Calcineurin Inhibitor (CNI)-Free Immunosuppressive Regimen in T1D Patients Receiving Islet Transplantation
Calcineurin Inhibitor (CNI)-Free Immunosuppressive Regimen in T1D Patients Receiving Islet Transplantation
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
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.
Inclusion Criteria:

 -  Male and female patients aged 18-65yr

 -  ability to provide written informed consent and comply with the study protocol
 procedures

 -  clinical history of type 1 diabetes with onset <40yr of age, on insulin for at least
 5yr at the time of enrollment

 -  absent stimulated C-peptide (<0.5ng/ml) in response to arginine

 -  multiple (three or more) daily insulin injections or insulin pump therapy

 -  self blood glucose monitoring ≥3 times/day, supervised by a specialist physician

 -  high glycemic instability and hypoglycemia unawareness

 -  inability to consistently attain a HbA1c < 7.5 % target without experiencing severe
 hypoglycemia (assistance by another person) in the past 36 months despite appropriate
 medical management.

 Exclusion Criteria:

 -  HbA1c >12%

 -  BMI >30 kg/m2, or insulin requirement of > 0.8 IU/kg/day;

 -  poorly controlled hypertension;

 -  untreated proliferative diabetic retinopathy;

 -  presence or history of macroalbuminuria (>300mg/g day) or measured glomerular
 filtration rate <60 ml/min/1.73 m2 for females and <70 ml/min/1.73 m2 for males

 -  for female participants: positive pregnancy test, presently breast-feeding, or
 unwilling to use effective contraceptive measures for the duration of the study and 3
 months after discontinuation

 -  for male participants: intent to procreate during the duration of the study or within
 3 months after discontinuation or unwillingness to use effective measures of
 contraception;

 -  any history of malignancy within the previous 5 years, except for completely resected
 squamous or basal cell carcinoma of the skin;