B-Lymphocyte Immunotherapy in Islet Transplantation

Type 1 diabetes is commonly treated with the administration of insulin, either by multiple
insulin injections or by a continuous supply of insulin through a wearable pump. Insulin
therapy allows long-term survival in individuals with type 1 diabetes; however, it does not
guarantee constant normal blood sugar control. Because of this, long-term type 1 diabetic
survivors often develop vascular complications, such as diabetic retinopathy, an eye disease
that can cause poor vision and blindness, and diabetic nephropathy, a kidney disease that
can lead to kidney failure. Some individuals with type 1 diabetes develop hypoglycemia
unawareness, a life-threatening condition that is not easily treatable with medication and
is characterized by reduced or absent warning signals for hypoglycemia. For such
individuals, pancreas or pancreatic islet transplantation are possible treatment options.
Unfortunately, insulin independence among islet transplant recipients tends to decline over
time. New strategies aimed at promoting engraftment of transplanted islets are needed to
improve the clinical outcomes associated with this procedure. The purpose of this study is
to determine the safety and efficacy of islet transplantation, when combined with an
immunosuppressive medication regimen containing rituximab. This regimen is intended to treat
type 1 diabetes in individuals experiencing hypoglycemia unawareness and severe hypoglycemic
episodes. This study will also seek to improve the understanding of determinants of success
and failure of islet transplants for type 1 diabetes.

Eligible participants will be randomly assigned to this study or the Phase 3 islet
transplantation study (DAIT CIT-07). Participants in this study will receive up to three
separate islet transplants and a regimen of immunosuppressive medications consisting of
antithymocyte globulin (ATG), sirolimus, and rituximab. They will begin receiving ATG,
sirolimus, and rituximab 2 days prior to the first islet transplant. ATG will continue to be
given until Day 2 post-transplant, and sirolimus will be given for the duration of the
study. They will receive additional rituximab on Days 5 and 12 post-transplant.

Transplantations will involve an inpatient hospital stay and infusion of islets into 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 islet 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 approximately 15 study visits following each transplant. A physical exam,
review of adverse events, and blood collection will occur at most visits. A chest x-ray,
abdominal ultrasound, electrocardiogram, quality of life questionnaires, urine collection,
and glomerular filtrating rate (GFR) testing will occur at some visits. Participants will
also test their own blood glucose levels at least four 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 at less than 40 years of
age, insulin dependence for at least 5 years at study entry, and a 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

- Under the direction of an endocrinologist, diabetologist, or diabetes specialist with
at least three evaluations the 12 months prior to study enrollment

- At least one episode of severe hypoglycemia in the past 12 months, 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 (BG)
level < 54 mg/dL [3.0 mmol/L] or prompt recovery after oral carbohydrate, intravenous
glucose, or glucagon administration, in the past 12 months prior to study enrollment

- Reduced awareness of hypoglycemia. More information about this criterion, including
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 20% by
flow cytometry. More information about this criterion is in the protocol.

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

- Active infection, including hepatitis B, hepatitis C, 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 within one year
prior to study enrollment

- 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 (fasting LDL cholesterol greater than 130
mg/dl, treated or untreated; and/or fasting triglycerides greater than 200 mg/dl)

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

- Treatment with antidiabetic medication other than insulin within the past 4 weeks

- Use of any investigational agents within the past 4 weeks

- Received a live attenuated vaccine(s) within 2 months of study entry

- Any medical condition that, in the opinion of the investigator, will 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 transplant occurred more than 6 months
prior to enrollment