Clinical trial NCT06871839: The Clinical Study of Synaptic Plasticity-based Lencanumab for the Treatment of Early Alzheimer's Disease
Official title: The Clinical Study of Synaptic Plasticity-based Lencanumab for the Treatment of Early Alzheimer's Disease
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Alzheimer&#39;s Disease
Lecanemab
Functional Magnetic Resonance Imaging
Keywords: Alzheimer&#39;s disease
Lecanemab
functional magnetic resonance imaging
Lead sponsor: Xuanwu Hospital, Beijing
Sponsor class: OTHER
Collaborators: name: Eisai (China) Pharmaceutical Co.
name: Jinan Hospital, Xuanwu Hospital, Capital Medical University
name: RenJi Hospital
name: First Hospital of China Medical University
name: Nanjing Brain Hospital
name: Guangdong Provincial People's Hospital
name: Zhejiang University
name: The First Affiliated Hospital of Anhui Medical University
name: The First Affiliated Hospital of University of Science and Technology of China
name: The First Hospital of Chongqing Medical University
name: Wuhan Union Hospital, China
name: West China Hospital
name: The First Hospital of Jilin University
First posted: 2025-03-12
Enrollment: 120
Sex: ALL
Minimum age (years): 50
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: We will recruit 120 early Alzheimer's disease (AD) patients from 13 hospitals, including Xuanwu Hospital of Capital Medical University. Among them, 60 cases will be in the Lecanemab treatment group, and 60 cases in the conventional treatment group.

Brief summary: Alzheimer's disease (AD) manifests itself in cognitive decline, impaired ability to perform daily life, and a variety of behavioral and psychiatric symptoms, seriously endangering the health of the elderly. The prevalence and disability rates of AD in China remain high, and the lack of effective treatment options has brought a heavy burden to patients and their families. Early intervention is regarded as an effective strategy to improve clinical symptoms, delay disease progression and maintain current quality of life. The humanized monoclonal antibody lencanemab (Lecanemab) was approved by the U.S. FDA in July 2023 for the treatment of mild cognitive impairment or mild dementia caused by AD, and was officially approved in January 2024 in China. Lencanemab highly targets soluble and insoluble neurotoxic β-amyloid (Aβ) proteins, reducing pathogenic Aβ plaque deposition and preventing its formation in the brains of AD patients, thus reducing neurotoxicity and improving patients' cognitive functions. In addition, lencanumab may also play a neuroprotective role by modulating synaptic plasticity and regulating neural network activity in brain neurons. However, there is a lack of clinical studies to prove this mechanism. In this study, we will enroll consecutive patients with early AD treated with lencanemab infusion as well as those receiving conventional anti-dementia therapy, and comprehensively assess the effects and intrinsic molecular mechanisms of lencanemab on synaptic function and neural networks using magnetic resonance imaging, molecular imaging positron emission tomography (PET), neuropsychological assessment, and analysis of blood cerebrospinal fluid samples.

Detailed description: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, impairment of daily living activities, and various behavioral and psychiatric symptoms. The most widely accepted hypothesis regarding the pathogenesis of AD is the amyloid cascade hypothesis. This hypothesis posits that the abnormal deposition of neurotoxic beta-amyloid (Aβ) is a key factor in the onset of AD. In the past two decades, anti-Aβ monoclonal antibodies aimed at reducing cerebral Aβ plaques have increasingly attracted attention in the field of AD drug development.

The humanized monoclonal antibody CAb (Lecanemab) highly targets soluble and insoluble A β\[1,2\] to reduce pathogenic A β plaques and prevent their formation in the brain of AD patients. Large global phase III clinical trials, including China, show that Lecanemab can slow the rate of cognitive decline in mild cognitive impairment (MCI) and mild AD within 18 months of treatment compared with placebo. However, the intrinsic mechanism by which Lecanemab delays disease progression by clearing pathogenic A β is not well understood. Previous studies have suggested that Lecanemab may have a role in improving synaptic plasticity. An animal experiment showed that the A β antibody can reverse the long-term enhanced (LTP) synaptic function defects caused by soluble A β oligomers and improve synaptic plasticity \[4\]. Synaptic plasticity is closely related to cognitive function. It refers to the ability to establish new connections between neurons or existing connections in the brain, which is manifested by changes in ultrastructure and functional changes of synapses, such as \[5\] of neurotransmitter level, neuroexcitability, electrical activity or changes in the number of postsynaptic receptors. It was shown that soluble A β oligomers are able to strongly inhibit synaptic plasticity in the normal rodent hippocampus, damage synaptic architecture, and ultimately lead to impaired cognitive \[6\]. Based on this, the scientific hypothesis is proposed that "Lecanemab may effectively reduce A β toxicity and protect synaptic function defects in AD brain". However, further clinical studies on the mechanism of Lecanemab on synaptic plasticity.

