Safety and Efficacy of Human Adipose-Derived Stem Cell Exosomes in Acute Ischemic Stroke

Official title

Clinical Study on the Safety and Efficacy of Human Adipose-Derived Stem Cell Exosomes in the Treatment of Acute Ischemic Stroke

Overview

This is a Phase I/II, randomized, double-blind, placebo-controlled, single/multiple ascending dose clinical study (Investigator-Initiated Trial, IIT) evaluating the safety and efficacy of Human Adipose-Derived Stem Cell Exosomes (ADSC-exo, STX11102 Nasal Spray) in treating acute ischemic stroke (AIS). The study consists of two sequential parts: a Single-Ascending Dose (SAD) study and a Multiple-Ascending Dose (MAD) study. The SAD part will enroll 12 subjects with mild stroke (NIHSS 1-4). They will be sequentially enrolled into three dose cohorts (4 subjects each: 2×10⁹, 4×10⁹, and 8×10⁹ particles/mL) to receive a single nasal spray dose alongside standard care, with safety monitoring for 14 days. Dose escalation is contingent upon the safety review of the preceding cohort. Upon confirming safety, the study proceeds to the MAD part, which will enroll 48 subjects with moderate stroke (NIHSS 5-12). They will be randomized into two dose groups (Low and High Dose), each containing an active treatment arm and a placebo arm (saline) in a 2:1 ratio (16 active:8 placebo per group). Subjects will self-administer the nasal spray daily for 14 days, with follow-up until Day 90. The primary objective is to evaluate safety, with secondary objectives assessing efficacy via neurological function scales (NIHSS, mRS, BI) and infarct volume change on MRI.

Detailed description

This clinical trial is designed to investigate the novel therapeutic agent Human Adipose-Derived Stem Cell Exosomes (ADSC-exo, STX11102) delivered via nasal spray for patients with acute ischemic stroke (AIS). The rationale is based on promising preclinical data demonstrating that intranasally administered ADSC-exo can cross the blood-brain barrier, modulate neuroinflammation, reduce infarct volume, and promote functional recovery in animal stroke models.

Study Design and Phases:

The trial employs a two-part, early-phase exploratory design integrating dose-finding and preliminary efficacy assessment.

Part 1: Single-Ascending Dose (SAD) Study: This is an open-label, dose-escalation phase to assess initial safety and tolerability. Twelve subjects with mild AIS (NIHSS 1-4, onset within 72 hours) will be enrolled at a single center. Three dose levels will be tested sequentially: Dose Cohort 1 (2×10⁹ particles/mL), Cohort 2 (4×10⁹ particles/mL), and Cohort 3 (8×10⁹ particles/mL), with 4 subjects per cohort. All subjects will receive a single dose of ADSC-exo nasal spray plus standard care. Escalation to the next higher dose cohort requires completion of the 14-day safety observation for all subjects in the current cohort and a formal safety review by the Principal Investigator (PI) and the sponsor. Escalation is permitted only if the number of subjects experiencing Grade ≥3 adverse events (AEs) considered related to the study drug is ≤50% (i.e., ≤2 subjects) within the completed cohort.

Part 2: Multiple-Ascending Dose (MAD) Study: This is a randomized, double-blind, placebo-controlled, dose-expansion phase to further evaluate safety and explore efficacy. Forty-eight subjects with moderate AIS (NIHSS 5-12, onset within 72 hours) will be enrolled across approximately five centers. Entry into this part requires a favorable safety review of all data from the SAD part. Subjects will be randomized into two sequential dose groups (Low Dose and High Dose). The specific doses (X and Y ×10⁹ particles/mL) for the MAD part will be determined based on SAD results. Each dose group consists of 24 subjects randomized in a 2:1 ratio to receive either ADSC-exo nasal spray (n=16) or matching placebo (saline, n=8) daily for 14 days, in addition to standard care. The Low Dose group must complete enrollment and 14-day safety follow-up before the High Dose group begins enrollment, applying the same safety criteria (≤50% of subjects with related Grade ≥3 AEs) for progression.

