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Anti-thymocyte globulin/G-CSF treatment preserves ? cell function in patients with established type 1 diabetes.

ABSTRACT: Previous efforts to preserve ? cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve ? cell function in patients with established T1D (duration of T1D >4 months and <2 years).A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m²; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years.Combination ATG/G-CSF treatment tended to preserve ? cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001-0.552, P = 0.050). A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs.Patients with established T1D may benefit from combination immunotherapy approaches to preserve ? cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease.Clinicaltrials.gov NCT01106157.The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi.

SUBMITTER: Haller MJ

PROVIDER: S-EPMC4382237 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes.

Haller Michael J MJ Gitelman Stephen E SE Gottlieb Peter A PA Michels Aaron W AW Rosenthal Stephen M SM Shuster Jonathan J JJ Zou Baiming B Brusko Todd M TM Hulme Maigan A MA Wasserfall Clive H CH Mathews Clayton E CE Atkinson Mark A MA Schatz Desmond A DA

The Journal of clinical investigation 20141215 1

<h4>Background</h4>Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years).<h4>Methods</h4>A randomi ...[more]

PMID: 25500887

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Project description:IntroductionType 1 diabetes (T1D) is a chronic autoimmune disease, characterised by progressive destruction of the insulin-producing β cells of the pancreas. One immunosuppressive agent that has recently shown promise in the treatment of new-onset T1D subjects aged 12-45 years is antithymocyte globulin (ATG), Thymoglobuline, encouraging further exploration in lower age groups.Methods and analysisMinimal effective low dose (MELD)-ATG is a phase 2, multicentre, randomised, double-blind, placebo-controlled, multiarm parallel-group trial in participants 5-25 years diagnosed with T1D within 3-9 weeks of planned treatment day 1. A total of 114 participants will be recruited sequentially into seven different cohorts with the first cohort of 30 participants being randomised to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg and 0.1 mg/kg ATG total dose in a 1:1:1:1:1 allocation ratio. The next six cohorts of 12-15 participants will be randomised to placebo, 2.5 mg/kg, and one or two selected middle ATG total doses in a 1:1:1:1 or 1:1:1 allocation ratio, as dependent on the number of middle doses, given intravenously over two consecutive days. The primary objective will be to determine the changes in stimulated C-peptide response over the first 2 hours of a mixed meal tolerance test at 12 months for 2.5 mg/kg ATG arm vs the placebo. Conditional on finding a significant difference at 2.5 mg/kg, a minimally effective dose will be sought. Secondary objectives include the determination of the effects of a particular ATG treatment dose on (1) stimulated C-peptide, (2) glycated haemoglobin, (3) daily insulin dose, (4) time in range by intermittent continuous glucose monitoring measures, (5) fasting and stimulated dry blood spot (DBS) C-peptide measurements.Ethics and disseminationMELD-ATG received first regulatory and ethical approvals in Belgium in September 2020 and from the German and UK regulators as of February 2021. The publication policy is set in the INNODIA (An innovative approach towards understanding and arresting Type 1 diabetes consortium) grant agreement (www.innodia.eu).Trial registration numberNCT03936634; Pre-results.

Dataset Information

Anti-thymocyte globulin/G-CSF treatment preserves ? cell function in patients with established type 1 diabetes.

Publications

Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes.

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