The Impact of GAD on Preservation on B Cell Function

描述（由申请人提供） 本申请的目标是：描述 儿童医院/多伦多大学作为临床中心， TrialNet和描述研究，以确定静脉治疗是否 谷氨酸脱羧酶（GAD）改变了针对 胰岛细胞，从而防止两组中持续的B细胞破坏。 受试者：（1）新诊断的1型糖尿病（DM 1）患者，使用 C肽分泌的保护作为主要终点（干预）;以及 (2)DM 1患者的亲属有患糖尿病的重大风险，如 定义为存在两种胰岛抗体，使用预防/延迟损失 第一时相胰岛素释放作为主要终点（预防）。 该临床中心包括：主要研究者和合作研究者Dr. Diane Wherrett、Denis Daneman和Jeffrey Mahon在以下方面拥有丰富的经验 临床试验，糖尿病预防试验，研究设计和免疫学 1型糖尿病;病童医院的强大基础设施 研究机构提供设施，临床试验， 提供方法和统计支助，并为开展 这些研究;一个儿科和成人机构的网络， 多伦多地区及其他地区将提供一个大型的研究主题库 参与，并有高水平参与的良好记录， 糖尿病预防试验，包括ENDIT和DPT-1。 干预研究将使用随机、双盲、安慰剂对照 设计旨在评估胃肠外GAD维持残余GAD的有效性和安全性 新发DM患者的胰岛素分泌1. 132例DM 1患者将 在胰岛素治疗开始后4周内确定。他们将被随机分组 2：1至2种不同剂量的GAD或安慰剂。研究终点将比较 GAD治疗组12个月时的平均膳食刺激C肽水平 通过双侧t检验比较安慰剂。将进行安全性中期分析 贯彻 预防研究将使用随机、双盲、安慰剂对照 旨在评估胃肠外GAD在预防 1型糖尿病患者一级亲属第一时相胰岛素释放 糖尿病它包括：筛查一级亲属的抗体， 胰岛素、IA-2和GAD（在1种抗体阳性的患者中为伊卡），如果其中2种 GAD、IA-2或胰岛素抗体大于第97百分位数，则; 用静脉葡萄糖耐量试验（IVGTT）进行分期，以测量第一时相 胰岛素释放（FPIR）、HLA分型以排除DQB 10602和确认 胰岛抗体状态，如果FPIR大于年龄的第1百分位数， 正常的口服葡萄糖耐量，然后; 1：1随机分配至GAD干预组 或对照组;每6个月进行IVGTT随访，如果少于第1次，则重复 百分位数，如果确认，受试者已达到研究终点。主 分析将检验受试者和对照者比例的差异， FPIR低于年龄的第1百分位数，使用双侧卡方检验， 连续性校正

DESCRIPTION (provided by applicant) The objectives of this application are: to describe the capability of the Hospital for Sick Children/University of Toronto site as a Clinical Center for TrialNet and to describe studies to determine whether intravenous treatment with glutamic acid decarboxylase (GAD) alters the immune response directed at islet cells thereby preventing ongoing B cell destruction in two groups of subjects: (1) patients with newly diagnosed Type 1 diabetes (DM1), using preservation of C-peptide secretion as the primary endpoint (Intervention); and (2) relatives of patients with DM1 who are at significant risk of diabetes, as defined by the presence of two islet antibodies, using prevention/delay of loss of first phase insulin release as the primary endpoint (Prevention). The clinical center includes: Principal and Co-investigators Drs. Diane Wherrett, Denis Daneman and Jeffrey Mahon, who have extensive experience in clinical trials, diabetes prevention trials, study design and immunology of Type 1 diabetes; the strong infrastructure of the Hospital for Sick Children Research Institute which provides the facilities, clinical trials, methodological and statistical support and scientific environment to carry out these studies; a network of pediatric and adult institutions within the Greater Toronto Area and beyond which will supply a large subject pool for study participation and have a proven track record of high levels of participation in diabetes prevention trials, both in ENDIT and DPT-1. The Intervention study will use a randomized, double-blind, placebo-controlled design to assess the efficacy and safety of parenteral GAD to maintain residual insulin secretion in persons with new-onset DM1. 132 patients with DM1 will be identified within 4 weeks of onset of insulin therapy. They will be randomized 2:1 to 2 different doses of GAD or placebo. The study endpoint will compare the mean meal-stimulated C-peptide level at 12 months in the GAD treated group versus placebo by a two-sided t-test. An interim analysis for safety will be carried out. The Prevention study will use a randomized, double-blind, placebo-controlled design to assess the efficacy of parenteral GAD in the prevention of loss of first phase insulin release in first degree relatives of those with Type 1 diabetes. It involves: screening first degree relatives for antibodies to insulin, IA-2, and GAD (and ICA in those with 1 positive antibody), if 2 of GAD, IA-2 or insulin antibodies are greater than the 97th percentile, then; staging with intravenous glucose tolerance test (IVGTT) to measure first phase insulin release (FPIR), HLA typing to exclude DQB10602 and confirmation of islet antibody status, if FPIR is greater than the 1st percentile for age and normal oral glucose tolerance, then; randomization 1:1 to intervention with GAD or control; follow up with IVGTT every 6 months, repeated if less than the 1st percentile, if confirmed, subject has reached study endpoint. The primary analysis will test the difference in proportion of subjects and controls with FPIR below 1st percentile for age, using a two-sided Chi Square test with continuity correction.