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

NCT06965062 | Recruiting DMC

• 1 other identifier: ClyVeB-AD-1
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Alzheimer Disease; Dementia Alzheimer Type; Dementia Alzheimer's Type; Alzheimer's Disease; Alzheimer's Disease (AD)

Keywords

Alzheimer's Disease; Dementia; lymphatic surgery; lymphaticovenous anastomosis; lymphaticovenous bypass; cervical lymph node; meningeal lymphatic system; glymphatic system

Outcome Measures

Primary Outcomes (10)

• Safety: Number of treatment-related adverse events

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

  Over 2 years

• Mini Mental State Examination

  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.

  Over 2 years

• Montreal Cognitive Assessment

  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.

  Over 2 years

• Clinical Dementia Rating (CDR)

  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.

  Over 2 years

• Neuropsychiatric Inventory (NPI)

  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.

  Over 2 years

• Geriatric Depression Scale-Short Form (GDS-SF)

  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.

  Over 2 years

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

  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.

  Over 2 years

• Zarit Burden Score

  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.

  Over 2 years

• Basic and instrumental Activities of Daily Living

  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.

  Over 2 years

• Basic Gait Assessment

  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.

  Over 2 years

Secondary Outcomes (3)

• Fluid biomarkers

  Over 1 year

• Magnetic Resonance Imaging (MRI) of the Brain

  Over 1 year

• Positron Emission Tomography (PET) of the brain

  Over 3 months

Study Arms (1)

Surgical Intervention

EXPERIMENTAL

This is single-arm, open-label proof of concept study.

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

Interventions

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.

Also known as: Lymphaticovenous anastomosis

Surgical Intervention

Eligibility Criteria

• Age: 50 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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)

Sponsors & Collaborators

• Vincent Tay Khwee Soon: lead
• Changi General Hospital: collaborator
• Singapore General Hospital: collaborator
• National Neuroscience Institute: collaborator

Study Sites (1)

Changi General Hospital

Singapore, Singapore

RECRUITING

MeSH Terms

Conditions

Alzheimer Disease; Dementia

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Central Study Contacts

Vincent KS Tay, MD, FAMS

CONTACT

+65 6788 8833; vincent.tay.k.s@singhealth.com.sg

Jeremy MF Sun, MBBS, FAMS

CONTACT

+65 90304976; jeremy.sun.m.f@singhealth.com.sg

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Consultant Plastic Surgeon

Study Record Dates

• First Submitted: January 17, 2025
• First Posted: May 11, 2025
• Study Start: April 1, 2025
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 31, 2030
• Last Updated: January 13, 2026

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

SG (1)