Strategies to Improve Islet Survival
Strategies to Improve Islet Survival
Type 1 diabetes is an autoimmune disease in which the insulin-producing pancreatic beta cells
 are destroyed, resulting in poor blood sugar control. The purpose of this study is to
 determine the safety and effectiveness of islet transplantation, combined with
 immunosuppressive medications and medications to support islet survival, for treating type 1
 diabetes in individuals experiencing hypoglycemia unawareness and severe hypoglycemic
 episodes.
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 for long-term survival in individuals with type 1 diabetes; however, it does
 not guarantee constant normal blood sugar control. As a result, 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 lisofylline (LSF). 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 assigned to this study will receive LSF.
 Participants in this study will receive up to three separate islet transplants and a regimen
 of immunosuppressive medications including antithymocyte globulin (ATG) for the first
 transplant, sirolimus, tacrolimus, and LSF to support the engrafting of the islets into the
 beta-cell mass. All participants will begin receiving ATG and sirolimus 2 days prior to
 transplantation. ATG will be continued until 2 days post-transplant. Sirolimus will be
 continued for the duration of the study. All participants will also receive tacrolimus
 starting one day post-transplant and continuing for the duration of the study. Basiliximab
 will be used in place of ATG with all subsequent transplants. Participants in the LSF group
 will begin to receive LSF one day prior to transplant and will continue to receive LSF until
 5 days 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 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. 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 filtration rate (GFR) 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
 24-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

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

 -  At least one episode of severe hypoglycemia 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/m^2 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

 -  Hemoglobin A1C (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 (GFR) using iohexol of less than 80 mL/min/1.73m2.
 More information about this criterion is in the protocol.

 -  Presence/history of macroalbuminuria (greater than 300 mg/g creatinine)

 -  Presence/history of panel-reactive anti-HLA antibodies above background 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

 -  Presence of history of active infection, including hepatitis B, hepatitis C, human
 immunodeficiency virus (HIV), or tuberculosis (TB). More information about this
 criterion is in the protocol.

 -  Negative for Epstein-Barr virus (EBV) 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 hemoglobin (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 low-density lipoprotein [LDL]
 cholesterol > 130 mg/dL, treated or untreated; and/or fasting triglycerides > 200
 mg/dL)

 -  Receiving treatment for a medical condition that requires chronic use of systemic
 steroids, except for 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 study medications within the past 4 weeks

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

 -  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 the transplant occurred more than 6 months
 prior to enrollment