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

University of Pennsylvania1 site in 1 country20 target enrollmentJanuary 2013

ConditionsAlzheimer's Disease Vascular Dementia Dementia Memory Impairment

InterventionsMetformin Placebos

DrugsMetformin Placebos

Overview

Phase: Phase 2
Intervention: Metformin
Conditions: Alzheimer's Disease
Sponsor: University of Pennsylvania
Enrollment: 20
Locations: 1
Primary Endpoint: Word List Memory Total - ADAS-cog
Status: Completed
Last Updated: 8 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

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.

Registry

clinicaltrials.gov

Start Date

January 2013

End Date

April 2017

Last Updated

8 years ago

Study Type

Interventional

Study Design

Crossover

Sex

All

Investigators

Sponsor

University of Pennsylvania

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•• Ages 55-
•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

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

Arms & Interventions

Metformin, Then Placebo

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.

Intervention: Metformin

Metformin, Then Placebo

Intervention: Placebos

Placebo, Then Metformin

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.

Intervention: Metformin