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Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD)

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ClinicalTrials.gov Identifier: NCT02002819
Recruitment Status : Recruiting
First Posted : December 6, 2013
Last Update Posted : July 19, 2018
Sponsor:
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute

October 25, 2013
December 6, 2013
July 19, 2018
June 2014
December 2019   (Final data collection date for primary outcome measure)
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 (i.e. 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 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.
  • Changes in Cognitive Function as Measured by a Standard Neuropsychological Assessment [ Time Frame: Assessed at weeks 0, 4, 8 , and 12 ]
    Cognitive function will be assessed using a 1-hour evaluation incorporating standardized clinical measures of attention, executive functioning, working memory, episodic memory, speech and language, visuospatial skills, and emotional processing. This evaluation involves a series of oral and pencil and paper tasks to assess these domains. 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 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.
Complete list of historical versions of study NCT02002819 on ClinicalTrials.gov Archive Site
  • 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.
Not Provided
  • 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.
Not Provided
 
Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability
Phase 2a Levetiracetam Trial for AD-Associated Network Hyperexcitability

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.

Not Provided
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Alzheimer's Disease
Drug: levetiracetam
Other Name: Keppra
  • Experimental: Levetiracetam-Placebo
    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.
    Intervention: Drug: levetiracetam
  • Experimental: Placebo-Levetiracetam
    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.
    Intervention: Drug: levetiracetam

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
36
Same as current
December 2019
December 2019   (Final data collection date for primary outcome measure)

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); Age ≤ 80 years at time of screening; Willing and able caregiver who has daily contact with the subject; Mini-Mental State Examination (MMSE) score ≥ 18 and/or Clinical Dementia Rating (CDR) < 2 at the initial screening assessment; 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 treatment for AD approved by the Food and Drug Administration (FDA), such as donepezil, galantamine, or rivastigmine, and memantine, must be stable for at least 30 days prior to screening and at least 60 days prior to study day 1. Other medications (except those listed under exclusion criteria) are allowed as long as the dose is stable for 30 days prior to screening.

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.; Previous history of a seizure disorder, excepting cases where the first seizure or detection of epileptiform activity was within 5 years of screening and the patient is not prescribed an anticonvulsant; 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.

Sexes Eligible for Study: All
45 Years to 80 Years   (Adult, Older Adult)
No
Contact: Kasey Ah Pook, BS 612-625-6631 ahpoo001@umn.edu
United States
 
 
NCT02002819
LEV-AD
PCTRB-13-288476 ( Other Grant/Funding Number: Alzheimer's Association Inc. )
No
Not Provided
Not Provided
University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
Not Provided
Principal Investigator: Keith A Vossel, MD, MSc University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
July 2018

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