Treating Hyperexcitability in AD With Levetiracetam

NCT ID: NCT03875638

Last Updated: 2024-12-05

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

85 participants

Study Classification

INTERVENTIONAL

Study Start Date

2019-08-22

Study Completion Date

2025-11-30

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Alzheimer Dementia Alzheimer Disease Dementia of Alzheimer Type Mild Cognitive Impairment

Keywords

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Mild Alzheimer's Disease Early Alzheimer's Disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Participants will be tested in a double-blind crossover design with twice daily, low-dose levetiracetam (125 mg twice daily) or high-dose levetiracetam (500mg twice daily) or placebo. Each dose and placebo will be administered for a four week period.The order of interventions will be counterbalanced across subjects, with randomization occurring in blocks of 6. There will be a 4 week washout period between each treatment period.
Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors
Subjects will be provided with identical-appearing tablets containing either placebo, levetiracetam 125 mg, or levetiracetam 500 mg.

Study Groups

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Early Alzheimer's Disease Group Low Dose

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

Group Type EXPERIMENTAL

Levetiracetam

Intervention Type DRUG

Levetiracetam is an antiepileptic medication that has been shown to reduced network cortical hyperexcitability

Early Alzheimer's Disease Group High Dose

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

Group Type EXPERIMENTAL

Levetiracetam

Intervention Type DRUG

Levetiracetam is an antiepileptic medication that has been shown to reduced network cortical hyperexcitability

Early Alzheimer's Disease Group Placebo

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

Group Type PLACEBO_COMPARATOR

Placebo oral capsule

Intervention Type DRUG

The placebo is a capsule that is identical in appearance to the levetiracetam

Healthy Control Group

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

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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Levetiracetam

Levetiracetam is an antiepileptic medication that has been shown to reduced network cortical hyperexcitability

Intervention Type DRUG

Placebo oral capsule

The placebo is a capsule that is identical in appearance to the levetiracetam

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* 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.


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

Exclusion Criteria

* 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.


* 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.


* 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.
Minimum Eligible Age

50 Years

Maximum Eligible Age

90 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Beth Israel Deaconess Medical Center

OTHER

Sponsor Role lead

Responsible Party

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Mouhsin Shafi

Assistant Professor of Neurology

Responsibility Role PRINCIPAL_INVESTIGATOR

Locations

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Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Site Status RECRUITING

Countries

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United States

Central Contacts

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Ann Connor, RN

Role: CONTACT

Phone: 6176670269

Email: [email protected]

Mouhsin Shafi, MD, PhD

Role: CONTACT

Phone: 6176670182

Email: [email protected]

Facility Contacts

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Brenna Hagan

Role: primary

Other Identifiers

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2019P000091

Identifier Type: -

Identifier Source: org_study_id