Everolimus + Very Low Tacrolimus vs Enteric-coated Mycophenolate Sodium + Low Tacrolimus in de Novo Renal Transplant

NCT ID: NCT02084446

Last Updated: 2019-02-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-12-31
• Study Completion Date: 2017-07-31

Brief Summary

This is a 12-month single center, randomized, open-label, single center study designed to compare the safety and efficacy of everolimus and very low dose tacrolimus versus enteric-coated sodium mycophenolate and low tacrolimus exposure in de novo kidney transplant recipients.

The purpose of this study is to compare safety and efficacy of two immunosuppressive regimens based on low tacrolimus exposure combined to everolimus or to enteric-coated mycophenolate sodium (EC-MPS) in de novo kidney transplant recipients.

Detailed Description

The study will consist of two periods: an initial period of 3 months during which all patients in both groups will be monitored in accordance with the same variation of C-0h tacrolimus and a second study period of 9 months (from month 4 to month 12) in which patients will be monitored according to two different targets of C-0h tacrolimus.

At the screening visit and before any assessment related to the study, patients must give their informed consent in writing.

All patients will receive induction with rabbit Thymoglobulin (r-ATG) in four doses of 1.5 mg/kg (maximum total dose of 6 mg/kg), administered according to center local practice.

The evaluations of baseline visit occur within 24 hours after transplantation and prior to the first dose of study drug.

Randomization will be performed within 24 hours after transplantation and after the baseline visit assessments. Patients will be randomized in a 1:1 ratio to one of two groups (everolimus with very low dose of tacrolimus versus sodium mycophenolate with low dose of tacrolimus).

Approximately 120 patients who meet the inclusion criteria will receive their first dose everolimus (initial dose of 1 mg twice a day) or sodium mycophenolate (initial dose of 720 mg twice a day) not more than 24 hours after transplantation. Everolimus trough blood levels will be measured at pre-specified timepoints in order to ensure that trough levels are above 3 ng/ml and below 8 ng/ml for the duration of the study.

Tacrolimus will be started within 48 hours after graft reperfusion at an initial dose of 0.1 mg/kg/day. The dose of tacrolimus will be adjusted to target the C-0h value within the pre-established desired range.

In the everolimus group with very low dose of tacrolimus, tacrolimus dose should be reduced at the end of months three after transplantation. Patients with either acute rejection grade ≥ Banff IIB or more than one treated acute rejection since entering the study and patients with either acute rejection during the third month will not have the dose of tacrolimus reduced; however, they will be encouraged to remain in the study. These patients will be excluded from the per protocol population analysis, but will be analyzed in the Intention To Treat population.

If patients present delayed graft function (DGF), the start of tacrolimus can be postponed for up to and including 7 days.

During the 12 months treatment period, patient visits will occur at the selection visit, baseline visit, at 1, 2, 4 and 8 weeks and at 3, 6 and 12 months. Day 1 is the day of the first administration of everolimus or sodium mycophenolate.

Population: Study population will consist of a group of male or female transplant recipients 18-75 years of age undergoing primary renal transplantation and who received an organ from a living or deceased donor.

Conditions

Transplantation Infection; Cytomegalovirus Infections

Study Design

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

Study Groups

Mycophenolate + Low Tacrolimus

Sodium Mycophenolate: initial dose of 720 mg twice a day starting at Day 1. Tacrolimus: initial dose of 0.05 mg/kg twice a day starting at Day 1. Dose will be adjusted to keep tacrolimus trough levels between 4 and 7 ng/mL.

Steroids: endovenous Methylprednisolone before doses of r-ATG; Prednisone per oral.

Thymoglobulin: all patients will receive induction in four doses of 1.5 mg/kg (maximum total dose of 6 mg/kg).

Group Type: ACTIVE_COMPARATOR

Low Tacrolimus

Intervention Type: DRUG

Tacrolimus: initial dose of 0.05 mg/kg twice a day starting at Day 1. Dose will be adjusted to keep tacrolimus trough levels between 4 and 7 ng/mL.

Steroids

Intervention Type: DRUG

Corticoids: endovenous Methylprednisolone will be administered 30-60 minutes before the first 3 doses of r-ATG: 250 mg (D0) and 125 mg (D2 and D4); Prednisone, 10 mg per oral, will be administered before the last dose of r-ATG (D6). Maintenance with Prednisone at post-transplant period will be performed in accordance with center local practice, i.e., only in patients with chronic previous use of corticosteroids, as well as in patients with autoimmune disease (systemic lupus erythematous, rheumatoid arthritis, etc).

Thymoglobulin

Intervention Type: DRUG

All patients will receive induction with rabbit Thymoglobulin (r-ATG) in four doses of 1.5 mg/kg (maximum total dose of 6 mg/kg), administered according to center local practice (before graft revascularization and at days 2, 4, and 6 post-transplant).

Sodium Mycophenolate

Intervention Type: DRUG

Sodium Mycophenolate: initial dose of 720 mg twice a day starting at Day 1.

Everolimus + Very Low Tacrolimus

Everolimus: initial dose of 1 mg twice a day starting at Day 1. Dose will be adjusted to keep everolimus trough levels between 3 and 8 ng/mL.

Tacrolimus: initial dose of 0.05 mg/kg twice a day starting at Day 1. Dose will be adjusted to keep tacrolimus trough levels between 4 and 7 ng/mL during the first 3 months and 2 and 4 ng/mL thereafter.

Corticoids: endovenous Methylprednisolone before doses of r-ATG; Prednisone per oral.

