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| ID | Type | Description | Link |
|---|---|---|---|
| RC2AG036419 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| aMCI_62.5mg drug first, then placebo | Experimental | Amnestic MCI: 62.5mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) |
|
| aMCI_Placebo first, then 62.5mg drug | Experimental | Amnestic MCI: Placebo capsule twice daily (two weeks), washout (4 weeks), and 62.5mg levetiracetam twice daily (two weeks) |
|
| aMCI_125mg drug first, then placebo | Experimental | Amnestic MCI: 125mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) |
|
| aMCI_Placebo first, then 125mg drug | Experimental | Amnestic MCI: Placebo capsule twice daily (two weeks), washout (4 weeks), and 125mg levetiracetam twice daily (two weeks) |
|
| aMCI_250mg drug first, then placebo | Experimental | Amnestic MCI: 250mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Levetiracetam 62.5mg | Drug | 62.5mg twice daily (2 weeks) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Brain Activity in the Dentate Gyrus / CA3 Subregion of the Hippocampus Measured With Blood Oxygenation Level Dependent (BOLD) Functional MRI | 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. | 2 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Behavioral Performance as Assessed in the Functional Magnetic Resonance Imaging (fMRI) Memory Task | Mnemonic similarity task which assesses long term memory function. Scale ranges from 0-100 with higher scores indicating better memory performance. | 2 weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gregory L Krauss, MD | Johns Hopkins University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Johns Hopkins University School of Medicine | Baltimore | Maryland | 21287 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18802001 | Background | 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. | |
| 18356518 | Background | 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. |
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Data for the 125mg BID treatment cohort was collected first. Analysis showed no effects of treatment order. As a result, data was collapsed and analyzed irrespective of order across all doses. All subsequent data analyses are thus provided collapsed across treatment orders in all reporting on this study, including the results reported here.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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) |
| FG001 | 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) |
| FG002 | aMCI_125mg Drug First, Then Placebo | Amnestic MCI: 125mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) |
| FG003 | aMCI_Placebo First, Then 125mg Drug | Amnestic MCI: Placebo capsule twice daily (two weeks), washout (4 weeks), and 125mg levetiracetam twice daily (two weeks) |
| FG004 | aMCI_250mg Drug First, Then Placebo | Amnestic MCI: 250mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) |
| FG005 | aMCI_Placebo First, Then 250mg Drug | Amnestic MCI: Placebo capsule twice daily (two weeks), washout (4 weeks), and 250mg levetiracetam twice daily (two weeks) |
| FG006 | Control_Placebo First, Then Placebo | Healthy control: placebo capsule twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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) |
| BG001 | aMCI_Placebo First, Then 62.5mg Drug |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Brain Activity in the Dentate Gyrus / CA3 Subregion of the Hippocampus Measured With Blood Oxygenation Level Dependent (BOLD) Functional MRI | 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. | Posted | Mean | Standard Error | mean beta coefficient | 2 weeks |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | aMCI_62.5 | 62.5 mg levetiracetam twice daily for two weeks | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| somnolence | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Gregory Krauss, M.D. | Johns Hopkins University School of Medicine | (410) 955-2822 | gkrauss@jhmi.edu |
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| ID | Term |
|---|---|
| D060825 | Cognitive Dysfunction |
| D008569 | Memory Disorders |
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D019954 | Neurobehavioral Manifestations |
