Islet Transplantation for Type 1 Diabetes

This is a Phase I/II study (a study that examines effectiveness and looks for side effects). The transplanting of islet cells has been studied in Type 1 diabetic patients whose blood sugar levels will not stay normal, despite intensive insulin therapy. A recent study conducted in Edmonton, Canada, was able to demonstrate that islet transplantation led to insulin independence in a majority of the patients treated. This study extends the results obtained from the Edmonton study, which used islet transplantation in Type 1 diabetic patients with steroid-free immunosuppression.

Eligible patients were randomly selected from the total pool of people who applied through the Immune Tolerance Network. Patients will receive at least 10,000 "islet equivalents" per kilogram (2.2 pounds) of body weight. This likely will require 2 separate islet infusions from 2 separate donors. Immediately before the first transplant, patients will be given anti-rejection (immune suppressing) drugs, including tacrolimus and sirolimus (orally) and daclizumab (intravenously). The islets will be infused into the liver through a tube placed in the portal vein. Heparin (a medication to prevent blood clots) will be administered with the islet infusion. A longer-acting form of heparin will also be given by daily injections during the next week after each transplant. After surgery, patients will receive insulin intravenously for 24 hours. Patients will have an abdominal ultrasound and blood tests to determine liver function. If fewer than 10,000 islets were transplanted, patients will continue insulin treatment, with the dosages adjusted if necessary to account for the transplanted islets. They will take daclizumab every 2 weeks for 8 weeks and tacrolimus and sirolimus daily. Patients will be given antibiotics to prevent infections. Blood tests to determine how much immunosuppressant drug is in the blood will be performed until the drug is at a stable level. Periodically there will be tests to see if the islet cells are functioning. Blood will be drawn to check drug levels and for other tests routinely. Daily insulin requirements will be checked, and these will be recorded monthly. Patients will be followed for at least 1 year post last islet transplantation. Additional follow-up may be provided at least annually for up to 9 years post first transplantation.

Inclusion criteria

Patients may be eligible for this study if they:

• Have had Type 1 diabetes mellitus for more than 5 years, and are exhibiting 1 of the following, despite intensive insulin management efforts: a) hypoglycemic unawareness, as defined by inability to sense hypoglycemia until the blood glucose falls to less than 54 mg/dL; b) metabolic instability, with 2 or more episodes of severe hypoglycemia (defined as an event with symptoms consistent with hypoglycemia in which the patient requires the assistance of another person and which is associated with a blood glucose below 54 mg/dL) or 2 or more hospital visits for diabetic ketoacidosis over the last year; or c) despite efforts at optimal glucose control, progressive secondary complications of diabetes as defined by retinopathy, nephropathy, or neuropathy.
• Are 18 to 65 years of age.

Exclusion criteria

Patients will not be eligible for this study if they:

• Have had severe cardiac disease as defined by: a) recent myocardial infarction within the past 6 months; b) angiographic evidence of non-correctable coronary artery disease; or c) evidence of ischemia on a functional cardiac exam.
• Actively abuse alcohol or substances, including cigarette smoking (must not have smoked within the last 6 months).
• Have psychiatric problems that prevent them from being a suitable candidate for transplantation (such as schizophrenia, bipolar disorder, or major depression that is not controlled or stable on current medication).
• Have a history of not following prescribed regimens.
• Have active infection including hepatitis C virus, hepatitis B virus, human immunodeficiency virus (HIV), or Tuberculosis (TB) (or under treatment for suspected TB).
• Have a history of malignancy, except squamous or basal skin cancer.
• Weigh more than 70 kilograms or have a Body Mass Index (BMI) greater than 26 kg/m^2 at time of screening.
• Have a C-peptide value of 0.3 ng/ml or more following a 5.0 gram intravenous arginine infusion challenge.
• Are unable to provide informed consent.
• Have gallstones or hemangioma in liver.
• Have untreated proliferative retinopathy.
• Are breast-feeding or pregnant, or intend to try and become pregnant (females) or to father a child (males), or fail to follow birth control methods.
• Have had a previous transplant, or evidence of anti-human leukocyte antigen (HLA) antibody.
• Have an insulin requirement of more that 0.7 International Units (IU)/kilograms/day.
• Have a blood glycosylated hemoglobin (HbA1c) higher than 12 percent.
• Are unable to reach the hospital for transplantation within 2 hours of notification.
• Have untreated or treated hyperlipidemia.
• Have a medical condition requiring chronic use of steroids.
• Use coumadin or other anticoagulants (aspirin is allowed).
• Have Addison's disease.
• Have a negative screen for Epstein-Barr virus (EBV).