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

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

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.

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.

Inclusion Criteria:

1. Men or women (women must be of non-child bearing potential), age 30-75 yrs.

2. Have a stroke that is observed within 90 days of the onset of symptoms

3. Radiologically

   1. Relevant lesions within the middle cerebral artery territory (MCA) as assessed using diffusion-weighted imaging (DWI).
   2. The maximum diameter of the stroke region in any dimension must be ≥15 mm.
   3. Not involving more than a half of the ipsilateral periventricular zone

4. Clinically (National Institutes of Health stroke scale, NIHSS)

   1. Moderate-to severe persistent neurologic deficit (NIHSS of 6-21 inclusive)
   2. 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.
   3. Must be alert or drowsy but easily arousable as defined by score of 0-1 on the NIHSS Level of Consciousness question (item 1).
   4. "Slow recovery" defined as Change in NIHSS ≤1 point/3 days

5. Willingness

   1. Reasonable likelihood of receiving standard physical, occupational and speech rehabilitation therapy as indicated for the post stroke deficits.
   2. Able to participate in the evaluation process to the point of accurate assessment.
   3. Willing and able to comply with scheduled visits, lifestyle guidelines, treatment plan, laboratory tests, and other study procedures.
   4. Evidence of a personally signed and dated informed consent document.

Exclusion Criteria:

1. 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.

2. Have a stroke that is either

   1. lacunar infarction
   2. Hematologic cause of stroke
   3. Recurrent or progressive stroke within 1 week at the time of screening.

3. Hematologic disorders or bone marrow suppression.

4. Have a severe medical illness

   1. Severe heart failure
   2. Severe febrile illness
   3. Hepatic or renal dysfunction
   4. Active cancer
   5. 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.

5. Presence of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or syphilis on admission blood tests

6. 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.

7. Presence of dementia prior to the current stroke that is likely to confound clinical evaluation.

8. Pregnant females as determined by positive urine human chorionic gonadotropin (hCG) test or lactating females.

9. Subjects considered unwilling or unable to comply with the procedures and study visit schedule outlined in the protocol

10. Subjects unwilling to undergo bone marrow aspiration