Anti-inflammatory therapy to improve outcomes in patients with chronic pancreatitis undergoing total pancreatectomy with islet autotransplant (TPIAT)

抗炎治疗可改善接受胰岛自体移植全胰腺切除术（TPIAT）的慢性胰腺炎患者的预后

• 批准号: 9335351
• 负责人: Melena D. Bellin
• 金额: $ 60.84万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335351
• 关键词: Acute; Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Area; Area Under Curve; Arginine; Autologous Transplantation; Back; Beta Cell; Blinded; C-Peptide; Cell Death; Cell Survival; Cell physiology; Cells; Clinical; Clinical Trials; DNA; Data; Development; Diabetes Mellitus; Educational workshop; Engraftment; Etanercept; Excision; Fasting; Future; Glucose; Glucose tolerance test; Goals; Graft Survival; Hospitalization; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Intravenous infusion procedures; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Liver; Measurement; Measures; Medical; Metabolic; Multi-Institutional Clinical Trial; Mus; Narcotic Addiction; National Institute of Diabetes and Digestive and Kidney Diseases; Oral; Pain; Pancreas; Pancreatectomy; Pancreatitis; Patients; Perioperative; Persons; Pharmaceutical Preparations; Pharmacotherapy; Postoperative Period; Procedures; Process; Randomized; Refractory; Replacement Therapy; Research; Risk; Serine Proteinase Inhibitors; Serum; Stimulus; Stress; TNF gene; Testing; Time; Total Pancreatectomy; Transplant Recipients; Transplantation; Vascular blood supply; allotransplant; alpha 1-Antitrypsin; arm; chemokine; chronic pancreatitis; cytokine; diabetes risk; graft function; improved; improved outcome; insulin secretion; islet; non-diabetic; nonhuman primate; novel therapeutics; polypeptide C; public health relevance; randomized trial; response; standard care; tumor necrosis factor-alpha inhibitor; type I diabetic

Abstract For patients with severe pancreatitis refractory to medical and endoscopic therapy, total pancreatectomy (TP) with islet autotransplantation (IAT) may be considered. While 90% of TPIAT recipients have some function of the transplanted islet graft, only about 1/3rd come completely off insulin. The long-term goal of the proposed research is to develop new therapies that will increase the number of patients who are non-diabetic following islet autotransplant. Such therapies may also benefit recipients of islet allotransplant for type 1 diabetes. Following islet transplantation, the islets must acutely survive the stress of the procedure, and then they must engraft in the liver and establish a vascular supply. The greater the functional islet mass engrafted, the lower the risk of post-operative diabetes. It has been estimated that more than half of the islet mass may be lost in the early post-transplant period in islet transplant recipients. Beta cell apoptosis is common during the first month post-transplant and is upregulated in the presence of inflammatory cytokines such as TNFα. Thus, a major contributor to islet loss is the inflammatory damage sustained by the transplanted islets in the early post-transplant period; we propose to directly target this destructive process. Two promising anti-inflammatory therapies are available to address this problem: (1) the TNFα inhibitor etanercept and (2) the serine protease inhibitor alpha-1 antitrypsin. Both agents are commercially available for clinical trials. Proof-of-principle for etanercept has been demonstrated in type 1 diabetic allotransplant recipients, in whom a 10 day course of etanercept early post-transplant significantly improved long-term insulin independence, due to better survival of the transplanted beta cell mass in the engraftment period. Alpha-1 antitrypsin (A1AT) reduces inflammatory cytokines, protects against cytokine-induced beta cell apoptosis, and prolongs islet graft survival in mice and intraportal IAT non-human primates. This initial 3-arm drug-treatment clinical trial will investigate the use of Etanercept and A1AT to improve IAT function at 90 days and 1 and 2 years post-TPIAT compared to standard care. Forty-five patients undergoing TPIAT will be randomized 1:1:1 to receive either: 1) etanercept (50 mg on day 0; 25 mg on days 3, 7, 10, 14, and 21), 2) alpha-1 antitrypsin (90 mg/kg IV days -1, +3, 7, 14, 21, 28) or 3) standard care. Patients will have mechanistic assessments drawn in the early post-operative period including inflammatory cytokines and chemokines and measures of beta cell loss. Metabolic testing will occur at 90, 365, and 730 days post-TPIAT, including mixed meal tolerance testing, IV glucose tolerance testing, and glucose-potentiated arginine-induced insulin secretion (GPAIS). The latter measures the maximally stimulated acute insulin response (AIRmax) as the best estimate of islet mass and the primary endpoint (at day 90) for this study. Results will be used to select the most promising agent for future study in a randomized, blinded multi-center clinical trial.

抽象的 对于患有医疗和内窥镜治疗难治性严重胰腺炎的患者，总胰腺切除术（TP） 可以考虑使用胰岛自动移植（IAT）。虽然90％的TPIAT接收者具有一定的功能 移植的胰岛移植物，只有大约1/3完全消除了胰岛素。拟议的长期目标 研究是开发新疗法，以增加非糖尿病患者的数量 胰岛自动移植。这种疗法还可能使1型糖尿病的胰岛同酶养殖者受益。 以下胰岛移植，胰岛必须急性地在过程的压力中生存，然后必须 植入肝脏并建立血管供应。植入功能性胰岛质量越大，较低 术后糖尿病的风险。据估计，胰岛质量的一半以上可能会丢失 胰岛移植接受者的移植后期早期。 β细胞细胞凋亡在第一次很常见 移植后月，在存在炎症细胞因子（例如TNFα）的情况下进行更新。那， 胰岛损失的主要贡献者是早期移植胰岛遭受的炎症损害 移植后期；我们建议直接针对这一破坏性过程。 可以使用两种承诺抗炎疗法来解决此问题：（1）TNFα抑制剂 依然酸酯和（2）丝氨酸蛋白抑制剂α-1抗胰蛋白酶。两种代理商都可以使用 临床试验。 Etanercept的原始证明已在1型糖尿病同植物中得到证明 接受者，其中10天的Etanercept培训早期移植后可以显着改善长期胰岛素 独立性，由于植入期在移植的β细胞质量的生存更好。 alpha-1 抗胰蛋白酶（A1AT）降低炎性细胞因子，可预防细胞因子诱导的β细胞凋亡， 并延长小鼠的胰岛移植物存活和室内IAT非人类隐私。 这项最初的3臂药物治疗临床试验将调查使用Etanercept和A1AT来改善IAT 与标准护理相比，TPIAT后90天，1和2年的功能。正在接受的45例患者 TPIAT将被随机分为1：1：1接收：1）Etanercept（第0天50毫克；第3、7、10、14天25 mg， 21），2）α -1抗胰蛋白酶（90 mg/kg IV天-1，+3、7、14、21、28）或3）标准护理。患者会有 在术后早期进行的机械评估，包括炎症细胞因子和 趋化因子和β细胞损失的度量。代谢测试将在TPIAT后90、365和730天进行 包括混合餐耐受性测试，IV葡萄糖耐量测试和葡萄糖启用精氨酸诱导的 胰岛素分泌（GPAI）。以后的测量最大刺激的急性胰岛素反应（AIRMAX）为 胰岛质量和主要终点的最佳估计（在第90天）。结果将用于 在一项随机的，盲人的多中心临床试验中选择最有前途的未来研究的药物。