Core Clinical Consortium for Blood and Marrow Transplant Clinical Trials Network

摘要 为了解决很少有造血细胞移植(HCT)患者，特别是异基因HCT患者 患者，进入临床试验，探索改善结果的策略，NHLBI和NCI特许血液 和骨髓临床试验网络(BMT CTN)于2001年成立。本申请的目标1建议继续 由佛罗里达大学(UF)和埃默里大学(EU)组成的UF联盟作为 BMT CTN核心联合体，继续参与多项正在进行的试验和即将实施的试验 在下一个资金周期。UF财团每年进行600次HCT。UF财团一直是 自2001年BMT CTN成立以来高度有效的核心中心，其一贯的跟踪记录证明 达到或超过所有年度BMT CTN性能标准。UF财团参与了41个 在42个BMT CTN试验中，一直超过年度目标登记人数，一直处于核心试验的前25% 在本供资周期内，中心/财团的注册人数增加了一倍，注册人数增加了一倍，达到BMT CTN 在上一个供资周期内进行的试验。Wingard博士和Waller博士以及UF财团的其他调查人员 提供强有力的科学领导，撰写了25篇出版物(4篇为第一作者，3篇为资深作者)，担任 14个礼宾委员会(2个)、6个终点审查委员会和7个行政和技术委员会 委员会(担任3个委员会的主席)。两人都曾在NIH国家科学研讨会上担任领导职务。 数据报告错误率一直远低于BMT CTN研究的目标错误率(2.0%或更低)。 同样，报告的及时性也超过了CTN的验收标准。UF联合体的优势 这一核心将能够继续扩大其对BMT CTN试验的应计费用。UF的独特优势 财团为下一轮资金带来的是获得大量镰状细胞病(SCD)患者的机会， 每个HCT团队与SCD合作者、经验丰富的免疫重建实验室、 树突状细胞制造和其他新型细胞疗法制造能力在两个地点都有 两个地点正在进行的细胞疫苗/HCT试验。 本申请的目的2提出协议概念以解决确定的2个高优先级研究主题 《科学状况研讨会：移植物抗宿主病(GVHD)和感染》。多样性的变化 异基因HCT后肠道微生物区系的变化与严重感染、GVHD、治疗- 相关死亡率、肺部并发症和复发。吲哚化合物，由肠道产生 微生物区系，具有免疫调节特性。我们对小鼠的先导研究表明，吲哚 益生素可以降低GVHD的风险，同时保留移植物抗白血病的作用。在此应用程序中，我们 建议测试一种吲哚益生素干预措施，以预防移植物抗宿主病和严重感染，首先在随机 第二阶段试验在多中心环境下评估可行性，然后在第三阶段随机试验中进行。这一新方法 预防移植物抗宿主病为避免目前免疫抑制方案的毒副作用提供了前景。

Abstract To address the concern that few hematopoietic cell transplant (HCT) patients, especially allogeneic HCT patients, enter clinical trials to explore strategies to improve outcomes, the NHLBI and NCI chartered the Blood and Marrow Clinical Trials Network (BMT CTN) in 2001. Aim 1of this application proposes continuation of participation of the UF Consortium, consisting of the University of Florida (UF) and Emory University (EU), as a core consortium of the BMT CTN for continued participation in multiple ongoing trials and trials to be implemented in the next funding cycle. The UF Consortium performs >600 HCTs annually. The UF Consortium has been a highly effective core center since the BMT CTN's inception in 2001 with a proven track record of consistently meeting or exceeding all annual BMT CTN performance standards. The UF Consortium has participated in 41 of 42 BMT CTN trials, has consistently exceeded annual target enrollments, has been in the top 25% of core centers/consortia in enrollment during the current funding cycle, and has doubled its enrollments to BMT CTN trials during the past funding cycle. Drs. Wingard and Waller and other UF consortium investigators have provided strong scientific leadership, authoring 25 publications (4 as first author and 3 as senior author), serving on 14 Protocol Committees (2 as PI), 6 Endpoint Review Committees, and 7 Administrative and Technical Committees (serving as chair of 3). Both have served in leadership roles in the NIH State of Science Symposia. Data reporting error rates have been well below the targeted error rate for the BMT CTN studies (2.0 % or lower). Similarly, timeliness of reports has exceeded CTN acceptance standards. The advantage of the UF Consortium is that this core will be able to continue to expand its accrual to BMT CTN trials. Unique strengths the UF Consortium brings to this next cycle of funding is access to large numbers of Sickle Cell Disease (SCD) patients, robust interactions of each HCT team with SCD collaborators, an experienced immune reconstitution laboratory, dendritic cell manufacturing and other novel cell therapy manufacturing capacity at both sites with multiple ongoing cell vaccine/HCT trials at both sites. Aim 2 of this application proposes a protocol concept to address 2 high priority research topics identified in the States of Science Symposia: graft versus host disease (GVHD) and infection. Alterations in the diversity of the gut microbiota after allogeneic HCT are associated with risks for serious infections, GVHD, treatment- related mortality, pulmonary complications and relapse. Indole compounds, produced by the intestinal microbiota, have immunoregulatory properties. Pilot murine studies by us indicate the ability of an indole prebiotic to reduce the risk for GVHD while preserving graft versus leukemia effects. In this application we propose to test an indole prebiotic intervention to prevent GVHD and serious infection, first in a randomized phase 2 trial to assess feasibility in a multicenter setting, then in a phase 3 randomized trial. This novel approach to prevent GVHD offers the prospect to avoid toxicities of current immunosuppressive regimens.