Stimulating Amyloid Clearance in Cerebral Amyloid Angiopathy (Clear-Brain)

A Partial Randomised Clinical Trial Investigating Stimulation of the Glymphatic System by Either Deepening Sleep With Lower-sodium Oxybate or Inhibiting Cortical Spreading Depressions With Non-invasive Vagus Nerve Stimulation, or Both, in Patients With Cerebral Amyloid Angiopathy (CAA)

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Cerebral Amyloid Angiopathy
• Intervention / Treatment: Drug: XYWAV; Device: gammaCore Sapphire

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333ZA
    • Leiden University Medical Center (LUMC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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:

• Sleep apnea; patients will be screened with respiratory polygraphy before inclusion and screening by questionnaire during intervention with 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)

• Use certain medication before inclusion:

  • When benzodiazepine is used: a two nights washout before the intervention (T3) will be started, is needed.
  • When LXB or SXB is used before inclusion: one week washout before inclusion and no use of LXB or SXB during inclusion except for the intervention dose.

Contraindications for lumbar puncture:

• Compression of the spinal cord
• Signs and symptoms of increased intracranial pressure
• Local infections of the skin at the puncture site
• Coagulopathy or thrombocytopenia (<100)
• (Use of acetylsalicylic acid, NSAIDs, COX2 inhibitors or prophylactic low-molecular-weight heparin are no contraindications for lumbar puncture.)
• Participants deemed at risk for brain replacement due to known aqueduct stenosis, Arnold chiari malformations.
• Participants with a lumbo-sacral neural tube defect or who have a ventriculo-atrial or ventriculo-peritoneal drain.

Contraindications for nVNS:

• An active implantable medical device such as a pacemaker, deep brain stimulator, or any implanted electronic device.
• A recent (< 1 month) brain infarction or transient ischemic attack due to a symptomatic stenosis or dissection of the carotid artery (in these patients the other side will be stimulated unless a significant stenosis or dissection on the other side is present as well).
• If someone knows to have a structural abnormality e.g. lymphadenopathy, previous surgery or abnormal anatomy (in these patients the other side will be stimulated)
• Metal cervical spine hardware or metallic implant near the stimulation site
• Cervical vagotomy (in these patients the other side will be stimulated)

Contraindications for 7 Tesla MRI as determined by the 7 Tesla safety committee. Examples of possible contra-indications are:

• Claustrophobia
• Pacemakers and defibrillators
• Nerve stimulators
• Intracranial clips
• Intraorbital or intraocular metallic fragments
• Cochlear implants
• Ferromagnetic implants
• Hydrocephalus pump
• Intra-uterine device
• Permanent make-up
• Tattoos above the shoulders

Specific contraindications for checkerboard functional Magnetic Resonance Imaging (fMRI):

• Seizure within prior year
• Photosensitive epilepsy
• Non-correctable visual impairment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-sodium oxybate (LXB); Deepening sleep	Drug: XYWAV; Daily before bedtime for 3 months
Experimental: Non-invasive vagus nerve stimulation (nVNS); Inhibiting cortical spreading depolarisations	Device: gammaCore Sapphire; Twice daily for 3 months
Experimental: Combination of both; Deepening sleep and inhibiting cortical spreading depolarisations	Drug: XYWAV; Daily before bedtime for 3 months; Device: gammaCore Sapphire; Twice daily for 3 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Morning amyloid-beta 40 and 42 levels in cerebrospinal fluid	Difference between before and after intervention	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI	Macrobleeds	2x 3 months
Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI	Cerebral microbleeds	2x 3 months
Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI	Cortical superficial siderosis	2x 3 months
Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI	Convexity subarachnoid haemorrhage	2x 3 months
Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI	Periventricular and deep white matter hyperintensity volume	2x 3 months
Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI	Cerebrovascular reactivity	2x 3 months
Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI	Interaction between CSF-mobility at the 4th ventricle and brain vasomotion	2x 3 months
Disease progression with (non-)haemorrhagic imaging markers on 7-T MRI	Total CAA-related cerebral small vessel disease (CAA-CSVD) score	2x 3 months
Activity of the glymphatic system by means of fluid dynamics on 7-T MRI	CSF-mobility (in mm2/s)	2x 3 months
Activity of the glymphatic system by means of fluid dynamics on 7-T MRI	Principal orientation of CSF-mobility	2x 3 months
Activity of the glymphatic system by means of fluid dynamics on 7-T MRI	Fractional anisotropy	2x 3 months
Other liquid biomarkers	Difference in Aβ-levels 40 and 42 in CSF comparing the three intervention groups and the BATMAN placebo control group.	3 months
Other liquid biomarkers	Levels of amyloid-beta 38, 43, t-tau and p-tau181 in CSF	3 months
Other liquid biomarkers	Levels of amyloid-beta 40 and 42 in serum	3 months
Questionnaires	Cognitive status using the Montreal Cognitive Assessment (MoCA)	2x 3 months
Questionnaires	Symptoms of depression and anxiety using the Hospital Anxiety and Depression Scale (HADS)	2x 3 months
Questionnaires	Quality of life using the 36-item Short Form healthy survey (SF-36)	2x 3 months
Questionnaires	Quality of sleep using the Pittsburgh Sleep Quality Index (PSQI)	2x 3 months
Questionnaires	Severity of insomnia using the Insomnia Severity Index (ISI)	2x 3 months
Intervention monitoring	Compliance, side effects and tolerability of nVNS and LXB	3 months
Intervention monitoring	The number of participants developing sleep apnoea during intervention	3 months

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: The Dutch Brain Foundation

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2025
• Primary Completion (Estimated): September 27, 2027
• Study Completion (Estimated): September 27, 2027

Study Registration Dates

• First Submitted: May 8, 2024
• First Submitted That Met QC Criteria: May 14, 2024
• First Posted (Actual): May 20, 2024

Study Record Updates

• Last Update Posted (Actual): February 24, 2026
• Last Update Submitted That Met QC Criteria: February 19, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Metabolic Diseases; Proteostasis Deficiencies; Intracranial Arterial Diseases; Cerebral Arterial Diseases; Amyloidosis; Nutritional and Metabolic Diseases; Cerebral Amyloid Angiopathy
• Other Study ID Numbers: P23.100

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes