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Immune Monitoring and CNI Withdrawal in Low Risk Recipients of Kidney Transplantation

This study has been terminated.
(Absence of equipoise on the basis of predetermined stopping rules.)
Sponsor:
Collaborator:
Clinical Trials in Organ Transplantation
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01517984
First received: January 20, 2012
Last updated: October 7, 2016
Last verified: October 2016
  Purpose
The study will compare how well transplanted kidneys work and the response of people's immune systems as tacrolimus, a calcineurin inhibitor (CNI), is withdrawn. In addition, this research study will evaluate whether reducing immunosuppression can decrease some of these side effects while still preventing rejection of the kidney.

Condition Intervention Phase
Kidney Transplant Recipients
Drug: Tacrolimus (CNI) Withdrawal
Drug: Standard Immunosuppressive Therapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Immune Monitoring and Calcineurin Inhibitor (CNI) Withdrawal in Low Risk Recipients of Kidney Transplantation

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Percentage of Participants With Incremental IF/A Scores >2 at 24 Months Post-Randomization [ Time Frame: IF/TA scores on protocol biopsies obtained at 24 months post-randomization will be compared to those obtained at the time of implantation for this measurement. ] [ Designated as safety issue: No ]
    The investigators were not able to assess this outcome, the effect of the intervention on interstitial fibrosis/tubular atrophy (IF/TA; on a 2-year graft biopsy) due to the study's premature termination by the Data Safety Monitoring Board (DSMB) because of absence of equipoise on the basis of predetermined stopping rules.


Secondary Outcome Measures:
  • Estimated GFR Using the Chronic Kidney Disease Epidemiology (CKD-EPI) Equation [ Time Frame: 6 months post-transplantation, 24 months post-transplantation ] [ Designated as safety issue: No ]
    Estimated glomerular filtration rate (eGFR) is a test to measure the level of kidney function. In this measure, the effects of tacrolimus withdrawal on long-term kidney function was assessed by comparing absolute 24 month eGFR (18 months post-randomization) and change in eGFR from 6 to 24 months (randomization to 18 months randomization). Lower numbers indicate poorer kidney function

  • Incidence of Acute Rejection [ Time Frame: 6 to 18 months post-randomization ] [ Designated as safety issue: Yes ]
    Acute renal allograft rejection is defined as histological reading of borderline or greater determined by the local pathology laboratory. Participants suspected of having a rejection episode on the basis of clinical signs, symptoms, or on the basis of laboratory tests, had a renal ultrasound and underwent a renal transplant biopsy. Any detection of acute cellular rejection or acute humoral rejection resulted in participants in the 'Randomized to Tacrolimus Withdrawal' group to be restarted on tacrolimus and followed per the reduced follow-up schedule of events.

  • Allograft Survival Rate [ Time Frame: 6 to 18 months post-randomization ] [ Designated as safety issue: Yes ]
    Allograft survival is defined as participants who did not need to be re-transplanted or placed on dialysis due to the failure of their allograft transplantation during the course of this study.

  • Participant Survival Rate [ Time Frame: 6 to 18 months post-transplantation ] [ Designated as safety issue: Yes ]
    Number of participants who did not die within the course of this study.

  • Percentage of Participants With New Donor Specific Antibodies (DSAs) [ Time Frame: 6 to 18 months post-randomization ] [ Designated as safety issue: No ]
    Donor specific antibodies are antibodies that are directed against antigens expressed on donor organs. These antibodies can result in an immune attack on the transplanted organ, increasing risk of graft loss and/or rejection.

  • Percentage of Participants With Donor-Specific Memory Using Elispot [ Time Frame: 6 to 18 months post-randomization ] [ Designated as safety issue: No ]
    This endpoint was unable to be analyzed because the study was terminated early after stopping rules were met.

  • Percentage of Participants in the Experimental Arm Off Tacrolimus [ Time Frame: 18 months post-randomization ] [ Designated as safety issue: No ]
    Participants in the 'Randomized to Tacrolimus Withdrawal' group were considered fully withdrawn once they no longer received any doses of tacrolimus. Participants met this endpoint if they did not resume taking tacrolimus as of 18 months post randomization with stable allograft function and without rejection of donor-specific antibodies.

