Islet Allotransplantation With Steroid Free Immunosuppression
Condition: Type 1 Diabetes; Hypoglycemia; Metabolic Diseases
MeSH terms: Diabetes Mellitus, Type 1; Hypoglycemia; Metabolic Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      The restoration of endogenous insulin secretion carries significant hopes for shifting the
      paradigm of life long exogenous insulin therapy in selected groups of patients with type 1
      diabetes(T1D). After decades of frustrating clinical attempts, the Edmonton group set up in
      2000 new standards for islet transplantation in patients with brittle T1D by achieving
      insulin independence in 80 percent of patients. These seminal results have however proved
      much more difficult to duplicate than initially expected.

      This single center phase 2 clinical trial, duplicating the Edmonton protocol, is designed for
      confirming the consistent short term efficacy and safety of sequential islet
      allotransplantation with steroid free immunosuppression in patients with severe T1D.
    

Detailed description: 
      The short term effectiveness of islet transplantation for alleviating hypoglycemia and
      controlling glucose homeostasis while limiting or even avoiding the nedd for exogenous
      insulin has been established despite protocol modifications in donor selection, islet
      preparation or recipient treatment, insulin independence with adequate metabolic control was
      however rarely prolonged beyond two years. The most frequently proposed explanations include
      chronic allogenic rejection, recurrence of autoimmunity and beta cell toxicity from
      administered immunosuppressive drugs.

      Fourteen patients were enrolled in this single center phase 2 trial initiated in 2003.
      Eligible patients were males or females between 18 and 65 years of age, with type 1 diabeted
      documented for more than 5 years, arginine stimulated C-peptide lower than 0.2ng/ml, and
      hypoglycemia awareness or documented metabolic lability. Exclusion criteria included body
      mass index greater than 28Kg/m2, unstable arteriopathy or heart disease, active infection,
      previous transplantation, insulin daily requirements above 1.2 UI/kg, creatinin clearance
      below 60 ml/mn/m2 or urinary albumin excretion above 300 mg/day, malignancy, smoking, desire
      for pregnancy, psychiatric disorders and lack of compliance. The study primary efficacy
      endpoint was graft survival defined as insulin independence and HbA1c<6.5%. Secondary
      outcomes were graft function and metabolic control.
    

Intervention name(s): islet transplantation; daclizumab - sirolimus - tacrolimus
Intervention type(s): Procedure; Drug
Intervention description(s): Islet transplantation consisted of up to three sequential fresh islet infusions within three months. Access to the portal vein was gained under general anesthesia by percutaneous catheterisation of a peripheral portal branch under ultrasound guidance or by surgical catheterisation of a small mesenteric vein.; Immunosuppressive consisted of Tacrolimus, target through level at 3-6 ng/ml, Sirolimus, target through level at 12-15 ng/ml for three months and at 7-10 ng/ml thereafter. A five-dose induction course of Daclizumab 1mg/Kg was administered biweekly beginning one hour prior to the first infusion
Other intervention name(s): surgical catheterisation; percutaneous catheterisation; Prograf; Rapamune; Zenapax
Intervention MeSH terms: Sirolimus; Tacrolimus; Daclizumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: diabetes; hypoglycemia