Safety of a Strategy Combining Etanercept Administration With Repeated Contrast Ultrasound in Patients With Alzheimer's Disease

NCT06585384 | Recruiting Phase 1

• 1 other identifier: CPX_2023_4
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Alzheimer Disease

Outcome Measures

Primary Outcomes (1)

• 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'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

Study Arms (1)

etanercept and repeated contrast ultrasound

EXPERIMENTAL

Combination Product: etanercept and repeated contrast ultrasound

Interventions

etanercept and repeated contrast ultrasound COMBINATION_PRODUCT

Strategy combining 9 weeks of etanercept administration (50mg/week) with 5 weeks of repeated contrast ultrasound of 2 sessions per day, 5 days per week (from the fifth week of etanercept treatment)

etanercept and repeated contrast ultrasound

Eligibility Criteria

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

You may qualify if:

• Positive diagnosis of Alzheimer's disease according to IWG2 criteria
• Biological profile in favour of Alzheimer's disease
• Age ≥ 50 years and ≤ 85 years
• Affiliated or beneficiary of a social insurance scheme
• Fazekas score \<=1
• Presence of a family or a person at home who can monitor the occurrence of adverse events
• Sufficient command of the French language to take neuropsychological tests.
• Have undergone a full neuropsychological assessment within 6 months.
• If anticholinesterase treatment, stability of treatment for at least three months.
• Signed, free and informed consent from the patient and the trusted support person.

You may not qualify if:

• Patient previously treated with anti-TNF alpha (e.g. etanercept).
• Other cause of major neurocognitive disorder.
• Participation in another drug study
• Absolute contraindication to MRI (e.g. pacemaker, implantable stimulator, intra-orbital metallic foreign body);
• Contraindication to lumbar puncture.
• History of bleeding diathesis;
• Severe chronic respiratory disease;
• Patient on anticoagulant therapy
• Right-to-left shunt, severe pulmonary arterial hypertension;
• Known cerebral vasculopathy; (Fazekas greater than 1), sequelae of ACI.
• Treatment with Anakinra, abatacept or sulfasalazine.
• Patients who have undergone major surgery within 28 days of the first day of the study.
• Allergy to gadolinium, or any contraindication to contrast products used for brain imaging (in particular severe renal insufficiency with a glomerular filtration rate \<30 ml / min / 1.73 m2).
• Allergy to xylocaine
• Epilepsy or drugs that lower the epileptogenic threshold (see Appendix 6).

Sponsors & Collaborators

• Fondation Ophtalmologique Adolphe de Rothschild: lead

Study Sites (1)

Fondation Adolphe de Rothschld

Paris, 75019, France

RECRUITING

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Etanercept

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; Immunoglobulin Constant Regions; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins

Central Study Contacts

Amélie Yavchitz

CONTACT

+33 1 48 03 64 54; ayavchitz@for.paris

Jean Claude SADIK, PHD

CONTACT

jcsadik@for.paris

Study Design

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

Study Record Dates

• First Submitted: July 31, 2024
• First Posted: September 5, 2024
• Study Start: April 15, 2025
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: May 12, 2026

Record last verified: 2026-05

Locations

FR (1)