Strategies to Improve Islet Survival
Condition: Type 1 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; 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, combined with
      immunosuppressive medications and medications to support islet survival, 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 for long-term survival in individuals with type 1 diabetes; however, it does
      not guarantee constant normal blood sugar control. As a result, 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,
      pancreas or pancreatic islet transplantation are possible treatment options. 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 to determine
      the safety and efficacy of islet transplantation, when combined with an immunosuppressive
      medication regimen containing lisofylline (LSF). This regimen is intended to treat 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 the Phase 3 islet
      transplantation study (DAIT CIT-07). Participants assigned to this study will receive LSF.
      Participants in this study will receive up to three separate islet transplants and a regimen
      of immunosuppressive medications including antithymocyte globulin (ATG) for the first
      transplant, sirolimus, tacrolimus, and LSF to support the engrafting of the islets into the
      beta-cell mass. All participants will begin receiving ATG and sirolimus 2 days prior to
      transplantation. ATG will be continued until 2 days post-transplant. Sirolimus will be
      continued for the duration of the study. All participants will also receive tacrolimus
      starting one day post-transplant and continuing for the duration of the study. Basiliximab
      will be used in place of ATG with all subsequent transplants. Participants in the LSF group
      will begin to receive LSF one day prior to transplant and will continue to receive LSF until
      5 days post-transplant. Transplantations will involve an inpatient hospital stay and infusion
      of islets into a branch of the portal vein. 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. Basiliximab will be used in place of ATG for the second and third transplants, if
      they are necessary. 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 approximately 15 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 glomerular filtration rate (GFR) 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): Islet transplant; Antithymocyte globulin; Basiliximab; Lisofylline; Sirolimus; Tacrolimus
Intervention type(s): Procedure; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Transplantation of pancreatic islet cells; Immunosuppressive that selectively depletes activated T-cells and depletes resting T-cells in a dose-dependent manner.; Will replace antithymocyte globulin in all islet transplantations after the first one; An anti-inflammatory that may reduce the rate at which islet cells die.; Maintenance immunosuppressive therapy; Maintenance immunosuppressive therapy
Intervention MeSH terms: Sirolimus; Lisofylline; Tacrolimus; Antilymphocyte Serum; Basiliximab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Allogeneic Islets; Allogeneic Islet Transplantation; Type 1 diabetes mellitus; Type 1 diabetes; T1D; T1DM; Insulin dependence; Hypoglycemia unawareness in T1D; Islet transplant; Islet transplantation; Islet graft