GAD-treatment of children and adolescents with recent-onset type 1 diabetes preserves residual insulin secretion after 30 months
Corresponding Author
Johnny Ludvigsson
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Pediatric clinic, County Council of Östergötland, Linköping, Sweden
Correspondence to: Johnny Ludvigsson, Department of Clinical Experimental Medicine, Faculty of Health Sciences, Linköping University Hospital, SE-58185 Linköping, Sweden.
E-mail: [email protected]
Search for more papers by this authorMikael Chéramy
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Search for more papers by this authorStina Axelsson
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Search for more papers by this authorMikael Pihl
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Search for more papers by this authorLinda Åkerman
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Search for more papers by this authorRosaura Casas
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Search for more papers by this authorfor the clinical GAD-study group in Sweden
Search for more papers by this authorCorresponding Author
Johnny Ludvigsson
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Pediatric clinic, County Council of Östergötland, Linköping, Sweden
Correspondence to: Johnny Ludvigsson, Department of Clinical Experimental Medicine, Faculty of Health Sciences, Linköping University Hospital, SE-58185 Linköping, Sweden.
E-mail: [email protected]
Search for more papers by this authorMikael Chéramy
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Search for more papers by this authorStina Axelsson
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Search for more papers by this authorMikael Pihl
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Search for more papers by this authorLinda Åkerman
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Search for more papers by this authorRosaura Casas
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Search for more papers by this authorfor the clinical GAD-study group in Sweden
Search for more papers by this authorAbstract
Background
This study aimed to analyse data from two different studies (phase II and phase III) regarding the safety and efficacy of treatment with alum formulated glutamic acid decarboxylase GAD65 (GAD-alum) at 30 months after administration to children and adolescents with type 1 diabetes.
Methods
The phase II trial was a double-blind, randomised placebo-controlled study, including 70 children and adolescents who were followed for 30 months. Participants received a subcutaneous injection of either 20 µg of GAD-alum or placebo at baseline and 1 month later. During a subsequent larger European phase III trial including three treatment arms, participants received two or four subcutaneous injections of either 20 µg of GAD-alum and/or placebo at baseline, 1, 3 and 9 months. The phase III trial was prematurely interrupted at 15 months, but of the 148 Swedish patients, a majority completed the 21 months follow-up, and 45 patients completed the trial at 30 months. Both studies included GAD65 auto-antibodies-positive patients with fasting C-peptide ≥0.10 nmol/l. We have now combined the results of these two trials.
Results
There were no treatment related adverse events. In patients treated with 2 GAD-alum doses, stimulated C-peptide area under the curve had decreased significantly less (9 m: p < 0.037; 15 m: p < 0.032; 21 m: p < 0.003 and 30 m: p < 0.004), and a larger proportion of these patients were also able to achieve a peak stimulated C-peptide >0.2 nmol/L (p < 0.05), as compared with placebo.
Conclusion
Treatment with two doses of GAD-alum in children and adolescents with recent-onset type 1 diabetes shows no adverse events and preserves residual insulin secretion. Copyright © 2013 John Wiley & Sons, Ltd.
References
- 1 The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–986.
- 2 Bojestig M, Arnqvist HJ, Hermansson G, Karlberg BE, Ludvigsson J. Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N Engl J Med 1994; 330: 15–18.
- 3 The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. Ann Intern Med 1998; 128: 517–523.
- 4 Madsbad S, Alberti KG, Binder C, et al. Role of residual insulin secretion in protecting against ketoacidosis in insulin-dependent diabetes. Br Med J 1979; 2: 1257–1259.
- 5 Steffes MW, Sibley S, Jackson M, Thomas W. Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care 2003; 26: 832–836.
- 6 Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 2009; 361: 2143–2152.
- 7 Ludvigsson J, Heding L, Lieden G, Marner B, Lernmark A. Plasmapheresis in the initial treatment of insulin-dependent diabetes mellitus in children. Br Med J (Clin Res Ed) 1983; 286: 176–178.
- 8 Feutren G, Papoz L, Assan R, et al. Cyclosporin increases the rate and length of remissions in insulin-dependent diabetes of recent onset. Results of a multicentre double-blind trial. Lancet 1986; 2: 119–124.
- 9 The Canadian-European Randomized Control Trial Group. Cyclosporin-induced remission of IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced insulin secretion. Diabetes 1988; 37: 1574–1582.
- 10 Eisenbarth GS, Srikanta S, Jackson R, et al. Anti-thymocyte globulin and prednisone immunotherapy of recent onset type 1 diabetes mellitus. Diabetes Res 1985; 2: 271–276.
- 11 Chase HP, Butler-Simon N, Garg S, McDuffie M, Hoops SL, O'Brien D. A trial of nicotinamide in newly diagnosed patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1990; 33: 444–446.
- 12 Pozzilli P, Visalli N, Signore A, et al. Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study). Diabetologia 1995; 38: 848–852.
- 13 Coutant R, Landais P, Rosilio M, et al. Low dose linomide in type I juvenile diabetes of recent onset: a randomised placebo-controlled double blind trial. Diabetologia 1998; 41: 1040–1046.
- 14 Ludvigsson J, Samuelsson U, Johansson C, Stenhammar L. Treatment with antioxidants at onset of type 1 diabetes in children: a randomized, double-blind placebo-controlled study. Diabetes Metab Res Rev 2001; 17: 131–136.
- 15 Ludvigsson J, Samuelsson U, Ernerudh J, Johansson C, Stenhammar L, Berlin G. Photopheresis at onset of type 1 diabetes: a randomised, double blind, placebo controlled trial. Arch Dis Child 2001; 85: 149–154.
