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

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.
 
ClinicalTrials.gov Identifier: NCT02292238
Recruitment Status : Completed
First Posted : November 17, 2014
Results First Posted : June 28, 2022
Last Update Posted : June 28, 2022
Sponsor:
Collaborators:
Burke Rehabilitation Hospital
Columbia University
National Institute on Aging (NIA)
Alzheimer's Drug Discovery Foundation
Montefiore Medical Center
Information provided by (Responsible Party):
Gary E. Gibson, Burke Medical Research Institute

Brief 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.

Condition or disease Intervention/treatment Phase
Alzheimer's Disease Drug: Benfotiamine Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 71 participants
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
Actual Study Start Date : February 15, 2015
Actual Primary Completion Date : July 20, 2020
Actual Study Completion Date : September 8, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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




Primary Outcome Measures :
  1. Change From Baseline in ADAS-Cog Score [ Time Frame: Baseline, 1 year ]
    The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is a brief neuropsychological assessment used to assess the severity of cognitive symptoms of dementia. It is one of the most widely used cognitive scales in clinical trials and is considered to be the "gold standard" for assessing antidementia treatments. The ADAS-Cog range from 0 to 70, where higher scores indicate greater cognitive dysfunction.


Secondary Outcome Measures :
  1. Change From Baseline in Brain Glucose Utilization [ Time Frame: Baseline, 1 year ]
    The AAL (Automatic Anatomical Labeling) atlas provides the taxonomy for 116 regions of interest, 90 of which capture non-cerebellar cortical regions. Signal averages from 9 cerebellar regions from each hemisphere were further averaged into one composite cerebellar region for each hemisphere, 'Cerebellum_L' and 'Cerebellum_R', which were comprised of the respective laterality averages of the regions: 'Cerebellum_Crus1 ' 'Cerebellum_Crus2 'Cerebellum_3' 'Cerebellum_4_5' 'Cerebellum_6' 'Cerebellum_7b' 'Cerebellum_8' 'Cerebellum_9' 'Cerebellum_10 '. Subsequently, these two composite regions are further combined with the bilateral paracentral lobules to provide one final composite for reference scaling. Concretely, the values from 'Cerebellum_L', 'Cerebellum_R', 'Paracentral_Lobule_L', and 'Paracentra_Lobule_R' were averaged. This final composite will serve as the denominator for the scaling operation of any ROI value prior to group-level analysis.

  2. Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score [ Time Frame: Baseline, 1 year ]
    Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) is a caregiver-based Activities of Daily Living (ADL) scale composed of 23 items developed for use in dementia clinical studies. It was designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, as well as making judgments and decisions. The range for the total ADCS-ADL score is 0 to 78. Higher scores equate with higher functioning.

  3. Change From Baseline in Neuropsychiatric Inventory (NPI) Score [ Time Frame: Baseline, 1 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 total score ranges from 0 to 144. Higher scores suggest greater psychiatric impairment.

  4. Change From Baseline in Clinical Dementia Rating (CDR) Score [ Time Frame: Baseline, 1 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. The CDR examines 6 categories of cognitive functioning domains. Each domain is scored on a scale ranging from 0 to 3 (including 0.5). A CDR-SB was generated as the sum of the values in each of the 6 domains. The CDR-SB sum scores range from 0 to 18, with higher scores indicating greater cognitive impairment and a 1 point worsening is considered a clinically significant symptom change.

  5. Change From Baseline in Buschke Selective Reminding Test (SRT) Score [ Time Frame: Baseline, 1 year ]
    The SRT is a standard diagnostic tool in the assessment of verbal memory. The Buschke SRT immediate total scores are compared between treated (benfotiamine) and control (placebo) groups. The immediate total score is the sum of correct responses over the 6 learning trials with scores ranging from 0 to 72. A score of 0 means severe impairment in memory. A score of 72 means there is no impairment in memory. For the purpose of determining effect over several trials between groups, the fractional change from the baseline of each group is compared.



Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
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

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


Locations
Layout table for location information
United States, New York
Burke
White Plains, New York, United States, 10605
Sponsors and Collaborators
Burke Medical Research Institute
Burke Rehabilitation Hospital
Columbia University
National Institute on Aging (NIA)
Alzheimer's Drug Discovery Foundation
Montefiore Medical Center
Investigators
Layout table for investigator information
Principal Investigator: Gary E Gibson, Ph.D. Burke Medical Research Institute
Principal Investigator: Pasquale Fonzetti, MD, PhD Burke Rehabilitation Hospital
  Study Documents (Full-Text)

Documents provided by Gary E. Gibson, Burke Medical Research Institute:
Publications of Results:
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Responsible Party: Gary E. Gibson, Professor of Neuroscience; Brain and Mind Institute; Weill Cornell Med College, Burke Medical Research Institute
ClinicalTrials.gov Identifier: NCT02292238    
Other Study ID Numbers: BRC-451
1R01AG043679-01A1 ( U.S. NIH Grant/Contract )
First Posted: November 17, 2014    Key Record Dates
Results First Posted: June 28, 2022
Last Update Posted: June 28, 2022
Last Verified: June 2022
Keywords provided by Gary E. Gibson, Burke Medical Research Institute:
Alzheimer's disease
benfotiamine
glucose
Amyloid
Additional relevant MeSH terms:
Layout table for MeSH terms
Alzheimer Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Dementia
Tauopathies
Benphothiamine
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action