Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability

NCT02002819 | Completed Phase 2 Results

• 2 other identifiers: NEUR-2017-25879PCTRB-13-288476
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 2

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.

Conditions

Alzheimer's Disease

Keywords

Alzheimer's disease; AD; Early-onset AD; EOAD; Early-onset Alzheimer's; Early-onset Alzheimer's disease

Outcome Measures

Primary Outcomes (1)

• Changes in Executive Function as Measured by the NIH EXAMINER Computer Battery

  Changes in executive function were measured using the NIH EXAMINER, 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. The Examiner assessment consists of the following scales: antisaccade , set shifting , flanker task, dot counting, spatial 1-back, category fluency, and letter fluency. Scores for this task have an indefinite range. Higher scores however do indicate better performance. Scores for this scale were generated using item response theory. For this study, scores with SEs greater than 0.55 were classified as unreliable and excluded from analysis. Composite scores from 2 participants were excluded on this basis.The EXAMINER ranges for the participants in the study were -2.59 to 1.33.

  Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Secondary Outcomes (7)

• Changes in Stroop Interference Naming

  Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

• Changes in ADAS-cog

  Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

• Clinical Dementia Rating Sum of Boxes (CDR-SOB)

  Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

• Changes in Behavior and Level of Disability - ADCS-ADL

  Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

• Changes in Behavior and Level of Disability - ADCS-CGIC

  Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Other Outcomes (9)

• Stroop Interference in AD With Epileptiform Activity

  Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

• ADAS-cog in AD With Epileptiform Activity

  Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

• Changes in Cognitive Function as Measured by a Virtual Route Learning Test

  Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)

Study Arms (2)

Levetiracetam-Placebo

EXPERIMENTAL

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.

Drug: levetiracetam

Placebo-Levetiracetam

EXPERIMENTAL

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.

Drug: levetiracetam

Interventions

levetiracetam DRUG

Also known as: Keppra

Levetiracetam-Placebo; Placebo-Levetiracetam

Eligibility Criteria

• Age: 45 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Minnesota: lead

Study Sites (2)

UCSF

San Francisco, California, 94158, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Related Publications (16)

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  PMID: 22541439 BACKGROUND

• 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.

  PMID: 22869752 BACKGROUND

• 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. doi: 10.1126/science.1141736.

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  PMID: 23835471 BACKGROUND

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  PMID: 18786655 BACKGROUND

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  PMID: 3780608 BACKGROUND

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  PMID: 6496779 BACKGROUND

• Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993 Nov;43(11):2412-4. doi: 10.1212/wnl.43.11.2412-a. No abstract available.

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  PMID: 7991117 BACKGROUND

• 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.

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• 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.

  PMID: 21861988 BACKGROUND

• Vossel K, Ranasinghe KG, Beagle AJ, La A, Ah Pook K, Castro M, Mizuiri D, Honma SM, Venkateswaran N, Koestler M, Zhang W, Mucke L, Howell MJ, Possin KL, Kramer JH, Boxer AL, Miller BL, Nagarajan SS, Kirsch HE. Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial. JAMA Neurol. 2021 Nov 1;78(11):1345-1354. doi: 10.1001/jamaneurol.2021.3310.

  PMID: 34570177 DERIVED

• Liu J, Wang LN. Treatment of epilepsy for people with Alzheimer's disease. Cochrane Database Syst Rev. 2021 May 11;5(5):CD011922. doi: 10.1002/14651858.CD011922.pub4.

  PMID: 33973646 DERIVED

Related Links

• Memory \& Aging Center Website

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Levetiracetam

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Keith Vossel
• Organization: UCLA Mary S. Easton Center for Alzheimer's Disease Research

neuroeaston@mednet.ucla.edu

310-794-3665,

Study Officials

• Keith A Vossel, MD, MSc

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 25, 2013
• First Posted: December 6, 2013
• Study Start: October 16, 2014
• Primary Completion: July 21, 2020
• Study Completion: July 21, 2020
• Last Updated: May 16, 2022
• Results First Posted: May 16, 2022

Record last verified: 2022-04

Locations

US (2)