Study Population: Key inclusion criteria: age 18-80, anterior circulation ischemic stroke, pre-stroke mRS ≤1. Key exclusion criteria: severe stroke (NIHSS \>12), lacunar/brainstem/cerebellar infarct, need for endovascular intervention, intracranial hemorrhage, malignancy, immunodeficiency, significant hepatic/renal impairment, active severe infection, and positive serology for HIV, HBV (with positive DNA), HCV, or syphilis.

Endpoints:

Primary Safety Endpoints: Incidence, severity, and causality of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs); changes in nasal mucosa, pulmonary function, and immunoglobulins.

Secondary Efficacy Endpoints:

SAD: Change from baseline in NIHSS, mRS, and Barthel Index (BI) at Day 14.

MAD: Change in NIHSS at Day 14; change in mRS and BI at Days 7, 14, 30, and 90; change in cerebral infarct lesion volume on MRI at Day 90.

Exploratory Endpoints (MAD): Changes in inflammatory cytokines (IL-2, IL-6, IL-12, IL-1β, TNF-α, IFN-γ).

Study Procedures: The schedule includes a 7-day screening period, treatment period (1 day for SAD, 14 days for MAD), and a follow-up period (14 days for SAD, 76 days for MAD). Assessments include neurological scales (NIHSS, mRS, BI), laboratory tests, vital signs, ECGs, MRI, and pulmonary function tests.

Statistical Analysis: This is an exploratory study with a sample size based on clinical practice. Safety will be analyzed in the Safety Set (SS). Efficacy will be analyzed descriptively for the SAD part. For the MAD part, efficacy will be analyzed in the Full Analysis Set (FAS) and Intent-to-Treat (ITT) set using appropriate statistical models (e.g., ANCOVA for continuous endpoints, Cochran-Mantel-Haenszel test for

Interventions

• Biological Human Adipose-Derived Stem Cell Exosomes
  This intervention involves the use of allogeneic Human Adipose-Derived Stem Cell Exosomes (ADSC-exo), provided as a sterile nasal spray (STX11102).
• Other Placebo
  This intervention serves as the placebo control. It is a sterile 0.9% sodium chloride (normal saline) solution formulated as a nasal spray

