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

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

• Umbilical Cord Blood (Biological), also known as cord blood, hematopoietic stem cells: 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.
• Placebo (Other): 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.

Primary outcomes

• Shift in Modified Rankin Scale (mRS) [baseline to 3 months post infusion]: The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 to 6, where 6 = death. Since a shift downward in the mRS scale is considered a clinical improvement, shift scores are calculated from baseline to ensure that, for hypothesis testing purposes, larger shift values represent more clinically desirable outcomes.

Secondary outcomes

• Number of Infusion Reactions [up to 1 year post infusion]
• Number of Product-related Infections [up to 1 year post infusion]
• Number of Alloimmunization Events [up to 1 year post infusion]
• Number of Graft vs. Host Disease Events [up to 1 year post infusion]
• Number of Study Related and Unexpected Adverse Events (AEs) [up to 1 year post infusion]
• Mortality [up to 1 year post infusion]
• Number of Participants With Functional Independence [90 days post infusion]: Functional independence at 90 days defined as a 90-day mRS (modified Rankin Scale) score of 0, 1, or 2. The mRS has a range of 0 to 5, where lower scores indicate a better outcome.
• Shift in Modified Rankin Scale (mRS) From Baseline to 30 Days Post Infusion [baseline to 30 days post infusion]: The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 to 6, where 6 = death. Since a shift downward in the mRS scale is considered a clinical improvement, shift scores are calculated from baseline to ensure that, for hypothesis testing purposes, larger shift values represent more clinically desirable outcomes.
• Shift in Modified Rankin Scale (mRS) From Baseline to 180 Days Post Infusion [baseline to 180 days post infusion]: The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 to 6, where 6 = death. Since a shift downward in the mRS scale is considered a clinical improvement, shift scores are calculated from baseline to ensure that, for hypothesis testing purposes, larger shift values represent more clinically desirable outcomes.
• The National Institutes of Health Stroke Scale (NIHSS) Score at 90 Days [90 days post infusion]: The NIHSS has a range of 0 to 42, where higher scores indicate greater impairment.
• Barthel Index (BI) Score at 90 Days [90 days post infusion]: The Barthel Index assesses functional independence, generally in stroke patients. The BI has a range of 0 to 100 with 0 indicating total dependency and 100 indicating complete independence.
• Stroke Impact Scale-16 (SIS-16) Score at 90 Days [90 days post infusion]: The SIS-16 has a range of 0 to 100 with higher scores indicating a higher quality of life.
• The European Quality of Life (EQ-5D-3L) Visual Analogue Score (VAS) at 90 Days [90 days post infusion]: The EQ-5D-3L VAS ranges from 0 to 100 with 0 being the worst possible health status and 100 being the best possible health status.
• Patient Health Questionnaire Scale (PHQ 8) Score at 90 Days [90 days post infusion]: The PHQ 8 has a range of 0 to 24 with 0 indicating no depression and 24 indicating severe depression.
• Telephone Interview for Cognitive Status (TICS) Total Score at 30 Days Post Infusion [30 days post infusion]: The TICS has a range of 0 to 41 with a higher score indicating better cognitive status.
• Telephone Interview for Cognitive Status (TICS) Total Score at 1 Year Post Infusion [1 year post infusion]: The TICS has a range of 0 to 41 with a higher score indicating better cognitive status.
• Trail Making Test Score at 90 Days Post Infusion (Trail A) [90 days post infusion]: Both parts of the Trail Making Test consist of 25 circles distributed over a sheet of paper. In Part A, the circles are numbered 1 - 25, and the patient should draw lines to connect the numbers in ascending order. Reported in seconds needed to complete Trail A.
• Trail Making Test Score at 90 Days Post Infusion (Trail B) [90 days post infusion]: Both parts of the Trail Making Test consist of 25 circles distributed over a sheet of paper. In Part B, the circles include both numbers (1 - 13) and letters (A - L); as in Part A, the patient draws lines to connect the circles in an ascending pattern, but with the added task of alternating between the numbers and letters. Reported in seconds needed to complete Trail B.
• Montreal Cognitive Assessment (MoCA) Score at 90 Days Post Infusion [90 days post infusion]: The MoCA has a range of 0 to 30 with lower scores indicating more severe cognitive impairment.
• Hopkins Verbal Learning Test-Revised (HVLT-R) Score at 90 Days Post Infusion [90 days post infusion]: The HVLT-R is a sum of three trials involving word recall. It has a total range of 0 to 36 with higher scores indicating better recall and greater cognition.
• Short Form 36 Health Survey (SF-36) Scores at 90 Days Post Infusion [90 days post infusion]: For all sub-components (Physical Functioning, Role Limitations Due to Physical Health, Role Limitations Due to Emotional Problems, Energy/Fatigue, Emotional Well-being, Social Functioning, Pain, and General Health), a higher score indicates better health. Scales are standardized to obtain a score ranging from 0 to 100 and a mean score of 50 has been articulated as a normative value for all scales.
• Controlled Oral Word Association Test (COWAT) Score at 90 Days Post Infusion [90 days post infusion]: The COWAT is a verbal fluency test in which participants are asked to say as many words as possible from a given category and in a specified timeframe (typically 60 seconds). Reported as the total number of words produced for F, A, and S. More words indicates better cognition.
• Oral Symbol Digit Modalities Test (SDMT) Score at 90 Days Post Infusion [90 days post infusion]: The SDMT is a measure of processing speed wherein the participant is given 120 seconds to orally match symbols with digits as quickly as possible. Reported as the number of correct associations where a larger number indicates better cognition.

Sex: All, ages: 18 Years to 90 Years

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

Participant flow

Outcome results

• Shift in Modified Rankin Scale (mRS) (Primary), Median, score on a scale: Umbilical Cord Blood 1 (0 to 2); Placebo 1 (0 to 2) (p 0.71)
• Number of Infusion Reactions (Secondary), Number, reactions: Umbilical Cord Blood 13; Placebo 4
• Number of Product-related Infections (Secondary), Number, infections: Umbilical Cord Blood 0; Placebo 0
• Number of Alloimmunization Events (Secondary), Number, events: Umbilical Cord Blood 0; Placebo 0
• Number of Graft vs. Host Disease Events (Secondary), Number, events: Umbilical Cord Blood 0; Placebo 0
• Number of Study Related and Unexpected Adverse Events (AEs) (Secondary), Number, events: Umbilical Cord Blood 0; Placebo 0
• Mortality (Secondary), Count of participants, Participants: Umbilical Cord Blood 4; Placebo 1
• Number of Participants With Functional Independence (Secondary), Count of participants, Participants: Umbilical Cord Blood 15; Placebo 6
• Shift in Modified Rankin Scale (mRS) From Baseline to 30 Days Post Infusion (Secondary), Median, shift in score: Umbilical Cord Blood 1 (0 to 1); Placebo 1 (0 to 1)
• Shift in Modified Rankin Scale (mRS) From Baseline to 180 Days Post Infusion (Secondary), Median, shift in score: Umbilical Cord Blood 1 (1 to 2); Placebo 1 (1 to 2)
• The National Institutes of Health Stroke Scale (NIHSS) Score at 90 Days (Secondary), Median, score on a scale: Umbilical Cord Blood 6 (3 to 9); Placebo 6 (3 to 10)
• Barthel Index (BI) Score at 90 Days (Secondary), Median, score on a scale: Umbilical Cord Blood 80 (50 to 100); Placebo 85 (45 to 97.5)
• Stroke Impact Scale-16 (SIS-16) Score at 90 Days (Secondary), Median, score on a scale: Umbilical Cord Blood 59 (42 to 76); Placebo 64 (41.5 to 76.5)
• The European Quality of Life (EQ-5D-3L) Visual Analogue Score (VAS) at 90 Days (Secondary), Median, score on a scale: Umbilical Cord Blood 70 (50 to 85); Placebo 75 (55 to 80)
• Patient Health Questionnaire Scale (PHQ 8) Score at 90 Days (Secondary), Median, score on a scale: Umbilical Cord Blood 4 (2 to 8); Placebo 5 (2 to 10)
• Telephone Interview for Cognitive Status (TICS) Total Score at 30 Days Post Infusion (Secondary), Median, score on a scale: Umbilical Cord Blood 27 (19 to 32); Placebo 21 (10 to 28)
• Telephone Interview for Cognitive Status (TICS) Total Score at 1 Year Post Infusion (Secondary), Median, score on a scale: Umbilical Cord Blood 31 (25 to 35); Placebo 30 (23 to 33)
• Trail Making Test Score at 90 Days Post Infusion (Trail A) (Secondary), Median, seconds: Umbilical Cord Blood 78 (56 to 178); Placebo 62 (44 to 90)
• Trail Making Test Score at 90 Days Post Infusion (Trail B) (Secondary), Median, seconds: Umbilical Cord Blood 278 (226 to 300); Placebo 300 (142 to 300)
• Montreal Cognitive Assessment (MoCA) Score at 90 Days Post Infusion (Secondary), Median, score on a scale: Umbilical Cord Blood 21 (14.5 to 24.5); Placebo 20 (8.5 to 24)
• 4 more outcome measures not shown.

Adverse events

Time frame: Up to 1 year

Serious adverse events by term

Other adverse events by term

36 more terms not shown.

• Study Protocol and Statistical Analysis Plan (PDF, 2018-02-19)

• Joanne Kurtzberg, MD, Principal investigator, Duke University