Treating Hyperexcitability in AD With Levetiracetam (LeAD)

  • STATUS
    Recruiting
  • End date
    Nov 20, 2023
  • participants needed
    85
  • sponsor
    Beth Israel Deaconess Medical Center
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Updated on 25 January 2022
See if I qualify
stroke
cognitive impairment
positron emission tomography
dementia
mini-mental state examination
alzheimer's disease
amyloid
amyloidosis
mental state examination
memantine
donepezil
cholinesterase inhibitors
rivastigmine
cholinesterase
speech therapy
amnesia
Accepts healthy volunteers

Summary

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.

Description

This is a randomized, placebo-controlled crossover study. Participants with early Alzheimer's Disease (AD) will be tested in a double-blind crossover design with placebo, low-dose levetiracetam (LEV) 125 mg twice daily or high-dose LEV 500mg twice daily. These results will be contrasted with results from a demographically similar control group who will undergo baseline testing only, without any intervention, to establish a comparison norm for the AD group.

Each subject will undergo four screening and baseline visits consisting of a baseline neurological, medical, and cognitive evaluation. If amyloid status is unknown in AD patients, the participant will have an amyloid PET scan. Additional baseline measures include: a high density electroencephalogram (EEG); a 24 hour ambulatory EEG; functional magnetic resonance imaging (fMRI); neuropsychological testing; and transcranial magnetic stimulation with electromyogram (EMG) and EEG measures to assess cortical excitability. AD participants will be randomized to one of six possible groups that consists of a varying order of 3 treatment periods (LEV 125 mg, LEV 500 mg and placebo). The group assignments will be counterbalanced across subjects. Each treatment period will last for 4 weeks with a 4 week washout between treatments. All participants will be assessed prior to initiation of a treatment period (with the initial assessment occurring as part of the baseline assessment) and at the end of each treatment period. The following measures will be repeated as done at baseline at these time points: fMRI; neuropsychological testing; and TMS-EMG-EEG. AD participants will be enrolled for approximately 5 months.

Details
Condition Alzheimer Dementia, Alzheimer Disease, Dementia of Alzheimer Type, Mild Cognitive Impairment
Treatment Levetiracetam, Placebo oral capsule
Clinical Study IdentifierNCT03875638
SponsorBeth Israel Deaconess Medical Center
Last Modified on25 January 2022

Eligibility

 Yes No Not Sure

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
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stroke
cognitive impairment
positron emission tomography
dementia
mini-mental state examination
alzheimer's disease
amyloid
amyloidosis
mental state examination
memantine
donepezil
cholinesterase inhibitors
rivastigmine
cholinesterase
speech therapy
amnesia
Accepts healthy volunteers

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