonance imaging (MRI) with contrast and computed tomography (CT) Agree that use of antiplatelet, anti-coagulant, or non-steroidal anti-inflammatory drugs to be determined by the local medical staff and 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, if applicable , provided that 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 Subjects must have had physical therapy prior to entry (and be willing to continue to the extent possible) Must be willing to discontinue herbal or non-traditional medicines for 1 week before and 1 week after the surgical procedure and be willing to continue to the extent possible Ability of patient or legal authorized representative to understand and sign an Informed Consent Exclusion Criteria: History or presence of any other major neurological disease other than stroke Cerebral infarct size >150 cm3 measured by MRI Primary intracerebral hemorrhage Myocardial infarction within prior 6 mos. Malignancy unless in remission >5 yrs. Clinically significant finding on MRI of brain not related to stroke Any seizures in the 3 months prior to Screening More than 5 degrees of contracture at shoulder, elbow, wrist, fingers, hip, knee and ankle Other neurologic, neuromuscular or orthopedic disease that limits motor function Uncontrolled systemic illness, including, but not limited to: hypertension; diabetes; renal, hepatic, or cardiac failure Positive findings on tests for occult malignancy, unless a non-malignant etiology is confirmed Uncontrolled major psychiatric illness, including depression symptoms (CESD R Scale of ≥16 is exclusionary) Total bilirubin >1.9 mg/dL at Screening Serum creatinine >1.5 mg/dL at Screening Hemoglobin <10.0 g/dL at Screening Absolute neutrophil count <2000 /mm3 at Screening Absolute lymphocytes <800 /mm3 at Screening Platelet count <100,000 /mm3 at Screening Liver disease supported by AST (SGOT) or ALT (SGPT) ≥2.5 x upper limit of normal at Screening Serum calcium >11.5 mg/dL at Screening 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 Presence of craniectomy or other contraindication to stereotactic surgery Participation in any other investigational trial within 4 weeks of initial screening and within 7 weeks of Baseline visit 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 Substance use disorder (per DSM-V criteria, including drug or alcohol) Contraindications to head MRI (with constrast) or CT Pregnant or lactating Female patients of childbearing potential unwilling to use an adequate birth control method during the 12 months of the study 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 Any prior SB623 cell implantation and/or any prior stem cell treatment for stroke or other reason regardless of mode of administration

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SB623 Implant (2.5M)<br>2.5 million SB623 cells | Biological: SB623 Implant (2.5M)<br>* 2.5 million SB623 cells<br>|
| Experimental: SB623 Implant (5.0M)<br>5 million SB623 cells | Biological: SB623 Implant (5.0M)<br>* 5 million SB623 cells<br>|
| Sham Comparator: Sham Control<br>Sham surgery | Procedure: Sham surgery<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Whose Fugl-Meyer Motor Total Score (FMMS) Improved by ≥ 10 Points at Month 6 From Baseline | The FMMS is used as a clinical measure of body function impairment after stroke that assesses several dimensions of motor impairment, including range of motion in both upper and lower limbs, reflex activity, volitional movement, and co-ordination. The FMMS motor component consists of the 33-item upper extremity subscale (UE-FMMS) and the 17-item lower extremity subscale (LE-FMMS). Items were scored on a 3-point ordinal scale: 0= cannot perform; 1= partial motion; 2= full motion Individual items were then summed to determine scores for the 2 subscale scores, as well as a motor total score (total of all item scores including the 2 subscales UE-FMMS and LE-FMMS). As a result, the UE-FMMS subscale score ranged from 0 to 66 and the LE-FMMS subscale score ranged from 0 to 34. The FMMS motor total score ranged from 0 (hemiplegia) to a maximum of 100 points (normal motor performance). Responders: subjects whose FMMS motor total score improve by ≥10 points at Month 6 from Baseline | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin Scale Response: The Proportion of Subjects That Improved at Least One Point on the mRS From Baseline | Responders: The subjects that improved at least one point on the mRS from Baseline Modified Rankin Scale (mRS): This scale is used to measure the degree of disability or dependence in the daily activities of people who had suffered a stroke. The mRS is an ordinal scale from 0 (no symptoms at all) to 5 (severe disability; requiring constant nursing care and attention, bedridden, incontinent) with a sixth category of death. | 6 months | 
| The Proportion of Subjects That Improved at Least 6 Points From Baseline on the ARAT Total Score at the Affected Side | Responders: The subjects that improved at least 6 points from Baseline on the ARAT total score at the affected side. Action Research Arm Test (ARAT): The test was scored for left and right side separately. Performance on each item was rated on a 4-point ordinal scale ranging from: 3 (performed test normally in less than 5 seconds); 2 (completed test, but took abnormally long or had great difficult, with time varying from 5 to 60 seconds; 1 (performed test partially); 0 (could perform no part of the test). The ARAT is a 19-item measure divided into 4 subtests: Grasp subscale (with 6 items and a score range of 0 to 18); Grip subscale with 4 items and a score range of 0 to 12); Pinch subscale with 6 items and a score range of 0 to 18); Gross arm movement subscale (with 3 items and a score range of 0 to 9). The maximum score on the ARAT is 57 points (possible range 0 to 57) for each side. | 6 months | 
| The Proportion of Subjects That Improved at Least 1 Functional Level From Baseline on Gait Velocity | Responders: The subjects that improved at least 1 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) from Baseline on Gait Velocity. Gait Velocity was measured on a standard 10 meter walk. Two trials were tested and the average result from both was used for analysis | 6 months | 
| Neurological Quality of Life Response: T-scores of the Change From Baseline in the 2 Sub-domains (Upper Extremity Function and Lower Extremity Function) | The Neurological Quality of Life (NeuroQOL) was used as a measure of change in the levels of Quality of Life, Satisfaction and Participation, secondary to improvements in the subject's upper and lower extremity motor function. NeuroQOL is summation of item scores for upper extremity (8 terms: score 8 - 40) and lower extremity (8 items: score 8 - 40) separately. The item scores are on a 1 to 5 scale (1 = unable to do; 2 = with much difficulty; 3 = with some difficulty; 4 = with little difficulty; 5 = without any difficulty). The result provided here shows NeuroQOL score converted to T-score. The range for Upper extremity T-score and Lower extremity T-score are 12.8 to 53.8 and 16.5 to 58.6 respectively. | 6 Months | 
| Global Rating of Perceived Change (GRPC): The Proportion of Subjects Scoring Either 7 or 6 on the Global Rating of Perceived Change by Both Subject and Clinician | Responders: Participants who scored either 7 [much better] or 6 [a little better, meaningful]) Global Rating of Perceived Change from Baseline: Subjects and Clinicians were 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 was completed by the subject (or by the caregiver using the subject's answers). The following 7-point Likert scale was used: Score 7 (much better); Score 6 (a little better, meaningful); Score 5 (a little better, not meaningful); Score 4 (about the same); Score 3 (a little worse, not meaningful); Score 2 (a little worse, meaningful); Score 1 (much worse) | 6 Months (LOCF) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ischemic stroke, chronic stroke, fixed motor deficits