Calcineurin Inhibitor-free, Steroid-free Immunosuppressive Regimen in Simultaneous Islet-Kidney Transplantation for Uremic Type 1 Diabetic Patients

This is a single center, open-label, non-randomized, prospective, pilot study of 8 Type 1
diabetic/uremic patients, ages 18-60 undergoing simultaneous islet-kidney transplantation.
Study to include both male and/or female subjects.

We hypothesize that a calcineurin inhibitor-free, steroid-free, co-stimulatory
blockade-based immunosuppressive regimen, in combination with a GLP-1 agonist, will reduce
the islet mass required to achieve and sustain insulin independence following simultaneous
islet-kidney transplantation.

Furthermore, we anticipate an improvement in creatinine clearance and a reduction in
Interstitial Fibrosis/Tubular Atrophy in the transplanted renal allograft, and a reduction
of "de novo" human anti-HLA antibody and auto-antibody formation against the respective
donors.

Without calcineurin inhibitors or steroids, we hypothesize that belatacept, in conjunction
with sirolimus and mycophenolic acid will provide balanced immunosuppression for combined
islet-kidney transplantation.

Inclusion Criteria:

- Subjects will include those with Type 1 Diabetes Mellitus, undergoing kidney
transplantation, and:

- are closely followed by a primary care provider and/or endocrinologist for >6
months prior to enrollment in the trial

- do not have psychogenic factors which preclude therapeutic compliance

- have a fasting C-peptide of <0.2 ng/mL• have diabetes for >5 years • are between
18 and 65 years of age

- have a creatinine clearance of less than 20 mL/min

- have a body mass index of less than or equal to 28

- In the case of women of childbearing potential (WOCBP), must have a negative
pregnancy test and avoid pregnancy throughout the study and 8 weeks after final
dose of study drug.

- WOCBP must use two adequate methods of contraception.

- A male subject of fathering potential must use an adequate method of
contraception to avoid conception throughout the study and for up to 8 weeks
after the last dose of study drug to minimize the risk of pregnancy.

Exclusion Criteria:

- Untreated proliferative diabetic retinopathy

- HgbA1C >12

- creatinine clearance > 20 ml/minute

- presence of panel reactive antibodies (PRA) >20% (per CDC-based assay)

- malignancy or previous malignancy, except for adequately treated skin cancers
(basal cell or squamous cell carcinoma) within the past 5 years

- sensitivity to iodine and/or shellfish (re: Iothalamate-based GFR testing)

- x-ray evidence of pulmonary infection

- active infections

- active peptic ulcer disease, gall stones, hemangioma, cirrhosis or portal
hypertension

- serological evidence of HIV, HBSAg or HCV

- abnormal liver function tests (elevated AST and ALT > 2x upper limit of normal)

- anemia (hemoglobin) <9 gm/dl

- serum triglycerides >200 mg/dl

- serum cholesterol >240 mg/dl

- body mass index above 28

- unstable cardiovascular status (including positive stress echocardiography if
>age 35); severe coexisting cardiac disease, myocardial infarction within the 6
months prior to enrollment in the study, left ventricular ejection fraction of
<30%, or evidence of ongoing ischemia

- prostate specific antigen (PSA) >4 in males >40 years old or with family history
of prostate cancer

- pregnancy or breastfeeding

- sexually-active females who are not: a) post-menopausal, b) surgically sterile,
or c) not using an acceptable method of contraception (oral contraceptives,
Norplant, Depo-Provera, and barrier devices are acceptable; condoms used alone
are not acceptable)

- alcohol abuse, substance abuse or smoking within the previous 6 months

- insulin requirement >1.5 u/kg/day

- negative for Epstein-Barr virus by IgG determination

- history of factor V deficiency

- acute or chronic pancreatitis

- recurrent attenuated vaccine(s) within the previous 2 months

- use of an investigational agent within the past 4 weeks

- sexually active, fertile men not using effective birth control, if their
partners are WOCBP

- prisoners, or subjects who are involuntarily incarcerated

- subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness

- Previous kidney transplant or previous non-renal transplant

- kidney transplant from expanded criteria donor (ECD)

- kidney cold ischemic time projected to be > 20 hours

- currently receiving immunosuppressive agents for autoimmune disease or other
conditions or have comorbidities that treatment with such agents are likely
during the trial

- any condition or circumstance that makes it unsafe to undergo an islet cell or
kidney transplant