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NCT Number: NCT06965062

Cervical Lymphatico-Venous Bypass for Treatment of Alzheimer's Disease - Proof of Concept Study (CLyVeB-AD-1 Study)

Alzheimer's disease (AD), one of the most common causes of dementia in Singapore and the developed world, is a neurodegenerative disorder with high socioeconomic impact. Accumulation of neurotoxic proteins (ie. amyloid, tau) are purported to lead to neuroinflammation, synaptic dysfunction and cognitive decline. The available pharmacotherapy provide limited symptomatic control, modest effect on disease progression with significant risk of side effects. Patients with AD eventually run out of effective pharmacotherapy and deteriorate.

Recent evidence implicated the glymphatic system, meningeal lymphatics of the brain, and downstream drainage to the cervical lymphatic system in the accumulation of neurotoxic proteins in AD. This presented the opportunity for extra-cranial intervention, and has since been demonstrated in preclinical models. Based on these development, Xie and colleagues pioneered the deep cervical lymph node to venous bypass (DCLNV-BP) procedure with very promising early outcomes. The observed improvement had been attributed to enhanced clearance of the neurotoxic proteins. Knowledge gap and clinical equipoise remain, and clinical trials are required to understand the safety, mechanism of action, patient selection, and long-term outcomes.

In this proof of concept study, the investigators aim to assess safety and preliminary efficacy of DCLNV-BP in AD. An approach using objective clinical assessments, biomarkers and neuroimaging, to assess safety, evaluate preliminary efficacy and elucidate the possible mechanism underlying the observed effects, is undertaken. Since there are limited effective treatment for AD, this procedure is potentially ground breaking if it proves to halt progression or even improve patients' cognition, function and behaviour. Indirectly, this will have enormous health economic benefit for Singapore and the developed world that is facing the silver tsunami. Findings from this pilot study will lay the groundwork for future trials and research collaboration in AD and other neurodegenerative diseases.

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Key information

Conditions

Alzheimer Disease Alzheimer's Disease Alzheimer's Disease (AD) Brain Diseases Central Nervous System Diseases Dementia Dementia Alzheimer Type Dementia Alzheimer's Type Mental Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Tauopathies

Age range

50 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Changi General Hospital

Singapore

Location status: Recruiting

Location contact

Vincent K S Tay, BSc(Hons), MD, MRCS, MMed, MCI

CONTACT

[email protected]

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Diagnosis of mild-moderate Alzheimer's disease (based on NIA-AA criteria);
  • Mini-Mental State Examination (MMSE) score 10-22;
  • Both participants and caregiver are able to understand English or Mandarin
  • Ability to provide informed consent or have a legally authorised representative to provide informed consent;
  • Good family support for post-treatment care and rehabilitation;
  • Fit for general anaesthesia/deep sedation and surgery (ASA 1-2; excluding the diagnosis of Alzheimer's Disease).

Exclusion criteria

  • Cognitive decline due to prior infection or autoimmune diseases;
  • History of major cerebrovascular events or significant cardiovascular diseases;
  • Inability to have the head turned passively by at least 40 degrees;
  • Previous neck lymph node surgery or irradiation;
  • Active infection or malignancy;
  • Any contraindications to surgery or lumbar puncture
  • Any contraindication to MRI/PET scan (eg. metallic implant that are not MRI-safe, known radiotracer allergy)
  • Experimental Alzheimer's Disease treatment within the past 6 months. • Current use of monoclonal antibodies treatment (eg. lecanemab/donanemab)

Treatment and study plan

Deep cervical lymph node to venous bypass (DCLNV-BP)

Procedure

Participants will under bilateral deep cervical lymph node to venous bypass procedure under general anaesthesia.

Other names: Lymphaticovenous anastomosis

Primary outcomes

  1. Safety: Number of treatment-related adverse events

    Time frame: Over 2 years

    Treatment related adverse events and postoperative side effects eg. anaesthetic complications, infection, seroma, nerve or vascular injuries, wound healing issues, death.

