The Impact of GAD on Preservation on B Cell Function

GAD 对 B 细胞功能保存的影响

• 批准号: 6798773
• 负责人: DIANE K WHERRETT
• 金额: $ 16.66万
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6798773
• 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） 该应用程序的目标是：描述 病童医院/多伦多大学作为临床中心 TrialNet 并描述确定是否进行静脉治疗的研究 谷氨酸脱羧酶 (GAD) 会改变针对以下部位的免疫反应 胰岛细胞从而阻止两组 B 细胞的持续破坏 受试者：（1）新诊断的1型糖尿病（DM1）患者，使用 将保留 C 肽分泌作为主要终点（干预）；和 (2) DM1患者的亲属有患糖尿病的显着风险，如 由两种胰岛抗体的存在定义，使用预防/延迟损失 第一阶段胰岛素释放作为主要终点（预防）。 临床中心包括： 首席研究员和联合研究员 Drs.黛安 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；病童医院基础设施强大 提供设施、临床试验、 方法和统计支持以及科学环境来开展 这些研究；大区内的儿科和成人机构网络 多伦多地区及其他地区将提供大量的学习科目 参与并拥有高水平参与的良好记录 ENDIT 和 DPT-1 中的糖尿病预防试验。 干预研究将使用随机、双盲、安慰剂对照 设计评估肠外 GAD 的有效性和安全性，以维持残留 新发 DM1 患者的胰岛素分泌。 132 名 DM1 患者将被 胰岛素治疗开始后 4 周内确定。他们将被随机分配 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 个月时膳食刺激的平均 C 肽水平 通过双边 t 检验与安慰剂进行比较。安全性的中期分析将是 执行。 预防研究将使用随机、双盲、安慰剂对照的研究 旨在评估胃肠外 GAD 在预防丢失中的功效 1 型患者一级亲属的第一阶段胰岛素释放 糖尿病。它涉及： 筛查一级亲属的抗体 胰岛素、IA-2 和 GAD（以及具有 1 个阳性抗体的患者中的 ICA），如果其中 2 个 GAD、IA-2 或胰岛素抗体大于第 97 个百分位，则； 通过静脉内葡萄糖耐量试验 (IVGTT) 进行分期以测量第一阶段 胰岛素释放 (FPIR)、HLA 分型以排除 DQB10602 并确认 胰岛抗体状态，如果 FPIR 大于年龄的第一个百分位数并且 正常口服葡萄糖耐量，则； GAD 干预的 1:1 随机分组 或控制；每 6 个月进行一次 IVGTT 随访，如果少于第一次则重复 百分位数，如果得到确认，则受试者已达到研究终点。初级 分析将测试受试者和对照比例的​​差异 FPIR 低于年龄第 1 个百分位，使用双面卡方检验 连续性校正。