Treating Hyperexcitability in AD With Levetiracetam

NCT03875638 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 2019P000091
• Study Type: interventional
• Target: 85
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Alzheimer Dementia; Alzheimer Disease; Dementia of Alzheimer Type; Mild Cognitive Impairment

Keywords

Mild Alzheimer's Disease; Early Alzheimer's Disease

Outcome Measures

Primary Outcomes (8)

• Neuropsychological Test Battery (NTB)

  Our primary cognitive outcome measure will be the mean z-score change relative to baseline on the NTB

  From enrollment until the end of the treatment periods at 5 months

• Transcranial magnetic stimulation (TMS) resting motor threshold

  Our primary electrophysiological outcome measure of cerebral cortical excitability will be the change in the TMS resting motor threshold

  From enrollment until the end of the treatment periods at 5 months

• Transcranial magnetic stimulation (TMS)-evoked electroencephalogram (EEG) hypersynchrony

  Our primary electrophysiological measure of cerebral network excitability will be TMS-evoked EEG hypersynchrony with stimulation of parietal cortex

  From enrollment until the end of the treatment periods at 5 months

• Resting-state electroencephalogram (EEG) beta band power

  Our primary electrophysiological measure of local network function will be resting-state EEG power in the beta band

  From enrollment until the end of the treatment periods at 5 months

• Resting-state electroencephalogram (EEG) beta band connectivity

  Our primary electrophysiological measure of brain network interactions will be resting-state EEG functional connectivity in the beta band

  From enrollment until the end of the treatment periods at 5 months

• Default-mode network resting-state functional magnetic resonance imaging (fMRI) functional connectivity

  Our primary imaging measure of integrity of macroscopic brain networks will be mean resting-state fMRI functional connectivity within the default-mode network

  From enrollment until the end of the treatment periods at 5 months

• Change in motor evoked potential (MEP) amplitude

  Our primary transcranial magnetic stimulation (TMS) measure of plasticity in cortical excitability will be the change in MEP amplitude 10 minutes after intermittent theta-burst stimulation

  From enrollment until the end of the treatment periods at 5 months

• Change in beta power after theta-burst stimulation

  Our primary transcranial magnetic stimulation (TMS) measure of plasticity in cortical oscillations will be change in resting-state electroencephalogram (EEG) beta power after theta-burst stimulation

  From enrollment until the end of the treatment periods at 5 months

Other Outcomes (2)

• Transcranial magnetic stimulation (TMS)-evoked N45 electroencephalogram (EEG) potential

  From enrollment until the end of the treatment periods at 5 months

• Interictal Epileptiform Discharges

  Baseline

Study Arms (4)

Early Alzheimer's Disease Group Low Dose

EXPERIMENTAL

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

Drug: Levetiracetam

Early Alzheimer's Disease Group High Dose

EXPERIMENTAL

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

Drug: Levetiracetam

Early Alzheimer's Disease Group Placebo

PLACEBO COMPARATOR

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

Drug: Placebo oral capsule

Healthy Control Group

NO INTERVENTION

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

Interventions

Levetiracetam DRUG

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

Early Alzheimer's Disease Group High Dose; Early Alzheimer's Disease Group Low Dose

Placebo oral capsule DRUG

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

Early Alzheimer's Disease Group Placebo

Eligibility Criteria

• Age: 50 Years - 90 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• Evidence of significant kidney impairment as defined as an estimated glomerular filtration rate (eGFR) \<30
• 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.

Sponsors & Collaborators

• Beth Israel Deaconess Medical Center: lead

Study Sites (1)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

RECRUITING

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction

Interventions

Levetiracetam

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Central Study Contacts

Ann Connor, RN

CONTACT

6176670269; aconnor@bidmc.harvard.edu

Mouhsin Shafi, MD, PhD

CONTACT

6176670182; mshafi@bidmc.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Subjects will be provided with identical-appearing tablets containing either placebo, levetiracetam 125 mg, or levetiracetam 500 mg.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Neurology

Model Details: 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.

Study Record Dates

• First Submitted: March 13, 2019
• First Posted: March 15, 2019
• Study Start: August 22, 2019
• Primary Completion: October 31, 2025
• Study Completion: November 30, 2025
• Last Updated: December 5, 2024

Record last verified: 2024-12

Locations

US (1)