LEA29Y (Belatacept) Emory Edmonton Protocol

• Register: ClinicalTrials.gov
• Last refreshed on: 17 October 2012
• Main ID: NCT00468403
• Date of registration: 01/05/2007
• Primary sponsor: National Institute of Allergy and Infectious Disease (NIAID)
• Public title: LEA29Y (Belatacept) Emory Edmonton Protocol LEEP
• Scientific title: Islet Transplantation in Type I Diabetes With LEA29Y (Belatacept) Maintenance Therapy
• Date of first enrolment: October 2008
• Target sample size: 10
• Recruitment status: Active, not recruiting
• URL: http://clinicaltrials.gov/show/NCT00468403
• Study type: Interventional
• Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Countries of recruitment

Canada, United States

Contacts

• Name: Nicole Turgeon, MD
• Affiliation: Clinical Islet Transplant Program, Emory University

• Name: A.M. James Shapiro, MD, PhD
• Affiliation: Clinical Islet Transplant Program, University of Alberta

Key inclusion & exclusion criteria

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/m2 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

- 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/1.73mm2.

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

- Presence or history of panel-reactive anti-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, HIV. Presence or history of
tuberculosis. More information about these criteria is in the protocol. - Negative
for Epstein-Barr virus by 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 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



Age minimum: 18 Years
Age maximum: 65 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Type 1 Diabetes Mellitus

Intervention(s)

Drug: Basiliximab

Drug: Belatacept

Drug: Mycophenolate Mofetil

Procedure: Islet transplant

Primary Outcome(s)

Proportion of subjects with insulin independence [Time Frame: 75 days after first islet transplant]

Secondary Outcome(s)

Basal (fasting) and 90-min glucose and C-peptide derived from the mixed-meal tolerance test (MMTT), beta-score, C-peptide [Time Frame: Two years 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 ratio [Time Frame: 365 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 [Time Frame: 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 [Time Frame: 75 Days after first and final islet transplant]

Glucose variability and hypoglycemia duration, derived from the continuous glucose monitoring system (CGMS), quality of life (QOL) measures [Time Frame: 365 days after first and final islet transplant]

Glucose variability and hypoglycemia duration, derived from the continuous glucose monitoring system (CGMS), quality of life (QOL) measures [Time Frame: 75 days after first and final islet transplant]

Glucose variability and hypoglycemia duration, derived from the continuous glucose monitoring system (CGMS), quality of life (QOL) measures [Time Frame: From 75 days to 365 days after final islet transplant]

Glucose variability and hypoglycemia duration, derived from the continuous glucose monitoring system (CGMS), quality of life (QOL) measures [Time Frame: Two years after final islet transplant]

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]

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]

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]

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]

Incidence of worsening retinopathy [Time Frame: 365 days following the first islet transplant]

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]

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 final islet transplant]

Insulin sensitivity and disposition index derived from the insulin-modified frequently-sampled intravenous glucose tolerance test (FSIGT) test [Time Frame: From 75 days to 365 days after final islet transplant]

Lipid profiles (triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol) [Time Frame: Throughout study participation]

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]

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: From 75 days to 365 days after final islet transplant]

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 final islet transplant]

Percent reduction in insulin requirements, number of severe hypoglycemic events from 28 days to 2 years, HbA1c, Clarke Score [Time Frame: Two years after final islet transplant]

Proportion of participants receiving a second or third islet transplant [Time Frame: 365 days after first and final islet transplant]

Proportion of participants receiving a second or third islet transplant [Time Frame: From 75 days to 365 days after final islet transplant]

Proportion of subjects with an HbA1c <7.0% AND free of severe hypoglycemic events [Time Frame: from Day 28 to Day 365, inclusive, after the final islet transplant]

Proportion of subjects with an HbA1c <7.0% AND free of severe hypoglycemic events [Time Frame: from Day 28 to Day 365, inclusive, after the first 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) [Time Frame: 365 days after first and 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) [Time Frame: From 75 days to 365 days after final islet transplant]

Renal function as measured by serum creatinine, GFR and other relevant laboratory parameters [Time Frame: Throughout study participation]

Safety associated with conventional immunosuppression [Time Frame: Throughout study participation]

Secondary ID(s)

DAIT CIT-04

Source(s) of Monetary Support

Please refer to primary and secondary sponsors