Randomized Conversion of Calcineurin-Inhibitors in Renal Allograft Recipients

NCT00866879

Last updated date
Study Location
Northwestern Memorial Hospital
Chicago, Illinois, 60611, United States
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Renal Transplant Rejection
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18-70 years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

1. Subjects should be adults ≥ 18- ≤ 70 years of age

2. Subjects can be either gender or of any ethnic background

3. Subjects should be single organ recipients (kidney only)

4. Subjects must be able to understand the protocol and provide informed consent.

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


1. Subjects with end-stage renal disease (ESRD) secondary to primary focal segmental
glomerulonephritis (FSGS).


2. Inability to comply with study procedures


3. Inability to sign the informed consent


4. Subjects with a significant or active infection


5. Subjects who are pregnant or nursing females


6. Subjects with a history of severe hyperlipidemia not controlled with statins, patients
with at total cholesterol of > 400 mg/dl


7. Subjects with a platelet count <100,000mm3 white blood cell (WBC)< 2,000mm3


8. Subjects with severe proteinuria at the time of randomization (>2gm/day)


9. Subjects with more then 2 episodes of acute cellular rejection post transplantation
will be excluded from this study


10. An estimated GFR<40 cc/min


11. A history of malignancy during the post-transplant period (other than treated basal
cell cancer and/or squamous cell cancer)


12. 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


13. A history of albumin-creatinine ratio (ACR) during the most recent previous 3 months
prior to randomization

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Renal Transplant RejectionRandomized Conversion of Calcineurin-Inhibitors in Renal Allograft Recipients
NCT00866879
  1. Chicago, Illinois
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE Randomized Conversion of Calcineurin-Inhibitors in Renal Allograft Recipients
Official Title  ICMJE Randomized Conversion of Calcineurin-Inhibitors(Tacrolimus to Sirolimus),6-24 Months Post Transplant Prednisone-Free Immunosuppression Regimen: Impact of Incidence of Acute Cellular Rejection,Renal Allograft Function & Lymphocytes Function
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.
Detailed Description

For this research study, between 6 and 24 Months post-transplant, we plan to prospectively randomize 2:1 renal transplant patients to either:

  • Substitute tacrolimus (TAC) with sirolimus and continue mycophenolate mofetil (MMF) or
  • Continue with tacrolimus (TAC) and mycophenolate mofetil (MMF)

A total of 400 patients are expected to be screened for the randomization. We expect to randomize 275 renal transplant patients into this protocol (275 donors to be recruited).

The following data will be collected at the time of randomization:

Recipient demographics: (i) age at transplantation, (ii) sex, and (iii) race.

Clinical history: (i) causes of end-stage renal disease, and (ii) past medical history.

Transplant related information: (i) donor age, (ii) cadaveric versus living kidney transplant, (iii) histocompatibility and cross match data, (iv) viral serology, (v) history of acute rejection and delayed graft function, (vi) use of induction therapy and immunosuppressants, (vii) use of ACEI and/or ARB, and (viii) level of renal allograft function-estimated GFR (e-GFR(12) using MDRD formula, proteinuria.

Peripheral blood leukocytes will be obtained from renal transplant recipients for baseline (prior to randomization) lymphocytes functional activity and characterization of lymphocytes subpopulations by flow cytometry analysis.

Peripheral donor leukocytes (from living donor patients) will also be 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.

The recipients assigned to continue with tacrolimus and MMF will be routinely followed at the outpatient Comprehensive Transplant Center (CTC) with monthly labs. In addition to labs at baseline pre-randomization, 6, 12 and 24 Months post-randomization, peripheral blood leukocytes will be obtained to study lymphocytes functional activity and to characterize lymphocytes subpopulations by flow cytometry analysis.

Post randomization: The recipients assigned to switch from tacrolimus to sirolimus and continue with MMF will be routinely followed at the CTC with monthly labs. During the period of conversion from tacrolimus to sirolimus, weekly labs will be obtained to monitor renal function and bone marrow function. In addition to labs at baseline pre-randomization, 6, 12 and 24 Months post-randomization, peripheral blood leukocytes will be obtained to study lymphocytes functional activity to characterize lymphocytes subpopulations by flow cytometry analysis. Urine will be collected to assess tubular toxicity by evaluating urinary biomarkers.

Both groups of patients will be followed for 2 years post-randomization. In addition to monitoring renal allograft function, we will evaluate the incidence of acute rejection, patient and graft survival, impact of CI conversion on the lipid profile, incidence of hypertension, malignancies, opportunistic infections, and post-transplant diabetes mellitus (DM). For those willing to undergo an optional kidney biopsy, one will be performed at the end of the second year in order to evaluate renal allograft pathology and renal allograft tissue gene expression profiles of the two groups.

