Study of Allogeneic Umbilical Cord Blood Infusion for Adults With Ischemic Stroke (CoBIS 2)

• ClinicalTrials.gov Identifier: NCT03004976
• Recruitment Status: Active, not recruiting
• First Posted: December 29, 2016
• Last Update Posted: August 17, 2020
• Sponsor: Joanne Kurtzberg, MD
• Collaborators: The Marcus Foundation; Emory University; M.D. Anderson Cancer Center
• Information provided by (Responsible Party): Joanne Kurtzberg, MD, Duke University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Stroke; Stroke, Acute; Brain Injury, Acute	Biological: Umbilical Cord Blood; Other: Placebo	Phase 2

Detailed Description:

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study of Allogeneic Umbilical Cord Blood Infusion for Adults With Ischemic Stroke - CoBIS 2
• Actual Study Start Date: March 14, 2017
• Actual Primary Completion Date: July 17, 2020
• Estimated Study Completion Date: March 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Umbilical Cord Blood; A single intravenous infusion of umbilical cord blood within 3-10 days following stroke.	Biological: Umbilical Cord Blood; Umbilical cord blood will be infused intravenously through a peripheral IV line after premedication with diphenhydramine, hydrocortisone, and acetaminophen. Units will be from a public cord blood bank with selection based on blood type, race, and the number of cells in the pre cryopreservation product, targeting a dose range of 0.5 to 5 x 10^7 TNCC/kg.; Other Name: cord blood, hematopoietic stem cells
Placebo Comparator: Placebo; A single intravenous infusion of diluent with the same appearance and odor as a cord blood unit within 3-10 days following stroke.	Other: Placebo; The placebo product will be acellular and will consist of tissue culture medium 199 (TC-199 [pink]) with 1% dimethyl sulfoxide (DMSO), which are standard components in cellular products. The volume of placebo product will be 50 mL, which is in the range of a typical UCB unit that has been washed and thawed after cryopreservation. Infusion and premedication procedures will be the same as those conducted for the umbilical cord blood arm.

Outcome Measures

Primary Outcome Measures :

1. Shift in modified Rankin Scale (mRS) [ Time Frame: 3 months post infusion ]
   shift in modified Rankin Scale (mRS) from baseline to 3 months post infusion.

Secondary Outcome Measures :

1. Incidence and severity of infusion reactions [ Time Frame: 1 year post infusion ]
   Incidence and severity of infusion reactions
2. Incidence and severity of product-related infections [ Time Frame: 1 year post infusion ]
   Incidence and severity of product-related infections
3. Incidence of alloimmunization [ Time Frame: 1 year post infusion ]
   Incidence of alloimmunization
4. Incidence and severity of graft vs. host disease [ Time Frame: 1 year post infusion ]
   Incidence and severity of graft vs. host disease
5. Incidence and severity of study related and unexpected AEs [ Time Frame: 1 year post infusion ]
   Incidence and severity of study related and unexpected AEs
6. Mortality [ Time Frame: 1 year post infusion ]
   Mortality
7. Functional independence [ Time Frame: 90 days post infusion ]
   Functional independence at 90 days defined as a 90-day mRS score of 0, 1, or 2
8. mRS shift [ Time Frame: 30 days post infusion ]
   shift in mRS score between baseline and day 30
9. mRS shift [ Time Frame: 180 days post infusion ]
   shift in mRS score between baseline and day 180
10. NIHSS [ Time Frame: 90 days post infusion ]
    The National Institutes of Health Stroke Scale (NIHSS) score at 90 days
11. Barthel Index [ Time Frame: 90 days post infusion ]
    The Barthel Index (BI) score at 90 days
12. Stroke Impact Scale [ Time Frame: 90 days post infusion ]
    Stroke Impact Scale-16 (SIS-16) score at 90 days
13. European Quality of Life [ Time Frame: 90 days post infusion ]
    The European Quality of Life (EQ-5D-3L) survey score at 90 days
14. Patient Health Questionnaire Scale [ Time Frame: 90 days post infusion ]
    Patient Health Questionnaire Scale (PHQ 8) score at 90 days
15. Telephone Interview for Cognitive Status [ Time Frame: 30 days post infusion ]
    Telephone Interview for Cognitive Status (TICS) total score at 30 days post infusion
16. Telephone Interview for Cognitive Status [ Time Frame: 1 year post infusion ]
    Telephone Interview for Cognitive Status (TICS) total score at 1 year post infusion
17. Trail Making Test [ Time Frame: 90 days post infusion ]
    Trail Making Test score at 90 days post infusion
18. Montreal cognitive Assessment (MoCA) [ Time Frame: 90 days post infusion ]
    Montreal cognitive Assessment score at 90 days post infusion
19. Hopkins Verbal Learning Test-Revised (HVLT-R) [ Time Frame: 90 days post infusion ]
    Hopkins Verbal Learning Test-Revised score at 90 days post infusion
20. Patient Health Questionnaire (PHQ-8) [ Time Frame: 90 days post infusion ]
    Patient Health Questionnaire score at 90 days post infusion
21. Short Form 36 Health Survey (SF-36) [ Time Frame: 90 days post infusion ]
    Short Form 36 Health Survey score at 90 days post infusion
22. Controlled Oral Word Association test (COWAT) [ Time Frame: 90 days post infusion ]
    Controlled Oral Word Association Test score at 90 days post infusion
23. Oral Symbol Digit Modalities Test (SDMT) [ Time Frame: 90 days post infusion ]
    Oral Symbol Digit Modalities Test score at 90 days post infusion

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 18-90 years old
2. Recent, acute, cortical, hemispheric, ischemic stroke in the MCA distribution without a clinically significant midline shift as detected by MRI as a DWI 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 >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 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 <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

Contacts and Locations

Locations

United States, Colorado

University of Colorado Anschutz Medical Campus

Aurora, Colorado, United States, 80045

United States, Florida

University of Florida Health Shands Hospital

Gainesville, Florida, United States, 32610

United States, Georgia

Emory University School of Medicine

Atlanta, Georgia, United States, 30303

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, United States, 27157

United States, Texas

Houston Methodist

Houston, Texas, United States, 77030

Sponsors and Collaborators

Joanne Kurtzberg, MD

The Marcus Foundation

Emory University

M.D. Anderson Cancer Center

Investigators

• Principal Investigator: Joanne Kurtzberg, MD; Duke University

More Information

• Responsible Party: Joanne Kurtzberg, MD, Director, Robertson Clinical and Translational Cell Therapy Program, Duke University
• ClinicalTrials.gov Identifier: NCT03004976
• Other Study ID Numbers: Pro00077580
• First Posted: December 29, 2016
• Last Update Posted: August 17, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Joanne Kurtzberg, MD, Duke University:

hematopoietic stem cells; umbilical cord blood; stroke; ischemic stroke

Additional relevant MeSH terms:

Stroke; Brain Injuries; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries