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Evaluation of Early Use of Everolimus (EVE) on Cytomegalovirus (CMV) Infection in Renal Transplant Recipients

Primary Purpose

Cytomegalovirus Infections

Status
Unknown status
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Everolimus+Tacrolimus+Prednisone
Mycophenolate+Tacrolimus+Prednisone
Sponsored by
Fundação Pró Rim
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cytomegalovirus Infections focused on measuring Certican, Renal Transplant, Cytomegalovirus Infection

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Primary kidney transplants (living or deceased donors);

Exclusion Criteria:

  • Recipients of a second transplant;
  • Recipients of multiple organs transplants;
  • PRA > 50%;
  • Chronic liver failure;
  • Presence of uncontrolled hypercholesterolemia (≥ 250 mg/dL);
  • Or hypertriglyceridemia (≥ 300 mg/dL).
  • Leucocytes count < 1500 per microliter;
  • Platelets count < 75000 per microliter;
  • Proteinuria > 800mg/day;

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Active Comparator

    Arm Label

    Everolimus+Tacrolimus+Prednisone

    Mycophenolate+Tacrolimus+Prednisone

    Arm Description

    Certican 3mg/daily for 12 months TACreduced 0,15mg/Kg/daily for 12 months Steroids 1mg/Kg/daily for 12 months

    Myfortic 720mg twice daily for 12 months TACreduced full dose/Kg/daily for 12 months Steroids 1mg/Kg/daily for 12 months

    Outcomes

    Primary Outcome Measures

    Cytomegalovirus (CMV) infection investigation
    Blood samples will be collected to perform antigenemia at baseline, 1 month, 3 months 6 months and 12 months after transplant to investigate CMV infection.

    Secondary Outcome Measures

    Transplant biopsies
    At 1, 3, and 12 month, a renal biopsy will be performed. Conventional staining and polyoma virus and CD4d immunohistochemical staining will be done. Methods for immunohistochemical staining procedures will be briefly described: 1. paraffin blocks were deparaffinized in multiple xylene baths, and tissues rehydrated in sequentially graduated ethyl alcohol baths; 2. Sample are predigested in 0.05% protease for 10 min at 37ºC to increase antigenic binding availability; 3.0 after rinsing in Trisbuffered saline, test slides and appropriate positive and negative controls are processed in an automated stainer. Primary antibody NCL-JCBK is applied for 2 hours (or overnight) at 37ºC temperature; then, the secondary antibody (anti-mouse peroxidase antibody) for 30 minutes at 37ºC.
    C4d method
    1. Tissue will be stained using standard procedures with monoclonal anti-C4d at 1:100 dilution. 2. Secondary anti-mouse FITC-conjungated antibody is applied at a concentration of 1:20; 3. Quantification of staining is recorded, using routine protocols, including pretreatment for 15 min in boiling citrate (pH 8.0), a primary antibody concentration of 1:20 or 1:40 (titered by antibody lot), and secondary goat anti-rabbit IgG antibody at 1:360 dilution. Detection is performed with streptavidin/horseradish peroxidase (Jackson ImmunoResearch) and developed with Stable DAB (Dako, Carpenteria, CA).
    Polyoma identification
    Urine samples will be collected to perform Decoy cells research and real time PCR analysis. Q-PCR amplification reactions will be set up in a reaction volume of 50 µl using the TaqMan Universal PCR Master Mix (PE Biosystems), containing 10 µl of purified DNA, 200 and 400 nM of VPf and VPr, and 50 nM of TaqMan probe. Thermal cycling was initiated with a 2-min incubation at 50 °C, followed by a first denaturation step of 10 min at 95 °C and then 40 cycles of 95 °C for 15 s (denaturation) and 60 °C for 1min. Real-time PCR amplification data will be collected continuously and analysed with the Sequence Detection System.

