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

Not Applicable

Withdrawn

• Conditions: Islets of Langerhans Transplantation; Diabetes Mellitus, Type 1; Kidney Transplantation
• Interventions: Drug: Belatacept

• Registration Number: NCT01033500
• Lead Sponsor: University of Wisconsin, Madison

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.

Study Timeline

• Study First Submitted: 2009-12-15
• Study First Submitted QC: 2009-12-15
• Study First Posted: 2009-12-16
• Study Start: 2010-07
• Primary Completion: 2012-12
• Study Completion: 2012-12
• Status Verified: 2013-05
• Last Update Submitted: 2013-05-06
• Last Update Posted: 2013-05-08

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
SIK	Belatacept	Basiliximab induction with maintenance immunosuppression consisting of belatacept, sirolimus or everolimus, and mycophenolate after simultaneous islet kidney transplantation.

Primary Outcome Measures

Name	Time	Method
Achieve and consistently maintain insulin independence in simultaneous islet-kidney transplant recipients for one year.	1 year

Trial Locations

Locations (1)

University of Wisconsin; 🇺🇸 Madison, Wisconsin, United States