Islet Allotransplantation With Steroid Free Immunosuppression

Phase 2

Completed

Interventions: Procedure: islet transplantation
Drug: daclizumab - sirolimus - tacrolimus

Brief 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.

Recruitment & Eligibility

Inclusion Criteria

type 1 diabetes documented for more than 5 years
arginine stimulated C-peptide lower than 0.2 ng/mL
one of the following:hypoglycemia unawareness OR metabolic lability documented by one or more severe hypoglycemias or two or more hospital admissions for ketoacidosis within the previous year.

Exclusion Criteria

Arm && Interventions

Group	Intervention	Description
islet transplantation	islet transplantation	Each participant received up to three sequential fresh islet infusions within three months.
islet transplantation	daclizumab - sirolimus - tacrolimus	Each participant received up to three sequential fresh islet infusions within three months.

Primary Outcome Measures

Name	Time	Method
Composite Criteria: Insulin Independence and Glycosylated Hemoglobin (HbA1c) Under 6.5% at One Year	1 year	The percentage of insulin independents subjects with an HbA1c less than 6.5% at one year after last transplant

Secondary Outcome Measures

Name	Time	Method
Hypoglycemic Events	day 0 to day 365	Percentage of subjects free of severe hypoglycemic events from day 0 to day 365 with the day of transplant designated day 0
Plasma C-peptide	1 year	Level of plasma C-peptide at 1 year after the first transplant
HbA1c < 6.5%	1 year	The percentage of subjects with HbA1c \< 6.5% at 1 year after the first transplant
Percentage of Time Spent in Hypoglycemia (<0.70 mg/L)	1 year	percentage of time spent in hypoglycemia derived from CGMS (Continuous Glucose Monitoring System)
Number of Adverse Events	1 year	The number of adverse events related to the procedure and to the immunosuppression