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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

Wilhelm-Benartzi, Charlotte S., Miller, Sarah E., Bruggraber, Sylvaine, Picton, Diane, Wilson, Mark, Gatley, Katrina, Chhabra, Anita, Marcovecchio, M. Loredana, Hendriks, A. Emile J., Morobé, Hilde, Chmura, Piotr Jaroslaw, Bond, Simon, Aschemeier-Fuchs, Bärbel, Knip, Mikael, Tree, Timothy, Overbergh, Lut, Pall, Jaivier, Arnaud, Olivier, Haller, Michael J., Nitsche, Almut, Schulte, Anke M., Mathieu, Chantal, Mander, Adrian and Dunger, David 2021. 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. BMJ Open 11 (12) , e053669. 10.1136/bmjopen-2021-053669

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Centre for Trials Research (CNTRR)
Additional Information: This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license
Publisher: BMJ Publishing Group
ISSN: 2044-6055
Date of First Compliant Deposit: 13 December 2021
Date of Acceptance: 8 November 2021
Last Modified: 31 Jan 2022 08:44
URI: https://orca.cardiff.ac.uk/id/eprint/146010

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