A Pilot Clinical Trial of Paricalcitol for Chronic Pancreatitis

摘要 拟议试验的主要目的，是研究测试 强效维生素D类似物帕立骨化醇对健康相关生活质量（HRQoL）、影像学和液体 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 开发的研究重点是帕立骨化醇改善CP结局的疗效。可悲的是，疼痛 对胰腺炎患者HRQoL降低和资源利用增加的最重要影响 患者在CP患者中开展临床试验，以改善治疗选择，减轻症状， 和防止外分泌功能衰竭，糖尿病和胰腺癌被广泛认为是一个领域， 巨大的未满足需求。有大量的临床前证据表明， 类似物对胰腺炎和胰腺癌都有显著的有益作用， 转化生长因子β（TGFβ）信号传导和减轻疼痛。 我们假设帕立骨化醇治疗将改善症状，根据患者报告的测量结果， HRQoL，并使胰腺纤维炎症过程的成像和液体生物标志物正常化， 这一高风险患者群体。因为治疗反应的替代生物标志物还没有 虽然已经为CP开发了生物标志物，但需要像这样的早期试验来帮助发现生物标志物， 未来验证。我们建议进行一项随机、双盲、安慰剂对照试验，以评估 12个月帕立骨化醇干预与安慰剂给药的可行性和安全性。我们将 收集HRQoL的测量值，以及纤维炎性指标（成像和液体）的变化 反应我们将24例CP患者以1：1的比例随机分配至帕立骨化醇组和安慰剂组，招募期为21个月 一个为期一年的随访期。重要的是，我们高效的研究设计将招募符合以下条件的患者： 参与我们正在进行的前瞻性纵向队列研究，PROCEED（前瞻性 慢性胰腺炎的流行病学和转化研究评价）， 在美国慢性胰腺炎、糖尿病和胰腺癌联盟的赞助下， （CPDPC）。PROCEED研究中的嵌套提供了一个明确定义的患者临床队列， 在频繁的医疗监督下，使我们能够协调患者招募，生物收集， 样本，并通过常规临床和研究预约和测试进行随访，确保高比率 招聘和保留。如果入组并完成研究的患者比例 12个月帕立骨化醇治疗≥计划的75%。重要的是，这项试验将提供一个平台， 用于研究设计和实施CP潜在治疗药物所需的测量。

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.