LEA29Y (Belatacept) Emory Edmonton Protocol
Condition: Type 1 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 2

Summary: 
      Type 1 diabetes is an autoimmune disease in which the insulin-producing pancreatic beta cells
      are destroyed, resulting in poor blood sugar control. The purpose of this study is to
      determine the safety and effectiveness of islet transplantation using a steroid-free,
      calcineurin-inhibitor-free belatacept based immunosuppressive medication, for treating type 1
      diabetes in individuals experiencing hypoglycemia unawareness and severe hypoglycemic
      episodes.
    

Detailed description: 
      Type 1 diabetes is commonly treated with the administration of insulin, either by multiple
      insulin injections or by a continuous supply of insulin through a wearable pump. Insulin
      therapy allows long-term survival in individuals with type 1 diabetes; however, it does not
      guarantee constant normal blood sugar control. Because of this, long-term type 1 diabetic
      survivors often develop vascular complications, such as diabetic retinopathy, an eye disease
      that can cause poor vision and blindness, and diabetic nephropathy, a kidney disease that can
      lead to kidney failure. Some individuals with type 1 diabetes develop hypoglycemia
      unawareness, a life-threatening condition that is not easily treatable with medication and is
      characterized by reduced or absent warning signals for hypoglycemia. For such individuals,
      transplantation of pancreatic islets is a possible treatment option. Unfortunately, insulin
      independence among islet transplant recipients tends to decline over time. New strategies
      aimed at promoting engraftment of transplanted islets are needed to improve the clinical
      outcomes associated with this procedure. The purpose of this study is determine the safety
      and efficacy of islet transplantation, when combined with an immunosuppressive medication
      regimen containing belatacept, for treating type 1 diabetes in individuals experiencing
      hypoglycemia unawareness and severe hypoglycemic episodes. This study will also seek to
      improve the understanding of determinants of success and failure of islet transplants for
      type 1 diabetes.

      Eligible participants will be randomly assigned to this study or a site-specific Phase 3
      islet transplantation study (CIT-07). Participants in this study will receive up to three
      separate islet transplants and a regimen of immunosuppressive medications consisting of
      belatacept, basiliximab (an IL-2 monoclonal antibody receptor blocker), and mycophenolate
      mofetil. Participants will begin receiving all three drugs on the day of the first islet
      transplant. Belatacept will also be administered again on Days 4, 14, 28, 56, and 84
      post-transplant and then every 4 weeks for the duration of the study.

      If the participant receives daclizumab, it will also be given again on Days 14, 28, 42, and
      56 post-transplant; if the participant receives basiliximab, it will also be given again on
      Day 4 post-transplant. Mycophenolate mofetil will also be given for the duration of the
      study.

      Transplantations will involve an inpatient hospital stay and intraportal infusion of islet
      cells. Participants who do not achieve or maintain insulin independence by Day 75
      post-transplant will be considered for a second islet transplant. Participants who remain
      dependent on insulin for longer than 1 month after the second transplant and who show partial
      graft function will be considered for a third islet transplant. Participants who do not meet
      the criteria for a subsequent transplant and do not have a functioning graft will enter a
      reduced follow-up period.

      There will be up to 25 study visits following each transplant. A physical exam, review of
      adverse events, and blood collection will occur at most visits. A chest x-ray, abdominal
      ultrasound, electrocardiogram, quality of life questionnaires, urine collection, and more
      extensive blood testing will occur at some visits. Participants will also test their own
      blood glucose levels at least five times per day throughout the study. A 24-month follow-up
      period will take place after the participant's last transplant.
    

Intervention name(s): Allogeneic Pancreatic Islet Cells; Belatacept; Basiliximab; Mycophenolate Mofetil; Tacrolimus; Intraportal infusion of islet cells
Intervention type(s): Biological; Biological; Biological; Drug; Drug; Procedure
Intervention description(s): Transplant of islet cells from a healthy pancreas. A dose of at least 5,000 Islet Equivalents (IEQ)/kg recipient body weight (BW) infused intraportally for the first transplant, and at least 4,000 IEQ/kg recipient BW infused intraportally for subsequent transplants.; Belatacept is an inhibitor of the 2 signals that stimulate T-cells. Subjects will receive NULOJIX® (belatacept)10mg/kg through a peripheral vein on Day 0 and post-operative days 4, 14, 28, 56, 84. After Day 84 subjects will receive belatacept at a maintenance dose of 5 mg/kg every 4 weeks for the duration of study follow-up (2 years after the final islet transplant). Infusion doses will be based upon the subject's actual body weight at study Day 0 and will not be modified during the course of the study unless there is a change in body weight plus or minus 10% of Day 0 body weight.; Immunosuppressive medication for prophylaxis of acute transplant rejection. Two Intravenous (IV) doses of basiliximab, a monoclonal antibody Interleukin 2 (IL-2) receptor blocker, will be given with the first and second (if necessary) transplants. The first dose will be 20 mg and will be given within two hours prior to islet transplant on the day of islet transplantation. The second 20 mg dose will be given on Day 4 after the transplant.If a third islet transplant is deemed necessary and performed more than 70 days after the second transplant, both doses of basiliximab will be repeated. No additional doses of basiliximab will be given with a third transplant that is performed between 30 and 70 days after the second transplant.; Maintenance immunosuppressive therapy. Subjects will receive mycophenolate mofetil starting immediately pre-transplant on Day 0 at a dose of 1g orally twice a day for the duration of study follow-up (2 years after the final islet transplant).; Tacrolimus may be used only as a supplement to maintenance mycophenolate mofetil (MMF) in those cases where the trough level is below the therapeutic range. Tacrolimus will be administered orally twice a day to maintain trough levels of 3-5 ng/mL. Generic equivalents of Prograf® will not be permitted.; The infusion of allogeneic pancreatic islet cells (islet transplant[s]) will occur intraportally.
Other intervention name(s): NUJOLIX; Simulect; Cellcept; Prograf
Intervention MeSH terms: Mycophenolic Acid; Abatacept; Tacrolimus; Basiliximab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Insulin dependence; Hypoglycemia; Hypoglycemia unawareness