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Belatacept Early Steroid Withdrawal Trial

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01729494
Recruitment Status : Active, not recruiting
First Posted : November 20, 2012
Last Update Posted : February 1, 2018
Sponsor:
Information provided by (Responsible Party):
E. Steve Woodle, University of Cincinnati

Brief Summary:

The study purpose is to determine the safety and efficacy of a belatacept-based immunosuppressive regimen (calcineurin inhibitor free) with alemtuzumab or rabbit antithymocyte globulin induction and early glucocorticoid withdrawal (CSWD) and a belatacept-based immunosuppressive regimen with tacrolimus-based regimen with rabbit antithymocyte globulin induction and early glucocorticoid withdrawal in renal transplant recipients.

The hypothesis is that a belatacept-based immunosuppressive regimen with alemtuzumab induction, mycophenolate mofetil (MMF)/mycophenolic acid (MPA), and early glucocorticoid withdrawal (Group A) in renal transplant recipients or Belatacept-based immunosuppressive regimen with rabbit antithymocyte globulin induction, MMF/MPA and early glucocorticoid withdrawal (Group B) will lead to less risk of graft loss, patient death, or reduced renal function at 12 months as compared to a tacrolimus-based immunosuppressive regimen with rabbit antithymocyte globulin, MMF/MPA, and early glucocorticoid withdrawal in renal transplant recipients (Group C).


Condition or disease Intervention/treatment Phase
Renal Transplantation Drug: Alemtuzumab Drug: rabbit antithymocyte globulin Drug: Belatacept Drug: Tacrolimus Drug: Mycophenolate mofetil Drug: early cessation of steroids Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 316 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized, Open Label, Multicenter Study of Belatacept-based Early Steroid Withdrawal Regimen With Alemtuzumab or rATG Induction Compared to Tacrolimus-based Early Steroid Withdrawal Regimen With rATG Induction in Renal Transplantation
Study Start Date : September 2012
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Group A
Alemtuzumab + belatacept + mycophenolate mofetil /Enteric coated mycophenolate sodium + early cessation of steroids
Drug: Alemtuzumab
Alemtuzumab will be dosed on day of transplant (Study Day 1) at dose of 30 mg given intravenously (IV) over a period of 2 hours after induction of anesthesia. Methylprednisolone IV will be administered 30-60 minutes prior to the administration of alemtuzumab.
Other Name: Campath

Drug: Belatacept
Belatacept will be administered via intravenous (IV) infusion according to the FDA approved dosage recommendations. Subjects randomized to belatacept arms will receive the first dose of IV belatacept (10 mg/kg) within 12-24 hours post reperfusion. The second dose will be given between post-transplant days 4 -6 (Study Days 5-7), and then study days 14, 28, 56, and 84 (12 weeks) and then subjects will receive belatacept at the maintenance dose of 5 mg/kg every 4 weeks until completion of the trial at 24 months (104 weeks). Study Day 1 is defined as the day of transplant.
Other Name: Nulojix

Drug: Mycophenolate mofetil
The first dose of mycophenolate mofetil/EC mycophenolate sodium will be administered pre-operatively. Patients receiving mycophenolate mofetil will be dosed 1000 mg twice daily (2000mg/day). Patients receiving EC mycophenolate sodium will be dosed 720 mg twice daily (1440 mg/day). Dose may be increased for African American transplant recipients to mycophenolate mofetil 1500 mg twice daily (3000mg/day) or EC mycophenolate sodium 1080 mg twice daily (2160 mg/day).
Other Name: Cellcept, various, Myfortic

Drug: early cessation of steroids

Glucocorticoid therapy will be administered as described. Methylprednisolone will be administered on Days 1 through 3. Additional tapering doses of glucocorticoids will continue to be given until Day 5 as below:

Day 1 (day of transplant): 500mg IV prior to alemtuzumab (Group A) or rabbit antithymocyte globulin (Groups B and C) Day 2: 250mg IV Day 3: 125mg IV Day 4: 80mg p.o. Day 5: 60mg p.o. No further steroids

Other Name: prednisone, various

Experimental: Group B
Rabbit antithymocyte globulin + belatacept + mycophenolate mofetil /Enteric coated (EC) mycophenolate sodium + early cessation of steroids
Drug: rabbit antithymocyte globulin
Rabbit antithymocyte globulin will be dosed post-operatively at a total cumulative dose of 4.0-6.0mg/kg given by days 5-10 post-transplant. It will be administered by local standards of care with the following recommendations. The initial intravenous intra-operative dose will be administered approximately one hour after the methylprednisolone dose. The first dose will be administered so that approximately 25% of the dose is infused prior to revascularization of the graft. Subsequent doses will be administered over a minimum of 4 hours. Premedication with acetaminophen 650mg p.o. and diphenhydramine 25mg p.o. prior to rabbit antithymocyte globulin dose will be given to reduce the incidence of infusion reactions.
Other Name: Thymoglobulin

Drug: Belatacept
Belatacept will be administered via intravenous (IV) infusion according to the FDA approved dosage recommendations. Subjects randomized to belatacept arms will receive the first dose of IV belatacept (10 mg/kg) within 12-24 hours post reperfusion. The second dose will be given between post-transplant days 4 -6 (Study Days 5-7), and then study days 14, 28, 56, and 84 (12 weeks) and then subjects will receive belatacept at the maintenance dose of 5 mg/kg every 4 weeks until completion of the trial at 24 months (104 weeks). Study Day 1 is defined as the day of transplant.
Other Name: Nulojix

Drug: Mycophenolate mofetil
The first dose of mycophenolate mofetil/EC mycophenolate sodium will be administered pre-operatively. Patients receiving mycophenolate mofetil will be dosed 1000 mg twice daily (2000mg/day). Patients receiving EC mycophenolate sodium will be dosed 720 mg twice daily (1440 mg/day). Dose may be increased for African American transplant recipients to mycophenolate mofetil 1500 mg twice daily (3000mg/day) or EC mycophenolate sodium 1080 mg twice daily (2160 mg/day).
Other Name: Cellcept, various, Myfortic

Drug: early cessation of steroids

Glucocorticoid therapy will be administered as described. Methylprednisolone will be administered on Days 1 through 3. Additional tapering doses of glucocorticoids will continue to be given until Day 5 as below:

Day 1 (day of transplant): 500mg IV prior to alemtuzumab (Group A) or rabbit antithymocyte globulin (Groups B and C) Day 2: 250mg IV Day 3: 125mg IV Day 4: 80mg p.o. Day 5: 60mg p.o. No further steroids

Other Name: prednisone, various

Active Comparator: Group C
Rabbit antithymocyte globulin + tacrolimus + mycophenolate mofetil /Enteric coated (EC) mycophenolate sodium + early cessation of steroids
Drug: rabbit antithymocyte globulin
Rabbit antithymocyte globulin will be dosed post-operatively at a total cumulative dose of 4.0-6.0mg/kg given by days 5-10 post-transplant. It will be administered by local standards of care with the following recommendations. The initial intravenous intra-operative dose will be administered approximately one hour after the methylprednisolone dose. The first dose will be administered so that approximately 25% of the dose is infused prior to revascularization of the graft. Subsequent doses will be administered over a minimum of 4 hours. Premedication with acetaminophen 650mg p.o. and diphenhydramine 25mg p.o. prior to rabbit antithymocyte globulin dose will be given to reduce the incidence of infusion reactions.
Other Name: Thymoglobulin

Drug: Tacrolimus
Tacrolimus will be administered orally twice daily (BID). The recommended total initial dose of tacrolimus is 0.1 mg/kg/day in two divided doses orally. Tacrolimus should be started post-transplant within 48 hours or when serum creatinine drops lower than 4mg/dL, whichever comes first. The initial targeted trough level of tacrolimus will be 8 - 12 ng/mL for Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter.
Other Name: Prograf, various

