Preservation of Beta Cells by Glutamate Decarboxylase

谷氨酸脱羧酶保存 Beta 细胞

• 批准号: 6442668
• 负责人: DIANE K WHERRETT
• 金额: $ 15.7万
• 依托单位: HOSPITAL FOR SICK CHLDRN (TORONTO)
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-29 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6442668
• 关键词: adolescence (12-20); blood tests; cell population study; clinical trials; cooperative study; cytoprotection; diabetes mellitus therapy; disease /disorder prevention /control; gene therapy; genetic susceptibility; glucose tolerance test; glutamate decarboxylase; human subject; human therapy evaluation; immunologic assay /test; immunoregulation; insulin dependent diabetes mellitus; intravenous administration; longitudinal human study; middle childhood (6-11); outcomes research; pancreatic islets; patient oriented research; protein structure function; statistics /biometry; young adult human (21-34)

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.

描述(由申请人提供) 本应用程序的目标是：描述 患病儿童医院/多伦多大学作为临床中心的网站 TrialNet和描述确定静脉治疗是否 与谷氨酸脱羧酶(GAD)一起改变针对 胰岛细胞，从而防止正在进行的B细胞破坏两组 对象：(1)新诊断的1型糖尿病(DM1)患者，使用 保留C-肽分泌作为主要终点(干预)；以及 (2)有显著糖尿病风险的DM1患者的亲属，如 由两种胰岛抗体的存在定义，使用预防/延迟丢失 将第一阶段胰岛素释放作为主要终点(预防)。 临床中心包括：首席和联合调查员戴安博士 Wherrett，Denis Daneman和Jeffrey Mahon，他们在 临床试验、糖尿病预防试验、研究设计和免疫学 1型糖尿病；患病儿童医院的强大基础设施 提供设备、临床试验、 执行的方法和统计支持以及科学环境 这些研究；大中华区的儿科和成人机构网络 多伦多地区及更远地区，这将为研究提供一个巨大的学科池 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、安慰剂对照的 评估肠外GAD维持残留的有效性和安全性的设计 新发糖尿病患者的胰岛素分泌。132名患有DM1的患者将被 在胰岛素治疗开始后4周内确诊。他们将被随机化 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 对安慰剂进行双侧t检验。对安全性的中期分析将是 被执行。 预防研究将使用随机、双盲、安慰剂对照的 评估肠外GAD预防失血的有效性的设计 1型患者一级亲属的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(在抗体1阳性的人中还有ICA)，如果2 GAD、IA-2或胰岛素抗体大于第97个百分位数； 静脉葡萄糖耐量试验(IVGTT)分期测定第一时相 胰岛素释放(FPIR)，排除DQB10602的人类白细胞抗原配型和确认 胰岛抗体状态，如果FPIR大于年龄的第一个百分位数，并且 正常的口服葡萄糖耐量；GAD的随机1：1干预 或对照组；每6个月进行一次IVGTT随访，如果不到1个月，重复进行 百分位数，如果确认，则表示受试者已达到研究终点。初级阶段 分析将测试受试者和对照组比例的差异 年龄的第一个百分位数以下，使用双侧卡方检验 连续性修正。