Efficacy and Safety of Induction Strategies Combined With Low Tacrolimus Exposure in Kidney Transplant Recipients Receiving Everolimus or Sodium Mycophenolate

Sponsor

Hospital do Rim e Hipertensão (Other)

Overall Status

Completed

CT.gov ID

NCT01354301

Collaborator

(none)

300

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Despite the improvement of efficacy results with current immunosuppressive regimens (about 15% of incidence of acute rejection), the security schemes used do not show the same results.The most worldwide used regime is tacrolimus, mycophenolate and prednisone. Despite the favorable efficacy results in our population, the use of this combination is associated with higher incidence of viral infections such as cytomegalovirus, and gastrointestinal events, two common causes of hospital readmissions after renal transplantation at our institution.Given this, the investigators propose a study of our own initiative that attends our local needs: identify the best strategy among the therapeutic options available to maintain the result of current effectiveness and improve the safety profile for kidney transplant recipients.This protocol is a prospective, randomized, single center, designed to compare the safety and efficacy of three immunosuppressive regimens: (1) single dose of antithymocyte globulin, reduced exposure to tacrolimus, everolimus starting on day 2 after transplantation and prednisone; ( 2) basiliximab, reduced exposure to tacrolimus, everolimus starting on day 2 after transplantation and prednisone; (3-control group) basiliximab, reduced exposure to tacrolimus, mycophenolate and prednisone.Our hypothesis is that a single dose of antithymocyte globulin or basiliximab induction therapy in combination with low doses of tacrolimus, everolimus and prednisone results in comparable efficacy observed in patients receiving tacrolimus / mycophenolate / prednisone, but with a better safety profile.

To ensure efficacy, the investigators added to the regimes the induction with monoclonal or polyclonal antibody. To improve the toxicities associated with the current scheme, the investigators replace the use of mycophenolate by everolimus and the investigators reduced the dose of tacrolimus.

Patients will be monitored for blood levels of tacrolimus and everolimus to ensure adequate exposure to immunosuppressive agents.

Condition or Disease	Intervention/Treatment	Phase
Cytomegalovirus Infection Renal Transplant Failure Transplant; Complication, Rejection	Drug: Thymoglobulin Drug: Everolimus Drug: Basiliximabe Drug: mycophenolate sodium Drug: Tacrolimus Drug: Tacrolimus Drug: Tacrolimus	Phase 4

Detailed Description

Primary end-point: The incidence of CMV infection or disease during the first year of transplantation.Secondary main end-point: the incidence of treatment failure defined as a composite end-point of BCAR, graft loss, death, loss to follow up.

The investigators anticipate enrolling 300 patients within 12 months. Only low risk adult candidates for first renal transplants from living or deceased donors will be considered for enrollment. Patients will be excluded if they have been receiving immunosuppressive therapy before transplantation; have received an investigational medication within the past 30 days; have a known contraindication to the administration of antithymocyte globulin; if tested positive for human immunodeficiency virus (HIV); if had had cancer (except nonmelanoma skin cancer) within the previous 2 years. Pregnant women, nursing mothers, and women of childbearing potential who will be not using condoms or oral contraceptives will be excluded. Patients with any panel reactive antibody (PRA) equal to or above 50%, class I or class II, will also be excluded. Study visits will be performed at pre transplant, days 0, 1, 7, every week up to month 6 and month 12.

Study Design

Study Type:

Interventional

Actual Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Efficacy and Safety of Induction Strategies Combined With Low Tacrolimus Exposure in Kidney Transplant Recipients Receiving Everolimus or Sodium Mycophenolate

Study Start Date :

May 1, 2011

Actual Primary Completion Date :

Apr 1, 2014

Actual Study Completion Date :

Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Thymoglobulin and everolimus single dose antithymocyte globulin, reduced concentration tacrolimus, everolimus starting at day 2 posttransplant and prednisone	Drug: Thymoglobulin intravenously, beginning within the first 24 hours after graft revascularization. Pre-treatment includes hydrocortisone and dipyrone before antithymocyte globulin infusion, which will be reconstituted according to the package insert. Drug: Everolimus initial 0.75 mg BID dose of everolimus on day 2. Doses will be adjusted from day 5 on to maintain everolimus whole blood trough concentrations between 4-8 ng/ml. Drug: Tacrolimus 0.05 mg/kg BID beginning on day 1. Doses will be adjusted to maintain tacrolimus whole blood trough concentrations between 3-5 ng/ml.
Experimental: Basiliximabe and everolimus basiliximab, reduced concentration tacrolimus, everolimus starting at day 2 posttransplant and prednisone	Drug: Everolimus initial 0.75 mg BID dose of everolimus on day 2. Doses will be adjusted from day 5 on to maintain everolimus whole blood trough concentrations between 4-8 ng/ml. Drug: Basiliximabe days 0 and 4, according to the package insert instructions. Drug: Tacrolimus 0.1 mg/kg BID beginning on day 1. Doses will be adjusted to maintain tacrolimus whole blood trough concentrations between 3-8 ng/ml and 3-5 ng/ml after 3 months.
Active Comparator: Basiliximabe and mycophenolate basiliximab, reduced concentration tacrolimus, mycophenolate and prednisone.	Drug: Basiliximabe days 0 and 4, according to the package insert instructions. Drug: mycophenolate sodium 720 mg BID. This dose will be reduced according to adverse events. Drug: Tacrolimus 0.1 mg/kg BID beginning on day 1. Doses will be adjusted to maintain tacrolimus whole blood trough concentrations between 3-8 ng/ml.

Arm

Intervention/Treatment

Experimental: Thymoglobulin and everolimus

single dose antithymocyte globulin, reduced concentration tacrolimus, everolimus starting at day 2 posttransplant and prednisone

Drug: Thymoglobulin

intravenously, beginning within the first 24 hours after graft revascularization. Pre-treatment includes hydrocortisone and dipyrone before antithymocyte globulin infusion, which will be reconstituted according to the package insert.

Drug: Everolimus

initial 0.75 mg BID dose of everolimus on day 2. Doses will be adjusted from day 5 on to maintain everolimus whole blood trough concentrations between 4-8 ng/ml.

Drug: Tacrolimus

0.05 mg/kg BID beginning on day 1. Doses will be adjusted to maintain tacrolimus whole blood trough concentrations between 3-5 ng/ml.

Experimental: Basiliximabe and everolimus

basiliximab, reduced concentration tacrolimus, everolimus starting at day 2 posttransplant and prednisone

Drug: Everolimus

initial 0.75 mg BID dose of everolimus on day 2. Doses will be adjusted from day 5 on to maintain everolimus whole blood trough concentrations between 4-8 ng/ml.

Drug: Basiliximabe

days 0 and 4, according to the package insert instructions.

Drug: Tacrolimus

0.1 mg/kg BID beginning on day 1. Doses will be adjusted to maintain tacrolimus whole blood trough concentrations between 3-8 ng/ml and 3-5 ng/ml after 3 months.

Active Comparator: Basiliximabe and mycophenolate

basiliximab, reduced concentration tacrolimus, mycophenolate and prednisone.

Drug: Basiliximabe

days 0 and 4, according to the package insert instructions.

Drug: mycophenolate sodium

720 mg BID. This dose will be reduced according to adverse events.

Drug: Tacrolimus

0.1 mg/kg BID beginning on day 1. Doses will be adjusted to maintain tacrolimus whole blood trough concentrations between 3-8 ng/ml.

Outcome Measures

Primary Outcome Measures

incidence of CMV infection or disease [1 year]

Secondary Outcome Measures

incidence of treatment failure defined as a composite end-point of BCAR, graft loss, death, loss to follow up. [1 year]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

low risk adult candidates for first renal transplants from living or deceased donors

Exclusion Criteria:

receiving immunosuppressive therapy before transplantation;
have received an investigational medication within the past 30 days;
have a known contraindication to the administration of antithymocyte globulin;
tested positive for human immunodeficiency virus (HIV);
had had cancer (except nonmelanoma skin cancer) within the previous 2 years;
Pregnant women, nursing mothers, and women of childbearing potential who will be not using condoms or oral contraceptives will be excluded;
Patients with any panel reactive antibody (PRA) equal to or above 50%, class I or class II.