Stimulating Amyloid Clearance in Cerebral Amyloid Angiopathy

NCT06421532 | Enrolling By Invitation Phase 2 FDA Drug

• 1 other identifier: P23.100
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

A pre-post study will be conducted to assess whether treatment with LXB, nVNS or a combination of both interventions can enhance the clearance of Aβ in patients with CAA. A total of 60 subjects, 30 with sCAA and 30 with D-CAA, will be randomly assigned to receive LXB, or both interventions. The primary outcome measure will be the morning levels of Aβ40 and Aβ42 in cerebrospinal fluid (CSF) before and after the intervention. The investigators will assess disease progression with (non-)haemorrhagic imaging markers on 7-Tesla Magnetic Resonance Imaging (7-T MRI) as a secondary outcome. Additionally, the activity of the glymphatic system by means of fluid dynamics will be assessed using 7-T MRI.

Conditions

Cerebral Amyloid Angiopathy

Outcome Measures

Primary Outcomes (1)

• Morning amyloid-beta 40 and 42 levels in cerebrospinal fluid

  Difference between before and after intervention

  3 months

Secondary Outcomes (21)

• Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI

  2x 3 months

• Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI

  2x 3 months

• Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI

  2x 3 months

• Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI

  2x 3 months

• Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI

  2x 3 months

Study Arms (3)

Low-sodium oxybate (LXB)

EXPERIMENTAL

Deepening sleep

Drug: XYWAV

Non-invasive vagus nerve stimulation (nVNS)

EXPERIMENTAL

Inhibiting cortical spreading depolarisations

Device: gammaCore Sapphire

Combination of both

EXPERIMENTAL

Deepening sleep and inhibiting cortical spreading depolarisations

Drug: XYWAV; Device: gammaCore Sapphire

Interventions

XYWAV DRUG

Daily before bedtime for 3 months

Combination of both; Low-sodium oxybate (LXB)

gammaCore Sapphire DEVICE

Twice daily for 3 months

Combination of both; Non-invasive vagus nerve stimulation (nVNS)

Eligibility Criteria

• Age: 30 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with D-CAA with a proven amyloid precursor protein (APP) mutation or a history of ≥1 lobar intracerebral haemorrhage (ICH) and a positive family history for D-CAA in ≥1 first degree relative
• Age ≥30 years old
• ≤ 2 symptomatic ICH (occurrence of ICH at least \> 1 year ago) or presence of ≥ 1 haemorrhagic marker (cortical superficial siderosis, cerebral microbleeds) or non-haemorrhagic marker (white matter hyperintensities, enlarged perivascular spaces).
• When presymptomatic, patients are aware that they have D-CAA
• Probable sporadic CAA (sCAA) according to the Modified Boston criteria 2.0
• Age ≥50 years old
• ≤ 2 symptomatic ICH (occurrence of ICH at least \> 1 year ago)
• Provisional CAA when the criteria for probable sCAA are not met due to presence of deep haemorrhagic lesions but there are mostly lobar microbleeds (MBs) and cortical superficial siderosis (cSS) present or a ratio of 10 times more lobar MBs than deep MBs without cSS.
• Age ≥50 years old
• ≤ 2 symptomatic ICH (occurrence of ICH at least \> 1 year ago)
• Participants able to read and understand the patient information folder and who freely provide written informed consent

You may not qualify if:

• Modified Rankin Score ≥ 4
• A life expectancy of less than six months
• Pregnancy/breast feeding
• Contraindications for lumbar puncture
• Unwillingness to refrain from consuming \> 1 alcohol unit per day and not later than 8 pm, during the intervention period.
• Contraindications for using LXB:
• Restless legs (RLS) needing active treatment with RLS medication.
• Currently suffering from severe depression and using medication or receiving cognitive therapy.
• Porphyria
• Succinic semialdehyde dehydrogenase (SSADH-)deficiency
• Use of opiates, barbiturates, sedatives (dexmedetomidine, temazepam, oxazepam, midazolam)
• When benzodiazepine is used: a two nights washout before the intervention (T3) will be started, is needed.
• Contraindications for lumbar puncture:
• Compression of the spinal cord
• Signs and symptoms of increased intracranial pressure

Sponsors & Collaborators

• Leiden University Medical Center: lead
• The Dutch Brain Foundation: collaborator

Study Sites (1)

Leiden University Medical Center (LUMC)

Leiden, 2333ZA, Netherlands

Location

Related Publications (1)

• Schriemer SE, Hirschler L, van Etten ES, van Zwet EW, Lammers GJ, Liebler EJ, van Walderveen MAA, Slats AM, van Es ACGM, Verbeek MM, van Osch MJP, Wermer MJH, Fronczek R. Stimulating amyloid-beta clearance in cerebral amyloid angiopathy with low-sodium oxybate and/or non-invasive vagus nerve stimulation (Clear-Brain): study protocol for a randomised pre-post trial. BMJ Open. 2026 Mar 11;16(3):e113194. doi: 10.1136/bmjopen-2025-113194.

  PMID: 41813043 DERIVED

MeSH Terms

Conditions

Cerebral Amyloid Angiopathy

Condition Hierarchy (Ancestors)

Cerebral Arterial Diseases; Intracranial Arterial Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Amyloidosis; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: principal investigator and neurologist

Model Details: pre-post study with additional randomisation

Study Record Dates

• First Submitted: May 8, 2024
• First Posted: May 20, 2024
• Study Start: March 27, 2025
• Primary Completion (Estimated): September 27, 2027
• Study Completion (Estimated): September 27, 2027
• Last Updated: February 24, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)