Using levetiracetam to treat hyperexcitability in early Alzheimer's Disease

Treating Hyperexcitability in Alzheimer's Disease With Levetiracetam to Improve Brain Function and Cognition

This study is testing if the medication levetiracetam can help improve brain function and thinking skills in people with early Alzheimer's Disease.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 85 (estimated)
• Ages: 50 Years to 90 Years
• Sex: All
• Sponsor: Beth Israel Deaconess Medical Center (Academic / other)
• Locations: 1 site (Boston, Massachusetts)
• Trial ID: NCT03875638 on ClinicalTrials.gov

What this trial studies

This study investigates the effects of the antiepileptic medication levetiracetam on cortical hyperexcitability and cognitive dysfunction in patients with early Alzheimer's Disease. It employs a randomized, placebo-controlled crossover design where participants will receive either low-dose or high-dose levetiracetam or a placebo over multiple treatment periods. Each participant will undergo extensive baseline evaluations, including neurological assessments and brain imaging, to establish a comprehensive understanding of their condition. The study aims to determine if levetiracetam can normalize brain function and improve cognitive abilities in affected individuals.

Who should consider this trial

Good fit: Ideal candidates are individuals aged 50-90 with early Alzheimer's Disease who are stable on memory medications and have positive amyloid status.

Not a fit: Patients with advanced Alzheimer's Disease or those not meeting the inclusion criteria will likely not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could enhance cognitive function and quality of life for patients with early Alzheimer's Disease.

How similar studies have performed: While the approach of using levetiracetam in this context is novel, similar studies exploring brain excitability and cognitive function have shown promising results.

Eligibility criteria

Inclusion Criteria:

Inclusion Criteria for the Subjects with early Alzheimer's Disease (AD)

* Age 50-90 years old.
* On a stable dose of medications for memory loss including cholinesterase inhibitors (for example: donepezil, rivastigmine or memantine) as defined by 4 consecutive weeks of treatment at an unchanging dose
* 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.
* Mini Mental State Examination (MMSE) ≥ 20.
* Positive amyloid status (as defined by cerebral spinal fluid biomarkers or amyloid positron emission tomography (PET) study.
* Clinician Dementia Rating (CDR) of 0.5-1.0.

Inclusion Criteria for Healthy Control Subjects

* Age 50-90 years old.
* Normal neurologic exam
* Mini Mental State Examination (MMSE) \> 28
* Clinician Dementia Rating (CDR) of 0

Exclusion Criteria:

Exclusion Criteria Subjects with early Alzheimer's Disease

* Diagnosis of epilepsy, or immediate (1st degree relative) family history epilepsy with the exception of a single seizure of benign etiology (e.g. febrile seizures) in the judgment of a board-certified neurologist. Evidence of epileptiform discharges and electroencephalogram (EEG) abnormalities will be included;
* Current or past history of any neurological disorder other than dementia, such as epilepsy, stroke (cortical stroke), progressive neurologic disease (e.g. multiple sclerosis) or intracranial brain lesions; and history of previous neurosurgery or head trauma that resulted in residual neurologic impairment. Non-cortical disease such as scattered white matter changes (including lacunar infarcts \< 1 cm) and asymptomatic, subacute, cerebellar infarcts may be included upon review of a medically responsible neurologist. However, subjects with significant vascular disease, as defined by a score greater than 2 on the age-related white matter changes (ARWMC) scale, will be excluded.
* Any current diagnosis of a major psychiatric disorder (e.g., schizophrenia, bipolar disorder) with the exception of depression. As co-morbidity of anxiety / depression in AD is high, anxiety / depression will not be an automatic exclusion. However, the study physician will assess any subject with a Geriatric Depression Score (GDS) score of 9 or above, and will exclude subjects with a past history of multiple psychiatric hospitalizations or suicide attempts, or current active suicidality.
* Evidence of significant kidney impairment as defined as an estimated glomerular filtration rate (eGFR) \<30
* Medications will be reviewed by the responsible covering physician and a decision about inclusion will be made based on the participant's past medical history, drug dose, history of recent medication changes or duration of treatment, and combination with other central nervous system active drugs. Current use of an antiepileptic drug will be an absolute exclusion.

Exclusion Criteria Healthy Control Subjects

* History of seizures, diagnosis of epilepsy, or immediate (1st degree relative) family history epilepsy with the exception of a single seizure of benign etiology (e.g. febrile seizures) in the judgment of a board-certified neurologist.
* Current or past history of any neurological disorder, such as epilepsy, stroke (cortical stroke), progressive neurologic disease (e.g. multiple sclerosis) or intracranial brain lesions; and history of previous neurosurgery or head trauma that resulted in residual neurologic impairment.
* Any current diagnosis of a major psychiatric disorder (e.g., schizophrenia, bipolar disorder, major depressive disorder).
* Abnormal Neurologic or Cognitive exam
* Use of medications that could alter cortical excitability, as determined by the investigators.

Exclusion Criteria for All Subjects regarding magnetic resonance imaging (MRI) and transcranial magnetic stimulation (TMS)

* History of head trauma resulting in prolonged loss of consciousness.
* Current history of poorly controlled headaches including chronic medication for migraine prevention.
* History of fainting spells of unknown or undetermined etiology that might constitute seizures.
* Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.).
* 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).
* Any devices such as pacemaker, medication pump, nerve stimulator, ventriculo-peritoneal shunt unless cleared by the responsible covering physician.
* Substance use disorders within the past six months.

Where this trial is running

Boston, Massachusetts

• Beth Israel Deaconess Medical Center — Boston, Massachusetts, United States (Recruiting)

Study contacts

• Study coordinator: Ann Connor, RN

Conditions Alzheimer Dementia; Alzheimer Disease; Dementia of Alzheimer Type; Mild Cognitive Impairment; Mild Alzheimer's Disease; Early Alzheimer's Disease