An Investigation of Levetiracetam in Alzheimer's Disease

NCT03489044 | Completed Phase 2

• 2 other identifiers: IRAS 2038492016-003109-32
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Alzheimer Disease; Epilepsy

Keywords

Alzheimer; Seizure; Epilepsy; Anti-epileptic drug; Levetiracetam

Outcome Measures

Primary Outcomes (1)

• Effect of Levetiracetam on hippocampal function in patients with Alzheimer's disease as assessed by a computerised test of hippocampal binding

  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

  18 months

Secondary Outcomes (5)

• Number of participants with treatment related serious adverse events as reported on the serious adverse events proforma

  18 months

• Effect of Levetiracetam on mood in patients with Alzheimer's disease

  18 months

• Effect of Levetiracetam on quality of life in patients with Alzheimer's disease as assessed by their principal carer

  18 months

• Effect of Levetiracetam on quality of life in patients with Alzheimer's disease

  18 months

• Determining role of the electroencephalogram in patients with Alzheimer's disease

  18 months

Study Arms (2)

Active treatment arm (Levetiracetam)

EXPERIMENTAL

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.

Drug: Levetiracetam

Control arm (placebo oral tablets)

PLACEBO COMPARATOR

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

Interventions

Levetiracetam DRUG

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

Active treatment arm (Levetiracetam)

Placebo Oral Tablet DRUG

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

Control arm (placebo oral tablets)

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or Female, 50 years or above.
• Diagnosed with mild to moderate AD (MMSE 10 to 26)
• Meets the National Institute of Aging-Alzheimer's Association criteria for probable AD (2011)
• Stable dose of current regular medication, including acetylcholinesterase inhibitors if applicable, for at least 4 weeks prior to trial entry.
• Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during the trial and for 3 months thereafter. Acceptable forms of contraception include: established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); total abdominal hysterectomy; barrier methods of contraception (condom or occlusive cap with spermicide); male sterilisation, if the vasectomised partner is the sole partner for the subject; true abstinence, when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence and withdrawal are not acceptable methods of contraception).
• Participant has clinically acceptable blood and urine test results (creatinine clearance \>75 ml/minute; liver function tests \<2x upper limit of normal) and ECG that does not demonstrate conduction block or significant ischaemia within three months of enrolment.
• In the Investigator's opinion, is able and willing to comply with all trial requirements.
• Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the trial.
• Reliable carer willing and available to assist with medication administration as well as to accompany participants during any home visits.

You may not qualify if:

• Pre-existing diagnosis of epilepsy
• Clinical or laboratory evidence of a cause other than AD as a cause of their dementia
• Laboratory evidence of significant renal impairment (creatinine clearance \<75 ml/minute) or liver dysfunction (liver function tests \>2x upper limit of normal) within the preceding three months
• Visual or motor impairment that investigator deems severe enough to impair ability to complete computerised based touch screen task
• Use of anti-epileptic medication for any indication (epilepsy, pain or migraine) within previous three months
• Other severe neurological or medical condition. Examples include, significant stroke, heart failure, chronic renal failure, chronic liver failure within last 3 months
• Major depression or other significant behavioural disturbance
• Known allergy to Levetiracetam or history of previous adverse reaction to Levetiracetam
• Female participant who is pregnant, lactating or planning pregnancy during the course of the trial.
• Scheduled elective surgery or other procedures requiring general anaesthesia during the trial.
• Participant with life expectancy of less than 6 months, or is inappropriate for placebo medication.
• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial.
• Participants who have participated in another research trial involving an investigational medicinal product in the past 12 weeks Carer of participant with AD
• Carer has significant medical illness that will preclude adequate data capture during the study

Sponsors & Collaborators

• University of Oxford: lead
• Oxford University Hospitals NHS Trust: collaborator
• Oxford Health NHS Foundation Trust: collaborator
• Northumberland, Tyne and Wear NHS Foundation Trust: collaborator
• UCB Pharma: collaborator

Study Sites (1)

Nuffield Department of Clinical Neuroscience

Oxford, Oxfordshire, OX39DU, United Kingdom

Location

Related Publications (2)

• Sen A, Akinola M, Tai XY, Symmonds M, Davis Jones G, Mura S, Galloway J, Hallam A, Chan JYC, Koychev I, Butler C, Geddes J, Van Der Putt R, Thompson S, Manohar SG, Frangou E, Love S, McShane R, Husain M. An Investigation of Levetiracetam in Alzheimer's Disease (ILiAD): a double-blind, placebo-controlled, randomised crossover proof of concept study. Trials. 2021 Jul 31;22(1):508. doi: 10.1186/s13063-021-05404-4.

  PMID: 34332638 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

MeSH Terms

Conditions

Alzheimer Disease; Epilepsy; Seizures

Interventions

Levetiracetam

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

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

Study Officials

• Arjune Sen, PhD, FRCPE

  Nuffield Department of Clinical Neurosciences

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double blind, block randomised,
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Placebo controlled

Study Record Dates

• First Submitted: March 9, 2018
• First Posted: April 5, 2018
• Study Start: October 28, 2018
• Primary Completion: March 21, 2022
• Study Completion: March 21, 2022
• Last Updated: April 24, 2024

Record last verified: 2024-04

Locations

GB (1)