PF-04494700 IN PARTICIPANTS WITH MILD-TO-MODERATE ALZHEIMERS'S DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这是一项II期随机、安慰剂对照、双盲、多中心、行业赞助的试验，调查了PF 04494700作为治疗轻、中度阿尔茨海默病患者的潜在治疗选择的使用情况。PF 100是一种口服生物可用的晚期糖基化终产物受体(RAGE)拮抗剂。已知RAGE参与淀粉样β蛋白从外周到中枢的转运，推测拮抗受体可能调节这种转运，导致血浆和脑脊液中淀粉样β蛋白的变化。此外，RAGE-配体已被发现可减少小鼠模型中淀粉样斑块的形成，证实了其作为阿尔茨海默病靶点的潜在临床益处。 PF-04494700已经在临床前动物和人体试验中进行了研究。已发现其毒性包括呕吐、厌食、心率减慢以及QTC间期延长。在单剂量第一阶段临床药代动力学研究中，发现高达65毫克的剂量耐受性良好。值得注意的是，这种药物在老年人中的平均半衰期被发现为421小时，即超过17天。同样值得注意的是，该药物是CYP3A4酶的部分抑制剂，在研究中限制同时使用已知的有效的CYP3A4抑制剂或诱导剂。 主要的研究终点是在使用这种新药物治疗18个月后，检测阿尔茨海默病评估量表认知测量(ADAS-COG)中基线的变化。这项研究将患者随机分为高剂量、低剂量或安慰剂，治疗持续18个月。这项研究的次要目标包括评估这种新药相对于安慰剂的治疗剂量反应，评估药物的药代动力学和药物与潜在生物标志物的药代动力学/药效学关系，以及相关的疗效和安全终点。符合条件的患者是那些患有轻度到中度阿尔茨海默病的人。随机抽样为1：1：1，预计将有399名参与者参加。在乔治敦的GCRC，预计将有10名患者入选。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a phase II, randomized, placebo-controlled, double-blinded, multi-center, industry-sponsored trial investigating the use of PF 04494700, an orally bioavailable antagonist of the Receptor for Advanced Glycation End-products (RAGE) as a potential treatment option for patients with mild to moderate Alzheimer's disease. RAGE is known to be involved in the transport of amyloid beta from peripheral to central components, and it is hypothesized that antagonizing the receptor may modulate this transport, resulting in changes of amyloid beta in both plasma and cerebrospinal fluid. In addition, RAGE-ligand has been found to reduce amyloid plaque formation in a murine model, confirming the potential clinical benefit of this as a target in Alzheimer's disease. PF-04494700 has been studied in both preclinical animal and human studies. Its toxicities have been found to include emesis, anorexia, decreased heart rate as well as increased QTc intervals. In single dose phase 1 clinical pharmacokinetic study, dosages of up to 65 mg have been found to be well tolerated. Of note, the mean half-life of this drug in the elderly has been found to be 421 hours, or over 17 days. Also of note is the fact that this drug is a partial inhibitor of the CYP3A4 enzyme, and concomitant use of drugs known to be potent CYP3A4 inhibitors or inducers is restricted in the study. The primary study endpoint is to detect a change in baseline in the Alzheimer's Disease Assessment Scale Cognitive measure (ADAS-cog) after 18 months of treatment with this new agent. This study will randomize patients to a high dose, a low dose, or placebo, with treatment lasting 18 months. Secondary objectives of this study include evaluating the dose response of treatment with this new drug relative to placebo, evaluating the pharmacokinetics and the pharmacokinetic/pharmacodynamic relationship of drug to potential biomarkers, and relevant efficacy and safety endpoints. Eligible patients are those with mild to moderate Alzheimer's disease. Randomization is a 1:1:1, and an expected 399 participants will be enrolled. At the GCRC at Georgetown, 10 patients are expected to be enrolled.