Primary outcome measures

• Safety and Tolerability of ADSC-exo Nasal Spray in Acute Ischemic Stroke. [Time frame: For Single-Dose Study: From first dose on Day 1 through the end of safety follow-up at Day 14. For Multiple-Dose Study: From first dose on Day 1 through the end of safety follow-up, which extends up to 14 days after the last dose on Day 14.]
• Safety and Tolerability of ADSC-exo Nasal Spray in Acute Ischemic Stroke. [Time frame: For Single-Dose Study: From first dose on Day 1 through the end of safety follow-up at Day 14. For Multiple-Dose Study: From first dose on Day 1 through the end of safety follow-up, which extends up to 14 days after the last dose on Day 14.]
• Safety and Tolerability of ADSC-exo Nasal Spray in Acute Ischemic Stroke. [Time frame: For Single-Dose Study: From first dose on Day 1 through the end of safety follow-up at Day 14. For Multiple-Dose Study: From first dose on Day 1 through the end of safety follow-up, which extends up to 14 days after the last dose on Day 14.]
• Safety and Tolerability of ADSC-exo Nasal Spray in Acute Ischemic Stroke [Time frame: For Single-Dose Study: From first dose on Day 1 through the end of safety follow-up at Day 14. For Multiple-Dose Study: From first dose on Day 1 through the end of safety follow-up, which extends up to 14 days after the last dose on Day 14.]
• Safety and Tolerability of ADSC-exo Nasal Spray in Acute Ischemic Stroke [Time frame: For Single-Dose Study: From first dose on Day 1 through the end of safety follow-up at Day 14. For Multiple-Dose Study: From first dose on Day 1 through the end of safety follow-up, which extends up to 14 days after the last dose on Day 14.]
• Safety and Tolerability of ADSC-exo Nasal Spray in Acute Ischemic Stroke. [Time frame: For Single-Dose Study: From first dose on Day 1 through the end of safety follow-up at Day 14. For Multiple-Dose Study: From first dose on Day 1 through the end of safety follow-up, which extends up to 14 days after the last dose on Day 14.]
• Safety and Tolerability of ADSC-exo Nasal Spray in Acute Ischemic Stroke. [Time frame: For Single-Dose Study: From first dose on Day 1 through the end of safety follow-up at Day 14. For Multiple-Dose Study: From first dose on Day 1 through the end of safety follow-up, which extends up to 14 days after the last dose on Day 14.]
• Safety and Tolerability of ADSC-exo Nasal Spray in Acute Ischemic Stroke [Time frame: For Single-Dose Study: From first dose on Day 1 through the end of safety follow-up at Day 14. For Multiple-Dose Study: From first dose on Day 1 through the end of safety follow-up, which extends up to 14 days after the last dose on Day 14.]
• Safety and Tolerability of ADSC-exo Nasal Spray in Acute Ischemic Stroke [Time frame: For Single-Dose Study: From first dose on Day 1 through the end of safety follow-up at Day 14. For Multiple-Dose Study: From first dose on Day 1 through the end of safety follow-up, which extends up to 14 days after the last dose on Day 14.]

Secondary outcome measures (6)

• Change in Neurological Function (For Single-Dose Study) [Time frame: Baseline (Day 1, pre-dose) to Day 14 post-dose.]
• Change in NIHSS Score after 14-Day Treatment (For Multiple-Dose Study) [Time frame: Baseline (Day 1, pre-dose) to Day 14 (end of treatment).]
• Change in Disability & Daily Function (For Multiple-Dose Study) [Time frame: Baseline (Day 1, pre-dose) to Day 7, Day 14, Day 30, and Day 90.]
• Change in Cerebral Infarct Volume on MRI (For Multiple-Dose Study) [Time frame: Baseline MRI (within screening period, Day -7 to -1) to Day 90 MRI.]
• Change in Neurological Function (For Single-Dose Study) [Time frame: Baseline (Day 1, pre-dose) to Day 14 post-dose.]
• Change in Neurological Function (For Single-Dose Study) [Time frame: Baseline (Day 1, pre-dose) to Day 14 post-dose.]

Eligibility criteria

Inclusion criteria

• Age 18-80 years, male or female
• Patients with acute ischemic stroke within 72 hours of symptom onset
• Internal carotid artery system stroke
• For the single-dose study: mild stroke patients (NIHSS score 1-4, inclusive of 1 and 4)
• For the multiple-dose study: moderate stroke patients (NIHSS score 5-12, inclusive of 5 and 12)
• Pre-stroke mRS score ≤ 1
• Subjects or their guardians voluntarily sign the informed consent form