  • Incremental Change in IF/TA Scores [ Time Frame: 6 to 18 months post-transplant ] [ Designated as safety issue: No ]
    This endpoint was unable to be analyzed because the study was terminated early after stopping rules were met.

  • Measurement of Urinary Parameters Before and After Randomization [ Time Frame: 6 months post-transplantation to 18 months post-randomization ] [ Designated as safety issue: No ]
    This endpoint was unable to be analyzed because the study was terminated early after stopping rules were met.


Enrollment: 52
Study Start Date: November 2010
Study Completion Date: May 2015
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tacrolimus (CNI) Withdrawal

Subjects randomized (2:1) to tacrolimus (CNI) withdrawal.

Recipients of living-donor kidney allografts are given induction therapy with rabbit antithymocyte globulin (RATG, Thymoglobulin®) and treated with a standard immunosuppressive regimen of mycophenolate mofetil (MMF), prednisone and tacrolimus.Subjects without any clinical acute rejection (AR) in the first 6 months, without borderline or acute rejection on the 6 month biopsy, and without donor-specific antibody (DSA) at anytime, including the 6 month test are randomized (2:1) to tacrolimus (CNI) withdrawal.

Drug: Tacrolimus (CNI) Withdrawal

Recipients of living-donor kidney allografts are given induction therapy with rabbit antithymocyte globulin (RATG, Thymoglobulin®) and treated with a regimen of mycophenolate mofetil (MMF), prednisone and tacrolimus.

Subjects without any clinical acute rejection (AR) in the first 6 months, without borderline or acute rejection on the 6 month biopsy, and without donor-specific antibody (DSA) at anytime, including the 6 month test will be randomized (2:1) to tacrolimus (CNI) withdrawal.

Other Names:
  • ATG Induction,Tacrolimus (CNI), MMF and Prednisone, Followed by CNI Withdrawal
  • rabbit antithymocyte globulin (RATG)
  • Thymoglobulin®
  • calcineurin inhibitor (CNI)
  • mycophenolate mofetil
  • CellCept®
Drug: Standard Immunosuppressive Therapy
Recipients of living-donor kidney allografts are given induction therapy with rabbit antithymocyte globulin (RATG, Thymoglobulin®) and treated with a regimen of mycophenolate mofetil (MMF), prednisone and tacrolimus.
Other Names:
  • ATG induction,Tacrolimus (CNI), MMF and Prednisone
  • rabbit antithymocyte globulin (RATG)
  • Thymoglobulin®
  • calcineurin inhibitor (CNI)
  • mycophenolate mofetil
  • CellCept®
Active Comparator: Standard Immunosuppressive Therapy

Subjects randomized to standard immunosuppressive therapy, without subsequent tacrolimus (CNI) withdrawal.

Recipients of living-donor kidney allografts are given induction therapy with rabbit antithymocyte globulin (RATG, Thymoglobulin®) and treated with a standard immunosuppressive regimen of mycophenolate mofetil (MMF), prednisone and tacrolimus. Tacrolimus (CNI) withdrawal does not occur.

Drug: Standard Immunosuppressive Therapy
Recipients of living-donor kidney allografts are given induction therapy with rabbit antithymocyte globulin (RATG, Thymoglobulin®) and treated with a regimen of mycophenolate mofetil (MMF), prednisone and tacrolimus.
Other Names:
  • ATG induction,Tacrolimus (CNI), MMF and Prednisone
  • rabbit antithymocyte globulin (RATG)
  • Thymoglobulin®
  • calcineurin inhibitor (CNI)
  • mycophenolate mofetil
  • CellCept®

Detailed Description:
Kidney transplantation is a treatment option for people with kidney disease. However, there is still much to learn about how to best care for the transplanted kidney and keep it functioning for a long time. Transplant recipients take immunosuppression (anti-rejection) drugs to prevent their body from rejecting the new kidney. These drugs are used to prevent the immune system from attacking the transplanted kidney. All anti-rejection medications have unwanted side effects. The purpose of this study is to evaluate the safety of slowly removing tacrolimus, a CNI.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA -

Initial Enrollment/Screening: Patients who meet all of the following criteria are eligible for enrollment as study subjects:

  • Subject must be able to understand and provide written informed consent;
  • Primary living-donor (related or unrelated) kidney transplant recipients;
  • Peak flow-based PRAs for class I and class II <30%(performed by local center);
  • Current (within 8 weeks prior to transplantation) flow-based PRAs for class I and class II <30% (performed by local center);
  • No donor specific antibody by flow solid phase method on the peak PRA serum (if serum available), or on the current PRA serum (within 8 weeks prior to transplantation) performed by central core laboratory. If the sera for the peak PRA is not available, then only the current PRA serum will be tested;
  • Negative T-cell and B-cell crossmatch by flow cytometry (performed by local center);
  • Female subjects of childbearing potential must have a negative pregnancy test (urine or serum) upon study entry;
  • Female and male subjects with reproductive potential must agree to use FDA approved methods of birth control while participating in the study.

