Hippocampal HyperactivationPhase 2ALEVIATE-2NCT07477431
Levetiracetam for Persons at Risk for Alzheimer's Disease
A Phase 2 study testing Levetiracetam (LEV) in people with Hippocampal Hyperactivation and Prodromal Alzheimer Disease, run by Sunnybrook Health Sciences Centre at 2 sites in Canada.
Trial summary
The goal of this clinical trial is to investigate whether very small doses of a drug called levetiracetam (LEV) may reduce elevated brain signaling in individuals who are at an increased risk for developing Alzheimer's Disease (AD). Read more about this study
- Who is it for?
- Ages 55 to 85 years
- Conditions the study is for
- Hippocampal Hyperactivation, Prodromal Alzheimer Disease
- What is being tested?
- Levetiracetam (LEV)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 2 sitesCanada
- Study dates
- 23 Oct 2025to Feb 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 55 to 85 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Willing to undergo all study procedures and has signed the informed consent form
- Within normal limits on the Montreal Cognitive Assessment (MoCA) at Screening
- Age 55-85
- 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
- Increased risk of Alzheimer's disease, as indicated by one or more of the following:
Show all 10Show fewer
- Participant has subjective cognitive complaints AND a family history of Alzheimer's disease (or of dementia suggestive of possible or probable Alzheimer's disease) in a first-degree relative; and/or
- Participant is known to be amyloid or tau positive; and/or
- Participant is known to be an APOE e4/e4 homozygote
- Hippocampal hyperactivation, defined as activation >1.5 MAD above the median, during the pattern separation task (PST) on BOLD fMRI.
Who cannot join
- 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
Show all 44Show fewer
- 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
- 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 (unless taken for a different indication than seizures)
- Methotrexate
- eGFR <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.
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Canada2 sites, 2 recruiting
- Recruiting
Sunnybrook Health Sciences Centre
Toronto, Ontario, M4N 3M5
Felicia Kwan, 416-480-6100 ext. 63385, felicia.kwan@sri.utoronto.ca
Jenieshaa Uthayakumar, 416-480-6100 ext. 685281, jenieshaa.uthayakumar@sri.utoronto.ca
- Recruiting
Toronto Western Hospital
Toronto, Ontario, M5T 2S8
Lily Jiang, 647-994-2112, tianrui.jiang@uhn.ca
Mary Pat McAndrews, PhD
About this study
Official title: 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
The goal of this clinical trial is to investigate whether very small doses of a drug called levetiracetam (LEV) may reduce elevated brain signaling in individuals who are at an increased risk for developing Alzheimer's Disease (AD). The study is looking for people who are currently performing within normal limits on memory testing but who have one or more of the following risk factors for developing AD:
- People who feel like their memory is getting worse and who have a parent or sibling with Alzheimer's disease (dementia)
- People with two copies of the APOE E4 gene
- People who have tested positive for a biomarker of AD (e.g., blood p-tau test, brain amyloid PET scan)
Read more
During the screening period, a functional MRI (fMRI) scan of the brain will identify those participants who have the increased 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.
Read the detailed description
Changes in the brain associated with AD begin years before people start showing symptoms. One of these early changes involves an increase in brain signaling activity (hyperactivity) in the hippocampus (the memory area of the brain). This increase is similar to what is seen in epilepsy but on a smaller, unrecognizable scale.
Studies have found that small doses of an antiepileptic medication called levetiracetam (LEV) reduce this hippocampal hyperactivity in people with amnestic Mild Cognitive Impairment, the phase of AD when people first begin showing memory symptoms. The study aims to determine if this hyperactivity can be detected and treated even earlier, before individuals start showing any symptoms.
Participation begins with 3 screening visits that are a combination of questionnaires, cognitive tests, brain imaging, and collection of information on participant medical history, medications, and demographics.
If participant eligibility is confirmed after the screening visits, they are randomly enrolled in one of the study arms. There are two treatment periods, one period where participants receive the study drug and one period where they receive a placebo (a substance that looks like the study drug but does not have any active or medicinal ingredients). Half of the study participants will receive LEV first, then placebo, while the other half will receive placebo first, then LEV. This crossover study design allows all eligible enrolled individuals to receive the study drug at some point. The study is double-blinded, meaning that the participants and study staff will not be aware of when participants are receiving the drug.
From the day of consent, those participants who pass screening are expected to be in the study for approximately 6 months. Study procedures include cognitive testing, questionnaires, MRI Scans, EEG-MEG scans, physical and neurological exams, ECGs, blood sample collection for APOE genetic testing \& blood biomarker testing, optional blood sample collection for biobanking, and an amyloid PET scan.
