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

NCT02084446 | Completed Phase 4

• 1 other identifier: CRAD001ABR25T
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

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.

Conditions

Transplantation Infection; Cytomegalovirus Infections

Keywords

Everolimus; Tacrolimus; Sodium Mycophenolate; CMV; Graft function; Acute rejection

Outcome Measures

Primary Outcomes (1)

• Incidence of cytomegalovirus (CMV) infection (viremia) or disease (syndrome or invasive disease) during the first year of transplantation

  Blood (for CMV detection) samples will be evaluated by PCR for the detection of viral infections

  Month 12

Secondary Outcomes (5)

• Composite efficacy failure rates demonstrated by treated biopsy proven acute rejection episodes (BPAR), graft loss, death, loss to follow-up at months 6 and 12

  Weeks 1 and 2, Months 1, 2, 3, 6 and 12

• • Graft function measured as calculated creatinine clearance according to the Cockcroft and Gault formula at 6 and 12 months after transplantation

  Weeks 1 and 2, and Months 1, 2, 3, 6 and 12

• Incidence of proteinuria

  Day 28 and months 3, 6, 9, and 12 after transplantation

• Safety Secondary Objectives - incidence of bone marrow suppression, gastrointestinal events, BKV infection, new onset diabetes mellitus; malignancies, dyslipidemia.

  Week 2 and Months 1, 2, 3, 6 and 12

• Incidence of cytomegalovirus (CMV) infection (viremia) or disease (syndrome or invasive disease) during the first year of transplantation

  Week 2, Months 1, 2, 3 and 6

Study Arms (2)

Mycophenolate + Low Tacrolimus

ACTIVE COMPARATOR

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).

Drug: Low Tacrolimus; Drug: Steroids; Drug: Thymoglobulin; Drug: Sodium Mycophenolate

Everolimus + Very Low Tacrolimus

EXPERIMENTAL

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).

Drug: Everolimus; Drug: Very Low Tacrolimus; Drug: Steroids; Drug: Thymoglobulin

Interventions

Everolimus 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.

Also known as: Certican, Zortress

Everolimus + Very Low Tacrolimus

Very Low Tacrolimus 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.

Also known as: Very low Prograf

Everolimus + Very Low Tacrolimus

Low Tacrolimus 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.

Also known as: Low Prograf

Mycophenolate + Low Tacrolimus

Steroids 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).

Also known as: Prednisone, Methylprednisolone

Everolimus + Very Low Tacrolimus; Mycophenolate + Low Tacrolimus

Thymoglobulin 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).

Also known as: ATG, rabbit Thymoglobulin (r-ATG)

Everolimus + Very Low Tacrolimus; Mycophenolate + Low Tacrolimus

Sodium Mycophenolate DRUG

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

Also known as: Myfortic

Mycophenolate + Low Tacrolimus

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Ronaldo de Matos Esmeraldo, MD: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

Hospital Geral de Fortaleza

Fortaleza, Ceará, 60175-295, Brazil

Location

Related Publications (1)

• 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.

  PMID: 29969826 DERIVED

MeSH Terms

Conditions

Cytomegalovirus Infections

Interventions

Everolimus; Steroids; Prednisone; Methylprednisolone; thymoglobulin; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienediols; Pregnadienes; Pregnanes; Prednisolone; Pregnadienetriols; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Study Officials

• Ronaldo M Esmeraldo, MD

  Hospital Geral de Fortaleza

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MsC, MD

Study Record Dates

• First Submitted: December 7, 2012
• First Posted: March 12, 2014
• Study Start: December 1, 2012
• Primary Completion: July 1, 2014
• Study Completion: July 1, 2017
• Last Updated: February 22, 2019

Record last verified: 2019-02

Locations

BR (1)