Thymoglobulin: all patients will receive induction in four doses of 1.5 mg/kg (maximum total dose of 6 mg/kg).

Group Type: EXPERIMENTAL

Everolimus

Intervention Type: DRUG

Everolimus: initial dose of 1 mg twice a day starting at Day 1. Dose will be adjusted to keep everolimus trough levels between 3 and 8 ng/mL.

Very Low Tacrolimus

Intervention Type: DRUG

Tacrolimus: initial dose of 0.05 mg/kg twice a day starting at Day 1. Dose will be adjusted to keep tacrolimus trough levels between 4 and 7 ng/mL during the first 3 months and 2 and 4 ng/mL thereafter.

Steroids

Intervention Type: DRUG

Corticoids: endovenous Methylprednisolone will be administered 30-60 minutes before the first 3 doses of r-ATG: 250 mg (D0) and 125 mg (D2 and D4); Prednisone, 10 mg per oral, will be administered before the last dose of r-ATG (D6). Maintenance with Prednisone at post-transplant period will be performed in accordance with center local practice, i.e., only in patients with chronic previous use of corticosteroids, as well as in patients with autoimmune disease (systemic lupus erythematous, rheumatoid arthritis, etc).

Thymoglobulin

Intervention Type: DRUG

All patients will receive induction with rabbit Thymoglobulin (r-ATG) in four doses of 1.5 mg/kg (maximum total dose of 6 mg/kg), administered according to center local practice (before graft revascularization and at days 2, 4, and 6 post-transplant).

Interventions

Everolimus

Everolimus: initial dose of 1 mg twice a day starting at Day 1. Dose will be adjusted to keep everolimus trough levels between 3 and 8 ng/mL.

Intervention Type: DRUG

Very Low Tacrolimus

Tacrolimus: initial dose of 0.05 mg/kg twice a day starting at Day 1. Dose will be adjusted to keep tacrolimus trough levels between 4 and 7 ng/mL during the first 3 months and 2 and 4 ng/mL thereafter.

Intervention Type: DRUG

Low Tacrolimus

Tacrolimus: initial dose of 0.05 mg/kg twice a day starting at Day 1. Dose will be adjusted to keep tacrolimus trough levels between 4 and 7 ng/mL.

Intervention Type: DRUG

Steroids

Corticoids: endovenous Methylprednisolone will be administered 30-60 minutes before the first 3 doses of r-ATG: 250 mg (D0) and 125 mg (D2 and D4); Prednisone, 10 mg per oral, will be administered before the last dose of r-ATG (D6). Maintenance with Prednisone at post-transplant period will be performed in accordance with center local practice, i.e., only in patients with chronic previous use of corticosteroids, as well as in patients with autoimmune disease (systemic lupus erythematous, rheumatoid arthritis, etc).

Intervention Type: DRUG

Thymoglobulin

All patients will receive induction with rabbit Thymoglobulin (r-ATG) in four doses of 1.5 mg/kg (maximum total dose of 6 mg/kg), administered according to center local practice (before graft revascularization and at days 2, 4, and 6 post-transplant).

Intervention Type: DRUG

Sodium Mycophenolate

Sodium Mycophenolate: initial dose of 720 mg twice a day starting at Day 1.

Intervention Type: DRUG

Other Intervention Names

Certican, Zortress; Very low Prograf; Low Prograf; Prednisone; Methylprednisolone; ATG; rabbit Thymoglobulin (r-ATG); Myfortic

Eligibility Criteria

Inclusion Criteria

• Male or female renal recipients 18-75 years of age undergoing kidney transplantation, from a primary deceased donor (including expanded criteria donor organs), living unrelated or non-HLA identical living related donor kidney;
• Recipient of a kidney with a cold ischemia time < 30 hours;
• Graft must be functional (producing greater than or equal to 300 ml of urine within 24 hours after transplantation) at time of randomization.

Exclusion Criteria

• Donor organ with a cold ischemic time > 30 hours;
• Patients who produce less than 300 ml of urine in the first 24 hours post-transplantation;
• Patients who are recipients of multiple organ transplants;
• Patients who are recipients of ABO incompatible transplants, or T or B cell cross match positive transplant;
• Patients with current Panel Reactive Antibodies (PRA) level ≥ 50%;
• Patients with severe hypercholesterolemia (350 mg/dl) or hypertriglyceridemia (500 mg/dl). Patients on lipid lowering treatment with controlled hyperlipidemia are acceptable;
• HIV positive patients;
• Females of childbearing potential who are planning to become pregnant, who are pregnant and/or lactating, who are unwilling to use effective means of contraception;
• Decisional impaired subjects who are not medically or mentally capable of providing consent themselves.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Ronaldo de Matos Esmeraldo, MD

OTHER_GOV

Sponsor Role: lead

Responsible Party

Ronaldo de Matos Esmeraldo, MD

MsC, MD

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Ronaldo M Esmeraldo, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Geral de Fortaleza

Locations

Hospital Geral de Fortaleza

Fortaleza, Ceará, Brazil

Countries

Brazil

References

de Sandes-Freitas TV, Pinheiro PMA, Sales MLMBO, Girao CM, Campos EF, Esmeraldo RM. The impact of everolimus in reducing cytomegalovirus events in kidney transplant recipients on steroid-avoidance strategy: 3-year follow-up of a randomized clinical trial. Transpl Int. 2018 Dec;31(12):1345-1356. doi: 10.1111/tri.13313. Epub 2018 Jul 31.

Reference Type: DERIVED

PMID: 29969826 (View on PubMed)

Other Identifiers

CRAD001ABR25T

Identifier Type: -

Identifier Source: org_study_id