Low-dose levetiracetam for people at increased risk of 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

This study will try short courses of low-dose levetiracetam to see if it reduces abnormal hippocampal brain activity in people who have memory complaints and a first-degree family history of Alzheimer's disease.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 40 (estimated)
• Ages: 55 Years to 85 Years
• Sex: All
• Sponsor: Sunnybrook Health Sciences Centre (Academic / other)
• Drugs / interventions: Methotrexate
• Locations: 2 sites (Toronto, Ontario and 1 other locations)
• Trial ID: NCT07477431 on ClinicalTrials.gov

What this trial studies

Participants with a parent or sibling who had Alzheimer's and with subjective memory complaints but normal cognitive testing are screened with questionnaires, cognitive tests, and brain imaging including fMRI to identify hippocampal hyperactivation. Eligible participants are randomly assigned in a double-blind crossover design to receive four weeks of low-dose levetiracetam and four weeks of matching placebo in random order, with cognitive testing, genetic testing, and brain imaging (including tasks such as pattern separation and EEG/MEG where used) before and after each treatment period. The study is a pilot Phase 2 trial conducted at Toronto-area centers and is designed to detect whether the drug can normalize early abnormal hippocampal signaling prior to symptomatic Alzheimer’s disease. Safety, tolerability, and short-term effects on cognition and brain activity are measured.

Who should consider this trial

Good fit: Ideal candidates are adults who have a first-degree relative with Alzheimer's or dementia, report memory complaints but perform within normal limits on cognitive testing, and can undergo MRI and other study procedures.

Not a fit: People without the specific hippocampal hyperactivation on screening fMRI, those with clear cognitive impairment, or those with contraindications to levetiracetam are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the approach could reduce early abnormal hippocampal activity and potentially delay or lower the risk of later memory decline.

How similar studies have performed: Previous small studies in people with amnestic mild cognitive impairment showed that low-dose levetiracetam can reduce hippocampal hyperactivity, but using it earlier in at-risk, asymptomatic individuals is a newer application.

Eligibility criteria

Inclusion Criteria:

* 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:

  1. 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.
  2. 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 Criteria:

* History of hypersensitivity to levetiracetam or any other ingredients in the study drug or placebo.
* Significant neurological disease, including but not limited to:

  1. Any type of cognitive impairment
  2. History of transient ischemic attacks within 12 months of Screening
  3. History of seizures within 12 months of Screening
  4. Epilepsy
  5. Parkinson's disease
  6. Stroke (aside from subcortical lacunar infarcts)
  7. Multiple sclerosis
  8. Huntington's disease
  9. Normal pressure hydrocephalus
  10. Brain tumour (aside from benign tumours without mass effect, which are to be judged on a case-by-case basis)
  11. Subdural hematoma
  12. History of traumatic brain injury with persistent neurological deficits
  13. Known structural brain abnormalities
* Significant or unstable psychiatric disease, including but not limited to:

  1. Schizophrenia
  2. Bipolar disorder
  3. Major depression which is not controlled in the opinion of the investigator
  4. Score ≥10 on the Geriatric Depression Scale (GDS) at Screening
  5. 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
  6. Answered "yes" to any of the suicide-related behaviours within the last 3 months on the Suicidal Behavior portion of the C-SSRS
  7. Hospitalized or treated for suicidal behavior within 5 years of Screening
  8. 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
  9. 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:

  1. History of malignancy within 3 years of screening (except of basal or squamous cell carcinoma of the skin)
  2. 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:

  1. Severe white matter disease (Fazekas score66 = 3)
  2. Stroke involving a major vascular territory
  3. Subcortical lacunar infarcts \>1.5cm in diameter
  4. Encephalomalacia
  5. Vascular malformations that are at high risk of hemorrhage
  6. Infective lesions
  7. Space-occupying lesions
  8. 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:

  1. Anticonvulsant medications
  2. Methotrexate
  3. 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.

Where this trial is running

Toronto, Ontario and 1 other locations

• Sunnybrook Health Sciences Centre — Toronto, Ontario, Canada (Recruiting)
• Toronto Western Hospital — Toronto, Ontario, Canada (Recruiting)

Study contacts

• Principal investigator: Sandra E. Black, MD, FRCP(C) — Sunnybrook Health Sciences Centre, University of Toronto
• Study coordinator: ALEVIATE-2 Project Manager

Conditions Hippocampal Hyperactivation; Prodromal Alzheimer Disease; EEG-MEG; fMRI; Pattern Separation Task; PST; Levetiracetam; Crossover Design