A Study of Modified Stem Cells in Traumatic Brain Injury (TBI)

Study Overview
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Brief Summary
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The primary purpose of the clinical study is to evaluate the clinical efficacy of intracranial administration of SB623 cells on patients with chronic motor deficit from Traumatic Brain Injury. A secondary purpose of the study is 1) to evaluate the effect of intracranial administration of SB623 cells on disability parameters and 2) to evaluate the safety and tolerability of intracranial administration of SB623 cells. Patients with stable, chronic motor deficits secondary to focal traumatic brain injury must be 12 months post TBI.

Detailed Description
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This study was a multicenter, randomized (3:1) double-blind, active and sham-surgery controlled study to evaluate the safety, tolerability, and efficacy of stereotactic intracranial injection of SB623 cells in patients with fixed motor deficits from TBI. The study was conducted at approximately 22 sites across the United States, Ukraine, and Japan. Two groups, Group 1 and Group 2, received investigational product SB623 and sham surgery, respectively, in a 3:1 randomization scheme. Group 1 was further randomized in a 1:1:1 ratio to receive either 2.5 million, 5 million, or 10 million SB623 cells. Randomization was performed via an interactive web response system (IWRS).

Official Title
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A Double-Blind, Controlled Phase 2 Study of the Safety and Efficacy of Modified Stem Cells (SB623) in Patients With Chronic Motor Deficit From Traumatic Brain Injury (TBI)

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Biological: SB623 cells
* Procedure: Sham Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented history of TBI, with correlated MRI or CT At least 12 months post-TBI Focal cerebral injury able to be identified on MRI (+/- concomitant diffuse axonal injury) Neurological motor deficit substantially due to focal cerebral injury observed on MRI GOS-E score of 3-6 (i.e. moderate or severe disability) Require Motricity Index 10-81 (UE Scale) and/or 10-78 (LE Scale) Able and willing to undergo computed tomography (CT) and magnetic resonance imaging (MRI) Subjects must be willing to participate in study related exercises to the extent possible Able to undergo all planned neurological assessments Exclusion Criteria: History or presence of any other major neurological disease Any seizures in the prior 3 months The presence of contracture at any joints that would interfere with interpretation of any of the neurological assessments (e.g. contracture preventing the detection of any increase in the range of motion or ability to perform a task) Other neurologic, neuromuscular or orthopedic disease that limits motor function Clincially significant finding on MRI of brain not related to TBI Known presence of any malignancy except squamous or basal cell carcinoma of the skin History of CNS malignancy Positive findings on tests for occult malignancy, unless a non-malignant etiology is confirmed Uncontrolled systemic illness, including, but not limited to: hypertension (systolic >150 mm Hg or diastolic >95 mm Hg); diabetes; renal, hepatic, or cardiac failure Uncontrolled major psychiatric illness, including depression symptoms (CESD-R Scale of ≥16) Unexplained abnormal preoperative test values (blood tests, electrocardiogram [ECG], chest X-ray); x-ray evidence of infection; uncontrolled atrial fibrillation or uncontrolled congestive heart failure Presence of craniectomy (without bone flap replacement) or other contraindication to stereotactic surgery Participation in any other investigational trial within 4 weeks of initial screening or within 7 weeks of study entry Botulinum toxin injection, phenol injection, intrathecal baclofen, or any other interventional treatments for spasticity (except bracing and splinting) 16 weeks priot to the Baseline visit. Ongoing use of other non-traditional drugs Substance use disorder (per DSM-V criteria, including drug or alcohol) Contraindications to head CT or MRI Pregnant or lactating Female patients of childbearing potential unwilling to use an adequate birth control method during the 12 months of the study

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 Cells<br>SB623 Cells: 2.5, 5 or 10 million cells | Biological: SB623 cells<br>* SB623 cells will be implanted in the peri-infarct area using stereotactic surgery.<br>|
| Sham Comparator: Sham Surgery<br>Control Sham Surgery | Procedure: Sham Control<br>* Sham Surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fugl-Meyer Motor Scale (FMMS) Score at Week 24 Among All Patients | 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). | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disability Rating Scale Score at Week 24 Among All Patients | DRS is an observer rated, 30-point ordinal scale that evaluates eight areas of functioning in four categories: Consciousness (eye opening, verbal response, motor response) Cognitive ability (feeding, toileting, grooming) Dependence on others Employability Each area of functioning was rated on a scale of 0 to either 3 or 5. The maximum score is 29 (extreme vegetative state) and the minimum score is 0 (person without disability). | 24 weeks | 
| Change From Baseline in ARAT Total Score at Week 24 Among Upper Extremity Deficit Patients | The ARAT total score is the sum of the scores from 19 tests spread across four subscales: grasp, grip, pinch, and gross movement. Each test is scored on an ordinal 4-point scale with 0= non movement, 1 = the movement task is partially performed, 2 = the movement task is completed but takes abnormally long, and 3 = the movement is performed normally. Summation of a 0-3 score in each item yields a total score between 0 and 57. | 24 weeks | 
| Change From Baseline in Gait Velocity (10 Meter Walk Time in Seconds) at Week 24 Among Lower Extremity Deficit Patients | Gait Velocity was measured on a standard 10 meter walk. | 24 weeks | 
| Change From Baseline in NeuroQOL T-scores at Week 24 of NeuroQOL Domains | Two NeuroQoL short form assessments were used (upper extremity function and lower extremity function); each has 8 items with 5 possible scores (e.g. 1= not at all, 2=a little bit, 3= somewhat, 4=quite a bit, 5=very much) or frequency (neverto always); Raw scores are converted to T-scores based on a consistent metric (i.e., the T distribution) and data from the US general population. The theoretical range in scale for Upper extremity T-score and Lower extremity T-score are 12.8 to 53.8 and 16.5 to 58.6 respectively. When interpreting these T-scores, higher scores correspond to higher levels of functioning whereas lower scores correspond to lower levels of functioning. | 24 weeks | 
| Global Rating of Perceived Change: The Percentage of Subjects Scoring Either 6 or 7 on the Global Rating of Perceived Change by Both Subject and Physician | The proportions of SB623 treated subjects (pooling all SB623 doses) scoring either 7 (much better) or 6 (a little better, meaningful) on the Global Rating of Perceived Change (from Baseline) - Subject at Week 24 and on the Global Rating of Perceived Change (from Baseline) - Clinician at Week 24 was compared to the corresponding proportions of sham surgery control subjects using logistic regression models with adjustment for the baseline Fugl-Meyer Motor Scale score and the GOS-E score at screening as continuous covariates. 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 | 24 weeks |