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Improved Induction and Maintenance Immunosuppression in Kidney Transplantation

Information source: University of Nebraska
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: End-stage Renal Disease

Intervention: rabbit anti-thymocyte globulin (Drug); mycophenolate mofetil (Drug); rabbit anti-thymocyte globulin (Drug); sirolimus (Drug); tacrolimus (Drug)

Phase: Phase 4

Status: Completed

Sponsored by: R. Brian Stevens, MD

Official(s) and/or principal investigator(s):
R. Brian Stevens, MD, PhD, Study Director, Affiliation: Wright State University Boonshoft School of Medicine, Dayton, OH

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.

Clinical Details

Official title: 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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria).

Average of Renal Function

Secondary outcome:

Safety Profile

Requirement for Additional Immunosuppression (Such as Corticosteroids, Antimetabolites or Other Immunosuppressive Agents)

Acute Rejection Per Kidney Biopsy (Banff Grading Criteria)

Acute Tubular Necrosis (ATN) Rate, Defined as the Requirement for Dialysis Within 7 Days Post-transplantation.

Graft Survival

Patient Survival

Lymphoid Cell Sub-type CD3 Absolute Numbers

New-onset Polyomavirus (BK Virus) Disease Per Kidney Biopsy

New-onset Diabetes and Hyperglycemia After Transplantation (NODAT)

Ratio of CD4/CD8 Lymphoid Cells

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.

Eligibility

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

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

Locations and Contacts

The Nebraska Medical Center, Omaha, Nebraska 68198, United States
Additional Information

Related publications:

Miles CD, Skorupa JY, Sandoz JP, Rigley TH, Nielsen KJ, Stevens RB. Albuminuria after renal transplantation: maintenance with sirolimus/low-dose tacrolimus vs. mycophenolate mofetil/high-dose tacrolimus. Clin Transplant. 2011 Nov-Dec;25(6):898-904. doi: 10.1111/j.1399-0012.2010.01353.x. Epub 2010 Nov 16.

Stevens RB. Modern approaches to combining sirolimus with calcineurin inhibitors. Transplant Proc. 2008 Dec;40(10 Suppl):S21-4. doi: 10.1016/j.transproceed.2008.10.012.

Sulanc E, Lane JT, Puumala SE, Groggel GC, Wrenshall LE, Stevens RB. New-onset diabetes after kidney transplantation: an application of 2003 International Guidelines. Transplantation. 2005 Oct 15;80(7):945-52.

Starting date: April 2004
Last updated: February 16, 2015

Page last updated: August 20, 2015

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