Blood Brain Barrier Opening in Alzheimer' Disease (BOREAL1)
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|ClinicalTrials.gov Identifier: NCT03119961|
Recruitment Status : Recruiting
First Posted : April 19, 2017
Last Update Posted : August 3, 2017
|Condition or disease||Intervention/treatment||Phase|
|Alzheimer Disease||Device: SONOCLOUD®||Phase 1 Phase 2|
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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.
1) What is the tolerance of LICU and the SonoCloud® device in a population of patients with mild AD? 2) What are the physiopathological impact of LICU BBB opening in these patients as asserted by amyloid and 18FDG PET-MRI?
For the first phase I clinical trial in the world using LICU in AD to repeatedly open the BBB.
Primary objective: To evaluate the tolerance of the BBB opening session in 5 AD patients (Adverse event recording, cognitive and MRI evaluations).
Co-primary objective: To assess the impact of BBB opening on the hallmark lesions of AD (Aß & Tau) through PET-MRI imaging (decrease of the standardized uptake value ratio (SUVR) after vs. before treatment in the left supramarginal gyrus and left (treated) vs. right (untreated) supramarginal gyrus).
Secondary objective: increase cognitive performance in AD patients through the repeated opening of the BBB in the left supramarginal gyrus
Ten patients suffering from mild AD will be included in the study.
Seven BBB opening session will be performed at a bi-monthly rate focusing on the left supramarginal gyrus, a cortical structure known to be affected by both amyloid and tau lesions early on during the evolution of the disease. All adverse events induced by surgery itself or by the LICU will be recorded. Amyloid ß and Tau lesion load will be evaluated benefiting from the PET-MRI that allows to clearly evaluate fine changes in SUVR taking into account loco-regional cortical specificity (cortical thickness). PET image analysis.
Mean Standard Uptake Values Ratios (SUVR) will be calculated with cerebellar gray matter activity as reference in volumes of interest. Voxel-wise uptake will then be divided by this reference value to get SUVR maps. PET images will be corrected for motion and partial volume effect thanks to simultaneous MRI acquisition. To analyze the longitudinal PET data, each follow-up T1-weighted MRI will be co-registered to the baseline MRI, and a within-subject template image will be calculated by averaging the coregistered T1-weighted images. This mean image will be used to calculate optimal transformation parameters to Montreal Neurological Institute (MNI) space. Next, baseline and follow-up PET images will be co-registered to the baseline MRI, spatially normalized to MNI using this optimal transformation, and scaled with cerebellar gray uptake. Individual percent annual changes maps will be then calculated. These maps will represent the voxel-wise calculation of percent metabolic change after BBB opening.
The investigators think that the clinical trial will be well tolerated by the patients as the rate of local adverse events is expected to be 1% since the SonoCloud device implantation is extra dural (without dura opening). The implantation is performed under local anaesthesia in an outclinic fashion.
Drawbacks and possible solution to overcome the problems :
Among expected drawback the investigators will have to be very vigilant for Amyloid related imaging anomalies (ARIAs) due to the sudden entry of endogenous antibodies in the brain parenchyma of patients with Aß and Tau prevalent lesions. If these ARIAs were to happen, an amendment of the protocol could be devised to add steroids, or reduce ultrasound intensity, or extend time during each opening session, or reduce number of BBB opening session, or in last use immunosuppressive drugs prior to the opening of the BBB.
This is the first study worldwide with the means to safely, repeatedly and reproductively open the BBB in AD, or more broadly, in any neurodegenerative disease. It is noteworthy to consider that it is only a phase I study aiming to demonstrate the feasibility of the technique in a mild form of AD. If this is the case and even in the absence of a positive effect on the lesions and symptoms it will then be possible to propose new projects aiming to associate these safe BBB opening to anti-AD drugs. In fact, this study could pave the way for further treatment venues of various neurodegenerative disease that share a brain accumulation of proteins that cannot be readily targeted in case of BBB integrity.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||10 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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)|
|Actual Study Start Date :||June 26, 2017|
|Estimated Primary Completion Date :||April 1, 2019|
|Estimated Study Completion Date :||July 1, 2019|
BBB opening by ultrasound
BBB opening by ultrasound
Other Name: BBB opening
- Florbetapir SUVr and Fluorodeoxyglucose MUV changes in BBB opening region of interest (ROI) [ Time Frame: Change from baseline at 4month and 8 month ]PET MRI evaluation
- Adverse events recording [ Time Frame: up to 9 months ]Clinical and MRI evaluation
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03119961
|Contact: Alexandre CARPENTIER, MD, PhD||33(0)1 42 16 34 05 / 34 email@example.com|
|Contact: Stephane EPELBAUM, MD, PhD||33(0)1 42 16 75 firstname.lastname@example.org|
|APHP - Pitié-Salpêtrière Hospital||Recruiting|
|Paris, France, 75651|
|Contact: Stephane EPELBAUM, MD, PhD 33(0)1 42 16 75 22 email@example.com|
|Principal Investigator:||Stephane EPELBAUM, MD, PhD||Assistance Publique Hoptiaux de Paris|