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: September 11, 2015
Last verified: September 2015
  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transplanted kidneys work and the response of people's immune systems as tacrolimus, a calcineurin inhibitor (CNI), is withdrawn.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 18 Months Post-Randomization [ Time Frame: IF/TA scores on protocol biopsies obtained at 18 months postrandomization will be compared to those obtained at the time of implantation for this measurement. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Estimated GFR Using the Chronic Kidney Disease Epidemiology (CKD-EPI) Equation [ Time Frame: 6 to 18 months post-randomization ] [ Designated as safety issue: Yes ]
  • Incidence of Acute Rejection [ Time Frame: 6 to 18 months post-randomization ] [ Designated as safety issue: Yes ]
  • Allograft Survival Rate [ Time Frame: 6 to 18 months post-randomization ] [ Designated as safety issue: Yes ]
  • Participant Survival Rate [ Time Frame: 6 to 18 months post-transplantation ] [ Designated as safety issue: Yes ]
  • Percentage of Participants with New Donor Specific Antibodies (DSAs) [ Time Frame: 6 to 18 months post-randomization ] [ Designated as safety issue: Yes ]
  • Percentage of Participants with Donor-Specific Memory Using Elispot [ Time Frame: 6 to 18 months post-randomization ] [ Designated as safety issue: Yes ]
  • Percentage of Participants in the Experimental Arm Off Tacrolimus [ Time Frame: 6 to 18 months post-randomization ] [ Designated as safety issue: Yes ]
  • Incremental Change in IF/TA Scores [ Time Frame: 6 to 18 months post-transplant ] [ Designated as safety issue: Yes ]
  • Measurement of Urinary Parameters Before and After Randomization [ Time Frame: 6 months post-transplant to 18 months post-randomization ] [ Designated as safety issue: Yes ]
    Urinary chemokines and gene expression)


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.

POST STUDY TERMINATION NOTE: Although the investigators were unable to assess the primary study end point due to early study termination,this trial supports the conclusion that risks associated with acute rejection and donor-specific antibodies outweigh any potential benefits of tacrolimus withdrawal, even in this highly selected, low-risk cohort of living donor recipients treated with antithymocyte globulin induction.

  Eligibility

Ages Eligible for Study:   18 Years and older
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 Hospital Case 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
Last Updated: September 11, 2015
Health Authority: United States: Federal Government
United States: Institutional Review Board
United States: Data and Safety Monitoring 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:
Antilymphocyte Serum
Immunosuppressive Agents
Mycophenolate mofetil
Mycophenolic Acid
Prednisone
Tacrolimus
Anti-Inflammatory Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Enzyme Inhibitors
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on February 09, 2016