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

NCT ID: NCT01354301

Last Updated: 2015-03-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-05-31
• Study Completion Date: 2014-12-31

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.

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.

Conditions

Cytomegalovirus Infection; Renal Transplant Failure; Transplant; Complication, Rejection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Thymoglobulin and everolimus

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

Group Type: EXPERIMENTAL

Thymoglobulin

Intervention Type: DRUG

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.

Everolimus

Intervention Type: DRUG

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.

Tacrolimus

Intervention Type: DRUG

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.

Basiliximabe and everolimus

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

Group Type: EXPERIMENTAL

Everolimus

Intervention Type: DRUG

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.

Basiliximabe

Intervention Type: DRUG

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

Tacrolimus

Intervention Type: DRUG

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.

Basiliximabe and mycophenolate

basiliximab, reduced concentration tacrolimus, mycophenolate and prednisone.

Group Type: ACTIVE_COMPARATOR

Basiliximabe

Intervention Type: DRUG

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

mycophenolate sodium

Intervention Type: DRUG

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

Tacrolimus

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Basiliximabe

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

Intervention Type: DRUG

mycophenolate sodium

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

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hospital do Rim e Hipertensão

OTHER

Sponsor Role: lead

Responsible Party

Helio Tedesco Silva Junior

PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Hélio Tedesco, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital do Rim e Hipertensão - Fundação Oswaldo Ramos

Locations

Hospital do rim e Hipertensao

São Paulo, São Paulo, Brazil

Countries

Brazil

References

Nunes Ficher K, Dreige Y, Gessolo Lins PR, Nicolau Ferreira A, Toniato de Rezende Freschi J, Linhares K, Stopa Martins S, Custodio L, Cristelli M, Viana L, Wagner Santos D, de Marco R, Gerbase-DeLima M, Proenca H, Aguiar W, Nakamura M, Rosso Felipe C, Medina Pestana J, Tedesco Silva H Jr. Long-term Efficacy and Safety of Everolimus Versus Mycophenolate in Kidney Transplant Recipients Receiving Tacrolimus. Transplantation. 2022 Feb 1;106(2):381-390. doi: 10.1097/TP.0000000000003714.

Reference Type: DERIVED

PMID: 33988338 (View on PubMed)

Tedesco-Silva H, Felipe C, Ferreira A, Cristelli M, Oliveira N, Sandes-Freitas T, Aguiar W, Campos E, Gerbase-DeLima M, Franco M, Medina-Pestana J. Reduced Incidence of Cytomegalovirus Infection in Kidney Transplant Recipients Receiving Everolimus and Reduced Tacrolimus Doses. Am J Transplant. 2015 Oct;15(10):2655-64. doi: 10.1111/ajt.13327. Epub 2015 May 18.

Reference Type: DERIVED

PMID: 25988935 (View on PubMed)

Other Identifiers

CRAD001ABR18T

Identifier Type: -

Identifier Source: org_study_id