Effect of Insulin Sensitizer Metformin on AD Biomarkers

Study Overview
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Brief Summary
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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory and other cognitive functions. It is the most common cause of dementia in older adults, affecting approximately 18 million people worldwide, including almost 500,000 in the Philadelphia tri-state area. After age 65, the incidence of AD rises exponentially, doubling every five years. By age 85, almost half of us will have AD. In 2030, as many as 7.7 million Americans could have AD, and by 2050 this number could rise to 11-16 million people. The annual cost of AD in the United States is about $200 billion. AD-related medical complications are among the most common causes of death in the elderly population. Despite these alarming statistics, a cure for AD may not be essential since delaying the onset of AD by just 5 years could have a profound impact on this disorder by reducing the incidence and cost of AD by 50% between now and 2050. AD is difficult to recognize in its earliest stages, in which the principal complaint is typically an increase in episodes of forgetfulness. This stage is now commonly referred to as mild cognitive impairment (MCI). Neuroimaging and CSF biomarkers have demonstrated good accuracy in predicting which MCI patients later convert to AD and which tend to remain stable or revert to more normal cognition. The diagnosis of AD itself is made when increased loss of memory and other cognitive abilities (eg, language, praxis, and executive function) affect daily functioning. As the symptoms of dementia inevitably worsen, patients may become incapable of even basic activities such as feeding and dressing themselves. The disease course often spans more than a decade, creating a vast social and financial burden on society and extracting an immeasurable emotional toll on family members. Clinical and preclinical evidence is accumulating that brain insulin resistance may play a role in the pathogenesis and/or progression of Alzheimer's disease and that ameliorating insulin action in the brain may benefit cognition symptomatically and modify disease pathology.

Official Title
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A Phase II Trial to Study the Effect of Metformin on AD Biomarkers: A Randomized Placebo Controlled Crossover Pilot Study of Metformin Effects on Cognitive, Physiological and Biochemical Biomarkers of MCI and Dementia Due to AD

Conditions
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Alzheimer's Disease, Vascular Dementia, Dementia, Memory Impairment

Intervention / Treatment
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* Drug: Metformin
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Ages 55-80. 2 Sex distribution: male and female Diagnosis of MCI due to AD127 or early dementia due to AD128 with: a) age 55 - 80, b) complaint of cognitive decline, c) abnormal performance on the Logical Memory subtest of the Wechsler Memory Scale, d) MMSE > 21, e) CDR 0.5-1, f) positive topographic (MRI, FDG-PET) or molecular (CSF, amyloid imaging) biomarker consistent with AD, and g) no history of diabetes or other exclusions. Fluent in English or Spanish Education >5, literate, and/or good working history that precludes consideration of mental retardation Visual and auditory acuity sufficient for neuropsychological testing and auditory evoked potential EEG Geriatric Depression Scale < 6 Modified Hachinski Ischemic Score < 4 No major health issues or diseases expected to interfere with the study Willing to complete all baseline assessments and study procedures Stable on all permitted medications for 8 weeks Not pregnant, lactating or of child-bearing potential (women must be >2 years post-menopausal or surgically sterile) No history of diabetes Fasting blood glucose <126 and/or HgbA1c < 6.4 Study partner with frequent contact with patient willing to accompany patient to visits and complete partner study forms No contraindication to metformin Exclusion Criteria: • Any CNS disease other than suspected incipient AD, such as clinical stroke, brain tumor, normal pressure hydrocephalus, brain tumor, multiple sclerosis, significant head trauma with persistent neurological of cognitive deficits or complaints, Parkinson's disease, frontotemporal dementia, or other neurodegenerative diseases Screening/baseline MRI scans with evidence of infarction or other focal lesions in critical memory structures that may be related to cognitive dysfunction Major active psychiatric illness (e.g., depression, bipolar disorder, obsessive compulsive disorder, schizophrenia) within the previous year History of alcohol or other substance abuse or dependence within the past two years Pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body or claustrophobia that would preclude MRI scanning History of past or current diabetes, pancreatic or liver disease, renal disease Any significant systemic illness or unstable medical condition that could affect compliance with study Laboratory abnormalities in B12, TFTs, RPR, Lyme or other common lab parameters that might contribute to cognition or participation in study Coagulopathy or anti-coagulant therapy (such as coumadin) increasing the risk for LP resulting in PT/PTT and INR within 1.5 standard deviations over the upper normal limit. Compromised renal function at screening as determined by creatinine clearance <30mL/min based on Cockcroft-Gault calculation Liver dysfunction at screening as evidenced by alanine transaminase (ALT/SGPT) values > 2X upper limit of normal or aspartate transaminase (AST/SGOT) values > 3X or total bilirubin > 2X. Has received acetylcholinesterase inhibitor and/or memantine and/or any other medicine that affects the central nervous system for less than 4 months or has less than 2 months stable therapy on these treatments by baseline visit. Current use of specified medications with psychoactive properties that deleteriously affect cognition (e.g., certain antidepressants, anticholinergics, anti-histamines, antipsychotics, sedative hypnotics, anxiolytics) Use of investigational agents one month prior to entry and for the duration of the trial Exceptions to these guidelines may be considered on a case-by-case basis at the discretion of the protocol director.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 80 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: Crossover Assignment
Interventional Model Description: This pilot study used a randomized, double-blinded, placebo-controlled 16 week crossover design to examine the effects of metformin on biochemical, neurophysiological, and cognitive biomarkers of AD.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin, Then Placebo<br>Participants first received metformin for 8 weeks, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached. After 8 weeks, subjects were switched to matching placebo for an additional 8 weeks. | Drug: Metformin<br> <br> Drug: Placebos<br> <br> |
| Experimental: Placebo, Then Metformin<br>Participants first received placebo for 8 weeks. After 8 weeks, subjects were switched to metformin, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached. | Drug: Metformin<br> <br> Drug: Placebos<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Word List Memory Total - ADAS-cog | Alzheimer's Disease Assessment Scale- Cognitive Sub scale (ADAS-COG). Three trials of 10 words each (30 words total) | 16 weeks (total) - measured at baseline, week 8 (crossover), and week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trails-B | Standard Trails-B assessment, in which subject is asked to begin at Number 1 and draw a line to Letter A, then to Number 2, then to Letter B, then so forth until he/she reaches the END, without lifting their pencil. They should draw the line as fast as possible, and are timed (in seconds). | 16 weeks- measured at baseline, week 8 (crossover), and week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, Vascular Dementia, Dementia, Memory Impairment