Anti-inflammatory Therapy to Improve Outcomes After TPIAT
Status:
Active, not recruiting
Trial end date:
2025-07-01
Target enrollment:
Participant gender:
Summary
Patients with severe chronic pancreatitis may be candidates to have their pancreas removed
and their islets transplanted into the liver to reduce the risk of diabetes mellitus, a
procedure called total pancreatectomy with islet autotransplant (TPIAT). However, over half
of patients who have a TPIAT will need to remain on some supplemental insulin life-long after
the procedure. We will study therapies that may reduce damage to transplanted islets, and
thereby improve long-term outcomes.
Two promising anti-inflammatory therapies are available to protect islets from damage at the
time of transplant: (1) the Tumor Necrosis Factor (TNF)-alpha inhibitor etanercept and (2)
the serine protease inhibitor alpha-1 antitrypsin. Both agents are commercially available for
clinical trials. Proof-of-principle for etanercept has been demonstrated in type 1 diabetic
allotransplant recipients, in whom a 10 day course of etanercept early post-transplant
significantly improved long-term insulin independence, due to better survival of the
transplanted beta cell mass in the engraftment period. Alpha-1 antitrypsin (A1AT) reduces
inflammatory cytokines, protects against cytokine-induced beta cell apoptosis, and prolongs
islet graft survival in mice and intraportal IAT non-human primates.
This initial 3-arm drug-treatment clinical trial will investigate the use of Etanercept and
A1AT to improve IAT function at 90 days and 1 and 2 years post-TPIAT compared to standard
care. Forty-five patients undergoing TPIAT will be randomized 1:1:1 to receive either: 1)
etanercept (50 mg on day 0; 25 mg on days 3, 7, 10, 14, and 21), 2) alpha-1 antitrypsin (90
mg/kg IV days -1, +3, 7, 14, 21, 28) or 3) standard care. Patients will have mechanistic
assessments drawn in the early post-operative period including inflammatory cytokines and
chemokines and measures of beta cell loss. Metabolic testing will occur at 90, 365, and 730
days post-TPIAT, including mixed meal tolerance testing, IV glucose tolerance testing, and
glucose-potentiated arginine-induced insulin secretion (GPAIS).
Phase:
Phase 4
Details
Lead Sponsor:
University of Minnesota University of Minnesota - Clinical and Translational Science Institute
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Treatments:
Alpha 1-Antitrypsin Anti-Inflammatory Agents Etanercept Protein C Inhibitor