The Effect of GD-iExo-003 in Acute Ischemic Stroke

Study Overview
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Brief Summary
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This is a multicenter, randomized, double-blinded, placebo-controlled, dose-escalation trial. The objective of this study is evaluating safety and preliminary efficacy of intravenous exosomes derived from human induced pluripotent stem cell (GD-iExo-003) in acute ischemic stroke.

Detailed Description
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This is a multicenter, randomized, double-blinded, placebo-controlled, dose-escalation trial. This study will consist of 2 parts, with part 1 being a dose-escalation study and part 2 being an expanded safety study based on part 1 findings. A traditional 3+3 dose escalation design will be implemented in part 1. Cohort 1 receive 20μg/kg; cohort 2 40μg/kg and cohort 3 80μg/kg. If no dose-limiting toxicities (DLTs) are observed for 2 weeks after administration of the first injection, a new cohort will be enrolled at the next planned dose level. If DLTs are observed in 1 participant in the cohort, another 3 participants will be treated in the same dose level. Dose escalation will be stopped until DLTs are observed in >33% of the participants. In part 2, 20 subjects will be randomized in a 1:1 ratio [exosome (n=10) or exosome placebo (n=10)]. The dose level will be determined by Data Safety Monitoring Board based on part 1.

Official Title
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The Effect of Exosomes Derived From Human Induced Pluripotent Stem Cell (GD-iExo-003) in Acute Ischemic Stroke: an Exploratory Study.

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: exosomes derived from human induced pluripotent stem cell for injection
* Drug: a placebo of exosomes derived from human induced pluripotent stem cell for injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of acute ischemic stroke Age 18-70 years, inclusion of both genders Modified Rankin Scale score before stroke of 0-1 NIHSS score 6-20 at inclusion that did not change by ≥4 points from screening to baseline assessment. Time of stroke onset is known and treatment can be started between day 1 and 7 of onset. Confirmation of hemispheric cortical infarct with magnetic resonance imaging or computed tomography Subjects who received intravenous thrombolysis or underwent mechanical reperfusion are eligible if they meet all other eligibility criteria. Adequate hepatic and renal function: serum aspartate aminotransferase ≤2.5× upper limit of normal; serum alanine aminotransferase ≤2.5× upper limit of normal; blood urea nitrogen ≤1.25× upper limit of normal; serum creatinine ≤1.25× upper limit of normal Adequate cardiac function. Subjects or legal representative can sign the informed consent and must be willing and able to comply with all aspects of treatment and follow-up schedule. Exclusion Criteria: Presence of intracranial hemorrhage on CT including hemorrhagic stroke, epidural hematoma, subdural hematoma, intraventricular hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage or hemorrhagic transformation, etc. Presence of a lacunar or a brainstem infarct as the etiology of current symptoms. Evidence of brain tumor or history of epilepsy or traumatic brain injury. Subjects with present malignant disease. Subjects with severe comorbidities including immunodeficiency or coagulation disorders. Subjects with Alzheimer's disease, Parkinson's disease or other degenerative neurological disease. Ongoing systemic infection, severe local infection or taking immunosuppressants. Subjects with negative hepatitis B surface antibody (HBsAg) and positive hepatitis B core antibody (HBcAb), or HBsAg-positive virus carriers, positive hepatitis C antibody, positive syphilis antibody or HIV Allergy to the study products. Documented allergies Participation in any clinical trial in the last 3 months Inability or unwillingness to comply with the study schedule Pregnancy, childbearing potential (unless it is certain that pregnancy is not possible), oe breast feeding Other serious medical or psychiatric illness that is not adequately controlled Other circumstances that the investigator considers inappropriate for participation in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exosomes group<br>Patients in this arm will be given exosomes derived from human induced pluripotent stem cell for injection once a day for 7 days. | Drug: exosomes derived from human induced pluripotent stem cell for injection<br>* Exosomes derived from human induced pluripotent stem cell for injection (3.0ml, protein concentration 1mg/mL).<br>* Other names: GD-iExo-003;|
| Placebo Comparator: Exosomes placebo group<br>Patients in this arm will be given a placebo of exosomes derived from human induced pluripotent stem cell for injection once a day for 7 days. | Drug: a placebo of exosomes derived from human induced pluripotent stem cell for injection<br>* Exosomes placebo, 3.0ml<br>* Other names: GD-iExo-003 placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who experienced dose-limiting Toxicities (DLTs) | DLTs related to exosome is defined as any of the following: (1) Grade 3-4 infusion-related allergic adverse events consisting of perturbation of cardiovascular, respiratory function, or allergic reactions occurring in the first 24h postinfusion of investigational product; (2) grade 3-4 adverse events through seven days after administration of the last injection; (3) neurologic worsening defined as a 4-point increase in NIHSS compared with baseline NIHSS assessed through seven-days after administration of the last injection; and (4) rate of intracranial hemorrhage. Adverse event is graded in Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0). | 14±2 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of severe adverse events | The proportion of patients who experienced severe adverse events. | 90±7 days | 
| Favorable functional outcome | Rate of favorable functional outcome defined as a modified Rankin Scale (mRS, scores range from 0 to 6, with 0 to 2 indicating favorable outcome and 3 to 6 indicating unfavorable outcome including 6 as death) score of 0-2. | 90±7 days | 
| Functional outcome | The range of mRS scores by shift analysis. | 90±7 days | 
| NIHSS score change | The change of National Institutes of Health Stroke Scale (NIHSS) score of day 7 to baseline. | 7 days | 
| NIHSS score change | The change of National Institutes of Health Stroke Scale (NIHSS) score of day 14 to baseline. | 14±2 days | 
| Quality of Life (EQ-5D-5L) | The value of EQ-5D-5L score. | 90±7 days | 
| Barthel Index (BI) | The value of BI | 90±7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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exosome