IMMUNOTHERAPY TRIAL FOR NEW ONSET TYPE 1 DIABETES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。我们提出了一项多中心、三臂随机、盲法、安慰剂对照的前瞻性研究，以检验霉酚酸酯(MMF)或霉酚酸酯与Daclizumab联用(DZB)将延长新发1型糖尿病患者的C-肽生成期的假设。代谢终点还将包括血红蛋白A1c和总胰岛素剂量。这项研究的第二个目的将检查拟议的治疗对免疫效果的替代标记物的影响，即疾病特异性终点(自身抗体决定因素、同种抗体的产生以及T细胞的反应性和频率)和免疫终点。这项研究将由芭芭拉·戴维斯儿童糖尿病中心和其他参与试验网的网站联合进行，其中包括西雅图的弗吉尼亚·梅森研究中心。这项研究的创新之处在于，被测试的药物以前从未在1型糖尿病中进行过评估，但它们是自身免疫性疾病干预措施的合理选择。我们相信这项研究是及时的，因为自从环孢素被发现可以保护新发患者的C-肽产生以来，在10年的时间里已经开发出毒性小得多的免疫抑制剂。我们的力量预测是基于之前广泛的干预研究，而被测试药物的选择也得到了动物研究的支持。MMF是心脏、肾脏和肝脏受者抗排斥治疗的有效成分。它对治疗牛皮癣很有效。选择与MMF一起使用的DZB抗IL2受体抗体在治疗急性肾排斥反应方面是有效的。这些药物在临床上的安全性证明了在1型糖尿病中进行试验是合理的，在1型糖尿病中，30%的新发患者的HbA1c水平在20年内使他们处于血管疾病的高风险之中。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We propose a multicenter, 3-arm randomized, blinded, placebo-controlled prospective study to test the hypothesis that mycophenolate (MMF) alone or MMF with daclizumab (DZB) will prolong the period of c-peptide production in subjects with new onset type 1 diabetes. Metabolic end-points will also include hemoglobin A1c and total insulin dose. A second aim of the study will examine the effect of the proposed treatment on surrogate markers for immunologic effects, namely disease-specific endpoints (autoantibody determinants, generation of alloantibodies, and T cell reactivity and frequency) and immunological endpoints. The study will be conducted jointly by the Barbara Davis Center for Childhood Diabetes and other participating TrialNet sites including the Virginia Mason Research Center in Seattle. The study is innovative in that the agents to be tested have not previously been evaluated in type 1 diabetes, but are rational choices for interventions in an autoimmune disorder. We believe the study is timely in that far less toxic immunosuppressive agents have been developed in the 10 year interval since Cyclosporine was found to preserve c-peptide production in new-onset patients. Our power projections are based on extensive previous intervention studies and the choice of agents to be tested is supported by animal studies. MMF is an effective component of anti-rejection treatment of heart, kidney and liver recipients. It is effective for the treatment of psoriasis. The DZB anti-IL2 receptor antibody selected for use with MMF is effective in treatment of acute renal rejection episodes. The safety of these agents in clinical use justifies a trial in type 1 diabetes, where 30% of new onset subjects run HbA1c levels that put them at high risk for vascular disease within 20 years.