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Levetiracetam for Alzheimer's Disease Neuropsychiatric Symptoms Related to Epilepsy Trial (LAPSE) (LAPSE)

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ClinicalTrials.gov Identifier: NCT04004702
Recruitment Status : Not yet recruiting
First Posted : July 2, 2019
Last Update Posted : July 2, 2019
Sponsor:
Information provided by (Responsible Party):
Walter Reed National Military Medical Center

Brief Summary:

Patients with Alzheimer's disease (AD) are increasingly recognized to have seizures in addition to cognitive decline. Seizures may contribute to memory problems as well as other symptoms common in AD like agitation, depression, or apathy. These symptoms are collectively called neuro-psychiatric symptoms. Studies of magnetic resonance imaging (MRI) in patients with AD have suggested that injury to certain parts of the brain can cause these neuro-psychiatric symptoms. Based on this evidence, the investigators hypothesize that seizures can also cause neuro-psychiatric symptoms in patients with AD and may be related to the injury seen on MRI.

The current study will follow participants for 1 year and will involve participants with AD who also have neuro-psychiatric symptoms. Participants will be examined with three brain wave studies to assess for seizure-like activity. Participants with seizure-like activity will all receive levetiracetam for 1 year. All participants will have their neuro-psychiatric symptoms, cognitive abilities, quality of life, and AD severity assessed throughout the year. The investigators plan to determine if levetiracetam changes the severity of the participants' neuro-psychiatric symptoms compared to their baseline as well as compared to participants without seizure-like activity. 65 participants will need to be recruited to test the study hypotheses. The study will take place at Walter Reed National Military Medical Center.


Condition or disease Intervention/treatment Phase
Alzheimer Disease Drug: Levetiracetam Phase 2

Detailed Description:

Alzheimer's Disease (AD) has long been known to carry an increased risk of seizure, with early estimates suggesting patients with AD have a 10-22% risk at least one unprovoked seizure and an 8- to 10-fold higher seizure rate over the general population. Retrospective data has suggested that the onset of both clinical seizure and abnormal discharge on electroencephalogram (EEG) may cluster around or even precede the onset of cognitive decline. With extended EEG and/or 1-hour magnetoencephalogram (MEG), up to 42% of patients with AD have evidence of subclinical seizure or epileptiform discharges, two-thirds of which were identified only during sleep. Recent evidence has also found a much higher incidence of dyscognitive seizure (47%) and other nonconvulsive semiologies (55%) than previously reported, including jamais vu, déjà vu, sensory phenomenon, speech arrest/aphasia, and amnestic spells.

A particularly problematic aspect of dementia in general and AD in particular is neuropsychiatric symptoms. Neuropsychiatric symptoms increase with duration and severity of dementia, observed in as much as 60-90% of these patients. To some extent, neuropsychiatric symptoms may also be associated with focal dysfunction, particularly of the non-dominant fronto-temporal lobes. Seizure or transient epileptiform discharges, then, might explain some of the neuropsychiatric manifestations associated with AD, especially since the most common areas of discharge are the fronto-temporal lobes in AD. Neuropsychiatric symptoms and their causes are of particular concern in the management of patients with AD given the strain on patients and families and their high association with nursing home placement.

This study will complete up to 3 serial EEGs on each participant, and all participants with epileptiform activity identified on EEG will be started on levetiracetam. All participants will be followed with serial neuro-psychiatric symptom, cognitive, severity, and quality-of-life metrics in order to analyze the effect of levetiracetam on these measures over 1 year.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 65 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Participants with clinical Alzheimer's disease and neuro-psychiatric symptoms will all be assessed with electroencephalogram, and all participants with epileptiform discharges will receive levetiracetam. Those without epileptiform discharges will be followed with serial inventories of symptom severity and functioning, but will not receive experimental treatment nor placebo.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Levetiracetam for Alzheimer's Disease Neuropsychiatric Symptoms Related to Epilepsy Trial (LAPSE) - A Phase II Exploratory Study
Estimated Study Start Date : January 2020
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : June 2025


Arm Intervention/treatment
Experimental: Levetiracetam
All patients with epileptiform activity on initial screening EEG will receive levetiracetam for 1 year
Drug: Levetiracetam
Levetiracetam 500mg twice a day
Other Name: Keppra




Primary Outcome Measures :
  1. Change in Neuropsychiatric Inventory Score (NPI) [ Time Frame: Assessed at enrollment, week 7, week 15, week 27, and month 12 ]
    Neuropsychiatric Symptom Metric


Secondary Outcome Measures :
  1. Change in Clinical Dementia Rating Sum of Boxes (CDR-SOB) [ Time Frame: Assessed at enrollment, week 7, week 15, week 27, and month 12 ]
    Patient/Informant AD Severity Metric

  2. Change in Alzheimer's Disease Cooperative study - Clinical Global Impression of Change (ADCS-CGIC) [ Time Frame: Assessed at enrollment, week 7, week 15, week 27, and month 12 ]
    Clinician AD Severity Metric

  3. Change in EuroQol 5-Dimension (EQ-5D) [ Time Frame: Assessed at enrollment, week 7, week 15, week 27, and month 12 ]
    Quality of Life Metric

  4. Change in Mini-Mental State Exam (MMSE) [ Time Frame: Assessed at enrollment, week 7, week 15, week 27, and month 12 ]
    Cognitive Ability Metric



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Meet the National Institute of Aging-Alzheimer's Association criteria for probable AD
  • Twelve-item Neuropsychiatric Inventory with score 4 or greater
  • MMSE <26
  • Stable doses current medications, including acetylcholinesterase inhibitors if applicable, for at least 4 weeks prior to trial entry
  • Reliable caregiver willing and available to assist with medication administration, outcome measures
  • MRI completed with no evidence of potential seizure focus as outlined in the exclusion criteria

Exclusion Criteria:

  • Imaging suggestive of potential seizure focus or alternative cause of dementia
  • Previous Epilepsy diagnosis
  • Use of anti-epileptic medication for any indication within previous three months
  • History of head trauma with loss of consciousness more than 30 minutes
  • Alcohol/Substance abuse within 5 years of dementia onset or previous 5 years
  • History of Korsakoff's syndrome
  • History of encephalitis/meningitis
  • Female participant who is pregnant, lactating or planning pregnancy during trial
  • Scheduled elective surgery or other procedures requiring general anesthesia during the trial
  • Participant with life expectancy of less than 12 months
  • Any cancer requiring current chemotherapy
  • Known allergy or history of previous adverse reaction to levetiracetam
  • Major depression or other significant behavioral disturbance preceding Alzheimer's Disease diagnosis
  • Enrollment in another clinical treatment trial
  • Laboratory evidence of an alternative cause of dementia or which might preclude treatment, including untreated vitamin B12 deficiency, untreated hypothyroidism, syphilis, positive human immunodeficiency virus testing, end-stage renal disease on dialysis, significant renal impairment (creatinine clearance <75 ml/minute), or liver function tests >2x upper limit of normal within the preceding three months

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04004702


Contacts
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Contact: Timothy R Malone, MD 301-295-4771 timothy.r.malone5.mil@mail.mil

Locations
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United States, Maryland
Walter Reed National Military Medical Center Not yet recruiting
Bethesda, Maryland, United States, 20889
Contact: Timothy R Malone, MD    301-295-4771    timothy.r.malone5.mil@mail.mil   
Principal Investigator: Timothy R Malone, MD         
Sub-Investigator: Margaret Swanberg, MD         
Sub-Investigator: Joseph V Brown, MD         
Sub-Investigator: Adriana Martinez, MSc         
Sub-Investigator: Tuamokumo Francois, PhD         
Sponsors and Collaborators
Walter Reed National Military Medical Center
Investigators
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Principal Investigator: Timothy R Malone, MD Walter Reed National Military Medical Center

Publications:

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Responsible Party: Walter Reed National Military Medical Center
ClinicalTrials.gov Identifier: NCT04004702     History of Changes
Other Study ID Numbers: 06272019
First Posted: July 2, 2019    Key Record Dates
Last Update Posted: July 2, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Walter Reed National Military Medical Center:
neuro-psychiatric symptoms
Additional relevant MeSH terms:
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Levetiracetam
Alzheimer Disease
Epilepsy
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Anticonvulsants
Nootropic Agents