Islet Transplantation in Type 1 Diabetes with LEA29Y Maintenance Therapy (CIT-04)

You may be enrolled into this study, if you:

• are 18 to 65 years of age;
• have been diagnosed with type 1 diabetes with symptoms prior to age 40;
• are insulin dependent for at least 5 years, with three or more injections each day or on insulin pump therapy;
• have blood tests that show your body does not make insulin;
• are managing your diabetes daily, by checking you blood sugar at least three times a day;
• have had at least one episode of severe hypoglycemia in the past year where you needed the help of another person; and
• have hypoglycemia unawareness, a condition in which you no longer experience the usual warning signs of hypoglycemia.

The main purpose of this study is to assess the safety and effectiveness of an immunosuppressive medication regimen, which includes an experimental drug called LEA29Y (belatacept), in people who have received an islet transplant.

The goal of this study is to find out if adding LEA29Y (belatacept) to the immunosuppressive medication regimen improves the function of the transplanted islets. The effectiveness of LEA29Y (belatacept) will be measured by the proportion of subject who are insulin-independent at day 75 of the study following the first islet transplant.

If you enroll, you will be randomly (by chance) assigned to this study which uses LEA29Y (belatacept) with the immunosuppressive medication regimen or another islet transplantation study at the site which does not use LEA29Y (belatacept) as part of the immunosuppressive regimen. The group you are assigned to is decided by chance (as by the toss of a coin). Neither you nor your doctor will be able to choose which group you are in.

If you are assigned to this study, you will receive up to three separate islet transplants and a regimen of immunosuppressive medications consisting of daclizumab, sirolimus, and belatacept. You will begin receiving all three drugs on the day of the first islet transplant. Daclizumab will also be given again on Days 14, 28, 42, and 56 post-transplant. Sirolimus will also be given for the duration of the study. Belatacept will also be administered again on Days 4, 14, 28, 56, and 84 post-transplant and then every 4 weeks for the duration of 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 islet transplant. 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 18 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 more extensive blood testing will occur at some visits. Participants will also test their own blood 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.

You cannot participate in any other research studies in which treatments are given. However, it may be possible for you to participate in other kinds of studies that do not involve intervention.

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