Benfotiamine in Alzheimer's Disease: A Pilot Study

NCT02292238 | Completed Phase 2 Results DMC

• 2 other identifiers: BRC-4511R01AG043679-01A1
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 1

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.

Conditions

Alzheimer's Disease

Keywords

Alzheimer's disease; benfotiamine; glucose; Amyloid

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in ADAS-Cog Score

  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.

  Baseline, 1 year

Secondary Outcomes (5)

• Change From Baseline in Brain Glucose Utilization

  Baseline, 1 year

• Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score

  Baseline, 1 year

• Change From Baseline in Neuropsychiatric Inventory (NPI) Score

  Baseline, 1 year

• Change From Baseline in Clinical Dementia Rating (CDR) Score

  Baseline, 1 year

• Change From Baseline in Buschke Selective Reminding Test (SRT) Score

  Baseline, 1 year

Study Arms (2)

Benfotiamine

EXPERIMENTAL

The patients in this arm will be treated with benfotiamine

Drug: Benfotiamine

Placebo

PLACEBO COMPARATOR

The patients in this arm will be treated with placebo

Drug: Benfotiamine

Interventions

Benfotiamine DRUG

* 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.

Also known as: S-[2-{[(4-amino-2- methylpyrimidin-5-yl)methyl] (formyl)amino}-5-(phosphonooxy)pent-2-en-3-yl] benzenecarbothioate

Benfotiamine; Placebo

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Burke Medical Research Institute: lead
• Burke Rehabilitation Hospital: collaborator
• Columbia University: collaborator
• National Institute on Aging (NIA): collaborator
• Alzheimer's Drug Discovery Foundation: collaborator
• Montefiore Medical Center: collaborator

Study Sites (1)

Burke

White Plains, New York, 10605, United States

Location

Related Publications (1)

• Gibson GE, Luchsinger JA, Cirio R, Chen H, Franchino-Elder J, Hirsch JA, Bettendorff L, Chen Z, Flowers SA, Gerber LM, Grandville T, Schupf N, Xu H, Stern Y, Habeck C, Jordan B, Fonzetti P. Benfotiamine and Cognitive Decline in Alzheimer's Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial. J Alzheimers Dis. 2020;78(3):989-1010. doi: 10.3233/JAD-200896.

  PMID: 33074237 RESULT

MeSH Terms

Conditions

Alzheimer Disease

Interventions

benphothiamine

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Gary E Gibson, Professor of Neuroscience
• Organization: Weill Cornell Med/ Burke Neurological Institute

ggibson@med.cornell.edu

9145972291

Study Officials

• Gary E Gibson, Ph.D.

  Burke Medical Research Institute

  PRINCIPAL INVESTIGATOR

• Pasquale Fonzetti, MD, PhD

  Burke Rehabilitation Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neuroscience; Brain and Mind Institute; Weill Cornell Med College

Study Record Dates

• First Submitted: November 10, 2014
• First Posted: November 17, 2014
• Study Start: February 15, 2015
• Primary Completion: July 20, 2020
• Study Completion: September 8, 2020
• Last Updated: June 28, 2022
• Results First Posted: June 28, 2022

Record last verified: 2022-06

Locations

US (1)