Etanercept combined with repeated contrast ultrasound for Alzheimer's disease

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

This will try giving etanercept together with brief ultrasound openings of the blood–brain barrier in people aged 50–85 with mild Alzheimer's disease to see if the combination is safe.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 5 (estimated)
• Ages: 50 Years to 85 Years
• Sex: All
• Sponsor: Fondation Ophtalmologique Adolphe de Rothschild (Research network)
• Locations: 1 site (Paris)
• Trial ID: NCT06585384 on ClinicalTrials.gov

What this trial studies

This Phase 1 study tests the safety of systemic etanercept administered alongside repeated contrast-enhanced focused ultrasound to transiently open the blood–brain barrier in people with mild Alzheimer's disease. Eligible participants have biomarker-supported Alzheimer's (IWG2 criteria), are 50–85 years old, have MMSE ≥20 and low white-matter lesion burden (Fazekas ≤1). The procedure aims to permit delivery of a large anti‑TNF biologic to the brain without intrathecal injection by using short, targeted BBB openings, and safety endpoints will monitor adverse events related to the drug and ultrasound procedures. Exploratory cognitive and imaging measures may be collected, and the study is conducted at Fondation Adolphe de Rothschild in Paris.

Who should consider this trial

Good fit: People aged 50–85 with biomarker-supported mild Alzheimer's disease (MMSE ≥20), low white-matter disease burden (Fazekas ≤1), able to speak French, with a caregiver and stable concomitant treatments are the intended candidates.

Not a fit: Patients with advanced dementia, other major neurocognitive disorders, prior anti‑TNF treatment, significant cerebrovascular disease, MRI contraindications, or who cannot attend a Paris treatment center are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could allow anti‑TNF drugs to reach the brain and potentially reduce neuroinflammation that contributes to Alzheimer's symptoms.

How similar studies have performed: Small intrathecal etanercept reports showed encouraging signals and preclinical plus early human studies support ultrasound-mediated BBB opening, but combining systemic etanercept with repeated contrast ultrasound in Alzheimer's patients is novel and unproven.

Eligibility criteria

Inclusion Criteria:

* 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
* Patient suffering from mild AD with little or no impact on autonomy, MMSE score ≥20 at inclusion
* 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.

Exclusion Criteria:

* 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).
* Major depressive syndrome despite appropriate treatment and/or psychotic symptoms (according to DSM IV);
* MRI characteristic of an active or acute neurological process (infection, tumour) or macro-haemorrhage.
* Non-menopausal women
* Patient benefiting from a legal protection measure other than guardianship or curatorship.
* Optic neuritis
* Manifestations of multiple sclerosis
* Live vaccinations (yellow fever, BCG) within 4 weeks of starting etanercept treatment.
* History of hepatitis B or C
* Patients with recent acute coronary syndrome or unstable ischaemic heart disease.
* History of recurrent or chronic infections, or a predisposing condition such as severe or poorly controlled diabetes.
* Patients who have undergone major surgery within 28 days of the first day of the study.

Contraindications related to etanercept :

* Hypersensitivity to etanercept or to any of the excipients of Benepali
* Sepsis or risk of sepsis
* Active infection including chronic or localised infections.

Contraindications associated with SonoVue (ultrasound contrast medium)

* Hypersensitivity to Sonovue.
* Right-to-left shunt
* Severe PAH (pulmonary arterial pressure greater than 90 mmHg)
* Uncontrolled hypertension
* Respiratory distress syndrome
* Conditions suggesting cardiovascular instability for which dobutamine is contraindicated

Where this trial is running

Paris

• Fondation Adolphe de Rothschld — Paris, France (Recruiting)

Study contacts

• Study coordinator: Amélie Yavchitz

Conditions Alzheimer Disease