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
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 glob...
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2021-12-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Simon Bond |
| collection | DOAJ |
| description | 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. |
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| publishDate | 2021-12-01 |
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| spelling | doaj-art-3be62c3bfb884f7a8feae2f2becbd4352025-08-20T01:54:51ZengBMJ Publishing GroupBMJ Open2044-60552021-12-01111210.1136/bmjopen-2021-053669Study 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 diabetesSimon Bond0David Dunger1Mark Wilson2Adrian Mander3Mikael Knip4Anita Chhabra5M Loredana Marcovecchio6Charlotte S Wilhelm-Benartzi7Michael J Haller8Timothy Tree9Hilde Morobé10Sarah E Miller11Sylvaine Bruggraber12Diane Picton13Katrina Gatley14A Emile J Hendriks15Bärbel Aschemeier-Fuchs16Lut Overbergh17Jaivier Pall18Olivier Arnaud19Almut Nitsche20Anke M Schulte21Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UKDepartment of Paediatrics, University of Cambridge, Cambridge, UKGraduate Medicine, Faculty of Science Medicine and Health, University of Wollongong, Wollongong, New South Wales, AustraliaCentre For Trials Research, Cardiff University, Heath Park, Cardiff, UKResearch Program for Clinical and Molecular Metabolism, University of Helsinki Faculty of Medicine, Helsinki, FinlandPharmacy, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK2 Department of Paediatric Diabetes and Endocrinology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UKCentre for Trials Research, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UKUniversity of Florida Diabetes Institute, Gainesville, Florida, USADepartment of Immunobiology, Kings College London, London, UKKatholieke Universiteit Leuven/ Universitaire Ziekenhuizen, Leuven, BelgiumDepartment of Paediatrics, University of Cambridge, Cambridge, UKDepartment of Paediatrics, University of Cambridge, Cambridge, UKDepartment of Paediatrics, University of Cambridge, Cambridge, UKCambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK2 Department of Paediatric Diabetes and Endocrinology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UKDiabetes Centre for Children and Adolescents, Children’s Hospital Auf der Bult, Hannover, GermanyKatholieke Universiteit Leuven/ Universitaire Ziekenhuizen, Leuven, BelgiumINNODIA Patient Advisory Committee, Madrid, SpainINNODIA Patient Advisory Committee, Paris, FranceSanofi-Aventis Deutschland GmbH, Frankfurt, GermanySanofi-Aventis Deutschland GmbH, Frankfurt, GermanyIntroduction 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.https://bmjopen.bmj.com/content/11/12/e053669.full |
| spellingShingle | 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 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://bmjopen.bmj.com/content/11/12/e053669.full |
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