Clinical Trial Evaluating the Efficacy of AGB101 for Reducing Hippocampal Overactivity in Older Adults

Phase 2

Recruiting

• Conditions: Hippocampal Overactivity; Dementia
• Interventions: Drug: AGB101; Drug: Placebo

• Registration Number: NCT06919926
• Lead Sponsor: Johns Hopkins University

Brief Summary

This randomized, crossover, placebo controlled clinical study will assess the efficacy and safety of a slow release form of levetiracetam (AGB101) in the treatment of cognitively normal adults by measuring change in several imaging measures over the course of a two week treatment period.

Detailed Description

In clinical studies, the magnitude of hippocampal over-activity longitudinally predicts subsequent cognitive decline/conversion to dementia, and hippocampal over-activity in subjects with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) is significantly correlated with the extent of neuronal injury affecting AD-specific regions of the brain. A previous study reported a significant correlation between greater hippocampal activation (fMRI) and more pronounced medial temporal lobe (MTL) atrophy (cortical thinning) indicative of AD-related neurodegeneration in subjects with MCI due to AD with a Clinical Dementia Rating (CDR) score of 0.5 selected by Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 criteria. This supports a therapeutic rationale to reduce over-activity in order to slow or prevent neuronal injury.

Modest hippocampal over-activity has also been observed in preclinical (asymptomatic) conditions in older adults. In previous studies, older adults showed increased hippocampal activation compared to young adults in the context of cognitive performance within the normal range for the participant's age. These findings suggest that hippocampal over-activity may be an opportunity for early intervention examining whether treatment of hippocampal over-activity early in the progression confers benefit to older adults at risk for AD dementia. The current study aims to test this hypothesis in cognitively normal subjects between the ages of 50 and 80.

Study Timeline

• Status Verified: 2025-04
• Study First Submitted: 2025-04-02
• Study First Submitted QC: 2025-04-02
• Study First Posted: 2025-04-09
• Study Start: 2025-04-17
• Last Update Submitted: 2025-04-23
• Last Update Posted: 2025-04-27
• Primary Completion: 2027-05
• Study Completion: 2028-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

Not provided

Exclusion Criteria

• Subjects must not meet any of the following exclusion criteria at screening:

  1. Use of anticonvulsant or anticoagulant medications within 1 month prior to the baseline visit.
  2. Participation in a therapeutic clinical study for any medical or psychiatric indications within 1 month of the screening visit, or at any time during the study. Subjects must understand that participants may only enroll in this clinical study once; participants may not enroll in any other clinical study while participating in the current study, and participants may not participate in a clinical study of a drug, biologic, therapeutic device, or medical food, in which the last dose/administration was received within 1 month prior to screening.
  3. History of hypersensitivity or lack of tolerability to AGB101 (levetiracetam).
  4. Severe renal impairment (creatinine clearance of < 30 mL/minute) or undergoing hemodialysis.
  5. Any significant neurological disease such as Parkinson's disease, Alzheimer's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder (lifetime history; infant febrile seizures are not exclusionary), subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits, or known structural brain abnormalities, that in the opinion of the investigator might interfere with the conduct of the study.
  6. Diagnosis of major depression within the last 3 years or prior diagnosis of schizophrenia, bipolar disorder or other psychotic disorder.
  7. Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments, or foreign objects in the eyes, skin, or body that constitute a contraindication to having an MRI scan.
  8. History of alcohol or substance abuse or dependence within the past 3 years (DSM-5 criteria).
  9. Any significant systemic illness or unstable medical condition that could lead to difficulty in complying with the protocol requirements.
  10. Any unstable medical condition that is likely to require new medical or surgical treatment during the course of the study and where such treatments might affect the collection of efficacy data.
  11. Current suicidal ideation.
  12. Female subjects must not be pregnant or lactating.
  13. Any other reason, which in the opinion of the investigator would confound proper interpretation of the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
AGB101 first, then placebo	AGB101	AGB101 (low-dose levetiracetam, 220 mg, extended release tablet) once daily for 2 weeks, washout (4 weeks), then placebo capsule once daily for 2 weeks.
AGB101 first, then placebo	Placebo	AGB101 (low-dose levetiracetam, 220 mg, extended release tablet) once daily for 2 weeks, washout (4 weeks), then placebo capsule once daily for 2 weeks.
placebo first, then AGB101	AGB101	Placebo capsule once daily for 2 weeks, washout (4 weeks), then AGB101 (low-dose levetiracetam, 220 mg, extended release tablet) once daily for 2 weeks.
placebo first, then AGB101	Placebo	Placebo capsule once daily for 2 weeks, washout (4 weeks), then AGB101 (low-dose levetiracetam, 220 mg, extended release tablet) once daily for 2 weeks.

Primary Outcome Measures

Name	Time	Method
Change in hippocampal overactivity as measured by fMRI (functional Magnetic Resonance Imaging)	Week 2, Week 8	The primary efficacy evaluation is confirmation of target engagement demonstrated by reduction in hippocampal overactivity comparing the end of the active treatment period compared to the end of the placebo treatment condition as measured by task-based functional magnetic resonance imaging.

Secondary Outcome Measures

Name	Time	Method
Change in functional connectivity measures as measured by fMRI (functional Magnetic Resonance Imaging)	Week 2, Week 8	Functional connectivity measures comparing the end of the active treatment period to the end of the placebo treatment condition as measured by resting state fMRI (functional Magnetic Resonance Imaging).

Trial Locations

Locations (1)

Johns Hopkins University School of Medicine; 🇺🇸 Baltimore, Maryland, United States