Levetiracetam for Alzheimer's Disease

(LeAD Trial)

Overseen By Mouhsin Shafi, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Beth Israel Deaconess Medical Center

Must be taking: Cholinesterase inhibitors

Must not be taking: Antiepileptic drugs

Disqualifiers: Epilepsy, Stroke, Schizophrenia, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 9

Duration: 12 weeks (treatment) + 8 weeks (washout)

85 Participants Needed

Trial Summary

What is the purpose of this trial?

The aim of this study is to explore the relationship between cortical hyperexcitability, abnormalities of brain network function, and cognitive dysfunction in human patients with AD and whether administration of the antiepileptic medication levetiracetam (LEV) normalizes these measures and improves cognition.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop your current medications, but you must be on a stable dose of memory loss medications for at least four weeks. The study physician will review your medications to decide on your inclusion, and current use of an antiepileptic drug will exclude you from participating.

Is levetiracetam safe for use in humans?

Levetiracetam is generally considered safe and well-tolerated in humans, with common mild side effects like drowsiness, weakness, and dizziness. It has a favorable safety profile in special populations, including the elderly and those with liver issues, but may cause behavioral issues in some patients with a history of psychiatric problems. ^{1 2 3 4 5}

How does the drug Levetiracetam differ from other treatments for Alzheimer's disease?

Levetiracetam is unique because it is primarily an anti-seizure medication that may help Alzheimer's patients by reducing abnormal brain activity and potentially improving memory. Unlike other treatments, it targets the electrical disturbances in the brain that are more common in Alzheimer's patients, which might contribute to cognitive decline. ^{3 6 7 8 9}

Eligibility Criteria

This trial is for adults aged 50-90 with early Alzheimer's Disease (AD) or mild cognitive impairment, having a Mini Mental State Examination (MMSE) score of ≥20 and positive amyloid status. They must be on stable memory loss medication for at least four weeks. Excluded are those with epilepsy, significant neurological history, major psychiatric disorders, metal implants not cleared for MRI/TMS, severe kidney issues, or uncontrolled medical conditions.

Inclusion Criteria

Meeting the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD.

Your neurological exam shows no abnormalities.

I've been on a steady dose of memory loss medication for at least 4 weeks.

Exclusion Criteria

I have had fainting spells that might be seizures.

You have had problems with drugs or alcohol in the past six months.

Any metal in the brain or skull (excluding dental fillings) or elsewhere in the body unless cleared by the responsible covering MD (e.g. MRI compatible joint replacement).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

4 visits (in-person)

Baseline Assessment

Baseline neurological, medical, and cognitive evaluation including EEG, fMRI, and neuropsychological testing

1-2 weeks

1 visit (in-person)

Treatment

Participants undergo three 4-week treatment periods with low-dose LEV, high-dose LEV, and placebo, each followed by a 4-week washout

12 weeks (treatment) + 8 weeks (washout)

4 visits (in-person) per treatment period

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Levetiracetam

Trial Overview The study tests if the antiepileptic drug Levetiracetam can normalize brain function and improve cognition in AD patients by reducing cortical hyperexcitability. Participants will either receive Levetiracetam or a placebo capsule to compare effects on cognitive dysfunction associated with AD.

Participant Groups

Group I: Early Alzheimer's Disease Group Low Dose Experimental Treatment 1 Intervention

Subjects with Alzheimer's Disease will undergo a four-week treatment period consisting of low-dose levetiracetam (125 mg twice daily)

Group II: Early Alzheimer's Disease Group High Dose Experimental Treatment 1 Intervention

Subjects with Alzheimer's Disease will undergo a four-week treatment period consisting of high-dose levetiracetam (500mg twice daily).

Group III: Healthy Control Group Active Control 1 Intervention

A group of demographically similar subjects without Alzheimer's Disease will undergo baseline testing only, without any intervention

Group IV: Early Alzheimer's Disease Group Placebo Placebo Group 1 Intervention

Subjects with Alzheimer's Disease will undergo a four-week treatment period consisting of placebo twice daily.

Who Is Running the Clinical Trial?

Beth Israel Deaconess Medical Center

Lead Sponsor

Trials

872

Recruited

12,930,000+

Findings from Research

In a study of 517 patients taking levetiracetam, 10.1% experienced psychiatric adverse events (PAE), indicating a notable risk associated with this medication.

Patients with a prior psychiatric history, a history of febrile convulsions, or status epilepticus were more likely to develop PAE, while co-therapy with lamotrigine appeared to reduce this risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psychiatric adverse events during levetiracetam therapy. Mula, M., Trimble, MR., Yuen, A., et al.[2022]

Levetiracetam is generally safe and well-tolerated, with common mild-to-moderate side effects like somnolence and dizziness occurring more frequently than in placebo groups, but these usually resolve without needing to stop the medication.

