Calcineurin Inhibitor-free, Steroid-free Immunosuppressive Regimen in Simultaneous Islet-Kidney Transplantation for Uremic Type 1 Diabetic Patients

Study Description

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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
Islets of Langerhans Transplantation; Diabetes Mellitus, Type 1; Kidney Transplantation	Drug: Belatacept	Not Applicable

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

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	0 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Calcineurin Inhibitor-free, Steroid-free Immunosuppressive Regimen in Simultaneous Islet-Kidney Transplantation for Uremic Type 1 Diabetic Patients
Study Start Date :	July 2010
Actual Primary Completion Date :	December 2012
Actual Study Completion Date :	December 2012

Arms and Interventions

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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

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Primary Outcome Measures :

1. Achieve and consistently maintain insulin independence in simultaneous islet-kidney transplant recipients for one year. [ Time Frame: 1 year ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 65 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

United States, Wisconsin
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

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	University of Wisconsin, Madison
ClinicalTrials.gov Identifier:	NCT01033500 History of Changes
Other Study ID Numbers:	H-2010-0042
First Posted:	December 16, 2009
Last Update Posted:	May 8, 2013
Last Verified:	May 2013

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Immunosuppressive Agents	Abatacept; Calcineurin Inhibitors; Immunologic Factors; Physiological Effects of Drugs; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents