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.

NCT ID: NCT02040584

Last Updated: 2019-06-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 217 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-20
• Study Completion Date: 2016-02-10

Brief 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 was 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.

Detailed Description

A multicentre, randomized, open-label, controlled, exploratory clinical trial with 12-months (52 weeks) of follow-up.

Conditions

Liver Transplant

Study Design

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

Study Groups

Minimisation of TAC

Treatment with rTAC+EVR+corticosteroids

Group Type: EXPERIMENTAL

Minimisation of TAC

Intervention Type: DRUG

•EVR: Treatment started at a total daily dose of 2 mg within 24 hours after randomisation. The dose of EVR was adjusted upon reaching trough levels (C-0h) in whole blood of 3-8 ng/mL. The daily dose (in two administrations) of EVR may have been modified to maintain trough levels (C-0h) in whole blood of 3-8 ng/mL until Week 52 post-transplant. •TAC: Once confirmation was obtained, beginning in Week 5, that trough levels (C-0h) in whole blood of EVR were between 3-8 ng/mL, minimisation of TAC began, 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 were levels that should have been maintained until Week 52 post-transplant. •MMF was withdrawn at the same time that EVR was introduced. •oral corticosteroids was administered in accordance with local clinical practice, although a therapeutic strategy free of corticosteroids was permitted

TAC + MMF + corticosteroids

Treatment with TAC + MMF + corticosteroids

Group Type: ACTIVE_COMPARATOR

TAC + MMF + corticosteroids

Intervention Type: DRUG

•Dose of TAC: Trough levels (C-0h) of TAC in whole blood should have been maintained between 6-10 ng/mL until Week 52 post-transplant. •Dose of MMF: Doses of 500-1000 mg/12 hrs was maintained until Week 52. •Corticosteroids: During the study, oral corticosteroids was administered in accordance with local clinical practice, although a therapeutic strategy free of corticosteroids was permitted (e.g. in patients with a history of HCV). It was 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 have followed the same administration protocol for corticosteroids based on history of HCV.

Interventions

Minimisation of TAC

•EVR: Treatment started at a total daily dose of 2 mg within 24 hours after randomisation. The dose of EVR was adjusted upon reaching trough levels (C-0h) in whole blood of 3-8 ng/mL. The daily dose (in two administrations) of EVR may have been modified to maintain trough levels (C-0h) in whole blood of 3-8 ng/mL until Week 52 post-transplant. •TAC: Once confirmation was obtained, beginning in Week 5, that trough levels (C-0h) in whole blood of EVR were between 3-8 ng/mL, minimisation of TAC began, 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 were levels that should have been maintained until Week 52 post-transplant. •MMF was withdrawn at the same time that EVR was introduced. •oral corticosteroids was administered in accordance with local clinical practice, although a therapeutic strategy free of corticosteroids was permitted

Intervention Type: DRUG

TAC + MMF + corticosteroids

•Dose of TAC: Trough levels (C-0h) of TAC in whole blood should have been maintained between 6-10 ng/mL until Week 52 post-transplant. •Dose of MMF: Doses of 500-1000 mg/12 hrs was maintained until Week 52. •Corticosteroids: During the study, oral corticosteroids was administered in accordance with local clinical practice, although a therapeutic strategy free of corticosteroids was permitted (e.g. in patients with a history of HCV). It was 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 have followed the same administration protocol for corticosteroids based on history of HCV.

Intervention Type: DRUG

Eligibility Criteria

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) - at time of patient's inclusion on the waiting list.

Anh: done.

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.

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).

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.

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Córdoba, Andalusia, Spain

Novartis Investigative Site

Málaga, Andalusia, Spain

Novartis Investigative Site

Seville, Andalusia, Spain

Novartis Investigative Site

Barakaldo, Basque Country, Spain

Novartis Investigative Site

Valladolid, Castille and León, Spain

Novartis Investigative Site

Barcelona, Catalonia, Spain

Novartis Investigative Site

Barcelona, Catalonia, Spain

Novartis Investigative Site

L'Hospitalet de Llobregat, Catalonia, Spain

Novartis Investigative Site

A Coruña, Galicia, Spain

Novartis Investigative Site

Santiago de Compostela, Galicia, Spain

Novartis Investigative Site

El Palmar, Murcia, Spain

Novartis Investigative Site

Pamplona, Navarre, Spain

Novartis Investigative Site

Oviedo, Principality of Asturias, Spain

Novartis Investigative Site

Valencia, Valencia, Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Santa Cruz de Tenerife, , Spain

Novartis Investigative Site

Zaragoza, , Spain

Countries

Spain

Other Identifiers

2013-001191-38

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CRAD001HES01

Identifier Type: -

Identifier Source: org_study_id