Special populations, including children and those with prior behavioral issues, may experience increased behavioral side effects, but overall, levetiracetam shows a favorable safety profile, with no significant changes in blood chemistry or weight reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam safety profiles and tolerability in epilepsy patients. Briggs, DE., French, JA.[2019]

In a study of 25 patients with advanced Alzheimer's disease and new-onset seizures, 72% achieved seizure freedom for at least one year while on levetiracetam (LEV) monotherapy at doses of 1000-1500 mg.

The study also noted that 16% of participants discontinued treatment due to intolerability, indicating a need for further controlled studies to evaluate the safety and efficacy of LEV as a first-choice treatment for seizures in Alzheimer's patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam monotherapy in Alzheimer patients with late-onset seizures: a prospective observational study. Belcastro, V., Costa, C., Galletti, F., et al.[2022]

In a study of 95 patients with seizures and Alzheimer's disease, levetiracetam (LEV) was found to have a better safety profile, causing fewer adverse events compared to phenobarbital (PB) and lamotrigine (LTG).

LEV not only controlled seizures effectively but also improved cognitive performance, particularly in attention and oral fluency, making it a suitable option for elderly patients with Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer's disease. Cumbo, E., Ligori, LD.[2022]

In a study of 29 patients who switched from levetiracetam (LEV) to brivaracetam (BRV), 93.1% experienced clinically meaningful reductions in nonpsychotic behavioral adverse events (BAEs) after 12 weeks, indicating BRV may be a safer alternative for these patients.

The switch to BRV also led to a significant improvement in health-related quality of life, with a mean increase of 12.1 points on the QOLIE-31-P scale, although 79.3% of patients reported treatment-emergent adverse events during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam. Yates, SL., Fakhoury, T., Liang, W., et al.[2022]

In a feasibility study involving patients with mild Alzheimer's disease, acute administration of a higher dose of levetiracetam (7.5 mg/kg) resulted in significant changes in EEG patterns, indicating potential neurophysiological benefits.

Despite these EEG changes, there were no significant improvements in cognitive performance after the single dose, suggesting that while levetiracetam may alter brain activity, its immediate impact on cognitive function needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam Alters Oscillatory Connectivity in Alzheimer's Disease. Musaeus, CS., Shafi, MM., Santarnecchi, E., et al.[2018]

Levetiracetam, an FDA-approved antiepileptic drug, effectively reduces seizure frequency in patients with epilepsy while preserving cognitive functions, making it a safe option for these individuals.

The drug shows potential cognitive improvement in patients with Alzheimer's disease and in animal models of cognitive decline, suggesting it may be beneficial for preventing or treating Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam might act as an efficacious drug to attenuate cognitive deficits of Alzheimer's disease. Xiao, R.[2019]

This study aims to evaluate the efficacy of levetiracetam, an established anti-seizure medication, in improving cognitive function in 30 patients with mild to moderate Alzheimer's disease, using a double-blind placebo-controlled crossover design.

If successful, the study could provide evidence that levetiracetam not only stabilizes memory function but also offers a safe and potentially cost-effective treatment option for Alzheimer's patients, leveraging its existing safety profile from epilepsy treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Investigation of Levetiracetam in Alzheimer's Disease (ILiAD): a double-blind, placebo-controlled, randomised crossover proof of concept study. Sen, A., Akinola, M., Tai, XY., et al.[2021]

Low doses of levetiracetam (LEV) improved memory defects and reduced tau phosphorylation in APP23/MAPT mice, suggesting potential benefits for cognitive function in Alzheimer's disease (AD).

High doses of LEV, while reducing amyloid β-peptide production, led to neuronal apoptosis and did not improve cognitive decline, indicating that higher concentrations may be harmful in the context of AD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam alleviates cognitive decline in Alzheimer's disease animal model by ameliorating the dysfunction of the neuronal network. Zheng, XY., Zhang, HC., Lv, YD., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Psychiatric adverse events during levetiracetam therapy. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Levetiracetam safety profiles and tolerability in epilepsy patients. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Levetiracetam monotherapy in Alzheimer patients with late-onset seizures: a prospective observational study. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer's disease. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Levetiracetam Alters Oscillatory Connectivity in Alzheimer's Disease. [2018]

7. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Levetiracetam might act as an efficacious drug to attenuate cognitive deficits of Alzheimer's disease. [2019]

8. England pubmed.ncbi.nlm.nih.gov

An Investigation of Levetiracetam in Alzheimer's Disease (ILiAD): a double-blind, placebo-controlled, randomised crossover proof of concept study. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Levetiracetam alleviates cognitive decline in Alzheimer's disease animal model by ameliorating the dysfunction of the neuronal network. [2022]