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| ID | Term |
|---|---|
| D000077287 | Levetiracetam |
| ID | Term |
|---|---|
| D000081 | Acetamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000085 | Acetates |
| D000144 |
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|
| aMCI_Placebo first, then 250mg drug | Experimental | Amnestic MCI: Placebo capsule twice daily (two weeks), washout (4 weeks), and 250mg levetiracetam twice daily (two weeks) |
|
| Control_Placebo first, then placebo | Placebo Comparator | Healthy control: placebo capsule twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) |
|
| Levetiracetam 125mg | Drug | 125mg twice daily (2 weeks) |
|
|
| Levetiracetam 250mg | Drug | 250mg twice daily (2 weeks) |
|
|
| Placebo | Drug | placebo capsule twice daily (2 weeks) |
|
| 17785178 | Background | 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. doi: 10.1016/j.neuron.2007.07.025. |
| 11756667 | Background | 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. doi: 10.1073/pnas.012467899. Epub 2001 Dec 26. |
| 16033897 | Background | 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. doi: 10.1523/JNEUROSCI.1744-05.2005. |
| 17046075 | Background | Wilson IA, Gallagher M, Eichenbaum H, Tanila H. Neurocognitive aging: prior memories hinder new hippocampal encoding. Trends Neurosci. 2006 Dec;29(12):662-70. doi: 10.1016/j.tins.2006.10.002. Epub 2006 Oct 13. |
| 20032967 | Background | 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. |
Amnestic MCI:
Placebo capsule twice daily (two weeks), washout (4 weeks), and 62.5mg levetiracetam twice daily (two weeks)
| BG002 | aMCI_125mg Drug First, Then Placebo | Amnestic MCI: 125mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) |
| BG003 | aMCI_Placebo First, Then 125mg Drug | Amnestic MCI: Placebo capsule twice daily (two weeks), washout (4 weeks), and 125mg levetiracetam twice daily (two weeks) |
| BG004 | aMCI_250mg Drug First, Then Placebo | Amnestic MCI: 250mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) |
| BG005 | aMCI_Placebo First, Then 250mg Drug | Amnestic MCI: Placebo capsule twice daily (two weeks), washout (4 weeks), and 250mg levetiracetam twice daily (two weeks) |
| BG006 | Control_Placebo First, Then Placebo | Healthy control placebo capsule twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) |
| BG007 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG002 |
| aMCI_125 |
125 mg Levetiracetam twice daily for two weeks. |
| OG003 | aMCI_125 Placebo | 125mg levetiracetam placebo comparator |
| OG004 | aMCI_250 | 250mg levetiracetam twice daily for two weeks |
| OG005 | aMCI_250 Placebo | 250mg levetiracetam placebo comparator |
| OG006 | Age Matched Control | Placebo capsule twice daily for two weeks |
|
|
| Secondary | Behavioral Performance as Assessed in the Functional Magnetic Resonance Imaging (fMRI) Memory Task | Mnemonic similarity task which assesses long term memory function. Scale ranges from 0-100 with higher scores indicating better memory performance. | Posted | Mean | Standard Error | percent correct recalled | 2 weeks |
|
|
|
| 24 |
| 0 |
| 24 |
| 5 |
| 24 |
| EG001 | aMCI_62.5 Placebo | 62.5 mg placebo comparator (placebo capsule twice daily for two weeks) | 0 | 24 | 0 | 24 | 0 | 24 |
| EG002 | aMCI_125 | 125 mg levetiracetam twice daily for two weeks | 0 | 23 | 0 | 23 | 3 | 23 |
| EG003 | aMCI_125 Placebo | 125 mg placebo comparator (placebo capsule twice daily for two weeks) | 0 | 23 | 0 | 23 | 0 | 23 |
| EG004 | aMCI_250 | 250 mg levetiracetam twice daily for two weeks | 0 | 22 | 0 | 22 | 5 | 22 |
| EG005 | aMCI_250 Placebo | 250 mg placebo comparator (placebo capsule twice daily for two weeks) | 0 | 22 | 0 | 22 | 7 | 22 |
| EG006 | Age Matched Control | placebo capsule twice daily for two weeks | 0 | 27 | 0 | 27 | 3 | 27 |
| Irritability | General disorders | Systematic Assessment |
|
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| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D024801 | Tauopathies |
| D019636 | Neurodegenerative Diseases |
| Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D011760 | Pyrrolidinones |
| D011759 | Pyrrolidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |