Deep Cervical Lymphatic Venous Anastomosis in the Treatment of Alzheimer's Disease (CLEAN-AD)

Alzheimer's Disease (AD) is a common neurodegenerative disorder affecting the elderly population. Global health data estimates that there are 50 million AD patients worldwide, and this number may triple to 150 million cases by 2050. Anti-amyloid β (Aβ) monoclonal antibodies have emerged as disease-modifying therapies for preclinical or mild AD, but the majority of candidate agents have failed to demonstrate clinical efficacy. For patients with moderate-to-severe AD, who comprise approximately 50% of the existing AD population, there are limitied treatment options in clinical practice. A series of case studies has suggested the efficacy of deep cervical lymphatic venous anastomosis (DC-LVA) in AD patients, however, there is currently no evidence from randomized controlled clinical trials.

The primary purpose of this study is to evaluate the efficacy and safety of deep cervical lymphatic venous anastomosis (DC-LVA) plus usual care versus usual care in reduing the score of clinical dementia rating-sum of boxes (CDR-SB) at 12 months in patients with moderate-to-severe Alzheimer's Disease (AD). This study also aims to assess the efficacy and safety of DC-LVA in reducing AD biomarker levels of brain Aβ PET imaging.

This trial is a multicenter, prospective, open-label, blinded-endpoint, randomized controlled trial. A total of 754 patients in 20 centers from China will be enrolled. Patients will be randomly assigned into DC-LVA plus usual care or usual care according to the ratio of 1:1. Face to face interviews will be made at baseline, 7 days (or hospital discharge), 3th months ± 7 days, 6th months ± 15 days, 9th months ± 15 days and 12th month ± 15 days after randomization. After 12 months, there will be 12 months open-label extension of follow-up, participants in the control group can choose to conduct DC-LVA. During the open-label extension phase, follow-up visits will be conducted every 3 months until 24th months after randomization.

Primary outcome is defined as the change of CDR-SB score at 12th months after randomization. The changes of CDR-SB score will be analyzed using a repeated measures mixed-effects model. Least squares means will be used to estimate the levels at each time point, and the mean difference with 95% confidence intervals will be calculated. Safety outcomes in the DC-LVA treatment group will be summarized using counts/percentages. Adverse events and serious adverse events will be summarized.

In exploratory outcome measures, the investigators will analyse the AD associated biomarkers in lymphatic tissue in the intervetnon group during the surgery, and analyse the change of fluid biomarkers ( AD associated biomarkers in peripheral blood, saliva, urine, and cerebrospinal fluid), the change of MRI brain volumes (total brain volume, hippocampal volume, lateral ventricle volume), the change of glymphatic function index(DTI-ALPS), the change of MRS metabolic markers (N-Acetylaspartate, Creatine, Choline, Lactate, Glutamate and Glutamine, myo-Inositol), and the change of artificial intelligence-assisted oculomotor/gait measurements during 12 months of follow-up.

Inclusion criteria

• Age 50-80 years, male or female.
• Diagnosed with AD according to NIA-AA criteria.
• Moderate-to-severe AD dementia, defined as Clinical Dementia Rating Scale Global Score (CDR-GS) ≥1.
• Mini-Mental State Examination (MMSE) score 10-20.
• The course of AD more than 6 months.
• If receiving an approved AD treatment, must be on a stable drug dose for at least 3 months prior to Baseline. AD Treatment-naïve subjects can be entered into the study.
• Have an identified caregiver (defined as a person able to support the subject for the duration of the study and who spends at least 8 hours per week with the subject). The caregiver must accompany with the participant at all study follow-up visits.
• Signed informed consent (from the participant or their relative, and the caregiver).

Exclusion criteria

• Any neurological condition other than AD that may affect cognitive function, including stroke, Parkinson's disease, epilepsy, intracranial tumors or space-occupying lesions, traumatic brain injury, intracranial infections, metabolic encephalopathy, etc.
• Other causes of dementia, including vascular dementia, hereditary cerebral small vessel disease, vitamin deficiency, or any other etiology leading to dementia.
• Previous evidence of severe stenosis (≥70%) in the middle cerebral artery and/or internal carotid artery.
• Presence of primary psychiatric disorders (such as schizophrenia, schizoaffective disorder, major depressive disorder, or bipolar disorder) rather than psychiatric symptoms caused by AD.
• Severe neurological deficits in limb movement, language, vision, hearing, or consciousness, or any condition that the investigator determines may prevent the completion of cognitive function assessments.
• History of drug or alcohol abuse or dependence.
• History of malignant tumors or prior radiotherapy or surgery involving the head and neck.
• Major surgical procedures or severe head or body trauma within the past 30 days.
• Presence of other life-threatening conditions with an expected survival time of less than 2 years.
• Contraindications to head MRI (including cardiac pacemakers/defibrillators, ferromagnetic metal implants, etc.).
• Severe diseases or functional impairment of the heart, lungs, liver, kidneys, or other solid organs, making the patient unable to tolerate anesthesia or DC-LVA.
• Severe bleeding tendency (including but not limited to): platelet count <100×10⁹/L; heparin therapy within the last 48 hours with APTT ≥35 seconds; ongoing warfarin use with INR >1.7.
• Requirement for long-term use of antithrombotic medications, with inability to discontinue them before surgery or potential risks associated with discontinuation.
• Uncontrolled persistent hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >95 mmHg).
• Co-infection with HIV or Treponema pallidum, or any uncontrolled infectious disease.
• Use of other investigational drugs or devices within 30 days prior to obtaining informed consent, or current participation in other interventional clinical studies.
• Pregnancy, lactation, potential for pregnancy, or plans for pregnancy during the study period.
• Immediate family members of the investigator (spouse, parents, children, or siblings), staff of the research institution or third-party organizations, or any other individuals with potential conflicts of interest related to the study.