Islet Transplantation for Type 1 Diabetes

Condition(s) targeted: Diabetes Mellitus, Insulin-Dependent

Intervention: Islet Transplantation (Procedure); Sirolimus (Drug); Tacrolimus (Drug); Daclizumab (Drug); Sulfamethoxazole (Drug); Ganciclovir (Drug); Trimethoprim (Drug); Pentamidine (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
James Shapiro, MD, PhD, Principal Investigator, Affiliation: University of Alberta

The purpose of this study is to test whether the islet cell transplantation procedures and results from a previous study in Edmonton, Canada, can be repeated. The study also is designed to learn more about diabetes control using islet cell transplantation. 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.

Official title: Islet Transplantation for Type 1 Diabetic Patients Using the Edmonton Protocol of Steroid Free Immunosuppression (ITN005CT)

Study design: Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Percent of Participants That Achieved Insulin Independence With Adequate Control of Blood Glucose Levels at One Year Post Final Islet Transplantation.

Secondary outcome:

Percent of Participants With Partial Islet Function One Year Post Final Islet Transplantation.

Percent of Participants That Achieved Insulin Independence From First Transplant

Percent of Participants With Detectable Fasting Basal C-Peptide Levels

Detailed description: 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.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

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).

Justus-Leibig University, Giessen 35385, Germany

University of Milan, Milan, Italy

University of Geneva, Geneva, Switzerland

University of Alberta, Edmonton, Alberta, Canada

University of Miami, Miami, Florida 33136, United States

Massachusetts General Hospital, Boston, Massachusetts 02114, United States

University of Minnesota, Minneapolis, Minnesota, United States

Washington University, St. Louis, Missouri 63110, United States

Benaroya Research Institute at Virginia Mason Research Center, Seattle, Washington 98101, United States

Click here for the Immune Tolerance Network Web Site

Immune Tolerance Network (ITN) TrialShare: open public access to participant-level data available for this trial

Starting date: April 2001
Last updated: June 4, 2014