Alzheimer Disease (AD)
Conditions
Keywords
Early-Onset Alzheimer's Disease, Moderate-to-Severe Alzheimer's Disease, Neural Stem Cell-Derived Exosomes, Intranasal Administration, Phase I Clinical Study, Frequency Escalation, Safety, Tolerability
Brief summary
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
BIOLOGICALNeural 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.
Sponsors
Shanghai Mental Health Center
Shanghai Angecon Biotechnology Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a sequential, open-label, single-center phase 1 study using a 3+3 frequency-escalation design. Participants are enrolled from the lowest-frequency group to the highest-frequency group. Each group starts with 3 participants, including a sentinel participant, and escalation proceeds only after protocol-defined safety review. Expansion is permitted according to protocol-defined dose-limiting toxicity criteria.
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Related Clinical Laboratory Abnormalities | Baseline to Week 4 | Number of participants with treatment-related clinical laboratory abnormalities during the treatment period. |
| Number of Participants With Treatment-Related Adverse Events | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Severe Impairment Battery (SIB) Score | Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment | Cognitive function will be assessed using the Severe Impairment Battery (SIB), a validated instrument for cognitive function in moderate-to-severe dementia. Total scores range from 0 to 100, with higher scores indicating better cognitive performance. |
| Change in Neuropsychiatric Inventory (NPI) Score | Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment | Neuropsychiatric symptoms will be assessed using the Neuropsychiatric Inventory (NPI), a standardized instrument for behavioral and psychological symptoms in dementia. Total scores range from 0 to 144, with higher scores indicating greater neuropsychiatric symptom burden. |
| Change in Geriatric Depression Scale (GDS) Score | Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment | Depressive symptoms will be assessed using the 30-item Geriatric Depression Scale (GDS-30), a questionnaire designed to assess depressive symptoms in older adults. Total scores range from 0 to 30, with higher scores indicating more severe depressive symptoms. |
| Change in Pittsburgh Sleep Quality Index (PSQI) Score | Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment | Sleep quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI), a questionnaire that evaluates subjective sleep quality and sleep disturbance. Total scores range from 0 to 21, with higher scores indicating poorer sleep quality. |
| Change in Zarit Burden Interview (ZBI) Score | Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment | Caregiver burden will be assessed using the Zarit Burden Interview (ZBI), a questionnaire used to evaluate the perceived burden experienced by caregivers. Total scores range from 0 to 88, with higher scores indicating greater caregiver burden. |
| 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 | Functional ability will be assessed using the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL), a caregiver-based instrument used to evaluate daily functioning in patients with Alzheimer's disease. Total scores range from 0 to 78, with higher scores indicating better functional ability. |
| 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 | Global dementia severity will be assessed using the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), which evaluates impairment across multiple cognitive and functional domains. Total scores range from 0 to 18, with higher scores indicating greater dementia severity. |
| Change in Chinese Mini-Mental Status (CMMS) Score | Baseline, Week 4 (end of treatment), and 4, 8, and 24 weeks after end of treatment | Cognitive function will be assessed using the Chinese Mini-Mental Status (CMMS), a Chinese-language screening instrument for global cognitive impairment. Total scores range from 0 to 30, with higher scores indicating better cognitive performance. |
Countries
China
Contacts
CONTACTYue Ling 岳玲, MD, PhD
Outcome results
None listed