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Belatacept With Early Steroid Withdrawal rATG and Everolimus in Renal Transplantation (BETTER Trial) (BETTER)

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ClinicalTrials.gov Identifier: NCT04849533
Recruitment Status : Recruiting
First Posted : April 19, 2021
Last Update Posted : April 19, 2021
Sponsor:
Information provided by (Responsible Party):
Rita Alloway, University of Cincinnati

Tracking Information
First Submitted Date  ICMJE June 29, 2020
First Posted Date  ICMJE April 19, 2021
Last Update Posted Date April 19, 2021
Actual Study Start Date  ICMJE April 9, 2021
Estimated Primary Completion Date July 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 14, 2021)
Composite endpoint of patient death, graft loss, or eGFR (MDRD) < 45ml/min mL/min/1.73m2 [ Time Frame: 12 months ]
Number of subjects with composite endpoint of either patient death, graft loss, or eGFR (MDRD) < 45 mL/min/1.73m2 at Month 12 post-transplantation compared to historical controls of the BEST Trial (groups B and C).
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: April 14, 2021)
  • Incidence of Biopsy-proven acute rejection (BPAR) by Banff 2007 criteria stratified by type (ACR, AMR, or Mixed rejection) [ Time Frame: 12 and 24 months ]
    To evaluate, by treatment group at 12 and 24 months incidence of various rejection types
  • Incidence of graft survival censored by patients who died with functioning graft [ Time Frame: 12 and 24 months ]
    Incidence of death-censored graft survival not including any patients who died with their graft still functioning
  • # of Patients with eGFR (MDRD) < 30 mL/min/1.73m2 [ Time Frame: 12 and 24 months ]
    # of subjects with eGFR (MDRD) < 30 mL/min/1.73m2
  • # Patients with development of de novo donor specific antibody (DSA) [ Time Frame: 12 and 24 months ]
    Patients with development of de novo donor specific antibody (DSA) after transplant
  • Composite endpoint of patient death, graft loss, or estimated eGFR (MDRD) < 45 mL/min/1.73m2 at Month 24 post-transplantation [ Time Frame: 24 months ]
    Composite endpoint of patients with either death, graft loss, or estimated eGFR (MDRD) < 45 mL/min/1.73m2 at Month 24 post-transplantation
  • # Patients with Incidence of Infections [ Time Frame: 12 and 24 months ]
    Incidence of infections, including CMV and BK virus
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Belatacept With Early Steroid Withdrawal rATG and Everolimus in Renal Transplantation (BETTER Trial)
Official Title  ICMJE A Randomized, Multicenter Study of Belatacept, Everolimus, rATG and Early Steroid Withdrawal Versus Belatacept, Mycophenolate, rATG and Chronic Steroids in Renal Transplantation
Brief Summary

This study is designed to determine the safety and efficacy of two calcineurin inhibitor free treatment groups 1) a belatacept, everolimus and early corticosteroid withdrawal (ECSWD) immunosuppressive regimen with rabbit antithymocyte globulin induction (rATG) and 2) a belatacept, mycophenolate, chronic steroid regimen with rATG and compare to historical controls of tacrolimus-based and belatacept-based regimens in combination with rATG induction, mycophenolate, and ESWD in renal transplant recipients.

The purpose is to evaluate the effect of 2 regimens (rATG induction/belatacept/everolimus/ESWD and rATG induction/belatacept/mycophenolate/CS) on the composite of patient death, graft loss, or eGFR (MDRD) < 45 mL/min/1.73m2 at Month 12 post-transplantation compared to historical controls of the BEST Trial (groups B and C).

Detailed Description

The BETTER trial is designed to determine the safety and efficacy of two calcineurin inhibitor free treatment groups 1) a belatacept, everolimus and early corticosteroid withdrawal (ESWD) immunosuppressive regimen with rabbit antithymocyte globulin induction (rATG) and 2) a belatacept, mycophenolate, chronic steroid regimen with rATG and compare to historical controls of tacrolimus-based and belatacept-based regimens in combination with rATG induction, mycophenolate, and ESWD in renal transplant recipients.

Study Hypotheses

  1. A belatacept-based immunosuppressive regimen with rATG induction, everolimus and ESWD in renal transplant recipients will lead to less risk of graft loss, patient death, or eGFR <45ml/min/1.73m2 at 12 and 24 months as compared to a tacrolimus-based immunosuppressive regimen with rATG, mycophenolate, and ESWD in renal transplant recipients (historical control from the BEST Trial-Group C).
  2. A belatacept-based immunosuppressive regimen with rATG induction, everolimus and ESWD in renal transplant recipients will lead to less risk of graft loss, patient death, or eGFR <45ml/min/1.73m2 at 12 and 24 months as compared to a belatacept-based immunosuppressive regimen with rATG and mycophenolate, and ESWD in renal transplant recipients (historical control from the BEST Trial-Group B).
  3. A belatacept-based immunosuppressive regimen with rATG, mycophenolate and CS in renal transplant recipients will lead to less risk of graft loss, patient death, or eGFR <45ml/min/1.73m2 at 12 and 24 months as compared to a tacrolimus-based immunosuppressive regimen with rATG, mycophenolate, and ESWD in renal transplant recipients (historical control from the BEST Trial-Group C).
  4. A belatacept-based immunosuppressive regimen with rATG induction, mycophenolate and CS in renal transplant recipients will lead to less risk of graft loss, patient death, or eGFR <45ml/min/1.73m2 at 12 and 24 months as compared to a belatacept-based immunosuppressive regimen with rATG, mycophenolate, and ESWD in renal transplant recipients (historical control from the BEST Trial-Group B).

A controlled, randomized group study is accepted in renal transplantation to evaluate new immunosuppressive regimens versus the current standard of care. Although the ideal study would employ a blinded methodology with a simultaneous control group to minimize bias, the study will not be blinded and evaluates a historical control groups conducted in similar centers.

To allow comparison between studies, the primary composite endpoint of death, graft loss, or eGFR <45ml/min/1.73m2 will be analyzed similarly. The secondary and tertiary endpoints are the similar as well.

The BETTER study proposes to compare two additional treatment groups of rATG/belatacept/everolimus/ESWD (Group D) and rATG/belatacept/mycophenolate/CS (Group E) to the historical control Groups B and C.

All immunosuppressive agents are approved by the FDA for the prophylaxis of renal transplant rejection, and will be dosed and administered consistent with current clinical practice.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Kidney Transplant Rejection
Intervention  ICMJE
  • Drug: Belatacept
    belatacept with everolimus is experimental regimen and it is compared to the labeled regimen of belatacept with mycophenolate with steroids for prevention of rejection in renal transplant recipients
    Other Name: Nulojix
  • Drug: Everolimus
    belatacept with everolimus is experimental regimen and it is compared to the labeled regimen of belatacept with mycophenolate with steroids for prevention of rejection in renal transplant recipients
    Other Name: Zortress
  • Drug: mycophenolate mofetil
    belatacept with mycophenolate is approved regimen for prevention of rejection
    Other Name: Cellcept
  • Drug: corticosteroids
    belatacept with chronic steroids is approved regimen for prevention of rejection
    Other Name: Prednisone
  • Drug: rabbit antithymocyte globulin
    rabbit antithymocyte globulin induction for prevention of rejection
    Other Name: rATG, thymoglobulin
Study Arms  ICMJE
  • Experimental: Group D Bela/EVR
    rATG induction/belatacept/everolimus/early steroid withdrawal rATG 1.5mg/kg IV X 4 doses over 10 days belatacept 10mg/kg IV X 1 on POD 1, POD 5, weeks 2, 4, 8, and 12 then 5mg/kg IV X 1 on week 16 and then every 4 weeks thereafter Steroid taper x 5 days (500mg IV, 250mg IV, 125mg IV, 80mg po, 60mg po) Everolimus started within 24hours at 2mg BID and dosed to level 3-8ng/ml
    Interventions:
    • Drug: Belatacept
    • Drug: Everolimus
    • Drug: rabbit antithymocyte globulin
  • Active Comparator: Group E Bela/MMF
    rATG induction/belatacept/mycophenolate/chronic steroidsrATG 1.5mg/kg IV X 4 doses over 10 days belatacept 10mg/kg IV X 1 on POD 1, POD 5, weeks 2, 4, 8, and 12 then 5mg/kg IV X 1 on week 16 and then every 4 weeks thereafter Steroid taper x 5 days (500mg IV, 250mg IV, 125mg IV, 80mg po, 60mg po) and then 5mg po daily thereafter MMF 1gm BID started pre-op and then continued throughout study
    Interventions:
    • Drug: Belatacept
    • Drug: mycophenolate mofetil
    • Drug: corticosteroids
    • Drug: rabbit antithymocyte globulin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 14, 2021)
120
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2024
Estimated Primary Completion Date July 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria

