Study protocol: Minimum effective low dose: anti-human thymocyte globulin (MELD-ATG): phase II, dose ranging, efficacy study of antithymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes
Simon Bond,
David Dunger,
Mark Wilson,
Adrian Mander,
Mikael Knip,
Anita Chhabra,
M Loredana Marcovecchio,
Charlotte S Wilhelm-Benartzi,
Michael J Haller,
Timothy Tree,
Hilde Morobé,
Sarah E Miller,
Sylvaine Bruggraber,
Diane Picton,
Katrina Gatley,
A Emile J Hendriks,
Bärbel Aschemeier-Fuchs,
Lut Overbergh,
Jaivier Pall,
Olivier Arnaud,
Almut Nitsche,
Anke M Schulte
Affiliations
Simon Bond
Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
David Dunger
Department of Paediatrics, University of Cambridge, Cambridge, UK
Mark Wilson
Graduate Medicine, Faculty of Science Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia
Adrian Mander
Centre For Trials Research, Cardiff University, Heath Park, Cardiff, UK
Mikael Knip
Research Program for Clinical and Molecular Metabolism, University of Helsinki Faculty of Medicine, Helsinki, Finland
Anita Chhabra
Pharmacy, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
M Loredana Marcovecchio
2 Department of Paediatric Diabetes and Endocrinology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Charlotte S Wilhelm-Benartzi
Centre for Trials Research, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK
Michael J Haller
University of Florida Diabetes Institute, Gainesville, Florida, USA
Timothy Tree
Department of Immunobiology, Kings College London, London, UK
Introduction Type 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 analysis Minimal 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 dissemination MELD-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 number NCT03936634; Pre-results.
