Improved Induction and Maintenance Immunosuppression in Kidney Transplantation

August 30, 2023 updated by: University of Nebraska

Prospective, Randomized 2 x 2 Factorial Trial of Rabbit Anti-thymocyte Globulin Induction (Single vs. Alternate Day Administration) at Renal Transplantation, With Delayed Calcineurin-inhibitor Withdrawal vs. Minimization

This 2 x 2 sequential factorial study evaluates two potential improvements to the standard immunosuppression regimen used at the investigators' institution to prevent rejection of transplanted kidneys. These two potential improvements are each applied in sequence to half of the study patients, creating 4 study arms; the other half receive the standard treatment. The two potential improvements are:

  1. Administering the immunosuppression induction agent rATG ("rabbit anti-thymocyte globulin") in a single dose at the time of transplantation, instead of in the usual series of 4 smaller doses over 6 days.
  2. After 6 months, modifying the maintenance immunosuppression used to prevent rejection by replacing the drug tacrolimus with mycophenolate mofetil (MMF).

The two interventions, spaced sequentially six months apart, enable independent analysis of the two treatments so long as it can be shown that there is no synergistic interaction between them.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The two treatment innovations in this study of immunosuppression in kidney transplantation are aimed at making the transplanted kidney function sooner and last longer than is usual with standard immunosuppression regimens, but without increasing the likelihood of rejection.

The first innovation, delivering the induction agent rATG in a single large dose rather than as a series of smaller doses over 6-8 days, is expected to produce better graft function right away, possibly by reducing some of the injury to the kidney that accompanies the restoration of blood flow during transplantation ("reperfusion injury"). Some evidence has been developed by investigators elsewhere to suggest this will happen.

The second innovation, replacing tacrolimus with MMF after 6 months, is intended to eliminate a well-established major cause of ongoing toxic damage to the kidney. While tacrolimus does a good job of preventing rejection, the cost in continuing toxic injury to the kidney is high, leading inevitably to eventual graft failure, the inability of the transplanted kidney to continue filtering the blood and making adequate volumes of high-quality urine.

Study Type

Interventional

Enrollment (Actual)

180

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Nebraska
      • Omaha, Nebraska, United States, 68198
        • Unversity of Nebraska Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Primary renal transplant recipient for end-stage renal disease

Exclusion Criteria:

  • Recipient age < 18 years or > 65 years
  • Previous history of CMV disease
  • Hepatitis B and C recipients
  • Primary disease states that require steroids for immunosuppression
  • Re-transplant with immunological cause of renal or pancreas loss
  • Non heart beating donors
  • Recipient of pediatric en bloc kidneys
  • Recipient with a Panel Reactive Antibody (PRA) score >75%
  • Patients who have received 3 or more prior transplants, excluding pancreas
  • Patients who are past recipients of other solid organ transplants
  • Previous history of BK virus
  • Previous treatment with Thymoglobulin
  • Allergy to rabbits
  • Simultaneous Kidney/Pancreas transplantation

