A Pilot Clinical Trial of Paricalcitol for Chronic Pancreatitis

摘要 拟议试验的主要目标是检查测试一种药物的效果的可行性 有效的维生素D类似物，帕利卡西醇，对健康相关的生活质量(HRQOL)以及成像和液体 慢性胰腺炎(CP)患者的生物标志物如果确定可行，后续试验将被 开发的重点是帕利卡西醇在改善CP预后方面的疗效。可悲的是，疼痛 胰腺炎患者HRQOL降低和资源利用增加的最重要影响 病人。开发CP患者的临床试验，以改善治疗选择，减轻症状， 和预防外分泌功能衰竭，糖尿病和胰腺癌被广泛认为是一个领域 巨大的未得到满足的需求。有大量临床前证据表明，有效的维生素D 类似物通过阻断对胰腺炎和胰腺癌都有显著的有益作用 转化生长因子β(转化生长因子β)信号和止痛。 我们假设，根据患者报告的结果，骨钙素治疗将改善症状。 HRQOL，并标准化胰腺纤维炎症过程的成像和液体生物标记物 这些高危患者群体。因为治疗反应的替代生物标记物没有 是为CP开发的，需要像这样的早期试验来帮助发现生物标记物 未来的验证。我们提出了一项试点随机、双盲、安慰剂对照试验来评估 为期12个月的骨钙素干预与安慰剂对照的可行性和安全性。我们会 收集HRQOL测量，以及纤维炎症测量(影像和液体)的变化 回应。我们将对24名CP患者进行为期21个月的随机分组，分别服用帕利西妥组和安慰剂组。 期间和一年的随访期。重要的是，我们的高效研究设计将纳入以下患者 是否参与了我们正在进行的前瞻性纵向队列研究，继续(前瞻性 评估慢性胰腺炎的流行病学和转化学研究)，这是进行 在美国慢性胰腺炎、糖尿病和胰腺癌联盟的赞助下 (CPDPC)。正在进行的研究中的嵌套研究提供了一个明确的临床队列，这些患者 在频繁的医学监测下，我们可以协调患者招募，收集生物 样本，并通过常规的临床和研究预约和测试进行后续检查，确保高比率 招聘和留住的问题。如果登记和完成的患者比例符合可行性 12个月的骨钙素治疗是计划的≥的75%。重要的是，这次试验将提供一个平台 用于实施CP潜在治疗药物所需的研究设计和措施。

ABSTRACT The primary objective of the proposed trial is to examine the feasibility of testing the effect of a potent vitamin D analogue, paricalcitol, on health-related quality of life (HRQoL), and imaging and liquid biomarkers in patients with chronic pancreatitis (CP). If determined feasible, subsequent trials will be developed that focus on the efficacy of paricalcitol in improving outcomes in CP. Tragically, pain has the most important influence on diminished HRQoL and increased resource utilization in pancreatitis patients. Development of clinical trials in CP patients to improve treatment options, attenuate symptoms, and prevent exocrine function failure, diabetes and pancreatic cancer is widely considered an area of enormous unmet need. There is a substantial body of preclinical evidence that potent vitamin D analogues have significant and beneficial effects on both pancreatitis and pancreatic cancer by blocking Transforming Growth Factor Beta (TGFβ) signaling and reducing pain. We hypothesize that paricalcitol treatment will improve symptoms, as measured by patient reported HRQoL, and normalize imaging and liquid biomarkers of the pancreatic fibro-inflammatory process in this high-risk patient population. Because surrogate biomarkers of response to therapeutics have not been developed for CP, early trials such as this one are needed to assist with biomarker discovery for future validation. We propose a pilot randomized double-blind, placebo-controlled trial to evaluate the feasibility and safety of a 12-month paricalcitol intervention versus placebo administration. We will collect measures of HRQoL, and changes in measures (imaging and liquid) of the fibro-inflammatory response. We will randomize 24 CP patients 1:1 to paricalcitol vs placebo with a 21-month recruitment period and a one-year follow-up period. Importantly, our efficient study design will enroll patients who are participants in our ongoing prospective longitudinal cohort study, PROCEED (PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies), which is conducted under the auspices of the US Consortium on Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC). Nesting in the PROCEED study provides a well-defined clinical cohort of patients who are under frequent medical surveillance allowing us to harmonize patient recruitment, collection of biological specimens, and follow-up with routine clinical and research appointments and tests, ensuring high rates of recruitment and retention. Feasibility will be met if the proportion of patients who enroll and complete the 12 months of paricalcitol therapy is ≥75% of planned. Importantly, this trial will provide a platform for study design and measurements needed for implementation of potential treatment agents for CP.