Islet Transplantation in Type 1 Diabetic Patients Using the University of Illinois at Chicago (UIC) Protocol

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