Inclusion Criteria for Randomization:

Participants who meet all of the following criteria are eligible for randomization:

  • No history of acute rejection episodes;
  • The pre-randomization protocol biopsy should confirm no rejection, including borderline rejection (based on the central pathology read);
  • No donor specific antibody as detected by flow solid phase method (performed by the central core laboratory).

EXCLUSION CRITERIA -

Initial Enrollment/Screening:

Participants who meet any of these criteria are not eligible for enrollment as study subjects:

  • Recipient of multiple organ transplants;
  • Prior history of organ transplantation;
  • Deceased-donor source;
  • Any condition that would preclude protocol biopsies;
  • HLA identical recipients;
  • Currently breast-feeding or plans to become pregnant during the timeframe of the study follow up period;
  • Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements;
  • Inability or unwillingness to comply with study protocol;
  • Use of investigational drugs within 4 weeks of study entry and for the duration of the study;
  • Recent recipient of any licensed or investigational live attenuated vaccine(s) within two months of prior to study entry.

Exclusion Criteria for Randomization:

Participants who meet any of these criteria are not eligible for randomization:

  • Subjects who receive less than 4.5mg/kg of Rabbit ATG (Thymoglobulin®) induction therapy;
  • Subjects who test positive for BKV by PCR in the blood at 6 months post-transplant;
  • Any condition that would preclude protocol biopsies;
  • Currently breast-feeding or plans to become pregnant during the timeframe of the study follow up period;
  • Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements;
  • Inability or unwillingness of a subject to give written informed consent or comply with study protocol;
  • Use of investigational drugs within 4 weeks of study entry and for the duration of the study;
  • Subjects who receive less than 1500 mg daily of Mycophenolate Mofetil (CellCept®) or equivalent.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01517984

Locations
United States, California
University of California Los Angeles
Los Angeles, California, United States, 90055
United States, Connecticut
Yale University School of Medicine
New Haven, Connecticut, United States, 06520-8029
United States, Massachusetts
Brigham & Women's Hospital
Boston, Massachusetts, United States, 02115
United States, Michigan
University of Michigan Hospital
Ann arbor, Michigan, United States, 48109
United States, Missouri
Washington University
St. Louis, Missouri, United States, 63110
United States, New York
Mount Sinai School of Medicine
New York, New York, United States, 10029
United States, Ohio
University Hospitals of Cleveland
Cleveland, Ohio, United States, 44106-5048
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
United States, Texas
The Methodist Hospital
Houston, Texas, United States, 77030
Canada, Manitoba
Health Sciences Centre
Winnipeg, Manitoba, Canada, R3A IR9
Canada, Ontario
Toronto General Hospital
Toronto, Ontario, Canada, M5G 2M1
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Trials in Organ Transplantation
Investigators
Study Chair: Donald Hricik, MD University Hospitals Cleveland Medical Center
Principal Investigator: Peter S. Heeger, MD Icahn School of Medicine at Mount Sinai
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01517984     History of Changes
Other Study ID Numbers: DAIT CTOT-09 
Study First Received: January 20, 2012
Results First Received: June 16, 2016
Last Updated: October 7, 2016
Health Authority: United States: Federal Government
United States: Data and Safety Monitoring Board
United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
recipients of living-donor kidney allografts
antithymocyte globulin (ATG) induction
calcineurin inhibitors (CNIs)
CNI withdrawal

Additional relevant MeSH terms:
Prednisone
Mycophenolic Acid
Tacrolimus
Mycophenolate mofetil
Immunosuppressive Agents
Antilymphocyte Serum
Calcineurin Inhibitors
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunologic Factors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic

ClinicalTrials.gov processed this record on December 02, 2016