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.