Overview

This trial is active, not recruiting.

Condition liver transplant
Treatments minimisation of tac, tac + mmf + corticosteroids
Phase phase 3
Sponsor Novartis Pharmaceuticals
Start date December 2013
End date February 2016
Trial size 235 participants
Trial identifier NCT02040584, CRAD001HES01

Summary

Assuming greater efficacy in the prevention of acute rejection in the EVR arm with minimisation of TAC levels, the hypothesis of the present trial is that the introduction of EVR in combination with the minimisation of TAC (rTAC) may offer improved kidney function compared with standard therapy with TAC-MMF.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Treatment with rTAC+EVR+corticosteroids
minimisation of tac
•EVR: Treatment will be started at a total daily dose of 2 mg within 24 hours after randomisation. The dose of EVR will be adjusted upon reaching trough levels (C-0h) in whole blood of 3-8 ng/mL. The daily dose (in two administrations) of EVR may be modified to maintain trough levels (C-0h) in whole blood of 3-8 ng/mL until Week 52 post-transplant. •TAC: Once confirmation is obtained, beginning in Week 5, that trough levels (C-0h) in whole blood of EVR are between 3-8 ng/mL, minimisation of TAC will begin, in order to reach trough levels (C-0h) of TAC in whole blood of ≤5 ng/mL no later than four weeks after randomisation (Week 8), which are levels that should be maintained until Week 52 post-transplant. •MMF will be withdrawn at the same time that EVR is introduced. •oral corticosteroids will be administered in accordance with local clinical practice, although a therapeutic strategy free of corticosteroids is permitted
(Active Comparator)
Treatment with TAC + MMF + corticosteroids
tac + mmf + corticosteroids
•Dose of TAC: Trough levels (C-0h) of TAC in whole blood should be maintained between 6-10 ng/mL until Week 52 post-transplant. •Dose of MMF: Doses of 500-1000 mg/12 hrs will be maintained until Week 52. •Corticosteroids: During the study, oral corticosteroids will be administered in accordance with local clinical practice, although a therapeutic strategy free of corticosteroids is permitted (e.g. in patients with a history of HCV). It is recommended in any case that corticosteroids not be administered beyond Week 24 post-transplant except in cases of hepatopathy of autoimmune origin. At each centre all patients should follow the same administration protocol for corticosteroids based on history of HCV.

Primary Outcomes

Measure
Difference in the percentage of patients showing clinical benefit
time frame: week 4, week 52.

Secondary Outcomes

Measure
Changes in creatinine clearance (Cockcroft-Gault formula) and in eGFR (MDRD-4, MDRD-6)
time frame: Screening visit, weeks 1,4,12,24,36 and 52 post-trasplant
Urine protein/creatinine ratio and proteinuria (g/day)
time frame: Screening visit, week 1,4,6,8,12,18,24,36,52
Acute rejection
time frame: As needed
BPAR, loss of the graft and death
time frame: As needed
Treated BPAR
time frame: As needed
• HCV-positive patients: HCV-RNA viral load, HCV genotype
time frame: Screening visit, week 4, 12, 24, 52
Biomarkers of immunosuppression
time frame: week 1,4,5,6,8,12,18,24,36,52

Eligibility Criteria

Male or female participants from 18 years up to 70 years old.

Screening Visit - Inclusion Criteria 1. Recipients age 18 or over receiving a first liver transplant from a cadaver donor. 2. Patients diagnosed with HCC must meet the Milan radiological criteria at the time of transplant (1 nodule ≤5 cm in diameter, or 2-3 nodules, all <3 cm in diameter). 3. Patients who have signed the informed consent to participate in the study. 4. Patients who by medical criteria are capable of complying with the study regimen. Screening Visit - Exclusion Criteria 1. Recipients who have received multiple transplants of solid organs or pancreatic islet cells. 2. Patients who have previously received an organ or tissue transplant. 3. Patients with a combined liver-kidney transplant. 4. Recipients of lobes or segments of liver from a live donor. 5. A history of malignancy of any organ system in the previous 3 years according to local protocols (regardless of signs of local recurrence or metastasis), other than non-metastasising basal cell carcinoma or squamous cell carcinoma (epidermoid carcinoma) of the skin, or HCC. 6. Patients with known hypersensitivity to the drugs used in the study or others of their class, or to any of their excipients. 7. Recipients of ABO-incompatible transplants. 8. Patients who test positive for HIV. 9. Recipients of organs from donors who tested positive for the hepatitis B surface antigen or HIV seropositive. 10. Patients with any medical or surgical condition that in the opinion of the investigator may significantly alter the absorption, distribution, metabolism or excretion of the study medication. 11. Women of childbearing potential (i.e. women who are not postmenopausal with amenorrhoea of more than 1 year or surgically sterile) who are planning to become pregnant, are pregnant and/or breastfeeding, or who do not wish to use effective contraception, e.g. hormonal contraceptives (implantation, patches, oral) and double-barrier methods (any double combination of: IUD, male or female condoms with spermicidal gel, diaphragm, contraceptive sponge, cervical cap). 12. Patients who are taking part in another clinical trial. Randomisation Visit - Inclusion Criteria 1. Functioning allograft at the time of randomisation. A functioning allograft is defined as: 1. levels of AST, ALT and total bilirubin ≤ 4 times the upper limit of normal, and 2. levels of alkaline phosphatase and GGT ≤ 5 times the upper limit of normal. 2. Glomerular filtrate ≥30 mL/min/1.73 m2 (calculated using the MDRD-4 equation). Randomisation Visit - Exclusion Criteria 1. Patients with proteinuria ≥1.0 g/24 hrs confirmed in the urine sample (protein/creatinine ratio) that cannot be explained by immediate post-operative causes. 2. Patients with severe hypercholesterolaemia (≥350 mg/dL; ≥9 mmol/L) or severe hypertriglyceridaemia (≥750 mg/dL; ≥8.5 mmol/L). 3. Patients with a platelet count ≤50,000/mm3. 4. Patients with an absolute neutrophil count ≤1,000/mm3 or WBC count ≤2,000/mm3. 5. Patients who cannot take oral medication. 6. Patients with clinically significant systemic infection who require active use of intravenous antibiotics. 7. Patients who are in intensive care units and require vital support measures such as mechanical ventilation, dialysis, or vasoactive drugs. 8. Patients who have required renal replacement therapy in the 7 days prior to randomisation. 9. Patients who have had an episode of acute rejection and have required antibody therapy or who have had more than one episode of corticosteroid-sensitive acute rejection.

Additional Information

Official title A Multicentre, Randomised, Open-label, Controlled, 12-month Follow-up Study to Assess Impact on Renal Function of an Immunosuppression Regimen Based on Tacrolimus Minimisation in Association With Everolimus in de Novo Liver Transplant Recipients. The REDUCE Study.
Trial information was received from ClinicalTrials.gov and was last updated in January 2016.
Information provided to ClinicalTrials.gov by Novartis.