Islet Allotransplantation With Steroid Free Immunosuppression

Type 1 Diabetes Clinical Trial

Official title:

Sequential Islet Transplantation With Steroid Free Immunosuppression for Type 1 Diabetes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00446264
• Other study ID #: CP 01/48
• Secondary ID: PHRCAFSSAPS 0302
• Status: Completed
• Phase: Phase 2
• First received: March 9, 2007
• Last updated: April 23, 2012
• Start date: May 2003
• Est. completion date: February 2009

Study information

• Verified date: February 2009
• Source: University Hospital, Lille
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: February 2009
• Est. primary completion date: October 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

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:

• body mass index greater than 28 kg/m2

• non stable arteriopathy or heart disease

• active infection

• previous transplantation

• hyperimmunization

• insulin daily needs above 1.2 U/Kg

• creatinine clearance below 60 ml/mn or urinary albumin excretion above 300 mg/d

• malignancy

• smoking

• desire for pregnancy

• psychiatric disorders

• lack of compliance

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 1
• Hypoglycemia
• Metabolic Diseases
• Type 1 Diabetes

Intervention

Procedure:
• islet transplantation
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.

Drug:
• daclizumab - sirolimus - tacrolimus
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

Locations

Country	Name	City	State
France	University Hospital of Lille	Lille

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Lille	Institut National de la Santé Et de la Recherche Médicale, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite Criteria: Insulin Independence and Glycosylated Hemoglobin (HbA1c) Under 6.5% at One Year	The percentage of insulin independents subjects with an HbA1c less than 6.5% at one year after last transplant	1 year	No
Secondary	Hypoglycemic Events	Percentage of subjects free of severe hypoglycemic events from day 0 to day 365 with the day of transplant designated day 0	day 0 to day 365	Yes
Secondary	Plasma C-peptide	Level of plasma C-peptide at 1 year after the first transplant	1 year	No
Secondary	HbA1c < 6.5%	The percentage of subjects with HbA1c < 6.5% at 1 year after the first transplant	1 year	No
Secondary	Percentage of Time Spent in Hypoglycemia (<0.70 mg/L)	percentage of time spent in hypoglycemia derived from CGMS (Continuous Glucose Monitoring System)	1 year	No
Secondary	Number of Adverse Events	The number of adverse events related to the procedure and to the immunosuppression	1 year	Yes