Metformin in Alzheimer's dementia Prevention (MAP)

这项名为“二甲双胍预防阿尔茨海默氏症(MAP)”的提案的目标是进行一个阶段 二甲双胍与安慰剂预防认知功能减退的II/III随机对照试验 阿尔茨海默氏症的风险，对PAR-18-028“光谱的第三阶段临床试验”的回应 阿尔茨海默病和与年龄相关的认知能力下降“。这份地图提案是基于一项 现场12个月早期II期安慰剂对照1：1短效二甲双胍1000 mg，每年2次的随机试验 在80名无糖尿病的晚期遗忘性轻度认知障碍患者中， 超重或肥胖(Clinicaltrials.gov ID NCT00620191；R01AG026413；ADDF 27091)，目标是进行 获得关于安全性、可行性和有效性的初步数据。这项初步研究表明， 其中一个主要结果是，在选择性提醒测试中，总回忆的变化明显大于 二甲双胍组与安慰剂组比较(9.7±8.5字对5.3±8.5字；p=0.02)，这一好处是 在服用最大剂量二甲双胍的患者中最高。我们建议将MAP作为后续多站点II/III阶段1：1 二甲双胍预防认知功能减退的随机安慰剂对照试验 与阿尔茨海默氏症有关。与之前的试点相比，MAP将有以下创新 研究：(A)使用耐受性更好的长效形式的二甲双胍(GLucphage XR)，最大剂量为 每天2,000毫克；b)排除每天不能耐受至少1000毫克二甲双胍的参与者；(C)重复 在二甲双胍滴定期间进行认知测试，以说明实践效果；(D)扩大定义 (E)将审判期限从12个月延长至24个月，并将认知能力 测试间隔为3个月至6个月；(F)使用自由和线索选择的总回忆分数 记忆测验(FC-SRT)作为主要认知结果与阿尔茨海默病临床前认知复合体 来自阿尔茨海默病合作研究(ADCS-PACC)作为次要认知结果；(G)包括 海马体体积作为神经退行性变的生物标志物，以及白质高信号作为标志物 脑磁共振成像(MRI)确定的脑血管疾病为次级亚临床 样本的一半的结果；(H)拟议的初始样本量为370人(每臂185人)，扩大到更大的 第三阶段试验基于先验定义的规则。我们的主要目标是比较从基线到24个月的变化 在言语记忆表现上，用FC-SRT的总回忆分数衡量，在 和安慰剂武器，遵循ITT的方法。我们将检查全球认知表现，用 ADC-PACC，作为次要结果。我们还将检查apoE-e4基因作为疗效的修饰性指标。 一种二甲双胍。我们的次要目标是比较神经退行性变的变化，确定为海马区 体积和脑血管疾病被确定为脑白质高信号，两者都在大脑上确定 从基线到二甲双胍和安慰剂之间的24个月的MRI。

The goal of this proposal, entitled “Metformin in Alzheimer’s dementia Prevention (MAP)”, is to conduct a phase II/III randomized controlled trial of metformin vs. placebo in the prevention of cognitive decline among persons at risk for Alzheimer’s dementia, in response to PAR-18-028 “Phase III Clinical Trials for the Spectrum of Alzheimer’s Disease and Age-related Cognitive Decline”. This MAP proposal is based on the results of a single site 12-month early Phase II placebo controlled 1:1 randomized trial of short acting metformin 1000 mg twice a day among 80 persons with late amnestic mild cognitive impairment (aMCI), without diabetes, who were overweight or obese (clinicaltrials.gov ID NCT00620191; R01AG026413; ADDF 27091), conducted with the goal of obtaining preliminary data on safety, feasibility, and efficacy. This pilot study showed that the improvement in one of the primary outcomes, changes in total recall in the selective reminding test was significantly greater in the metformin arm compared with the placebo arm (9.7 ± 8.5 vs. 5.3 ± 8.5 words; p = 0.02), and this benefit was highest in those taking the highest dose of metformin. We propose MAP as a follow-up multisite phase II/III 1:1 randomized placebo-controlled trial to test the efficacy of metformin in the prevention of the cognitive decline associated with Alzheimer’s dementia. MAP will have the following innovations compared with the previous pilot study: (a) use of the better tolerated long acting form of metformin (Glucophage XR©), with a maximum dose of 2,000 mg a day; b) exclusion of participants who cannot tolerate at least 1000 mg a day of metformin; (c) repeated cognitive testing during the metformin titration period to account for practice effects; (d) Extension of the definition of aMCI to include early aMCI; (e) Extension of the trial duration from 12 months to 24 months and the cognitive testing interval from 3 months to 6 months; (f) use of the Total Recall Score of the Free and Cued Selective Reminding Test (FC-SRT) as a primary cognitive outcome and the Preclinical Alzheimer Cognitive Composite from the Alzheimer’s Disease Cooperative Study (ADCS-PACC) as a secondary cognitive outcome; (g) include hippocampal volume as a biomarker of neurodegeneration, and white matter hyperintensities (WMH) as a marker of cerebrovascular disease ascertained on brain magnetic resonance imaging (MRI) as secondary subclinical outcomes in half of the sample; (h) a proposed initial sample size of 370 (185 per arm), extending to a larger phase III trial based on a priori defined rules. Our primary aim is to compare changes from baseline to 24 months in verbal memory performance, measured with the Total Recall Score of the FC-SRT, between the metformin and placebo arms, following an ITT approach. We will examine global cognitive performance, measured with the ADCS-PACC, as a secondary outcome. We will also examine APOE-e4 genotype as a modifier of the efficacy of metformin. Our secondary aims are to compare changes in neurodegeneration, ascertained as hippocampal volume, and cerebrovascular disease ascertained as white matter hyperintensities, both ascertained on brain MRI from baseline to 24 months between metformin and placebo.