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

• Assess the incidence and severity of hypoglycemia in type 1 diabetic subjects receiving an islet allotransplant and immunotherapy during the first year posttransplant. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
• Assess liver laboratory tests during the first year following intraportal islet allotransplantation. [ Time Frame: 1 yr ] [ Designated as safety issue: Yes ]
• Assess the incidence, type, and severity of islet transplant-related infectious complications during the first year posttransplant. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
• Assess the proportion of recipients who develop alloantibodies directed at donor alloantigens during the first year posttransplant. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
• 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. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

• • Assess the incidence and severity of hypoglycemia in type 1 diabetic subjects receiving an islet allotransplant and immunotherapy during the first year posttransplant.
• • Assess liver laboratory tests during the first year following intraportal islet allotransplantation.
• • Assess the incidence, type, and severity of islet transplant-related infectious complications during the first year posttransplant.
• • Assess the proportion of recipients who develop alloantibodies directed at donor alloantigens during the first year posttransplant.
• • 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.

• 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. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Assess the proportion of type 1 diabetic islet allograft recipients with full and partial alloislet function at one year post transplant. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Assess the glycemic control, insulin secretory responses, and the glucose disposal rate during the first year posttransplant. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• 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. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Assess, in a selected group of islet allotransplant recipients, the autoimmune and alloimmune responses to transplanted islets at intervals during the first year posttransplant. [ Time Frame: 1 year ] [ Designated as safety issue: No ]

• • 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.
• • Assess the proportion of type 1 diabetic islet allograft recipients with full and partial alloislet function at one year post transplant.
• • Assess the glycemic control, insulin secretory responses, and the glucose disposal rate during the first year posttransplant.
• • Assess the effect of donor age, pretransplant islet insulin secretory response in vitro, number of transplanted islet equivalents (IEQ), number of transplanted beta cells, pretransplant recipient insulin action, recipient body mass index (BMI), and im
• • Assess, in a selected group of islet allotransplant recipients, the autoimmune and alloimmune responses to transplanted islets at intervals during the first year posttransplant.

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.

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.

• Type 1 Diabetes
• Hypoglycemia

Inclusion Criteria:

1. Primary islet allotransplant

2. 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:

   1. Metabolic lability/instability;
   2. Reduced awareness of hypoglycemia;
   3. Persistently poor glucose control (as defined by HgbA1c>10% at the end of six months of intensive management efforts with the diabetes care team);
   4. Progressive secondary complications.
3. Age 18 and older
4. Able to give written informed consent

Exclusion Criteria:

1. Known hypersensitivity to rabbit proteins.
2. Presence of history of panel-reactive anti-HLA antibodies (>10%).
3. Insufficient cardiovascular reserve.
4. Creatinine clearance <60 mL/min/m2.
5. Portal hypertension, abnormal liver enzyme tests, or history of significant liver disease.
6. History of malignancy within 5 years.
7. Active peptic ulcer disease.
8. Severe unremitting diarrhea or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications.
9. Pregnancy or breast-feeding.
10. Active infections.
11. Serological evidence of infection with HIV, or HBsAg or HCVAb positive within the previous 12 months prior to transplantation.
12. Negative screen for Epstein-Barr Virus (EBV) by an EBNA method
13. Evidence of infiltrate, cavitation, or consolidation on chest x-ray during pre-study screening.
14. Schizophrenia, bipolar disorder, or major depression that is unstable or uncontrolled on current medications.
15. Ongoing substance abuse; drug or alcohol.
16. Recent history of noncompliance.
17. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial.

• Roche Pharma AG
• Juvenile Diabetes Research Foundation