Kidney Biopsy Controlled Trial of Calcineurin Inhibitor Withdrawal

This study is enrolling participants by invitation only.
Sponsor:
Collaborators:
Novartis
University of Washington
Information provided by:
University at Buffalo
ClinicalTrials.gov Identifier:
NCT00896012
First received: May 8, 2009
Last updated: NA
Last verified: May 2009
History: No changes posted
  Purpose

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.


Condition Intervention Phase
Kidney Transplantation
Procedure: Kidney Biopsy
Drug: Rapamune (sirolimus/rapamycin)
Drug: Tacrolimus
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 4 Study: Comparison of Myfortic and Early Rapamycin Conversion vs. Low-Dose Tacrolimus in Preventing Acute Rejection and Chronic Allograft Fibrosis: A Protocol Biopsy Directed Approach

Resource links provided by NLM:


Further study details as provided by University at Buffalo:

Primary Outcome Measures:
  • equivalent patient and graft survival at one year [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • either equivalent or improved GFR (Cockcroft-Gault) at one year in the Rapamycin group [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • lack of a significant difference in clinical or subclinical acute rejections between the 2 treatment arms [ Time Frame: during the entire study time frame ] [ Designated as safety issue: Yes ]
  • equivalent time to first biopsy proven acute rejection [ Time Frame: 3 and 12 months ] [ Designated as safety issue: Yes ]
  • improved histology at 12 months in the Rapamycin group [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • composite end point of clinical and subclinical rejection free graft and patient survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • improved blood pressure control requiring fewer anti-hypertensive medications in the Rapamycin group [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • improved glucose control at one year in the Rapamycin group [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • improved compliance with medications in the Rapamycin group [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • improved quality of life measures in the Rapamycin group [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • equivalent rates of infectious complications [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • equivalent rates of readmission to the hospital and length of stay over the 12 months [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • equivalent lipid control using statin therapy [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • equivalent dose changes of immunosuppression regimen [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 120
Study Start Date: January 2008
Estimated Study Completion Date: December 2010
Estimated Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1. Low-dose tacrolimus arm
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
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.
Drug: Tacrolimus
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).
Experimental: 2. Rapamune conversion arm:
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
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.
Drug: Rapamune (sirolimus/rapamycin)
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.

Detailed Description:

The purpose of this study is to determine if tacrolimus can be safely lowered to potentially non-nephrotoxic levels or discontinued completely in favor of Rapamycin 3 months after kidney transplantation. In this study, all patients will be maintained on full-dose (720 mg BID) mycophenolate sodium (Myfortic) to ensure adequate immunosuppression. In addition, we will compare the immunosuppressive regimens of Rapamune/mycophenolate sodium/Prednisone to Low-Dose Prograf/ mycophenolate sodium /Prednisone for their long-term effects on renal function, cardiovascular risk factors, subclinical rejection and chronic allograft fibrosis.

We also plan to examine the clinical benefit of protocol biopsies. The first protocol biopsy would occur at the time of implantation. This would provide an assessment of the state of the donor kidney. The severity of donor disease would provide a baseline to which all subsequent biopsies can be compared. The second protocol biopsy would be performed at the time of tacrolimus withdrawal. Patients found to have subclinical rejection on this biopsy would not undergo tacrolimus withdrawal but may benefit from increased immunosuppression. The protocol biopsy would provide an additional level of safety ensuring that only "low-risk" (histologically) patients undergo tacrolimus withdrawal. A third biopsy would be performed one year after transplantation. Renal allograft tissue would be examined for the presence of progressive fibrosis or persistent subclinical rejection both of which lead to graft failure. The efficacy of tacrolimus withdrawal can be assessed using both clinical and pathologic criteria.

A third aim of this trial is to examine whether changes in immunosuppressive therapy leads to differential expression of immunological markers or serum mediators such as cytokines. Recent studies suggest that, in vitro, thymoglobulin induces the generation of "regulatory" cells. This study will examine the in vivo relevance of this novel observation. In addition, we will measure the circulatory mediators of renal fibrosis to examine if the two treatment arms differ in their effects on such cytokine/growth factors. Blood samples will be collected and the PBMC will be analyzed by FACS for their composition and the presence of cell surface antigens that may reflect a state of immunological regulation or "suppression". Tissue samples will be analyzed by immunohistochemistry for the presence of immunologically relevant cellular subtypes such as CD4/CD25 regulatory T cells. Serum samples will be collected and analyzed for cytokine or growth factor expression.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

  1. If less than 18 years of age
  2. Severe hyperlipidemia
  3. If pregnant or cannot comply with proper birth control during the study
  4. Recipients of kidney together with another solid organ or bone marrow transplant
  5. Patients receiving any investigational medications or participating in a clinical trial
  6. Patients receiving a second or third renal allograft
  7. PRA > 30%
  8. Active infections
  9. Chronic antiarrhythmic therapy for ventricular arrhythmia
  10. Malignancy except for basal cell carcinoma
  11. HIV
  12. ANC count < 1,000/ mm3, Platelet count < 100,00/mm3
  13. Fasting triglycerides > 400 mg/dl and cholesterol > 300 mg/dl
  14. HCV-positive, HBVSAg-positive, HBVCoreAb-positive and HBVSAntibody negative or HCV/HBV co-infected patients
  15. Breastfeeding women
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00896012

Locations
United States, New York
Buffalo General Hospital Multi-Organ Transplant Department
Buffalo, New York, United States, 14203
Sponsors and Collaborators
University at Buffalo
Novartis
University of Washington
Investigators
Principal Investigator: Mark R Laftavi, MD, FACS University at Buffalo School of Medicine Deparment of Surgery
Principal Investigator: Oleh G. Pankewycz, MD University at Buffalo
  More Information

Publications:

Responsible Party: Mark Laftavi, MD, FACS, University at Buffalo School of Medicine Deparment of Surgery
ClinicalTrials.gov Identifier: NCT00896012     History of Changes
Other Study ID Numbers: CERL080AUS59
Study First Received: May 8, 2009
Last Updated: May 8, 2009
Health Authority: United States: Institutional Review Board

Keywords provided by University at Buffalo:
Kidney Transplant
Immunosuppression drugs
Rapamune
tacrolimus
calcineurin inhibitor
Kidney Biopsy, Needle

Additional relevant MeSH terms:
Mycophenolate mofetil
Sirolimus
Everolimus
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 23, 2014