Levetiracetam and Memory Function in Amnestic Mild Cognitive Impairment (MCI)

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ClinicalTrials.gov Identifier: NCT01044758

Recruitment Status : Completed

First Posted : January 8, 2010

Results First Posted : August 21, 2017

Last Update Posted : August 21, 2017

Sponsor:

Collaborator:

National Institute on Aging (NIA)

Information provided by (Responsible Party):

Johns Hopkins University

Study Description

Brief Summary:

This research is being done to find out if daily use of the drug levetiracetam can improve memory function in individuals with memory problems like those associated with Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD).

Condition or disease	Intervention/treatment	Phase
Mild Cognitive Impairment (MCI)	Drug: Levetiracetam 62.5mg Drug: Levetiracetam 125mg Drug: Levetiracetam 250mg Drug: Placebo	Phase 2

Detailed Description:

Increasing research is focused on conditions that precede the clinical diagnosis of Alzheimer's disease (AD) in order to detect patients at risk for early intervention. One such condition is mild cognitive impairment (MCI). Functional magnetic resonance imaging (fMRI) studies in this group of patients have reported increased activation in the Medial Temporal Lobe (MTL) during performance of memory tasks. The functional significance of increased activation is unclear. One possibility is that greater activity reflects the increased effort needed in order to maintain performance, and as such would be a compensatory response. An alternative possibility is that increased activation reflects aberrant physiology related to the disease process itself and as such would be a sign of greater underlying disease severity and would interfere with brain function.

Data in animal models suggest the possibility that low dose levetiracetam (well-tolerated anti-convulsant) treatment may reduce the observed hyperactivity and improve memory performance among individuals with MCI. The investigators are therefore conducting a within-subjects trial of 8 weeks duration, involving 144 subjects and low dose treatment with levetiracetam. During the course of the study, each subject may receive both drug and placebo for two weeks, with the order of administering those treatments counterbalanced. Cognitive testing and fMRI imaging will be obtained after 2-weeks on drug/placebo. The overall goal of the study is to determine if treatment of MCI subjects with low dose levetiracetam reduces hyperactivity within the MTL and improves memory performance.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	96 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Basic Science
Official Title:	Bridging Cognitive Aging in Rodents to Man Using fMRI in Amnestic MCI
Study Start Date :	December 2009
Actual Primary Completion Date :	July 2012
Actual Study Completion Date :	July 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Memory

Drug Information available for: Levetiracetam

Genetic and Rare Diseases Information Center resources: Familial Alzheimer Disease

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: aMCI_62.5mg drug first, then placebo Amnestic MCI: 62.5mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks)	Drug: Levetiracetam 62.5mg 62.5mg twice daily (2 weeks) Other Name: Keppra Drug: Placebo placebo capsule twice daily (2 weeks)
Experimental: aMCI_Placebo first, then 62.5mg drug Amnestic MCI: Placebo capsule twice daily (two weeks), washout (4 weeks), and 62.5mg levetiracetam twice daily (two weeks)	Drug: Levetiracetam 62.5mg 62.5mg twice daily (2 weeks) Other Name: Keppra Drug: Placebo placebo capsule twice daily (2 weeks)
Experimental: aMCI_125mg drug first, then placebo Amnestic MCI: 125mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks)	Drug: Levetiracetam 125mg 125mg twice daily (2 weeks) Other Name: Keppra Drug: Placebo placebo capsule twice daily (2 weeks)
Experimental: aMCI_Placebo first, then 125mg drug Amnestic MCI: Placebo capsule twice daily (two weeks), washout (4 weeks), and 125mg levetiracetam twice daily (two weeks)	Drug: Levetiracetam 125mg 125mg twice daily (2 weeks) Other Name: Keppra Drug: Placebo placebo capsule twice daily (2 weeks)
Experimental: aMCI_250mg drug first, then placebo Amnestic MCI: 250mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks)	Drug: Levetiracetam 250mg 250mg twice daily (2 weeks) Other Name: Keppra Drug: Placebo placebo capsule twice daily (2 weeks)
Experimental: aMCI_Placebo first, then 250mg drug Amnestic MCI: Placebo capsule twice daily (two weeks), washout (4 weeks), and 250mg levetiracetam twice daily (two weeks)	Drug: Levetiracetam 250mg 250mg twice daily (2 weeks) Other Name: Keppra Drug: Placebo placebo capsule twice daily (2 weeks)
Placebo Comparator: Control_Placebo first, then placebo Healthy control: placebo capsule twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks)	Drug: Placebo placebo capsule twice daily (2 weeks)

Outcome Measures

Primary Outcome Measures :

Brain Activity in the Dentate Gyrus / CA3 Subregion of the Hippocampus Measured With Blood Oxygenation Level Dependent (BOLD) Functional MRI [ Time Frame: 2 weeks ]
Measurement of average brain activity in the dentate gyrus / CA3 subregion of the hippocampus measured with BOLD functional MRI in patients with mild cognitive impairment on placebo and on drug compared to average brain activity in this brain area in control subjects.

