Blood Brain Barrier Opening in Alzheimer' Disease

NCT03119961 | Completed Phase 1 DMC

• 3 other identifiers: P1501012016-004145-82B2016-A01637-44
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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

Conditions

Alzheimer Disease

Keywords

Amyloid Amyloid Plaque; Tau Protein; Sonication

Outcome Measures

Primary Outcomes (1)

• Florbetapir SUVr and Fluorodeoxyglucose MUV changes in BBB opening region of interest (ROI)

  PET MRI evaluation

  Change from baseline at 4month and 8 month

Secondary Outcomes (1)

• Adverse events recording

  up to 9 months

Study Arms (1)

SONOCLOUD®

EXPERIMENTAL

BBB opening by ultrasound

Device: SONOCLOUD®

Interventions

SONOCLOUD® DEVICE

BBB opening by ultrasound

Also known as: BBB opening

SONOCLOUD®

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).
• 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
• Chronic and abusive consumption of toxic (alcohol or drugs) except tobacco.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• CarThera: collaborator
• BPIfrance: collaborator

Study Sites (1)

APHP - Pitié-Salpêtrière Hospital

Paris, 75651, France

Location

Related Publications (33)

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Related Links

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MeSH Terms

Conditions

Alzheimer Disease; Plaque, Amyloid; Frontotemporal Dementia

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Frontotemporal Lobar Degeneration; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Stephane EPELBAUM, MD, PhD

  Assistance Publique Hoptiaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 27, 2017
• First Posted: April 19, 2017
• Study Start: June 26, 2017
• Primary Completion: October 2, 2020
• Study Completion: October 7, 2020
• Last Updated: April 12, 2022

Record last verified: 2020-11

Locations

FR (1)