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Improved Induction and Maintenance Immunosuppression in Kidney Transplantation

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ClinicalTrials.gov Identifier: NCT00556933
Recruitment Status : Completed
First Posted : November 12, 2007
Results First Posted : March 2, 2015
Last Update Posted : March 2, 2015
Sponsor:
Collaborator:
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
R. Brian Stevens, MD, University of Nebraska

Tracking Information
First Submitted Date  ICMJE November 9, 2007
First Posted Date  ICMJE November 12, 2007
Results First Submitted Date  ICMJE January 29, 2015
Results First Posted Date  ICMJE March 2, 2015
Last Update Posted Date March 2, 2015
Study Start Date  ICMJE April 2004
Actual Primary Completion Date April 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 16, 2015)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 9, 2007)
  • Chronic Allograft Nephropathy (cumulative calcineurin-inhibitor nephrotoxicity/transplant nephropathy) per clinically-indicated and protocol surveillance biopsies (Banff grading criteria). [ Time Frame: Two years ]
  • Renal function by either measured 24-hour urine creatinine clearance at 1, 3, 6, 12 and 24 months or calculated GFR (Glomerular Filtration Rate) by using the abbreviated MDRD (aMDRD) formula and patient serum creatinine and demographic data. [ Time Frame: Two years ]
Change History Complete list of historical versions of study NCT00556933 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 16, 2015)
  • 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.
  • Requirement for Additional Immunosuppression (Such as Corticosteroids, Antimetabolites or Other Immunosuppressive Agents) [ Time Frame: Two years ]
  • Acute Rejection Per Kidney Biopsy (Banff Grading Criteria) [ Time Frame: Two years ]
  • Acute Tubular Necrosis (ATN) Rate, Defined as the Requirement for Dialysis Within 7 Days Post-transplantation. [ Time Frame: Seven days ]
  • Graft Survival [ Time Frame: Two years ]
    Graft failure = permanent return of patient to dialysis.
  • Patient Survival [ Time Frame: Two years ]
  • Lymphoid Cell Sub-type CD3 Absolute Numbers [ Time Frame: One year ]
  • New-onset Polyomavirus (BK Virus) Disease Per Kidney Biopsy [ Time Frame: Two years ]
  • New-onset Diabetes and Hyperglycemia After Transplantation (NODAT) [ Time Frame: Six months ]
  • Ratio of CD4/CD8 Lymphoid Cells [ Time Frame: One year ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 9, 2007)
  • Safety profile to consist of CMV disease, opportunistic infections, PTLD, hyperlipidemia, wound healing problems, and lymphoceles [ Time Frame: Two years ]
  • Requirement for Additional Immunosuppression (Such as Corticosteroids, Antimetabolites or Other Immunosuppressive Agents) [ Time Frame: Two years ]
  • Acute Rejection Per Kidney Biopsy (Banff Grading Criteria) [ Time Frame: Two years ]
  • Acute Tubular Necrosis (ATN) Rate, Defined as the Requirement for Dialysis Within 7 Days Post-transplantation. [ Time Frame: Two years ]
  • Graft Survival [ Time Frame: Two years ]
  • Patient Survival [ Time Frame: Two years ]
  • Immunological parameters, i.e., lymphoid cell sub-type absolute numbers and ratios [ Time Frame: Two years ]
  • New-onset BK virus infection per kidney biopsy [ Time Frame: Two years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Improved Induction and Maintenance Immunosuppression in Kidney Transplantation
Official Title  ICMJE 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
Brief Summary

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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE End-stage Renal Disease
Intervention  ICMJE
  • Drug: rabbit anti-thymocyte globulin
    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
  • 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
    • MMF
    • mycophenolic acid
    • Myfortic
  • Drug: rabbit anti-thymocyte globulin
    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 Name: Thymoglobulin
  • Drug: sirolimus
    Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
    Other Name: 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: rabbit anti-thymocyte globulin
    • Drug: sirolimus
    • Drug: tacrolimus
  • 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.
    Interventions:
    • Drug: rabbit anti-thymocyte globulin
    • Drug: sirolimus
    • Drug: tacrolimus
  • 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.
    Interventions:
    • Drug: rabbit anti-thymocyte globulin
    • Drug: mycophenolate mofetil
    • Drug: sirolimus
    • Drug: tacrolimus
  • 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.
    Interventions:
    • Drug: mycophenolate mofetil
    • Drug: rabbit anti-thymocyte globulin
    • Drug: sirolimus
    • Drug: tacrolimus
Publications *

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: November 9, 2007)
180
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE June 2011
Actual Primary Completion Date April 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00556933
Other Study ID Numbers  ICMJE 286-03
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party R. Brian Stevens, MD, University of Nebraska
Study Sponsor  ICMJE R. Brian Stevens, MD
Collaborators  ICMJE Genzyme, a Sanofi Company
Investigators  ICMJE
Study Director: R. Brian Stevens, MD, PhD Wright State University Boonshoft School of Medicine, Dayton, OH
PRS Account University of Nebraska
Verification Date February 2015

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