NCT03875638 (LeAD Trial) is a Phase 2 randomized, quadruple-blind, placebo-controlled crossover study evaluating levetiracetam as a treatment for neural hyperexcitability in early Alzheimer's disease["@shafi2019"]. The trial investigates whether reducing aberrant neural hyperactivity can improve cognitive function in patients with mild cognitive impairment (MCI) due to AD or early-stage AD.
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Overview
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NCT03875638 (LeAD Trial) is a Phase 2 randomized, quadruple-blind, placebo-controlled crossover study evaluating levetiracetam as a treatment for neural hyperexcitability in early Alzheimer's disease["@shafi2019"]. The trial investigates whether reducing aberrant neural hyperactivity can improve cognitive function in patients with mild cognitive impairment (MCI) due to AD or early-stage AD.
This trial is based on the growing evidence that epileptiform activity and neural hyperexcitability are common in AD patients, even in the absence of clinical seizures, and may contribute to cognitive decline["@vossel2013"][@vossel2016].
Trial Details
| Field | Value | |-------|-------| | NCT Number | NCT03875638 | | Official Title | Treating Hyperexcitability in Alzheimer's Disease With Levetiracetam to Improve Brain Function and Cognition | | Acronym | LeAD | | Phase | Phase 2 | | Status | RECRUITING | | Study Type | Interventional | | Design | Randomized, quadruple-blind, placebo-controlled crossover | | Enrollment | 85 participants (estimated) | | Sponsor | Beth Israel Deaconess Medical Center | | Principal Investigator | Mouhsin Shafi, MD, PhD | | Start Date | August 22, 2019 (actual) | | Primary Completion | October 31, 2025 (estimated) | | Study Completion | November 30, 2025 (estimated) |
Keywords: Mild Alzheimer's Disease, Early Alzheimer's Disease
Interventions
| Arm | Intervention | Dose | |-----|--------------|------| | Early AD Group | Levetiracetam | 125 mg twice daily (low dose) | | Early AD Group | Levetiracetam | 500 mg twice daily (high dose) | | Early AD Group | Placebo | Twice daily | | Healthy Control Group | No Intervention | — |
The trial uses a crossover design where participants receive each intervention (low dose, high dose, placebo) in sequence, with washout periods between treatments.
Eligibility Criteria
Inclusion - AD Subjects
Age 50-90 years
Stable dose of memory loss medications for ≥4 weeks
Meeting NINCDS-ADRDA criteria for probable AD
MMSE ≥20
Positive amyloid status (CSF or PET)
CDR 0.5-1.0
Inclusion - Healthy Controls
Age 50-90 years
Normal neurologic exam
MMSE >28
CDR 0
Exclusion (All Subjects)
Epilepsy diagnosis or family history
Neurological disorders other than dementia
Major psychiatric disorders (except depression)
Significant kidney impairment (eGFR <30)
Current antiepileptic drug use
Contraindications for MRI/TMS (metal implants, pacemaker, etc.)
Substance use disorders (past 6 months)
Study Locations
Facility: Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, United States
The rationale for this trial rests on several key findings:
Subclinical epileptiform activity is common in AD, with studies showing that 22-50% of AD patients exhibit epileptiform discharges on EEG without clinical seizures[@vossel2013].
Network dysfunction — Hyperactive neural networks may contribute to memory impairment and cognitive decline in AD through mechanisms including:
Disruption of sleep-dependent memory consolidation
Impaired synaptic plasticity
Accelerated tau pathology spread
Seizures as a risk factor — Clinical or subclinical seizures are associated with:
More rapid cognitive decline
Earlier age of onset
Greater disease severity
Levetiracetam Mechanism
Levetiracetam is an antiepileptic drug that works through:
SV2A modulation — Binds to synaptic vesicle protein 2A (SV2A), reducing neurotransmitter release
GABA-independent mechanisms — Does not directly affect GABA receptors, avoiding sedation
Neuroprotective properties — May reduce excitotoxicity and oxidative stress
Evidence from Preclinical and Clinical Studies
Animal models of AD show that levetiracetam:
Reduces hippocampal hyperexcitability
Improves memory performance
Decreases amyloid and tau pathology markers
Human studies have demonstrated:
Improved functional connectivity in AD patients[@vossel2016]
Enhanced memory encoding with low-dose levetiracetam
Good tolerability with minimal side effects
Connection to NeuroWiki
This trial is closely related to several mechanisms and conditions in NeuroWiki:
[Neuronal Hyperexcitability](/mechanisms/neuronal-hyperexcitability) — The primary mechanism being targeted
[SV2A Protein](/proteins/sv2a-protein) — The molecular target of levetiracetam
[SV2A Gene](/genes/sv2a) — Encoding the synaptic vesicle protein
[Epilepsy-Neurodegeneration Mechanism](/mechanisms/epilepsy-neurodegeneration) — Overlap between seizure disorders and neurodegenerative diseases
[GABAergic Dysfunction](/mechanisms/gabaergic-dysfunction) — Related neurotransmitter system
[Synaptic Dysfunction in Neurodegeneration](/mechanisms/synaptic-dysfunction-neurodegeneration) — Downstream effects
Oversight
FDA Regulated Drug: Yes
FDA Regulated Device: No
Data Monitoring Committee: Yes
Expanded Access: No
References
[Shafi M et al. Treating Hyperexcitability in Alzheimer's Disease With Levetiracetam to Improve Brain Function and Cognition (NCT03875638)](https://clinicaltrials.gov/study/NCT03875638)
[Vossel KA et al. Seizures and epileptiform activity in the early stages of Alzheimer disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23599933/)
[Vossel KA et al. Targeting aberrant neural oscillations in a developmental language disorder model (2016)](https://pubmed.ncbi.nlm.nih.gov/27452460/)