Exclusion criteria

• Moderate or severe stroke (NIHSS score > 12).
• Lacunar infarction, brainstem or cerebellar infarction (confirmed by DWI-MRI).
• Requirement for endovascular interventional treatment for the current episode.
• Intracranial hemorrhagic diseases (including parenchymal, intraventricular, subarachnoid hemorrhage, etc.).
• Patients with malignant tumors.
• Patients with severe traumatic brain injury.
• Patients with primary or secondary immunodeficiency diseases or requiring immunosuppressant medication.
• Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) exceeding 3 times the upper limit of normal.
• Chronic kidney disease or current serum creatinine exceeding 1.5 times the upper limit of normal or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m².
• Presence of severe infection or fever; patients with severe respiratory diseases.
• Positive for hepatitis B virus surface antigen (HBsAg); or positive for hepatitis B core antibody (HBcAb) with positive HBV-DNA; or positive for hepatitis C virus antibody (HCVAb), Treponema pallidum antibody (TPAb/RPR), or human immunodeficiency virus antibody (HIV).
• Patients who are pregnant or lactating at screening, or wish to become pregnant during the study period. Patients allergic to the product
• Patients allergic to the product or with severe allergic constitution.
• Patients deemed unsuitable for participation by the investigator, or for whom participation may pose a greater risk.
• Patients who have participated in another clinical trial within the past 3 months.
• Patients with prior use of exosomes.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Xie X, Song Q, Dai C, Cui S, Tang R, Li S, Chang J, Li P, Wang J, Li J, Gao C, Chen H, Chen S, Ren R, Gao X, Wang G. Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer's disease: a phase I/II clinical trial. Gen Psychiatr. 2023 Oct 11;36(5):e101143. doi: 10.1136/gpsych-2023-101143. eCollection 2023. PMID 37859748
• Li Y, Tang Y, Yang GY. Therapeutic application of exosomes in ischaemic stroke. Stroke Vasc Neurol. 2021 Sep;6(3):483-495. doi: 10.1136/svn-2020-000419. Epub 2021 Jan 11. PMID 33431513
• Sonoda T, Matsuzaki J, Yamamoto Y, Sakurai T, Aoki Y, Takizawa S, Niida S, Ochiya T. Serum MicroRNA-Based Risk Prediction for Stroke. Stroke. 2019 Jun;50(6):1510-1518. doi: 10.1161/STROKEAHA.118.023648. Epub 2019 Apr 15. PMID 31136284
• Dehghani L, Khojasteh A, Soleimani M, Oraee-Yazdani S, Keshel SH, Saadatnia M, Saboori M, Zali A, Hashemi SM, Soleimani R. Safety of Intraparenchymal Injection of Allogenic Placenta Mesenchymal Stem Cells Derived Exosome in Patients Undergoing Decompressive Craniectomy Following Malignant Middle Cerebral Artery Infarct, A Pilot Randomized Clinical Trial. Int J Prev Med. 2022 Jan 19;13:7. doi: 10.4 PMID 35281985
• Yang Y, Cai Y, Zhang Y, Liu J, Xu Z. Exosomes Secreted by Adipose-Derived Stem Cells Contribute to Angiogenesis of Brain Microvascular Endothelial Cells Following Oxygen-Glucose Deprivation In Vitro Through MicroRNA-181b/TRPM7 Axis. J Mol Neurosci. 2018 May;65(1):74-83. doi: 10.1007/s12031-018-1071-9. Epub 2018 Apr 29. PMID 29705934
• Yang J, Zhang X, Chen X, Wang L, Yang G. Exosome Mediated Delivery of miR-124 Promotes Neurogenesis after Ischemia. Mol Ther Nucleic Acids. 2017 Jun 16;7:278-287. doi: 10.1016/j.omtn.2017.04.010. Epub 2017 Apr 13. PMID 28624203
• Xin H, Katakowski M, Wang F, Qian JY, Liu XS, Ali MM, Buller B, Zhang ZG, Chopp M. MicroRNA cluster miR-17-92 Cluster in Exosomes Enhance Neuroplasticity and Functional Recovery After Stroke in Rats. Stroke. 2017 Mar;48(3):747-753. doi: 10.1161/STROKEAHA.116.015204. PMID 28232590
• Altmann P, Mildner M, Haider T, Traxler D, Beer L, Ristl R, Golabi B, Gabriel C, Leutmezer F, Ankersmit HJ. Secretomes of apoptotic mononuclear cells ameliorate neurological damage in rats with focal ischemia. F1000Res. 2014 Jun 19;3:131. doi: 10.12688/f1000research.4219.2. eCollection 2014. PMID 25383184

Identifiers

NCT: NCT07398612 · IIT-ATMP-2025011

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