MGA031, Sirolimus and Tacrolimus in Islet Transplantation
This clinical trial is designed to extend the observations made in our pilot clinical trial (IND 8971, Study #1) on the safety and efficacy of immunotherapy with the anti-CD3 monoclonal antibody hOKT3γ1 (Ala-Ala), (currently called MGA031) combined with sirolimus and tacrolimus in preventing rejection and autoimmune destruction of deceased donor pancreatic islet transplants in type 1 diabetic recipients.
Type 1 Diabetes Mellitus
Biological: Allogeneic Islets of Langerhans
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||hOKT3γ1 (Ala-Ala), Sirolimus and Low Dose Tacrolimus Therapy in Type 1 Diabetic Islet Allograft Recipients|
- Subjects With Full Islet Function. [ Time Frame: At one year after initial transplant. ] [ Designated as safety issue: No ]Proportion of subjects with full islet function (i.e. insulin independent) at one year after initial islet transplant.
- Serious Adverse Events Related to Immunosuppressive Therapy. [ Time Frame: Day 0 - Day 365 ] [ Designated as safety issue: Yes ]Number of serious adverse events related to immunosuppressive therapy.
- Subjects With Partial Islet Function and no Episodes of Severe Hypoglycemia; [ Time Frame: At one year after initial transplant ] [ Designated as safety issue: No ]Proportion of subjects with partial islet function and no episodes of severe hypoglycemia at one year after initial islet transplant.
- Insulin Independent Single-donor Subjects. [ Time Frame: At 75 days after transplant ] [ Designated as safety issue: No ]Proportion of insulin independent single-donor subjects at day 75 after transplant
- Insulin Independent Multiple-donor Subjects. [ Time Frame: At one year after final transplant ] [ Designated as safety issue: No ]Proportion of insulin independent multiple-donor subjects at one year after final transplant. Participant received more than one islet transplant.
|Study Start Date:||November 2005|
|Study Completion Date:||June 2010|
|Primary Completion Date:||May 2010 (Final data collection date for primary outcome measure)|
Experimental: Allogeneic Islets of Langerhans
Biological: Allogeneic Islets of Langerhans
Intraportal infusion of islets of Langerhans
Type 1 diabetes mellitus continues to be a therapeutic challenge. Previous studies have shown that failure to prevent hypoglycemia and hyperglycemia results in acute and chronic complications, leading to poor quality of life, premature death, and considerable health care costs in 30% to 50% of diabetic patients. Therefore, establishing safe and effective ways to achieve and maintain normoglycemia would have substantial implications for the well-being of individuals with diabetes. Intensive insulin therapy has been shown to reduce the risk of chronic complications in patients who achieve near-normalization of glycemia. However, such therapy is labor-intensive, difficult to implement for many patients, and limited by the accompanying increased frequency of severe hypoglycemia. Currently, the only way to restore and sustain normoglycemia without the associated risk of hypoglycemia is by replacing the patient's islets of Langerhans, either by transplanting a vascularized pancreas or, much less invasively, by infusing isolated islets.
Strategies that selectively inactivate autoreactive T cells and prevent allorejection of transplanted islets in the absence of diabetogenic side effects need to be developed for islet transplants to survive in autoimmune diabetic recipients. The current clinical study will extend the observations made in our first pilot clinical trial (IND 8971, Study #1) that provided preliminary information on the safety and efficacy of immunotherapy with the anti-CD3 monoclonal antibody hOKT3γ1 (Ala-Ala), (currently called MGA031) combined with sirolimus and tacrolimus in preventing rejection and autoimmune destruction of deceased donor pancreatic islet transplants in type 1 diabetic recipients.
In the pilot study 4 of 6 single islet transplant recipients remained insulin independent with normal HbA1c and no episodes of hypoglycemia throughout the 1 year post-transplant period. Three of those four participants have maintained insulin independence for > 3.5, >4.5 and >5 years post islet transplant. These preliminary findings warrant an extension study involving more recipients and more comprehensive immunologic monitoring to examine in greater detail the impact of MGA031 induction immunotherapy on T cell responses operative in rejection and autoimmune destruction of transplanted islets as well as on formation of regulatory T cell function for the protection of transplanted islets.
A total of 5 patients with type 1 diabetes will be transplanted under this protocol. Islet transplant recipients will be admitted for 5 days and followed for one year after transplantation.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00265473
|United States, Minnesota|
|University of Minnesota|
|Minneapolis, Minnesota, United States, 55455|
|Principal Investigator:||Bernhard J. Hering, M.D.||University of Minnesota - Clinical and Translational Science Institute|