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[1]. 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[2][3].
| 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) |
| 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.
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[2:1].
Network dysfunction — Hyperactive neural networks may contribute to memory impairment and cognitive decline in AD through mechanisms including:
Seizures as a risk factor — Clinical or subclinical seizures are associated with:
Levetiracetam is an antiepileptic drug that works through:
Animal models of AD show that levetiracetam:
Human studies have demonstrated:
This trial is closely related to several mechanisms and conditions in NeuroWiki:
Shafi M et al. Treating Hyperexcitability in Alzheimer's Disease With Levetiracetam to Improve Brain Function and Cognition. 2019. ↩︎
Vossel KA et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurology. 2013. ↩︎ ↩︎
Vossel KA et al. Targeting aberrant neural oscillations in a developmental language disorder model: Levetiracetam efficacy supports the therapeutic role of neural hyperconnectivity. Neurobiology of Disease. 2016. ↩︎ ↩︎