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Kidney TransplantationPhase 4NCT00896012

Kidney Biopsy Controlled Trial of Calcineurin Inhibitor Withdrawal

A Phase 4 study testing Kidney Biopsy, Rapamune (sirolimus/rapamycin) and Tacrolimus in people with Kidney Transplantation, run by University at Buffalo at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Kidney Transplantation
What is being tested?
Kidney Biopsy, Rapamune (sirolimus/rapamycin) and Tacrolimus
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
58 participants
Where
1 siteUnited States
Study dates
Jan 2008to Dec 2011
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

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

Who cannot join

  • 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
Show all 15Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Buffalo General Hospital Multi-Organ Transplant Department

    Buffalo, New York, 14203

Other trials in United States

About this study

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

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.

Read the 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.

Being tested
Kidney Biopsy, Rapamune (sirolimus/rapamycin), Tacrolimus
Keywords
Kidney Transplant, Immunosuppression drugs, Rapamune, tacrolimus, calcineurin inhibitor, Kidney Biopsy, Needle

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Kidney BiopsyProcedure or surgery

    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.

  • 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.

  • TacrolimusDrug

    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).

Study groups in NCT00896012
Study groupRoleWhat they receive
1. Low-dose tacrolimus armExperimentalPatients 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.
Receives: Procedure: Kidney Biopsy; Drug: Tacrolimus
2. Rapamune conversion arm:ExperimentalPatients 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.
Receives: Procedure: Kidney Biopsy; Drug: Rapamune (sirolimus/rapamycin)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Graft Survival at 12 Months

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

    Measured: Number of participants biopsied at 12 months post-transplant

  2. 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.

    Measured: 1 year post-transplant

  3. 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. .

    Measured: 3 and 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 May 2009 (estimated)
  2. Study startJan 2008
  3. Primary completion11 Nov 2011
  4. Study completionDec 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
58 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00896012
Sponsor's protocol ID
CERL080AUS59
Status last verified
Aug 2023
First submitted
8 May 2009
Last updated
14 Aug 2023
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 12883194
  • 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.

    PubMed 15548969
  • 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.

    PubMed 15147430
  • 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.

    PubMed 16468960
  • 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.

    PubMed 14974944

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Kidney Biopsy, Rapamune (sirolimus/rapamycin) and Tacrolimus in people with Kidney Transplantation, run by University at Buffalo at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Aug 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 1 Dec 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Graft Survival at 12 Months (time frame: Number of participants biopsied at 12 months post-transplant). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00896012, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Aug 2023.

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