Study of AGB101 in Mild Cognitive Impairment Due to Alzheimer's Disease

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the efficacy of AGB101 on slowing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score as compared with placebo in participants with mild cognitive impairment due to Alzheimer's Disease (MCI due to AD) also known as prodromal AD. Participants will be randomized to receive placebo or AGB101 (220 mg), once daily for 78 weeks. Secondary objectives are to assess the effect of AGB101 compared with placebo on clinical progression as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-cog14), Mini-Mental State Examination (MMSE) and Functional Activities Questionnaire (FAQ).

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of AGB101 (Low-dose Levetiracetam, 220 mg, Extended Release Tablet) on Slowing Progression of Mild Cognitive Impairment Due to Alzheimer's Disease.

Conditions
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Mild Cognitive Impairment, Prodromal Alzheimer's Disease

Intervention / Treatment
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* Drug: AGB101
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects between 55 and 85 years old (inclusive) in good general health: Willing and able to consent and participate for the duration of the study. Have eighth-grade education or good work history sufficient to exclude mental retardation. Have visual and auditory acuity adequate for neuropsychological testing. Have proficient fluency of the native local language to participate in all the neuropsychological test assessments. Have a study partner who has sufficient contact with the subject to be able to provide assessment of memory changes, who can accompany the subject to the screening and all major clinic visits for the duration of those visits, and who is able to provide an independent evaluation of the subject's functioning. Have MCI due to AD as defined by all of the following criteria and consistent with the National Institute on Aging-Alzheimer's Association criteria: MMSE scores between 24 and 30 (inclusive; exceptions may be made for subjects with < 8 years of education at the discretion of the sponsor). A memory complaint reported by the subject or his/her study partner. Evidence of lower memory performance based on the delayed recall portion of the ISLT. A Clinical Dementia Rating (CDR) score of 0.5 with a memory box score of ≥ 0.5. Essentially preserved activities of daily living. Cognitive decline not primarily caused by vascular, traumatic, or medical problems (alternative causes of cognitive decline are ruled out). A screening blood-based biomarker consistent with amyloid positivity Have an apolipoprotein E genotype that does not include one or more E4 alleles Permitted medications: With potential pro-cognitive effects, such cholinesterase inhibitors and memantine, must be at a stable dose for ≥ 3 months prior to screening and expected to remain stable throughout the study; estrogen replacement therapy, Ginkgo biloba, and vitamin E must be at a stable dose for ≥ 4 weeks prior to screening and expected to remain stable throughout the study. Other psychotropics, such as antidepressants and antipsychotics, must be at a stable dose for ≥ 3 months prior to screening and expected to remain stable throughout the study. Willing and able to undergo an MRI scan (3 Tesla) with no contraindications to the MRI or documented evidence of an MRI scan. Willing to allow collection of blood for blood-based biomarkers and genome-wide association study (GWAS), apolipoprotein E (ApoE) genotyping, and DNA banking. Exclusion Criteria: Carrying one or more copies of the apolipoprotein E4 (ApoE4) allele. Use of anticonvulsant medications or excluded psychotropic medications within 3 months prior to the baseline visit. Participation in a therapeutic clinical study for any medical or psychiatric indications within 3 months (6 months for biologics) of the screening visit, or at any time during the study. Subjects must understand that they may only enroll in this clinical study once; they may not enroll in any other clinical study while participating in the current study, and they 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 3 months (6 months for biologics) prior to screening. History of hypersensitivity or lack of tolerability to AGB101 (levetiracetam). Severe renal impairment (creatinine clearance of < 30 mL/minute) or undergoing hemodialysis. Any significant neurological disease other than suspected incipient AD, such as Parkinson'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. If no documented MRI scan, 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. Diagnosis of bipolar disorder, or major depression within the past 3 years, as described in the Diagnostic and Statistical Manual of Mental Disorders, 5th Ed (DSM-5). Psychotic features, agitation, or behavioral problems within the last 3 months that could lead to difficulty complying with the protocol. Subjects must not have a major depressive disorder or other types of depression that could confound diagnosis of MCI due to AD, or clinical assessments, in the opinion of the investigator. The Geriatric Depression Scale (long form score > 9 suggests depression) results should be reviewed by the investigator to assist in this determination. Modified Hachinski Ischemic Scale (HIS) score > 4. History of schizophrenia (DSM-5 criteria). History of alcohol or substance abuse or dependence within the past 3 years (DSM-5 criteria). Any significant systemic illness or unstable medical condition that could lead to difficulty in complying with the protocol requirements. Patients with a history of cancer with a high risk of recurrence and preventing completion of the trial. 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. Clinically significant abnormalities in B12 or thyroid function test that might interfere with the study. A low B12 (below normative range for elderly) is exclusionary, unless follow-up labs (homocysteine and methylmalonic acid) indicate that it is not physiologically significant. If the B12 deficiency is treated, subjects may become eligible to participate in the study. Residence in a skilled nursing facility. Individuals in independent living communities, assisted living facilities, residential care facilities, or continuing care communities are eligible provided they engage in a sufficient spectrum of activity to permit assessment of all 6 domains contributing to the Clinical Dementia Rating-Sum of Boxes (CDR-SB). Individuals in these facilities must also have a study partner who has the ability to observe the subject during the study and can participate in clinical evaluations. Any use of excluded medications (eg, antiepileptics, certain antidepressants or antipsychotics, antihistamines with anticholinergic properties, opiates). Participation in clinical studies using the ISLT, BPS-O task, or the trail making test (A, B) within 1 month of screening.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Oral Tablet<br>Matching placebo to AGB101 tablet once daily, taken orally, for 78 weeks | Drug: Placebo<br>* Placebo oral tablet<br>|
| Experimental: AGB101 220 mg tablet<br>Single 220 mg AGB101 tablet once daily, taken orally, for 78 weeks. | Drug: AGB101<br>* low-dose levetiracetam, 220 mg, extended release tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CDR-SB | Change in CDR-SB score from baseline | 78 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ADAS-cog14 | Change in ADAS-cog14 score from baseline | 78 weeks | 
| FAQ | Change in FAQ score from baseline | 78 weeks | 
| MMSE | Change in MMSE score from baseline | 78 weeks |