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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
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:
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

Condition or disease Intervention/treatment Phase
Alzheimer Disease Device: SONOCLOUD® Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: SONOCLOUD®
BBB opening by ultrasound
BBB opening by ultrasound
Other Name: BBB opening

Primary Outcome Measures :
  1. 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

Secondary Outcome Measures :
  1. Adverse events recording [ Time Frame: up to 9 months ]
    Clinical and MRI evaluation

Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 85 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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> 0.11.
  • 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.

Exclusion Criteria:

  • 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).

Information from the National Library of Medicine

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 30 alexandre.carpentier@aphp.fr
Contact: Stephane EPELBAUM, MD, PhD 33(0)1 42 16 75 22 stephane.epelbaum@aphp.fr

APHP - Pitié-Salpêtrière Hospital Recruiting
Paris, France, 75651
Contact: Stephane EPELBAUM, MD, PhD    33(0)1 42 16 75 22    stephane.epelbaum@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Principal Investigator: Stephane EPELBAUM, MD, PhD Assistance Publique Hoptiaux de Paris

Additional Information:
Ossenkoppele R, Jansen WJ, Rabinovici GD, Knol DL, van der Flier WM, van Berckel BN, Scheltens P, Visser PJ; Amyloid PET Study Group, Verfaillie SC, Zwan MD, Adriaanse SM, Lammertsma AA, Barkhof F, Jagust WJ, Miller BL, Rosen HJ, Landau SM, Villemagne VL, Rowe CC, Lee DY, Na DL, Seo SW, Sarazin M, Roe CM, Sabri O, Barthel H, Koglin N, Hodges J, Leyton CE, Vandenberghe R, van Laere K, Drzezga A, Forster S, Grimmer T, Sánchez-Juan P, Carril JM, Mok V, Camus V, Klunk WE, Cohen AD, Meyer PT, Hellwig S, Newberg A, Frederiksen KS, Fleisher AS, Mintun MA, Wolk DA, Nordberg A, Rinne JO, Chételat G, Lleo A, Blesa R, Fortea J, Madsen K, Rodrigue KM, Brooks DJ. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA. 2015 May 19;313(19):1939-49. doi: 10.1001/jama.2015.4669.

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03119961     History of Changes
Other Study ID Numbers: P150101
2016-004145-82 ( EudraCT Number )
B2016-A01637-44 ( Other Identifier: IDRCB )
First Posted: April 19, 2017    Key Record Dates
Last Update Posted: August 3, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Amyloid Amyloid Plaque
Tau Protein

Additional relevant MeSH terms:
Alzheimer Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders