Clinical trial NCT00286624: Anti-Thymocyte Globulin, Cyclosporine, and RAD in Islet Transplantation
Official title: A One-Year, Single-Center, Prospective, Open-Label Study of the Safety, Tolerability, and Preliminary Efficacy of Anti-Thymocyte Globulin, Cyclosporine, and RAD in Type 1 Diabetic Islet Transplant Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Type 1 Diabetes Mellitus
Hypoglycemia
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: Juvenile Diabetes Research Foundation
name: National Institutes of Health (NIH)
name: Novartis
First posted: 2006-02-03
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study was designed to test the safety and efficacy of up to 3 pancreatic alloislet transplants in type 1 diabetic patients with hypoglycemia unawareness. 6 subjects were transplanted under this protocol using anti-thymocyte globulin induction immunosuppression and everolimus with cyclosporine maintenance immunosuppression.

Detailed description: This is a Phase I/II study designed to assess the safety and efficacy of sequential islet allotransplantation for the reestablishment of stable glycemic control in type 1 diabetic recipients. A total of 6 patients with type 1 diabetes have received up to three transplants of islets from different donor pancreases.

Potential candidates for islet allotransplantation included patients age 18 and older with type 1 diabetes. Induction immunotherapy for the first transplant consisted of anti-thymocyte globulin; basiliximab was used for any subsequent transplants. Peritransplant anti-inflammatory treatment with etanercept was given for each islet transplant. Maintenance immunosuppression is with cyclosporine and RAD. It is felt that those patients in whom metabolic lability/instability, reduced awareness of hypoglycemia, poor glycemic control, and progressive secondary complications persist despite continued and intensive efforts made in close cooperation with their diabetes care team are particularly likely to have a favorable benefit/risk ratio.

Adverse events, irrespective of their presumed relationship to the transplantation of allogeneic islets and/or protocol-regulated treatment products (concomitant therapy), are being monitored and recorded throughout the first year after the final islet transplant.

The proportion of single and sequential donor islet allograft recipients with full (insulin independence and HbA1c \<7%) and partial (insulin dependence, basal or arginine-stimulated C-peptide levels of greater or equal to 0.5 ng/mL and HbA1c \<7%) islet graft function at one year after the final islet transplant will be assessed. The impact of islet transplantation on quality of life will also be assessed.

The predictive value for posttransplant insulin independence of factors such as insulin resistance before and at intervals after pancreatectomy, cellular composition of the transplant, number of beta cells transplanted; and viability and insulin secretory response of isolated islets are being assessed.

Eligibility criteria: Inclusion Criteria:

* Primary islet allotransplant
* Patients with type 1 diabetes mellitus under intensive insulin management
* Age 18 or older
* Ability to give written informed consent

Exclusion Criteria:

* Age less than 18 years.
* BMI \>26 kg/m2.
* Insulin requirement of \> 50 IU per day.
* Positive C-peptide response to intravenous arginine stimulation.
* Untreated proliferative retinopathy.
* Creatinine clearance \< 60 ml/min/1.73 m2 for females and 70 ml/min/1.73 m2 for males.
* Serum creatinine \>1.3 mg/dl for females, \>1.5 mg/dl for males.
* Previous pancreas or islet transplant.
* Presence of history of panel-reactive anti-HLA antibodies \>10%.
* Positive pregnancy test, or presently breast-feeding, or failure to follow effective contraceptive measures.
* Active infection including hepatitis C, hepatitis B, HIV, or TB (or under treatment for suspected TB).
* Negative screen for Epstein-Barr Virus (EBV).
* Invasive aspergillus infection within year prior to study entry.
* History of malignancy.
* Active alcohol or substance abuse
* History of non-adherence to prescribed regimens.
* Psychiatric disorder making the subject not a suitable candidate for transplantation.
* Inability to provide informed consent.
* Baseline Hgb \< 11.7 g/dl in females, or \< 13 g/dl in males; lymphopenia (\<1,000/microL), or leukopenia (\<3,000 total leukocytes/microL), or an absolute CD4+ count \<500/microL., or platelets \<150,000/microL
* History of coagulopathy or medical condition requiring long-term anticoagulant therapy after transplantation or patient with INR \>1.5.
* Severe co-existing cardiac disease.
* Baseline liver function tests outside of normal range or history of significant liver disease.
* Active peptic ulcer disease.
* Severe unremitting diarrhea or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications.
* Presence of severe allergy requiring acute or chronic treatment, or hypersensitivity to drugs similar to RAD (e.g., macrolides).
* Known hypersensitivity to rabbit proteins.
* Hyperlipidemia (fasting LDL cholesterol \> 130 mg/dl, treated or untreated; and/or fasting triglycerides \> 200 mg/dl).
* Addison's disease.
* Under treatment requiring chronic use of systemic steroids.
* Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial.

Primary outcomes:
measure: • The incidence, timing, and severity of adverse events during one year after the first and any subsequent islet transplants.
timeFrame: 1 year
measure: • Incidence and severity of hypoglycemia during the first year after the first and any subsequent islet transplants.
timeFrame: 1 yr
measure: • The proportion of recipients who develop alloantibodies directed at islet donor alloantigens during the first year after the first and any subsequent islet transplants.
timeFrame: 1 year
Secondary outcomes:
measure: • The proportion of subjects who achieve insulin independence in the first year after single-donor or sequential transplantation.
timeFrame: 1 year
measure: • The proportion of islet allograft recipients with full and partial islet graft function at one year after the most recent islet transplant.
timeFrame: 1 year
measure: • Glycemic control and insulin secretory responses during the first year after the first and any subsequent transplants.
timeFrame: 1 year
measure: • 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 requirements and action, recipient body mass index (BM
timeFrame: Day of transplant
measure: • The impact of islet transplantation on the quality of life of transplant recipients.
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: