Calcineurin Inhibitor (CNI)-Free Immunosuppressive Regimen in T1D Patients Receiving Islet Transplantation
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Our final objective is to develop an adoptive therapy with tolerogenic donor-specific Tr1
      cells in T1D patients undergoing pancreatic islet transplantation (Tx). The achievement of
      this objective depends by the availability of an immunosuppressive treatment (IS) compatible
      with the survival, function, and expansion of the transferred Tr1 cells. For this purpose the
      investigators design a CNI-free single-group, phase 1-2 trial excluding the ATG or anti-CD25
      induction therapy after the 1st islet infusion
    

Detailed description: 
      We designed the clinical trial as a single-arm, phase 1-2 trial conducted in two transplant
      centers (San Raffaele Scientific Institute, Milan, Italy; Cell Isolation and Transplantation
      Center, University of Geneva, Geneva, Switzerland) which used a common protocol for islet
      preparation, post-transplantation patient management and data collection. The trial is
      exploratory in nature and the target enrollment is 10 patients. The recruitment is
      competitive between the two centers and each patient is to receive at least 10,000 IE/kg. Up
      to three islet infusions are allowed per patients until insulin independence is reached,
      provided that partial islet function (i.e., fasting C-peptide ≥0.3 ng/mL) is maintained
      between infusions. We planned an individual follow-up of 3 years after the last islet
      infusion.

      Patients with type 1 diabetes are eligible for this study. Major criteria for inclusion are:
      age 18-65 years; type 1 diabetes with onset <40 years of age; insulin treatment of at least 5
      years at the time of enrollment; stimulated C-peptide in response to arginine <0.5 ng/ml;
      multiple (three or more) daily insulin injections or Continuous Subcutaneous Insulin
      Infusion; self-blood glucose monitoring ≥3 times/day; high glycemic instability and/or
      hypoglycemia unawareness; inability to consistently attain a glycated hemoglobin target of
      <7.5 % without severe hypoglycemia (defined as an hypoglycemic episode requiring the
      assistance by another person for its resolution) in the past 36 months despite medical
      management by a diabetes specialist. Major criteria for exclusion are: HbA1c >12%; BMI >30
      kg/m2, or insulin requirement > 0.8 IU/kg/day; poorly controlled hypertension; untreated
      proliferative diabetic retinopathy; presence or history of macroalbuminuria (>300mg/g day) or
      estimated glomerular filtration rate <60 ml/min/1.73 m2 for females or <70 ml/min/1.73 m2 for
      males.
    

Intervention name(s): CNI free immunosuppression
Intervention type(s): Drug
Intervention description(s): Immunosuppression consisted of: (i) pre-Tx rapamycin treatment (0.1 mg/kg/day) for at least 30 days; (ii) induction therapy with ATG (1.5 mg/kg/day for 4 days starting at day -1) and a steroid bolus (methyl-prednisolone 500 mg, day -1) plus low dose steroids (prednisone, 10 mg/day) and interleukin-1 (IL-1) receptor antagonist (100 mg/day) for 2 weeks (with ATG and steroid bolus administered only prior to the 1st islet infusion; (iii) maintenance with rapamycin (0.1 mg/kg/day) plus mycophenolate mofetil (2 g/day).
Other intervention name(s): Kineret, Rapamune, Thymoglobulin, Myfortic
Intervention MeSH terms: Thymoglobulin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: islet transplantation; brittle diabetes; type 1 diabetes