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

• DOI: 10.1136/bmjopen-2021-053669
• Publication Date: 2021-12-07T16:27:38Z
• Authors: Charlotte S Wilhe...; Sarah E Miller; Sylvaine Bruggraber; Diane Picton; Mark Wilson; Katrina Gatley; Anita Chhabra; M Loredana Marcov...; A Emile J Hendriks; Hilde Morobé; Piotr Jaroslaw Ch...; Simon Bond; Bärbel Aschemeier...; Mikael Knip; Timothy Tree; Lut Overbergh; Jaivier Pall; Olivier Arnaud; Michael J Haller; Almut Nitsche; Anke M Schulte; Chantal Mathieu; Adrian Mander; David Dunger
• Keywords: Blood Glucose; Alternative medicine; Endocrinology, Diabetes and Metabolism; statistics & research methods; THERAPY; DOUBLE-BLIND; Diabetes mellitus; Endocrinology; 0302 clinical medicine; Globulin; Dose-ranging study; Pathology; Multicenter Studies as Topic; Child; Internal medicine; Genetics and Pathogenesis of Type 1 Diabetes; Randomized Controlled Trials as Topic; Thymocytes; Diabetes; R; Cohort; Gastroenterology; statistics & research methods; Life Sciences; Middle Aged; Management of Diabetes Mellitus and Hypoglycemia; 16. Peace & justice; General medicine, internal medicine and other clinical medicine; PREVALENCE; 3. Good health; Diabetes and Endocrinology; Treatment Outcome; Type 1 diabetes; Randomized controlled trial; Type 1 Diabetes; Medicine; paediatric endocrinology; Adult; Insulin Therapy; Adolescent; DURATION; 610; C-PEPTIDE; Anti-thymocyte globulin; Young Adult; 03 medical and health sciences; Clinical Trials, Phase II as Topic; BETA-CELL FUNCTION; Biochemistry, Genetics and Molecular Biology; Health Sciences; Genetics; Humans; Double blind; Pancreatic Islet Dysfunction and Regeneration; Clinical endpoint; Placebo; Antilymphocyte Serum; general diabetes; Blood Glucose Self-Monitoring; RECENT-ONSET; Diabetes Mellitus, Type 1; FOS: Biological sciences; Continuous Glucose Monitoring; Surgery

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.