Phase II trial of extended release exenatide (Bydureon) and teplizumab in patients with new onset Type 1 Diabetes.

在新发 1 型糖尿病患者中进行缓释艾塞那肽 (Bydureon) 和 teplizumab 的 II 期试验。

• 批准号: 9143838
• 负责人: Kevan C Herold
• 金额: $ 25.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9143838
• 关键词: Address; Affect; Age; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Beta Cell; Binding; Biological Assay; C-Peptide; CD3 Antigens; CD8B1 gene; Caring; Cell physiology; Child; Clinical; Clinical Trials; Control Groups; Data; Development; Diabetes Mellitus; Disease; Disease remission; Documentation; Drug Combinations; Event; Flow Cytometry; Frequencies; Gastric Emptying; Genes; Genetic; Glucagon; Glucose; Glycosylated hemoglobin A; Grant; Hypoglycemia; Immune; Immune Tolerance; Immune system; Immunologics; Immunotherapy; Impairment; Inbred NOD Mice; Incidence; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Lamina Propria; MS4A1 gene; Measurement; Measures; Mediating; Metabolic; Non-Insulin-Dependent Diabetes Mellitus; Organ; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Population Heterogeneity; Preparation; Protocols documentation; RNA; Randomized; Randomized Controlled Clinical Trials; Randomized Controlled Trials; Reporting; Schedule; Site; T-Lymphocyte; Technology; Testing; Translating; Work; alefacept; arm; base; cell killing; clinical care; clinical effect; clinical remission; design; drug mechanism; efficacy testing; exenatide; genetic signature; glucagon-like peptide 1; gut microbiota; humanized mouse; improved; insulin dependent diabetes mellitus onset; insulin secretion; microbiome; migration; novel; novel therapeutics; phase II trial; pre-clinical; prevent; randomized trial; receptor; response; rituximab; small molecule; therapy development; treatment planning; Address; Affect; Age; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Beta Cell; Binding; Biological Assay; C-Peptide; CD3 Antigens; CD8B1 gene; Caring; Cell physiology; Child; Clinical; Clinical Trials; Control Groups; Data; Development; Diabetes Mellitus; Disease; Disease remission; Documentation; Drug Combinations; Event; Flow Cytometry; Frequencies; Gastric Emptying; Genes; Genetic; Glucagon; Glucose; Glycosylated hemoglobin A; Grant; Hypoglycemia; Immune; Immune Tolerance; Immune system; Immunologics; Immunotherapy; Impairment; Inbred NOD Mice; Incidence; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Lamina Propria; MS4A1 gene; Measurement; Measures; Mediating; Metabolic; Non-Insulin-Dependent Diabetes Mellitus; Organ; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Population Heterogeneity; Preparation; Protocols documentation; RNA; Randomized; Randomized Controlled Clinical Trials; Randomized Controlled Trials; Reporting; Schedule; Site; T-Lymphocyte; Technology; Testing; Translating; Work; alefacept; arm; base; cell killing; clinical care; clinical effect; clinical remission; design; drug mechanism; efficacy testing; exenatide; genetic signature; glucagon-like peptide 1; gut microbiota; humanized mouse; improved; insulin dependent diabetes mellitus onset; insulin secretion; microbiome; migration; novel; novel therapeutics; phase II trial; pre-clinical; prevent; randomized trial; receptor; response; rituximab; small molecule; therapy development; treatment planning

There have been great advances in understanding the immunologic mechanisms of Type 1 diabetes (T1D) but these advances have not translated into new therapies for the disease. The results of recent “successful” trials have shown transient improvement in insulin secretion but sustained improvement has not been uniformly seen. The basis for this proposal is that the successful development of an immune therapy requires addressing the metabolic impairment as well. This R34 planning grant is to design and complete the administrative and other tasks needed to commence a randomized Phase II clinical trial to compare the combination of teplizumab (a non-FcR binding anti-CD3 mAb) with Bydureon (extended release exenatide) to either drug alone in patients with new onset T1D. Teplizumab has been shown, in 4 randomized controlled clinical trials, to improve C- peptide responses in patients with new and recent onset T1D. In previous studies, we have identified immunologic mechanisms that are associated with clinical responses, involving modulation of the CD8+ T cell compartment. In addition, we found that the drug causes migration of T cells to the gut and acquisition of regulatory function. Bydureon, the GLP-1 receptor agonist, is approved for treatment of T2D. Its mechanisms of action target dysfunctional features of T1D. It inhibits glucagon levels, slows gastric emptying, stimulates insulin release, and has been postulated to stimulate beta cell replication. It also may have anti-inflammatory effects. Short term use of exenatide has been shown to have dramatic effects reducing post-prandial glucose excursions. The primary endpoint of the proposed trial is to test whether the combination of teplizumab + Bydureon is more effective than either drug alone in inducing clinical remission defined as a HbA1c< 7.0% and insulin use < 0.25U/kg/d: These parameters were chosen based on ADA standards of care the analysis of previous clinical trials. The secondary endpoints including a comparison of C-peptide responses in the treatment arms, the frequency of insulin independent remissions, and glycemic excursion. An important part of the proposed studies is to build on our previous studies and those from collaborative work with the ITN to identify the basis for immunologic responses. We will expand our studies of the gene signatures found in clinical responders and the changes in diabetes antigen specific CD8+ T cells as well as the rates of β cell killing. In addition, we will test the novel hypothesis that the microbiome modulates responses to teplizumab which has been suggested by our studies in humanized mice. This clinical trial proposal is unique because it is the first that addresses two relevant disease mechanisms. It also uses, as endpoints, measurements that are likely to be widely accepted and enable the development of treatments that will improve the clinical condition for patients.

在理解1型糖尿病（T1D）的免疫机制方面取得了巨大进步，但是 这些进步尚未转化为该疾病的新疗法。最近的“成功”试验的结果 已经显示出胰岛素分泌的短暂改善，但持续改进并不统一 看到。该提案的基础是，免疫疗法的成功开发需要解决 代谢障碍也是如此。 R34计划赠款是设计和完成行政管理 开始进行一项随机II期临床试验所需的其他任务，以比较Teplizumab的组合 （一种非FCR结合抗CD3 mAb）与bydureon（扩展释放艾烯肽）单独使用患者的任何一种药物 使用新的发作T1D。在4项随机对照临床试验中，Teplizumab已显示出来，以改善C- 新发作T1D患者的肽反应。在先前的研究中，我们已经确定了 与临床反应相关的免疫机制，涉及CD8+ T细胞的调节 车厢。此外，我们发现该药物会导致T细胞迁移到肠道并获得 调节功能。 GLP-1受体激动剂Bydureon被批准用于治疗T2D。它的机制 T1D的动作目标功能障碍特征。它抑制胰高血糖素水平，减慢胃排空，刺激 胰岛素释放，已被张贴以刺激β细胞复制。它也可能具有抗炎 效果。短期使用艾烯肽具有巨大的效应，可减少后葡萄糖 游览。拟议试验的主要终点是测试teplizumab +的组合 在定义为HbA1c <7.0％的诱导临床缓解中，Bydureon比单独使用任何一种药物更有效 胰岛素使用<0.25U/kg/d：根据ADA护理标准选择这些参数 先前的临床试验。次要终点包括对C肽反应的比较 治疗臂，胰岛素独立复原的频率和血糖游览。一个重要的部分 拟议的研究是基于我们以前的研究以及与ITN合作工作的研究 确定免疫反应的基础。我们将扩大对在 临床反应和糖尿病抗原特异性CD8+ T细胞的变化以及β细胞的速率 杀人。此外，我们将测试微生物组调节对Teplizumab的反应的新假设 我们在人性化小鼠中的研究提出了这一点。该临床试验建议是独一无二的 第一个解决了两种相关疾病机制。它还用作终点，是 可能被广泛接受，并能够开发可以改善临床状况的治疗方法 适用于患者。