An Investigation of Levetiracetam in Alzheimer's Disease (ILiAD)
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|ClinicalTrials.gov Identifier: NCT03489044|
Recruitment Status : Enrolling by invitation
First Posted : April 5, 2018
Last Update Posted : October 16, 2018
The study proposed aims to evaluate the effect of Levetiracetam in patients with Alzheimer's disease (AD) in a Phase 2 Clinical Trial.
Levetiracetam is an established anti-epileptic medication that has been approved by NICE (UK) as a first line treatment for focal epilepsy. Levetiracetam is now generic and acts, as all anti-epileptic medications do, by stabilising neuronal networks. However, Levetiracetam appears unique amongst the anti-epileptic medications in being able to stabilise aberrant neuronal networks in Alzheimer's disease. In both animal models of AD and in patients with mild cognitive impairment, Levetiracetam can offer benefit to cognition.
The investigators therefore aim to test whether Levetiracetam, through stabilisation of neuronal networks, may offer benefit to cognition in patients with AD.
|Condition or disease||Intervention/treatment||Phase|
|Alzheimer Disease Epilepsy||Drug: Levetiracetam Drug: Placebo Oral Tablet||Phase 2|
Alzheimer's disease affects around 800,000 people in the UK alone and costs almost £23 billion per year. The only currently licensed treatments for Alzheimer's disease offer modest benefit at best. Seizures are more common in people with Alzheimer's disease and people with Alzheimer's disease may also have evidence of abnormal brainwave activity without having obvious seizures. Seizures may contribute to the loss of nerve cells and abnormal brainwave activity can disrupt thinking and memory. This abnormal electrical activity is therefore a potentially important drug target.
The anti-epileptic drug Levetiracetam can reduce abnormal brainwave activity and reverse memory deficits in a mouse model of Alzheimer's disease. Levetiracetam can also improve memory difficulties seen in people with mild cognitive impairment, a pre-cursor to Alzheimer's disease. Clinical use of Levetiracetam is already widespread and it is recommended by The National Institute of Health and Care Excellence as a first line treatment for seizures. Levetiracetam is generic (off-patent), is not known to interact with any other drugs and is well tolerated. A promising, cheap and safe approach might be to use Levetiracetam as a treatment to help with memory difficulties in Alzheimer's disease.
The proposed project is a proof of concept study. The investigators wish to allocate thirty patients with Alzheimer's disease with no history of previous seizure to initially receive either Levetiracetam or placebo before patients 'cross-over' so that the participants who initially received Levetiracetam are then given placebo and vice-versa. The effect that Levetiracetam has on memory in Alzheimer's disease will be studied using several standardised scales. Tests that the investigators have developed to better detect subtle improvements in thinking will also be used. Patients will have a straightforward, non-invasive test called an electroencephalogram to look at their brainwave activity at the start of the study, as there may be brainwave markers that might help to predict which patients would benefit most from Levetiracetam.
This study evaluates if an anti-epileptic medication can offer meaningful benefit to patients with Alzheimer's disease. If this study is successful, 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.
- Treatment with the anti-epileptic drug Levetiracetam will be of benefit to cognitive deficits in Alzheimer's disease because electrophysiological disruption of neuronal networks contributes to the pathophysiology of the condition.
- Treatment with Levetiracetam at a dose that is routinely utilized in older people with epilepsy will be well tolerated in patients with Alzheimer's disease and, in particular, will not adversely affect mood
- Electroencephalography (EEG) may offer a biomarker to predict which patients with Alzheimer's disease might be especially suited to treatment with Levetiracetam
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Crossover Assignment|
|Intervention Model Description:||Placebo controlled|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Masking Description:||Double blind, block randomised,|
|Official Title:||An Investigation of Levetiracetam in Alzheimer's Disease (ILiAD): a Proof of Concept Study|
|Estimated Study Start Date :||November 2018|
|Estimated Primary Completion Date :||November 1, 2019|
|Estimated Study Completion Date :||January 2020|
Experimental: Active treatment arm (Levetiracetam)
When in the active arm, after a baseline visit, participants will up-titrate Levetiracetam in 250mg steps at intervals of one week to Levetiracetam 500mg twice daily (two tablets twice daily). Participants will be maintained on Levetiracetam 500mg bd for four weeks and have a further full assessment at 8 weeks after being on Levetiracetam. Participants will then down-titrate Levetiracetam by 250mg every week until weaned to nil.
To up-titrate Levetiracetam to 500mg (two tablets) twice daily followed by maintenance on Levetiracetam 500mg twice daily for four weeks and then down-titrate to nil over four weeks
Placebo Comparator: Control arm (placebo oral tablets)
When in the control arm, after a baseline visit, participants will up-titrate placebo (manufactured to look identical to Levetiracetam 250mg) in one tablet steps at intervals of one week to two tablets twice daily. Participants will be maintained on placebo for four weeks and have a further full assessment at 8 weeks after being on placebo. Participants will then down-titrate placebo by one tablet every week until weaned to nil.
Drug: Placebo Oral Tablet
To up-titrate placebo to two tablets twice daily followed by maintenance on placebo two tablets twice daily for four weeks and then down-titrate to nil over four weeks
- Effect of Levetiracetam on hippocampal function in patients with Alzheimer's disease as assessed by a computerised test of hippocampal binding [ Time Frame: 18 months ]Change from baseline in measures of hippocampal binding on a standardised computer based test. Participants will be shown fractals on a screen, followed by a blank screen. The participants will be then shown one of the fractals they saw previously and a foil. The participants will have to identify which of the fractals they saw initially and then drag that fractal on the screen to the location where it appeared before. The computer will assess whether the participant correctly identifies which fractal had been seen previously and also assess how accurately the participant remembers the location of the previously shown fractal. The investigators will then evaluate whether there are any changes in the accuracy of remembering fractals/fractal position after exposure to Levetiracetam/placebo
- Number of participants with treatment related serious adverse events as reported on the serious adverse events proforma [ Time Frame: 18 months ]To determine if use of Levetiracetam associates with significant side effects in patients with AD that have not experienced an overt seizure
- Effect of Levetiracetam on mood in patients with Alzheimer's disease [ Time Frame: 18 months ]Number of participants reporting change from baseline on the Neuropsychiatric Inventory
- Effect of Levetiracetam on quality of life in patients with Alzheimer's disease as assessed by their principal carer [ Time Frame: 18 months ]Number of participants with a change from baseline on Dementia Severity Rating Scale
- Effect of Levetiracetam on quality of life in patients with Alzheimer's disease [ Time Frame: 18 months ]Number of participants with a change from baseline on the Euro-QoL (EQ5D) measure
- Determining role of the electroencepahlogram in patients with Alzheimer's disease [ Time Frame: 18 months ]Correlation of electroencephalogram recording with effect of Levetiracetam on cognition as assessed by a computer based test of hippocampal binding
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03489044
|Nuffield Department of Clinical Neuroscience|
|Oxford, Oxfordshire, United Kingdom, OX39DU|
|Study Director:||Arjune Sen, PhD, FRCPE||Nuffield Department of Clinical Neurosciences|