Indiana University (IU) Clinical Center for Chronic Pancreatitis Clinical Research Network

 描述(申请人提供)：慢性胰腺炎(CP)是一种进行性疾病，通常会导致外分泌和内分泌功能丧失，并导致虚弱的腹痛。目前尚不清楚为什么有些人会进展并出现并发症，包括胰源性糖尿病(PDM)和/或胰腺癌(PDAC)。在这个联盟中，研究人员建议对风险因素、环境影响和概念验证研究进行强有力的研究，以推动该领域的发展，特别是那些增加PDM和PDAC风险的因素。我们提出以下具体目标(SA)以满足RFA-DK-14-027的目标。SA#1：为了明确确诊为慢性胰腺炎或急性复发性胰腺炎的儿童和成人患者的自然病史，我们提出了一项前瞻性观察性队列研究。我们将把重点放在识别那些发展成pdm和/或pdac的患者的危险因素和表型。将获得生物标本，以便于研究可能有助于疾病早期诊断和管理的生物标志物。SA#2：糖尿病的发病机制以及非内分泌性胰腺疾病与胰岛功能障碍的相互作用还不是很清楚。我们将在横断面和前瞻性研究中使用胰岛功能的测量(口服葡萄糖耐量试验、精氨酸增强的高血糖钳夹)来确定CP患者代谢紊乱和糖尿病的患病率和生理基础。我们还将前瞻性地确定胰岛功能的变化和向显性PDM的过渡，并将代谢状态的变化与胰腺炎症和功能的变化联系起来。SA#3：为了评估磁共振成像对可疑早期CP的无创性评估的诊断效果，我们提出了一项前瞻性研究，将CP患者与胰腺外分泌功能正常的对照组进行比较。对分泌素刺激的反应，T1加权MR信号降低、弥散减少和十二指肠液量减少可能提示CP。SA#4：Galectin-3(Gal-3)是一种碳水化合物结合蛋白，似乎参与了CP的纤维化和组织重塑。Gal-3抑制剂似乎是安全的，并显示出减少人体器官纤维化的潜力。为了确定Gal-3抑制剂的安全性和有效性，我们提出了一项针对66名CP患者的随机安慰剂对照试验。治疗后十二指肠液碳酸氢盐水平的改善将是主要疗效终点。我们预计该药将逆转纤维化，表现为十二指肠碳酸氢盐水平的改善。还将评估其他终点，包括核磁共振/磁共振胆胰管成像外观、GAL-3水平、生活质量、腹痛评分和β细胞功能。

 DESCRIPTION (provided by applicant): Chronic pancreatitis (CP) is a progressive disease, often leading to loss of exocrine and endocrine function and debilitating abdominal pain. It is unknown why some individuals progress and develop complications, including pancreatogenic diabetes (PDM) and/or pancreas cancer (PDAC). In this consortium, investigators propose to conduct well-powered studies of risk factors, environmental influences, and proof-of-concept studies to move the field forward, particularly those factors that increase the risk of PDM and PDAC. We propose the following specific aims (SA) to meet the goals of RFA-DK-14-027. SA #1: To define the natural history of pediatric and adult patients with an established diagnosis of CP or acute recurrent pancreatitis, we propose a prospective observational cohort study. We will place emphasis on identifying risk factors and phenotypes for those patients who develop PDM and/or PDAC. Biological specimens will be obtained to facilitate the study of possible biomarkers which might facilitate early disease diagnosis and management. SA #2: The pathogenesis of PDM and the interactions of non-endocrine pancreatic disease with islet dysfunction are not well understood. We will use measurements of islet function (oral glucose tolerance tests, arginine- augmented hyperglycemic clamps) in cross-sectional and prospective studies to define the prevalence and physiologic basis for metabolic dysregulation and diabetes in CP. We will also prospectively ascertain changes in islet function and transition to overt PDM, and correlate changes in metabolic status with changes in pancreatic inflammation and function. SA #3: To evaluate the diagnostic efficacy of Magnetic Resonance (MR) imaging in the non-invasive evaluation of suspected early CP, we propose a prospective study comparing CP patients to a control population with normal pancreatic exocrine function. A reduced T1-weighted MR signal, reduced diffusion and decreased duodenal fluid volume in response to secretin stimulation may suggest CP. SA #4: Galectin-3 (Gal-3) is a carbohydrate-binding protein which appears to be involved in fibrogenesis and tissue remodeling in CP. A Gal-3 inhibitor appears to be safe and shows potential for reducing organ fibrosis in humans. To determine the safety and efficacy of a Gal-3 inhibitor, we propose a randomized placebo- controlled trial in 66 CP patients. Improvement in post-therapy duodenal fluid bicarbonate level will be the primary efficacy endpoint. We anticipate that this drug will reverse fibrosis, as manifested by improvement in duodenal bicarbonate level. Additional endpoints including MRI/MRCP appearance, Gal-3 level, quality of life, abdominal pain scores and β-cell function will also be assessed.