The first objective of this application is describe the strengths and successes of the TrialNet Clinical Center at the Hospital for Sick Children/University of Toronto. The Toronto Clinical Center has shown a high level of recruitment for the TrialNet Natural History of the Development of Type 1 Diabetes Study through its highly capable investigators, Drs. Diane Wherrett and Jeffrey Mahon, providing expertise in diabetes, clinical trials and immunology of type 1 diabetes, its excellent coordinators, institutional support and resources, a productive Canadian affiliate network and extensive local partnerships in the Toronto area. Recruitment to this study ranks 4th of the 14 North American TrialNet Clinical Centers. This center has provided leadership in TrialNet studies: Dr. Mahon, chair of the Natural History Study of the Development of Type 1 Diabetes Study and Dr. Wherrett, chair of the Effects of Recombinant Human Glutamic Acid Decarboxylase (rhGAD65) Formulated in Alum (GAD-alum) on the Progression of Type 1 Diabetes in New Onset Subjects Study. It has contributed actively to all of TrialNet's studies to preserve insulin secretion in recent onset diabetes. The second objective is to determine the efficacy and safety of the incretin mimetic exenatide (Byetta(), alone and in combination with the anti-CD20 monoclonal antibody rituximab (Rituxan(), in patients with newly recognized immune-mediated Type 1 Diabetes. The proposal's primary objective will be to test the hypothesis that the combination of exenatide and rituxamab more effectively preserves endogenous insulin secretion compared to either drug alone. The primary outcome will be the area under the stimulated C-peptide curve (AUC) during a 2 hour mixed meal glucose tolerance test one year after study entry. The study will be placebo controlled and double blinded. The rationale for this proposed study combines the immunomodulatory effect of rituximab to reduce beta cell autoimmunity with the beta cell regenerative potential of exenatide to improve insulin secretion. Preserved endogenous insulin secretion has been found to be associated with reduced of rates of the diabetes complications of hypoglycemia, nephropathy and retinopathy.
Finding methods to preserve insulin secretion in type 1 diabetes are crucial in preventing the disease and in reducing the severity in those affected. The combination of rituximab and exenatide has the potential to both reduce the loss of insulin-producing cells and to promote their development. Success of this therapy could result in the improvement of long term health for those with type 1 diabetes.
|Orban, Tihamer; Beam, Craig A; Xu, Ping et al. (2014) Reduction in CD4 central memory T-cell subset in costimulation modulator abatacept-treated patients with recent-onset type 1 diabetes is associated with slower C-peptide decline. Diabetes 63:3449-57|
|Orban, Tihamer; Bundy, Brian; Becker, Dorothy J et al. (2014) Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment. Diabetes Care 37:1069-75|
|Arif, Sefina; Leete, Pia; Nguyen, Vy et al. (2014) Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes. Diabetes 63:3835-45|
|Beam, Craig A; Gitelman, Stephen E; Palmer, Jerry P et al. (2014) Recommendations for the definition of clinical responder in insulin preservation studies. Diabetes 63:3120-7|
|Wherrett, Diane K (2014) Trials in the prevention of type 1 diabetes: current and future. Can J Diabetes 38:279-84|
|Pescovitz, Mark D; Greenbaum, Carla J; Bundy, Brian et al. (2014) B-lymphocyte depletion with rituximab and *-cell function: two-year results. Diabetes Care 37:453-9|
|Kroll, Jing Lu; Beam, Craig; Li, Shaobing et al. (2013) Reactivation of latent viruses in individuals receiving rituximab for new onset type 1 diabetes. J Clin Virol 57:115-9|
|Krischer, Jeffrey P; Type 1 Diabetes TrialNet Study Group (2013) The use of intermediate endpoints in the design of type 1 diabetes prevention trials. Diabetologia 56:1919-24|
|Loechelt, Brett J; Boulware, David; Green, Michael et al. (2013) Epstein-Barr and other herpesvirus infections in patients with early onset type 1 diabetes treated with daclizumab and mycophenolate mofetil. Clin Infect Dis 56:248-54|
|Sosenko, Jay M; Skyler, Jay S; Palmer, Jerry P et al. (2013) The prediction of type 1 diabetes by multiple autoantibody levels and their incorporation into an autoantibody risk score in relatives of type 1 diabetic patients. Diabetes Care 36:2615-20|
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