Type 1 Diabetes TrialNet: Toronto Clinical Centre

描述(由申请人提供)：本申请的第一个目标是描述多伦多大学患病儿童医院TrialNet临床中心的优势和成功。多伦多临床中心通过其能力很强的研究人员Diane Wherrett博士和Jeffrey Mahon博士为TrialNet的1型糖尿病发展自然史研究显示出高水平的招聘，提供糖尿病、临床试验和1型糖尿病免疫学方面的专业知识、出色的协调人、机构支持和资源、富有成效的加拿大附属网络以及多伦多地区广泛的当地合作伙伴关系。这项研究的招募人员在北美14个TrialNet临床中心中排名第四。该中心在TrialNet研究中处于领先地位：1型糖尿病自然史研究主席Mahon博士和新发病受试者研究中重组人谷氨酸脱羧酶(RhGAD65)对1型糖尿病进展的影响(GAD-明矾)主席Wherrett博士。它对TrialNet的所有研究都做出了积极贡献，以保护新近发病的糖尿病患者的胰岛素分泌。第二个目标是确定单用和联合抗CD20单抗利妥昔单抗(Rituxan())治疗新发现的免疫介导型1型糖尿病患者的疗效和安全性。该提案的主要目标将是检验这样一种假设，即与单独使用这两种药物相比，埃塞那肽和利妥沙单抗联合使用更有效地保护内源性胰岛素分泌。主要结果将是在研究进入一年后进行2小时混合餐糖耐量试验时刺激的C-肽曲线(AUC)下的面积。这项研究将是安慰剂对照和双盲。这项拟议研究的基本原理是将利妥昔单抗降低β细胞自身免疫的免疫调节作用与埃塞那肽促进胰岛素分泌的β细胞再生潜力结合起来。内源性胰岛素分泌的保存被发现与糖尿病并发症低血糖、肾病和视网膜病变的发生率降低有关。 公共卫生相关性：在1型糖尿病患者中找到保护胰岛素分泌的方法对于预防疾病和减轻患者的严重程度至关重要。利妥昔单抗和埃塞那肽的联合使用既可以减少胰岛素产生细胞的损失，又可以促进它们的发展。这种疗法的成功可能会改善1型糖尿病患者的长期健康状况。

DESCRIPTION (provided by applicant): The first objective of this application is describe the strengths and successes of the TrialNet Clinical Center at the Hospital for Sick Children/University of Toronto. The Toronto Clinical Center has shown a high level of recruitment for the TrialNet Natural History of the Development of Type 1 Diabetes Study through its highly capable investigators, Drs. Diane Wherrett and Jeffrey Mahon, providing expertise in diabetes, clinical trials and immunology of type 1 diabetes, its excellent coordinators, institutional support and resources, a productive Canadian affiliate network and extensive local partnerships in the Toronto area. Recruitment to this study ranks 4th of the 14 North American TrialNet Clinical Centers. This center has provided leadership in TrialNet studies: Dr. Mahon, chair of the Natural History Study of the Development of Type 1 Diabetes Study and Dr. Wherrett, chair of the Effects of Recombinant Human Glutamic Acid Decarboxylase (rhGAD65) Formulated in Alum (GAD-alum) on the Progression of Type 1 Diabetes in New Onset Subjects Study. It has contributed actively to all of TrialNet's studies to preserve insulin secretion in recent onset diabetes. The second objective is to determine the efficacy and safety of the incretin mimetic exenatide (Byetta(), alone and in combination with the anti-CD20 monoclonal antibody rituximab (Rituxan(), in patients with newly recognized immune-mediated Type 1 Diabetes. The proposal's primary objective will be to test the hypothesis that the combination of exenatide and rituxamab more effectively preserves endogenous insulin secretion compared to either drug alone. The primary outcome will be the area under the stimulated C-peptide curve (AUC) during a 2 hour mixed meal glucose tolerance test one year after study entry. The study will be placebo controlled and double blinded. The rationale for this proposed study combines the immunomodulatory effect of rituximab to reduce beta cell autoimmunity with the beta cell regenerative potential of exenatide to improve insulin secretion. Preserved endogenous insulin secretion has been found to be associated with reduced of rates of the diabetes complications of hypoglycemia, nephropathy and retinopathy. PUBLIC HEALTH RELEVANCE: Finding methods to preserve insulin secretion in type 1 diabetes are crucial in preventing the disease and in reducing the severity in those affected. The combination of rituximab and exenatide has the potential to both reduce the loss of insulin-producing cells and to promote their development. Success of this therapy could result in the improvement of long term health for those with type 1 diabetes.