Study of Allogeneic Umbilical Cord Blood Infusion for Adults With Ischemic Stroke

Phase 2 Study of Allogeneic Umbilical Cord Blood Infusion for Adults With Ischemic Stroke - CoBIS 2

The primary objective of this study is to determine the efficacy of a single intravenous infusion of unrelated donor umbilical cord blood (UCB) for improving functional outcomes in patients with ischemic stroke. Eligible subjects will receive an intravenous infusion of UCB or placebo 3-10 days following stroke. Subjects will not receive immunosuppressive or myeloablative medications prior to the infusion. Subjects will be followed for one year post infusion for safety and efficacy. Assessments will examine safety and tolerability of the infusion, change in neurological symptoms, change in quality of life, and emotional and cognitive status. Assessments will occur at 24 hours post infusion, and at 30, 90, 180 and 365 days post infusion.

This is a multicenter, placebo controlled, randomized, double blinded Phase 2 study in 100 subjects 18-90 years of age who have sustained a recent ischemic stroke. Potential subjects can be screened and consented the day of their stroke (Day 1). Treatment with umbilical cord blood (UCB) cells or placebo will be administered intravenously as a single infusion as early as 3 days but no later than 10 days after the patient's stroke. UCB units will be selected from an accredited U.S. public cord bank based on blood type, race and a targeted cell dose ranging between 0.5 to 5 x 10^7 total nucleated cell count (TNCC)/kg. Study subjects will not receive immunosuppressive or myeloablative medications prior to infusion of the cord blood or placebo.

All subjects, families and medical staff will be blinded to treatment arm. When a subject is randomized to study drug at a clinical site without a cord blood bank, the selected cord blood units (CBU) will be shipped frozen overnight to the site. Once selected and available on site, each CBU will be thawed, washed, tested, released and infused intravenously using common standard operating procedures (SOPs) at all sites. For subjects randomized to placebo, a diluent with the same appearance and odor as a CBU will be prepared.

Patients will have baseline magnetic resonance imaging (MRI) and will be assessed at 1, 3, 6, and 12 months for functional outcomes. All patients will receive standard of care therapy while enrolled in this study and all subjects will be strongly encouraged to participate in rehabilitative therapy.

The primary objective of the study is to determine, in a randomized, placebo controlled trial, the efficacy of a single intravenous (IV) infusion of unrelated donor UCB for improving functional outcomes in patients with ischemic stroke. The secondary objectives are as follows:

1. To describe the safety and tolerability of a single IV infusion of unrelated donor UCB in patients with ischemic stroke
2. To evaluate the efficacy of a single IV infusion of unrelated donor UCB for improvement of neurological symptoms following ischemic stroke
3. To evaluate the efficacy of a single IV infusion of unrelated donor UCB for improvement in quality of life and emotional and cognitive status in patients with ischemic stroke

Inclusion Criteria:

1. 18-90 years old

2. Recent, acute, cortical, hemispheric, ischemic stroke in the MCA (middle cerebral artery) distribution without a clinically significant midline shift as detected by MRI as a DWI (diffusion-weighted imaging) abnormality. If unable to obtain a MRI scan, patients may be included if there is clear evidence of ischemic cortical involvement in the MCA distribution demonstrated by computed tomography and a clinical exam consistent with cortical involvement.

3. NIHSS 6-15 (R) and 6-20 (L) at the time of informed consent. Subjects with a >4-point increase of NIHSS from time of consent (worsening of score) will not be eligible for infusion.

4. Subjects must have a platelet count >100,000/uL, hemoglobin >8gm/dL, absolute lymphocyte count (ALC) ≥ 1200 for African American patients and ≥1500 for all other racial-ethnic groups, and WBC (white blood cell) count >2,500/uL OR Historical pre-stroke value of ALC ≥ 1200 for African American and ≥1500 for all other racial-ethnic groups within 6 months of stroke

   -And- a post stroke ALC value of ≥ 1000, platelet count >100,000/uL, hemoglobin >8gm/dL and WBC >2,500/uL.

5. Subjects who received tPA (Tissue plasminogen Activator) or underwent endovascular reperfusion may be included in the study

6. Able to provide consent to study or consent is obtained from the patient's legal representative

7. Subjects of childbearing potential must practice effective contraception during the study, and be willing to continue contraception for at least 6 months after intervention so that, in the opinion of the Investigator, they will not become pregnant during the course of the study

8. Is a good candidate for the trial, in the opinion of the Investigator

9. Agrees to participate in follow-up visits

10. ABO/Rh and race matched CBU(s) with a minimum of 0.5 x 10^7 TNCC/kg based on the pre-cryopreservation TNCC is available for infusion

11. Has not had a disease or therapy that would compromise current immune function.

12. Has a serum creatinine ≤2 mg/dL OR Glomerular Filtration Rate (GFR) ≥30mL/min

Exclusion Criteria:

An individual is ineligible to participate if any of the following apply:

Exclusionary Medical Conditions:

1. Medical history of neurological or orthopedic pathology with a deficit as a consequence that results in a modified Rankin Scale >1 before stroke or has a pre existing cognitive deficit
2. Clinically significant and/or symptomatic hemorrhage associated with stroke
3. Evidence of significant midline shift as assessed by CT or MRI who are felt to be at high risk for neurological decompensation or need for decompressive hemicraniectomy due to hemispheric edema
4. New intracranial hemorrhage, edema, or mass effect that may place patient at increased risk for secondary deterioration when assessed prior to infusion
5. Hypotension as defined as the need for IV pressor support of SBP (systolic blood pressure) <90
6. Isolated brain stem stroke
7. Pure lacunar stroke
8. At time of consent, patients who are mechanically ventilated or, at the investigator's discretion are felt to be likely to need mechanical ventilation are excluded.
9. Requires a craniotomy
10. Serious psychiatric or neurological disease which could alter evaluation on functional or cognitive scales
11. Active systemic infection that is felt, at the discretion of the Investigator, to place the patient at increased risk for participation in this study
12. Documentation of human immunodeficiency virus positive (HIV+) status in the medical record
13. Active malignancy within 3 years prior to the start of screening excluding skin cancers other than melanoma
14. Known hypercoagulable state or coagulopathy deficiencies such as Factor V Leiden, Antiphospholipid Syndrome (APC), Protein C, Protein S, anticardiolipin antibody, phospholipid syndrome or Sickle Cell Disease
15. History of or currently active autoimmune disease, or current immunomodulatory therapy or a recipient of immunomodulatory therapy in the past year.
16. Concurrent illness or condition that in the opinion of the Investigator might interfere with treatment or evaluation of safety
17. Current or recent history of alcohol or drug abuse, or stroke associated with drug abuse that Investigator feels may impair therapy or assessments
18. Pregnant as documented by blood test

Prohibited Concomitant or Prior Therapies

1. Patients currently receiving immunosuppressant drugs, not including glucocorticoid taper, topical/inhaled glucocorticoids
2. History of prior transfusion reaction
3. Currently on dialysis
4. Recipient of bone marrow or organ transplant
5. Hepatic insufficiency (bilirubin >2.5mg/dL or transaminases >5x the ULN) Patients with Gilberts syndrome are eligible for study enrollment if other liver function tests are normal, regardless of bilirubin level
6. Previous or current treatment with angiogenic growth factors, cytokines, gene or stem cell therapy
7. Participating in another interventional clinical trial of an investigational therapy within 30 days of consent.

Other Exclusion Criteria

1. Pregnant or lactating women
2. Unable or unwilling to be evaluated for follow-up visits