Planning a Multicenter Oral Itraconazole Trial in Chronic Rhinosinusitis Patients

描述（由申请人提供）：慢性鼻窦炎（CRS）是一种经常报道的慢性疾病，鼻窦炎症持续超过12周。没有药物获得FDA批准用于治疗CRS。CRS诊断和治疗的主要争议包括病因、分类和疾病严重程度的评估。目前提出了三种病因假说：由空气中过敏原引起的过敏性炎症；细菌超抗原对T细胞活化和局部IgE产生的影响CRS患者对鼻窦黏液中真菌抗原反应的免疫细胞活化。为了解决CRS可能的真菌病因，一些对照和开放标签临床试验之前已经测试了鼻内抗真菌药物作为CRS的潜在治疗方法。然而，这些研究的结果却相互矛盾。为了解决这些争议，本R34临床试验计划基金建议开展一项前瞻性、多中心、双盲、安慰剂对照的临床试验，研究口服伊曲康唑对CRS合并鼻息肉患者的疗效。这项新颖的研究将提出，在6周的磨合期后，CRS患者将口服伊曲康唑（400mg /天）或安慰剂治疗12周。具体目标包括建立一个由6个不同医疗中心组成的多中心研究小组，确定患者招募策略，制定研究方案，编写研究者手册和操作/程序手册，以及开发数据管理和研究监督工具。为了解决关于CRS严重程度的分类和评估的争议，将根据最近的共识描述精确定义患者的纳入标准。标准化的治疗方案将在所有研究中心使用，这些研究中心将在地理上分开。我们将提出传统的监测工具和新颖的策略来研究口服康内唑对CRS合并鼻息肉患者的疗效。本临床试验的目的是：1)研究口服伊曲康唑治疗的临床和免疫学疗效，2)确定从治疗中获益的患者的临床参数。该项目完成后将产生U01申请，即NIAID临床试验实施合作协议，包含所有已开发的要素。这项工作的最终目标是为CRS患者开发新的治疗和预防方法。这项研究将直接影响CRS的临床实践和决策，并将有助于为这种常见、昂贵且致残的疾病提供具体有效的治疗方法。该提案将建立来自美国不同地区的6个医疗团队，研究慢性鼻窦炎的新治疗方法。它将为这些团队提供一套一致和连贯的研究指南，以测试口服抗真菌药物的安全性和有效性，并调查患者慢性鼻窦炎的原因。

DESCRIPTION (provided by applicant): Chronic Rhinosinusitis (CRS) is a frequently reported chronic disease with sinus inflammation persisting more than 12 weeks. No medication has FDA approval to treat CRS. Major controversies in the diagnosis and treatment of CRS include etiology, classification, and assessment of disease severity. Three hypotheses for etiology have been proposed: allergic inflammation in response to airborne allergens; T cell activation and local IgE production in response to bacterial superantigens; and immune cell activation in the response of CRS patients to fungal antigens in sinus mucus. To address the possible fungal etiology of CRS, several controlled and open-label clinical trials have previously tested intranasal antifungal agents as a potential therapy for CRS. However, the results from these studies are conflicting. To resolve these controversies, this R34 Clinical Trial Planning Grant proposes to develop a prospective, multicenter, double-blind, placebo-controlled clinical trial to investigate the efficacy of oral itraconazole in patients with CRS with nasal polyps. This novel study will propose that after a 6-week run-in period, CRS patients will be treated with oral itraconazole (400 mg daily) or placebo for 12 weeks. The specific aims include establishing a multicenter research team from 6 different medical centers, defining patient recruitment strategies, developing the study protocol, writing the investigator's brochure and the manual of operations/procedures, and developing tools for data management and research oversight. To address the controversies regarding classification and assessment of CRS severity, the inclusion criteria for patients will be defined precisely based on recent consensus descriptions. A standardized treatment protocol will be used throughout all the study centers, which will be separated geographically. Both conventional monitoring tools and original strategies will be proposed to investigate the efficacy of oral intraconazole in patients with CRS with nasal polyps. The goals of this clinical trial will be as follows: 1) to study the clinical and immunological efficacy of oral itraconazole treatment, and 2) to identify clinical parameters for those patients who are benefited by the treatment. Completion of this project will produce the U01 application, namely the NIAID Clinical Trial Implementation Cooperative Agreement, incorporating all the developed elements. The ultimate goals for this effort are to develop novel treatment and preventive approaches for CRS patients. This study will directly impact both the clinical practice and decisions in CRS and will help to provide specific and effective therapies for this common, costly, and incapacitating disorder. This proposal will establish 6 medical teams from different areas of the U.S. to study a new treatment method for chronic rhinosinusitis. It will provide these teams with a consistent and coherent set of research guidelines to test both the safety and the effectiveness of an antifungal medication taken by mouth and to investigate the cause of the chronic rhinosinusitis in patients.