  2. Mini Mental State Examination

    Time frame: Over 2 years

    Quick assessment of the cognitive domain. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 3; (3) PO day 7; (4) PO day 14; (5) PO 6 week; (6) PO 3 months; (7) PO 6 months; (8) PO 1 year; (9) PO 2 years.

  3. Montreal Cognitive Assessment

    Time frame: Over 2 years

    Brief assessment of the cognitive domains, especially in mild cognitive impairment, for memory, visuospatial skills, executive function. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.

  4. Clinical Dementia Rating (CDR)

    Time frame: Over 2 years

    Assessment administered to the participant and caregiver to test various cognitive domains (ie. orientation, attention and working memory, memory, visuospatial, language, executive function) and activities of daily living. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.

  5. Neuropsychiatric Inventory (NPI)

    Time frame: Over 2 years

    A comprehensive assessment of neuropsychiatric symptoms in patients with dementia, specifically behavioral changes, and administered to the main caregiver over about 5 minutes. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.

  6. Geriatric Depression Scale-Short Form (GDS-SF)

    Time frame: Over 2 years

    This assessment will take 5-7 minutes and will be administered to the participant to measure depressive symptoms. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.

  7. Quality of Life - Alzheimer's Disease (QoL-AD)

    Time frame: Over 2 years

    This assessment will take 5-10 minutes and will be administered to the participant to measure Quality of Life measures in AD. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.

  8. Zarit Burden Score

    Time frame: Over 2 years

    This assessment will take take 5-10 minutes and will be administered to the main caregiver to ascertain changes in caregiver burden.. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.

  9. Basic and instrumental Activities of Daily Living

    Time frame: Over 2 years

    This evaluation checklist will take under 5 minutes to assess participant's function status. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.

  10. Basic Gait Assessment

    Time frame: Over 2 years

    Basic gait assessment will be performed including (A) Gait Speed, (B) Timed up and go test, (C) 5X sit to stand test. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.

Secondary outcomes

  1. Fluid biomarkers

    Time frame: Over 1 year

    Blood plasma and cerebrospinal fluids will be analysed for biomarkers related to Alzheimer's disease, neurodegeneration and lymphatic dysfunction. Blood plasma will be sampled at (1) Operative day; (2) Postoperative(PO) day 3; (3) PO day 7; (4) PO day 14; (5) PO 6 weeks; (6) PO 3 months; (7) PO 6 months; (8) PO 1 year. CSF will be sampled at (1) Operative day; (2) PO day 7; (3) PO 6 weeks [Optional]; (4) PO 3 months [Optional].

  2. Magnetic Resonance Imaging (MRI) of the Brain

    Time frame: Over 1 year

    Participants will undergo pre- and post-intervention MRI of the brain for evaluation of neuroanatomical pathology and surrogate markers of glymphatic function (eg. DTI-ALPS). The scans will be performed at (1) Baseline, (2) Postoperative Day 7, (3) Postoperative 3 months.

  3. Positron Emission Tomography (PET) of the brain

    Time frame: Over 3 months

    Participants will undergo pre- and post-intervention PET fluorodeoxyglucose (FDG) brain scan to provide functional spatial information on changes before and after the surgery (at 3 months).

Study contacts

Contact information is provided by the study sponsor or research team.

Jeremy MF Sun, MBBS, FAMS

CONTACT

[email protected]

+65 90304976

Vincent KS Tay, MD, FAMS

CONTACT

[email protected]

+65 6788 8833

Sponsors and collaborators

Lead sponsor

Vincent Tay Khwee Soon

Other

Collaborators

  • Changi General Hospital
  • National Neuroscience Institute
  • Singapore General Hospital

Registry information

Acronym: CLyVeB-AD-1

Important dates

Study start
2025
Primary completion
2028
Study completion
2030
First posted
May 11, 2025
Registry last updated
Jan 13, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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