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

PF-04494700 适用于患有轻度至中度阿尔茨海默病的参与者

• 批准号: 7952009
• 负责人: BRIGID REYNOLDS
• 金额: $ 5.44万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7952009
• 关键词: Advanced Glycosylation End Products; Alzheimer' s Disease; Amyloid beta-Protein; Animals; Anorexia; Bioavailable; Biological Markers; CYP3A4 gene; Cerebrospinal Fluid; Clinical; Clinical Research; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Disease; Dose; Double-Blind Method; Drug Kinetics; Drug usage; Elderly; Enrollment; Enzymes; Funding; Grant; Half-Life; Heart Rate; Hour; Human; Industry; Institution; Ligands; Measures; Modeling; Mus; New Agents; Participant; Patients; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebo Control; Placebos; Plasma; Randomized; Relative (related person); Research; Research Personnel; Resources; Safety; Senile Plaques; Source; Toxic effect; United States National Institutes of Health; Vomiting; dosage; inhibitor/antagonist; pre-clinical; receptor; treatment response

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 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，研究 PF 04494700 的用途，PF 04494700 是一种口服生物可利用的高级糖基化终产物受体 (RAGE) 受体拮抗剂，作为轻度至中度阿尔茨海默病患者的潜在治疗选择。 已知RAGE参与β淀粉样蛋白从外周成分到中枢成分的转运，并且推测拮抗受体可能调节这种转运，导致血浆和脑脊液中β淀粉样蛋白的变化。 此外，在小鼠模型中，RAGE 配体被发现可以减少淀粉样斑块的形成，证实了其作为阿尔茨海默病靶标的潜在临床益处。 PF-04494700 已在临床前动物和人体研究中进行了研究。 已发现其毒性包括呕吐、厌食、心率降低以及 QTc 间期延长。 在单剂量 1 期临床药代动力学研究中，发现高达 65 mg 的剂量具有良好的耐受性。 值得注意的是，该药物在老年人中的平均半衰期为 421 小时，即超过 17 天。 另外值得注意的是，该药物是 CYP3A4 酶的部分抑制剂，并且在研究中限制同时使用已知为有效 CYP3A4 抑制剂或诱导剂的药物。 主要研究终点是检测使用这种新药治疗 18 个月后阿尔茨海默病评估量表认知测量 (ADAS-cog) 基线的变化。 这项研究将患者随机分为高剂量组、低剂量组或安慰剂组，治疗持续 18 个月。 本研究的次要目标包括评估该新药相对于安慰剂的剂量反应、评估药物的药代动力学和药代动力学/药效学与潜在生物标志物的关系，以及相关的疗效和安全性终点。 符合条件的患者是患有轻度至中度阿尔茨海默病的患者。 随机化为 1:1:1，预计将招募 399 名参与者。 乔治城 GCRC 预计将招募 10 名患者。