Allogeneic Adipose Tissue-derived Mesenchymal Stem Cells in Ischemic Stroke

Study Overview
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Brief Summary
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This is a multicenter, doble blind, placebo controlled clinical trial to asses de safety and efficacy of intravenous administration of alogenic adipose tissue-derived mesenchymal stem cells in the first four days from acute ischemic stroke.

Detailed Description
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Two spanish hospitals with teams experienced in stroke management will participate in this study, recruiting a total of 30 patients between them both. After confirming that patients fulfill the inclusion criteria and none of the exclusion criteria, informed consent will be signed and randomization will take place (1:1). There are two different groups of treatment; the first group will be treated with intravenous alogenic adipose tissue-derived stem cells (at a concentration of one million cells per kg) within the first four days from stroke onset, the second group will be treated will an intravenous placebo solution. Follow-up will last for 24 months during which safety issues such as adverse events and neurological and systemic complications will be assessed at 24 hours, 7 days and 3, 6, 12,18 and 24 months after treatment. Neurological disability using the modified Rankin Scale and National Institute of Health Stroke Scale will also be registered in every scheduled visit. Biochemical markers of tissue repair (GM-CSF, BDNF, VEGF, TGF-1, GFAP, MBP, MMP-3) as well as extracellular vesicles will be extracted on baseline visit as well as 7 days and 3 months after treatment.

Official Title
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Allogeneic Adipose Tissue-derived Mesenchymal Stem Cells in Ischemic Stroke. A Phase IIB Multicenter Double Blind Placebo Controlled Clinical Trial

Conditions
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Ischemic Stroke, Adipose Tissue-derived Stem Cell, Functional Status

Intervention / Treatment
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* Other: Alogenic adipose tissue-derived stem cells
* Drug: Placebo solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ischemic stroke patients > 18 years old Patients must be able to be treated within the first 4 days (+/- 1) from acute stroke symptoms onset. If the time of symptom onset is unknown, this shall refer to the last time the patient was observed as asymptomatic. A computed tomography (CT) or magnetic resonance imaging (MRI) scan compatible with the clinical diagnosis of acute non-lacunar IS in the region of the middle cerebral artery (with cortical or subcortical involvement). A score on the National Institute of Health Stroke Scale (NIHSS) of 8-20, with at least two of these points in sections 5 and 6 (motor deficit) at the time of inclusion. NIHSS evaluation for screening of these patients will take place after finalization of reperfusion therapies (if they have been performed) providing that the clinical condition of the patient is stable with no prevision of immediate recovery. A measurable focal neurologic disabilty must persist to the time of treatment. A prestroke score on the Modified Rankin Scale (mRS) ≤1 (no significant disability). Female subjects non-child bearing potential. Female subjects who are of non-childbearing potential are defined as meeting at least 1 of the following criteria: Have undergone a documented hysterectomy and/or bilateral oophorectomy; Have medically confirmed ovarian failure; or Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause. Female subjects of child-bearing potential need a negative pregnancy test and must agree to use adequate contraception for the duration of the study (from screening through the final of the study). The following types of contraception are considered adequate provided they are locally authorized for use: oral, transdermal, or injectable (depot) estrogen and/or progestogen, selective estrogen receptor modulator therapy, intrauterine contraceptive device, double barrier method (e.g., condom and diaphragm or spermicidal gel) or vasectomy. Signed informed consent Exclusion Criteria: Comatose patients; patients with a score of 2 or more on item 1a of the NIHSS related to the degree of awareness. Evidence on neuroimaging of brain tumour, cerebral oedema with midline shift and a clinically significant compression of ventricles, cerebellar or brainstem infarction and intraventricular, intracerebral or subarachnoid haemorrhage. Small petechial haemorrhages are not exclusion criteria. Current drug or alcohol use or dependence Active infectious disease, including human immunodeficiency virus, hepatitis B, and hepatitis C. A controlled infection is not an exclusion criterion. Pre-existing dementia. A health status, any clinical condition (eg, short life expectancy, and coexisting disease or a surgical or endovascular planned procedure) or other characteristic that precludes appropriate diagnosis, treatment, or follow-up in the trial. Patients who are participating in another clinical trial. Inability or unwillingness of the individual or their legal guardian/representative to provide written informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two different treatment grupos; intravenous alogenic adipose tissue-derived mesenchymal stem cells or intravenous placebo solution
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group<br>15 patients will receive intravenous alogenic adipose tissue-derived stem cells in a single dose of one million cells per kg. | Other: Alogenic adipose tissue-derived stem cells<br>* Concentration of the cells: 10 million cells / ml<br>|
| Placebo Comparator: Placebo group<br>15 patients will receive a single intravenous placebo solution with the same appearance as the treatment group. | Drug: Placebo solution<br>* Placebo intravenous solution, same appearance stem cells solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of administration of adipose tissue-derived mesenchymal stem cells measured as reported adverse events | Adverse events reported spontaneously or in response to questions not addressed. | Up to 24 months after treatment or placebo administration | 
| Safety of administration of adipose tissue-derived mesenchymal stem cells measured as neurological o systemic complications | Neurological or systemic complications | Up to 24 months after treatment or placebo administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of administration of adipose tissue-derived mesenchymal stem cells measured by the Modified Rankin Scale | Modified Rankin Scale (mRS): success is considered when the patient obtains a score of 0-3, and failure include scores of 4 to 6 at months 3,6,12 and 24. An additional exploratorry efficacy analysis of mRS shift at months 3,6,12 and 24 will also be made. | Up to 24 months after treatment or placebo administration | 
| Efficacy of administration of adipose tissue-derived mesenchymal stem cells measured by the NIHSS | National Institute of Health Stroke Scale. It will be measured at all scheluded visits. Success is defined as an improvement of 75% or more from baseline. An additional exploratory analysis will look for differences in the distribution of median (IQR) and in the frequency of NIHSS ≤ 1between groups. | Up to 24 months after treatment or placebo administration | 
| Efficacy of administration of adipose tissue-derived mesenchymal stem cells measuring blood brain repair biomarkers | Brain repair biomarkers in blood samples (GM-CSF, PDGF-BB, BDNF, VEGF, TGF-1, GFAP, MBP, MMP-3 and extracelular vesicles) measured at baseline, day 7 and mnth 3 after treatment or placebo administration. | Up to 3 months after treatment or placebo administration |