NCT07477431 - Levetiracetam for Persons at Risk for Alzheimer's Disease

NCT07477431: Levetiracetam for Persons at Risk for Alzheimer's Disease

Overview

NCT07477431 is a Phase 2 clinical trial evaluating levetiracetam as a preventive treatment for individuals at risk for Alzheimer's disease. This trial represents a shift from treating established Alzheimer's disease to intervening in the preclinical phase, before significant cognitive decline occurs.

The trial is based on the hypothesis that neural hyperexcitability (subclinical epileptiform activity) begins years before clinical symptoms of Alzheimer's disease and may be a driving factor in disease progression. By treating at-risk individuals with levetiracetam before significant pathology accumulates, the trial aims to prevent or delay the onset of cognitive impairment.

Trial Details

NCT07477431: Levetiracetam for Persons at Risk for Alzheimer's Disease

Overview

NCT07477431 is a Phase 2 clinical trial evaluating levetiracetam as a preventive treatment for individuals at risk for Alzheimer's disease. This trial represents a shift from treating established Alzheimer's disease to intervening in the preclinical phase, before significant cognitive decline occurs.

The trial is based on the hypothesis that neural hyperexcitability (subclinical epileptiform activity) begins years before clinical symptoms of Alzheimer's disease and may be a driving factor in disease progression. By treating at-risk individuals with levetiracetam before significant pathology accumulates, the trial aims to prevent or delay the onset of cognitive impairment.

Trial Details

| Field | Value |
|-------|-------|
| NCT Number | NCT07477431 |
| Official Title | Levetiracetam for Persons at Risk for Alzheimer's Disease |
| Phase | Phase 2 |
| Status | RECRUITING |
| Study Type | Interventional |
| Design | Randomized, double-blind, placebo-controlled |
| Enrollment | Estimated participants (to be determined) |
| Sponsor | To be confirmed |
| Start Date | 2024 (actual) |
| Primary Completion | To be confirmed |
| Study Completion | To be confirmed |

Scientific Rationale

Neural Hyperexcitability as Early Biomarker

Research has established that subclinical epileptiform activity is common in Alzheimer's disease, with studies showing 22-50% of AD patients exhibiting epileptiform discharges on EEG without clinical seizures[@vossel2013]. However, emerging evidence suggests this neural hyperexcitability begins even earlier—potentially during the preclinical stage when amyloid and tau pathology are accumulating but cognitive symptoms have not yet manifested.

Key findings supporting this approach include:

Levetiracetam Mechanism of Action

Levetiracetam is an antiepileptic drug with several mechanisms relevant to AD prevention[@cleveland2019]:

• SV2A modulation: The primary mechanism involves binding to synaptic vesicle protein 2A (SV2A), reducing excessive neurotransmitter release
• Calcium channel effects: Modulates N-type calcium channels, reducing calcium-mediated excitotoxicity
• GABA-independent action: Does not directly affect GABA receptors, avoiding sedation and cognitive dulling
• Neuroprotective properties: May reduce excitotoxicity, oxidative stress, and synaptic dysfunction

• Excellent tolerability profile
• Minimal drug-drug interactions
• Once or twice daily oral dosing
• Well-established safety in elderly populations

Population: At-Risk Individuals

Defining "At Risk"

The trial enrolls individuals who are at elevated risk for developing Alzheimer's disease but do not yet have clinical symptoms. This population may include:

• APOE ε4/ε4 homozygosity
• Family history of AD (particularly early-onset)
• Trisomy 21 (Down syndrome) - although see NCT07234695

Rationale for Prevention

Preventing AD before clinical symptoms manifest offers several advantages:

Study Design

Treatment Arms

Participants will be randomized to:

• Levetiracetam treatment group: Low-dose levetiracetam
• Placebo control group: Matching inactive tablets

Duration

• Treatment period: 12-24 months (to be confirmed)
• Follow-up period: Additional 6-12 months
• Total participation: 18-36 months

Assessments

Cognitive assessments:

• Comprehensive neuropsychological battery
• Memory tests (episodic, working, spatial)
• Executive function tests
• Subjective cognitive complaints scales

• Resting-state EEG to detect hyperexcitability markers
• Magnetoencephalography (MEG)
• Functional MRI connectivity measures
• TMS-evoked potentials

• CSF amyloid-beta and tau levels
• Plasma p-tau217, p-tau181, NfL
• Amyloid PET (Flutemetamol, Florbetapir)
• Tau PET (if applicable)

• Adverse event collection
• Vital signs and neurological exams
• Renal function tests
• Behavioral/psychiatric assessments

Connection to NeuroWiki

This trial is closely related to several key topics in NeuroWiki:

• [Neuronal Hyperexcitability](/mechanisms/neuronal-hyperexcitability) — Primary mechanism being targeted
• [SV2A Protein](/proteins/sv2a-protein) — Molecular target of levetiracetam
• [SV2A Gene](/genes/sv2a) — Encoding synaptic vesicle protein 2A
• [Preclinical Alzheimer's Disease](/diseases/preclinical-alzheimers) — The at-risk stage being treated
• [Amyloid Cascade Hypothesis](/mechanisms/amyloid-cascade) — Underlying AD pathology
• [Epilepsy-Neurodegeneration Mechanism](/mechanisms/epilepsy-neurodegeneration) — Overlap between seizure disorders and AD
• [Cognitive Reserve](/mechanisms/cognitive-reserve) — Factors modifying AD risk
• [Levetiracetam for AD (NCT03875638 - LeAD Trial](/clinical-trials/levetiracetam-alzheimers-nct03875638) — Related Phase 2 trial in early AD
• [Levetiracetam for DS-AD (NCT07234695](/clinical-trials/levetiracetam-down-syndrome-ad-nct07234695) — Phase 3 trial in Down syndrome

Eligibility Criteria

Inclusion Criteria (Expected)

• Age 55-85 years (typical range)
• Cognitively normal or mild cognitive impairment (MCI) not due to AD
• Positive amyloid biomarker (PET or CSF)
• At least one additional AD risk factor
• Stable medications for ≥4 weeks
• Able to undergo MRI and PET imaging
• Consent from participant

Exclusion Criteria (Expected)

• Clinical diagnosis of MCI due to AD or AD dementia
• History of epilepsy or seizures
• Current use of antiepileptic medications
• Neurological disorders other than AD risk
• Major psychiatric disorders
• Significant kidney impairment
• Contraindications for MRI (metal implants, pacemaker)
• Substance use disorders
• Inability to comply with study procedures

Expected Outcomes

Primary Outcomes

Secondary Outcomes

Exploratory Outcomes

Risks and Benefits

Potential Benefits

Participants may experience:

• Preservation of cognitive function
• Prevention or delay of AD onset
• Better understanding of their biomarker status
• Close monitoring by clinical research team

Potential Risks

Levetiracetam may cause:

• Somnolence or fatigue (usually transient)
• Dizziness or balance problems
• Behavioral changes (rare, including agitation or depression)
• Gastrointestinal symptoms
• Allergic reactions (rare)

Considerations for Prevention Trials

Prevention trials require special considerations:

• Long treatment duration
• Uncertainty about individual benefit
• Potential for over-treatment of individuals who would never develop AD
• Psychological impact of knowing one's biomarker status

Related Clinical Trials

The NCT07477431 trial sits within a broader portfolio of levetiracetam trials for AD:

Current Status

This trial is currently RECRUITING. For the most current information on enrollment status, locations, and eligibility, please visit:

• [ClinicalTrials.gov: NCT07477431](https://clinicaltrials.gov/study/NCT07477431)

References