  1. Male and female patients ≥ 18 years of age.
  2. Patient who is receiving a renal transplant from a living or heart-beating 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 PRA of >25% or calculated PRA >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 PI to be associated with significant risk of rejection.
  7. Patient has received an ABO incompatible donor kidney.
  8. The deceased donor and/or deceased donor kidney meet any of the following extended criteria for organ donation (ECD):

    1. Donor age ≥ 60 years OR
    2. Donor age 50-59 years and 1 of the following:

    i. Cerebrovascular accident (CVA) + hypertension + SCr > 1.5 mg/dL OR ii. CVA + hypertension OR iii. CVA + SCr > 1.5 mg/dL OR iv. Hypertension + SCr > 1.5 mg/dL OR c. CIT ≥ 24 hours, donor age > 10 years OR d. 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 receiving a kidney from a donor with HCV viremia (detected through nucleic acid testing or other means)
  13. Recipients with a positive hepatitis B viral load or positive hepatitis B surface antigen testing within 1 year of consent.
  14. Hepatitis B surface antibody negative recipients receiving a kidney from a donor seropositive for hepatitis B core antibody or hepatitis B nucleic acid.
  15. Recipient or donor is known to be seropositive for human immunodeficiency virus (HIV).
  16. Recipient who is seronegative for Epstein Barr Virus (EBV)
  17. Patient has uncontrolled concomitant infection or any other unstable medical condition that could interfere with the study objectives.
  18. Patients with thrombocytopenia (PLT <75,000/mm3), and/or leukopenia (WBC < 2,000/mm3), or anemia (hemoglobin < 6 g/dL) prior to study inclusion.
  19. Patient is taking or has been taking an investigational drug in the 30 days prior to transplant.
  20. Patient who has undergone desensitization therapy within 6 months prior to transplant.
  21. Patient has a known hypersensitivity to belatacept, tacrolimus, mycophenolate mofetil/mycophenolic acid, everolimus, rabbit anti-thymocyte globulin, or glucocorticoids.
  22. Patient is receiving chronic steroid therapy at the time of transplant.
  23. 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%.
  24. 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.
  25. Women of childbearing potential must use reliable contraception simultaneously, unless they are status post bilateral tubal ligation, bilateral oophorectomy, or hysterectomy.
  26. 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.
  27. Inability to cooperate or communicate with the investigator.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rita R Alloway, PharmD 5135581568 rita.alloway@uc.edu
Contact: Adele R Shields, PharmD 5135852145 adele.rike@uc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04849533
Other Study ID Numbers  ICMJE IM103-423
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Rita Alloway, University of Cincinnati
Study Sponsor  ICMJE University of Cincinnati
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Rita R Alloway, PharmD University of Cincinnati
PRS Account University of Cincinnati
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP