Safety of a Strategy Combining Etanercept Administration with Repeated Contrast Ultrasound in Patients with Alzheimer&#39;s Disease
NCT Number: NCT06585384
Acronym: BRAINWAVES
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE1
Conditions: Alzheimer Disease
Sponsor: Fondation Ophtalmologique Adolphe de Rothschild
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 5
Study Design: Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2025-03
Completion Date: 2027-09

Summary:
Alzheimer's disease (AD) is a clinico-pathological entity combining multiple and varied neuropathological lesions with characteristic abnormal accumulations (amyloid Beta (Aβ) plaques and neurofibrillary degeneration (NFD)), neuroinflammation, as well as neuronal and synaptic suffering.

To date, only symptomatic treatments are available, with no proven effect on neuropathological lesions or on the clinical course of the disease.

Anti-TNF alpha could be a therapeutic agent of choice in the treatment of central nervous sytem (CNS) diseases with an inflammatory component, such as AD. Unfortunately, their high molecular weight prevents them from passively crossing the blood brain barrier (BBB). In a pilot study published in 2006, etanercept was administered intrathecally to AD patients with encouraging clinical effects.

Transient opening of the tight junctions between the endothelial cells of the BBB by delivering High Intensity Focalised Ultrasounds (HIFU) in combination with an intravenous injection of microbubbles is a strategy that could improve bioavailability. Studies suggest that the oscillation of microbubbles in the ultrasound field generates microcurrents that induce shear forces responsible for a transient opening of the BBB. Ultrasound can be focused or unfocused and open the BBB diffusely or selectively over defined regions of the brain. This technique was first used to open the BBB in humans in 2001.

Transient opening of the BBB is also thought to modulate the immune response in the CNS, leading to a reduction in the intracerebral load of Aβ. In an Alzheimer's mouse model, several studies using ultrasound devices to open the BBB have shown a reduction in the intracerebral load of Aβ (up to 75%) and an improvement in the memory faculties and cognitive performance of the animals.

In humans, two clinical trials have assessed the safety of using ultrasound-assisted BBB disruption devices in AD patients. These were the Sonocloud® (Carthera) and ExAblate® (InSightec) devices. The Sonocloud® device is an extra-dural ultrasound emitter implanted under local anaesthetic. Enrolment was completed in October 2020, but the results of the trial are not yet available (NCT03119961). The phase I study on 5 patients evaluating the ExAblate® device coupled with the injection of gas microbubbles demonstrated reversible opening of the BBB with no serious adverse effects for the patients. No effect on intracerebral Aβ load or cognitive or behavioural improvement was demonstrated. The ExAblate® device is not implantable and is therefore less invasive than the Sonocloud® device. However, it requires MRI monitoring and the transducers used often generate high levels of heat, requiring the use of a water cooling system to avoid the risk of transducer deterioration.

In this project, our aim is to assess the safety of using a non-focused ultrasound device, the General Electric VIVID S70 clinical device (CE mark G1 023782 0112 ), to perform BBB ruptures in patients suffering from AD, combined with the administration of etanercept, whose bioavailability would thus be improved.

Primary Outcome Measures: To assess the safety of a strategy combining 9 weeks of etanercept administration with 5 weeks of repeated contrast ultrasound of 2 sessions per day, 5 days per week (from the fifth week of etanercept treatment) in patients with Alzheimer&#39;s disease., Number of patients presenting related adverse events (CTCAE v4.0), from Day1 of repeated contrast ultrasound to Month 3 after the end of repeated contrast ultrasound