    Full Information

    First Posted
    August 20, 2013
    Last Updated
    August 20, 2013
    Sponsor
    Fundação Pró Rim
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01927588
    Brief Title
    Evaluation of Early Use of Everolimus (EVE) on Cytomegalovirus (CMV) Infection in Renal Transplant Recipients
    Official Title
    An Exploratory Evaluation of Early Use of Everolimus (EVE) on Tacrolimus (TAC)-Based Immunosuppressive Regiment vs. Mycophenolate Sodium (MPS) on Cytomegalovirus (CMV) Infection in Renal Transplant Recipients.
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2013
    Overall Recruitment Status
    Unknown status
    Study Start Date
    August 2013 (undefined)
    Primary Completion Date
    November 2015 (Anticipated)
    Study Completion Date
    November 2015 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Fundação Pró Rim

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    CMV infection is common in transplant patients and can cause graft loss. CMV is a major factor in increasing morbidity, and post-transplant costs. The CMV infection is associated with many deleterious indirect effects including rejection, interstitial fibrosis and tubular atrophy, mortality. In addition to the potential for undesirable clinical outcomes associated with CMV, there is also a negative economic aspect. Patients who developed CMV events have been found to use significantly more inpatient and outpatient resources than patients without CMV disease. Universal prophylaxis is associated with high treatment cost and the potential for drug-related toxicity. It can be speculated that use of EVR may offer additional economic benefits in terms of decreased utilization associated with prevention of CMV disease, and reduce use of costly prophylaxis. Any efforts to reduce costs in renal transplants are very important and may have a great impact in total cost of a renal program. And the other hand, the clinical data suggest that EVR is associated with a decrease in CMV incidence compared to mycophenolic acid (MPA). CMV replication is dependent upon 1 ou 2 mTor pathways and in vitro studies support an association between mTor inhibitors and decreased CMV infection and disease. In cardiac transplantation, the use of EVR was associated with a lower incidence of CMV events. Some clinical trials data have also shown that use of EVR was associated with a lower incidence of CMV infection compared to MPA following renal transplantation. Brennan et al compared the incidence of CMV in three clinical trials using EVR versus MPA in De Novo renal transplants. They pooled for analysis the studies B201, B251 and A2309, all double-blind, randomized, parallel-groups that compared the incidence of freedom form and incidence of CMV between EVR groups and MPA groups. The results of this pooled analysis of over 2000 patients de novo renal transplant demonstrated that EVR was associated with a decrease in and delay in the time of onset of CMV events compared to MPA. Our hypothesis is that basiliximab in combination with low dose tacrolimus, everolimus and prednisone may result in comparable efficacy (BCAR) observed in patients receiving tacrolimus/mycophenolate/prednisone but with a better safety profile (CMV infection) and cost-effectiveness.
    Detailed Description
    Objectives: Primary To investigate the effect of early use of EVL plus TAC dose reduced vs. MPS plus TAC full dose on CMV infection by antigenemia 12 month after transplantation in stable kidney transplant recipients. Secondaries To evaluate renal function by cGFR (MDRD) To evaluate the incidence of acute rejection and nephrotoxicity by protocol biopsies; To evaluate the incidence of poliomavirus, according to treatment group, by quantitative PCR the BKviremia in urine and biopsy sample.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Cytomegalovirus Infections
    Keywords
    Certican, Renal Transplant, Cytomegalovirus Infection

