Targeting CXCR1/2 in the first multicenter,double-blinded,randomized trial in autologous islet transplant recipients |
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| Authors: | Piotr Witkowski Martin Wijkstrom Piotr J Bachul Katherine A Morgan Marlon Levy Nicholas Onaca Sushela S Chaidarun Timothy Gardner AM James Shapiro Andrew Posselt Syed A Ahmad Luisa Daffonchio Pier A Ruffini Melena D Bellin |
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| Institution: | 1. The Transplantation Institute, University of Chicago, Chicago, Illinois, USA;2. University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;3. The Medical University of South Carolina, Charleston, South Carolina, USA;4. Virginia Commonwealth University, Richmond, Virginia, USA;5. Baylor University Medical Center, Dallas, Texas, USA;6. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA;7. University of Alberta, Edmonton, Alberta, Canada;8. University of California San Francisco, San Francisco, California, USA;9. University of Cincinnati, Cincinnati, Ohio, USA;10. Research and Development, Dompé farmaceutici, Milan, Italy;11. University of Minnesota Medical Center, Minneapolis, Minnesota, USA |
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| Abstract: | Several cytokines and chemokines are elevated after islet infusion in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT), including CXCL8 (also known as interleukin-8), leading to islet loss. We investigated whether use of reparixin for blockade of the CXCL8 pathway would improve islet engraftment and insulin independence after TPIAT. Adults without diabetes scheduled for TPIAT at nine academic centers were randomized to a continuous infusion of reparixin or placebo (double-blinded) for 7 days in the peri-transplant period. Efficacy measures included insulin independence (primary), insulin dose, hemoglobin A1c (HbA1c), and mixed meal tolerance testing. The intent-to-treat population included 102 participants (age 39.5 ± 12.2 years, 69% female), n = 50 reparixin-treated, n = 52 placebo-treated. The proportion insulin-independent at Day 365 was similar in reparixin and placebo: 20% vs. 21% (p = .542). Twenty-seven of 42 (64.3%) in the reparixin group and 28/45 (62.2%) in the placebo group maintained HbA1c ≤6.5% (p = .842, Day 365). Area under the curve C-peptide from mixed meal testing was similar between groups, as were adverse events. In conclusion, reparixin infusion did not improve diabetes outcomes. CXCL8 inhibition alone may be insufficient to prevent islet damage from innate inflammation in islet autotransplantation. This first multicenter clinical trial in TPIAT highlights the potential for future multicenter collaborations. |
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| Keywords: | clinical trial cytokines / cytokine receptors innate immunity insulin / C-peptide islets of Langerhans pancreatitis TPIAT total pancreatectomy |
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