A Pilot Clinical Trial of Paricalcitol for Chronic Pancreatitis

帕立骨化醇治疗慢性胰腺炎的初步临床试验

• 批准号: 10434603
• 负责人: Marc T Goodman
• 金额: $ 32.07万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434603
• 关键词: Abdominal Pain; Afferent Neurons; Alcohol abuse; Animal Model; Appointment; Area; Attenuated; Biological; Biological Markers; Cancer Etiology; Cessation of life; Chronic inflammatory pain; Climacteric; Clinical; Clinical Research; Clinical Trials; Collection; Conduct Clinical Trials; Cytoplasm; DNA Sequence Alteration; Data; Desmoplastic; Development; Diabetes Mellitus; Disease; Disease Progression; Double-Blind Method; Drug Screening; Enrollment; Ensure; Environment; Evaluation; Exocrine pancreas; Extracellular Matrix Proteins; FDA approved; Failure; Fatality rate; Fibrosis; Future; Genes; Genomics; Goals; High Fat Diet; Image; Inflammatory; Inflammatory Response; Intervention; Lead; Letters; Lipids; Liquid substance; Longitudinal cohort study; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Measures; Mediating; Medical Surveillance; Monitor; Myeloid Cells; Outcome; Pain; Pancreas; Pancreatic Diseases; Pancreatic enzyme; Pancreatitis; Participant; Patient Outcomes Assessments; Patient Recruitments; Patients; Pilot Projects; Placebo Control; Placebos; Process; Production; Quality of life; Randomized; Recurrence; Research Design; Resources; Risk Factors; Schools; Signal Transduction; Smoking; Social Functioning; Specimen; Surrogate Markers; Symptoms; TGFB1 gene; Testing; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Validation; Vitamin A; Vitamin D; Vitamin D Analog; Vitamin D3 Receptor; Work; acute pancreatitis; analog; base; biomarker discovery; cell type; chemotherapeutic agent; chronic pancreatitis; clinical development; clinical outcome measures; cohort; double-blind placebo controlled trial; epidemiology study; feasibility testing; follow-up; health related quality of life; high risk; imaging biomarker; improved; improved outcome; macrophage; pain reduction; pancreatic stellate cell; paricalcitol; patient population; pilot trial; pre-clinical; prevent; prospective; recruit; reduce symptoms; response biomarker; safety and feasibility; stellate cell; symptomatic improvement; therapeutically effective; therapy development; translational study; treatment duration; treatment response

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.

抽象的 拟议试验的主要目的是检验测试效果的可行性 强效维生素 D 类似物帕立骨化醇对健康相关生活质量 (HRQoL) 以及成像和液体的影响 慢性胰腺炎（CP）患者的生物标志物。如果确定可行，将进行后续试验 开发的重点是帕立骨化醇在改善脑瘫预后方面的功效。可悲的是，疼痛已经 对胰腺炎 HRQoL 降低和资源利用率增加的最重要影响 患者。开展脑瘫患者的临床试验，以改善治疗选择、减轻症状、 并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 巨大的未满足的需求。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具有显着且有益的作用 转化生长因子β (TGFβ) 信号并减轻疼痛。 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 这一高危患者群体。因为治疗反应的替代生物标志物尚未 是为 CP 开发的，需要像这样的早期试验来协助发现 CP 的生物标志物 未来的验证。我们提出了一项随机双盲、安慰剂对照试验来评估 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 测量值以及纤维炎症测量值（影像学和液体）的变化 回复。我们将 24 名 CP 患者以 1:1 的比例随机分组，接受帕立骨化醇与安慰剂，进行为期 21 个月的招募 期和一年的随访期。重要的是，我们高效的研究设计将招募以下患者： 是我们正在进行的前瞻性纵向队列研究 PROCEED（PROCEED 慢性胰腺炎流行病学和转化研究的评估），该项目已进行 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的临床患者队列，这些患者 在频繁的医疗监视下，使我们能够协调患者的招募、生物样本的收集 标本，并进行常规临床和研究预约和测试的后续工作，确保高比率 招聘和保留。如果注册并完成治疗的患者比例满足可行性 帕立骨化醇治疗的 12 个月≥计划的 75%。重要的是，这次试验将提供一个平台 用于实施潜在的脑瘫治疗药物所需的研究设计和测量。