The purpose of this study is to prospectively evaluate the impact of continuous use of luncanemab infusion therapy on brain neural networks and synaptic plasticity in early Alzheimer's disease (AD) patients, and to explore the underlying molecular pathological mechanisms. According to the inclusion and exclusion criteria, eligible subjects are included in the screening visit period. During the screening visit, informed consent is signed, and demographic assessments are completed, along with the collection of past medical history, medication history, physical examination, and laboratory tests. Baseline neuropsychological scales, resting-state fMRI, three-dimensional structural MRI, Amyloid-PET, and blood and cerebrospinal fluid sample data are also collected. Patients are divided into a luncanemab treatment group and a conventional treatment group based on whether they receive luncanemab, and are followed up for data collection over a period of 12 months. This includes four neuropsychological assessments at 3 months, 6 months, 9 months, and 12 months of follow-up; collection of neuropsychological, resting-state fMRI, three-dimensional structural MRI, Amyloid-PET, and blood samples at baseline and at the 12-month follow-up, in accordance with patient wishes for cerebrospinal fluid sample collection; and two resting-state fMRI, three-dimensional structural MRI assessments, and blood sample collection at 6 months and 12 months of follow-up.

Eligibility criteria: Inclusion Criteria:

1. Age between 50 and 90 years.
2. Male or female patients.
3. Patients with MCI and mild AD.
4. MMSE score ≥20, CDR overall score of 0.5 or 1.
5. Amyloid-positive confirmed by Amyloid-PET or CSF.
6. Have a reliable caregiver to accompany the patient during study visits and supervise the use of study medication during the trial.
7. Agree to participate in the study and sign the informed consent form.

Exclusion Criteria:

1. Patients with cognitive impairment due to reasons other than AD.
2. A history of transient ischemic attack (TIA), stroke, cerebral hemorrhage, or seizure within the 12 months prior to screening.
3. A score of \>17 on the Hamilton Depression Scale at screening, or any suicidal behavior within 6 months prior to screening, at screening, or at the baseline visit, as well as any psychiatric diagnosis or symptoms that interfere with the study procedure (such as hallucinations, anxiety disorder, or paranoia).
4. Patients with a bleeding disorder or receiving anticoagulant therapy, as well as any with malignant tumors, severe gastrointestinal, kidney, liver, respiratory, immune, endocrine, and cardiovascular system diseases that affect this study.
5. A hypersensitivity reaction to ranucimab or any other ingredient in the injection solution, or to any monoclonal antibody treatment.
6. Contraindications to MRI scanning, including those with a pacemaker/defibrillator or ferromagnetic metal implants (except for skull and cardiac devices approved as safe for MRI scanning).
7. A known or suspected history of drug or alcohol abuse or dependence within the 2 years prior to screening.
8. Participation in a clinical study involving any therapeutic monoclonal antibody or novel compounds for the treatment of AD within the 6 months prior to screening, unless it can be proven that the subject was in the placebo treatment group.
9. Planning to undergo surgery requiring general anesthesia during the study period.
10. A positive pregnancy test result, lactation, or pregnancy in females at screening or baseline.

Primary outcomes:
measure: Resting-state fMRI brain network metrics (Independent Component Analysis)
timeFrame: 2 years
Secondary outcomes:
measure: Other resting-state fMRI brain network indicators: functional connectivity (FC)
timeFrame: 2 years
measure: Other resting-state fMRI brain network indicators: Granger Causality Analysis (GCA)
timeFrame: 2 years
measure: Other resting-state fMRI brain network indicators: Spectral Dynamic Causal Model (spDCM)
timeFrame: 2 years
measure: Rate of change in global cognition as measured by Clinical Dementia Rating (CDR)
timeFrame: 2 years
measure: Rate of change in the severity of cognitive impairment as assessed by Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-cog)
timeFrame: 2 years
measure: Rate of change in global cognition as measured by Mini-Mental State Examination (MMSE)
timeFrame: 2 years
measure: Rate of change in global cognition as measured by Montreal Cognitive Assessment (MoCA)
timeFrame: 2 years
measure: Alzheimer's Disease Composite Score (ADCOMS)
timeFrame: 2 years
measure: The Integrated Alzheimer's Disease Rating Scale (iADRS)
timeFrame: 2 years
measure: Five Levels Five-Dimensional Health Scale (EQ-5D-5L)
timeFrame: 2 years
measure: Alzheimer's Disease Quality of Life Scale (QOL-AD)
timeFrame: 2 years
measure: Rate of change in activities of daily living as assessed by Alzheimer's Disease Cooperative Study-Activity of Daily Living (ADCS-ADL)
timeFrame: 2 years
measure: Rate of change in psychobehavioral symptoms as assessed by Neuropsychiatric Inventory (NPI)
timeFrame: 2 years
measure: Hamilton Anxiety Scale (HAMA)
timeFrame: 2 years
measure: Hamilton Depression Rating Scale (HAMD)
timeFrame: 2 years
measure: Zarit Caregiver Burden Interview Scale (ZBI)
timeFrame: 2 years
measure: Blood AD molecular pathology and synaptic structural protein content indicators
timeFrame: 2 years
measure: Cerebrospinal Fluid Synaptic Function Protein Content Assessment Indicator
timeFrame: 2 years
measure: Neuroimaging biomarkers: Aβ-PET centiloid values
timeFrame: 2 years
Other outcomes:
measure: Blood neuron-derived exosome transcriptomics-related indicators
timeFrame: 2 years
Locations:
city: Beijing
country: China
facility: Capital Medical University Xuanwu Hospital
Study officials:
affiliation: Xuan Wu Hospital of Capital Medical University
name: Cui bai Wei
role: PRINCIPAL_INVESTIGATOR
References: