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Benfotiamine in Alzheimer's Disease: A Pilot Study (Benfotiamine)

This study is currently recruiting participants.
Verified July 2016 by Gary E. Gibson, Burke Medical Research Institute
Sponsor:
ClinicalTrials.gov Identifier:
NCT02292238
First Posted: November 17, 2014
Last Update Posted: July 19, 2016
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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Burke Rehabilitation Hospital
Columbia University
National Institute on Aging (NIA)
Alzheimer’s Drug Discovery Foundation
Information provided by (Responsible Party):
Gary E. Gibson, Burke Medical Research Institute
  Purpose

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.

Condition Intervention Phase
Alzheimer's Disease Drug: Benfotiamine Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Benfotiamine in Alzheimer's Disease: A Pilot Study

Resource links provided by NLM:


Further study details as provided by Gary E. Gibson, Burke Medical Research Institute:

Primary Outcome Measures:
  • ADAS-cog as the primary clinical outcome [ Time Frame: Trial is for one year ]
    The ADAS-Cog, our primary outcome measures a 70-point scale designed to measure the severity of cognitive impairment; higher numbers represent greater impairments.It consists of 11 tasks assessing learning and memory, language production and comprehension, constructional and ideational praxis, and orientation. We will conduct sub-analyses looking at domain-specific changes. The ADAS-Cog has been proven to clearly distinguish clinically diagnosed AD dementia patients from non-dementia control subjects. The ADAS-Cog total score and its items are sensitive to the severity and degree of AD. Alternate word lists are available to reduce the incidence of learning effects in repeated measures and we will use these in our study. Longitudinal studies indicate that AD patients show an increase in the ADAS-Cog total score of 7 to 11 points per year. After being successfully introduced as a primary evaluation instrument in the first double-blind multicenter study with tacrine, the ADAS-Cog has


Secondary Outcome Measures:
  • Brain glucose utilization [ Time Frame: Trial is for one year ]
    Biological/mechanistic outcome measures and FDG-PET scanning procedures. The second AIM for this pilot clinical trial is to detect whether there is a differential change in neuro-degeneration as assessed by glucose utilization that is measured by FDG-PET in the posterior cingulate region of the brain among the treatment and control groups. In addition to the primary region of interest, and as part of the Secondary Aims, glucose utilization will also be analyzed in the following regions: precuneus, parietotemporal and frontal cortices. Once patients are consented and enrolled, they will receive initial PET. At completion of the benfotiamine trial, patients will receive follow-up scans to determine if the decline in glucose utilization is less in those receiving benfotiamine than in those receiving placebo. A single value will be used to compare glucose utilization.

  • Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) [ Time Frame: Trial is for one year ]
    . The ADCS-ADL-SIV is a caregiver-based ADL scale composed of 19 items developed for use in dementia clinical studies. The scores for the multiple items are summarized in one score.

  • Neuropsychiatric Inventory (NPI). [ Time Frame: Trial is for one year ]
    The NPI assesses a wide range of behaviors encountered in dementia patients to provide a means of distinguishing frequency and severity of behavioral changes. Ten behavioral and two neuro-vegetative domains are evaluated through an interview with the caregiver. The scores for the multiple items are summarized in one score.

  • Clinical Dementia Rating Scale (CDR). [ Time Frame: Trial is for one year ]
    The CDR was developed primarily for use in persons with dementia of the Alzheimer type (the equivalent of probable Alzheimer's Disease) and can also be used to stage dementia in other illnesses as well. The scores for the multiple items are summarized in one score.

  • Buschke Selective Reminding Test (SRT). [ Time Frame: Trial is for one year ]
    Buschke Selective Reminding Test (SRT). The SRT [64] is a standard diagnostic tool in the assessment of verbal memory. Several studies attest to its predictive value for dementia. The scores for the multiple items are summarized in one score.


Estimated Enrollment: 76
Study Start Date: November 2014
Estimated Study Completion Date: November 2019
Estimated Primary Completion Date: November 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Benfotiamine
The patients in this arm will be treated with benfotiamine
Drug: Benfotiamine
  • 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.
Other Name: S-[2-{[(4-amino-2- methylpyrimidin-5-yl)methyl] (formyl)amino}-5-(phosphonooxy)pent-2-en-3-yl] benzenecarbothioate
Placebo Comparator: Placebo
The patients in this arm will be treated with placebo
Drug: Benfotiamine
  • 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.
Other Name: S-[2-{[(4-amino-2- methylpyrimidin-5-yl)methyl] (formyl)amino}-5-(phosphonooxy)pent-2-en-3-yl] benzenecarbothioate

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   65 Years to 95 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  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): NCT02292238


Contacts
Contact: Rosanna Cirio, MA, CRC 914-597-2476 RCIRIO@BURKE.ORG
Contact: Pasquale Fonzetti, PhD, MD 914-597-2502 pfonzett@burke.org

Locations
United States, New York
Burke Recruiting
White Plains, New York, United States, 10605
Contact: Nancy Geibel, MS    914-368-3159    grants@burke.org   
Sponsors and Collaborators
Burke Medical Research Institute
Burke Rehabilitation Hospital
Columbia University
National Institute on Aging (NIA)
Alzheimer’s Drug Discovery Foundation
Investigators
Principal Investigator: Gary E Gibson, Ph.D. Burke Medical Research Institute
Principal Investigator: Barry D Jordan, MD, MPH Burke Rehabilitation Hospital
  More Information

Responsible Party: Gary E. Gibson, Professor of Neuroscience; Brain and Mind Institute; Weill Cornell Med College, Burke Medical Research Institute
ClinicalTrials.gov Identifier: NCT02292238     History of Changes
Other Study ID Numbers: BRC-451
1R01AG043679-01A1 ( U.S. NIH Grant/Contract )
First Submitted: November 10, 2014
First Posted: November 17, 2014
Last Update Posted: July 19, 2016
Last Verified: July 2016

Keywords provided by Gary E. Gibson, Burke Medical Research Institute:
Alzheimer's disease
benfotiamine
glucose
Amyloid

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Benphothiamine
Thiamine
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances