Study of intra-carotid injection of autologous CD34-positive cells in chronic ischemic stroke between 150 and 365 days after onset

JRCT ID: jRCT2052200112

Registered date:15/01/2021

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: chronic ischemic stroke
• Date of first enrollment: 14/06/2021
• Target sample size: 16
• Study type: Interventional

Intervention(s)

Randomization: Participants will be randomly assigned to either CD34 cell therapy or placebo group with a 1:1 allocation by minimization as dynamic allocation. Randomization will be calculated within the following score of the FMA-upper extremity (at S2) and age (at the time of consent) as allocation adjustment factors (minimization factors). This approach will be incorporated into the electronic data capture (EDC) system.
Intervention: In the treatment period, all patients enrolled in this study will receive subcutaneous administration of granulocyte-colony stimulating factor (G-CSF) for 5 days (on Day 1-5). Subsequently, mononuclear cells mobilized from bone marrow to peripheral blood by G-CSF treatment will be collected by leukaheresis on Day 5. CD34+ cells will be isolated using a magnetic cell sorting system (MB-001) on Day 6. The patients allocated to CD34+ cell therapy group will receive intracarotid injection of CD34+ cells suspended in normal saline (via a catheter inserted into the internal carotid artery from the femoral artery), and the patients allocated to placebo group will receive intravenous injection of normal saline (via a sheath placed in the femoral vein) on Day 6. Post-treatment observation will be performed up to 24 weeks after injection.
In this study, rescue treatment will be provided for the patients in placebo group who complete the double-blind period. As a rescue treatment, frozen-thawed CD34+ cells will be injected into the internal carotid artery. The post-treatment observation period and items after injection will be the same as in the double-blind study.

Outcome(s)

• Primary Outcome: The primary endpoint of FMA (upper extremity including hand) score change from baseline(S2) at 24 weeks of study drug adminitration.

Secondary Outcome

The secondary endpoints are efficacy and safety categories.

Efficacy. We will evaluate the efficacy of the investigational
drug based on the following parameters:
FMA (upper extremity including hand) score: change from baseline at 4 and 12 weeks.
FMA (lower extremity) score: change from baseline at 4, 12 and 24 weeks.
NIHSS score: change from baseline at 4, 12 and 24 weeks.
BRS score: change from baseline at 4, 12 and 24 weeks.
MAS score: change from baseline at 4, 12 and 24 weeks.
FIM score: change from baseline at 4, 12 and 24 weeks.
BI score: change from baseline at 4, 12 and 24 weeks.
MMSE score: change from baseline at 4, 12 and 24 weeks.

Safety. The safety evaluation indices of this clinical trial are as follows:
Adverse events, including adverse event incidence rate, serious, adverse event, grade, and outcome. Laboratory tests change, including hematological examination, blood biochemical examination, and vital signs change.

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: <= 85age old
• Gender: Both

Include criteria

1) Ischemic stroke of the middle cerebral artery territory
2) Modified Rankin Scale (mRS) score of more than 0 or 1 before the onset of ischemic stroke, and 3 or 4 at the time of signing the consent
3) Onset of between 150 and 365 days at the time of informed consent
4) Change in NIHSS score during the screening period (4 weeks) is 1 or less
5) Both of Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score at S1 and S2 are between 15 and 50, and change in FMA-UE score is 5 or less during the screening period.
6) Mini-Mental State Examination (MMSE) score of 24 or more
7) Modified Ashworth scale (MAS) score of the wrist and elbow is 3 or less each.
8) No contraindication to brain magnetic resonance imaging (MRI)
9) Patients who meet the following conditions at screening: WBC count 3,000 to 10,000 per uL, Platelet count greater than or equal to 100,000 per uL, Hemoglobin greater than or equal to 8.0 g per dL, Serum AST or ALT less than or equal to 2.5 times the upper limit of normal, Serum creatinine less than or equal to 1.5 times the upper limit of normal, Serum albumin greater than or equal to 2.5 g per dL
10) Age between 20 and 85 years at the time of signing the consent
11) Female patients of childbearing potential, who have a negative serum or urine pregnancy test and agree to use an adequate method of contraception during the study period
12) Male patients who agree to use an adequate method of contraception during the study period
13) Patient or patient's legally authorized representative has signed an Informed Consent Form.

Exclude criteria

1) Patients who have undergone endovascular treatment (percutaneous endothelial angioplasty, stenting surgery, etc.) or surgical treatment (carotid endarterectomy, bypass surgery, etc.) within 3 months prior to the time of infrmed consent or are scheduled within the study period
2) Recurrence of ischemic stroke or transient ischemic attack after the first onset of ischemic stroke
3) Patients with hemorrhagic diathesis or abnormal blood coagulation
4) [missing number] (Exclusion criteria deleted)
5) Baseline brain MRI reveals any cerebral aneurysm, Moyamoya disease or Cerebral artery dissection requiring endovascular treatment or surgery on brain MRI
6) Patients with cardiogenic cerebral infarction, who are not properly controlled by anticoagulants
7) Imaging test (including echocardiography, cardiac MRI or cardiac CT) reveals any intracardiac thrombus, atrial myxoma, other cardiac tumor or valve vegitation
8) Patients with non-cardiogenic cerebral infarction, who does not receive any antiplatelet drugs
9) Ischemic stroke of the posterior cerebral artery territory
10) Malignant tumor within 5 years prior to the time of signing the consent
11) Patients undergoing radiation therapy, cancer chemotherapy, or receiving any oral steroids or immunosuppressive drugs
12) Patients who are complicated with the following conditions:
Liver cirrhosis and/or clinically significant abnormality in liver function, Uncontrolled endocrine metabolic disorders, New-onset of unstable angina or myocardial infarction after ischemic stroke, Uncontrolled severe arrhythmia (asymptomatic and well controlled atrial fibrillation is permitted), Congestive heart failure (more than or equal to NYHA Grade II)
13) Uncontrolled hypertension (systolic blood pressure more than 160mmHg or diastolic blood pressure more than 100mmHg)
14) Uncontrolled Diabetes mellitus (HbA1c more than 8.0%)
15) Uncontrolled dyslipidemia (total cholesterol more than 400 mg per dL)
16) Allergy or hypersensitivity to human serum albumin
17) History of allergy, hypersensitivity or any serious adverse reaction to G-CSF and apheresis
18) History of allergy, hypersensitivity or any adverse reaction to mouse-derived protein, iron or iron-dextran complex
19) Proliferative diabetic retinopathy
20) Myeloproliferative disease or myelodysplastic syndrome
21) Autoimmune diseases, or patients receiving any oral immunosuppressive drugs
22) History or presence of interstitial pneumonia
23) Screening laboratory tests reveal positivity for hepatitis B virus, hepatitis C virus, human immunodeficiency virus, or human T-cell leukemia virus type 1 or syphilis
24) Abdominal CT reveals a clinically significant splenomegaly
25) History of allergy to contrast agents (more than or equal to Grade 2)
26) History of significant alcohol or drug abuse
27) Patients with psychiatric disease or symptoms, judged as difficulty participating in this study by the investigators
28) Patients who has participated in another clinical study within 3 months prior to signing the consent, or are scheduled to participate in another clinical study during the course of this study
29) Preganant or breastfeeding
30) Patients judged inappropriate by the investigators

Related Information

• Primary Sponsor: Sakai Nobuyuki
• Secondary Sponsor: Kawamoto Atsuhiko
• Source(s) of Monetary Support: Foundation for Biomedical Research and Innovation at Kobe,SENSHIN Medical Research Foundation