Drug: Mycophenolate mofetil
The first dose of mycophenolate mofetil/EC mycophenolate sodium will be administered pre-operatively. Patients receiving mycophenolate mofetil will be dosed 1000 mg twice daily (2000mg/day). Patients receiving EC mycophenolate sodium will be dosed 720 mg twice daily (1440 mg/day). Dose may be increased for African American transplant recipients to mycophenolate mofetil 1500 mg twice daily (3000mg/day) or EC mycophenolate sodium 1080 mg twice daily (2160 mg/day).
Other Name: Cellcept, various, Myfortic

Drug: early cessation of steroids

Glucocorticoid therapy will be administered as described. Methylprednisolone will be administered on Days 1 through 3. Additional tapering doses of glucocorticoids will continue to be given until Day 5 as below:

Day 1 (day of transplant): 500mg IV prior to alemtuzumab (Group A) or rabbit antithymocyte globulin (Groups B and C) Day 2: 250mg IV Day 3: 125mg IV Day 4: 80mg p.o. Day 5: 60mg p.o. No further steroids

Other Name: prednisone, various




Primary Outcome Measures :
  1. Composite endpoint [ Time Frame: 12 months ]
    Patient Death or Graft Loss or estimated GFR (eGFR) (MDRD) < 45 mL/min


Secondary Outcome Measures :
  1. Secondary endpoint [ Time Frame: 6, 12 and 24 months ]
    1. Composite endpoint at 6 and 24 months (12 months was selected as the time for evaluating the composite endpoint as the primary endpoint, as above)
    2. Incidence by Banff 2007 criteria of biopsy proven acute rejection (BPAR) stratified by type (ACR, antibody mediated rejection (AMR), or Mixed rejection)
    3. Death-Censored Graft Survival
    4. Proportion of patients with eGFR (MDRD) < 30 mL/min
    5. Proportion of patients developing anti-human leukocyte antigen (HLA) antibodies against the donor (donor specific antibodies) (DSA) after transplantation


Other Outcome Measures:
  1. Tertiary endpoints [ Time Frame: 6,12, 24 months ]
    1. Severity of rejection by Banff 2007 criteria, treatment, and outcome of BPAR stratified by type (ACR, AMR, or Mixed rejection)
    2. Proportion of patients requiring anti-lymphocyte therapy for BPAR
    3. Causes of patient and graft loss
    4. Incidence, severity and treatment of metabolic and cardiovascular comorbidity (new onset diabetes after transplantation (NODAT), hyperlipidemias [total serum cholesterol, HDL, LDL, triglycerides], hypertension, number of anti-hypertensive medications)
    5. Patient weight change and BMI from pre-transplant
    6. Change in Framingham Heart Study Coronary Score Heart Disease Risk Point Total
    7. Cardiovascular events (myocardial infarction, angina, cerebral vascular accident, transient ischemic attack, cardiovascular intervention/procedure or sudden death)
    8. Incidence of infections and posttransplant malignancies (including PTLD)
    9. Incidence of leukopenia ( White Blood Cell Count < 2000 cells/uL)
    10. Incidence of anemia (Hg < 7 g/dL)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male and female patients > 18 years of age.
  2. Patient who is receiving a renal transplant from a living or deceased donor.
  3. Female patients of child bearing potential must have a negative urine or serum pregnancy test within the past 48 hours prior to study inclusion.
  4. The patient has given written informed consent to participate in the study.

Exclusion Criteria:

  1. Patient has previously received an organ transplant other than a kidney.
  2. Patient is receiving an HLA identical living donor transplant.
  3. Patient who is a recipient of a multiple organ transplant.
  4. Patient has a most recent cytotoxic panel reactive antibody (PRA) of >25% or calculated PRA of > 50% where multiple moderate level HLA antibodies exist and in the opinion of the PI represents substantial HLA sensitization.
  5. Patient with a positive T or B cell crossmatch that is primarily due to HLA antibodies.
  6. Patient with a donor specific antibody (DSA) as deemed by the local PI to be associated with significant risk of rejection.
  7. Patient has received an ABO incompatible donor kidney.
  8. The donor and/or donor kidney meet any of the following extended criteria for organ donation (ECD):

    • Donor age >/= 60 years OR
    • Donor age 50-59 years and 1 of the following:

