MGA031, Sirolimus and Tacrolimus in Islet Transplantation
Condition: Type 1 Diabetes Mellitus; Hypoglycemia
MeSH terms: Diabetes Mellitus, Type 1; Hypoglycemia
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Allogeneic Islets of Langerhans
Intervention type(s): Biological
Intervention description(s): Intraportal infusion of islets of Langerhans
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment