Clinical trial NCT00446264: Islet Allotransplantation With Steroid Free Immunosuppression
Official title: Sequential Islet Transplantation With Steroid Free Immunosuppression for Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 1 Diabetes
Hypoglycemia
Metabolic Diseases
Keywords: diabetes
hypoglycemia
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2007-03-12
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Composite Criteria: Insulin Independence and Glycosylated Hemoglobin (HbA1c) Under 6.5% at One Year
timeFrame: 1 year
Secondary outcomes:
measure: Hypoglycemic Events
timeFrame: day 0 to day 365
measure: Plasma C-peptide
timeFrame: 1 year
measure: HbA1c < 6.5%
timeFrame: 1 year
measure: Percentage of Time Spent in Hypoglycemia (<0.70 mg/L)
timeFrame: 1 year
measure: Number of Adverse Events
timeFrame: 1 year
Other outcomes:
Locations:
city: Lille
country: France
facility: University Hospital of Lille
Study officials:
affiliation: University Hospital, Lille
name: Francois Pattou, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Lille
name: Marie-Christine Vantyghem, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Université de Lille 2
name: Julie Kerr-Conte, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vantyghem MC, Chetboun M, Gmyr V, Jannin A, Espiard S, Le Mapihan K, Raverdy V, Delalleau N, Machuron F, Hubert T, Frimat M, Van Belle E, Hazzan M, Pigny P, Noel C, Caiazzo R, Kerr-Conte J, Pattou F; Members of the Spanish Back Pain Research Network Task Force for the Improvement of Inter-Disciplinary Management of Spinal Metastasis. Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study. Diabetes Care. 2019 Nov;42(11):2042-2049. doi: 10.2337/dc19-0401.
citation: Benomar K, Chetboun M, Espiard S, Jannin A, Le Mapihan K, Gmyr V, Caiazzo R, Torres F, Raverdy V, Bonner C, D'Herbomez M, Pigny P, Noel C, Kerr-Conte J, Pattou F, Vantyghem MC. Purity of islet preparations and 5-year metabolic outcome of allogenic islet transplantation. Am J Transplant. 2018 Apr;18(4):945-951. doi: 10.1111/ajt.14514. Epub 2017 Nov 11.
citation: Caiazzo R, Vantyghem MC, Raverdi V, Bonner C, Gmyr V, Defrance F, Leroy C, Sergent G, Hubert T, Ernst O, Noel C, Kerr-Conte J, Pattou F. Impact of Procedure-Related Complications on Long-term Islet Transplantation Outcome. Transplantation. 2015 May;99(5):979-84. doi: 10.1097/TP.0000000000000458.
citation: Vantyghem MC, Raverdy V, Balavoine AS, Defrance F, Caiazzo R, Arnalsteen L, Gmyr V, Hazzan M, Noel C, Kerr-Conte J, Pattou F. Continuous glucose monitoring after islet transplantation in type 1 diabetes: an excellent graft function (beta-score greater than 7) Is required to abrogate hyperglycemia, whereas a minimal function is necessary to suppress severe hypoglycemia (beta-score greater than 3). J Clin Endocrinol Metab. 2012 Nov;97(11):E2078-83. doi: 10.1210/jc.2012-2115. Epub 2012 Sep 20.