In an earlier Phase 1/2 clinical trial using the Edmonton Protocol of steroid free immunosuppression, investigators at University of Illinois at Chicago (UIC) demonstrated the safety of islet preparation, iset transplantation, and medical treatment at UIC. Therefore, the primary purpose of the present Phase 3 clinical trial is to demonstrate the safety and efficacy of allogeneic islet transplantation in improving glycemic control in Type 1 diabetic patients using the UIC protocol that was developed and proven effective during the Phase 1/2 clinical trial.

This study is a Phase 3 single center, uncontrolled trial in which 1-3 allogeneic pancreatic islet transplants are performed for each study subject. Follow-up evaluations after transplant continue for 52 weeks after the final islet transplantation. Thereafter, subjects may enroll for a 5-year follow-up study and an additional 5 year to 10 year follow-up study to evaluate the function of the islets and to measure and regulate immunosuppressive drug levels and side effects.

The safety of islet transplantation depends primarily on the incidence of serious and unexpected complications or adverse events and the ability of the cell isolation laboratory to produce uncontaminated islet cell preparations with minimal endotoxin content.

All study subjects are followed for safety for one year. An independent Data Monitoring Committee (DMC), composed of 3 members who have training in medicine and/or organ transplantation, will review eligibility and safety data within 2 weeks after each islet transplantation and every two months thereafter. An independent monitor, who is knowledgeable about Good Clinical Practice (GCP) guidelines and regulations, monitors the study for compliance with 21 CFR and according to ICH GCP Guidelines. Within the Clinical Research Center, representatives of the Scientific Advisory Committee and the Research Subject Advocacy Program monitor safety. These entities report to the UIC Institutional Review Board (IRB), which also reviews safety data annually and on occurrence of serious adverse events. The principal investigator also reports serious adverse events to the US Food and Drug Administration (FDA).

Success: Islet transplantation is considered a success when subjects do not use insulin, and they achieve a fasting glucose level not exceeding 140 mg/dL more than three times in a week, and not exceeding two-hour post-prandial values of 180 mg/dL more than four times in a week.

Partial Success: Subjects who have a reduction in insulin requirements but who do not achieve insulin independence and present with a reduction in HbA1c and number of hypoglycemic episodes are considered to have partial success of islet transplantation. Reduction in insulin-requirements are assessed by comparing the pre-transplant insulin requirement recorded over two consecutive days (expressed as insulin units per kg) with the requirement on the two consecutive days preceding the subsequent islet infusion, and the requirements on two consecutive days at six months and again on two consecutive days at one year after the final transplant.

Failure: Absence of measurable levels of C-peptide after transplantation is considered as failure of islet cell transplantation.

Inclusion Criteria:

• Type 1 diabetes mellitus for more than 5 years complicated by the following situations that persist despite intensive insulin management efforts:
• At least one episode of severe hypoglycemia in the past 3 years defined as an event with symptoms compatible with hypoglycemia in which the subject required the assistance of another person, and which was associated with either a blood glucose level <50 mg/dL (2.8 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration
• Reduced awareness of hypoglycemia, defined by the absence of adequate autonomic symptoms at capillary glucose levels of <54 mg/dL (3 mmol/l) as reported by the subject

Exclusion Criteria:

• Co-existing cardiac disease: myocardial infarction within the past 6 months, angiographic evidence of non-correctable coronary artery disease, ischemia on functional cardiac exam, heart failure
• Active alcohol or substance abuse, including cigarette smoking (must be abstinent for six months)
• Psychiatric disorder: schizophrenia, bipolar disorder, or major depression that is unstable on medication
• History of non-adherence to prescribed regimens
• Active infection including hepatitis C, hepatitis B, HIV
• TB by history, current infection, or under treatment for suspected TB
• History of malignancies except squamous or basal skin cancer
• Family history of MEN2 or MCT
• Stroke within the past 6 months
• BMI >27 kg/m2
• C-peptide response to glucagon stimulation, any C-peptide >0.3 ng/mL
• Inability to provide informed consent
• Age less than 18 or greater than 75 years
• Creatinine clearance <80 mL/min/1.73 m2 by 24-hour urine collection
• Serum creatinine consistently >1.5 mg/dL
• Macroalbuminuria >300 mg/24h
• Baseline Hb <12 gm/dL in women, <13 gm/dL in men
• Baseline liver function tests outside normal range
• Untreated proliferative retinopathy
• Positive pregnancy test, intent for pregnancy, male's intent to procreate, unwilling to use effective contraception, breast feeding
• Previous transplant or PRA reactivity >80%
• Insulin requirement >0.7 IU/kg/day
• HbA1c >12%
• Hyperlipidemia (fasting cholesterol >130 mg/dL or fasting triglycerides >200 mg/dL
• Medical condition requiring chronic use of steroids
• Use of Coumadin or other antiplatelet or anticoagulant therapy, or PT-INR >1.5
• Factor V deficiency
• Smoking tobacco
• Addison's disease
• Allergy to radiographic contrast material
• Symptomatic cholecystolithiasis
• Acute or chronic pancreatitis
• Symptomatic peptic ulcer disease
• Severe unremitting diarrhea, vomiting, or other gastrointestinal disorders that could interfere with medication absorption
• Treatment with antidiabetic medication other than insulin within 4 weeks of enrollment
• Use of any study medication within 4 weeks of enrollment
• Received live attenuated vaccine(s) within 2 months of enrollment
• Any medical condition that, in the opinion of the investigator, might interfere with safe participation

From first islet transplant through one year after last transplant (maximum 3 infusions possible), an average of 1 year.