NCT03875638 - Levetiracetam for Alzheimer's Disease

Overview

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.

Overview

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) |

Conditions Studied

• Alzheimer Dementia
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• Dementia of Alzheimer Type
• [Mild Cognitive Impairment](/diseases/mild-cognitive-impairment)
• 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
• Status: RECRUITING
• Contact: Brenna Hagan, Phone: 617-667-0358, Email: bhagan1@bidmc.harvard.edu

Primary Contacts

• Ann Connor, RN: aconnor@bidmc.harvard.edu, 617-667-0269
• Mouhsin Shafi, MD, PhD: mshafi@bidmc.harvard.edu, 617-667-0182

Outcome Measures

Primary Outcomes

Other Outcomes

• TMS-evoked N45 EEG potential
• Interictal Epileptiform Discharges (baseline measure)

Scientific Rationale

Neural Hyperexcitability in AD

The rationale for this trial rests on several key findings:

• Disruption of sleep-dependent memory consolidation
• Impaired synaptic plasticity
• Accelerated tau pathology spread

• 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
• Calcium channel effects — Modulates N-type calcium channels
• 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

• 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