Safety, tolerability, and efficacy outcomes of the Investigation of Levetiracetam in Alzheimer's disease (ILiAD) study: a pilot, double-blind placebo-controlled crossover trial

Abstract

Objective: To assess whether the antiseizure medication levetiracetam may improve cognition in individuals with Alzheimer's disease who have not previously experienced a seizure.

Methods: We performed a randomized, double-blind, placebo-controlled crossover pilot study in individuals with mild-to-moderate Alzheimer's disease. Electroencephalography was performed at baseline and those with active epileptiform discharges were excluded. Eligible participants were randomized to placebo for 12 weeks or an active arm of oral levetiracetam (4 weeks up-titration to levetiracetam 500 mg twice daily, 4 weeks maintained on this dose followed by 4 weeks down-titration to nil). Participants then crossed over to the other arm. The primary outcome was change in cognitive function assessed by the Oxford Memory Task, a task sensitive to hippocampal memory binding. Secondary outcomes included tolerability, other neuropsychological scales, and general questionnaires.

Results: Recruitment numbers were severely limited owing to restrictions from the COVID-19 pandemic at the time of the study. Eight participants completed both arms of the study (mean age 68.4 years [SD = 9.2]; 5 females [62.5%]). No participants withdrew from the study and there was no significant difference between reported side effects in the active levetiracetam or placebo arm. Measures of mood and quality of life were also not significantly different between the two arms based on participant or carer reports. In limited data analysis, there was no statistically significant difference between participants in the active levetiracetam and placebo arm on the memory task.

Significance: This pilot study demonstrates that levetiracetam was well tolerated in individuals with Alzheimer's disease who do not have a history of seizures and has no detrimental effect on mood or quality of life. Larger studies are needed to assess whether levetiracetam may have a positive effect on cognitive function in subsets of individuals with Alzheimer's disease.

Plain language summary: Abnormal electrical activity within the brain, such as is seen in seizures, might contribute to memory problems in people with dementia. We completed a clinical trial to see if an antiseizure medication, levetiracetam, could help with memory difficulties in people with Alzheimer's disease (the most common cause of dementia). In this pilot study, we could not prove whether levetiracetam helped memory function. We did show that the drug is safe and well tolerated in people with dementia who have not had a seizure. This work, therefore, offers a platform for future research exploring antiseizure medications in people with dementia.

Keywords: Oxford Memory Test; antiseizure medications; dementia; epilepsy; seizure.

FIGURE 1

Schema for the ILiAD trial. ILiAD trial flowsheet from recruitment through crossover and monitoring (adapted from ¹⁶ ) After baseline assessments, recruited participants were randomized to first receive either levetiracetam or placebo. Detailed assessments were performed at 8 weeks to compare to baseline data. After weaning away levetiracetam/placebo, participants crossed over to the second arm and received the opposite of what they had been given in the first arm (namely people receiving levetiracetam now received placebo and vice versa). Assessment at 20 weeks was compared to data acquired at 12 weeks and levetiracetam/placebo was then down‐titrated to nil by 24 weeks.

FIGURE 2

“What was where?” Oxford Memory task (OMT). Participants were presented with either 1 or 2 fractals randomly distributed on the screen. After a 4 s delay two fractals appeared at the center of the screen, one of which had appeared in the memory array whereas the other one was a distractor. Firstly, they needed to identify the object they had seen previously (‘what’), and then drag it back to its original location (‘where’).

FIGURE 3

Individual datapoints for Fractals 1 testing. Values are presented as color‐coded individual datapoints, for all subjects who took part in the study. Randomization status is represented by different subplots for each metric (left for placebo, right for levetiracetam). Lev = levetiracetam. Proportion correct = proportion of correctly identified items. Identification time = time in seconds identify the correct object. Absolute Error = distance between the original item location to the participant's response location. Localization Time = the time in seconds to drag the chosen object to its remembered location. Higher values correspond to better localization for proportion correct, and to worse performance for absolute error, identification, and localization time.

FIGURE 4

Number of adverse reporting instances. Four study participants accounted for all the adverse reporting instances in the active arm of the study. Nineteen adverse instances were reported while participants were in the non‐active, placebo arm (red) of the study, and 16 were reported during the active, levetiracetam arm (blue).