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Group 1
Kidney transplant recipients given a single large dose of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression.
Drug: sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
Other Names:
  • Rapamune, rapamycin
Drug: tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Other Names:
  • FK506
  • ProGraf
Drug: rabbit anti-thymocyte globulin - single dose
A single 6 mg/kg dose of rATG administered intravenously over 24 hours, beginning before kidney transplantation. Administration of the drug is begun as early as practical, usually after general anesthesia has been established but before surgery has started. The rATG is therefore administered for about two hours before blood flow is restored to the kidney undergoing transplantation.
Other Names:
  • Thymoglobulin
  • rATG
Experimental: Group 2
Kidney transplant recipients given 4 small doses of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression.
Drug: sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
Other Names:
  • Rapamune, rapamycin
Drug: tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Other Names:
  • FK506
  • ProGraf
Drug: rabbit anti-thymocyte globulin - 4 doses
6 mg/kg rabbit anti-thymocyte globulin delivered in 4 doses of 1.5 mg/kg each, the first administered at the time of kidney transplantation. Subsequent doses are administered on days 2, 4, and 6.
Other Names:
  • Thymoglobulin
Experimental: Group 3
Kidney transplant recipients given a single large dose of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression until tacrolimus is replaced with mycophenolate mofetil after about 6 months.
Drug: sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
Other Names:
  • Rapamune, rapamycin
Drug: tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Other Names:
  • FK506
  • ProGraf
Drug: mycophenolate mofetil
Patients are switched approximately 6 months after kidney transplantation from maintenance immunosuppression with tacrolimus and sirolimus to maintenance with mycophenolate mofetil and sirolimus. The drug is administered orally, taken daily, with dose adjusted in proportion to measured blood levels, and is required indefinitely to prevent rejection of the transplanted kidney.
Other Names:
  • CellCept
  • Myfortic
  • MMF
  • mycophenolic acid
Drug: rabbit anti-thymocyte globulin - single dose
A single 6 mg/kg dose of rATG administered intravenously over 24 hours, beginning before kidney transplantation. Administration of the drug is begun as early as practical, usually after general anesthesia has been established but before surgery has started. The rATG is therefore administered for about two hours before blood flow is restored to the kidney undergoing transplantation.
Other Names:
  • Thymoglobulin
  • rATG
Experimental: Group 4
Kidney transplant recipients given 4 small doses of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression until tacrolimus is replaced with mycophenolate mofetil after about 6 months.
Drug: sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
Other Names:
  • Rapamune, rapamycin
Drug: tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Other Names:
  • FK506
  • ProGraf
Drug: mycophenolate mofetil
Patients are switched approximately 6 months after kidney transplantation from maintenance immunosuppression with tacrolimus and sirolimus to maintenance with mycophenolate mofetil and sirolimus. The drug is administered orally, taken daily, with dose adjusted in proportion to measured blood levels, and is required indefinitely to prevent rejection of the transplanted kidney.
Other Names:
  • CellCept
  • Myfortic
  • MMF
  • mycophenolic acid
Drug: rabbit anti-thymocyte globulin - 4 doses
6 mg/kg rabbit anti-thymocyte globulin delivered in 4 doses of 1.5 mg/kg each, the first administered at the time of kidney transplantation. Subsequent doses are administered on days 2, 4, and 6.
Other Names:
  • Thymoglobulin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria).
Time Frame: Two years
Protocol kidney biopsies collected at approximately 12 and 24 months were scored by a transplant renal pathologist blinded to treatment group assignment for evidence of rejection, BK virus nephropathy, antibody-mediated rejection, recurrent disease, inflammation, and Banff 2005 categories of chronic renal injury. Chronic injury categories were arteriolar hyaline thickening (ah), allograft glomerulopathy (cg), interstitial fibrosis (ci), tubular atrophy (ct), and vascular fibrous intimal thickening (cv). Severity scores within each category could be 0 (<5%; none or minimal), 1 (>5% - <25%; mild), 2 (>25% - <50%, moderate), or 3 (>50%, severe). The proportions of patients in each severity grade (0, 1, 2, and 3) for both the individual categories and a composite were compared using Fisher's exact test.
Two years
Average of Renal Function
Time Frame: Two years
Calculated Glomerular Filtration Rate (GFR) by using the abbreviated MDRD (aMDRD) formula and patient serum creatinine and demographic data; averaged values from months four through 24.
Two years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety Profile
Time Frame: Two years
Number of events: cytomegalovirus (CMV) disease, opportunistic infections (bacteremia, abscess, pneumonia, fungal), Post-transplantation Lymphoproliferative Disorder (PTLD), wound healing problems within 30 days, and lymphoceles.
Two years
Requirement for Additional Immunosuppression (Such as Corticosteroids, Antimetabolites or Other Immunosuppressive Agents)
Time Frame: Two years
Two years
Acute Rejection Per Kidney Biopsy (Banff Grading Criteria)
Time Frame: Two years
Two years
Acute Tubular Necrosis (ATN) Rate, Defined as the Requirement for Dialysis Within 7 Days Post-transplantation.
Time Frame: Seven days
Seven days
Graft Survival
Time Frame: Two years
Graft failure = permanent return of patient to dialysis.
Two years
Patient Survival
Time Frame: Two years
Two years
Lymphoid Cell Sub-type CD3 Absolute Numbers
Time Frame: One year
One year
New-onset Polyomavirus (BK Virus) Disease Per Kidney Biopsy
Time Frame: Two years
Two years
New-onset Diabetes and Hyperglycemia After Transplantation (NODAT)
Time Frame: Six months
Six months
Ratio of CD4/CD8 Lymphoid Cells
Time Frame: One year
One year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Nebraska

Collaborators

Genzyme, a Sanofi Company

Investigators

  • Study Director: R. Brian Stevens, MD, PhD, Wright State University Boonshoft School of Medicine, Dayton, OH

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2004

Primary Completion (Actual)

April 1, 2011

Study Completion (Actual)

June 1, 2011

Study Registration Dates

First Submitted

November 9, 2007

First Submitted That Met QC Criteria

November 9, 2007

First Posted (Estimated)

November 12, 2007

Study Record Updates

Last Update Posted (Actual)

September 18, 2023

Last Update Submitted That Met QC Criteria

August 30, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0286-03-FB

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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