Randomized Conversion of Calcineurin-Inhibitors in Renal Allograft Recipients

NCT00866879 | Completed Phase 4 Results

• 2 other identifiers: STU8308 0773-0170468H1-4472
• Study Type: interventional
• Target: 275
• Locations: 1 country
• Sites: 1

Brief Summary

This study is being done to investigate the impact of changing immunosuppressive medications from tacrolimus (Prograf®) to sirolimus (Rapamune®) between 6 and 24 months post transplant. The primary purpose of this research study is to evaluate whether the use of mycophenolate mofetil(MMF)/Cellcept® and tacrolimus(TAC)/Prograf® (Group 1) or mycophenolate mofetil(MMF)/Cellcept® and sirolimus/Rapamune® (Group 2) impacts the incidence of acute cellular rejection in post kidney transplant patients. This study will examine whether switching from tacrolimus to sirolimus will better preserve long-term kidney function.

Conditions

Renal Transplant Rejection

Keywords

Sirolimus; Rapamune; Immunosuppression; Renal allograft function; Lymphocytes function

Outcome Measures

Primary Outcomes (1)

• Incidence of Acute Cellular Rejection

  The primary purpose of this research study is to evaluate whether the use of mycophenolate mofetil/Cellcept ® and either tacrolimus/Prograf ® (Group #1) or mycophenolate mofetil/Cellcept ® and sirolimus/Rapamune® (Group #2) impacts the incidence of acute cellular rejection in post-kidney transplant patients. This study will examine whether switching from tacrolimus to sirolimus will better preserve long-term kidney function.

  Assessed at 6 Months, 12 Months, 24 Months, months 24 reported

Secondary Outcomes (4)

• Renal Allograft Function Calculated With e-GFR and Proteinuria

  Assessed at 6 Months, 12 Months, 24 Months, months 24 reported

• Evaluate if CI Conversion Impacts on Lipid Profile, Incidence of Hypertension, Malignancies, and Opportunistic Infections and Post-transplant DM

  Assessed at 6 Months, 12 Months, 24 Months, months 24 reported

• Patient and Graft Survival

  Assessed at 6 Months, 12 Months, 24 Months, months 24 reported

• Percentage of Regulatory T Cells

  Assessed at 6 Months, 12 Months, 24 Months, months 24 reported

Study Arms (3)

Control

ACTIVE COMPARATOR

Group 1 will continue immunosuppression medication per standard of care (SOC) at Northwestern by taking mycophenolate mofetil and tacrolimus.

Other: Demographic Data, Medical History, and Donor Data; Procedure: Blood Draws for Control Group; Procedure: Kidney Biopsy

Transition to Sirolimus Group

EXPERIMENTAL

Group 2 will switch immunosuppression medication to taking mycophenolate mofetil and sirolimus

Drug: Sirolimus; Other: Demographic Data, Medical History, and Donor Data; Procedure: Blood Draws for Experimental Group; Procedure: Kidney Biopsy

Donors

OTHER

Data and blood samples from the donors are collected in this study to contribute to the general knowledge to be used in assessing the two donor recipient groups, which are the target of this study.

Procedure: Donor Blood Draws; Other: Donor Information

Interventions

Sirolimus DRUG

Sirolimus will initially be given at a dose of 2-4 mg orally (PO) daily. The dose will be modified to achieve 24 hours trough concentrations of 6-10 ng/ml by high-performance liquid chromatography (HPLC) assay. This medication will be given in an open label fashion. The first dose of sirolimus will be given at the time of randomization to those patients assigned to have tacrolimus switched to sirolimus.

Also known as: Rapamune

Transition to Sirolimus Group

Demographic Data, Medical History, and Donor Data OTHER

Age at transplant, sex, race, cause of end-stage renal disease, medical history, donor age, cadaveric vs. living kidney transplant, histocompatibility/cross match data, viral serology, history of acute rejection and delayed graft function, use of induction therapy and immunosuppressants, use of Angiotensin Converting Enzyme Inhibitor (ACEI) and/or Angiotensin Receptor Blockers (ARB) level of renal allograft function-estimated GFR (e-GFR(12) using Modification of Diet in Renal Disease (MDRD) formula, proteinuria.

Control; Transition to Sirolimus Group

Blood Draws for Control Group PROCEDURE

Subjects maintaining standard of care drug treatment of TAC and MMF will have monthly labs in addition to the baseline pre-randomization labs, at 6, 12, and 24 Months post-randomization. Peripheral blood leukocytes will be obtained.

Control

Blood Draws for Experimental Group PROCEDURE

This group will have monthly labs taken but will also have weekly labs during the period of conversion to monitor renal function and bone marrow function. In addition to the baseline pre-randomization labs, and labs collected at 6, 12, and 24 Months post-randomization, peripheral blood leukocytes will be obtained.

Transition to Sirolimus Group

Donor Blood Draws PROCEDURE

Peripheral blood leukocytes from living donors obtained at the time of randomization. These donor leukocytes will be used as stimulator cells to study the functional activity of the recipient's lymphocytes function.

Donors

Donor Information OTHER

Donor age, cadaveric vs. living donor, and histocompatibility and cross match to recipient

Donors

Kidney Biopsy PROCEDURE

Kidney biopsy at 24 Months to compare to the standard of care biopsy taken at 12 Months. This information will help evaluate renal allograft pathology and renal allograft tissue gene expression profiles of the two groups. Renal allograft biopsies will be stored in RNA later (preservative) to further extend knowledge on the effect of calcineurin-inhibitors (CI) free immunosuppression on gene expression profiles.

Control; Transition to Sirolimus Group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects should be adults ≥ 18- ≤ 70 years of age
• Subjects can be either gender or of any ethnic background
• Subjects should be single organ recipients (kidney only)
• Subjects must be able to understand the protocol and provide informed consent.

