Kidney Biopsy Controlled Trial of Calcineurin Inhibitor Withdrawal

NCT00896012 | Completed Phase 4 Results DMC

• 1 other identifier: CERL080AUS59
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 1

Brief Summary

Current therapy to prevent organ rejection relies on the use of calcineurin inhibitors either cyclosporine or tacrolimus. Although these agents have been very successful in preventing early acute rejection, this success has not translated into improved long-term kidney transplant function. One of the important factors that leads to premature kidney transplant failure is chronic allograft nephropathy (CAN). CAN is characterized by progressive interstitial fibrosis or "scarring", vascular wall thickening, and finally glomerular sclerosis leading to slow progressive loss of kidney function. Calcineurin inhibitors have been shown to play an important role in the pathogens of CAN. Renal transplant recipients in whom calcineurin inhibitors are discontinued enjoy better and longer kidney function. Therefore, immunosuppressive strategies are being designed with the intention of withdrawing calcineurin inhibitors. The purpose of this trial is to test if tacrolimus can be safely substituted by sirolimus (Rapamycin) and this substitution will yield improved renal function, less CAN and better graft survival rates over the first year.

Conditions

Kidney Transplantation

Keywords

Kidney Transplant; Immunosuppression drugs; Rapamune; tacrolimus; calcineurin inhibitor; Kidney Biopsy, Needle

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Graft Survival at 12 Months

  Graft survival is defined as no rejection or inflammation at 12 months.

  Number of participants biopsied at 12 months post-transplant

• Either Equivalent or Improved Estimated Glomerular Filtration Rate (eGFR) at One Year in the Rapamycin Group

  Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula.

  1 year post-transplant

• Improved Histology at 12 Months in the Rapamycin Group

  Chronic allograft damage index (CADI) scores. It's a sum score of six histo- pathological lesions commonly seen in biopsies taken from transplanted kidneys that correlate with the function and outcome of the graft. The maximum CADI score can go up to 18. In this case the lesions found were Interstitial fibrosis (IF) and Tubular Atrophy (TA) subscales from 0 (min) to 5 (max) . A score of 0 to 1 means absence of chronic allograft damage, a score of 4 is severe damage. .

  3 and 12 months

Study Arms (2)

1. Low-dose tacrolimus arm

EXPERIMENTAL

Patients in this group will continue to receive tacrolimus at reduced doses. Doses will be titrated to achieve tacrolimus trough blood levels between 4 and 6. Myfortic at doses of 720 mg BID and steroids will be continued for the duration of the study (12 months). All patients will undergo a second protocol biopsy at 12 months.

Procedure: Kidney Biopsy; Drug: Tacrolimus

2. Rapamune conversion arm:

EXPERIMENTAL

Patients in this group will undergo a gradual conversion from tacrolimus to Rapamune therapy. Tacrolimus will be withdrawn progressively over a period of 7-10 days. Dosage adjustments will be made with the aim of reducing the blood levels of tacrolimus by 25% every other day until tacrolimus is discontinued. Rapamune will be given at a dose of 5mg/day for two days beginning at the initiation of tacrolimus reduction. Thereafter, Rapamune will be given at a dose of 3 mg/day. The dose of Rapamune will be titrated to achieve a blood level (by HPLC) between 5 and 10 for the duration of the study.

Procedure: Kidney Biopsy; Drug: Rapamune (sirolimus/rapamycin)

Interventions

Kidney Biopsy PROCEDURE

Skin over the kidney will be cleansed and disinfected. The skin and deeper tissue will be numbed with novocaine like solution. A special needle will be inserted guided by ultrasound into the kidney for an instant to withdraw the small specimen.

1. Low-dose tacrolimus arm; 2. Rapamune conversion arm:

Rapamune (sirolimus/rapamycin) DRUG

Rapamune will be given at a dose of 5mg/day for two days beginning at the initiation of tacrolimus reduction. Thereafter, Rapamune will be given at a dose of 3 mg/day. The dose of Rapamune will be titrated to achieve a blood level (by HPLC) between 5 and 10 for the duration of the study.

2. Rapamune conversion arm:

Tacrolimus DRUG

Patients in this group will continue to receive tacrolimus at reduced doses. Doses will be titrated to achieve tacrolimus trough blood levels between 4 and 6. Myfortic at doses of 720 mg BID and steroids will be continued for the duration of the study (12 months).

