Diabetes Mellitus, Type 1, Islets of Langerhans Transplantation, Kidney Transplantation
Conditions
Brief summary
The investigators hypothesize that a calcineurin inhibitor-free, steroid-free, co-stimulatory blockade-based immunosuppressive regimen, in combination with a GLP-1 agonist, will reduce the islet mass required to achieve and sustain insulin independence following simultaneous islet-kidney transplantation.
Detailed description
This is a single center, open-label, non-randomized, prospective, pilot study of 8 Type 1 diabetic/uremic patients, ages 18-60 undergoing simultaneous islet-kidney transplantation. Study to include both male and/or female subjects. We hypothesize that a calcineurin inhibitor-free, steroid-free, co-stimulatory blockade-based immunosuppressive regimen, in combination with a GLP-1 agonist, will reduce the islet mass required to achieve and sustain insulin independence following simultaneous islet-kidney transplantation. Furthermore, we anticipate an improvement in creatinine clearance and a reduction in Interstitial Fibrosis/Tubular Atrophy in the transplanted renal allograft, and a reduction of de novo human anti-HLA antibody and auto-antibody formation against the respective donors. Without calcineurin inhibitors or steroids, we hypothesize that belatacept, in conjunction with sirolimus and mycophenolic acid will provide balanced immunosuppression for combined islet-kidney transplantation.
Interventions
DRUGBelatacept
Belatacept 10mg/kg on Days 0, 4, 14, 28, 56, and 84 post-transplant, and then 5mg/kg every 4 weeks for the duration of the study.
Sponsors
Bristol-Myers Squibb
University of Wisconsin, Madison
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Subjects will include those with Type 1 Diabetes Mellitus, undergoing kidney transplantation, and: * are closely followed by a primary care provider and/or endocrinologist for \>6 months prior to enrollment in the trial * do not have psychogenic factors which preclude therapeutic compliance * have a fasting C-peptide of \<0.2 ng/mL• have diabetes for \>5 years • are between 18 and 65 years of age * have a creatinine clearance of less than 20 mL/min * have a body mass index of less than or equal to 28 * In the case of women of childbearing potential (WOCBP), must have a negative pregnancy test and avoid pregnancy throughout the study and 8 weeks after final dose of study drug. * WOCBP must use two adequate methods of contraception. * A male subject of fathering potential must use an adequate method of contraception to avoid conception throughout the study and for up to 8 weeks after the last dose of study drug to minimize the risk of pregnancy.
Exclusion criteria
* Untreated proliferative diabetic retinopathy * HgbA1C \>12 * creatinine clearance \> 20 ml/minute * presence of panel reactive antibodies (PRA) \>20% (per CDC-based assay) * malignancy or previous malignancy, except for adequately treated skin cancers (basal cell or squamous cell carcinoma) within the past 5 years * sensitivity to iodine and/or shellfish (re: Iothalamate-based GFR testing) * x-ray evidence of pulmonary infection * active infections * active peptic ulcer disease, gall stones, hemangioma, cirrhosis or portal hypertension * serological evidence of HIV, HBSAg or HCV * abnormal liver function tests (elevated AST and ALT \> 2x upper limit of normal) * anemia (hemoglobin) \<9 gm/dl * serum triglycerides \>200 mg/dl * serum cholesterol \>240 mg/dl * body mass index above 28 * unstable cardiovascular status (including positive stress echocardiography if \>age 35); severe coexisting cardiac disease, myocardial infarction within the 6 months prior to enrollment in the study, left ventricular ejection fraction of \<30%, or evidence of ongoing ischemia * prostate specific antigen (PSA) \>4 in males \>40 years old or with family history of prostate cancer * pregnancy or breastfeeding * sexually-active females who are not: a) post-menopausal, b) surgically sterile, or c) not using an acceptable method of contraception (oral contraceptives, Norplant, Depo-Provera, and barrier devices are acceptable; condoms used alone are not acceptable) * alcohol abuse, substance abuse or smoking within the previous 6 months * insulin requirement \>1.5 u/kg/day * negative for Epstein-Barr virus by IgG determination * history of factor V deficiency * acute or chronic pancreatitis * recurrent attenuated vaccine(s) within the previous 2 months * use of an investigational agent within the past 4 weeks * sexually active, fertile men not using effective birth control, if their partners are WOCBP * prisoners, or subjects who are involuntarily incarcerated * subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness * Previous kidney transplant or previous non-renal transplant * kidney transplant from expanded criteria donor (ECD) * kidney cold ischemic time projected to be \> 20 hours * currently receiving immunosuppressive agents for autoimmune disease or other conditions or have comorbidities that treatment with such agents are likely during the trial * any condition or circumstance that makes it unsafe to undergo an islet cell or kidney transplant
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Achieve and consistently maintain insulin independence in simultaneous islet-kidney transplant recipients for one year. | 1 year |
Countries
United States
Outcome results
None listed