You may not qualify if:

• Subjects with end-stage renal disease (ESRD) secondary to primary focal segmental glomerulonephritis (FSGS).
• Inability to comply with study procedures
• Inability to sign the informed consent
• Subjects with a significant or active infection
• Subjects who are pregnant or nursing females
• Subjects with a history of severe hyperlipidemia not controlled with statins, patients with at total cholesterol of \> 400 mg/dl
• Subjects with a platelet count \<100,000mm3 white blood cell (WBC)\< 2,000mm3
• Subjects with severe proteinuria at the time of randomization (\>2gm/day)
• Subjects with more then 2 episodes of acute cellular rejection post transplantation will be excluded from this study
• An estimated GFR\<40 cc/min
• A history of malignancy during the post-transplant period (other than treated basal cell cancer and/or squamous cell cancer)
• Subjects, who, due to the existence of a surgical, medical or psychiatric condition, other than the current transplant, which in the opinion of the investigator, precludes enrollment into this trial
• A history of albumin-creatinine ratio (ACR) during the most recent previous 3 months prior to randomization

Sponsors & Collaborators

• Northwestern University: lead
• Wyeth is now a wholly owned subsidiary of Pfizer: collaborator

Study Sites (1)

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

Related Publications (12)

• Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003 Sep 4;349(10):931-40. doi: 10.1056/NEJMoa021744.

  PMID: 12954741 BACKGROUND

• Stoves J, Lindley EJ, Barnfield MC, Burniston MT, Newstead CG. MDRD equation estimates of glomerular filtration rate in potential living kidney donors and renal transplant recipients with impaired graft function. Nephrol Dial Transplant. 2002 Nov;17(11):2036-7. doi: 10.1093/ndt/17.11.2036. No abstract available.

  PMID: 12401874 BACKGROUND

• Gonwa TA, Mai ML, Melton LB, Hays SR, Goldstein RM, Levy MF, Klintmalm GB. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation. 2001 Dec 27;72(12):1934-9. doi: 10.1097/00007890-200112270-00012.

  PMID: 11773892 BACKGROUND

• Fisher NC, Nightingale PG, Gunson BK, Lipkin GW, Neuberger JM. Chronic renal failure following liver transplantation: a retrospective analysis. Transplantation. 1998 Jul 15;66(1):59-66. doi: 10.1097/00007890-199807150-00010.

  PMID: 9679823 BACKGROUND

• Hornberger J, Best J, Geppert J, McClellan M. Risks and costs of end-stage renal disease after heart transplantation. Transplantation. 1998 Dec 27;66(12):1763-70. doi: 10.1097/00007890-199812270-00034.

  PMID: 9884274 BACKGROUND

• Goldstein DJ, Zuech N, Sehgal V, Weinberg AD, Drusin R, Cohen D. Cyclosporine-associated end-stage nephropathy after cardiac transplantation: incidence and progression. Transplantation. 1997 Mar 15;63(5):664-8. doi: 10.1097/00007890-199703150-00009.

  PMID: 9075835 BACKGROUND

• Myers BD, Ross J, Newton L, Luetscher J, Perlroth M. Cyclosporine-associated chronic nephropathy. N Engl J Med. 1984 Sep 13;311(11):699-705. doi: 10.1056/NEJM198409133111103.

  PMID: 6382005 BACKGROUND

• Bennett WM, DeMattos A, Meyer MM, Andoh T, Barry JM. Chronic cyclosporine nephropathy: the Achilles' heel of immunosuppressive therapy. Kidney Int. 1996 Oct;50(4):1089-100. doi: 10.1038/ki.1996.415. No abstract available.

  PMID: 8887265 BACKGROUND

• Bennett WM. Insights into chronic cyclosporine nephrotoxicity. Int J Clin Pharmacol Ther. 1996 Nov;34(11):515-9.

  PMID: 8937936 BACKGROUND

• Myers BD. Cyclosporine nephrotoxicity. Kidney Int. 1986 Dec;30(6):964-74. doi: 10.1038/ki.1986.280. No abstract available.

  PMID: 3546916 BACKGROUND

• Puschett JB, Greenberg A, Holley J, McCauley J. The spectrum of ciclosporin nephrotoxicity. Am J Nephrol. 1990;10(4):296-309. doi: 10.1159/000168123. No abstract available.

  PMID: 2240057 BACKGROUND

• Young EW, Ellis CN, Messana JM, Johnson KJ, Leichtman AB, Mihatsch MJ, Hamilton TA, Groisser DS, Fradin MS, Voorhees JJ. A prospective study of renal structure and function in psoriasis patients treated with cyclosporin. Kidney Int. 1994 Oct;46(4):1216-22. doi: 10.1038/ki.1994.387.

  PMID: 7861719 BACKGROUND

MeSH Terms

Interventions

Sirolimus; Demography; Health Records, Personal; Blood Specimen Collection; Control Groups

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Population Characteristics; Epidemiologic Measurements; Public Health; Environment and Public Health; Medical Records; Records; Data Collection; Epidemiologic Methods; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Epidemiologic Research Design; Research Design; Methods

Results Point of Contact

• Title: Lorenzo Gallon, MD
• Organization: Northwestern University

l-gallon@northwestern.edu

3126954457

Study Officials

• Lorenzo Gallon, MD

  Northwestern Univesity, Northwestern Memorial Hospital, Northwestern Medical Faculty Foundation

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: March 19, 2009
• First Posted: March 23, 2009
• Study Start: June 1, 2007
• Primary Completion: December 1, 2017
• Study Completion: March 1, 2019
• Last Updated: June 28, 2019
• Results First Posted: May 31, 2019

Record last verified: 2019-06

Locations

US (1)