Type 1 Diabetes TrialNet Clinical Center: Effects of Alefacept in New Onset T1D

1 型糖尿病 TrialNet 临床中心：Alefacept 对新发 T1D 的影响

• 批准号: 7938585
• 负责人: JENNIFER B MARKS
• 金额: $ 62.04万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938585
• 关键词: Adolescent; Adult; Adverse effects; Affect; Ancillary Study; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; Basic Science; Beta Cell; Biological Markers; Biological Preservation; C-Peptide; CD8B1 gene; Cell physiology; Cells; Child; Chronic; Chronic small plaque psoriasis; Clinical; Clinical Research; Clinical Trials; Consensus; Data; Dependence; Development; Diabetes Mellitus; Diabetes prevention; Disease; Disease Progression; Dose; Endocrinologist; Enrollment; Ensure; Environment; Evaluation; FDA approved; Frequencies; Funding; Future; Genetic; Goals; Hour; Human Resources; Immune; Immunology; Immunosuppressive Agents; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Intervention Trial; Investigation; Life; Link; Lymphocyte; Masks; Mediating; Memory; Metabolic; Molecular; Natural History; Oral; Other Genetics; Outcome; Participant; Pathogenesis; Patients; Performance; Pharmaceutical Preparations; Phase; Placebo Control; Population; Positioning Attribute; Prevention; Principal Investigator; Process; Protocols documentation; Randomized; Research; Research Personnel; Role; Safety; Secretory Cell; Self Tolerance; Site; Solid; Structure of beta Cell of islet; T memory cell; T-Lymphocyte; Testing; Therapeutic; alefacept; autoreactive T cell; base; design; expectation; experience; follow-up; innovation; insulin secretion; islet; member; novel; placebo controlled study; prevent; primary outcome; public health relevance; randomized placebo controlled trial; response; restoration; safety testing; success

DESCRIPTION (provided by applicant): T1D occurs in genetically predisposed individuals as a consequence of the progressive, selective destruction of pancreatic beta-cells which is primarily mediated by autoreactive T-cells. The disease process results in loss of insulin secretion and life-long insulin-dependence. At present there is no treatment that fully interdicts islet autoimmunity. Our long-range scientific goals are to understand the natural history of T1D and its molecular basis and implement clinical trials evaluating new strategies to prevent or ameliorate this disease. The objectives of this proposal are twofold: 1) to remain an active participant in the research network. Type 1 Diabetes TrialNet, involved in the design and implementation of new intervention strategies; and 2) to propose a novel intervention strategy with alefacept in individuals with recent onset T1D. Our central hypothesis is that alefacept will have therapeutic value in T1D, and temper the perpetuation of the destructive autoimmune process resulting in T1D, preserving beta-cells and their insulin-secreting capacity. There is a solid rationale for attempting new trials to target memory T cells in T1D: growing evidence links memory T cells with diabetes development, and alefacept specifically targets these cells. It is FDA-approved for the treatment of adult patients with moderate to severe chronic plaque psoriasis, which is also an immune-mediated disease. Importantly, alefacept has an excellent safety profile without the typical side effects of other immunosuppressive agents, which makes it ideally suited for potential chronic treatment of immune-mediated diseases. We propose a phase l/ll double-masked, randomized, placebo-controlled trial to test the hypothesis that alefacept will preserve C-peptide secretion in patients with recent onset T1D. Importantly, there is growing evidence for a role of memory T cells in T1D, and the memory compartment is likely to be enriched in islet-specific autoreactive T cells. We propose two treatment courses during a 1-year period and follow-up for an additional year. The primary metabolic outcome will be stimulated insulin secretion as assessed by C-peptide levels after the mixed meal tolerance test. The primary immunological outcome will be a 50-60% reduction in the frequency of memory T cells during the treatment phases. PUBLIC HEALTH RELEVANCE: Type 1 diabetes is caused by autoimmune destruction of pancreatic beta cells, resulting in loss of insulin secretion and life-long insulin dependence, and unfortunately often affects children and adolescents. Previous clinical trials have shown that it is possible to interfere with this autoimmune destructive process. If treatment with alefacept safely stops or slows this destructive process, it would be a major advance toward the prevention of a lifelong disease associated with significant morbid complications.

描述(申请人提供)：T1D发生在遗传易感性个体中，是胰腺β细胞逐渐的、选择性的破坏的结果，这主要是由自身反应性T细胞介导的。疾病过程导致胰岛素分泌丧失和终生胰岛素依赖。目前还没有完全阻断胰岛自身免疫的治疗方法。我们的长期科学目标是了解T1D的自然历史及其分子基础，并实施临床试验，评估预防或改善这种疾病的新策略。这项提议的目标有两个：1)继续成为研究网络的积极参与者。参与设计和实施新的干预策略；以及2)提出一种使用alefacept的新干预策略，用于新近发病的T1D患者。我们的中心假设是，alefacept将在T1D具有治疗价值，并缓和导致T1D的破坏性自身免疫过程的永久化，保护β细胞及其胰岛素分泌能力。尝试以T1D中的记忆T细胞为靶点的新试验有坚实的理由：越来越多的证据表明，记忆T细胞与糖尿病的发生有关，而alefacept专门针对这些细胞。FDA批准它用于治疗患有中重度慢性斑块型牛皮癣的成年患者，这也是一种免疫介导性疾病。重要的是，alefacept具有极好的安全性，没有其他免疫抑制剂的典型副作用，这使其非常适合潜在的免疫介导性疾病的慢性治疗。我们提出了一项L/11期双掩蔽、随机、安慰剂对照试验，以检验阿尔法塞特将保留新发T1D患者C-肽分泌的假设。重要的是，越来越多的证据表明记忆T细胞在T1D中发挥作用，记忆隔间可能富含胰岛特异的自身反应性T细胞。我们建议在一年内进行两个疗程，并进行额外一年的随访。主要的代谢结果将是刺激胰岛素分泌，通过混合餐耐量试验后的C-肽水平进行评估。主要的免疫学结果将是在治疗阶段记忆T细胞的频率减少50%-60%。 公共卫生相关性：1型糖尿病是由胰腺β细胞的自身免疫破坏引起的，导致胰岛素分泌丧失和终生胰岛素依赖，不幸的是，儿童和青少年经常受到影响。此前的临床试验表明，干扰这种自身免疫破坏过程是可能的。如果使用alefacept的治疗安全地阻止或减缓这种破坏性的过程，这将是朝着预防一种与重大病态并发症相关的终身疾病的方向取得的重大进展。