1. 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
- Author
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Maffi P., Lundgren T., Tufveson G., Rafael E., Shaw J. A. M., Liew A., Saudek F., Witkowski P., Golab K., Bertuzzi F., Gustafsson B., Daffonchio L., Ruffini P. A., Piemonti L., Nano R., Mercalli A., Lampasona V., Magistretti P., Sordi V., Antonio S., Antonioli B., Galuzzi M., Tosca M. C., De Carlis L., Colussi G., Korsgren O., Pollard H., 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, Maffi, P, Lundgren, T, Tufveson, G, Rafael, E, Shaw, J, Liew, A, Saudek, F, Witkowski, P, Golab, K, Bertuzzi, F, Gustafsson, B, Daffonchio, L, Ruffini, P, Piemonti, L, Nano, R, Mercalli, A, Lampasona, V, Magistretti, P, Sordi, V, Antonio, S, Antonioli, B, Galuzzi, M, Tosca, M, De Carlis, L, Colussi, G, Korsgren, O, and Pollard, H
- Subjects
Male ,Time Factors ,Endocrinology, Diabetes and Metabolism ,Islets of Langerhans Transplantation ,Placebo-controlled study ,Gastroenterology ,Receptors, Interleukin-8B ,Receptors, Interleukin-8A ,law.invention ,Placebos ,0302 clinical medicine ,Randomized controlled trial ,law ,Insulin Secretion ,Postoperative Period ,030212 general & internal medicine ,Sulfonamides ,geography.geographical_feature_category ,Clinical Care/Education/Nutrition/Psychosocial Research ,Area under the curve ,Middle Aged ,Islet ,Combined Modality Therapy ,Female ,Immunosuppressive Agents ,Adult ,medicine.medical_specialty ,Adolescent ,030209 endocrinology & metabolism ,Placebo ,Drug Administration Schedule ,Young Adult ,Islets of Langerhans ,03 medical and health sciences ,Double-Blind Method ,Internal medicine ,CXCR1/2, insulin secretion, pancreatic islet transplantation ,Internal Medicine ,medicine ,Humans ,Aged ,Advanced and Specialized Nursing ,geography ,Type 1 diabetes ,business.industry ,medicine.disease ,Transplantation ,Diabetes Mellitus, Type 1 ,Pancreatic islet transplantation ,business - Abstract
OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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, P = 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P = 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%, P = 0.09) when antithymocyte globulin was used as induction immunosuppression. CONCLUSIONS 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.
- Published
- 2020
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