The STem Cell Application Researches and Trials In NeuroloGy-2 (STARTING-2) Study

Study Overview
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Brief Summary
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The objectives of this study was to test hypothesis that ischemic stroke patients having moderate to severe persistent neurologic deficit will have better outcomes with intravenous transplantation of autologous mesenchymal stem cells (MSCs) expanded with autologous serum that is obtained at acute phase of stroke than patients receiving standard treatment.

Detailed Description
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In this study, we will use autologous 'ischemic' serum that obtained at the earliest time point as possible (immediate after randomization) for the purpose of ischemic preconditioning. We have recently conducted preclinical studies on the effects of ischemic preconditioning on the MSC functions. We have evaluated the characteristics of rat MSCs after culture with fetal bovine serum (FBS) or serum obtained from rat stroke model. Compared to FBS, the use of serum obtained from rat stroke model resulted in more rapid expansion of MSCs, which reduces cell preparation time by increase in G2/M phase, decreased cell death/senescence, increased trophic factor secretion, and increased migration capacity.

Official Title
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Intravenous Administration of Autoserum-cultured Autologous Mesenchymal Stem Cells in Ischemic Stroke: A Single Center, Randomized, Open Label, Prospective, Phase 3 Study

Conditions
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Stroke, Ischemic

Intervention / Treatment
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* Other: Mesenchymal stem cell


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women (women must be of non-child bearing potential), age 30-75 yrs. Have a stroke that is observed within 90 days of the onset of symptoms Radiologically Relevant lesions within the middle cerebral artery territory (MCA) as assessed using diffusion-weighted imaging (DWI). The maximum diameter of the stroke region in any dimension must be ≥15 mm. Not involving more than a half of the ipsilateral periventricular zone Clinically (National Institutes of Health stroke scale, NIHSS) Moderate-to severe persistent neurologic deficit (NIHSS of 6-21 inclusive) New onset of extremity paresis on the affected side, defined as a score of 2-4 on the NIHSS Motor Arm (item 5) or Leg (item 6) question. Must be alert or drowsy but easily arousable as defined by score of 0-1 on the NIHSS Level of Consciousness question (item 1). Slow recovery defined as Change in NIHSS ≤1 point/3 days Willingness Reasonable likelihood of receiving standard physical, occupational and speech rehabilitation therapy as indicated for the post stroke deficits. Able to participate in the evaluation process to the point of accurate assessment. Willing and able to comply with scheduled visits, lifestyle guidelines, treatment plan, laboratory tests, and other study procedures. Evidence of a personally signed and dated informed consent document. Exclusion Criteria: Presence of significant disability prior to the current stroke. Significant disability is defined as having a pre-stroke modified Rankin score of 2 or more. Have a stroke that is either lacunar infarction Hematologic cause of stroke Recurrent or progressive stroke within 1 week at the time of screening. Hematologic disorders or bone marrow suppression. Have a severe medical illness Severe heart failure Severe febrile illness Hepatic or renal dysfunction Active cancer Any evidence of chronic co-morbid condition or unstable acute systemic illnesses which, in the opinion of the investigator, could shorten the subject's survival or limit ability to complete the study. Presence of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or syphilis on admission blood tests Presence of depression that is active and not adequately controlled such that it interfere with major activities of daily living immediately prior to the current stroke. Presence of dementia prior to the current stroke that is likely to confound clinical evaluation. Pregnant females as determined by positive urine human chorionic gonadotropin (hCG) test or lactating females. Subjects considered unwilling or unable to comply with the procedures and study visit schedule outlined in the protocol Subjects unwilling to undergo bone marrow aspiration

Ages Eligible for Study
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Minimum Age: 30 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mesenchymal stem cell treatment<br> | Other: Mesenchymal stem cell<br>* intravenous transplantation of autologous mesenchymal stem cells expanded with autologous serum<br>|
| No Intervention: Standard treatment<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Categorical shift in modified Rankin scale (mRS) | Categorical shift in mRS at 90 days after the cell treatment | 90 days after the cell treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of National Institutes of Health stroke scale (NIHSS) | Change of NIHSS between pre- and post-treatment 90 days | 90 days after the cell treatment | 
| Early improvement of National Institutes of Health stroke scale (NIHSS) | ≥5 points improvement or score of 0-2 on NIHSS score at 14 days after treatment | 14 days after the cell treatment | 
| Dichotomized modified Rankin scale (mRS) | mRS ≤2 at 90 days after treatment | 90 days after the cell treatment | 
| Change of modified Rankin scale (mRS) | Change of mRS between pre- and post-treatment 90 days | 90 days after the cell treatment | 
| Dichotomized modified Barthel index (mBI) | mBI ≥60 at 90 days after treatment | 90 days after the cell treatment | 
| Change of modified Barthel index (mBI) | Change of mBI between pre- and post-treatment 90 days | 90 days after the cell treatment | 
| Change of gross motor function | Change of Gross motor function (Motricity index and Fugl-Meyer assessment)between pre- and post-treatment 90 days | 90 days after the cell treatment | 
| Change of Fine motor function | Change of Fine motor function (Purdue Pegboard test and Box and block test) between pre- and post-treatment 90 days | 90 days after the cell treatment | 
| Change of Mobility | Change of Mobility (Functional ambulatory category and 10m-Gait speed) between pre- and post-treatment 90 days | 90 days after the cell treatment | 
| Change of mini-mental status exam (MMSE) | Change of MMSE between pre- and post-treatment 90 days | 90 days after the cell treatment | 
| Change of quality of life | Change of EuroQol 5d (EQ-5D) between pre- and post-treatment 90 days | 90 days after the cell treatment | 
| Safety outcome | Death: All causes of death Recurrence: Recurrent stroke or transient ischemic attack The immediate reaction: Allergic reactions (tachycardia, fever, skin eruption, leukocytosis) Local complications (hematoma or local infection at the site of bone marrow aspiration) Vascular obstruction (tachypnea, oliguria, or peripheral vascular insufficiency) Systemic complications (infections,laboratory findings). Long-term adverse effects possibly related to MSC treatment Tumor formation (physical examination, plain x-ray, f/u MRI at 90 days after treatment), Aberrant connections (newly diagnosed seizure or arrhythmia) | During 90 days after the cell treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stroke, Mesenchymal stem cells, Stem cells, Neurogenesis