Peritransplant Deoxyspergualin in Islet Transplantation in Type 1 Diabetes

Type 1 diabetes, also known as insulin-dependent diabetes, is a chronic disease in which the
pancreas produces insufficient insulin to properly regulate blood sugar levels.
Hypoglycemia, low blood sugar, and hyperglycemia, high blood sugar, can lead to significant
complications in people with type 1 diabetes. Intensive insulin therapy has been shown to
reduce the risk of chronic complications in people who achieve near normalization of
glycemia. However, this therapy is labor intensive, difficult to implement, and associated
with an increased frequency of severe hypoglycemia. Transplantation of islets from a healthy
pancreas has been successful in restoring normal blood sugar levels and has led to initial
insulin independence in people with type 1 diabetes. Rejection of these islets by the
recipient's immune system, however, makes the treatment ineffective within a couple of
years. Immunosuppressant drugs may be an effective way to maintain islet function
post-transplant. The purpose of this study is to assess the safety and efficacy of an
immunosuppressive regimen that includes DSG on post-transplant islet function in people with
type 1 diabetes who have not responded to intensive insulin therapy. The study will also
seek to improve the understanding of determinants of success and failure of islet
transplants for type 1 diabetes.

Following screening procedures and 2 days prior to islet transplant, participants will be
randomly assigned to either this Phase 2 trial or a multicenter Phase 3 trial. Participants
in this study will receive up to three separate islet transplants. They will begin receiving
antithymocyte globulin (ATG) and sirolimus 2 days prior to the first islet transplant. ATG
will continue to be given until Day 2 post-transplant. Participants will continue taking
sirolimus for the duration of the study. On the day of transplant, participants will receive
DSG and etanercept, in addition to ATG and sirolimus. The DSG infusion will be administered
over 3 hours and will immediately precede the islet transplant. Participants will continue
receiving daily 3-hour infusions of DSG through Day 6 post-transplant. Etanercept will also
be administered on Days 3, 7, and 10 post-transplant. Tacrolimus will be administered on Day
1 post-transplant and continued throughout the study.

Transplantations will involve an inpatient hospital stay and infusion of islets into a
branch of the portal vein. Participants who do not achieve or maintain insulin independence
by Day 75 post-transplant will be considered for a second islet transplant. Participants who
remain dependent on insulin for longer than 1 month after the second transplant and who show
partial graft function will be considered for a third transplant. Daclizumab or basiliximab
will be used in place of ATG for the second and third transplants, if they are necessary.
Participants who do not meet the criteria for a subsequent transplant and do not have a
functioning graft will enter a reduced follow-up period.

There will be up to 21 study visits following each transplant. A physical exam, review of
adverse events, blood collection, urine tests, and measures of immunosuppression levels will
occur at most visits. An abdominal ultrasound and glomerular filtration rate testing will
occur at some study visits. Participants will also self-test their glucose levels at least
five times per day throughout the study. A 12-month follow-up period will take place after
the participant's last transplant.

Inclusion Criteria:

- Mentally stable and able to comply with study procedures

- Clinical history compatible with type 1 diabetes, with onset of disease at less than
40 years of age; insulin dependence for at least 5 years at study entry; AND sum of
age and insulin-dependent diabetes duration of at least 28

- Absent stimulated C-peptide (less than 0.3 ng/ml) 60 and 90 minutes post mixed-meal
tolerance test

- Involvement of intensive diabetes management, defined as:

1. Self monitoring of glucose values no less than a mean of three times each day,
averaged over each week

2. Administration of three or more insulin injections each day or insulin pump
therapy

3. Under the direction of an endocrinologist, diabetologist, or diabetes
specialist, with at least three clinical evaluations during the past 12 months
prior to study enrollment

- At least one episode of severe hypoglycemia, defined as an event with one of the
following symptoms: memory loss; confusion; uncontrollable behavior; irrational
behavior; unusual difficulty in awakening; suspected seizure; seizure; loss of
consciousness; or visual symptoms, in which the participant was unable to treat
him/herself and which was associated with either a blood glucose level less than 54
mg/dl or prompt recovery after an oral carbohydrate, intravenous glucose, or glucagon
administration in the 12 months prior to study enrollment.

- Reduced awareness of hypoglycemia. More information about this criterion, including
the specific definition of hypoglycemia unawareness, is in the protocol.

Exclusion Criteria:

- Body mass index (BMI) greater than 30 kg/m2 or weight less than or equal to 50 kg

- Insulin requirement of more than 1.0 IU/kg/day or less than 15 U/day

- HbA1c greater than 10%

- Untreated proliferative diabetic retinopathy

- Systolic blood pressure higher than 160 mmHg or diastolic blood pressure higher than
100 mmHg

- Measured glomerular filtration rate using iohexol of less than 80 ml/min/1.73m2. More
information about this criterion is in the protocol.

- Presence or history of macroalbuminuria (greater than 300 mg/g creatinine)

- Presence or history of panel-reactive anti-HLA antibody levels greater than
background by flow cytometry. More information about this criterion is in the
protocol.

- Pregnant, breastfeeding, or unwilling to use effective contraception throughout the
study and for 4 months after study completion

- Active infection, including hepatitis B virus, hepatitis C virus, HIV, or
tuberculosis. More information about this criterion is in the protocol.

- Negative for Epstein-Barr virus by IgG determination

- Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection in the past
year

- History of malignancy except for completely resected squamous or basal cell carcinoma
of the skin

- Known active alcohol or substance abuse

- Baseline Hgb below the lower limits of normal, lymphopenia, neutropenia, or
thrombocytopenia

- History of Factor V deficiency

- Any coagulopathy or medical condition requiring long-term anticoagulant therapy after
transplantation or individuals with an INR greater than 1.5

- Severe coexisting cardiac disease, characterized by any one of the following
conditions:

1. Heart attack within the last 6 months

2. Evidence of ischemia on functional heart exam within the year prior to study
entry

3. Left ventricular ejection fraction less than 30%

- Persistent elevation of liver function tests at the time of study entry

- Symptomatic cholecystolithiasis

- Acute or chronic pancreatitis

- Symptomatic peptic ulcer disease

- Severe unremitting diarrhea, vomiting, or other gastrointestinal disorders that could
interfere with the ability to absorb oral medications

- Hyperlipidemia despite medical therapy, defined as fasting LDL cholesterol greater
than 130 mg/dl (treated or untreated) and/or fasting triglycerides greater than 200
mg/dl

- Currently receiving treatment for a medical condition that requires chronic use of
systemic steroids except for the use of less than or equal to 5 mg prednisone daily,
or an equivalent dose of hydrocortisone, for physiological replacement only

- Treatment with any anti-diabetic medication other than insulin within 4 weeks prior
to study entry

- Use of any study medications within the past 4 weeks

- Received a live attenuated vaccine within the past 2 months

- Any medical condition that, in the opinion of the investigator, might interfere with
safe participation in the trial

- Treatment with any immunosuppressive regimen at the time of enrollment.

- A previous islet transplant.

- A previous pancreas transplant, unless the graft failed within the first week due to
thrombosis, followed by pancreatectomy and the transplant occurred more than 6 months
prior to enrollment