1. Low-dose tacrolimus arm

Eligibility Criteria

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

You may qualify if:

• All patients receiving their first renal allograft transplant will be considered eligible for study
• Patients receiving both living and cadaveric donors will be eligible

You may not qualify if:

• If less than 18 years of age
• Severe hyperlipidemia
• If pregnant or cannot comply with proper birth control during the study
• Recipients of kidney together with another solid organ or bone marrow transplant
• Patients receiving any investigational medications or participating in a clinical trial
• Patients receiving a second or third renal allograft
• PRA \> 30%
• Active infections
• Chronic antiarrhythmic therapy for ventricular arrhythmia
• Malignancy except for basal cell carcinoma
• HIV
• ANC count \< 1,000/ mm3, Platelet count \< 100,00/mm3
• Fasting triglycerides \> 400 mg/dl and cholesterol \> 300 mg/dl
• HCV-positive, HBVSAg-positive, HBVCoreAb-positive and HBVSAntibody negative or HCV/HBV co-infected patients
• Breastfeeding women

Sponsors & Collaborators

• University at Buffalo: lead
• Novartis: collaborator
• University of Washington: collaborator

Study Sites (1)

Buffalo General Hospital Multi-Organ Transplant Department

Buffalo, New York, 14203, United States

Location

Related Publications (5)

• Oberbauer R, Kreis H, Johnson RW, Mota A, Claesson K, Ruiz JC, Wilczek H, Jamieson N, Henriques AC, Paczek L, Chapman J, Burke JT; Rapamune Maintenance Regimen Study Group. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation. 2003 Jul 27;76(2):364-70. doi: 10.1097/01.TP.0000074360.62032.39.

  PMID: 12883194 BACKGROUND

• Ruiz JC, Campistol JM, Grinyo JM, Mota A, Prats D, Gutierrez JA, Henriques AC, Pinto JR, Garcia J, Morales JM, Gomez JM, Arias M. Early cyclosporine a withdrawal in kidney-transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions. Transplantation. 2004 Nov 15;78(9):1312-8. doi: 10.1097/01.tp.0000137322.65953.0a.

  PMID: 15548969 BACKGROUND

• Mota A, Arias M, Taskinen EI, Paavonen T, Brault Y, Legendre C, Claesson K, Castagneto M, Campistol JM, Hutchison B, Burke JT, Yilmaz S, Hayry P, Neylan JF; Rapamune Maintenance Regimen Trial. Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant. 2004 Jun;4(6):953-61. doi: 10.1111/j.1600-6143.2004.00446.x.

  PMID: 15147430 BACKGROUND

• Larson TS, Dean PG, Stegall MD, Griffin MD, Textor SC, Schwab TR, Gloor JM, Cosio FG, Lund WJ, Kremers WK, Nyberg SL, Ishitani MB, Prieto M, Velosa JA. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant. 2006 Mar;6(3):514-22. doi: 10.1111/j.1600-6143.2005.01177.x.

  PMID: 16468960 BACKGROUND

• Salvadori M, Holzer H, de Mattos A, Sollinger H, Arns W, Oppenheimer F, Maca J, Hall M; ERL B301 Study Groups. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant. 2004 Feb;4(2):231-6. doi: 10.1046/j.1600-6143.2003.00337.x.

  PMID: 14974944 BACKGROUND

MeSH Terms

Interventions

Sirolimus; Tacrolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Oleh G. Pankewycz, MD
• Organization: University at Buffalo

opankewycz@kaleidahealth.org

Study Officials

• Mark R Laftavi, MD, FACS

  University at Buffalo School of Medicine Deparment of Surgery

  PRINCIPAL INVESTIGATOR

• Oleh G. Pankewycz, MD

  University at Buffalo

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, Nephrology

Study Record Dates

• First Submitted: May 8, 2009
• First Posted: May 11, 2009
• Study Start: January 1, 2008
• Primary Completion: November 11, 2011
• Study Completion: December 1, 2011
• Last Updated: August 14, 2023
• Results First Posted: December 1, 2020

Record last verified: 2023-08

Locations

US (1)