With the peripheral leukocytes obtained at baseline prior to randomization and at 6, 12 and 24 Months post-randomization, we will investigate possible modifications of lymphocytes function and the lymphocytes subpopulations that might have occurred as a consequence of the switch from tacrolimus to sirolimus.

Obtaining renal allograft tissue samples at 24 months post randomization can have potential important ramifications to help explain the mechanisms of fibrosis and tubular atrophy typically associated with CI and the role of CI elimination with the substitution of sirolimus (SRL). All data will then be analyzed comparing gene expression profiles of peripheral blood (Pax gene tubes are routinely collected at the different time points as part of the original study). Based on power analysis, we will perform 24 months post randomization biopsies in 70% of the total subjects enrolled in the study (approximately 46 subjects from the tacrolimus/MMF group and approximately 93 subjects from the sirolimus/MMF group).

We plan to obtain renal allograft biopsies at 24 Months for those that consent for this additional biopsy. This will be compared to the standard of care 12 months post-transplant biopsy to allow us to address the effect of immunosuppressive modifications on renal allograft pathology at 24 months post randomization. Renal allograft biopsies will also be stored in RNA later to further extend our knowledge on the effect of CI free immunosuppression on gene expression profiles.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Renal Transplant Rejection
Intervention  ICMJE
  • Drug: Sirolimus
    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.
    Other Name: Rapamune
  • Other: Demographic Data, Medical History, and Donor Data
    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.
  • Procedure: Blood Draws for Control Group
    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.
  • Procedure: Blood Draws for Experimental Group
    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.
  • Procedure: Donor Blood Draws
    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.
  • Other: Donor Information
    Donor age, cadaveric vs. living donor, and histocompatibility and cross match to recipient
  • Procedure: Kidney Biopsy
    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.
Study Arms  ICMJE
  • Active Comparator: Control
    Group 1 will continue immunosuppression medication per standard of care (SOC) at Northwestern by taking mycophenolate mofetil and tacrolimus.
    Interventions:
    • Other: Demographic Data, Medical History, and Donor Data
    • Procedure: Blood Draws for Control Group
    • Procedure: Kidney Biopsy
  • Experimental: Transition to Sirolimus Group
    Group 2 will switch immunosuppression medication to taking mycophenolate mofetil and sirolimus
    Interventions:
    • Drug: Sirolimus
    • Other: Demographic Data, Medical History, and Donor Data
    • Procedure: Blood Draws for Experimental Group
    • Procedure: Kidney Biopsy
  • Donors
    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.
    Interventions:
    • Procedure: Donor Blood Draws
    • Other: Donor Information
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 17, 2012)
275
Original Estimated Enrollment  ICMJE
 (submitted: March 20, 2009)
200
Actual Study Completion Date  ICMJE March 2019
Actual Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

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

Exclusion Criteria:

  1. Subjects with end-stage renal disease (ESRD) secondary to primary focal segmental glomerulonephritis (FSGS).
  2. Inability to comply with study procedures
  3. Inability to sign the informed consent
  4. Subjects with a significant or active infection
  5. Subjects who are pregnant or nursing females
  6. Subjects with a history of severe hyperlipidemia not controlled with statins, patients with at total cholesterol of > 400 mg/dl
  7. Subjects with a platelet count <100,000mm3 white blood cell (WBC)< 2,000mm3
  8. Subjects with severe proteinuria at the time of randomization (>2gm/day)
  9. Subjects with more then 2 episodes of acute cellular rejection post transplantation will be excluded from this study
  10. An estimated GFR<40 cc/min
  11. A history of malignancy during the post-transplant period (other than treated basal cell cancer and/or squamous cell cancer)
  12. 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
  13. A history of albumin-creatinine ratio (ACR) during the most recent previous 3 months prior to randomization
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00866879
Other Study ID Numbers  ICMJE STU8308 0773-017
0468H1-4472 ( Other Identifier: Pfizer (Wyeth) )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Lorenzo Gallon, Northwestern University
Study Sponsor  ICMJE Northwestern University
Collaborators  ICMJE Wyeth is now a wholly owned subsidiary of Pfizer
Investigators  ICMJE
Principal Investigator:Lorenzo Gallon, MDNorthwestern Univesity, Northwestern Memorial Hospital, Northwestern Medical Faculty Foundation
PRS Account Northwestern University
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP