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.

摘要 对于药物和内镜治疗难治性重症胰腺炎患者，全胰腺切除术（TP） 胰岛自体移植（IAT）可以考虑。虽然90%的TPIAT接受者有一定的功能， 移植的胰岛移植物，只有约1/3完全脱离胰岛素。拟议的长期目标 研究的目的是开发新的治疗方法，增加非糖尿病患者的数量， 胰岛自体移植此类疗法也可能使1型糖尿病的胰岛同种异体移植接受者受益。 在胰岛移植后，胰岛必须在手术的压力下迅速存活，然后它们必须 植入肝脏建立血管供应移植的功能性胰岛质量越大， 术后糖尿病的风险。据估计，超过一半的胰岛质量可能会损失， 胰岛移植受者移植后早期。β细胞凋亡是常见的，在第一次 移植后1个月，在炎性细胞因子如TNFα存在下上调。因此 胰岛损失的主要原因是移植胰岛在早期的炎性损伤 移植后时期;我们建议直接针对这一破坏性过程。 两种有前途的抗炎疗法可用于解决这个问题：（1）TNFα抑制剂 依那西普和（2）丝氨酸蛋白酶抑制剂α-1抗胰蛋白酶。这两种试剂都是市售的， 临床试验依那西普的原理验证已在1型糖尿病同种异体移植中得到证实 移植后早期接受10天依那西普治疗的受者， 由于移植的β细胞团在植入期的存活率更高，因此具有更好的独立性。Alpha-1 抗胰蛋白酶（A1 AT）减少炎性细胞因子，保护免受精氨酸诱导的β细胞凋亡， 以及小鼠和门静脉内IAT非人灵长类动物的胰岛移植物存活率。 这项最初的3组药物治疗临床试验将研究使用依那西普和A1 AT改善IAT 与标准治疗相比，TPIAT后90天、1年和2年的功能。45名患者接受 TPIAT将以1：1：1随机接受：1）依那西普（第0天50 mg;第3、7、10、14天25 mg， 和21），2）α-1抗胰蛋白酶（90 mg/kg IV，第-1、+3、7、14、21、28天）或3）标准护理。患者会出现 在术后早期进行的机械评估，包括炎性细胞因子和 趋化因子和β细胞损失的测量。代谢检测将在TPIAT后90、365和730天进行， 包括混合餐耐量试验、IV葡萄糖耐量试验和葡萄糖增强的奎宁诱导的 胰岛素分泌（GPAIS）。后者测量最大刺激的急性胰岛素反应（AIRmax）， 本研究的胰岛质量和主要终点（第90天）的最佳估计值。结果将用于 在随机、盲法多中心临床试验中选择最有前途的药物用于未来的研究。