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 4
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    50 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Everolimus+Tacrolimus+Prednisone
    Arm Type
    Experimental
    Arm Description
    Certican 3mg/daily for 12 months TACreduced 0,15mg/Kg/daily for 12 months Steroids 1mg/Kg/daily for 12 months
    Arm Title
    Mycophenolate+Tacrolimus+Prednisone
    Arm Type
    Active Comparator
    Arm Description
    Myfortic 720mg twice daily for 12 months TACreduced full dose/Kg/daily for 12 months Steroids 1mg/Kg/daily for 12 months
    Intervention Type
    Drug
    Intervention Name(s)
    Everolimus+Tacrolimus+Prednisone
    Other Intervention Name(s)
    Certican, Tacrolimus, Prednisone
    Intervention Description
    Certican, introduced at Day7 post transplant + TACreduced + Steroids.
    Intervention Type
    Drug
    Intervention Name(s)
    Mycophenolate+Tacrolimus+Prednisone
    Other Intervention Name(s)
    Myfortic, Tacrolimus, Prednisone
    Intervention Description
    Myfortic + Tacrolimus full + Steroids, as control arm.
    Primary Outcome Measure Information:
    Title
    Cytomegalovirus (CMV) infection investigation
    Description
    Blood samples will be collected to perform antigenemia at baseline, 1 month, 3 months 6 months and 12 months after transplant to investigate CMV infection.
    Time Frame
    one year
    Secondary Outcome Measure Information:
    Title
    Transplant biopsies
    Description
    At 1, 3, and 12 month, a renal biopsy will be performed. Conventional staining and polyoma virus and CD4d immunohistochemical staining will be done. Methods for immunohistochemical staining procedures will be briefly described: 1. paraffin blocks were deparaffinized in multiple xylene baths, and tissues rehydrated in sequentially graduated ethyl alcohol baths; 2. Sample are predigested in 0.05% protease for 10 min at 37ºC to increase antigenic binding availability; 3.0 after rinsing in Trisbuffered saline, test slides and appropriate positive and negative controls are processed in an automated stainer. Primary antibody NCL-JCBK is applied for 2 hours (or overnight) at 37ºC temperature; then, the secondary antibody (anti-mouse peroxidase antibody) for 30 minutes at 37ºC.
    Time Frame
    One year
    Title
    C4d method
    Description
    1. Tissue will be stained using standard procedures with monoclonal anti-C4d at 1:100 dilution. 2. Secondary anti-mouse FITC-conjungated antibody is applied at a concentration of 1:20; 3. Quantification of staining is recorded, using routine protocols, including pretreatment for 15 min in boiling citrate (pH 8.0), a primary antibody concentration of 1:20 or 1:40 (titered by antibody lot), and secondary goat anti-rabbit IgG antibody at 1:360 dilution. Detection is performed with streptavidin/horseradish peroxidase (Jackson ImmunoResearch) and developed with Stable DAB (Dako, Carpenteria, CA).
    Time Frame
    one year
    Title
    Polyoma identification
    Description
    Urine samples will be collected to perform Decoy cells research and real time PCR analysis. Q-PCR amplification reactions will be set up in a reaction volume of 50 µl using the TaqMan Universal PCR Master Mix (PE Biosystems), containing 10 µl of purified DNA, 200 and 400 nM of VPf and VPr, and 50 nM of TaqMan probe. Thermal cycling was initiated with a 2-min incubation at 50 °C, followed by a first denaturation step of 10 min at 95 °C and then 40 cycles of 95 °C for 15 s (denaturation) and 60 °C for 1min. Real-time PCR amplification data will be collected continuously and analysed with the Sequence Detection System.
    Time Frame
    One year

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    70 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Primary kidney transplants (living or deceased donors); Exclusion Criteria: Recipients of a second transplant; Recipients of multiple organs transplants; PRA > 50%; Chronic liver failure; Presence of uncontrolled hypercholesterolemia (≥ 250 mg/dL); Or hypertriglyceridemia (≥ 300 mg/dL). Leucocytes count < 1500 per microliter; Platelets count < 75000 per microliter; Proteinuria > 800mg/day;
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Luciane M Deboni, Doctor, PI
    Phone
    +55 47 96094320
    Email
    lmdeboni@terra.com.br
    First Name & Middle Initial & Last Name or Official Title & Degree
    Karjan H Mazzoleni, Nurse, SC
    Phone
    +55 47 99141713
    Email
    karjanhelena@gmail.com
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Luciane M. Deboni, Msc
    Organizational Affiliation
    Fundação Pró Rim
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Learn more about this trial

    Evaluation of Early Use of Everolimus (EVE) on Cytomegalovirus (CMV) Infection in Renal Transplant Recipients

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