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)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 406
- 试验地点
- 72
- 主要终点
- Phase 2A: The rate of tolerability events (TEs).
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 50 Years 至 89 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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).
研究组 & 干预措施
Low Dose Benfotiamine
Participants will take 300mg benfotiamine capsules twice a day (BID; once in the morning and once in the evening).
干预措施: Low Dose Benfotiamine (Drug)
High Dose Benfotiamine
Participants will take 600mg benfotiamine capsules twice a day (BID; once in the morning and once in the evening).
干预措施: High Dose Benfotiamine (Drug)
Placebo
Participants will take placebo capsules twice a day (BID; once in the morning and once in the evening). In the placebo group, capsules will be filled with inactive microcrystalline cellulose. The other capsule components, shape and color are identical between benfotiamine and placebo arms.
干预措施: Placebo (Drug)
结局指标
主要结局
Phase 2A: The rate of tolerability events (TEs).
时间窗: Up to 72 weeks
The primary safety outcome in phase 2A is the rate of tolerability events (TEs) compared between active arms (benfotiamine) and placebo arms, at each dose. A TE is counted when either a participant discontinues study drug due to intolerability or experiences a moderate or severe adverse event (AE) that is determined to be possibly, probably or definitely related to study drug.
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).
时间窗: 72 weeks
ADAS-Cog13 is a structured psychometric scale that evaluates memory (immediate and delayed word recall; immediate word recognition), receptive and expressive language, orientation, ideational praxis (preparing a letter for mailing), constructional praxis (copying figures), and attention (number cancellation). Ratings of spoken language, language comprehension, word finding difficulty, and ability to remember test instructions also are obtained. ADAS-Cog13 total score has a range of 0-85; with higher scores indicating greater impairment.
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).
时间窗: 72 weeks
CDR-SB is a composite rating of cognition and everyday function which incorporates both informant input and direct assessment of performance. It assesses through semi-structured interview three cognitive domains (memory, orientation, and judgement/problem solving) and three everyday functional domains (community affairs, home and hobbies, personal care). Level of impairment in each of the six domains is rated from none (score=0) to severe (score=3). The six domain scores are then summed to create the CDR-SB. Range 0-18; higher scores indicate greater impairment.
次要结局
- 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).(72 weeks)
- Number of Participant Drug Discontinuations.(72 weeks)
- Mean and Median Thiamine levels (nmol/L).(Baseline, week 72)
- Mean and Median Thiamine Diphosphate (ThDP) levels (nmol/L).(Baseline, week 72)
- Mean and Median Thiamine Monophosphate (ThMP) levels (nmol/L).(Baseline, week 72)
- Number of Participants With Adverse Events (AEs) and Serious AEs.(72 weeks)
- Number of Participant Withdrawals from the study.(72 weeks)
- Mean and Median levels of ThDP Activation of Transketolase (U/g haemoglobin (U/gHb)).(Baseline, week 72)
- Phase 2B: within-participant change from baseline to 72 weeks compared between active arms (benfotiamine) and placebo arm on the Montreal Cognitive Assessment (MoCA).(72 weeks)
- Mean Thiamine levels (nmol/L).(Baseline, week 72)
- Median Thiamine levels (nmol/L).(Baseline, week 72)
- Mean Thiamine Diphosphate (ThDP) levels (nmol/L).(Baseline, week 72)
- Median Thiamine Diphosphate (ThDP) levels (nmol/L).(Baseline, week 72)
- Mean Thiamine Monophosphate (ThMP) levels (nmol/L).(Baseline, week 72)
- Median Thiamine Monophosphate (ThMP) levels (nmol/L).(Baseline, week 72)
- Mean levels of ThDP Activation of Transketolase (U/g haemoglobin (U/gHb)).(Baseline, week 72)
- Median levels of ThDP Activation of Transketolase (U/g haemoglobin (U/gHb)).(Baseline, week 72)