Levetiracetam for Alzheimer's Disease-Associated Epileptiform Activity
Information source: University of California, San Francisco
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Early-onset Alzheimer's Disease
Intervention: levetiracetam (Drug)
Phase: Phase 2
Status: Recruiting
Sponsored by: University of California, San Francisco Official(s) and/or principal investigator(s): Keith A Vossel, MD, MSc, Principal Investigator, Affiliation: University of California, San Francisco
Overall contact: Alexander J Beagle, BA, Phone: 415-476-2906, Email: abeagle@memory.ucsf.edu
Summary
Patients with Alzheimer's disease (AD) have seizures in addition to losing their memory and
other mental functions (referred to as cognitive functions). The seizures, and other
examples of overactive electrical activity in the brain that is not noticeable, contribute
to the loss of cognitive function. Studies in animal models suggest that a drug that
prevents seizures called levetiracetam may reduce neuronal over-excitation and improve
cognition in individuals with AD. We propose to determine if levetiracetam can also be used
to treat patients with AD-associated seizures and loss of mental functions. We developed
novel instruments for this population that will also be used in future large-scale clinical
trials.
The current study will last for 12 weeks and will involve people with early-onset AD and
epileptic brain activity. Participants will be initially examined and then assigned to
groups in a randomized manner. One group will receive levetiracetam for 4 weeks, then no
drug for 4 weeks, and then placebo for 4 weeks. For another group, the order of treatments
will be reversed. The cognitive abilities of participants will be retested every 4 weeks and
compared to those at the beginning. The cognitive tests include a virtual-reality navigation
test of memory and computerized tests of mental flexibility and problem solving. The
participants will be monitored with a magnetoencephalogram (MEG) with simultaneous EEG
(M/EEG) at their initial visit and after each treatment phase (levetiracetam and placebo).
M/EEG is a highly effective non-invasive method for identifying brain regions of epileptic
activity. We will need to recruit 36 randomized participants to test our hypotheses. This
study will take place at the University of California, San Francisco (UCSF) Memory and Aging
Center, which is a large referral site for early-onset dementias, and the Department of
Radiology. Our overall goal is to demonstrate that levetiracetam engages the intended brain
target by suppressing epileptic activity and provides cognitive benefit in a select group of
patients who would be predicted to respond favorably to this treatment.
Clinical Details
Official title: Phase 2a Levetiracetam Trial for AD-Associated Network Hyperexcitability
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Primary outcome: Changes in Executive Function as Measured by the E.X.A.M.I.N.E.R. Computer Battery
Secondary outcome: Changes in Epileptiform Activity FrequencyChanges in Cognitive Function Changes in Behavior and Level of Disability
Eligibility
Minimum age: 45 Years.
Maximum age: 80 Years.
Gender(s): Both.
Criteria:
To be included in the trial all of the following inclusion criteria must be met:
Ability to obtain written informed consent from the patient or caregiver as a surrogate;
Meets National Institute on Aging-Alzheimer's Association Workgroups criteria for probable
AD dementia (McKhann et al. 2011), with symptom onset < age 70; Presence of epileptiform
activity on initial screening M/EEG; Willing and able caregiver who has daily contact with
the subject; Mini-Mental State Examination (MMSE) score of ≥ 18 at the initial screening
assessment, and/or Clinical Dementia Rating (CDR) < 2 within 180 days of enrollment;
Subjects and caregivers must be able to comply with prescribed regime of study treatment
throughout the course of the study, and meet the required time commitment of four days of
in-person visits; Any concurrent FDA-approved treatment for AD (such as donepezil,
galantamine, or rivastigmine, and memantine) must be stable for at least 2 months prior to
enrollment. Other medications (except those listed under exclusion criteria) are allowed
as long as the dose is stable for 30 days prior to enrollment.
The following criteria are considered grounds for exclusion:
Any conditions which could account for cognitive deficits in addition to AD, including but
not limited to Vitamin B12 or folate deficiency, abnormal thyroid function, posttraumatic
conditions, syphilis, multiple sclerosis or another neuroinflammatory disorder,
Parkinson's disease, vascular or multi-infarct dementia, Huntington's disease, normal
pressure hydrocephalus, central nervous system (CNS) tumor, progressive supranuclear
palsy, subdural hematoma, etc.; Seizure disorders, excepting cases where the first seizure
was within 10 years of the AD diagnosis and the patient is not prescribed anticonvulsants;
Significant systemic medical illnesses; Use of medications likely to affect CNS functions
(e. g., benzodiazepines, narcotics); Severe renal dysfunction with creatine clearance < 30
ml/min, which would affect serum LEV levels; Participation in another AD clinical trial
within 3 months of Screening, or any AD clinical trial, such as a vaccine, that has
potential long-term effects; Treatment with another study drug or investigational drug
within 30 days of Screening; Pregnant or lactating; Any other medical condition which is
determined by the investigators to potentially create an undue risk for an adverse effect;
Biomarker evidence unsupportive of a diagnosis of AD.
Locations and Contacts
Alexander J Beagle, BA, Phone: 415-476-2906, Email: abeagle@memory.ucsf.edu
UCSF, San Francisco, California 94158, United States; Recruiting Alexander J Beagle, BA, Phone: 415-476-2906, Email: abeagle@memory.ucsf.edu Keith A Vossel, MD, MSc, Principal Investigator
Additional Information
Memory & Aging Center Website
Related publications: Verret L, Mann EO, Hang GB, Barth AM, Cobos I, Ho K, Devidze N, Masliah E, Kreitzer AC, Mody I, Mucke L, Palop JJ. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell. 2012 Apr 27;149(3):708-21. doi: 10.1016/j.cell.2012.02.046. 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. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, Yassa MA, Bassett SS, Shelton AL, Gallagher M. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012 May 10;74(3):467-74. doi: 10.1016/j.neuron.2012.03.023. 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. Mares P, Mikulecká A. Different effects of two N-methyl-D-aspartate receptor antagonists on seizures, spontaneous behavior, and motor performance in immature rats. Epilepsy Behav. 2009 Jan;14(1):32-9. doi: 10.1016/j.yebeh.2008.08.013. Epub 2008 Sep 30. Molaie M, Culebras A, Miller M. Effect of interictal epileptiform discharges on nocturnal plasma prolactin concentrations in epileptic patients with complex partial seizures. Epilepsia. 1986 Nov-Dec;27(6):724-8. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984 Nov;141(11):1356-64. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993 Nov;43(11):2412-4. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994 Dec;44(12):2308-14. Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, Ferris S. An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S33-9. Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, Schmitt FA, Grundman M, Thomas RG, Ferris SH. Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S22-32. Walker MP, Ayre GA, Cummings JL, Wesnes K, McKeith IG, O'Brien JT, Ballard CG. The Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale. Two methods to assess fluctuating confusion in dementia. Br J Psychiatry. 2000 Sep;177:252-6. Hinkley LB, Vinogradov S, Guggisberg AG, Fisher M, Findlay AM, Nagarajan SS. Clinical symptoms and alpha band resting-state functional connectivity imaging in patients with schizophrenia: implications for novel approaches to treatment. Biol Psychiatry. 2011 Dec 15;70(12):1134-42. doi: 10.1016/j.biopsych.2011.06.029. Epub 2011 Sep 8.
Starting date: June 2014
Last updated: May 26, 2015
|