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: 8286332
• 负责人: JENNIFER B MARKS
• 金额: $ 68.96万
• 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/8286332
• 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（由申请人提供）：T1D发生在遗传易感个体中，主要由自身反应性t细胞介导的胰腺β细胞的进行性、选择性破坏的结果。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。该提案的目标是双重的：1)继续积极参与研究网络。1型糖尿病试验网，参与设计和实施新的干预策略；2)对新近发病的T1D患者提出一种新的干预策略。我们的中心假设是，alefacept将对T1D具有治疗价值，并缓和导致T1D的破坏性自身免疫过程的延续，保护β细胞及其胰岛素分泌能力。在T1D中尝试针对记忆T细胞的新试验有一个坚实的理论基础：越来越多的证据表明记忆T细胞与糖尿病的发展有关，而alefacept专门针对这些细胞。它已被fda批准用于治疗中度至重度慢性斑块性银屑病的成人患者，这也是一种免疫介导的疾病。重要的是，alefacept具有良好的安全性，没有其他免疫抑制剂的典型副作用，这使得它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/ll期双盲、随机、安慰剂对照试验，以验证alefacept能维持新近发病的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中的作用，记忆室可能富含胰岛特异性自身反应性T细胞。我们建议在1年期间进行两个疗程的治疗，并进行额外一年的随访。混合膳食耐量试验后通过c肽水平评估，主要代谢结果将是刺激胰岛素分泌。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%。