An Investigation of Levetiracetam in Alzheimer's Disease (ILiAD): a double-blind, placebo-controlled, randomised crossover proof of concept study

Abstract

Background: Although Alzheimer's disease affects around 800,000 people in the UK and costs almost £23 billion per year, currently licenced treatments only offer modest benefit at best. Seizures, which are more common in patients with Alzheimer's disease than age matched controls, may contribute to the loss of nerve cells and abnormal brain discharges can disrupt cognition. This aberrant electrical activity may therefore present potentially important drug targets. The anti-seizure medication levetiracetam can reduce abnormal cortical discharges and reverse memory deficits in a mouse model of Alzheimer's disease. Levetiracetam has also been shown to improve memory difficulties in patients with mild cognitive impairment, a precursor to Alzheimer's disease. Clinical use of levetiracetam is well-established in treatment of epilepsy and extensive safety data are available. Levetiracetam thus has the potential to provide safe and efficacious treatment to help with memory difficulties in Alzheimer's disease.

Methods: The proposed project is a proof of concept study to test whether levetiracetam can help cognitive function in people with dementia. We plan to recruit thirty patients with mild to moderate Alzheimer's disease with no history of previous seizures or other significant co-morbidity. Participants will be allocated to a double-blind placebo-controlled crossover trial that tests levetiracetam against placebo. Standardised scales to assess cognition and a computer-based touchscreen test that we have developed to better detect subtle improvements in hippocampal function will be used to measure changes in memory. All participants will have an electroencephalogram (EEG) at baseline. The primary outcome measure is a change in the computer-based touchscreen cognitive task while secondary outcomes include the effect of levetiracetam on mood, quality of life and modelling of the EEG, including time series measures and feature-based analysis to see whether the effect of levetiracetam can be predicted. The effect of levetiracetam and placebo will be compared within a given patient using the paired t-test and the analysis of covariance adjusting for baseline values.

Discussion: This is the first study to evaluate if an anti-seizure medication can offer meaningful benefit to patients with Alzheimer's disease. If this study demonstrates at least stabilisation of memory function and/or good tolerability, the next step will be to rapidly progress to a larger study to establish whether levetiracetam may be a useful and cost-effective treatment for patients with Alzheimer's disease.

Trial registration: ClinicalTrials.gov NCT03489044 . Registered on April 5, 2018.

Keywords: Anti-seizure medication; Cognition; Dementia; Epilepsy; Levetiracetam; Pilot; Proof of concept; Randomised controlled trial; Seizure.

Conflict of interest statement

The authors declare no direct competing interests. No author receives monies directly as a result of the ILiAD study.

© 2021. The Author(s).

Figures

Fig. 1

ILiAD trial outline. The ILiAD trial is a double-blind, placebo-controlled crossover study with study visits each month. It is a designed to provide pilot data to determine whether there may be a role for levetiracetam, an anti-seizure medication, in helping memory problems in people with Alzheimer’s disease (EEG = electroencephalogram; MoCA = Montreal Cognitive Assessment)

Fig. 2

ILiAD visit schedule The tasks to be completed by the participant, carer and researcher are listed. Visits can typically be completed within 2 h although the screening and baseline visit can take around 4 h. IMP is provided at each visit also. * = tests will not be repeated if acceptable results are already available from within 3 months of recruitment date. Abbreviations: TC = telephone consultation; BADLS = Bristol Activities of Daily Living Scale; DSRS = Dementia Severity Rating Scale; MoCA = Montreal Cognitive Assessment; NPI = Neuropsychiatry Inventory; QoL = Quality of Life; EQ-5D = Euro-QoL Quality of Life Measure

Fig. 3

ILiAD drug administration chart with each provision of IMP, carers are provided with a drug administration chart. Each day, the carer crosses off the tablet on the chart as the IMP is given to the participant. Researchers review these charts at the end of each month to ensure concordance with IMP administration. The example above is for weeks 1 to 4 in the study

Fig. 4

Administration of IMP during the ILiAD trial. Randomised participants will attend site pharmacies to collect IMP as outlined. Each participant has a designated carton held at the trial pharmacies. IMP is randomly allocated as placebo or levetiracetam to arm1 and to arm 2. Participants then collect IMP from carton 1 and then carton 2 and titrate medication/placebo as per the administration schedules