Study Background: Patients with severe chronic pancreatitis undergo total pancreatectomy followed by islet autotransplantation into the liver. However, over half require lifelong supplemental insulin. Reducing islet damage can improve long-term glycemic control and quality of life. ## Trial Design: A Phase 4 clinical trial led by the University of Minnesota, randomizing TPIAT patients into three groups: etanercept, alpha-1 antitrypsin, and standard care. The study will evaluate islet function and metabolic markers at 90 days, 1 year, and 2 years. Etanercept is a TNF-α inhibitor, and A1AT is a serine protease inhibitor that reduces inflammation and prevents beta-cell death. ## Expected Outcomes: Both drugs have the potential to reduce the dependence on supplemental insulin. Etanercept has previously shown improved long-term insulin independence in existing type 1 diabetes transplantation. A1AT has demonstrated prolonged islet survival in animal models. ## Clinical Significance: If successful, this trial could significantly reduce treatment costs and patient burden for TPIAT patients. Furthermore, an anti-inflammatory-based islet protection strategy could be extended to other organ transplantation fields.