CLINICAL TRIAL: TYPE 1 DIABETES: CELLCEPT ALONE OR IN COMBINATION WITH DACLIZUMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们建议采用三组随机、部分盲、安慰剂对照的方法，将霉酚酸酯(MMF)单独使用、MMF与Daclizumab联合使用以及仅口服安慰剂进行比较。将研究治疗对b细胞功能丧失、糖尿病特异性免疫反应和一般免疫反应的影响。我们将确定这些治疗是否具有临床疗效，并试图通过定义药物如何改变糖尿病特异性免疫反应和一般免疫反应来确定潜在的作用机制。在这项试验中，糖尿病特异性免疫反应的机制研究将包括自身抗体效价的研究、糖尿病特异性T细胞的功能研究和召回抗原反应性的评估。如果药剂(S)被证明是有效的，这项试验将开发出可用于更大规模研究的信息。 具体目标1是一项临床试验，以检验这一假设：在确诊时，仅MMF将使1型糖尿病患者的C-肽水平保持两年或更长时间。这项研究将招募60名受试者，他们将被随机分成30组，每天两次口服750 mg/m2或2000 mg/天的MMF，或在两年的随访期内服用MMF的安慰剂。B细胞功能终点是基础和刺激的C-肽，其次是胰岛素剂量、HbA1c和降糖事件的数量。 具体目标2将检查和开发拟议治疗的免疫效果的替代标记物。它们是：疾病特定终点：自身抗体测定、T细胞反应性和频率。有免疫学的终点：T细胞对召回抗原的反应性和活化T细胞的频率。

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 3-arm randomized, partially-blind, placebo-controlled comparison of Mycophenolate Mofetil (MMF) alone, MMF with Daclizumab, and oral placebo only. The effects of the treatment on the loss of b-cell function, diabetes-specific immune responses and general immune responses will be studied. We will determine whether these treatments have clinical efficacy and attempt to determine the potential mechanism of action by defining how the drug alters both diabetes-specific and general immune responses. The mechanistic studies of diabetes-specific immune responses in this trial will include studies of titers of autoantibodies, functional studies of diabetes specific T-cells and assessment of recall antigen reactivity. This trial will develop information which can be used in larger studies should the agent(s) prove to be effective. Specific Aim 1 is a clinical trial to test the hypothesis: MMF alone will preserve C-peptide levels in type 1 diabetics for 2 or more years when started at diagnosis. The study will enroll 60 subjects who will be randomized into groups of 30 to receive 750 mg/m2 or 2000 mg/day of MMF by mouth twice daily or a placebo for the MMF over the 2-yr follow-up period. The b-cell function endpoints are basal and stimulated C-peptide following Sustacal¿ and, secondarily, insulin dose, HbA1c and number of hypoglycemic events. Specific Aim 2 will examine and develop surrogate markers for immunologic effects of the proposed treatments. These are: disease-specific endpoints: autoantibody determinations, T-cell reactivity and frequency. There are immunological endpoints: T-cell reactivity to recall antigens and frequency of activated T-cells.