Phase 1/2 Open Single-arm Monocentric Study Evaluating the Tolerance and Interest of Transient Opening of the Blood-Brain Barrier by Low Intensity Pulsed Ultrasound With the SONOCLOUD® Implantable Medical Device in Mild Alzheimer's Disease Patients (MMSE 20-26)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 2
- 主要终点
- Florbetapir SUVr and Fluorodeoxyglucose MUV changes in BBB opening region of interest (ROI)
研究概览
简要总结
In Alzheimer's disease (AD) an imbalance between the production and clearance of the ß-amyloid peptide is hypothesized as the driving event of the disease. The decreased clearance of Aß could be partly linked to a progressive dysfunction of the brain vasculature and of the blood brain barrier (BBB). Among many possible explanations for these failures of the multiple clinical trials evaluating innovative drugs in AD, one is the lack of target engagement, as none of these drugs is able to readily cross BBB. This barrier acts as a wall that actively and passively prevents the crossing of molecules between the blood and the brain parenchyma compartments. Only 0.3% of intravenously injected anti-Aß immunoglobulins reach the brain despite a half-life of 15-20 days. Low intensity Focal ultrasound associated to microbubble injection can open the BBB in a non invasive way. These openings are reversible in 2 hours to 2 days depending on the intensity of the ultrasound. Ultrasound opening of the BBB was initially used in a transgenic mouse model of AD to increase the brain delivery of an anti-Aß antibody. In this article, the Aß load was reduced in ultrasound treated brain region. Surprisingly it was then demonstrated that the simple opening of the BBB without any adjunct anti-Aß treatment was able to drive the same Aß clearance effects. This is probably linked to endogenous antibodies that are able to penetrate the brain parenchyma and target Aß plaques. Four opening sessions elicited positive promnesic effects in these mice. Our group conceived and developed a mean to easily, reproductively and innocuously open the BBB. A unique extra-dural ultrasound emitter (sonoCloud®) is surgically implanted in the skull under local anesthesia. It emits low intensity contact ultrasound (LICU) that are not deterred by bone and thus are able to open the BBB.Preclinical studies show the SonoCloud® device is safe and efficient as it allowed reproducible and repeatable opening of the BBB in rabbits, dogs and non human primates. Drugs up to 2000 Kilo Daltons (kDa) are able to cross the BBB to reach the brain parenchyma in which the concentration of Carboplatin was increased by 700% in the BBB opened region. No adverse event was evidenced both clinically, by EEG, Evoked potential, MRI, 18 Fluorodeoxyglucose (FDG) PET and histology in the primates after 7 bi-monthly sessions of LICU BBB opening. SonoCloud® and its external generator have been certified by the academic start-up CarThéra (APHP, UPMC). Our multidisciplinary skills (neurology, neurosurgery, neuroimaging, basic science departments in the same University hospital setting) and our previous experience of BBB opening in Man give us the unique opportunity to translate this procedure from neuro-oncology to AD which could 1) Have a positive effect on brain lesion load and symptoms by itself and 2) allow anti-AD (or more broadly, central nervous system) drugs to engage their targe
详细描述
Background:
Alzheimer's disease is the most prevalent neurodegenerative disease totalizing 33 million patients worldwide. If nothing is done to decrease the incidence of 1.8 Million patient/year, the prevalence will double in the next 20 years.
Physiopathologically, the amyloid cascade remains the predominant hypothesis. It states that an imbalance between the production and clearance of the ß-amyloid peptide is the driving event of the disease, leading to Tau hyperphosphorylation and accumulation in neurons as neurofibrillary tangles, neurodegeneration (synaptic and neuronal loss) and cognitive impairment. The decreased clearance of Aß could be partly linked to a progressive dysfunction of the brain vasculature and of the BBB.
