Clinical trial NCT00285233: Delayed Mycophenolate Mofetil in Single-Donor Islet Allotransplantation in Type 1 Diabetes
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Type 1 Diabetes
Hypoglycemia
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
name: Juvenile Diabetes Research Foundation
First posted: 2006-02-01
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Assess the incidence and severity of hypoglycemia in type 1 diabetic subjects receiving an islet allotransplant and immunotherapy during the first year posttransplant.
timeFrame: 1 year
measure: Assess liver laboratory tests during the first year following intraportal islet allotransplantation.
timeFrame: 1 yr
measure: Assess the incidence, type, and severity of islet transplant-related infectious complications during the first year posttransplant.
timeFrame: 1 year
measure: Assess the proportion of recipients who develop alloantibodies directed at donor alloantigens during the first year posttransplant.
timeFrame: 1 year
measure: 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.
timeFrame: 1 year
Secondary outcomes:
measure: 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.
timeFrame: 1 year
measure: Assess the proportion of type 1 diabetic islet allograft recipients with full and partial alloislet function at one year post transplant.
timeFrame: 1 year
measure: Assess the glycemic control, insulin secretory responses, and the glucose disposal rate during the first year posttransplant.
timeFrame: 1 year
measure: 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.
timeFrame: 1 year
measure: Assess, in a selected group of islet allotransplant recipients, the autoimmune and alloimmune responses to transplanted islets at intervals during the first year posttransplant.
timeFrame: 1 year
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
Study officials:
affiliation: University of Minnesota
name: Bernhard J. Hering, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hering BJ, Kandaswamy R, Ansite JD, Eckman PM, Nakano M, Sawada T, Matsumoto I, Ihm SH, Zhang HJ, Parkey J, Hunter DW, Sutherland DE. Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. JAMA. 2005 Feb 16;293(7):830-5. doi: 10.1001/jama.293.7.830.