• Proportion of participants with insulin independence [ Time Frame: 75 days after first islet transplant ] [ Designated as safety issue: No ]
  

• Percent reduction in insulin requirements, HbA1c, Mean amplitude of glycemic excursions (MAGE), Glycemic lability index (LI), Ryan hypoglycemia severity (HYPO) score [ Time Frame: 75 Days after first and subsequent islet transplant ] [ Designated as safety issue: No ]
  
• Basal (fasting) and 90-min glucose and C-peptide derived from the mixed-meal tolerance test (MMTT), beta-score, C-peptide: glucose-creatinine ration, acute insulin response to glucose, [ Time Frame: 75 Days after first and subsequent islet transplant ] [ Designated as safety issue: No ]
  
• Insulin sensitivity and disposition index derived from the insulin-modified frequently-sampled intravenous glucose tolerance test (FSIGT) test, [ Time Frame: 75 days after first and subsequent islet transplant ] [ Designated as safety issue: No ]
  
• Glucose variability and hypoglycemia duration, derived from the continuous glucose monitoring system, quality of life measures [ Time Frame: 75 days after first and subsequent islet transplant ] [ Designated as safety issue: No ]
  
• Proportion of participants with an HbA1c greater than 7.0 percent [ Time Frame: 365 days after first islet transplant ] [ Designated as safety issue: No ]
  
• Proportion of participants receiving a second or third islet transplant [ Time Frame: 365 days after first islet transplant ] [ Designated as safety issue: No ]
  
• Proportion of insulin-independent participants, percent reduction in insulin requirements, HbA1c, Mean amplitude of glycemic excursions (MAGE), Glycemic lability index (LI), Clarke Score, Ryan hypoglycemia severity (HYPO) score [ Time Frame: 365 days after first and final islet transplant ] [ Designated as safety issue: No ]
  
• Basal (fasting) and 90-min glucose and C-peptide derived from the mixed-meal tolerance test (MMTT), beta-score, C-peptide: glucose-creatinine ratio [ Time Frame: 365 days after first and final islet transplant ] [ Designated as safety issue: No ]
  
• Insulin sensitivity and disposition index derived from the insulin-modified frequently-sampled intravenous glucose tolerance test (FSIGT) test [ Time Frame: 365 days after first and final islet transplant ] [ Designated as safety issue: No ]
  
• Glucose variability and hypoglycemia duration, derived from the continuous glucose monitoring system, quality of life measures [ Time Frame: 365 days after first and subsequent islet transplant ] [ Designated as safety issue: No ]
  
• QOL measures [ Time Frame: 365 days after first and final islet transplant ] [ Designated as safety issue: No ]
  
• Incidence and severity of AEs related to the islet transplant procedure [ Time Frame: 75 days following each transplant and 365 days following the first and final islet transplant ] [ Designated as safety issue: Yes ]
  
• Incidence and severity of AEs related to immunosuppression therapy [ Time Frame: 75 days following each transplant and 365 days following the first and final islet transplant ] [ Designated as safety issue: Yes ]
  
• Incidence of change in the immunosuppression drug regimen [ Time Frame: 75 days following each transplant and 365 days following the first and final islet transplant ] [ Designated as safety issue: Yes ]
  
• Incidence of immune sensitization defined by presence of HLA antibodies absent prior to transplantation [ Time Frame: 75 days following each transplant and 365 days following the first and final islet transplant ] [ Designated as safety issue: Yes ]
  
• Incidence of worsening retinopathy [ Time Frame: 365 days following the first islet transplant ] [ Designated as safety issue: Yes ]
  

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, transplantation of pancreatic islets is a possible treatment option. 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 determine the safety and efficacy of islet transplantation, when combined with an immunosuppressive medication regimen containing belatacept, for treating 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 a site-specific Phase 3 islet transplantation study (CIT-07). Participants in this study will receive up to three separate islet transplants and a regimen of immunosuppressive medications consisting of an IL-2 monoclonal antibody receptor blocker (daclizumab or basiliximab), mycophenolate mofetil, and belatacept. They will begin receiving all three drugs on the day of the first islet transplant. If the participant receives daclizumab, it will also be given again on Days 14, 28, 42, and 56 post-transplant; if the participant receives basiliximab, it will also be given again on Day 4 post-transplant. Mycophenolate mofetil 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.