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

• 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: Burke Medical Research Institute
• 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

Tracking Information

• First Submitted Date: November 10, 2014
• First Posted Date: November 17, 2014
• Results First Submitted Date: March 8, 2022
• Results First Posted Date: June 28, 2022
• Last Update Posted Date: June 28, 2022
• Actual Study Start Date: February 15, 2015
• Actual Primary Completion Date: July 20, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 2, 2022)

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.

Original Primary Outcome Measures (submitted: November 14, 2014)

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

Current Secondary Outcome Measures (submitted: June 2, 2022)

• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: November 14, 2014)

• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Benfotiamine in Alzheimer's Disease: A Pilot Study
• Official Title: Benfotiamine in Alzheimer's Disease: A Pilot Study

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.

Detailed Description

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).

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Alzheimer's Disease

Intervention

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

Study Arms

• Experimental: Benfotiamine
  The patients in this arm will be treated with benfotiamine
  Intervention: Drug: Benfotiamine
• Placebo Comparator: Placebo
  The patients in this arm will be treated with placebo
  Intervention: Drug: Benfotiamine

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 2, 2022): 71
• Original Estimated Enrollment (submitted: November 14, 2014): 76
• Actual Study Completion Date: September 8, 2020
• Actual Primary Completion Date: July 20, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02292238
• Other Study ID Numbers: BRC-451; 1R01AG043679-01A1 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Gary E. Gibson, Burke Medical Research Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Burke Medical Research Institute
• Original Study Sponsor: Same as current

Collaborators

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

Investigators

• Principal Investigator: Gary E Gibson, Ph.D.; Burke Medical Research Institute
• Principal Investigator: Pasquale Fonzetti, MD, PhD; Burke Rehabilitation Hospital

• PRS Account: Burke Medical Research Institute
• Verification Date: June 2022