Study of Neural Stem Cell-Derived Exosomes in Moderate-to-Severe Early-Onset Alzheimer's Disease

Official title

A Phase I, Open-Label, Single-Center, Frequency-Escalation Study of the Safety, Tolerability, and Preliminary Efficacy of Neural Stem Cell-Derived Exosomes in Patients With Moderate-to-Severe Early-Onset Alzheimer's Disease

Overview

This is an open-label, single-center, phase I clinical study in patients with moderate-to-severe early-onset Alzheimer's disease. The study aims to evaluate the safety, tolerability, and preliminary efficacy of neural stem cell-derived exosomes (NSC-EVs) administered by the intranasal route. A total of 9 participants will be enrolled in 3 frequency-escalation groups: once every 3 days, once every other day, and once daily, each for 28 days. Participants will undergo screening and baseline assessment, a 28-day treatment period, and follow-up visits at 4, 8, and 24 weeks after the end of treatment.

Detailed description

Early-onset moderate-to-severe Alzheimer's disease imposes a substantial burden on patients and families, and there is currently no truly effective treatment capable of reversing the pathological process. Neural stem cell-derived exosomes (NSC-EVs) are considered a promising therapeutic approach because they may have low immunogenicity, the ability to cross the blood-brain barrier, and a more standardized manufacturing pathway than cell-based therapy.

This study is designed as an open-label, single-center, three-group phase I clinical study to explore the safety, tolerability, and preliminary efficacy of intranasal NSC-EVs in patients with moderate-to-severe early-onset Alzheimer's disease. The study uses a 3+3 frequency-escalation design with sentinel-participant monitoring to determine the highest tolerated dosing frequency and to generate preliminary clinical data for future larger-scale studies.

A total of 9 participants are planned for enrollment. Participants will be assigned sequentially to 1 of 3 dosing-frequency groups: low-frequency, medium-frequency, or high-frequency. All groups will receive the same investigational product by intranasal administration for 28 days, with differences only in dosing frequency. The low-frequency group will receive treatment on Days 1, 4, 7, 10, 13, 16, 19, 22, 25, and 28; the medium-frequency group will receive treatment on Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27; and the high-frequency group will receive treatment daily from Day 1 through Day 28.

After the 4-week treatment period, participants will enter a follow-up phase with visits scheduled at 4 weeks, 8 weeks, and 24 weeks after the end of treatment. Assessments during treatment and follow-up will include safety monitoring, clinical laboratory testing, cognitive and neuropsychiatric evaluations, and protocol-defined biomarker and imaging assessments as applicable. The primary objective is to evaluate safety and tolerability, while secondary and exploratory objectives include preliminary evaluation of cognitive, behavioral, functional, and biomarker changes over time.

Interventions

• Biological Neural Stem Cell-Derived Exosomes
  The investigational product is a neural stem cell-derived exosome preparation administered intranasally. The product specification is 6 × 10\^9 particles per 2 mL vial. The product is thawed to room temperature before administration and delivered into both nostrils. The same investigational product is used in all study groups; the groups differ only in dosing frequency.

Primary outcome measures

• Number of Participants With Treatment-Related Adverse Events [Time frame: Baseline to Week 4]
• Number of Participants With Treatment-Related Clinical Laboratory Abnormalities [Time frame: Baseline to Week 4]

Secondary outcome measures (8)

• Change in Chinese Mini-Mental Status (CMMS) Score [Time frame: Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment]
• Change in Severe Impairment Battery (SIB) Score [Time frame: Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment]
• Change in Neuropsychiatric Inventory (NPI) Score [Time frame: Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment]
• Change in Geriatric Depression Scale (GDS) Score [Time frame: Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment]
• Change in Pittsburgh Sleep Quality Index (PSQI) Score [Time frame: Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment]
• Change in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score [Time frame: Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment]
• Change in Zarit Burden Interview (ZBI) Score [Time frame: Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment]
• Change in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score [Time frame: Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment]

Eligibility criteria

• Inclusion Criteria:
• Male or postmenopausal female, aged 50 to 75 years.
• Meets the 2011 NIA-AA criteria for probable Alzheimer's disease dementia.
• Age at onset ≤65 years.
• CMMS score 5-20
• Stable dose for at least 2 months before enrollment if receiving pro-cognitive or psychiatric medications.
• Primary school education or above and able to complete study-required cognitive assessments.
• Hachinski Ischemic Score ≤4.
• GDS-30 total score ≤10.
• Screening brain MRI+DWI+SWI meeting protocol-defined cerebrovascular exclusion thresholds and no major structural abnormalities inconsistent with Alzheimer's disease.
• Positive amyloid pathology confirmed by Aβ-PET at screening or before enrollment.
• Adequate vision and hearing to complete assessments.
• Has a reliable caregiver able to accompany the participant to study visits and provide information for assessments.
• Willing to participate and sign informed consent.

Exclusion criteria

• Dementia due to causes other than Alzheimer's disease.
• Brain MRI showing any of the following: Fazekas white matter hyperintensity score >2; more than 2 lacunar infarcts >1.5 cm; lacunar infarcts involving critical regions such as the thalamus, hippocampus, entorhinal cortex, or parahippocampal region; cerebral hemorrhage, subdural hematoma, aneurysm, arteriovenous malformation, intracranial mass lesion, or other clinically significant structural abnormalities.
• Allergy to stem cell-derived exosomes or PET examination.
• Severe psychiatric disorder or symptoms.
• Significant active physical illness, including severe cardiac disease, severe systemic infection, or severe liver/kidney dysfunction.
• Elevated tumor markers or tumor history.
• Immune-related disease.
• Significant nasal obstruction.
• Serious suicide risk.
• Participation in another clinical trial or stem cell therapy within the past 6 months.
• Any other condition judged inappropriate by the investigator.
• Contraindications to MRI or inability to complete MRI examinations, including non-MRI-compatible metallic implants, certain stents, plates, pacemakers, or severe claustrophobia.

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

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Shanghai Mental Health Center — Shanghai

Identifiers

NCT: NCT07554872 · SMHC-EOAD-NSCEV-2026-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