New sets of diagnosis criteria for AD have been proposed to address the low specificity (70%) of the previous ones, that could be one of the causes of failure of previous clinical trials. Among these new criteria, cerebrospinal fluid (CSF) biomarkers and positon emission tomography (PET) with new ligands of amyloid plaques and more recently tau deposition are indicators of the underlying histopathology of the disease, and can also be used to evaluate early intervention efficacy as they are pathologic in the preclinical phase of AD, its prodromal phase.
the investigators aim to test an innovative BBB opening procedure that could drastically decrease AD patients' brain lesion load and alleviate their symptomatology.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
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
- •Age between 50 and 85 years old
- •Alzheimer's disease, typical or atypical according to International Working Group-2 (IWG-2) criteria,
- •diagnosed on the basis of a cognitive assessment and an MRI, showing one of the three most frequent phenotypic presentations of the disease (hippocampal amnesia or logopenic aphasia or syndrome of posterior cortical atrophy)
- •certified by the CSF assay of biomarkers of the AD ratio PTau / Aβ> 0.
- •Mild disease (MMSE 20-26) but presently pejorative outcome: relatively young subject (<80 years), "rapid" cognitive decline and high CSF tau rate (> 600pg / mL, for A diagnostic threshold of Alzheimer's disease of 450pg / mL). The evaluation of the pejorative evolution will be validated by the Committee of Experts of the Memory Center (IM2A at Pitié-Salpêtrière Hospital)
- •Patients under stable Alzheimer's treatment for at least 3 months prior to entry into the study and in which no change is envisaged in the next months in order to avoid a loss of chance for the patient and to consider an aggravation at cessation of treatment as an adverse event due to the opening of the BBB.
- •Affiliate or beneficiary of Affiliated to the French Health care system
- •Patient and caregiver (undertaking to accompany the participant to the various necessary medico-surgical visits and spending at least 3 hours per day with the patient) having signed, free and informed consent.
排除标准
- •Allergy to Gadolinium, Xylocaine or any contraindication to contrast products used for brain imaging, or to drugs used in perioperative procedures.
- •Contraindications to SonoVue®
- •hypersensitivity to sulfur hexafluoride
- •recent acute coronary syndrome or unstable ischemic heart disease
- •heart failure, chronic or acute stage III or IV,
- •patient undergoing drug therapy incorporating dobutamine,
- •severe pulmonary arterial hypertension
- •uncontrolled systemic hypertension,
- •respiratory distress syndrome
- •Severe renal impairment with glomerular filtration rate (GFR) <30 mL / min / 1.73 m2 (Gadolinium IC)
- •Hepatic impairment characterized by international normalized ratio (INR)> 1.5 or Factor V <50% of the standard.
- •Patient taking an associated treatment considered potentially toxic to the central nervous system (CNS).
- •Patient included or having participated in the 5 years preceding the inclusion in this study in another research protocol on Alzheimer's (medical treatment or medical device).
- •Epilepsy or potentially pro-convulsive medication
- •Ischemic or haemorrhagic stroke consisting of supracentimetric vascular leucopathy with a grade greater than 2 in the classification of Fazekas and Schmidt
- •Presence of at least one lobar micro-bleeding identified in MRI performed in current care prior to inclusion (SWI sequence) in the sonication zone (left supramarginal gyrus)
- •Chronic and abusive consumption of toxic (alcohol or drugs) except tobacco.
- •Contra-indication to MRI (intracorporeal metallic material, claustrophobia)
- •Hemostasis disorders (thrombocytopenia <75,000, prothrombin ratio (PR) <60%, INR> 1.5, antiplatelet therapy or anticoagulant in progress)
- •Phlebitis or active pulmonary embolism
- •Patient unable to perform cognitive tests (less than 7 years of study, mother tongue different from French, severe unpaired sensory disorder).
- •Patient under judicial protection
- •Absence of accompanying person
- •Patient with an ongoing infection clinically characterized by febrile syndrome and possible calling points (cough, pain, skin lesion, etc.) OR biologically suspected on C-reactive protein(CRP)> 10, Procalcitonin> 0.1, positive examination of the urine (CBEU).
结局指标
主要结局
Florbetapir SUVr and Fluorodeoxyglucose MUV changes in BBB opening region of interest (ROI)
时间窗: Change from baseline at 4month and 8 month
PET MRI evaluation
次要结局
- Adverse events recording(up to 9 months)