- 16 Mastrandrea L, Yu J, Behrens T, et al. Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo-controlled, double-blind study. Diabetes Care 2009; 32: 1244–1249.
- 17 Couri CEB, Oliveira MCB, Stracieri ABPL, et al. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. J Am Med Assoc 2009; 301: 1573–1579.
- 18
Raz I,
Elias D,
Avron A,
Tamir M,
Metzger M,
Cohen IR. Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. Lancet 2001; 358: 1749–1753.
10.1016/S0140-6736(01)06801-5 Google Scholar
- 19 Schloot NC, Meierhoff G, Lengyel C, et al. Effect of heat shock protein peptide DiaPep277 on beta-cell function in paediatric and adult patients with recent-onset diabetes mellitus type 1: two prospective, randomized, double-blind phase II trials. Diabetes Metab Res Rev 2007; 23: 276–285.
- 20 Lazar L, Ofan R, Weintrob N, et al. Heat-shock protein peptide DiaPep277 treatment in children with newly diagnosed type 1 diabetes: a randomised, double-blind phase II study. Diabetes Metab Res Rev 2007; 23: 286–291.
- 21 Rother KI, Brown RJ, Morales MM, et al. Effect of ingested interferon-alpha on beta-cell function in children with new-onset type 1 diabetes. Diabetes Care 2009; 32: 1250–1255.
- 22 Herold KC, Gitelman SE, Masharani U, et al. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 2005; 54: 1763–1769.
- 23 Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005; 352: 2598–2608.
- 24 Sherry N, Hagopian W, Ludvigsson J, et al. Teplizumab for treatment of type 1 diabetes (protege study): 1-year results from a randomised, placebo-controlled trial. Lancet 2011; 378: 487–497.
- 25 Gottlieb P, Pozzilli P. DEFEND presented during session: treatment of type 1 diabetes-update on clinical trialsADA 71st scientific sessions. San Diego California, 2011.
- 26 Ludvigsson J. Adequate doses of autoantigen administered using the appropriate route may create tolerance and stop autoimmunity. Diabetologia 2009; 52: 175–176.
- 27 Jasinski JM, Eisenbarth GS. Insulin as a primary autoantigen for type 1A diabetes. Clin Dev Immunol 2005; 12: 181–186.
- 28 Baekkeskov S, Nielsen JH, Marner B, Bilde T, Ludvigsson J, Lernmark A. Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature 1982; 298: 167–169.
- 29 Agardh CD, Lynch KF, Palmer M, Link K, Lernmark A. GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes. Diabetologia 2009; 52: 1363–1368.
- 30 Ludvigsson J, Faresjo M, Hjorth M, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med 2008; 359: 1909–1920.
- 31 Ludvigsson J, Krisky D, Casas R, et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med 2012; 366: 433–442.
- 32 Wherrett DK, Bundy B, Becker DJ, et al. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet 2011; 378: 319–327.
- 33 Ludvigsson J, Hjorth M, Cheramy M, et al. Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial. Diabetologia 2011; 54: 634–640.
- 34 Greenbaum CJ, Mandrup-Poulsen T, McGee PF, et al. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes. Diabetes Care 2008; 31: 1966–1971.
- 35 Axelsson S, Hjorth M, Akerman L, Ludvigsson J, Casas R. Early induction of GAD(65)-reactive Th2 response in type 1 diabetic children treated with alum-formulated GAD(65). Diabetes Metab Res Rev 2010; 26: 559–568.
- 36 Hjorth M, Axelsson S, Ryden A, Faresjo M, Ludvigsson J, Casas R. GAD-alum treatment induces GAD65-specific CD4 + CD25highFOXP3+ cells in type 1 diabetic patients. Clin Immunol 2011; 138: 117–126.
- 37 Skoglund C, Cheramy M, Casas R, Ludvigsson J, Hampe CS. GAD autoantibody epitope pattern after GAD-alum treatment in children and adolescents with type 1 diabetes. Pediatr Diabetes 2012; 13: 244–250.
- 38 Axelsson S, Cheramy M, Hjorth M, et al. Long-lasting immune responses 4 years after GAD-alum treatment in children with type 1 diabetes. PLoS One 2011; 6: e29008.
- 39 Cheramy M, Skoglund C, Johansson I, Ludvigsson J, Hampe CS, Casas R. GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD65 enzyme activity and humoral response. Clin Immunol 2010; 137: 31–40.
- 40 Pozzilli P, Schloot NC, Hosszúfalusi N, et al. Time dependent C-peptide decline in 4411 patients with recent onset type 1 diabetes followed for up to 10 years: a meta-analysis from 8 European centres. EASD Presentation Abstract 161 2011.
- 41 Skyler JS, Krischer JP, Wolfsdorf J, et al. Effects of oral insulin in relatives of patients with type 1 diabetes: the diabetes prevention trial–type 1. Diabetes Care 2005; 28: 1068–1076.
- 42 Raz I, Pozzilli P. Current Ongoing Trials and the Issue of Multiple Intervention Strategies in Newly Diagnosed patients World Diabetes Congress. IDF: Dubai, 2011.
- 43 Mathieu C, Gysemans C, Giulietti A, Bouillon R. Vitamin D and diabetes. Diabetologia 2005; 48: 1247–1257.
- 44 Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A. 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol 2001; 167: 4974–4980.
- 45 Mandrup-Poulsen T, Pickersgill L, Donath MY. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat Rev Endocrinol 2010; 6: 158–166.
- 46 Ludvigsson J. Why diabetes incidence increases – a unifying theory. Ann N Y Acad Sci 2006; 1079: 374–382.
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