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出境医 / 临床实验 / Levetiracetam for Alzheimer's Disease Neuropsychiatric Symptoms Related to Epilepsy Trial (LAPSE) (LAPSE)

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

Study Description
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.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 65 participants
Allocation: N/A
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
Arms and Interventions
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
Outcome Measures
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


Eligibility Criteria
Layout table for eligibility information
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
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Timothy R Malone, MD 301-295-4771 timothy.r.malone5.mil@mail.mil

Locations
Layout table for location information
United States, Maryland
Walter Reed National Military Medical Center
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
Layout table for investigator information
Principal Investigator: Timothy R Malone, MD Walter Reed National Military Medical Center
Tracking Information
First Submitted Date  ICMJE June 27, 2019
First Posted Date  ICMJE July 2, 2019
Last Update Posted Date July 2, 2019
Estimated Study Start Date  ICMJE January 2020
Estimated Primary Completion Date December 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 27, 2019) 		Change in Neuropsychiatric Inventory Score (NPI) [ Time Frame: Assessed at enrollment, week 7, week 15, week 27, and month 12 ]
Neuropsychiatric Symptom Metric
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 27, 2019)
  • 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
  • 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
  • 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
  • Change in Mini-Mental State Exam (MMSE) [ Time Frame: Assessed at enrollment, week 7, week 15, week 27, and month 12 ]
    Cognitive Ability Metric
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Levetiracetam for Alzheimer's Disease Neuropsychiatric Symptoms Related to Epilepsy Trial (LAPSE)
Official Title  ICMJE Levetiracetam for Alzheimer's Disease Neuropsychiatric Symptoms Related to Epilepsy Trial (LAPSE) - A Phase II Exploratory Study
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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
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
Condition  ICMJE Alzheimer Disease
Intervention  ICMJE Drug: Levetiracetam
Levetiracetam 500mg twice a day
Other Name: Keppra
Study Arms  ICMJE Experimental: Levetiracetam
All patients with epileptiform activity on initial screening EEG will receive levetiracetam for 1 year
Intervention: Drug: Levetiracetam
Publications *
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  • Romanelli MF, Morris JC, Ashkin K, Coben LA. Advanced Alzheimer's disease is a risk factor for late-onset seizures. Arch Neurol. 1990 Aug;47(8):847-50.
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  • Fox NC, Kennedy AM, Harvey RJ, Lantos PL, Roques PK, Collinge J, Hardy J, Hutton M, Stevens JM, Warrington EK, Rossor MN. Clinicopathological features of familial Alzheimer's disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic factor. Brain. 1997 Mar;120 ( Pt 3):491-501.
  • Lopera F, Ardilla A, Martínez A, Madrigal L, Arango-Viana JC, Lemere CA, Arango-Lasprilla JC, Hincapíe L, Arcos-Burgos M, Ossa JE, Behrens IM, Norton J, Lendon C, Goate AM, Ruiz-Linares A, Rosselli M, Kosik KS. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA. 1997 Mar 12;277(10):793-9.
  • Axelman K, Basun H, Lannfelt L. Wide range of disease onset in a family with Alzheimer disease and a His163Tyr mutation in the presenilin-1 gene. Arch Neurol. 1998 May;55(5):698-702.
  • Janssen JC, Hall M, Fox NC, Harvey RJ, Beck J, Dickinson A, Campbell T, Collinge J, Lantos PL, Cipolotti L, Stevens JM, Rossor MN. Alzheimer's disease due to an intronic presenilin-1 (PSEN1 intron 4) mutation: A clinicopathological study. Brain. 2000 May;123 ( Pt 5):894-907.
  • Cabrejo L, Guyant-Maréchal L, Laquerrière A, Vercelletto M, De la Fournière F, Thomas-Antérion C, Verny C, Letournel F, Pasquier F, Vital A, Checler F, Frebourg T, Campion D, Hannequin D. Phenotype associated with APP duplication in five families. Brain. 2006 Nov;129(Pt 11):2966-76. Epub 2006 Sep 7.
  • Irizarry MC, Jin S, He F, Emond JA, Raman R, Thomas RG, Sano M, Quinn JF, Tariot PN, Galasko DR, Ishihara LS, Weil JG, Aisen PS. Incidence of new-onset seizures in mild to moderate Alzheimer disease. Arch Neurol. 2012 Mar;69(3):368-72. doi: 10.1001/archneurol.2011.830.
  • Mendez MF, Catanzaro P, Doss RC, ARguello R, Frey WH 2nd. Seizures in Alzheimer's disease: clinicopathologic study. J Geriatr Psychiatry Neurol. 1994 Oct-Dec;7(4):230-3.
  • Risse SC, Lampe TH, Bird TD, Nochlin D, Sumi SM, Keenan T, Cubberley L, Peskind E, Raskind MA. Myoclonus, seizures, and paratonia in Alzheimer disease. Alzheimer Dis Assoc Disord. 1990 Winter;4(4):217-25.
  • Vossel KA, Beagle AJ, Rabinovici GD, Shu H, Lee SE, Naasan G, Hegde M, Cornes SB, Henry ML, Nelson AB, Seeley WW, Geschwind MD, Gorno-Tempini ML, Shih T, Kirsch HE, Garcia PA, Miller BL, Mucke L. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013 Sep 1;70(9):1158-66. doi: 10.1001/jamaneurol.2013.136.
  • Vossel KA, Ranasinghe KG, Beagle AJ, Mizuiri D, Honma SM, Dowling AF, Darwish SM, Van Berlo V, Barnes DE, Mantle M, Karydas AM, Coppola G, Roberson ED, Miller BL, Garcia PA, Kirsch HE, Mucke L, Nagarajan SS. Incidence and impact of subclinical epileptiform activity in Alzheimer's disease. Ann Neurol. 2016 Dec;80(6):858-870. doi: 10.1002/ana.24794. Epub 2016 Nov 7.
  • Förstl H, Burns A, Levy R, Cairns N, Luthert P, Lantos P. Neurologic signs in Alzheimer's disease. Results of a prospective clinical and neuropathologic study. Arch Neurol. 1992 Oct;49(10):1038-42.
  • 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.
  • Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):E2895-903. doi: 10.1073/pnas.1121081109. Epub 2012 Aug 6.
  • Kleen JK, Scott RC, Holmes GL, Roberts DW, Rundle MM, Testorf M, Lenck-Santini PP, Jobst BC. Hippocampal interictal epileptiform activity disrupts cognition in humans. Neurology. 2013 Jul 2;81(1):18-24. doi: 10.1212/WNL.0b013e318297ee50. Epub 2013 May 17.
  • McAreavey MJ, Ballinger BR, Fenton GW. Epileptic seizures in elderly patients with dementia. Epilepsia. 1992 Jul-Aug;33(4):657-60.
  • Heyman A, Wilkinson WE, Hurwitz BJ, Helms MJ, Haynes CS, Utley CM, Gwyther LP. Early-onset Alzheimer's disease: clinical predictors of institutionalization and death. Neurology. 1987 Jun;37(6):980-4.
  • Oh H, Jagust WJ. Frontotemporal network connectivity during memory encoding is increased with aging and disrupted by beta-amyloid. J Neurosci. 2013 Nov 20;33(47):18425-37. doi: 10.1523/JNEUROSCI.2775-13.2013.
  • Huijbers W, Mormino EC, Schultz AP, Wigman S, Ward AM, Larvie M, Amariglio RE, Marshall GA, Rentz DM, Johnson KA, Sperling RA. Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression. Brain. 2015 Apr;138(Pt 4):1023-35. doi: 10.1093/brain/awv007. Epub 2015 Feb 11.
  • Scharfman HE. Alzheimer's disease and epilepsy: insight from animal models. Future Neurol. 2012 Mar 1;7(2):177-192.
  • Savva GM, Zaccai J, Matthews FE, Davidson JE, McKeith I, Brayne C; Medical Research Council Cognitive Function and Ageing Study. Prevalence, correlates and course of behavioural and psychological symptoms of dementia in the population. Br J Psychiatry. 2009 Mar;194(3):212-9. doi: 10.1192/bjp.bp.108.049619.
  • Gitlin LN, Kales HC, Lyketsos CG. Nonpharmacologic management of behavioral symptoms in dementia. JAMA. 2012 Nov 21;308(19):2020-9. doi: 10.1001/jama.2012.36918.
  • Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer's disease. Neurology. 1996 Jan;46(1):130-5.
  • Lyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JC. Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am J Psychiatry. 2000 May;157(5):708-14.
  • Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA. 2002 Sep 25;288(12):1475-83.
  • Sink KM, Covinsky KE, Newcomer R, Yaffe K. Ethnic differences in the prevalence and pattern of dementia-related behaviors. J Am Geriatr Soc. 2004 Aug;52(8):1277-83.
  • Peters KR, Rockwood K, Black SE, Bouchard R, Gauthier S, Hogan D, Kertesz A, Loy-English I, Beattie BL, Sadovnick AD, Feldman HH. Characterizing neuropsychiatric symptoms in subjects referred to dementia clinics. Neurology. 2006 Feb 28;66(4):523-8.
  • Rosen HJ, Allison SC, Schauer GF, Gorno-Tempini ML, Weiner MW, Miller BL. Neuroanatomical correlates of behavioural disorders in dementia. Brain. 2005 Nov;128(Pt 11):2612-25. Epub 2005 Sep 29.
  • Gallagher-Thompson D, Brooks JO 3rd, Bliwise D, Leader J, Yesavage JA. The relations among caregiver stress, "sundowning" symptoms, and cognitive decline in Alzheimer's disease. J Am Geriatr Soc. 1992 Aug;40(8):807-10.
  • Scarmeas N, Brandt J, Blacker D, Albert M, Hadjigeorgiou G, Dubois B, Devanand D, Honig L, Stern Y. Disruptive behavior as a predictor in Alzheimer disease. Arch Neurol. 2007 Dec;64(12):1755-61.
  • O'Donnell BF, Drachman DA, Barnes HJ, Peterson KE, Swearer JM, Lew RA. Incontinence and troublesome behaviors predict institutionalization in dementia. J Geriatr Psychiatry Neurol. 1992 Jan-Mar;5(1):45-52.
  • Morriss RK, Rovner BW, Folstein MF, German PS. Delusions in newly admitted residents of nursing homes. Am J Psychiatry. 1990 Mar;147(3):299-302.
  • Scarmeas N, Brandt J, Albert M, Hadjigeorgiou G, Papadimitriou A, Dubois B, Sarazin M, Devanand D, Honig L, Marder K, Bell K, Wegesin D, Blacker D, Stern Y. Delusions and hallucinations are associated with worse outcome in Alzheimer disease. Arch Neurol. 2005 Oct;62(10):1601-8.
  • McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. doi: 10.1016/j.jalz.2011.03.005. Epub 2011 Apr 21.
  • Ponomareva NV, Korovaitseva GI, Rogaev EI. EEG alterations in non-demented individuals related to apolipoprotein E genotype and to risk of Alzheimer disease. Neurobiol Aging. 2008 Jun;29(6):819-27. Epub 2007 Feb 12.
  • Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, Ogar JM, Rohrer JD, Black S, Boeve BF, Manes F, Dronkers NF, Vandenberghe R, Rascovsky K, Patterson K, Miller BL, Knopman DS, Hodges JR, Mesulam MM, Grossman M. Classification of primary progressive aphasia and its variants. Neurology. 2011 Mar 15;76(11):1006-14. doi: 10.1212/WNL.0b013e31821103e6. Epub 2011 Feb 16.
  • Mendez MF, Ghajarania M, Perryman KM. Posterior cortical atrophy: clinical characteristics and differences compared to Alzheimer's disease. Dement Geriatr Cogn Disord. 2002;14(1):33-40.
  • Wessels AM, Siemers ER, Yu P, Andersen SW, Holdridge KC, Sims JR, Sundell K, Stern Y, Rentz DM, Dubois B, Jones RW, Cummings J, Aisen PS. A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer's Disease Rating Scale (iADRS). J Prev Alzheimers Dis. 2015 Dec 1;2(4):227-241.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: June 27, 2019) 		65
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2025
Estimated Primary Completion Date December 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Timothy R Malone, MD 301-295-4771 timothy.r.malone5.mil@mail.mil
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04004702
Other Study ID Numbers  ICMJE 06272019
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Walter Reed National Military Medical Center
Study Sponsor  ICMJE Walter Reed National Military Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Timothy R Malone, MD Walter Reed National Military Medical Center
PRS Account Walter Reed National Military Medical Center
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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