Clinical trial NCT06223360: A Trial to Evaluate the Safety and Efficacy of Benfotiamine in Patients With Early Alzheimer's Disease (BenfoTeam)
Official title: A Seamless Phase 2A-Phase 2B Randomized Double-Blind Placebo- Controlled Trial to Evaluate the Safety and Efficacy of Benfotiamine in Patients With Early Alzheimer's Disease (BenfoTeam)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Alzheimer Disease
Keywords: Mild Cognitive Impairment
Mild Alzheimer's Disease
Early Alzheimer's disease
Lead sponsor: Alzheimer's Disease Cooperative Study (ADCS)
Sponsor class: OTHER
Collaborators: name: Burke Medical Research Institute
name: National Institute on Aging (NIA)
First posted: 2024-01-25
Enrollment: 406
Sex: ALL
Minimum age (years): 50
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to learn more about the safety, effectiveness and tolerability of the study drug called Benfotiamine which may delay or slow the progression of the symptoms of early Alzheimer's disease.

Detailed description: This is a randomized, double-blind, placebo-controlled 18-month clinical trial of benfotiamine in early AD. This trial will include a seamless phase 2A-2B design with a randomized total sample of 406 participants. Participants who are randomized but drop out prior to study drug exposure will be replaced.

Phase 2A of the trial will randomize approximately 150 participants total, in a 1:1:1 to treatment with 1200 mg/day benfotiamine, 600 mg/day benfotiamine or placebo. The primary objective of phase 2A is to determine the highest safe and well tolerated dose of benfotiamine (600 mg or 1200 mg), as evaluated by the rate of tolerability events (TEs), for advancement to long-term 72 week exposure. The highest tolerated dose of benfotiamine will be carried forward from phase 2A to phase 2B.

At the start of phase 2B, all participants enrolled in the two phase 2A active dose arms will receive a new supply of benfotiamine at the selected phase 2B dose. All phase 2A participants will be included in the phase 2 intent-to-treat efficacy population, as assigned to active or placebo treatment. The primary objective of phase 2B is to assess efficacy of benfotiamine on global function and cognition over 72 weeks. In phase 2B, a composite cognitive and functional measure as well as PD biomarkers will be used to evaluate efficacy during the extended treatment period. Phase 2B will also evaluate longer-term safety and tolerability of benfotiamine treatment over 72 weeks.

Eligibility criteria: Key Inclusion Criteria:

* Aged 50 to 89 (inclusive) at screening
* Mild Cognitive Impairment (MCI) due to AD or Mild dementia due to AD according to workgroups of the Diagnostic Guidelines of the National Institute on Aging and Alzheimer's Association (NIA-AA)
* Mini-Mental State Examination (MMSE) score 20-30 inclusive at screening-. Montreal Cognitive Assessment score (MoCA) \< 26 at screening
* Clinical Dementia Rating (CDR) global score of 0.5 or 1 with memory score of greater or equal to 0.5 at screening
* Positive plasma AD biomarker signature
* Participants who are treated with FDA-approved acetylcholinesterase inhibitors (AchEI)and/or memantine will have to be on a stable dosage regimen for at least 3 months prior to screening.
* Participants must have a study partner who has frequent interaction with them (approximately \>3-4 times per week), will be available for all clinic visits in person or remotely, and can assist in compliance with study procedures.
* Female participants must be post-menopausal for at least one year or surgically sterile(bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months prior to screening.
* Fluent in English or Spanish to ensure compliance with cognitive testing and study visit procedures.
* Ambulatory, or able to walk with an assistive device.
* Provision of informed consent from the participant (or the participant's legally authorized representative (LAR) if unable to provide consent) and the study partner.

Key Exclusion Criteria:

* Significant neurological disorder other than AD (e.g. hypoxia, stroke, traumatic brain injury
* Significant neurodegenerative diseases, other than AD, and causes of dementias, Parkinson's disease and Huntington's disease, vascular dementia, CJD (Creutzfeldt-Jakob disease), LBD (Lewy Body dementia), PSP (Progressive Supranuclear Palsy), AIDS (Acquired Immunodeficiency Syndrome), or NPH (normal pressure hydrocephalus).
* Meeting Diagnostic Criteria for Possible AD according to workgroups of the Diagnostic Guidelines of the NIA-AA.
* A current diagnosis of uncontrolled Type I or Type II diabetes mellitus, as defined by Hemoglobin A1C (Hb A1C ≥ 8).
* A current active, uncontrolled seizure disorder.
* Diagnosis of cancer, except for those participants who have undergone potentially curative therapy with no evidence of recurrence for \> 5 years.
* History of alcoholism or substance abuse, current or within past 5 years.
* Previous exposure to Benfotiamine within past 3 months.
* Contraindication to MRI.
* Participation in another clinical trial for an investigational agent and having taken at least one dose of study drug, unless confirmed as having been on placebo, within 4 weeks prior to the baseline visit. The end of a previous investigational trial is defined as the date of the last dose of an investigational agent.
* Initiation of a monoclonal antibody treatment targeting brain amyloid within 6 months prior to the baseline visit.
* A disability that may prevent the patient from completing all study requirements e.g.,blindness, deafness, severe language difficulty).

