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Diabetes Care. 2020 Feb 4. pii: dc191480. doi: 10.2337/dc19-1480. [Epub ahead of print]

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 information

1
San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
2
Department of Clinical Science, Intervention and Technology, Karolinska Institute, Karolinska, Sweden.
3
Uppsala University, Uppsala, Sweden.
4
Skåne University Hospital, Malmö, Sweden.
5
Institute of Cellular Medicine, Newcastle University, and Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, U.K.
6
Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
7
Transplantation Institute, University of Chicago Medicine, Chicago, IL.
8
Ospedale Niguarda Ca' Granda, Milan, Italy.
9
University of Gothenburg, Göteborg, Sweden.
10
Research and Development Department, Dompé farmaceutici S.p.A., Milan, Italy.
11
San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy piemonti.lorenzo@hsr.it.

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 allo-transplant recipients.

RESEARCH DESIGN AND METHODS:

A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allo-transplants 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.

PMID:
32019854
DOI:
10.2337/dc19-1480

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