Benfotiamine in Alzheimer's Disease: A Pilot Study
Condition: Alzheimer's Disease
MeSH terms: Alzheimer Disease
Intervention: Benfotiamine
Intervention description: To test whether increasing brain thiamine by administering 600 mg per day (300 mg/morning and 300 mg/evening) of benfotiamine for one year can slow cognitive decline in these patients as measured with the Alzheimer's Disease Assessment Scale (ADAS-COG).
To determine whether increasing brain thiamine availability with 600 mg (300 mg/morning and 300 mg/evening) per day of benfotiamine for one year can slow the decline in brain glucose metabolism in these patients as measured with Fluorodeoxyglucose Positron Emission Tomography(FGPET) in the posterior cingulate.
Intervention MeSH terms: Benphothiamine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 71.0
Sex: All
Minimum age: 60 Years
Healthy volunteers: No
Keywords: Alzheimer's disease; benfotiamine; glucose; Amyloid

Summary:

      General Investigational Plan

      Study Objectives The goal of this proposal is to determine whether enhancing brain glucose
      utilization minimizes cognitive decline in patients with Amnestic Mild Cognitive Impairment
      (AMCI) or mild Alzheimer's disease (AD) dementia. We propose a proof of concept double-blind,
      placebo controlled pilot study to determine if increasing brain thiamine availability with
      the investigational new drug benfotiamine, will minimize the decline in glucose utilization
      and slow the cognitive decline associated with the progression AMCI/AD dementia.

      Specifically, our objectives are two-fold:

        -  To test whether increasing brain thiamine by administering 600 mg per day (300
           mg/morning and 300 mg/evening) of benfotiamine for one year can slow cognitive decline
           in these patients as measured with the Alzheimer's Disease Assessment Scale (ADAS-COG).

        -  To determine whether increasing brain thiamine availability with 600 mg (300 mg/morning
           and 300 mg/evening) per day of benfotiamine for one year can slow the decline in brain
           glucose metabolism in these patients as measured with Fluorodeoxyglucose Positron
           Emission Tomography(FGPET) in the posterior cingulate.

      We will also carry out the following secondary objectives:

        -  Assess if there are differences in secondary clinical outcome measures (NPI, ADCSADL,
           CDR, Buschke) between benfotiamine and placebo groups and whether specific cognitive
           domains (ie: activities of daily living, learning and memory verbal memory, behavioral,
           etc.) are driving these changes.

        -  Compare ADAS-COG change scores in the benfotiamine and placebo groups within and between
           strata that were defined by initial cognitive impairment, to attempt to identified the
           population that most benefits from benfotiamine.

        -  Compare changes in glucose utilization between the benfotiamine and placebo groups in
           secondary Regions of Interest (ROIs) including the hippocampus, prefrontal regions and
           entorhinal cortex.

        -  Compare changes in whole brain glucose utilization between the benfotiamine and placebo
           groups using statistical parametric mapping (SPM).

        -  Assess the correlation between changes in glucose utilization with changes in ADAS Cog.

        -  Determine if ApoE4 genotype alters the response to benfotiamine.
    

Eligibility criteria:

        Inclusion Criteria:

          -  60 years of age or older

          -  Clinical diagnosis of AMCI by the Peterson criteria or probable AD dementia according
             to the National Institute of Neurological Disorders and stroke and the Alzheimer's
             Disease related Disorders Association (NINCDS/ADRDA)

          -  MMSE score > or equal to 21

          -  CDR score > or equal to 0.5 and < or equal to1

          -  Cornell Scale for Depression in Dementia(CSDD) score <10.

          -  Ambulatory or ambulatory with aide

          -  Have a caregiver willing to accompany the patient to each visit, accept responsibility
             for supervising treatment and provided input to clinical outcome assessments

          -  Reside at home

          -  Speak English

          -  Amyloid positive PET-scan

          -  If they are on AD medications they must be stable on AD medications for at least three
             months prior to baseline

          -  Subjects ore willing/able to provide informed consent.

        Exclusion Criteria:

          -  Patients with significant neurological disorder other than AD including hypoxia,
             stroke, traumatic brain injury

          -  A current psychiatric disorder according the DSM-IV diagnosis of major depression
             unless successfully treated on a stable dose of an antidepressant for at least 4 weeks
             and continues on stable dose throughout the study

          -  Any other DSM-IV Axis l diagnosis including other primary neurodegenerative dementia
             schizophrenia or bipolar depression

          -  A current diagnosis of uncontrolled diabetes mellitus (glucose values > 200 mg/ml).

          -  Patients with uncontrolled diabetes will be excluded because high glucose will alter
             the FDG-PET studies. The clinic that does PET (Columbia University Medical Center)
             excludes patients if glucose values exceed 200 mg/ml.

          -  A current diagnosis of active, uncontrolled seizure disorder

          -  A current diagnosis of probable or possible vascular dementia according to NINDS-AIREN

          -  An investigational drug during the previous 4 weeks

          -  A current diagnosis of severe unstable cardiovascular disease

          -  A current diagnosis of acute severe, or unstable asthmatic condition (e.g., severe
             chronic obstructive pulmonary disease (COPD),

          -  A current diagnosis of cardiac, renal or hepatic disease

          -  History of alcoholism, current or within past 5 years

          -  A disability that may prevent the patient from completing all study requirements
             (e.g., blindness, deafness, severe language difficulty)

          -  A1C less than or equal to 8

          -  Current diagnosis of cancer/active treatments