Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD)
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|ClinicalTrials.gov Identifier: NCT02002819|
Recruitment Status : Active, not recruiting
First Posted : December 6, 2013
Last Update Posted : January 31, 2018
Patients with Alzheimer's disease (AD) can 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 of AD suggest that a drug that prevents seizures called levetiracetam may reduce neuronal over-excitation and improve cognition. Based on this evidence, the investigators propose to determine if levetiracetam can be used to treat patients with AD. The investigators 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 AD. Participants will be initially examined with an overnight brain wave study to assess for silent epileptic (seizure-like) activity. Presence of epileptic activity on the screening exam is not required to enter the trial. Participants will then be 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 each visit. M/EEG is a highly effective non-invasive method for identifying brain regions of epileptic activity. The investigators will need to recruit 36 randomized participants to test the study 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 dementias, and the Department of Radiology. The overall goal of the study is to demonstrate that levetiracetam provides cognitive benefit in AD, particularly in patients who have silent epileptic activity.
|Condition or disease||Intervention/treatment||Phase|
|Alzheimer's Disease||Drug: levetiracetam||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||36 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||Phase 2a Levetiracetam Trial for AD-Associated Network Hyperexcitability|
|Study Start Date :||June 2014|
|Estimated Primary Completion Date :||December 2019|
|Estimated Study Completion Date :||December 2019|
U.S. FDA Resources
This group receives levetiracetam for 4 weeks twice daily, then has a break where no treatment is given for 4 weeks, and then receives placebo for 4 weeks.
Other Name: Keppra
This group receives placebo for 4 weeks twice daily, then has a break where no treatment is given for 4 weeks, and then receives levetiracetam for 4 weeks.
Other Name: Keppra
- Changes in Executive Function as Measured by the E.X.A.M.I.N.E.R. Computer Battery [ Time Frame: Assessed at weeks 0, 4, 8 , and 12 ]Changes in executive function will be measured using a 1-hour computer-based battery of various executive function tasks. The subject's performance after the study treatment will be compared with results from a baseline assessment done before the study treatment, using statistical tests to assess whether there was any significant change.
- Changes in Epileptiform Activity Frequency [ Time Frame: Assessed at weeks 4, 8, and 12. ]
Epileptiform activity will be measured using a 1-hr resting magnetoencephalogram/electroencephalogram (M/EEG). M/EEG can detect abnormal epileptiform findings called "spikes". The M/EEG will be read by an epileptologist with specialized training to assess whether there are any spikes. If spikes are observed during the M/EEG they will be counted to determine their frequency (e.g., 5 spikes per 1 hour recording).
The frequency of spikes will then be compared to baseline values from before beginning the study treatment, using statistical tests to determine if the frequency changed with treatment.
- Changes in Cognitive Function [ Time Frame: Assessed at weeks 0, 4, 8 , and 12 ]
The secondary outcome of changes in cognitive function will be assessed at all timepoints utilizing the following two tests:
Stroop Test - The Stroop Test (Stroop 1935) will be used to assess executive functions including selective attention, cognitive flexibility and processing speed. Subtasks include Stroop color naming and Stroop interference naming, and each subtask is restricted to 1 minute.
Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) - The ADAS-cog rating instrument (Rosen et al. 1984) will be used to evaluate the global cognitive functioning. The ADAS-cog is a 70-point scale that includes an assessment of verbal memory, language, orientation, reasoning, and praxis.
- Changes in Behavior and Level of Disability [ Time Frame: Assessed at weeks 0, 4, 8, 12 ]
The effects of LEV versus placebo on degree of disability and behavior in patients with Alzheimer's disease will be assessed using the following four measures:
Clinical Dementia Rating Sum of Boxes (CDR-SOB) - The CDR will be used to as a global measure of dementia severity (Morris 1993). The CDR consists of questions addressed to the caregiver/informant.
Alzheimer's Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL) - The ADCS-ADL rating instrument (Galasko et al. 1997) will be used to evaluate functional capacity. The ADCS-ADL is a caregiver rated questionnaire.
ADCS-Clinical Global Impression of Change (ADCS-CGIC) - The ADCS-CGIC is a seven-point scale that gives a global rating of change from baseline (Schneider et al. 1997). The baseline and follow up assessments are based on interviews with the subject and the informant.
Neuropsychiatric Inventory (NPI) - The NPI (Cummings et al. 1994) will be used to evaluate the severity of behavioral symptoms.
- Changes in Cognitive Function as Measured by a Virtual Navigation Task [ Time Frame: Assessed at weeks 0, 4, 8 , and 12 ]A 20-minute computer-based virtual navigation test will be used to assess how well a subject can navigate a virtual community to reach a goal destination. The subjects will then be measured on their ability to accurately navigate the virtual community after a period of a few hours. The subject's performance after the study treatment will be compared with results from a baseline assessment done before the study treatment, using statistical tests to assess whether there was any significant change.
- Standardized Assessments of Clinical Fluctuations [ Time Frame: Assessed at weeks 0, 4, 8, 12 ]Two standardized methods will be used to quantitate fluctuations of dementia symptoms: The Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale (Walker et al. 2000). These scales consist of a series of questions addressed to the caregiver/informant.
- MEG Power Spectrum Measures [ Time Frame: Assessed at screening and weeks 4, 8, 12 ]The power spectral density for different frequency bands will be measured via resting-state magnetoencephalography (MEG). A 60-second artifact-free recording segment from the first 10 minutes of recording (prior to sleep onset) will be manually selected for analysis. In participants who are able to complete additional tests, the investigators will measure dynamics of neural responses during cognitive tasks such as speech preparation and execution.
- MEG Functional Connectivity Measures [ Time Frame: Assessed at screening and weeks 4, 8, 12 ]Whole-brain alpha-band functional connectivity will be derived from MEG-imaging (MEG-I) using the 60-second artifact-free recording epoch that is selected for the MEG spectral analysis. MEG-I uses MEG sensor data with millisecond precision and applies source reconstruction algorithms to overlay cortical oscillatory activity onto structural brain images. Source-space MEG-I reconstructions and functional connectivity metrics will be computed with the NUTMEG software suite (http://nutmeg.berkeley.edu). The investigators will compute imaginary coherence, which is a reliable metric for functional connectivity with MEG reconstruction. Functional connectivity will measure the strength of coherence between a given region and the rest of the brain. The investigators will perform an unbiased search for MEG-I functional connectivity deficits that correlate with specific cognitive, behavioral, and functional deficits. Hinkley et al. 2011 provides details of the methodology.
- Blood Serum Levetiracetam and Prolactin Levels [ Time Frame: Assessed at screening and weeks 4, 8, 12 ]Blood samples intended for Quest Diagnostics LEV and prolactin serum levels (one 6 mL tube) will be processed in the following manner, as outlined in the Quest Diagnostics lab manual. The whole blood will be allowed to clot for 60 minutes and centrifuged at 2200 - 2500 revolutions per minute (RPM) for at least 15 minutes. The resulting serum will be split into 2 cryovials which will be stored at -20°C and immediately shipped for external assessment of LEV and prolactin levels. Prolactin will be assessed via immunoassay. The concentration of LEV in serum will be measured using validated liquid chromatography/tandem mass spectrometry (LC/MS-MS) methods.
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): NCT02002819
|United States, California|
|San Francisco, California, United States, 94158|
|United States, Minnesota|
|University of Minnesota|
|Minneapolis, Minnesota, United States, 55455|
|Principal Investigator:||Keith A Vossel, MD, MSc||University of Minnesota - Clinical and Translational Science Institute|