Delayed Mycophenolate Mofetil in Single-Donor Islet Allotransplantation in Type 1 Diabetes

Study Overview
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Brief Summary
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The objective of this study is to assess the safety and efficacy of islet allotransplantation for the reestablishment of stable glycemic control in patients with type 1 diabetes, using anti-thymocyte globulin induction immunosuppression with sirolimus, mycophenolate mofetil and low dose tacrolimus maintenance immunosuppression.

Detailed Description
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To assess the safety and efficacy of a new single-donor islet allotransplant protocol focusing on minimization of ischemic damage by the two-layer pancreas preservation technique, attenuation of posttransplant nonspecific inflammatory responses by etanercept and anti-thymocyte globulin, deletion/inactivation of autoreactive T cells by anti-thymocyte globulin and daclizumab induction immunotherapy, and potent yet non-diabetogenic maintenance immunosuppression with sirolimus and delayed mycophenolate mofetil instead of tacrolimus for the reestablishment of stable glycemic control in recipients with type 1 diabetes.

Official Title
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An Open-label Pilot Study of Delayed Mycophenolate Mofetil Instead of Tacrolimus Combined With Anti-thymocyte Globulin, Daclizumab, Etanercept, and Sirolimus in Single-donor, Solitary Islet Allograft Recipients With Type 1 Diabetes

Conditions
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Type 1 Diabetes, Hypoglycemia

Intervention / Treatment
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* Biological: Allogeneic islets of Langerhans transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary islet allotransplant Type 1 diabetes mellitus, complicated by at least one of the following situations that persist despite intensive efforts in close cooperation with their diabetes care team: Metabolic lability/instability; Reduced awareness of hypoglycemia; Persistently poor glucose control (as defined by HgbA1c>10% at the end of six months of intensive management efforts with the diabetes care team); Progressive secondary complications. Age 18 and older Able to give written informed consent Exclusion Criteria: Known hypersensitivity to rabbit proteins. Presence of history of panel-reactive anti-HLA antibodies (>10%). Insufficient cardiovascular reserve. Creatinine clearance <60 mL/min/m2. Portal hypertension, abnormal liver enzyme tests, or history of significant liver disease. History of malignancy within 5 years. Active peptic ulcer disease. Severe unremitting diarrhea or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications. Pregnancy or breast-feeding. Active infections. Serological evidence of infection with HIV, or HBsAg or HCVAb positive within the previous 12 months prior to transplantation. Negative screen for Epstein-Barr Virus (EBV) by an EBNA method Evidence of infiltrate, cavitation, or consolidation on chest x-ray during pre-study screening. Schizophrenia, bipolar disorder, or major depression that is unstable or uncontrolled on current medications. Ongoing substance abuse; drug or alcohol. Recent history of noncompliance. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial.

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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Accepts Healthy Volunteers

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

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Biological: Allogeneic islets of Langerhans transplant<br>* Allogeneic islets of Langerhans transplant<br>* Other names: Islet transplant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the incidence and severity of hypoglycemia in type 1 diabetic subjects receiving an islet allotransplant and immunotherapy during the first year posttransplant. |  | 1 year | 
| Assess liver laboratory tests during the first year following intraportal islet allotransplantation. |  | 1 yr | 
| Assess the incidence, type, and severity of islet transplant-related infectious complications during the first year posttransplant. |  | 1 year | 
| Assess the proportion of recipients who develop alloantibodies directed at donor alloantigens during the first year posttransplant. |  | 1 year | 
| Monitor the incidence, timing, and severity of adverse events as well as their relationship to the islet transplant procedure and additional protocol-regulated treatment products during the first year after islet transplantation. |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the proportion of type 1 diabetic subjects receiving delayed mycophenolate mofetil instead of tacrolimus who achieve insulin independence in the first year after transplantation of allogeneic islets. |  | 1 year | 
| Assess the proportion of type 1 diabetic islet allograft recipients with full and partial alloislet function at one year post transplant. |  | 1 year | 
| Assess the glycemic control, insulin secretory responses, and the glucose disposal rate during the first year posttransplant. |  | 1 year | 
| Effect of donor age, pretransplant islet insulin secretory response, # of transplanted islet equivalents, # of transplanted beta cells, pretransplant insulin action, recipient BMI and immunosuppressive therapy on safety and efficacy. |  | 1 year | 
| Assess, in a selected group of islet allotransplant recipients, the autoimmune and alloimmune responses to transplanted islets at intervals during the first year posttransplant. |  | 1 year |