Northwest Clinical Center for Type 1 Diabetes - TrialNet

描述（由申请人提供）：本申请重新选择为糖尿病TrialNet临床中心包括（1）拟定的临床试验（2）我们在开展1型糖尿病临床研究方面的活动描述（3）我们的招募工作描述，以及（4）可用于开展TrialNet方案的临床设施描述。 先前的研究已经证明，短期施用抗T细胞、抗B细胞和基于抗原的治疗至少暂时改变了β细胞破坏的过程。延长治疗益处可能需要联合治疗，例如消除T效应子应答、保护β细胞、活化T调节细胞和增强胰岛素作用。TrialNet和其他团队已经成功开发了一个平台，可以在新诊断的受试者中快速测试治疗方法。我们认为，系统地测试各种各样的代理和谨慎地使用临床样本进行探索性数据分析是唯一的出路。 为此，我们建议测试Tocilizumab（抗IL 6 Rab）对最近诊断为1型糖尿病的受试者的影响，以确定它是否会保留β细胞功能。我们选择抗IL 6 Rab是基于以下观察：（1）在机制上，抗IL 6 Rab可以具有几种重要的作用，既作为促进T调节细胞活性的治疗，允许延长疾病的缓解，又作为改变局部胰腺炎性浸润的抗炎剂，允许增强的β细胞功能和/或允许增强的胰岛素作用，（2）存在关于使用抗-IL 6 Rab的临床安全性数据，包括在儿童中的数据。（3）抗-IL 6 Rab在治疗其它自身免疫性疾病中临床有效。 本试验的具体目的是： （证明抗IL 6 Rab在新诊断患者中的短期安全性， （证明抗IL 6 Rab在新诊断的患者中关于保留IL 6 Rab的功效。 β细胞功能 （测试抗IL 6 Rab疗法和对疗法的响应对与我们的主要假设作用机制-促进调节性T细胞的活性-相关的测量的影响。 公共卫生相关性：1型糖尿病涉及产生胰岛素的β细胞的免疫介导的破坏，导致对外源性胰岛素的终身依赖。T1 DM是儿童及其家庭的一个特别负担，是最常见的慢性儿童疾病之一。可以延迟或停止β细胞破坏的治疗将显著改善糖尿病受试者的日常管理并减少长期并发症，从而对T1 DM患者产生显著的临床影响。

DESCRIPTION (provided by applicant): This application for re-selection as a Diabetes TrialNet Clinical Center consist of (1) a proposed clinical trial (2) a description of our activities in the conduct of Type 1 diabetes clinical research (3) a description of our recruitment efforts, and (4) a description of the clinical facilities available for the conduct of TrialNet protocols. Previous studies have demonstrated that short term administration of anti-T cell, anti-B cell, and antigen-based therapy at least temporarily alters the course of beta cell destruction. Extending therapeutic benefits will likely require combination therapy such as elimination of the T effector response, protection of beta cells, activation of T regulatory cells, and enhancement of insulin action. TrialNet and other groups have successfully developed a platform to rapidly test therapies in newly diagnosed subjects. We believe that systematic testing of a wide variety of agents and careful use of clinical samples for exploratory analysis of data is the only way forward. To that end, we propose to test the effect of Tocilizumab (Anti-IL6Rab) on recently diagnosed subjects with Type 1 diabetes to determine whether it will preserve beta cell function. Our selection of Anti- IL6Rab is based on the following observations: (1) mechanistically, Anti-IL6Rab may have several important effects both as a therapy promoting the activity of T-regulatory cells allowing prolonged remission of disease, and as an anti-inflammatory altering the local pancreatic inflammatory infiltrate allowing enhanced beta cell function and/or allowing enhanced insulin action, (2) there is clinical safety data on the use of Anti-IL6Rab including data in children, (3) Anti-IL6Rab is clinically efficacious in treatment of other autoimmune diseases. The specific aims of this trial are to: ( Demonstrate the short term safety of Anti-IL6Rab in newly diagnosed patients, ( Demonstrate the efficacy of Anti-IL6Rab in newly diagnosed patients with respect to preservation of beta cell function ( Test the impact of Anti-IL6Rab therapy and response to therapy on measures associated with our primary hypothesized mechanism of action - promoting the activity of T regulatory cells. PUBLIC HEALTH RELEVANCE: Type 1 diabetes involves immune mediated destruction of insulin producing beta cells leading to lifelong dependence upon exogenous insulin. T1DM is a particular burden to children and their families, representing one of the most common chronic childhood diseases. A therapy that could delay or halt beta cell destruction would significantly improve the day-to-day management for subjects with diabetes and reduce long-term complications, thereby having significant clinical impact on patients with T1DM.