IND 20212 (03-25-99) PHASE 3: ORBEC (ORAL BDP) -PATIENTS WITH GI GVHD-FDA-11-12-0

描述（由申请人提供）： 在美国，大约有30，000名患者接受造血细胞移植（HCT）。 大约三分之一（10，000）的移植受者接受同种异体HCT。在这些患者中，少于50%至70%或5，000至7，000名患者将发展为急性GVHD。发生GI GVHD的患者是这些患者的子集。 该拨款申请要求提供资金，以继续对用于治疗GVHD的二丙酸倍氯米松（BDP）的两种专利制剂的独特组合进行3期临床评价，即速释片剂和肠溶包衣胃耐药片剂。DOR BioPharma，Inc.称这个公式为Bec（r）。 研究设计使用诱导剂量的泼尼松来控制GI GVHD的表现，然后在症状对初始治疗有反应的受试者中快速递减泼尼松剂量，同时受试者继续服用研究药物[安慰剂片剂或口服局部活性糖皮质激素（丙酸倍氯米松，BDP）]。BDP及其代谢产物17-丙酸倍氯米松（17-BMP）是强效糖皮质激素，在胃肠道粘膜中的滞留时间延长，全身生物利用度有限。因此，使用具有有限全身作用的口服局部活性糖皮质激素来控制GVHD的GI炎性过程应使全身泼尼松暴露最小化。既往研究表明，口服BDP治疗GI GVHD是安全的;本研究旨在提供令人信服的证据，证明其在泼尼松减量后控制GVHD的疗效。 共需要166例受试者（每组83例）在双侧显著性水平0.05下达到90%的把握度，以检测治疗组和安慰剂组之间26%的差异（65% vs. 39%，基于既往III期数据预测）。当第80天GVHD治疗失败的总事件达到约87起时，将终止试验。 可能会招募更多的患者，以允许在试验期间脱落。 在试验完成时，DOR打算向FDA提交文件，以允许针对这一未满足的临床需求的新治疗获得上市批准。

DESCRIPTION (provided by applicant): In the United States, approximately 30,000 patients undergo hematopoietic cell transplantation (HCT). Approximately one-third (10,000) of transplant recipients undergo allogeneic HCT. Of these patients less than 50 to 70%, or 5,000 to 7,000 patients, will develop acute GVHD. The patients that develop GI GVHD are a subset of these patients. This grant application requests funding to continue the Phase 3 clinical evaluation of a unique combination of two patented formulations of beclomethasone dipropionate (BDP) for use in treating GVHD, an immediate release tablet and an enteric-coated gastro-resistant tablet. DOR BioPharma, Inc. calls this formulation orBec(r). The study design uses an induction dose of prednisone to control the presenting manifestations of GI GVHD, then rapidly tapers the dose of prednisone in subjects whose symptoms have responded to initial treatment, while subjects continue to take the study drug [placebo tablets or an oral topically-active glucocorticoid (beclomethasone dipropionate, BDP)]. BDP and its metabolite 17-beclomethasone monopropionate (17-BMP) are potent glucocorticoids with prolonged residence time in the GI mucosa and limited systemic bioavailability. Thus, the use of an oral topically-active glucocorticoid with limited systemic effects to control the GI inflammatory process of GVHD should minimize systemic prednisone exposure. Previous studies have shown that oral BDP is safe in the treatment of GI GVHD; this study is designed to provide compelling evidence of its efficacy in controlling GVHD following a prednisone taper. A total of 166 subjects (83 per group) will be required to achieve 90% power at a 2-sided significance level of 0.05 to detect a difference of 26% of difference between treatment and placebo (65% vs. 39% projected, based on the previous Phase 3 data). The trial will be terminated when the total events for GVHD treatment failure at Day 80 has reached approximately 87. Slightly more patients may be recruited to allow for dropouts during the trial. At the completion of the trial DOR intends to file documents with the FDA to allow for marketing approval of the new treatment for this unmet clinical need.