Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial
Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial
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DOI：
10.1186/1743-7075-6-31
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发表时间：
2009-08-10
影响因子：
4.5
通讯作者：
Costantini, Lauren C.
中科院分区：
文献类型：
--
作者：
Henderson, Samuel T.;Vogel, Janet L.;Costantini, Lauren C.
背景：阿尔茨海默病（AD）的特征是脑葡萄糖代谢的早期和区域特异性下降。酮体是在葡萄糖剥夺期间由身体产生的，并由大脑代谢。一种口服生酮化合物，AC-1202，在可能AD的受试者进行测试，以检查酮症是否可以改善认知performance.Methods：AC-1202的每日管理进行了评估，在152例诊断为轻度至中度AD在美国为基础的，90天，随机，双盲，安慰剂对照，平行组研究。受试者饮食正常，并继续服用获批的AD药物。主要认知终点为AD评估量表-认知子量表（ADAS-Cog）较基线的平均变化和AD合作研究-临床总体印象变化（ADCS-CGIC）的总体评分。在多个人群组中比较AC-1202与安慰剂，包括：意向治疗（ITT）组、符合方案组和剂量依从性组。结果还按APOE 4携带状态分层（基于载脂蛋白E基因的E4（E4）变体的预定义分析）。该试验在ClinicalTrials.gov注册，注册号NCT 00142805，信息可在http://clinicaltrials.gov/ct2/show/NCT00142805获得。结果：与安慰剂相比，AC-1202给药后2小时血清酮体（β-羟基丁酸酯）显著升高。在每个人群组中，发现AC-1202与安慰剂之间第45天ADAS-Cog评分较基线的平均变化存在显著差异：ITT组差异为1.9分，p = 0.0235;符合方案组差异为2.53分，p = 0.0324;剂量依从性组差异为2.6分，p = 0.0215。在不携带APOE 4等位基因（E4（-））的受试者中，第45天和第90天的ADAS-Cog评分较基线的平均变化在AC-1202和安慰剂之间存在显著差异。在ITT人群中，与安慰剂相比，AC-1202给药的E4（-）受试者（N = 55）在第45天ADAS-Cog评分较基线的平均变化存在显著性差异4.77分（p = 0.0005），在第90天存在显著性差异3.36分（p = 0.0148）。在符合方案人群中，接受AC-1202的E4（-）受试者（N = 37）在第45天与安慰剂的差异为5.73分（p = 0.0027），在第90天差异为4.39分（p = 0.0143）。在剂量依从性人群中，接受AC-1202的E4（-）受试者在第45天与安慰剂的差异为6.26分（p = 0.0011，N = 38），在第90天为5.33分（p = 0.0063，N = 35）。此外，在第90天，在E4（-）受试者的血清β-羟基丁酸酯水平和ADAS-Cog评分变化之间观察到显著的药理学应答（p = 0.008）。AC-1202受试者的不良事件发生频率更高，主要限于胃肠道系统，严重程度主要为轻度至中度，性质为一过性。结论：AC-1202可迅速升高AD患者的血清酮体，与安慰剂相比，ADAS-Cog评分存在显著差异。在剂量依从性的APOE 4（-）受试者中效果最显著。
Background: Alzheimer's disease (AD) is characterized by early and region-specific declines in cerebral glucose metabolism. Ketone bodies are produced by the body during glucose deprivation and are metabolized by the brain. An oral ketogenic compound, AC-1202, was tested in subjects with probable AD to examine if ketosis could improve cognitive performance.Methods: Daily administration of AC-1202 was evaluated in 152 subjects diagnosed with mild to moderate AD in a US-based, 90-day, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were on a normal diet and continued taking approved AD medications. Primary cognitive end points were mean change from Baseline in the AD Assessment Scale-Cognitive subscale (ADAS-Cog), and global scores in the AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). AC-1202 was compared to Placebo in several population groups, including: intention-to-treat (ITT), per protocol, and dosage compliant groups.Results were also stratified by APOE4 carriage status (a predefined analysis based on the epsilon 4 (E4) variant of the apolipoprotein E gene). This trial was registered with ClinicalTrials.gov, registry number NCT00142805, information available at http://clinicaltrials.gov/ct2/show/NCT00142805 Results: AC-1202 significantly elevated a serum ketone body (beta-hydroxybutyrate) 2 hours after administration when compared to Placebo. In each of the population groups, a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45: 1.9 point difference, p = 0.0235 in ITT; 2.53 point difference, p = 0.0324 in per protocol; 2.6 point difference, p = 0.0215 in dosage compliant. Among participants who did not carry the APOE4 allele (E4(-)), a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45 and Day 90. In the ITT population, E4(-) participants (N = 55) administered AC-1202 had a significant 4.77 point difference in mean change from Baseline in ADAS-Cog scores at Day 45 (p = 0.0005) and a 3.36 point difference at Day 90 (p = 0.0148) compared to Placebo. In the per protocol population, E4(-) participants receiving AC-1202 (N = 37) differed from placebo by 5.73 points at Day 45 (p = 0.0027) and by 4.39 points at Day 90 (p = 0.0143). In the dosage compliant population, E4(-) participants receiving AC-1202 differed from placebo by 6.26 points at Day 45 (p = 0.0011, N = 38) and 5.33 points at Day 90 (p = 0.0063, N = 35). Furthermore, a significant pharmacologic response was observed between serum beta-hydroxybutyrate levels and change in ADAS-Cog scores in E4(-) subjects at Day 90 (p = 0.008). Adverse events occurred more frequently in AC-1202 subjects, were primarily restricted to the gastrointestinal system, and were mainly mild to moderate in severity and transient in nature.Conclusion: AC-1202 rapidly elevated serum ketone bodies in AD patients and resulted in significant differences in ADAS-Cog scores compared to the Placebo. Effects were most notable in APOE4(-) subjects who were dosage compliant.