Levetiracetam for Persons at Risk for Alzheimer's Disease
A Proof-of-Concept, Multicentre, Phase IIb, Randomized Double-Blind Crossover Trial of Levetiracetam vs Placebo for Hippocampal Hyperactivity in Cognitively Normal Individuals at Risk for Alzheimer's Disease
Sunnybrook Health Sciences Centre
40 participants
Oct 23, 2025
INTERVENTIONAL
Conditions
Summary
The goal of this clinical trial is to investigate whether very small doses of a drug called levetiracetam (LEV) may reduce abnormal brain signaling in individuals who are at an increased risk for developing Alzheimer's Disease (AD). The study is looking for individuals who have a parent or sibling with Alzheimer's disease (dementia), and who have memory complaints but are currently performing within normal limits on cognitive testing. During the screening period, a functional MRI (fMRI) scan of the brain will identify those participants who have the abnormal brain signaling that the study is looking to treat. All participants will receive 4 weeks of treatment with LEV and 4 weeks of treatment with placebo (a sugar pill), but it will not be known what order they will receive them in. Participants will undergo cognitive testing, genetic testing, and several brain imaging scans as part of the study. This is a pilot study, meaning that it is being carried out for the first time in a small number of participants. If the results show that treatment with LEV appears to be more beneficial than placebo in normalizing brain signaling, a larger study may follow. This study is only being carried out in Toronto, Canada.
Eligibility
Inclusion Criteria12
- Willing to undergo all study procedures and has signed the informed consent form.
- Has a friend or family member who has weekly contact with the participant and is willing to sign the study partner informed consent and complete study questionnaires.
- Female participants must be post-menopausal (amenorrheic for at least 12 consecutive months without other known or suspected cause) or surgically sterile (bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy).
- Sufficiently fluent in English to undergo cognitive testing, per investigator judgment.
- Presence of subjective cognitive complaints, indicated by score \>7 on MyCog portion of the Subjective Cognitive Decline Questionnaire (SCD-Q) at Screening.
- Family history of Alzheimer's disease or of dementia suggestive of possible or probable Alzheimer's disease in a first-degree relative.
- Head circumference \<60cm.
- Within normal limits on all domains of the Toronto Cognitive Assessment (TorCA) at Screening or in the previous 6 months, with the exceptions noted below:
- A borderline score on the executive domain may be acceptable if in the opinion of the investigator it is solely attributable to the participant having ADHD.
- A borderline score on the language domain may be acceptable if in the opinion of the investigator it is solely attributable to English not being the participant's primary language.
- Known to be within normal limits on the Montreal Cognitive Assessment (MoCA), Cogniciti Brain Health Assessment (BHA), or Toronto Cognitive Assessment (TorCA) in the previous 6 months, or within normal limits on the MoCA at Screening.
- Hippocampal hyperactivation, defined as activation \>1.5 SD above the mean, during the pattern separation task (PST) on BOLD fMRI.
Exclusion Criteria46
- History of hypersensitivity to levetiracetam or any other ingredients in the study drug or placebo.
- Significant neurological disease, including but not limited to:
- Any type of cognitive impairment
- History of transient ischemic attacks within 12 months of Screening
- History of seizures within 12 months of Screening
- Epilepsy
- Parkinson's disease
- Stroke (aside from subcortical lacunar infarcts)
- Multiple sclerosis
- Huntington's disease
- Normal pressure hydrocephalus
- Brain tumour (aside from benign tumours without mass effect, which are to be judged on a case-by-case basis)
- Subdural hematoma
- History of traumatic brain injury with persistent neurological deficits
- Known structural brain abnormalities
- Significant or unstable psychiatric disease, including but not limited to:
- Schizophrenia
- Bipolar disorder
- Major depression which is not controlled in the opinion of the investigator
- Score ≥10 on the Geriatric Depression Scale (GDS) at Screening
- Presence of active suicidal ideation within the last 3 months as indicated by "yes" response to Question 4 or 5 on the Suicidal Ideation portion of the C-SSRS at Screening
- Answered "yes" to any of the suicide-related behaviours within the last 3 months on the Suicidal Behavior portion of the C-SSRS
- Hospitalized or treated for suicidal behavior within 5 years of Screening
- Psychotic features, agitation, or behavioral problems within the last 3 months that could lead to difficulty complying with the protocol in the opinion of the investigator
- Score ≥9 on the Mild Behavioural Impairment Checklist (MBI-C) at Screening
- Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening).
- Significant or unstable systemic illness or medical condition that would in the investigator's judgment make the participant unsuitable for inclusion in the study, including but not limited to:
- History of malignancy within 3 years of screening (except of basal or squamous cell carcinoma of the skin)
- Moderate-severe chronic kidney disease, chronic obstructive pulmonary disease, or congestive heart failure
- Any of the following findings on a current (completed during screening) or previous brain MRI/CT scan:
- Severe white matter disease (Fazekas score66 = 3)
- Stroke involving a major vascular territory
- Subcortical lacunar infarcts \>1.5cm in diameter
- Encephalomalacia
- Vascular malformations that are at high risk of hemorrhage
- Infective lesions
- Space-occupying lesions
- Any other abnormality that would in the opinion of the investigator make the participant unsuitable for participation in the study
- Any contraindications to MRI or MEG (e.g., pacemaker, ferromagnetic metal implants, claustrophobia).
- Treatment with the following medications at time of screening or while in the study:
- Anticonvulsant medications
- Methotrexate
- Anticholinergic agents and medications with anticholinergic properties
- Creatinine clearance \<50ml/min/1.73m2 on screening bloodwork.
- QTc interval \>470 msec (males) or \>480 msec (females) on screening ECG.
- Clinically significant abnormal results on screening bloodwork that would in the opinion of the investigator make the participant unsuitable for inclusion in the study.
Interventions
Levetiracetam 125mg capsules BID for 28-35 days
Placebo capsules BID for 28-35 days
Locations(2)
View Full Details on ClinicalTrials.gov
For the most up-to-date information, visit the official listing.
NCT07477431