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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 这是一项II期，随机，安慰剂对照，双盲，多中心，由行业赞助的试验，调查了PF 04494700的使用，PF 04494700是高级糖化终极产物（RAGE）的口服可生物利用的拮抗剂（RAGE）轻度至中度阿尔茨海默氏病的患者的治疗选择。 众所周知，RAGE参与了淀粉样蛋白β从外围成分转移到中心成分，并且假设对受体的拮抗剂可能调节该转运，从而导致血浆和脑脊液中淀粉样蛋白β的变化。 此外，已经发现愤怒的配体可以减少鼠模型中的淀粉样菌斑的形成，从而证实了这一临床益处的潜在临床益处，这是阿尔茨海默氏病的靶标。 PF-04494700在临床前动物和人类研究中均已研究。 已经发现它的毒性包括呕吐，厌食症，心率降低以及QTC间隔增加。 在单剂量1期临床药代动力学研究中，已发现高达65 mg的剂量耐受性良好。 值得注意的是，已经发现这种药物的平均半衰期是421小时或超过17天。 还要注意的是，该药物是CYP3A4酶的部分抑制剂，并且在研究中限制了已知的有效CYP3A4抑制剂或诱导剂的药物的使用。 主要的研究终点是在与该新药物进行18个月的治疗后，在阿尔茨海默氏病评估量表认知量度（ADAS-COG）中检测基线变化。 这项研究将使患者随机治疗持续18个月，将患者随机增加到高剂量，低剂量或安慰剂。 这项研究的次要目标包括评估与安慰剂相对于安慰剂的治疗的剂量反应，评估药代动力学和药代动力学/药物学与潜在生物标志物的药物学关系以及相关的功效和安全性和安全性终点。 合格的患者是患有轻度至中度阿尔茨海默氏病的患者。 随机分配为1：1：1，预期的399名参与者将被录取。 在乔治敦的GCRC上，预计将入学10名患者。