Allogeneic Islet Transplantation for the Treatment of Type 1 Diabetes

Study Overview
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Brief Summary
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It is a multicentre, sequential, phase II clinical trial, aiming at evaluating the allogeneic islet transplantation for the treatment of type 1 diabetes. 19 patients with type 1 diabetes will be included and ideally distributed evenly: patients with unstable diabetes without renal insufficiency (AI group for islet alone by the international customary determination) and patients with a functioning kidney transplant (IAK group for islet after kidney). The main endpoint will be defined by the restoration of normal glycemic control without insulin at 6 months after graft.

Official Title
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Allogeneic Islet Transplantation for the Treatment of Type 1 Diabetes

Conditions
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Patients With Type 1 Diabetes

Intervention / Treatment
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* Procedure: Allogeneic transplantation of intrahepatic islet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with type 1 diabetes 18 <Age <55 years Plasma C-peptide <0.2 ng/ml basal and stimulated glucagon Evolution of diabetes for more than 5 years Regular patient follow-up (> or equal to 2 visits per year from the same diabetologist) Patient who received the information and have given their consent in writing Absence of HIV, hepatitis B and hepatitis C, HTLV-1-2 ABO compatibility with the donor Cross match negative Anti-HLA antibodies (class I and / or class II) detected by lymphocytotoxicity <20% PCR negative for the BK virus in the blood (so as not to amplify the BK virus replication with the ATG). Accepting patients effective contraception during the study period For patients in group IA Glomerular filtration rate estimated by the MDRD> 50 ml/min/1.73m2 No perception of hypoglycaemia (less than 0.54 mg/dl glucose) at least one value documented in the two years preceding and/or Occurrence of at least one severe hypoglycemic episode (with a third required) and unexplained in the two years before and/or at least two episodes of ketoacidosis per year Average HbA1c> 8.5% over two years, despite intensified treatment (basal pattern, bolus) • For patients in the IAK functional renal graft for at least 1 year glomerular filtration rate> 50 ml/min/1.73 m2 proteinuria <0.5 g/day Absence of acute rejection in renal previous 6 months Exclusion Criteria: BMI > 28 Need insulin > 1 U/kg per day Pregnancy, lactation Intention of childbearing for the two sexes Psychiatric Disorders Inability to communicate or cooperate with the investigator Lack of therapeutic compliance, including HbA1C > 12% Chronic liver disease Progressive heart disease myocardial infarction within 6 months prior to inclusion, unbalanced CHD) Proliferative retinopathy unstabilized History of cancer, whatever the date, except for basal or squamous cell skin cancers over 1 year. Systemic infection Chronic high risk of requiring corticosteroids Need for long-term corticosteroid, outside that specified in renal transplantation, the patients will be weaned before transplantation Anticoagulant vitamin K or antiplatelet treatments Disorders of hemostasis TP <60 % TCA > 1.5 times the control Anti-HLA antibodies ( class I and/or class II ) detected by lymphocytotoxicity > 20% Platelets < 100 giga/L and/or neutrophils <1.5 giga/L Chronic intoxication by alcohol, tobacco, or other substance (abstinence > 6 months required) Active infection by hepatitis B, hepatitis C and HIV, HTLV-1-HTLV2 Ascites

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allogeneic transplantation of intrahepatic islet<br>Allogeneic transplantation of intrahepatic islet number required for insulin independence of obtaining, with a threshold dose of 9,000 IEQ/kg body weight of the recipient and a maximum sequence number of 3 infusions. The patient will receive after transplantation immunosuppressive therapy with Thymoglobulin for induction, Prograf and Cellcept, both of which are given throughout the duration of the study | Procedure: Allogeneic transplantation of intrahepatic islet<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| restoration of normal glycemic control without insulin | the restoration of normal glycemic control without insulin therapy will be evaluated by measuring - A fasting glucose (> 8 hours) less than 1.25 g/L and a 2 hours glucose after oral intake of 75g of glucose, less than 2 g/L in a patient without insulin for at least 15 consecutive days during the the first 6 months from day 0. | 6 months after graft | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Restoration of normal glycemic control without insulin for a year |  | 1 year | 
| Obtaining an improvement in glycemic control | HbA1c <6.5%, with lower insulin doses by 30% | within 2 years after inclusion | 
| Obtaining a remission of diabetes | The remission of diabetes is defined by the normality of blood glucose or insulin without lHbA1c. The normality of blood glucose is defined below 1.20 g/L and postprandial fasting glycemia less than 1.60 g/L in the book self-monitoring (including 6/7 blood glucoses during the previous 3 days evaluation visit). Normal HbA1c is defined as less than 6.5%. | within 2 years after inclusion | 
| Improved metabolic profile determined by the OGTT and hyperglycemic clamp |  | within 2 years after inclusion | 
| Decreased glycemic variability | defined on blood glucose and / or glucose holter | within 2 years after inclusion | 
| Reduction of oxidative stress assessed by the urinary excretion of 24 hours of 8-iso-PGF2 rates. |  | within 2 years after inclusion | 
| Decrease in the frequency, severity or poor perception of hypoglycaemia defined Hypo score |  | within the 2 years after inclusion | 
| quality of life | defined by questionnaires DQOL and SF-36 | within 2 years after inclusion | 
| term graft survival | defined by the rate of C-peptide | within 2 years of inclusion | 
| beta-cell function | based on beta-score | 2 years | 
| potential of each infusion of islets | number of IEQ/kg of recipient required to reduce the daily insulin dose of 1 unit | within 2 years after inclusion | 
| degenerative complications of diabetes |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, transplantation