Treating cutaneous leishmaniasis by radio-frequency induced heat (RFH) therapy

描述（由申请方提供）：利什曼原虫属原虫寄生虫引起的感染包括皮肤（CL）、粘膜（ML）和内脏利什曼病（VL）。目前有1 200多万人患有利什曼病，每年约有200万新病例，使其成为一个重大的全球健康问题。最近，CL已经在美国的犬群以及在伊拉克和阿富汗服役的军队人员中发现。全身五价锑剂如葡萄糖酸锑钠（SSG）是全球推荐的CL治疗方法，但它们具有毒性，并且治疗依从性较差，因为需要每日注射3周或更长时间。此外，在免疫功能低下的个体中，锑治疗与复发有关。我们感兴趣的是新的治疗CL是安全的，易于管理和有效地诱导长期治愈。最近，射频热（RFH）疗法已用于治疗CL。这种治疗在局部麻醉下将受控和局部的射频输送到病变中30-60秒。几项短期随访（4-5个月）研究和一项长期随访（12个月）研究涉及感染L。在伊拉克的一位少校发现RFH疗法与全身性锑疗法相当，甚至更好。我们最近发现RFH疗法在诱导SSG难治的HIV感染患者的CL治愈方面也有效。此外，我们发现RFH治疗诱导近98%的免疫活性CL患者在6个月内完全临床治愈，长达1年无复发。这些研究结果表明，RFH治疗应该是有效的诱导长期治愈CL的免疫功能正常以及免疫功能低下的患者，因此可以代表一种新的一线治疗。然而，需要进行临床试验来确定RFH疗法治疗由传统药物难以治疗的其他利什曼原虫属引起的CL的治愈率和长期疗效，并确定疾病复发的风险（如果有的话）生活在利什曼原虫流行地区的患者。这项R34申请的目标是计划一项开放标签的III期临床试验，以比较长期 RFH治疗与SSG治疗利什曼原虫流行区患者CL的疗效比较。我们建议在印度、埃塞俄比亚、秘鲁和危地马拉进行本试验，因为这些地区的感染是由不同的利什曼原虫属引起的，它们代表了临床上不同形式的CL。该R34申请将允许我们选择研究团队成员，确定入组研究中心和当地实验室，并获得当地监管机构和机构审查委员会的批准（目标1），并最终确定临床试验方案，包括统计分析计划，数据管理和安全性监测计划以及知情同意过程和文件（目标2）。这些目标的实现将为我们的多中心临床试验奠定良好的基础。 公共卫生相关性：皮肤利什曼病由利什曼原虫寄生虫引起。这种感染是一个全球性的健康问题，也是一种被忽视的热带疾病。这种疾病还影响了在伊拉克和阿富汗服役的几名美国陆军人员以及美国的犬群。目前CL的治疗涉及20次五价锑药物注射，这些药物有毒，患者依从性差。本提案的目标是计划一项III期开放标签多中心临床试验，以比较传统锑注射治疗与单一局部射频诱导热疗法治疗印度、秘鲁、危地马拉和埃塞俄比亚利什曼原虫流行地区患者CL的长期疗效。

DESCRIPTION (provided by applicant): Infections caused by protozoan parasites of the genus Leishmania include cutaneous (CL), mucosal (ML) and visceral leishmaniasis (VL). Over 12 million people are currently suffering from leishmaniasis, and approximately 2 million new cases occur annually, making it a major global health problem. Recently, CL has been seen in canine populations in the US as well as army personnel serving in Iraq and Afghanistan. Systemic pentavalent antimonials such as sodium stibogluconate (SSG) are the recommended treatment for CL world-wide, but they are toxic, and compliance with treatment is poor because daily injections for 3 weeks or longer are required. Furthermore, in immunocompromised individuals antimonial treatment is associated with relapses. We are interested in novel treatments for CL that are safe, easy to administer and effective in inducing long-term cure. Recently, radio-frequency-induced heat (RFH) therapy has been used in the treatment of CL. This treatment delivers controlled and localized radiofrequencies into lesions for 30-60 seconds under local anesthesia. Several short-term follow-up (4-5 months) studies and one long-term follow-up (12 months) study involving US soldiers who were infected with L. major in Iraq found that RFH therapy was comparable, or even better, than systemic antimonial therapy. We recently found that RFH therapy was also effective in inducing cure of CL in HIV-infected patients who were refractory to SSG. Furthermore, we found that RFH therapy induced complete clinical cure in nearly 98% of immunocompetent CL patients by 6 months with no relapses for up to 1 year. These findings suggest that RFH therapy should be effective in inducing long-term cure of CL in immunocompetent as well as immunocompromised patients, and could therefore represent a novel first line of treatment. However, a clinical trial is needed o determine cure rates and establish long-term efficacy of RFH therapy in treatment of CL caused by other Leishmania species that are difficult to treat with conventional drugs, and to determine the risk of disease recurrence (if any) in patients living in Leishmania endemic regions. The goal of this R34 application is to plan an open-label phase III clinical trial to compare the long- term efficacy of RFH therapy versus SSG in the treatment of CL in patients residing in Leishmania endemic regions. We propose to perform this trial in India, Ethiopia, Peru and Guatemala because infections in these regions are caused by different Leishmania species, and they represent clinically diverse forms of CL. This R34 application will allow us to select study team members, identify enrollment sites and local laboratories, and obtain approvals from local regulators and Institutional Review Boards (Aim 1), and to finalize the clinical trial protocol including a statistical analysis plan, data management and safety monitoring plans, and informed consent process and documents (Aim 2). Accomplishing these aims will lay a sound foundation for our multicenter clinical trial. PUBLIC HEALTH RELEVANCE: Cutaneous leishmaniasis is caused by Leishmania parasites. This infection is a global health problem and a neglected tropical disease. This disease has also affected several US Army personnel serving in Iraq and Afghanistan as well as canine populations in the US. Current treatment of CL involves 20 injections of pentavalent antimonial drugs which are toxic and have poor patient compliance. The goal of this proposal is to plan a Phase III open label multicenter clinical trial to compare long-term efficacies of conventional antimonial injection treatment versus a single topical RF-induced heat therapy in treatment of CL in patients living in Leishmania endemic regions of India, Peru, Guatemala and Ethiopia.