Safety and Efficacy of Human Adipose-Derived Stem Cell Exosomes in 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.

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