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
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Number of Participants With Treatment-Related Adverse Events
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 50 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 ≤
- •GDS-30 total score ≤
- •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.
排除标准
- •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.
研究组 & 干预措施
Medium-Frequency NSC-EVs
Participants receive neural stem cell-derived exosomes by intranasal administration every other day for 28 days. The single dose is 6 × 10^9 particles administered into both nostrils. In the medium-frequency group, dosing is scheduled on Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27, for a total of 14 doses.
干预措施: Neural Stem Cell-Derived Exosomes (Biological)
Low-Frequency NSC-EVs
Participants receive neural stem cell-derived exosomes by intranasal administration once every 3 days for 28 days. The single dose is 6 × 10^9 particles administered into both nostrils. In the low-frequency group, dosing is scheduled on Days 1, 4, 7, 10, 13, 16, 19, 22, 25, and 28, for a total of 10 doses.
干预措施: Neural Stem Cell-Derived Exosomes (Biological)
High-Frequency NSC-EVs
Participants receive neural stem cell-derived exosomes by intranasal administration once daily for 28 days. The single dose is 6 × 10^9 particles administered into both nostrils. In the high-frequency group, dosing is scheduled daily from Day 1 through Day 28, for a total of 28 doses.
干预措施: Neural Stem Cell-Derived Exosomes (Biological)
结局指标
主要结局
Number of Participants With Treatment-Related Adverse Events
时间窗: Baseline to Week 4
Number of participants experiencing treatment-related adverse events assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Number of Participants With Treatment-Related Clinical Laboratory Abnormalities
时间窗: Baseline to Week 4
Number of participants with treatment-related clinical laboratory abnormalities during the treatment period.
次要结局
- Change in Chinese Mini-Mental Status (CMMS) Score(Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment)
- Change in Severe Impairment Battery (SIB) Score(Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment)
- Change in Neuropsychiatric Inventory (NPI) Score(Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment)
- Change in Pittsburgh Sleep Quality Index (PSQI) Score(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(Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment)
- Change in Zarit Burden Interview (ZBI) Score(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(Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment)
- Change in Geriatric Depression Scale (GDS) Score(Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment)
研究者
Ling YUE
Principal Investigator
Shanghai Mental Health Center