LEA29Y (Belatacept) Emory Edmonton Protocol

Phase 2

Completed

Conditions: Type 1 Diabetes Mellitus

Interventions: Biological: Allogeneic Pancreatic Islet Cells
Biological: Belatacept
Biological: Basiliximab
Drug: Mycophenolate Mofetil
Drug: Tacrolimus
Procedure: Intraportal infusion of islet cells

Registration Number: NCT00468403

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: 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 using a steroid-free, calcineurin-inhibitor-free belatacept based immunosuppressive medication, for treating type 1 diabetes in individuals experiencing hypoglycemia unawareness and severe hypoglycemic episodes.

Detailed Description: 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 belatacept, basiliximab (an IL-2 monoclonal antibody receptor blocker), and mycophenolate mofetil. Participants will begin receiving all three drugs on the day of the first islet transplant. 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.

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.

Transplantations will involve an inpatient hospital stay and intraportal infusion of islet cells. 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 25 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 24-month follow-up period will take place after the participant's last transplant.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

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 (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 no less than a mean of three times each day averaged over each week
2. Three or more insulin injections each day or insulin pump therapy
3. Under the care of an endocrinologist, diabetologist, or diabetes specialist with at least three clinical evaluations during the past 12 months prior to study enrollment
At least one episode of severe hypoglycemia, defined as an event with one of the following symptoms: memory loss; confusion; uncontrollable behavior; irrational behavior; unusual difficulty in awakening; suspected seizure; seizure; loss of consciousness; or visual symptoms, in which the participant was unable to treat him/herself and which was associated with either a blood glucose level less than 54 mg/dL or prompt recovery after oral carbohydrate, intravenous glucose, or glucagons in the 12 months prior to study enrollment
Reduced awareness of hypoglycemia. More information about this criterion 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 (110 lbs)
Insulin requirement of more than 1.0 IU/kg/day or less than 15 U/day
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 using iohexol of less than 80 mL/min/1.73m^2.
Presence or history of macroalbuminuria (greater than 300 mg/g creatinine)
Presence or history of panel-reactive anti-Histocompatibility Antigen (HLA) antibody levels greater than 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
All women more than 35 years and women of any age who have first degree relatives with a history of breast carcinoma or who have other risk factors of breast carcinoma. More information about this criterion is in the study protocol.
Active infection, including hepatitis B, hepatitis C, human immunodeficiency virus (HIV). Presence or history of tuberculosis. More information about these criteria is in the protocol.
Negative for Epstein-Barr virus (EBV) by anti-viral capsid antigen (VCA) IgG (EBV VCA-IgG) determination
Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection in the past year
History of malignancy except for completely resected squamous or basal cell carcinoma of the skin
Known active alcohol or substance abuse
Baseline 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 international normalized ratio (INR) greater than 1.5.
Severe coexisting cardiac disease, defined as:
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 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, defined as fasting LDL cholesterol greater than 130 mg/dL and/or fasting triglycerides greater than 200 mg/dL
Currently 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 any antidiabetic medication other than insulin within the past 4 weeks
Previous receipt of belatacept
Use of any investigational agents within the past 4 weeks
Received a live attenuated vaccine(s) within the past 2 months
Any medical condition that, in the opinion of the investigator, might 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.
Known hypersensitivity to mycophenolate mofetil or any of its components
Imprisonment or involuntary incarceration for treatment of either a psychiatric or physical illness
Rare hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) such as Lesch-Nyhan and Kelly-Seegmiller syndrome
Dietary restriction of phenylalanine

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Allogeneic Pancreatic Islet Cells	Allogeneic Pancreatic Islet Cells	Participants will receive up to three islet transplantations and continuous immunosuppressive therapy including belatacept
Allogeneic Pancreatic Islet Cells	Belatacept	Participants will receive up to three islet transplantations and continuous immunosuppressive therapy including belatacept
Allogeneic Pancreatic Islet Cells	Basiliximab	Participants will receive up to three islet transplantations and continuous immunosuppressive therapy including belatacept
Allogeneic Pancreatic Islet Cells	Mycophenolate Mofetil	Participants will receive up to three islet transplantations and continuous immunosuppressive therapy including belatacept
Allogeneic Pancreatic Islet Cells	Intraportal infusion of islet cells	Participants will receive up to three islet transplantations and continuous immunosuppressive therapy including belatacept
Allogeneic Pancreatic Islet Cells	Tacrolimus	Participants will receive up to three islet transplantations and continuous immunosuppressive therapy including belatacept

Primary Outcome Measures

Name	Time	Method
Proportion of subjects with insulin independence	75 days after first islet transplant

Secondary Outcome Measures

Name	Time	Method
Percent reduction in insulin requirements, HbA1c, Mean amplitude of glycemic excursions (MAGE), Glycemic lability index (LI), Clarke Score, Ryan hypoglycemia severity (HYPO) score	From 75 days to 365 days after final islet transplant
Proportion of subjects with an HbA1c <7.0% AND free of severe hypoglycemic events	from Day 28 to Day 365, inclusive, after the final islet transplant
Percent reduction in insulin requirements, HbA1c, Mean amplitude of glycemic excursions (MAGE), Glycemic lability index (LI), Ryan hypoglycemia severity (HYPO) score	75 Days after first and final islet transplant
Insulin sensitivity and disposition index derived from the insulin-modified frequently-sampled intravenous glucose tolerance test (FSIGT) test	From 75 days to 365 days after final islet transplant
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	75 Days after first and final islet transplant
Basal (fasting) and 90-min glucose and C-peptide derived from the mixed-meal tolerance test (MMTT), beta-score, C-peptide: glucose-creatinine ratio	From 75 days to 365 days after final islet transplant
Rate of favorable outcome at each center preparing islets (rate of subjects with an HbA1c < 7.0% and free of severe hypoglycemic events)	From 75 days to 365 days after final islet transplant
Incidence of change in the immunosuppression drug regimen	75 days following each transplant and 365 days following the first and final islet transplant
Incidence of immune sensitization defined by presence of Histocompatibility Antigen (HLA) antibodies absent prior to transplantation	75 days following each transplant and 365 days following the first and final islet transplant
Percent reduction in insulin requirements, number of severe hypoglycemic events from 28 days to 2 years, HbA1c, Clarke Score	Two years after final islet transplant
Lipid profiles (triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol)	Two years after final islet transplant
Incidence and severity of adverse events related to the islet transplant procedure	75 days following each transplant and 365 days following the first and final islet transplant
Basal (fasting) and 90-min glucose and C-peptide derived from the mixed-meal tolerance test (MMTT), beta-score, C-peptide	Two years after final islet transplant
Safety associated with conventional immunosuppression	Two years after final islet transplant
Renal function as measured by serum creatinine, glomerular filtration rate (GFR) and other relevant laboratory parameters	Two years after final islet transplant
Glucose variability and hypoglycemia duration, derived from the continuous glucose monitoring system (CGMS), quality of life (QOL) measures	Two years after final islet transplant
Proportion of participants receiving a second or third islet transplant	From 75 days to 365 days after final islet transplant
Incidence and severity of adverse events related to immunosuppression therapy	75 days following each transplant and 365 days following the first and final islet transplant
Incidence of worsening retinopathy	365 days following the first islet transplant