This study is only being carried out in Toronto, Canada. Participants will be recruited at several Toronto sites, but most of the study visits (for all participants) will take place at Toronto Western Hospital, part of the University Health Network.
- Being tested
- Levetiracetam (LEV), Placebo
- Keywords
- EEG-MEG, fMRI, Pattern Separation Task, PST, Levetiracetam, Crossover Design, AD, Prodromal AD, Hippocampal hyperactivation, Subjective cognitive complaints, Alzheimer Disease
- Medical subject headings
- Alzheimer Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Levetiracetam (LEV)Drug
Levetiracetam 125mg capsules BID for 28-35 days
PlaceboOther
Placebo capsules BID for 28-35 days
| Study group | Role | What they receive |
|---|---|---|
| Arm 1: Drug then Placebo | Other | Participants randomized to Arm 1 will receive LEV in Treatment Phase I and placebo in Treatment Phase II. Receives: Drug: Levetiracetam (LEV); Other: Placebo |
| Arm 2: Placebo then Drug | Other | Participants randomized to Arm 2 will receive placebo in Treatment Phase I and LEV in Treatment Phase II. Receives: Drug: Levetiracetam (LEV); Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Level of fMRI activity in the hippocampus and entorhinal cortex during a pattern separation task (PST), as a function of LEV vs placebo
Measured: Before and after each treatment phase (Screening/Baseline, Week 4, Week 8, Week 12)
Secondary outcomes (4)
Behavioural performance on the PST as a function of LEV vs placebo
Evaluation of participant's ability to correctly discriminate between presented stimuli as old, new, or similar. The lure discrimination index (LDI) is based on the proportion of the presented lures correctly called similar and the proportion of lures incorrectly called old.
Measured: Before and after each treatment phase (Screening/Baseline, Week 4, Week 8, Week 12)
Frequency of epileptiform discharges on EEG as a function of LEV vs placebo
Resting-state EEG
Measured: Before and after each treatment phase (Screening/Baseline, Week 4, Week 8, Week 12)
Power spectrum analysis for hippocampus in resting-state MEG as a function of LEV vs placebo
Power in specific frequency bands (theta, alpha, beta) will be analyzed.
Measured: Before and after each treatment phase (Screening/Baseline, Week 4, Week 8, Week 12)
Changes in hippocampal signal in MEG during repetition suppression task as a function of LEV vs placebo
Beta band power (desynchronization) will be measured with novel versus repeated presentation of images in the repetition suppression task.
Measured: Before and after each treatment phase (Screening/Baseline, Week 4, Week 8, Week 12)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2026
- Study start23 Oct 2025
- Primary completionDec 2027 (estimated)
- Study completionFeb 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hippocampal HyperactivationStudies of the same condition, open and under way.
- More trials run by Sunnybrook Health Sciences CentreThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sunnybrook Health Sciences Centre
- Sponsor type
- University, hospital or other
- Collaborators
- University Health Network, Toronto, Weston Brain Institute
- Responsible party
- Sponsor
- Investigators
- Sandra E. Black, MD, FRCP(C), Principal investigator, Sunnybrook Health Sciences Centre, University of Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07477431
- Sponsor's protocol ID
- 4811
- Acronym
- ALEVIATE-2
- Status last verified
- Nov 2025
- First submitted
- 18 Nov 2025
- Last updated
- 29 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: All collected IPD.
Study at a glance
From the registry record, last updated by the sponsor on 29 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT07477431
- Acronym / sponsor ID
- ALEVIATE-2 / 4811
- Keywords
- EEG-MEG, fMRI, Pattern Separation Task, PST, Levetiracetam, Crossover Design, AD, Prodromal AD
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Sunnybrook Health Sciences CentreUniversity, hospital or other
- Collaborators
- University Health Network, Toronto, Weston Brain Institute
- Study start
- 23 Oct 2025 (actual)
- Primary completion
- Dec 2027 (estimated)
- Study completion
- Feb 2028 (estimated)
- First posted
- 17 Mar 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this clinical trial is to investigate whether very small doses of a drug called levetiracetam (LEV) may reduce elevated brain signaling in individuals who are at an increased risk for developing Alzheimer's Disease (AD). The study is looking for people who are currently performing within normal limits on memory testing but who have one or more of the following risk factors for developing AD:
- People who feel like their memory is getting worse and who have a parent or sibling with Alzheimer's disease (dementia)
- People with two copies of the APOE E4 gene
- People who have tested positive for a biomarker of AD (e.g., blood p-tau test, brain amyloid PET scan)
During the screening period, a functional MRI (fMRI) scan of the brain will identify those participants who have the increased 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.
Detailed description
Changes in the brain associated with AD begin years before people start showing symptoms. One of these early changes involves an increase in brain signaling activity (hyperactivity) in the hippocampus (the memory area of the brain). This increase is similar to what is seen in epilepsy but on a smaller, unrecognizable scale.
Studies have found that small doses of an antiepileptic medication called levetiracetam (LEV) reduce this hippocampal hyperactivity in people with amnestic Mild Cognitive Impairment, the phase of AD when people first begin showing memory symptoms. The study aims to determine if this hyperactivity can be detected and treated even earlier, before individuals start showing any symptoms.
Participation begins with 3 screening visits that are a combination of questionnaires, cognitive tests, brain imaging, and collection of information on participant medical history, medications, and demographics.
If participant eligibility is confirmed after the screening visits, they are randomly enrolled in one of the study arms. There are two treatment periods, one period where participants receive the study drug and one period where they receive a placebo (a substance that looks like the study drug but does not have any active or medicinal ingredients). Half of the study participants will receive LEV first, then placebo, while the other half will receive placebo first, then LEV. This crossover study design allows all eligible enrolled individuals to receive the study drug at some point. The study is double-blinded, meaning that the participants and study staff will not be aware of when participants are receiving the drug.
From the day of consent, those participants who pass screening are expected to be in the study for approximately 6 months. Study procedures include cognitive testing, questionnaires, MRI Scans, EEG-MEG scans, physical and neurological exams, ECGs, blood sample collection for APOE genetic testing \& blood biomarker testing, optional blood sample collection for biobanking, and an amyloid PET scan.
This study is only being carried out in Toronto, Canada. Participants will be recruited at several Toronto sites, but most of the study visits (for all participants) will take place at Toronto Western Hospital, part of the University Health Network.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm 1: Drug then Placebo | Other | Drug: Levetiracetam (LEV), Other: PlaceboParticipants randomized to Arm 1 will receive LEV in Treatment Phase I and placebo in Treatment Phase II. |
| Arm 2: Placebo then Drug | Other | Drug: Levetiracetam (LEV), Other: PlaceboParticipants randomized to Arm 2 will receive placebo in Treatment Phase I and LEV in Treatment Phase II. |
Who may qualify
- Ages
- 55 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Willing to undergo all study procedures and has signed the informed consent form
- Within normal limits on the Montreal Cognitive Assessment (MoCA) at Screening
- Age 55-85
- 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
Key exclusion criteria (44 listed)
- History of hypersensitivity to levetiracetam or any other ingredients in the study drug or placebo.
- Significant neurological disease, including but not limited to:
- Significant or unstable psychiatric disease, including but not limited to:
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Levetiracetam (LEV)Levetiracetam 125mg capsules BID for 28-35 days | Drug | Arm 1: Drug then Placebo, Arm 2: Placebo then Drug |
| PlaceboPlacebo capsules BID for 28-35 days | Other | Arm 1: Drug then Placebo, Arm 2: Placebo then Drug |
Primary outcome
Level of fMRI activity in the hippocampus and entorhinal cortex during a pattern separation task (PST), as a function of LEV vs placebo
Time frame: Before and after each treatment phase (Screening/Baseline, Week 4, Week 8, Week 12)
4 secondary outcomes
Behavioural performance on the PST as a function of LEV vs placebo
Time frame: Before and after each treatment phase (Screening/Baseline, Week 4, Week 8, Week 12)
Frequency of epileptiform discharges on EEG as a function of LEV vs placebo
Time frame: Before and after each treatment phase (Screening/Baseline, Week 4, Week 8, Week 12)
Power spectrum analysis for hippocampus in resting-state MEG as a function of LEV vs placebo
Time frame: Before and after each treatment phase (Screening/Baseline, Week 4, Week 8, Week 12)
Changes in hippocampal signal in MEG during repetition suppression task as a function of LEV vs placebo
Time frame: Before and after each treatment phase (Screening/Baseline, Week 4, Week 8, Week 12)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jul 2026.
- Individual participant dataSharing planned: Yes. All collected IPD.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Sandra E. Black, MD, FRCP(C) principal investigator
Sunnybrook Health Sciences Centre, University of Toronto
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Levetiracetam (LEV) in people with Hippocampal Hyperactivation and Prodromal Alzheimer Disease, run by Sunnybrook Health Sciences Centre at 2 sites in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 44 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 29 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact ALEVIATE-2 Project Manager (416-480-6100 ext. 63004, aleviate-2@sunnybrook.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Level of fMRI activity in the hippocampus and entorhinal cortex during a pattern separation task (PST), as a function of LEV vs placebo (time frame: Before and after each treatment phase (Screening/Baseline, Week 4, Week 8, Week 12)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jul 2026.