Novel Personalized Non Invasive Combined Magnetic and Electrical Stimulation of the Default Mode Network in Mild AD Patients (CMES-AD)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 60
- 试验地点
- 4
- 主要终点
- integrated Alzheimer Disease Rating Scale (iADRS)
研究概览
简要总结
Alzheimer's disease (AD) is increasingly recognized as a disorder marked by early synaptic dysfunction and disrupted brain network connectivity, beyond the traditional focus on amyloid pathology. Synaptic plasticity (crucial for learning and memory) is compromised in AD and represents a promising therapeutic target. In particular, alterations in the Default Mode Network (DMN), especially in regions like the precuneus, suggest that restoring connectivity and enhancing plasticity may improve cognitive outcomes. This project proposes a novel, precision-delivered non-invasive brain stimulation protocol that combines repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) over the DMN. The intervention will be evaluated through cognitive testing, blood-based biomarkers, MRI and TMS-EEG, alongside immersive virtual environments to assess sensorimotor and cognitive function. This approach aims to test neuromodulation strategies capable of slowing neurodegeneration and supporting early detection and rehabilitation in AD.
详细描述
Patients will be screened at trial sites for determination of eligibility to enter the study on the basis of diagnostic evaluations, according to current diagnostic criteria for probable AD, and safety assessments (vital sign complete physical and neurological examinations). The efficacy assessments (cognitive/behavioral evaluations) will be performed at Baseline before starting treatment and repeated on- treatment at Weeks 0, 12 and 24. Plasma biomarkers will be collected at baseline and at Week 12 and 24. Visit windows are ±7 days for all the scheduled visits. In case a visit is performed outside its window, subsequent visits will be performed in keeping with the original visit schedule. At each in-clinic visit (or upon early termination), AEs will be recorded, at screening, baseline, Week 12 and 24 vital signs measured, and physical and neurological examination performed.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Four-blinded
入排标准
- 年龄范围
- 50 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with a diagnosis of AD according to IWG criteria
- •20 > MMSE < 28
- •Patients with CSF specific biomarker profile or with a positive Amyloid Pet Scan consistent with the presence of amyloid pathology
- •Global Clinical Dementia Rating (CDR) ≤1
- •Previous decline in cognition for more than six months as documented in patient medical records
- •A caregiver available and living in the same household or interacting with the patient and available
- •Patients living at home or nursing home setting without continuous nursing care
- •General health status acceptable for a participation in a 6-month clinical trial
- •Stable pharmacological treatment for at least one month prior to screening
- •No regular intake of prohibited medications.
- •Signed informed consent by the patient. If there are any doubts that the patient is mentally capable of giving informed consent, the patient will be examined and verified to be mentally capable by an independent physician/ neurologist, prior to the initiation of any study specific procedure. Signed consent of the caregiver
排除标准
- •Failure to undergo screening or baseline exams
- •Hospitalization or change in chronic concomitant medications one month before the screening or during the screening period
- •Clinical, laboratory, or neuroimaging results consistent with:
- •other primary degenerative dementia (Lewy body dementia, frontotemporal dementia, Huntington's disease, Creutzfeldt-Jakob disease, Down syndrome, etc.);
- •other neurodegenerative conditions (Parkinson's disease, amyotrophic lateral sclerosis, etc.);
- •orthostatic hypotension and autonomic disorders
- •cerebrovascular disease (major infarction, a strategic infarction or multiple lacunar infarctions, extensive white matter lesions > one quarter of total white matter);
- •other central nervous system diseases (severe traumatic brain injury, tumors, subdural hematoma, or other space-occupying processes, etc.);
- •seizure disorder.
- •Other infectious, metabolic, or systemic diseases affecting the central nervous system (syphilis, existing hypothyroidism, current vitamin B12 or folate deficiency, serum electrolytes outside normal limits, juvenile diabetes, etc.).
- •A current DSM-V diagnosis of major depression, schizophrenia, or bipolar disorder.
- •Clinically significant, advanced, or unstable disease that may interfere with primary or secondary variable assessments and may affect the assessment of the patient's clinical or mental state, or expose the patient to special risk, such as:
- •Disability that may prevent the patient from completing all study requirements (e.g., blindness, deafness, severe language difficulties, etc.);
- •Opioid-containing analgesics
- •Suspected or known drug or alcohol abuse, i.e., more than about 60 g of alcohol (about 1 liter of beer or 500 ml of wine) per day, indicated by a high mean corpuscular volume (MCV) above the normal value at screening;
- •Any condition that, in the investigator's judgment, makes the patient unsuitable for inclusion
研究组 & 干预措施
combined iTBS-tACS
32 sessions of combined iTBS-tACS (5 times/week for 2 weeks -intensive phase-; 1 time/week for 22 weeks -maintenance phase-)
干预措施: Combined iTBS-tACS (Device)
iTBS-sham tACS
32 sessions of combined iTBS-sham tACS (5 times/week for 2 weeks -intensive phase-; 1 time/week for 22 weeks -maintenance phase-)
干预措施: iTBS-sham tACS (Device)
sham iTBS- sham tACS
32 sessions of sham iTBS- sham tACS (5 times/week for 2 weeks -intensive phase-; 1 time/week for 22 weeks -maintenance phase-)
干预措施: sham iTBS- sham tACS (Device)
结局指标
主要结局
integrated Alzheimer Disease Rating Scale (iADRS)
时间窗: Change from baseline to the end of treatment at week 24.
The iADRS is an integrated assessment of cognition and daily function from the 13-item cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog13) and Alzheimer Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL), measuring global disease severity across the Alzheimer disease continuum as a single summary score. The iADRS is validated and captures clinical progression from MCI due to Alzheimer disease through moderate dementia due to Alzheimer disease, and treatment effects have been demonstrated across MCI and Alzheimer disease with mild dementia. The possible scores on the iADRS range from 0 to 144 (lower scores indicate greater impairment).
次要结局
- Change in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score.(Change from baseline to the end of treatment at week 24.)
- Alzheimer Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL).(Change from baseline to week 24.)
- Change in the Clinical Dementia Rating scale Sum of Boxes (CDR-SoB) score.(Change from baseline to the end of treatment at week 24.)
- Change in the Alzheimer Disease Assessment Cognitive Scale (ADAS-Cog13) score.(Change from baseline to the end of treatment at week 24.)
- Change in the Neuropsychiatric Personal Inventory (NPI) score.(Change from baseline to the end of treatment at week 24.)
- Change in the Mini-Mental State Examination (MMSE) score.(Change from baseline to the end of treatment at week 24.)
- Change in the Montreal Overall Cognitive Assessment (MoCA) score.(Change from baseline to the end of treatment at week 24.)
- Change in Face-Name Association Task (FNAT) score.(Change from baseline to the end of treatment at week 24.)
- Change in Apathy Motivation index (AMI) score.(Change from baseline to the end of treatment at week 24.)
- Change in the Frontal Assessment Battery (FAB) score.(Change from baseline to the end of treatment at week 24.)