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Cerebral Amyloid AngiopathyPhase 2Clear-BrainNCT06421532

Stimulating Amyloid Clearance in Cerebral Amyloid Angiopathy

A Phase 2 study testing XYWAV and gammaCore Sapphire in people with Cerebral Amyloid Angiopathy, run by Leiden University Medical Center at 1 site in Netherlands.

Enrolling by invitation

Enrolling by invitation. The study team selects and invites participants, usually from an existing group of patients.

Sites and contacts
Official record
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Trial 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. Read more about this study

Who is it for?
Ages 30 years and older
Conditions the study is for
Cerebral Amyloid Angiopathy
What is being tested?
XYWAV and gammaCore Sapphire
Type of treatment
Medical device
Could I receive a placebo?
No, everyone receives an active treatment
How many people
60 participants
Where
1 siteNetherlands
Study dates
27 Mar 2025to 27 Sep 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 30 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 11Show fewer
  • ≤ 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

Who cannot join

  • 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:
Show all 45Show fewer
  • 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

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Netherlands1 site

  • Leiden University Medical Center (LUMC)

    Leiden, 2333ZA

Other trials in Netherlands

About this study

Official title: 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.

Being tested
XYWAV, gammaCore Sapphire
Medical subject headings
Cerebral Amyloid Angiopathy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • XYWAVDrug

    Daily before bedtime for 3 months

  • gammaCore SapphireDevice

    Twice daily for 3 months

Study groups in NCT06421532
Study groupRoleWhat they receive
Low-sodium oxybate (LXB)ExperimentalDeepening sleep
Receives: Drug: XYWAV
Non-invasive vagus nerve stimulation (nVNS)ExperimentalInhibiting cortical spreading depolarisations
Receives: Device: gammaCore Sapphire
Combination of bothExperimentalDeepening sleep and inhibiting cortical spreading depolarisations
Receives: Drug: XYWAV; Device: gammaCore Sapphire

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Morning amyloid-beta 40 and 42 levels in cerebrospinal fluid

    Difference between before and after intervention

    Measured: 3 months

Secondary outcomes (21)

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

    Macrobleeds

    Measured: 2x 3 months

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

    Cerebral microbleeds

    Measured: 2x 3 months

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

    Cortical superficial siderosis

    Measured: 2x 3 months

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

    Convexity subarachnoid haemorrhage

    Measured: 2x 3 months

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

    Periventricular and deep white matter hyperintensity volume

    Measured: 2x 3 months

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

    Cerebrovascular reactivity

    Measured: 2x 3 months

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

    Interaction between CSF-mobility at the 4th ventricle and brain vasomotion

    Measured: 2x 3 months

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

    Total CAA-related cerebral small vessel disease (CAA-CSVD) score

    Measured: 2x 3 months

  9. Activity of the glymphatic system by means of fluid dynamics on 7-T MRI

    CSF-mobility (in mm2/s)

    Measured: 2x 3 months

  10. Activity of the glymphatic system by means of fluid dynamics on 7-T MRI

    Principal orientation of CSF-mobility

    Measured: 2x 3 months

  11. Activity of the glymphatic system by means of fluid dynamics on 7-T MRI

    Fractional anisotropy

    Measured: 2x 3 months

  12. Other liquid biomarkers

    Difference in Aβ-levels 40 and 42 in CSF comparing the three intervention groups and the BATMAN placebo control group.

    Measured: 3 months

  13. Other liquid biomarkers

    Levels of amyloid-beta 38, 43, t-tau and p-tau181 in CSF

    Measured: 3 months

  14. Other liquid biomarkers

    Levels of amyloid-beta 40 and 42 in serum

    Measured: 3 months

  15. Questionnaires

    Cognitive status using the Montreal Cognitive Assessment (MoCA)

    Measured: 2x 3 months

  16. Questionnaires

    Symptoms of depression and anxiety using the Hospital Anxiety and Depression Scale (HADS)

    Measured: 2x 3 months

  17. Questionnaires

    Quality of life using the 36-item Short Form healthy survey (SF-36)

    Measured: 2x 3 months

  18. Questionnaires

    Quality of sleep using the Pittsburgh Sleep Quality Index (PSQI)

    Measured: 2x 3 months

  19. Questionnaires

    Severity of insomnia using the Insomnia Severity Index (ISI)

    Measured: 2x 3 months

  20. Intervention monitoring

    Compliance, side effects and tolerability of nVNS and LXB

    Measured: 3 months

  21. Intervention monitoring

    The number of participants developing sleep apnoea during intervention

    Measured: 3 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 May 2024
  2. Study start27 Mar 2025
  3. Primary completion27 Sep 2027 (estimated)
  4. Study completion27 Sep 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
pre-post study with additional randomisation
Masking
None (open label)
Enrolment
60 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06421532
Sponsor's protocol ID
P23.100
Acronym
Clear-Brain
Status last verified
Feb 2026
First submitted
8 May 2024
Last updated
24 Feb 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 41813043

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing XYWAV and gammaCore Sapphire in people with Cerebral Amyloid Angiopathy, run by Leiden University Medical Center at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 45 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: enrolling by invitation, as of the sponsor's last update on 24 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Morning amyloid-beta 40 and 42 levels in cerebrospinal fluid (time frame: 3 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06421532, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Feb 2026.

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