      • Cerebrovascular accident (CVA) + hypertension + serum creatinine (SCr) > 1.5 mg/dL OR
      • CVA + hypertension OR
      • CVA + SCr > 1.5 mg/dL OR
      • Hypertension + SCr > 1.5 mg/dL OR
    • Cold ischemia time (CIT) > 24 hours, donor age > 10 years OR
    • Donation after cardiac death (DCD)
  9. Recipients will be receiving a dual or en bloc kidney transplant.
  10. Donor anticipated cold ischemia is > 30 hours.
  11. Recipient that is seropositive for hepatitis C virus (HCV) with detectable Hepatitis C viral load are excluded. HCV seropositive patients with a negative HCV viral load testing may be included.
  12. Recipients who are Hepatitis B core antibody seropositive are eligible if their hepatitis B viral loads are negative. After transplant, their hepatitis B viral loads will be monitored every three months for the first year after transplant. If hepatitis B viral loads become positive, patients will be treated per institutional standard of care.
  13. Patients who are Hepatitis B surface antibody seropositive and who receive a kidney from a Hepatitis B core surface antibody positive donor may be included.
  14. Recipient or donor is known to be seropositive for human immunodeficiency virus (HIV).
  15. Recipient who is seronegative for Epstein Barr virus (EBV).
  16. Patient has uncontrolled concomitant infection or any other unstable medical condition that could interfere with the study objectives.
  17. Patients with thrombocytopenia (PLT < 75,000/mm3), and/or leucopoenia (WBC < 2,000/mm3), or anemia (hemoglobin < 6 g/dL) prior to study inclusion.
  18. Patient is taking or has been taking an investigational drug in the 30 days prior to transplant.
  19. Patient who has undergone desensitization therapy within 6 months prior to transplant.
  20. Patient has a known hypersensitivity to belatacept, tacrolimus, mycophenolate mofetil, alemtuzumab, rabbit anti-thymocyte globulin, or glucocorticoids.
  21. Patient is receiving chronic steroid therapy at the time of transplant.
  22. Patients with a history of cancer (other than non-melanoma skin cell cancers cured by local resection) within the last 5 years, unless they have an expected disease free survival of > 95%.
  23. Patient is pregnant, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by positive human Chorionic Gonadotropin (hCG) laboratory test.
  24. Women of childbearing potential must use reliable contraception simultaneously, unless they are status post bilateral tubal ligation, bilateral oophorectomy, or hysterectomy.
  25. Patient has any form of substance abuse, psychiatric disorder or a condition that, in the opinion of the investigator, may invalidate communication with the investigator.
  26. Inability to cooperate or communicate with the investigator.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01729494


Locations
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United States, California
California Pacific Medical Center
San Francisco, California, United States, 94107
United States, Colorado
University of Colorado Denver
Denver, Colorado, United States, 80045
United States, Florida
Tampa General Hospital
Tampa, Florida, United States, 33606
United States, Illinois
University of Illinois Medical Center at Chicago
Chicago, Illinois, United States, 60612
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Ohio
The Christ Hospital
Cincinnati, Ohio, United States, 45219
University of Cincinnati
Cincinnati, Ohio, United States, 45219
United States, Wisconsin
University of Wisconsin-Madison
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
University of Cincinnati
Investigators
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Principal Investigator: E. Steve Woodle, MD University of Cincinnati

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Responsible Party: E. Steve Woodle, MD, FACS, University of Cincinnati
ClinicalTrials.gov Identifier: NCT01729494     History of Changes
Other Study ID Numbers: BEST
First Posted: November 20, 2012    Key Record Dates
Last Update Posted: February 1, 2018
Last Verified: January 2018

Keywords provided by E. Steve Woodle, University of Cincinnati:
belatacept
rabbit antithymocyte globulin
alemtuzumab
corticosteroid withdrawal

Additional relevant MeSH terms:
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Tacrolimus
Thymoglobulin
Antilymphocyte Serum
Abatacept
Mycophenolic Acid
Alemtuzumab
Methylprednisolone
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Immunological