Secondary Outcome Measures :

Behavioral Performance as Assessed in the Functional Magnetic Resonance Imaging (fMRI) Memory Task [ Time Frame: 2 weeks ]
Mnemonic similarity task which assesses long term memory function. Scale ranges from 0-100 with higher scores indicating better memory performance.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	50 Years to 85 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

All: English as a first language; right handed; able to complete written informed consent.
MCI subjects: In addition to above, must meet criteria for amnestic Mild Cognitive Impairment (MCI). This includes a memory complaint corroborated by an informant; impaired memory function for age and educational level; preserved general cognitive function; intact abilities of daily living; no clinical dementia.
Age matched Controls: Must have memory and cognitive status that is normal for their age.

Exclusion Criteria:

Familial Alzheimer's Disease (AD) due to known genetic mutations
AD with Parkinsonian features; major psychiatric or behavioral disorders (e.g. depression, agitation, psychosis, manic-depressive disorder)
Primary or metastatic intracranial neoplasm
History of severe head trauma
Intra-cerebral hemorrhage
Seizure disorder
Hemispheric stroke
Presence of a progressive central nervous system disease
Presence of lacunar infarcts
Medical contraindications to MRI including cardiac pacemaker, presence of intraocular or intracranial metallic objects
Any known allergy to levetiracetam or behavioral problems that are a contraindication to taking Levetiracetam (e.g. agitation)
Prescribed use of anti-seizure medications.

Contacts and Locations

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): NCT01044758

Locations

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United States, Maryland
Johns Hopkins University School of Medicine
Baltimore, Maryland, United States, 21287

Sponsors and Collaborators

Johns Hopkins University

National Institute on Aging (NIA)

Investigators

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Principal Investigator:	Gregory L Krauss, MD	Johns Hopkins University

More Information

Publications:

Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, Staufenbiel M, Konnerth A, Garaschuk O. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease. Science. 2008 Sep 19;321(5896):1686-9. doi: 10.1126/science.1162844.

Bakker A, Kirwan CB, Miller M, Stark CE. Pattern separation in the human hippocampal CA3 and dentate gyrus. Science. 2008 Mar 21;319(5870):1640-2. doi: 10.1126/science.1152882.

Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 6;55(5):697-711.

Sperling R, Greve D, Dale A, Killiany R, Holmes J, Rosas HD, Cocchiarella A, Firth P, Rosen B, Lake S, Lange N, Routledge C, Albert M. Functional MRI detection of pharmacologically induced memory impairment. Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):455-60. Epub 2001 Dec 26.

Wilson IA, Ikonen S, Gallagher M, Eichenbaum H, Tanila H. Age-associated alterations of hippocampal place cells are subregion specific. J Neurosci. 2005 Jul 20;25(29):6877-86.

Wilson IA, Gallagher M, Eichenbaum H, Tanila H. Neurocognitive aging: prior memories hinder new hippocampal encoding. Trends Neurosci. 2006 Dec;29(12):662-70. Epub 2006 Oct 13. Review.

Koh MT, Haberman RP, Foti S, McCown TJ, Gallagher M. Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology. 2010 Mar;35(4):1016-25. doi: 10.1038/npp.2009.207. Epub 2009 Dec 23.

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Responsible Party:	Johns Hopkins University
ClinicalTrials.gov Identifier:	NCT01044758
Other Study ID Numbers:	NA_00030573 RC2AG036419 ( U.S. NIH Grant/Contract )
First Posted:	January 8, 2010 Key Record Dates
Results First Posted:	August 21, 2017
Last Update Posted:	August 21, 2017
Last Verified:	July 2017

Keywords provided by Johns Hopkins University:


Mild Cognitive Impairment Amnestic Mild Cognitive Impairment Functional Magnetic Resonance Imaging Levetiracetam Keppra	Medial Temporal Lobe Memory Impairment Alzheimer's Disease AD

Additional relevant MeSH terms:

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Cognitive Dysfunction Cognition Disorders Neurocognitive Disorders Mental Disorders	Levetiracetam Anticonvulsants Nootropic Agents

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