Clinical trial NCT02002819: Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability
Official title: Phase 2a Levetiracetam Trial for AD-Associated Network Hyperexcitability
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Keywords: Alzheimer's disease
AD
Early-onset AD
EOAD
Early-onset Alzheimer's
Early-onset Alzheimer's disease
Lead sponsor: University of Minnesota
Sponsor class: OTHER
First posted: 2013-12-06
Enrollment: 34
Sex: ALL
Minimum age (years): 45
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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) and the University of Minnesota.

Detailed description: For a more detailed explanation of the study and what our results were, please read our publication at https://jamanetwork.com/journals/jamaneurology/fullarticle/2784539

Eligibility 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); 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.

Primary outcomes:
measure: Changes in Executive Function as Measured by the NIH EXAMINER Computer Battery
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
Secondary outcomes:
measure: Changes in Stroop Interference Naming
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: Changes in ADAS-cog
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: Clinical Dementia Rating Sum of Boxes (CDR-SOB)
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: Changes in Behavior and Level of Disability - ADCS-ADL
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: Changes in Behavior and Level of Disability - ADCS-CGIC
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: Changes in Behavior and Level of Disability - Neuropsychiatric Inventory (NPI)
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: Changes in Epileptiform Events
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
Other outcomes:
measure: Stroop Interference in AD With Epileptiform Activity
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: ADAS-cog in AD With Epileptiform Activity
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: Changes in Cognitive Function as Measured by a Virtual Route Learning Test
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: Standardized Assessments of Clinical Fluctuations -The Clinician Assessment of Fluctuation
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: Blood Serum Prolactin Level
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: NIH EXAMINER in AD With Epileptiform Activity
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: Standardized Assessments of Clinical Fluctuations - One Day Fluctuation Assessment Scale
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: MEG Power Spectrum Measures
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
measure: MEG Functional Connectivity Measures
timeFrame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
Locations:
city: San Francisco
country: United States
facility: UCSF
state: California
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
Study officials:
affiliation: University of Minnesota
name: Keith A Vossel, MD, MSc
role: PRINCIPAL_INVESTIGATOR
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