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.

Study Design

This study will be conducted at the Burke Rehabilitation Hospital under an IRB protocol. Wplan to accrue a total of 76 male and/or female patients (> 65 years) with a diagnosis of AMCI/AD dementia that are also amyloid positive by PET scan. Patients will be randomized and blinded to either a benfotiamine or placebo group. Because it is unknown whether there will be differential responses to treatment according to initial cognitive impairment, participants will be stratified according to the median MMSE cut-off score of our historical METS population who are > 65 years old and have an MMSE >21.

In this double-blind study, patients and their caregivers, as well as all physicians, clinicians, coordinators and investigators interacting with the patients, will be unaware of the treatment assignments. Treatment assignments will be available to the safety-monitoring physician, Dr. Michael Reding, who will have no unnecessary subject contact. If necessary, the code will be revealed to Dr. Reding by the pharmacist, Dr. Thomas Grandville.

Each patient will make six visits to the Memory Evaluation and Treatment Service (METS) clinic at Burke Rehabilitation Hospital. Information on medication use, vital signs, outcome measures, compliance and safety/tolerability will be collected at each time point. The screening visit (visit 1) will take place within 30 days prior to baseline visit (visit 2). Informed consent/assent will be obtained from each subject or his/her caregiver prior to conducting any study related procedures. During the screening visit a review of inclusion/exclusion criteria will be completed along with the collection of demographic data, disease history, and information about prior and concomitant medications. A complete medical history, physical examination, neurological examination, including the MMSE, CDR, CSDD and vital signs, will be collected. Blood will be drawn to assess blood glucose Patients that are diagnosed as likely Alzheimer patients that are not hyperglycemic will then have an amyloid PET scan. Only patients with a diagnosis of AD and a positive amyloid scan will be included. Prior to baseline (visit 2), FDGPET studies will be completed for each subject. At the baseline visit (visit 2) blood will be drawn to determine APOE and thiamine (vitamin B1 status). At visits 2-6, information on concomitant medications will be updated, vitals will be taken, medication compliance will be assessed and the following study measures will be administered: Alzheimer's Disease Assessment Scale (ADASCog), Buschke SRT, Neuropsychological Inventory (NPI), Clinical Dementia Rating Scale (CDR) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADLs). The final PET scan will be conducted approximately one week prior to the last visit. In addition to safety assessments at time of each visit, each patient will receive a call from the clinical coordinator at weeks 2 and 6 to assess for adverse events.

The benfotiamine and placebo will be dispensed by the pharmacy at Burke under the direction of Thomas Grandville, D. Pharm. The caregiver will administer the drug since patients with memory problems may forget to take it on a regular basis. In the placebo group, the active compound benfotiamine will be replaced with microcrystalline cellulose. The other components, shape and color are identical to the treatment. Caregivers will be instructed to oversee the administration of the study medication as prescribed to ensure compliance. A record of the number of capsules dispensed, number returned, and actual number taken will be recorded at scheduled visits. Each patient will be treated for 12 months.

The study cognitive measures include: the ADAS-Cog (our primary outcome measure), Alzheimer's Disease Cooperative Study-Activities of Daily Living, Neuropsychiatric Inventory, Clinical Dementia Rating Scale, Buschke Selective Reminding Test (SRT). is a standard diagnostic tool in the assessment of verbal memory. The Biological/Mechanistic Outcome Measures will be FDG-PET Scanning Procedures

Data Analysis Preliminary analyses will be conducted to describe the study sample and to confirm the relationship between level of glucose utilization and severity of cognitive impairment. For continuous variables (eg cognitive function, glucose utilization), we will first examine distributions to assess normality assumptions. We will perform transformations as needed to stabilize the variance, and to reduce skewness and kurtosis. We will use means (sd) and proportions n (%) to characterize the study sample. T-tests and Chi-square, or Wilcoxon rank sum test and Fisher, where appropriate, will be used to assess for any differences in patient characteristics according to treatment group. We will use spearman correlation coefficients and linear regression, unadjusted and adjusted for covariates, to assess the relationship between FDG-PET and MMSE in the whole population as well as in MMSE stratified groups to examine the relationship between initial MMSE score and glucose uptake.

All analyses to test study hypotheses will be run as intention to treat (ITT). Missing observations will be addressed by using the method of last observation carried forward (LOCF).

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

1 subject on the placebo arm was excluded from analysis due to taking benfotiamine from a commercial vendor.

1 year

1 subject on the placebo arm was excluded from analysis due to taking benfotiamine from a commercial vendor.