Efficacy of Islet After Kidney 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 and thus kidney transplant. 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. The purpose of this study is to assess the benefit of islet transplantation in type
1 diabetic kidney transplant recipients.

Participants in this study will be type I diabetics who have received a kidney transplant for
ESRD.. If subjects have not received ITT in the 12 months prior to enrollment, they must
undergo a period of standardized diabetes care by an experienced diabetologist at the
transplant center using the current ADA's standards of medical care in diabetes. Throughout
the study, all participants will remain on the immunosuppressive therapy intended for their
kidney. Participants will receive up to three separate islet transplants and a regimen of
immunosuppressive medications consisting of antithymocyte globulin (ATG) and etanercept. They
will begin receiving ATG 2 days prior to transplant and will continue to receive ATG until
Day 2 post-transplant. Etanercept will be given on the day of transplant and on Days 3, 7,
and 10 post-transplant.

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
30 post-transplant will be considered for a second islet transplant. Participants who remain
dependent on insulin for longer than 30 days after the second transplant and who show partial
graft function will be considered for a third islet transplant. Daclizumab 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 will enter a reduced follow-up period.

There will be approximately 15 study visits. 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, and urine collection will occur at some
visits. Participants will also test their own blood glucose levels throughout the study. A
36-month follow-up period will take place after the participant's last transplant, consisting
of 8 additional visits.

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 a sum of age
and insulin dependent diabetes duration of at least 28;

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

- Received kidney transplant for ESRD and are taking appropriate calcineurin inhibitor
(CNI) based maintenance immunosuppressive therapy;

- Stable renal function as defined as creatinine of no more than one third greater than
the average creatinine determination performed in the 3 previous months prior to islet
transplantation, until rejection, obstruction or infection is ruled out;

- Intensive diabetes management followed by reduced awareness of hypoglycemia or an
HbA1c ≥ 7.5%.

Exclusion Criteria:

- Body mass index (BMI) greater than 30 kg/m2 or weight more than 90 kg;

- Insulin requirement of >1.0 IU/kg/day or <15 U/day;

- Other (non-kidney) organ transplants except prior failed pancreatic graft where the
graft failed within the first two weeks due to thrombosis, followed by pancreatectomy
and the pancreas transplant occurred more than 6 months prior to enrollment;

- Untreated proliferative diabetic retinopathy;

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

- Calculated glomerular filtration rate of less than 40 ml/min/1.73meter-squared. More
information about this criterion is in the protocol;

- Proteinuria (albumin/creatinine ratio or ACr > 300 mg/g) of new onset since kidney
transplantation;

- Either Class I or Class II panel-reactive anti-HLA antibodies > 50%; Participants with
either Class I or Class II panel reactive anti-HLA antibodies of 50% or less will be
excluded if any of the following are detected:

1. Positive cross match;

2. Islet donor-directed anti-HLA antibodies detected my Luminex Single
Antigen/specificity bead assay, including weakly reactive antibodies that would
not be detected by a flow cross-match; or

3. Antibodies to the renal donor (i.e. presumed de novo).

- 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 (EBV) by (VCA) IgG determination;

- Invasive aspergillus infection, histoplasmosis, and coccidioidomycosis infection 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;

- History of Factor V Leiden mutation;

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

- Severe co-existing cardiac disease, characterized by any one of these conditions:

1. Recent MI (within past 6 months);

2. Evidence of ischemia on functional cardiac exam within the last year;

3. Left ventricular ejection fraction < 30%; or

4. Valvular disease requiring replacement with prosthetic valve.

- Persistent elevation of liver function tests at the time of study entry. Persistent
serum glutamic-oxaloacetic transaminase (SGOT [AST]), serum glutamate pyruvate
transaminase (SGPT [ALT],) alkaline phosphatase or total bilirubin, with values > 1.5
times normal upper limits will exclude a subject;

- Active infections (except mild skin and nail fungal infections);

- Acute or chronic pancreatitis;

- Active peptic ulcer disease, symptomatic gallstones, or portal hypertension;

- Treatment with any anti-diabetic medication other than insulin within the past 4
weeks;

- Use of any investigational agents within the past 4 weeks;

- Received live attenuated vaccine(s) within the past 2 months;

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

- Male participants with elevation of prostate specific antigen (PSA) of more than 4
unless cancer has been excluded;

- Any condition other than T1D as the primary cause of end stage renal disease (ESRD) in
the native kidney;

- Positive screen for BK virus by polymerase chain reaction (PCR) determination at time
of screening;

- A previous islet transplant;

- A kidney transplant recipient with T1D who has an HbA1c < 7.5% and no history of
severe hypoglycemia.