Cadaveric Islet Transplantation in Patients With Insulin-Dependent Diabetes Mellitus

Study Overview
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Brief Summary
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We hypothesize that the following improvements to islet transplantation will increase the islet mass successfully isolated and allow for engraftment from a single pancreas. The improvements are: Using Two-Layer method preservation to improve pancreas quality before islet isolation Maintaining isolated islets in culture before transplantation Using a steroid-free immunosuppression regimen Transplanting the best combination of donor and recipient possible after human leukocyte antigens (HLA) screening and final crossmatching

Detailed Description
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We hypothesize that the following improvements to islet transplantation will increase the islet mass successfully isolated and allow for engraftment from a single pancreas: using Two-Layer method preservation to improve pancreas quality before islet isolation, maintaining isolated islets in culture before transplantation, using a steroid-free immunosuppression regimen, and transplanting the best combination of donor and recipient possible after HLA screening and final crossmatching.

Official Title
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Cadaveric Islet Transplantation in Patients With Insulin-Dependent Diabetes Mellitus

Conditions
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Islets of Langerhans Transplantation, Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Islets of Langerhans


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Group 1: Diagnosis of Type-1 diabetes mellitus for more than 5 years with at least one of the following complications: Metabolic lability/instability (two or more episodes of severe hypoglycemia) or two or more hospital visits for diabetic ketoacidosis during the previous year Progression of secondary complications of diabetes as determined by The Nebraska Medical Center/University of Nebraska Medical Center staff endocrinologists Group 2: Diagnosis of Type-1 diabetes with successful renal transplant on steroid-free, FK506/rapamycin-based immunosuppression Exclusion Criteria: Severe co-existing cardiac disease Active alcohol or substance abuse, including cigarette smoking Psychiatric disorder making the subject not a suitable candidate for transplantation History of medical non-compliance Active infection, including hepatitis C and B, HIV, and tuberculosis (or suspected tuberculosis) Any history of malignancy except squamous or basal cell skin cancer BMI >28 kg/meter-squared, or body weight >80kg at screening visit, or >85kg on the day of transplantation (due to the difficulty of obtaining a sufficiently large islet mass to adequately treat either large patients or those whose obesity elevates their insulin needs) Positive C-peptide response to intravenous glucose tolerance test and Mixed Meal glucose tolerance test: any C-peptide >0.3 ng/mL post infusion Inability to provide informed consent Age less than 19 or greater than 70 years Creatinine clearance <60 mL/min/1.73 meter-squared for Group 1 and creatinine clearance <40 mL/min/1.73 meter-squared for Group 2 (those subjects currently on immunosuppression due to previous kidney transplant) Macroalbuminuria (urinary albumin excretion rate >300 mg/24h) for Group 1 and macroalbuminuria (urinary albumin excretion rate >600mg/24h) for Group 2 Baseline Hb <10 gm/dL Baseline liver function tests outside of normal range Presence of gallstones or hemangioma in liver on baseline ultrasound exam Positive pregnancy test, intention of future pregnancy, or presently breast-feeding Evidence of sensitization on panel reactive antibodies (PRA) Insulin requirement >0.7 IU/kg/day or HbA1c >15% Hyperlipidemia Under treatment for a medical condition requiring chronic use of steroids Use of Coumadin or other anticoagulant therapy (except aspirin) or a prothrombin time/international normalized ratio (PT-INR) >1.5 Diagnosis of Addison's disease Additional Exclusion Criteria for Group 2 Subjects: Any history of organ transplantation other than kidney or pancreas Any previous graft lost to rejection Any history of early, multiple, or vascular renal allograft rejection

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 70 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: Transplantation of Islets of Langerhans<br>Subjects will receive islets isolated from one donor pancreas per transplantation event. Subjects will receive a cumulative dose of 8,000 International Units/kg. Islets will be infused intraportally. If necessary, additional transplantation events will be performed. | Drug: Islets of Langerhans<br>* Subjects will receive islets isolated from one donor pancreas per transplantation event. Subjects will receive a cumulative dose of 8,000IE/kg. Islets will be infused intraportally. If necessary, additional transplantation events will be performed.<br>* Other names: transplanted islets of Langerhans;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of insulin independence with a single islet transplant | Incidence of insulin independence with a single transplantation measured at one year post-transplantation. | 1 year post-transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Islet mass resulting in insulin independence/reduced exogenous insulin requirement | Insulin independence or reduced exogenous insulin required measured at one year post-transplantation. | 1 year post-transplantation | 
| Graft survival | The survival of the Islets of Langerhans graft as measured at three years post-transplantation. | 3 years post-transplantation | 
| Metabolic functional assessments of the islet graft | An assessment of the metabolic function of the islet of Langerhans graft as measured three years post-transplantation. | 3 years post-transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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islet transplantation, type 1 diabetes mellitus, steroid-free immunosuppression, rabbit anti-thymocyte globulin