PROJECT SUMMARY / ABSTRACT 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 (T3cDM) and/or pancreas cancer (PDAC). In this Consortium, investigators have proposed and initiated several 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 T3cDM and PDAC. Many of these studies are ongoing, while new innovative proposals will address other research objectives identified by the participating NIH institutes. We propose several specific aims (SA) to meet the goals of RFA-DK-19-009. In SA #1, we propose to continue the CPDPC's three main longitudinal studies: PROCEED, INSPPIRE 2 and NOD, as well as those two studies designed to better define and characterize T3cDM, DETECT and DEPICT. In SA #2, we propose to continue the ancillary study begun during the first funding cycle, specifically MINIMAP. SA #3: 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 is safe and shows potential for reducing hepatic fibrosis in non-alcoholic steatohepatitis. We propose to test the hypothesis that a Gal-3 inhibitor is safe and efficacious in patients with CP, and may reverse or halt the fibrosis observed in CP. We will evaluate changes in pancreatic fibrosis as assessed by MRI, as well as serum and pancreatic fluid exploratory biomarkers. In SA #4, we propose innovative studies evaluating different strategies and interventions focused on alleviating abdominal pain in CP patients. Lacosamide, an anti-epileptic drug, appears to inhibit opioid-induced hyperalgesia. In SA #4a, we will perform a dose-escalation trial to evaluate the safety and tolerability of adding lacosamide to opioid therapy, followed by a pilot randomized trial to obtain preliminary data regarding change in pain control, opioid use and quality of life after adding lacosamide to an opioid. SA #4b: Quantitative sensory testing (QST) uses electrical and pressure stimulation at different dermatomes in order to unravel the pain system. We will investigate: (i) the association between QST profiles and demographic and clinical characteristics in patients with suspected or definite CP; (ii) whether the QST profile can be used to predict the clinical outcome of endoscopic or surgical treatment. SA #4c: Pancreatic duct stones may complicate CP, contributing to abdominal pain, and removal of these stones at ERCP frequently leads to significant pain relief. In this proposal, we compare the efficacy of two adjunctive procedures to ERCP for the treatment of main pancreatic duct stones in painful CP.