A Non-Inferiority Randomized Single Blind Controlled Trial Comparing One and Two Dose Regimes of Oxfendazole versus a Two Dose Regime of Triclabendazole to Treat Chronic Fascioliasis

比较奥芬达唑一剂和两剂方案与三氯苯达唑两剂方案治疗慢性片形吸虫病的非劣效随机单盲对照试验

• 批准号: 10328194
• 负责人: MIGUEL MAURICIO CABADA
• 金额: $ 43.91万
• 依托单位: UNIVERSIDAD PERUANA CAYETANO HEREDIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-17 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328194
• 关键词: Address; Adult; Affect; Animals; Anthelmintics; Antiparasitic Agents; Area; Biological Availability; Case Study; Child; Chile; Chronic; Clinical Trials; Communities; Conduct Clinical Trials; Controlled Clinical Trials; Country; Cysticercosis; Data; Developing Countries; Development; Dose; Drug Exposure; Drug Kinetics; Enrollment; Ensure; Environment; Epidemiology; Evaluation; Exposure to; Fasciola; Fasciola hepatica; Fascioliasis; Formulation; Helminths; Human; Infection; Literature; Liver diseases; Livestock; Logistics; Measures; Meleagris gallopavo; Methods; Modeling; Nature; Netherlands; Oral; Parasites; Parasitic infection; Parasitology; Persons; Peru; Pharmaceutical Preparations; Phase; Population; Portugal; Principal Investigator; Procedures; Published Comment; Randomized; Regimen; Reporting; Research; Research Personnel; Resistance; Safety; Sheep; Single-Blind Study; Solid; Taenia solium; Tissues; Toxicology; Treatment Protocols; Variant; Work; Zoonoses; arm; benzimidazole; climate change; comparative efficacy; design; drug development; effective therapy; efficacy evaluation; experience; farmer; helminth infection; human tissue; multidisciplinary; novel therapeutics; pharmacokinetic model; phase 1 study; programs; randomized, clinical trials; standard of care; trial comparing

Oxfendazole in Fascioliasis Principal Investigators/Program Directors: GARCIA, Hector H./ CABADA, Miguel M. A Non-Inferiority Randomized Single Blind Controlled Trial Comparing One and Two Dose Regimes of Oxfendazole versus a Two Dose Regime of Triclabendazole to Treat Chronic Fascioliasis ABSTRACT Fasciola hepatica infection causes human liver disease in wide endemic regions around the world. Triclabendazole is the only effective drug to treat human fascioliasis. However, it is not widely available and recently reports about resistance in livestock and decreased efficacy in humans raise concerns for the availability of effective treatment in human infections. Triclabendazole (TCBZ) resistance in human has been reported in The Netherlands, Turkey, Chile, Portugal, and Peru. In our experience in Cusco, Peru, more than 40% of children treated with one triclabendazole dose failed to achieve parasitological cure and 60% of these failed a second dose of treatment. Oxfendazole (OXF) is a veterinary benzimidazole with a wide anti-helminthic spectrum. Our group has demonstrated that OXF is highly efficacious against Taenia solium cysticercosis and other helminths. A preliminary study in naturally infected sheep showed that OXF is also highly efficacious against Fasciola hepatica. We have completed animal toxicology and phase 1 OXF studies in humans, confirming the high bioavailability of OXF and, importantly, its safety. These data strongly suggest that OXF is an excellent candidate for the treatment of human fascioliasis. Therefore, we propose to compare two oral OXF treatment regimens, a single 20 mg/kg dose and two 20 mg/kg doses, against the standard of care of two 10 mg/kg oral doses of TCBZ for the treatment of 336 children and adults with chronic Fasciola hepatica infection in endemic areas of Cusco, Peru. In addition, population PK modeling will be performed among subjects randomized to the OXF arms. This study will evaluate the efficacy, safety, and population pharmacokinetics of OXF in the groups most affected by fascioliasis. This application builds upon our 25-years of experience working with OXF and takes advantage of the solid expertise of the PIs in helminth infections, prior pivotal randomized clinical trials of anti- parasitic treatment in cysticercosis, and our continued work in a well-known Fasciola-endemic region in the Andes Mountains of Cusco. The investigators supported by the Oxfendazole Development Group will form a multidisciplinary team of accomplished experts in fascioliasis, field epidemiology, clinical trials, and new drug development that will ensure the successful completion of this study. This trial has the potential to provide a new standard of care for the treatment of chronic fascioliasis. In addition, it will be the first evaluation of OXF efficacy for a human tissue parasite and constitutes a significant step forward towards making this promising drug available for the treatment of human. It will provide additional pharmacokinetic and safety data to advance OXF development as a human drug.

奥芬达唑在肝片吸虫病中的主要研究者/项目负责人：GARCIA，Hector H./米格尔·卡巴达 一项非劣效性随机单盲对照试验比较一种和 奥芬达唑的两个剂量方案与 三氯苯达唑治疗慢性肝片吸虫病 摘要 肝片吸虫感染在世界各地广泛流行的地区引起人类肝病。 三氯苯达唑是目前治疗肝片吸虫病的唯一有效药物。然而，它并没有广泛使用 最近关于家畜抗药性和人类药效下降的报道引起了人们的关注 对于人类感染的有效治疗的可用性。三氯苯达唑（TCBZ）耐药 在荷兰、土耳其、智利、葡萄牙和秘鲁都有人类感染的报道。根据我们在 在秘鲁的库斯科，超过40%的儿童接受一剂三氯苯达唑治疗后未能达到 寄生虫学治愈，其中60%的人第二次治疗失败。 奥芬达唑（OXF）是一种具有广谱抗蠕虫作用的兽用苯并咪唑。我们集团 已经证明，OXF对猪带绦虫囊虫病和其他 蠕虫在自然感染的绵羊中进行的初步研究表明，OXF也非常有效 对抗肝片吸虫我们已经完成了动物毒理学和人类1期OXF研究， 证实了OXF的高生物利用度，重要的是，它的安全性。这些数据有力地表明， OXF是治疗人类肝片吸虫病的极好候选物。因此，我们建议 比较两种口服OXF治疗方案，单次20 mg/kg剂量和两次20 mg/kg剂量， 治疗336名儿童和成人的标准治疗为两次10 mg/kg口服剂量的TCBZ 秘鲁库斯科流行区慢性肝片吸虫感染。此外，群体PK 将在随机分配至OXF组的受试者中进行建模。本研究将评估 OXF在受片形吸虫病影响最严重的人群中的疗效、安全性和群体药代动力学。 此应用程序建立在我们25年的经验与OXF的工作，并利用 PI在蠕虫感染方面的扎实专业知识，之前的抗蠕虫关键随机临床试验 囊尾蚴病的寄生虫治疗，以及我们在一个著名的片形吸虫病流行地区的持续工作 在库斯科的安第斯山脉。研究人员得到了奥芬达唑开发公司的支持， 小组将组成一个多学科小组，由在片形吸虫病，现场流行病学， 临床试验和新药开发，以确保本研究的成功完成。这 这项试验有可能为慢性肝片吸虫病的治疗提供一种新的护理标准。在 此外，这将是第一次评估OXF对人体组织寄生虫的疗效，并构成了一个新的研究领域。 这是朝着使这种有前途的药物用于治疗人类迈出的重要一步。它将 提供额外的药代动力学和安全性数据，以推进OXF作为人用药物的开发。