Improved Induction and Maintenance Immunosuppression in Kidney Transplantation

NCT00556933 | Completed Phase 4 Results

• 1 other identifier: 0286-03-FB
• Study Type: interventional
• Target: 180
• Locations: 1 country
• Sites: 1

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. 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. 2.After 6 months, modifying the maintenance immunosuppression used to prevent rejection by replacing the drug tacrolimus with mycophenolate mofetil (MMF).

Conditions

End-stage Renal Disease

Keywords

Induction; rATG; Calcineurin-inhibitor withdrawal

Outcome Measures

Primary Outcomes (2)

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

  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

  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 Outcomes (10)

• Safety Profile

  Two years

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

  Two years

• Acute Rejection Per Kidney Biopsy (Banff Grading Criteria)

  Two years

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

  Seven days

• Graft Survival

  Two years

Study Arms (4)

Group 1

EXPERIMENTAL

Kidney transplant recipients given a single large dose of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression.

Drug: rabbit anti-thymocyte globulin - single dose; Drug: sirolimus; Drug: tacrolimus

Group 2

EXPERIMENTAL

Kidney transplant recipients given 4 small doses of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression.

Drug: rabbit anti-thymocyte globulin - 4 doses; Drug: sirolimus; Drug: tacrolimus

Group 3

EXPERIMENTAL

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: rabbit anti-thymocyte globulin - single dose; Drug: mycophenolate mofetil; Drug: sirolimus; Drug: tacrolimus

Group 4

EXPERIMENTAL

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: mycophenolate mofetil; Drug: rabbit anti-thymocyte globulin - 4 doses; Drug: sirolimus; Drug: tacrolimus

Interventions

rabbit anti-thymocyte globulin - single dose DRUG

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.

Also known as: Thymoglobulin, rATG

Group 1; Group 3

mycophenolate mofetil DRUG

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.

Also known as: CellCept, MMF, mycophenolic acid, Myfortic

Group 3; Group 4

rabbit anti-thymocyte globulin - 4 doses DRUG

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.

Also known as: Thymoglobulin

Group 2; Group 4

sirolimus DRUG

Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection

Also known as: Rapamune, rapamycin

Group 1; Group 2; Group 3; Group 4

tacrolimus DRUG

Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.

Also known as: FK506, ProGraf

Group 1; Group 2; Group 3; Group 4

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Primary renal transplant recipient for end-stage renal disease

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Nebraska: lead
• Genzyme, a Sanofi Company: collaborator

Study Sites (1)

Unversity of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

Related Publications (8)

• 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.

  PMID: 21077952 BACKGROUND

• 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.

  PMID: 19100901 BACKGROUND

• 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. doi: 10.1097/01.tp.0000176482.63122.03.

  PMID: 16249743 BACKGROUND

• Stevens RB, Foster KW, Miles CD, Lane JT, Kalil AC, Florescu DF, Sandoz JP, Rigley TH, Nielsen KJ, Skorupa JY, Kellogg AM, Malik T, Wrenshall LE. A randomized 2x2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes. Transplantation. 2015 Jan;99(1):197-209. doi: 10.1097/TP.0000000000000250.

  PMID: 25083614 RESULT

• Stevens RB, Lane JT, Boerner BP, Miles CD, Rigley TH, Sandoz JP, Nielsen KJ, Skorupa JY, Skorupa AJ, Kaplan B, Wrenshall LE. Single-dose rATG induction at renal transplantation: superior renal function and glucoregulation with less hypomagnesemia. Clin Transplant. 2012 Jan-Feb;26(1):123-32. doi: 10.1111/j.1399-0012.2011.01425.x. Epub 2011 Mar 14.

  PMID: 21401720 RESULT

• Snow MH, Cannella AC, Stevens RB, Mikuls TR. Presumptive serum sickness as a complication of rabbit-derived antithymocyte globulin immunosuppression. Arthritis Rheum. 2009 Sep 15;61(9):1271-4. doi: 10.1002/art.24788. No abstract available.

  PMID: 19714613 RESULT

• Stevens RB, Mercer DF, Grant WJ, Freifeld AG, Lane JT, Groggel GC, Rigley TH, Nielsen KJ, Henning ME, Skorupa JY, Skorupa AJ, Christensen KA, Sandoz JP, Kellogg AM, Langnas AN, Wrenshall LE. Randomized trial of single-dose versus divided-dose rabbit anti-thymocyte globulin induction in renal transplantation: an interim report. Transplantation. 2008 May 27;85(10):1391-9. doi: 10.1097/TP.0b013e3181722fad.

  PMID: 18497677 RESULT

• Stevens RB, Foster KW, Miles CD, Kalil AC, Florescu DF, Sandoz JP, Rigley TH, Malik T, Wrenshall LE. A Randomized 2x2 Factorial Clinical Trial of Renal Transplantation: Steroid-Free Maintenance Immunosuppression with Calcineurin Inhibitor Withdrawal after Six Months Associates with Improved Renal Function and Reduced Chronic Histopathology. PLoS One. 2015 Oct 14;10(10):e0139247. doi: 10.1371/journal.pone.0139247. eCollection 2015.

  PMID: 26465152 DERIVED

MeSH Terms

Conditions

Kidney Failure, Chronic

Interventions

Antilymphocyte Serum; thymoglobulin; Mycophenolic Acid; Sirolimus; Tacrolimus

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Macrolides; Lactones

Limitations and Caveats

The trial is designed for analysis as 1st, rATG dosing, and 2nd, CNI withdrawal status. Results published as analysis of 2 induction protocols followed by analysis of 2 CNI maintenance regimens. Potential limitations = single-center \& non-blinded.

Results Point of Contact

• Title: R. Brian Stevens, MD, PhD
• Organization: Wright State University, Dayton, Ohio

rbstevens1@icloud.com

937-545-4817

Study Officials

• R. Brian Stevens, MD, PhD

  Wright State University Boonshoft School of Medicine, Dayton, OH

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2007
• First Posted: November 12, 2007
• Study Start: April 1, 2004
• Primary Completion: April 1, 2011
• Study Completion: June 1, 2011
• Last Updated: September 18, 2023
• Results First Posted: March 2, 2015

Record last verified: 2023-08

Locations

US (1)