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

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.

Figure 1

Patient disposition diagram showing patient recruitment, random assignment to treatment, discontinuation, and inclusion in analysis sets.

Figure 2

Reparixin treatment and islet transplantation outcome in patients with T1D. A: Box plots representing AUC of C-peptide (C-pep) after a 2-h MMTT normalized by the number of IEQ/kg. Box = 25th and 75th percentiles; bars = 5th and 95th percentiles. MMTT was performed at day 75 after the first islet infusion and at day 365 after the last islet infusion. MMTT was performed after an overnight fast, as described by Greenbaum et al. (35). Comparison was made using a Student t test estimated from the ANOVA model. B: Probability of insulin independence after islet transplantation according to Kaplan-Meier method. Top panel: gain of insulin independence after either the first or the second islet infusion. Bottom panel: gain of insulin independence after the first islet infusion. P value determined by log-rank test.

Figure 3

Reparixin treatment and islet transplantation outcome. A: β₂-Score was evaluated at day 75 after first islet infusion and at day 365 after the last islet infusion. Comparison was made using Mann-Whitney U test. B: Metabolic outcomes according to Igls criteria in transplant recipients. Optimal β-cell graft function: HbA_1c ≤48 mmol/mol (6.5%), the absence of severe hypoglycemia, the absence of an exogenous insulin requirement or other glucose-lowering (antihyperglycemic) drugs, and documentation of an increase in C-peptide levels compared with the pretransplant condition. Good β-cell graft function: HbA_1c <53 mmol/mol (7.0%), the absence of severe hypoglycemia, a reduction by >50% from baseline in insulin requirements or the use of noninsulin glucose-lowering drugs, and documentation of an increase in C-peptide levels compared with the pretransplant condition. Marginal β-cell graft function: failure to achieve HbA_1c <53 mmol/mol (7.0%), occurrence of any severe hypoglycemia, or <50% reduction in insulin requirements when there is documentation of an increase over pretransplant measurement of C-peptide that reached >0.17 nmol/L. Failure of β-cell graft function: absence of any evidence for a clinical impact with C-peptide ≤0.17 nmol/L, even if quantifiably higher than before transplant.