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Sponsors and Collaborators: |
University of Minnesota National Institutes of Health (NIH) Juvenile Diabetes Research Foundation |
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Information provided by: | University of Minnesota |
ClinicalTrials.gov Identifier: | NCT00265473 |
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.
Condition | Intervention | Phase |
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Type 1 Diabetes Mellitus Hypoglycemia |
Biological: Islets of Langerhans Drug: MGA031 Drug: Sirolimus Drug: Tacrolimus |
Phase I Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study |
Official Title: | hOKT3γ1 (Ala-Ala), Sirolimus and Low Dose Tacrolimus Therapy in Type 1 Diabetic Islet Allograft Recipients |
Estimated Enrollment: | 10 |
Study Start Date: | November 2005 |
Estimated Study Completion Date: | June 2010 |
Estimated Primary Completion Date: | June 2010 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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1: Experimental
Islet infusion with MGA031 induction and sirolimus and tacrolimus maintenance immunosuppression.
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Biological: Islets of Langerhans
Up to 3 intraportal infusions of cadaveric pancreatic islets of Langerhans. First infusion to contain at least 5,000 islet equivalents/kg body weight (IE/kg) and subsequent infusions to contain at least 3,000 IE/kg.
Drug: MGA031
Visit Day: MGA031 Dose Day -2: 51 μg/m2 Day -1: 103 μg/m2 Day 0: 207 μg/m2 Day +1: 413 μg/m2 Days +2 to +11: 826 μg/m2 Total subject dose for a70 kg subject: 9034 μg/m2 (assumes a body surface area of 1.92m2) ~17 mg
Initial dose 0.1 mg/kg PO on day -2, followed by 0.05 mg/kg daily, whole blood 24-hour trough adjusted to target 5-15 ng/ml as tolerated.
Drug: Tacrolimus
Initial dose 0.015 mg/kg PO BID on day +8, whole blood trough adjusted to 3-6 ng/ml.
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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 10 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.
Ages Eligible for Study: | 18 Years to 65 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contact: Jayne Pederson | 612-624-8402 | peder059@umn.edu |
United States, Minnesota | |
University of Minnesota | Recruiting |
Minneapolis, Minnesota, United States, 55455 | |
Contact: Jayne Pederson 612-624-8402 peder059@umn.edu | |
Contact: Barb Lervik, RN 612 626-4883 lervi001@umn.edu | |
Principal Investigator: Bernhard J. Hering, M.D. | |
Sub-Investigator: David ER Sutherland, MD, PhD | |
Sub-Investigator: Raja Kandaswamy, MD | |
Sub-Investigator: David Radosevich, RN, PhD | |
Sub-Investigator: Pratima Bansal-Pakala, PhD | |
Sub-Investigator: David Hunter, MD | |
Sub-Investigator: Jeffrey A. Bluestone, PhD | |
Sub-Investigator: Antoinette Moran, M.D. | |
Sub-Investigator: Melena Bellin, M.D. | |
Sub-Investigator: James V. Harmon, M.D. |
Principal Investigator: | Bernhard J. Hering, M.D. | University of Minnesota |
Responsible Party: | University of Minnesota ( Bernhard J. Hering, M.D. ) |
Study ID Numbers: | 0407M62505 |
Study First Received: | December 12, 2005 |
Last Updated: | October 16, 2008 |
ClinicalTrials.gov Identifier: | NCT00265473 |
Health Authority: | United States: Food and Drug Administration |
Sirolimus Metabolic Diseases Autoimmune Diseases Clotrimazole Miconazole Tioconazole Diabetes Mellitus |
Endocrine System Diseases Tacrolimus Hypoglycemia Diabetes Mellitus, Type 1 Endocrinopathy Glucose Metabolism Disorders Metabolic disorder |
Anti-Bacterial Agents Anti-Infective Agents Immunologic Factors Immune System Diseases Antineoplastic Agents Antifungal Agents |
Therapeutic Uses Physiological Effects of Drugs Antibiotics, Antineoplastic Immunosuppressive Agents Pharmacologic Actions |