PHASE II/III trial for Slowing Progression in Mild Cognitive Impairment

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 DESCRIPTION: No therapy has FDA approval for amnestic MCI, a symptomatic stage of Alzheimer's disease when patients are at increased risk for progression to dementia. Using an agent with proven safety/tolerability, we propose a novel approach for slowing progression in MCI due to AD. The use of the atypical antiepileptic levetiracetam (LEV) is indicated by evidence that hippocampal hyperactivity is characteristic of this stage of disease, predicts subsequent longitudinal cognitive decline/conversion to a dementia diagnosis, and is correlated with the extent of neuronal injury as measured in structural MRI. Supporting the proposed therapy, low dose treatment with LEV reduces hippocampal hyperactivity in both animal models and aMCI subjects, concurrently improving cognitive function. In the longer-term, treatment with LEV is expected to reduce degenerative processes driven by failure to control excess neural activity in the vulnerable entorhinal/hippocampal network. The proposed randomized, placebo-controlled 24 month trial will test the efficacy of LEV therapy on a sole primary outcome, the CDR sum of boxes, and a key secondary measure of entorhinal cortex thinning to assess neuronal injury. The trial will also acquire a rich database, e.g. genetic/DNA, additional imaging modalities (resting state fMRI, and diffusion tensor imaging scans), along with both standardized neuropsychological testing and novel cognitive assessments as secondary measures. Funding under this application would provide partial support (approximately 15% of total trial cost) in a public/private partnership for this Phase II/III trial, which would be the first to target hippocamal hyperactivity and will be registered with the FDA. A pre-IND meeting with the FDA (March 2014) on the proposed protocol provided supportive background on all aspects of the trial plan including appropriate enrollment criteria, adequacy of outcome measures, drug safety, and CMC formulation of an extended release medication. Importantly, the FDA confirmed that no further preclinical or clinical data are required to proceed with the trial. The Hopkins investigators under this award, who have exceptional expertise in biostatistics, imaging, clinical trial design, and data analysis have worked together with the Sponsor (AgeneBio, Inc) and its CRO to develop the protocol and plans to implement it. NIH support would not only contribute to the main purpose of the trial, but also ensure an open resource for data sharing to advance clinical trial design in AD prevention, including biomarker development.