Primary outcomes:
measure: Phase 2A: The rate of tolerability events (TEs).
timeFrame: Up to 72 weeks
measure: Phase 2B: The primary cognitive endpoint is the within-participant change from baseline to 72 weeks compared between active arms (benfotiamine) and placebo on the Alzheimer's Disease Assessment Scale - Cognitive Subscale 13 (ADAS-Cog13).
timeFrame: 72 weeks
measure: Phase 2B: The primary functional endpoint is the within-participant change from baseline to 72 weeks compared between active arm (benfotiamine) and placebo on the Clinical Dementia Rating - Sum of Boxes (CDR-SB).
timeFrame: 72 weeks
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious AEs.
timeFrame: 72 weeks
measure: Number of Participant Withdrawals from the study.
timeFrame: 72 weeks
measure: Number of Participant Drug Discontinuations.
timeFrame: 72 weeks
measure: Mean and Median Thiamine levels (nmol/L).
timeFrame: Baseline, week 72
measure: Mean and Median Thiamine Diphosphate (ThDP) levels (nmol/L).
timeFrame: Baseline, week 72
measure: Mean and Median Thiamine Monophosphate (ThMP) levels (nmol/L).
timeFrame: Baseline, week 72
measure: Mean and Median levels of ThDP Activation of Transketolase (U/g haemoglobin (U/gHb)).
timeFrame: Baseline, week 72
measure: Phase 2B: within-participant change from baseline to 72 weeks compared between active (benfotiamine) arms and placebo arm on The Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale for use in Mild Cognitive Impairment (ADCS-ADL-MCI).
timeFrame: 72 weeks
measure: Phase 2B: within-participant change from baseline to 72 weeks compared between active arms (benfotiamine) and placebo arm on the Montreal Cognitive Assessment (MoCA).
timeFrame: 72 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center/Barrow Neurological Institute
state: Arizona
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Lemon Grove
country: United States
facility: Pacific Research Network
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai, Los Angeles
state: California
city: Santa Ana
country: United States
facility: Syrentis Clinical Research
state: California
city: Atlantis
country: United States
facility: JEM Research Institute
state: Florida
city: Delray Beach
country: United States
facility: Brain Matters Research
state: Florida
city: Fort Myers
country: United States
facility: Neuropsychiatric Research Center of Southwest Florida
state: Florida
city: Miami
country: United States
facility: CCM Clinical Research Group, LLC
state: Florida
city: Miami
country: United States
facility: Miami Jewish Health
state: Florida
city: Miami
country: United States
facility: Blue Medical Research Inc.
state: Florida
city: Stuart
country: United States
facility: Brain Matters Research (Kane Center)
state: Florida
city: Atlanta
country: United States
facility: Emory University Goizueta Alzheimer's Disease Research Center(GADRC)
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Waltham
country: United States
facility: MedVadis Research
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan, Ann Arbor
state: Michigan
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Amherst
country: United States
facility: Dent Neurologic Institute
state: New York
city: Brooklyn
country: United States
facility: Integrative Clinical Trials
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: New York
country: United States
facility: Nathan Kline Institute for Psychiatric Research
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University (OHSU)
state: Oregon
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Ralph H. Johnson VA Health Care System
state: South Carolina
city: Tennessee
country: United States
facility: KCA Neurology
state: Tennessee
city: Fort Worth
country: United States
facility: University of North Texas Health Science Center
state: Texas
Study officials:
affiliation: Alzheimer's Disease Cooperative Study (ADCS)
name: Howard Feldman, MDCM
role: PRINCIPAL_INVESTIGATOR
affiliation: Burke Neurological Institute
name: Gary E. Gibson, PhD
role: STUDY_DIRECTOR
affiliation: Columbia University
name: Jose A. Luchsinger, MD MPH
role: STUDY_DIRECTOR
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