Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes

• Published in: Diabetes care Vol. 43; no. 4; pp. 710 - 718
• Main Authors: Maffi, Paola, Lundgren, Torbjörn, Tufveson, Gunnar, Rafael, Ehab, Shaw, James A M, Liew, Aaron, Saudek, Frantisek, Witkowski, Piotr, Golab, Karolina, Bertuzzi, Federico, Gustafsson, Bengt, Daffonchio, Luisa, Ruffini, Pier Adelchi, Piemonti, Lorenzo
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-04-2020
• Subjects: Adolescent; Adult; Aged; Allografts; antiinflammatory strategies; Antilymphocyte serum; beta-cell function; Clinical Care/Education/Nutrition/Psychosocial Research; Clinical trials; Combined Modality Therapy; Damage prevention; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - therapy; Double-Blind Method; Double-blind studies; Drug Administration Schedule; Endocrinology & Metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; engraftment; Female; Globulins; Glucose monitoring; Humans; Immunological tolerance; Immunosuppression; Immunosuppressive Agents - administration & dosage; induction; Inflammation; inhibition; Insulin; Insulin secretion; Insulin Secretion - drug effects; Islet cells; Islets of Langerhans Transplantation; Male; Medicin och hälsovetenskap; Middle Aged; Motivation; Pancreas transplantation; Pancreatic islet transplantation; Patients; Peptides; Placebos; Postoperative Period; Receptors, Interleukin-8A - antagonists & inhibitors; Receptors, Interleukin-8B - antagonists & inhibitors; regimen; Research design; Statistical analysis; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - pharmacology; survival; Thymocytes; Time Factors; Transplantation; Transplants & implants; Young Adult
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc19-1480

Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients.
A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control.
The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo,
= 0.99) and day 365 (24 on reparixin vs. 15 on placebo,
= 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%,
= 0.09) when antithymocyte globulin was used as induction immunosuppression.
In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage.