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Effect of Insulin Sensitizer Metformin on AD Biomarkers

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01965756
First Posted: October 18, 2013
Last Update Posted: September 21, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
University of Pennsylvania
  Purpose

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.


Condition Intervention Phase
Alzheimer's Disease Vascular Dementia Dementia Memory Impairment Drug: Metformin Drug: Placebos Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by University of Pennsylvania:

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


Secondary Outcome Measures:
  • Trails-B [ Time Frame: 16 weeks- measured at baseline, week 8 (crossover), and week 16 ]
    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).


Other Outcome Measures:
  • Cerebrospinal Fluid Amyloid Beta Concentration [ Time Frame: baseline and 8 weeks ]
  • Cerebrospinal Fluid Total Tau Concentration [ Time Frame: baseline and 8 weeks ]
  • Cerebrospinal Fluid Phosphorylated Tau Concentration [ Time Frame: baseline and 8 weeks ]

Enrollment: 20
Study Start Date: January 2013
Study Completion Date: April 2017
Primary Completion Date: December 22, 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: Metformin Drug: Placebos
Experimental: 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.
Drug: Metformin Drug: Placebos

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   55 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
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): NCT01965756


Locations
United States, Pennsylvania
University of Pennsylvania, Penn Memory Center
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
University of Pennsylvania
Investigators
Principal Investigator: Steven E Arnold, MD University of Pennsylvania
  More Information

Additional Information:
Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT01965756     History of Changes
Other Study ID Numbers: UPenn-AHAF_A2012116
First Submitted: October 16, 2013
First Posted: October 18, 2013
Results First Submitted: June 6, 2017
Results First Posted: September 21, 2017
Last Update Posted: September 21, 2017
Last Verified: August 2017

Keywords provided by University of Pennsylvania:
Alzheimer's Disease
Vascular Dementia
Dementia
Memory Impairment

Additional relevant MeSH terms:
Dementia
Dementia, Vascular
Alzheimer Disease
Memory Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cerebrovascular Disorders
Intracranial Arteriosclerosis
Intracranial Arterial Diseases
Leukoencephalopathies
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Neurobehavioral Manifestations
Neurologic Manifestations
Signs and Symptoms
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs