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Network-Level Mechanisms for Preclinical Alzheimer's Disease Development

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ClinicalTrials.gov Identifier: NCT03461861
Recruitment Status : Recruiting
First Posted : March 12, 2018
Last Update Posted : May 13, 2019
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Shi-Jiang Li, PhD, Medical College of Wisconsin

Brief Summary:
The purpose of this project is to test the hypothesis that AGB101 low dose levetiracetam extended release formulation can reduce abnormal hyperfunctional activity in the hippocampus in normal, healthy adults who are APOE 4 carriers. The investigators will compare the results to normal, healthy adults who are APOE 4 non-carriers.

Condition or disease Intervention/treatment Phase
APOE 4 Drug: AGB101 220 mg Other: Placebo Phase 2

Detailed Description:

In this study the investigators want to find out whether the use of a perturbation, such as AGB101 low dose of levetiracetam extended release formulation, in healthy adults with the Apolipoprotein e4 gene (APOE 4) can reduce abnormal hippocampal network activity. The investigators also want to study whether this low dose of LEV can improve memory function.

Generic levetiracetam is a type of drug called an anti-epileptic or anti-seizure medication. It is FDA approved worldwide for adults and children as young as one month with seizures. It is a generic drug used in long-term epilepsy treatment. It is relatively safe and has an acceptable side-effect profile.

AGB101 has been developed as a novel extended release formulation of low dose levetiracetam (below clinically marketed doses for epilepsy) for slowing the progression of amnestic mild cognitive impairment.

It is known that age and the APOE 4 gene are important risk factors for late-onset Alzheimer's disease. Further studies have shown that cognitively normal, older adults with the APOE 4 gene have more hyperfunctional brain network activity, increased alpha beta accumulation, decreased memory function, and decreased brain volume, which is consistent with Alzheimer's disease patterns.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: This is a randomized, double-blind, placebo-controlled crossover study in which a low dose of AGB101 (220mg QD) or placebo will be administered to 50 healthy 55-75-year-old subjects (comprising 25 APOE 4 carriers and 25 noncarriers), with the order of treatments counterbalanced in a within-subject crossover design.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Network-Level Mechanisms for Preclinical Alzheimer's Disease Development
Actual Study Start Date : April 11, 2019
Estimated Primary Completion Date : March 31, 2020
Estimated Study Completion Date : March 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: AGB101 220 mg, then Placebo
AGB101 220 mg/day capsule, once daily dosing for 2 weeks. After a 4 week washout, to be followed by Placebo, given as a capsule, once daily dosing for 2 weeks.
Drug: AGB101 220 mg
AGB101 oral dose of 220 mg/day capsule, given as once-daily dosing.

Other: Placebo
Placebo, oral capsule given once-daily.

Experimental: Placebo, then AGB101 220 mg
Placebo, given as a capsule, once daily for 2 weeks. After a 4 week washout, to be followed by AGB101 220 mg/day capsule, once daily dosing for 2 weeks.
Drug: AGB101 220 mg
AGB101 oral dose of 220 mg/day capsule, given as once-daily dosing.

Other: Placebo
Placebo, oral capsule given once-daily.




Primary Outcome Measures :
  1. Functional connectivity strengths of neural networks [ Time Frame: At the baseline and 2 weeks after treatment ]
    The seed-based functional connectivity strengths of the hippocampus network and the default mode network will be employed to measure the changes before and after the AGB101 perturbation. The functional connectivity strengths will be measured with the median of the Pearson cross-correlation coefficients over entire brain regions and the maps of the functional connectivity strengths.


Secondary Outcome Measures :
  1. Rey Auditory Verbal Learning Test (AVLT) [ Time Frame: At the baseline and 2 weeks after treatment ]
    AVLT will be employed to measure the episodic memory changes before and after AGB101 treatment. The AVLT score will be recorded and later integrated with LMT score to provide the composite EM score. The EM score for a subject is a standardized z-score converted from AVLT and LMT scores.

  2. Logical memory test (LMT) [ Time Frame: At the baseline and 2 weeks after treatment ]
    LMT will be employed to measure the episodic memory changes before and after AGB101 treatment. The LMT score will be recorded and later integrated with AVLT score to provide the composite EM score. The EM score for a subject is a standardized z-score converted from AVLT and LMT scores.



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Ages Eligible for Study:   55 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Fluent in English
  • At least eight (8) years of education
  • Geriatric Depression Scale (GDS) (62) score < 6
  • Hachinski Ischemic Score ≤ 4
  • Normal general cognitive function as well as 1) normal memory function, documented by MOCA score of 23 or greater, and a RBANS Delayed Memory Index score of 85 or greater.

Exclusion Criteria:

  • Neurological disease, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or a history of significant head trauma or known structural brain abnormalities
  • Major psychiatric disease or chronic unstable medical conditions
  • History of drug abuse
  • History of alcohol abuse (4 or greater drinks per day on average)
  • Unable to complete MRI scans (no Pacemaker/Defibrillator)
  • Known clinically significant abnormalities in B12 or thyroid function tests
  • End Stage Renal Disease (ESRD)
  • Hemodialysis (HD)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03461861


Contacts
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Contact: Rebecca Rehborg 414-955-0667 rrehborg@mcw.edu
Contact: Barbara Blaney 414-955-0609 bblaney@mcw.edu

Locations
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United States, Wisconsin
Froedtert & The Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Rebecca Rehborg    414-955-0667    rrehborg@mcw.edu   
Contact: Barbara Blaney    414-955-0609    bblaney@mcw.edu   
Principal Investigator: Shi-Jiang Li, PhD         
Sub-Investigator: Malgorzata Franczak, MD         
Sub-Investigator: Elias Granadillo Deluque, MD         
Sub-Investigator: Piero Antuono, MD         
Sponsors and Collaborators
Medical College of Wisconsin
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Shi-Jiang Li, PhD The Medical College of Wisconsin

Publications:

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Responsible Party: Shi-Jiang Li, PhD, Professor of Biophysics, Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT03461861     History of Changes
Other Study ID Numbers: PRO00031146
R21AG056882-01 ( U.S. NIH Grant/Contract )
First Posted: March 12, 2018    Key Record Dates
Last Update Posted: May 13, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Shi-Jiang Li, PhD, Medical College of Wisconsin:
Healthy
Adult
Normal Memory
APOE 4
Brain
Magnetic Resonance Imaging
MRI
Alzheimer's disease
Hippocampus
Genetic testing
Dementia
AGB101

Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders