Islet Transplantation for Type 1 Diabetes Mellitus

Phase 1

Terminated

Brief Summary: The complex program of insulin replacement for type 1 diabetes that is current clinical standard of care is difficult to implement for long periods of time, associated with an increased risk of severe hypoglycemia and implemented by less than 50 % of the population of such patients. Outcomes of transplantation of isolated human islets have substantially improved and been performed at about 40 institutions around the world. We are proposing a clinical phase 1/phase 2 study of islet transplantation alone evaluating safety and efficacy in five patients with type 1 diabetes. Islet isolation from deceased donor pancreases will be performed at the Mayo Rochester Islet Isolation facility and islets infused by Interventional Radiology into the portal venous system. Following islet infusion, patients will be hospitalized for 48 hours in the General Clinical Research Center (GCRC) or at the Rochester Methodist Hospital. Multiple safety and efficacy outcomes will be followed on multiple occasions during the first year and periodically thereafter.

Recruitment & Eligibility

Inclusion Criteria

Duration of diabetes: 5 years or more
Type 1 diabetes with C-peptide < 200 pmol/L and a simultaneous plasma glucose between 60 and 250 mg/dl
Complex insulin program supervised by an endocrinologist for at least 6 months
Hypoglycemic unawareness diagnosed using Clarke Awareness Questionnaire
Body weight < 70 kg
Body Mass Index < 30 kg/m^2
Insulin requirement < 40 units/day by multiple daily injections or < 30 units /day by external insulin pump or < 0.6 unit/kg/day with a HbA1c < 7.0 % ( Normal < 6 %)
No overt cardiovascular disease
No laser treatment for retinopathy
Retinopathy diagnosed by ophthalmologist to be stable and requiring no further evaluation for at least one year
Women of child bearing age will have a negative pregnancy test at screening and time of trial initiation
Women enrolled in the trial should be willing to practice birth control while on immunosuppression
No psychologic issues that would interfere with adherence to safe clinical practice
Blood type (ABO) compatibility
No evidence of chronic liver disease (aspartate aminotransferase (AST) < 2.5 times normal, alanine aminotransferase (ALT) < 2.5 times normal, international normalized ratio (INR) < 1.4, No evidence of fatty liver on abdominal ultrasound.

Exclusion Criteria

Ongoing infection
Ongoing alcohol or drug abuse
Clinical portal hypertension
Gall stones
Liver hemangioma on ultrasound interfering with islet infusion
Lack of updated immunization
Unstable cardiovascular status as defined by:
1. Myocardial infarction/acute coronary syndrome in last year
2. Significant coronary atherosclerosis on angiography
3. Active ischemia at evaluation
Pre-trial low-density lipoprotein (LDL) cholesterol > 100 and triglycerides > 200 mg/dl with or without lipid lowering therapy
Active peptic ulcer disease
Previous organ transplantation except islet transplantation
Negative serology for Epstein-Barr Virus (EBV) or ongoing acute EBV infection
Previous malignancy unless
1. 5 years ago
2. basal cell cancer
3. squamous cell cancer
Requiring steroid therapy for any reason
Positive Purified Protein Derivative (PPD - Tuberculosis Skin Test)
Serological evidence of HIV, Hepatitis C or Hepatitis B
Chronic anemia
Single Antigen B (SAB) normalized value >1500
Renal disease
1. Iothalamate clearance < 70 cc/min
2. 24 hour urine protein > 500 mg/24 hours

Arm && Interventions

Group	Intervention	Description
Islet Transplant	Islet Transplant	Subjects will receive standard intraportal transplantation or portal venous system infusion via laparotomy of purified pancreatic islets.

Primary Outcome Measures

Name	Time	Method
Mean Number of Hypoglycemic Events After Transplant	3, 6, 9, and 12 months since islet transplantation	Hypoglycemia is an abnormally diminished content of glucose in the blood.

Secondary Outcome Measures

Name	Time	Method
Mean Glycated Hemoglobin (HbA1c) Since Transplant	3, 6, 9, and 12 months since islet transplantation	HbA1c is a lab test that shows the average level of blood sugar (glucose) over the previous 3 months. It shows how well the subject is controlling his/her diabetes.