Human Islet Transplantation in Brittle Type 1 Diabetes Mellitus. The GRAGIL 2 Study.

Study Overview
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Brief Summary
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This research project is supported by a multicentric network of collaborators whose goal is to assess the efficacy of transplanting allogenic pancreas islets to restore insulin secretion in patients with brittle type 1, insulin-dependent diabetes mellitus and to improve their metabolic control.

Detailed Description
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The general objective is to demonstrate the beneficial effect of islet allotransplantation in patients with brittle type 1 diabetes with no endogenous insulin secretion, for whom the risk of the spontaneous course of the disease is judged to be worse than the transplantation-related risk. The specific objective is to establish reference data for islet transplantation in non-uremic patients with brittle diabetes, in a multicentric network setting, using the Edmonton protocol.

Official Title
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Transplantation d'Ilots Pancreatiques Allogeniques Adultes Pour le Traitement du Diabete Insulino-dependant: Etude GRAGIL 2.

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Procedure: human pancreatic islet transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Type 1 diabetes mellitus Disease duration > 5 years Despite intensive insulin therapy with tight endocrinologist supervision, persistence of the following conditions : hypoglycemia unawareness (< 54 mg/dl) ; brittleness with at least two episodes of severe hypoglycemia ((defined by the need for assistance to correct the blood glucose level) or ketoacidosis per year , or often enough that the diabetologist judges the frequency to be life-threatening, the risk of transplantation and immunosuppression being judged to be less than the risk of the spontaneous course of uncontrolled diabetes Basal and stimulated plasma C-peptide < 0.2 ng/ml Creatinine clearance ≥ 50 ml/min/1.73 m2 and proteinuria < 0.5 g/24h Exclusion criteria: Severe cardiovascular disease (recent myocardial infarction, unstable coronaropathy…) Severe systemic infection, including hepatitis C or B viral infection, HIV infection or tuberculosis Past or present neoplasia (with the exception of non melanoma skin cancers) Body weight > 70 kg in women and BW > 75 kg in men or BMI > 26 Stimulated C-peptide ≥ 0.3 ng/ml upon Glucagon or Arginine stimulation Age < 18 years or > 65 years Creatinine clearance < 50 ml/min/1.73 m2 Albuminuria > 300 mg /24h or proteinuria > 0.5 g/24h Hemoglobinemia < 120 g/l in women or < 130 g/l in men Liver disease (enzymes > 1.5 N) such as cirrhosis or hepatitis Liver hemangioma Untreated proliferating diabetic retinopathy Pregnancy, lactation, pregnancy project or absence of efficient contraception Previous transplantation or immunization as judged by anti-HLA antibodies (> 20%) Insulin needs > 0.7 IU/kg/d or > 50 IU HbA1c > 12 % Any medical condition needing the chronic use of steroids Addison disease Any hemostasis disorder needing a prolonged treatment with anticoagulation drugs. Low-dose aspirin is permitted. coagulation disorders contraindicating the procedure, such as platelet count < 100000/mm3. Serious life-threatening disease Medical or surgical history potentially influencing the absorption, distribution, metabolism and clearance of drugs Uncontrolled hypercholesterolemia (> 350 mg/dl, 9.1 mmol/l) or hypertriglyceridemia (> 500 mg/dl, 5.6 mmol/l) Leukocytes < 4500/mm3, neutrophils < 2000/mm3, platelets < 100000/mm3 Any medical or psychosocial condition susceptible to interfere with the study, such as drug abuse or recent alcohol abuse Poor therapeutic observance Failure to communicate or cooperate with the investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Procedure: human pancreatic islet transplantation|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of insulin-independence, judged upon the following criteria : HbA1c < 6.1%, |  |  | 
| post-prandial blood glucose < 180 mg/dl, mean amplitude of glycemic excursion (MAGE index) |  |  | 
| < 60 mg/dl, basal C-peptide > 0.5 ng/ml. This insulin independent rate will be assessed 6 months |  |  | 
| and 12 months following transplantation. |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of success according to the DiaCell composite score defined by the following 4 items : functional islet graft, defined by a basal C-peptide > 0.5 ng/ml; |  |  | 
| good metabolic control, defined by HbA1c ≤ 6.5%; disappearance of hypoglycemic events; reduction in exogenous insulin needs ≥ 30%. |  |  | 
| Morbidity and quality of life will also be assessed. |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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islet transplantation, brittle diabetes, severe hypoglycemia, type 1 diabetes mellitus