Calcineurin Inhibitor-free, Steroid-free Immunosuppressive Regimen in Simultaneous Islet-Kidney Transplantation for Uremic Type 1 Diabetic Patients
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| N/A |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: SIK Basiliximab induction with maintenance immunosuppression consisting of belatacept, sirolimus or everolimus, and mycophenolate after simultaneous islet kidney transplantation. |
Drug: Belatacept
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.
|
Outcome Measures
Primary Outcome Measures
- Achieve and consistently maintain insulin independence in simultaneous islet-kidney transplant recipients for one year. [1 year]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Subjects will include those with Type 1 Diabetes Mellitus, undergoing kidney transplantation, and:
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are closely followed by a primary care provider and/or endocrinologist for >6 months prior to enrollment in the trial
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do not have psychogenic factors which preclude therapeutic compliance
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have a fasting C-peptide of <0.2 ng/mL• have diabetes for >5 years • are between 18 and 65 years of age
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have a creatinine clearance of less than 20 mL/min
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have a body mass index of less than or equal to 28
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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.
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WOCBP must use two adequate methods of contraception.
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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:
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Untreated proliferative diabetic retinopathy
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HgbA1C >12
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creatinine clearance > 20 ml/minute
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presence of panel reactive antibodies (PRA) >20% (per CDC-based assay)
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malignancy or previous malignancy, except for adequately treated skin cancers (basal cell or squamous cell carcinoma) within the past 5 years
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sensitivity to iodine and/or shellfish (re: Iothalamate-based GFR testing)
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x-ray evidence of pulmonary infection
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active infections
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active peptic ulcer disease, gall stones, hemangioma, cirrhosis or portal hypertension
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serological evidence of HIV, HBSAg or HCV
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abnormal liver function tests (elevated AST and ALT > 2x upper limit of normal)
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anemia (hemoglobin) <9 gm/dl
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serum triglycerides >200 mg/dl
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serum cholesterol >240 mg/dl
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body mass index above 28
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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
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prostate specific antigen (PSA) >4 in males >40 years old or with family history of prostate cancer
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pregnancy or breastfeeding
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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)
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alcohol abuse, substance abuse or smoking within the previous 6 months
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insulin requirement >1.5 u/kg/day
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negative for Epstein-Barr virus by IgG determination
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history of factor V deficiency
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acute or chronic pancreatitis
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recurrent attenuated vaccine(s) within the previous 2 months
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use of an investigational agent within the past 4 weeks
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sexually active, fertile men not using effective birth control, if their partners are WOCBP
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prisoners, or subjects who are involuntarily incarcerated
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subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
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Previous kidney transplant or previous non-renal transplant
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kidney transplant from expanded criteria donor (ECD)
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kidney cold ischemic time projected to be > 20 hours
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currently receiving immunosuppressive agents for autoimmune disease or other conditions or have comorbidities that treatment with such agents are likely during the trial
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any condition or circumstance that makes it unsafe to undergo an islet cell or kidney transplant
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Wisconsin | Madison | Wisconsin | United States | 53792 |
Sponsors and Collaborators
- University of Wisconsin, Madison
- Bristol-Myers Squibb
Investigators
- Principal Investigator: Luis Fernandez, MD, University of Wisconsin, Madison
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- H-2010-0042