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.

NCT02040584 | Completed Phase 3 Results

• 2 other identifiers: CRAD001HES012013-001191-38
• Study Type: interventional
• Target: 217
• Locations: 1 country
• Sites: 20

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.

Conditions

Liver Transplant

Keywords

De Novo Liver Transplant, Tacrolimus Minimisation, Everolimus, Renal Function, Liver transplant, allograft rejection, xenograft rejection, host vs graft disease

Outcome Measures

Primary Outcomes (1)

• Percentages of Participants Showing Clinical Benefit by Renal Function Stratification

  Clinical benefit is defined as: • an improvement in 1 or 2 ranges of the eGFR, according to MDRD-4 at Week 52 post-transplant in patients with values of 30-\<45 or 45-\<60 mL/min/1.73 m2 in Week 4. or • stabilisation of eGFR in patients with values ≥60 mL/min/1.73 m2 at Week 4 and maintained at Week 52 post-transplant.

  week 4, week 52.

Secondary Outcomes (10)

• Changes in Creatinine Clearance - Cockcroft-Gault Formula

  Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant

• Changes in eGFR Based on the MDRD-4 Formula

  Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant

• eGFR Values(MDRD-4 Formula) According to the MELD Score

  Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant

• Urine Protein/Creatinine Ratio

  Screening visit, week 1,4,18,24, and 52

• Percentage of Participants With Incidence of Proteinuria

  Screening visit, week 1,4,18,24, and 52

Study Arms (2)

Minimisation of TAC

EXPERIMENTAL

Treatment with rTAC+EVR+corticosteroids

Drug: Minimisation of TAC

TAC + MMF + corticosteroids

ACTIVE COMPARATOR

Treatment with TAC + MMF + corticosteroids

Drug: TAC + MMF + corticosteroids

Interventions

Minimisation of TAC 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

Minimisation of TAC

TAC + MMF + corticosteroids 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.

TAC + MMF + corticosteroids

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Recipients age 18 or over receiving a first liver transplant from a cadaver donor.
• Anh: done.
• Patients who have signed the informed consent to participate in the study.
• Patients who by medical criteria are capable of complying with the study regimen.

You may not qualify if:

• Recipients who have received multiple transplants of solid organs or pancreatic islet cells.
• Patients who have previously received an organ or tissue transplant.
• Patients with a combined liver-kidney transplant.
• Recipients of lobes or segments of liver from a live donor.
• 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.
• Patients with known hypersensitivity to the drugs used in the study or others of their class, or to any of their excipients.
• Recipients of ABO-incompatible transplants.
• Patients who test positive for HIV.
• Recipients of organs from donors who tested positive for the hepatitis B surface antigen or HIV seropositive.
• 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.
• 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).
• Patients who are taking part in another clinical trial.
• Functioning allograft at the time of randomisation. A functioning allograft is defined as:
• levels of AST, ALT and total bilirubin ≤ 4 times the upper limit of normal, and
• levels of alkaline phosphatase and GGT ≤ 5 times the upper limit of normal.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (20)

Novartis Investigative Site

Córdoba, Andalusia, 14004, Spain

Location

Novartis Investigative Site

Málaga, Andalusia, 29010, Spain

Location

Novartis Investigative Site

Seville, Andalusia, 41013, Spain

Location

Novartis Investigative Site

Barakaldo, Basque Country, 48903, Spain

Location

Novartis Investigative Site

Valladolid, Castille and León, 47012, Spain

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

Barcelona, Catalonia, 08036, Spain

Location

Novartis Investigative Site

L'Hospitalet de Llobregat, Catalonia, 08907, Spain

Location

Novartis Investigative Site

A Coruña, Galicia, 15006, Spain

Location

Novartis Investigative Site

Santiago de Compostela, Galicia, 15706, Spain

Location

Novartis Investigative Site

El Palmar, Murcia, 30120, Spain

Location

Novartis Investigative Site

Pamplona, Navarre, 31008, Spain

Location

Novartis Investigative Site

Oviedo, Principality of Asturias, 33011, Spain

Location

Novartis Investigative Site

Valencia, Valencia, 46026, Spain

Location

Novartis Investigative Site

Madrid, 28007, Spain

Location

Novartis Investigative Site

Madrid, 28034, Spain

Location

Novartis Investigative Site

Madrid, 28041, Spain

Location

Novartis Investigative Site

Madrid, 28222, Spain

Location

Novartis Investigative Site

Santa Cruz de Tenerife, 38009, Spain

Location

Novartis Investigative Site

Zaragoza, 50009, Spain

Location

MeSH Terms

Conditions

Graft vs Host Disease

Interventions

Adrenal Cortex Hormones

Condition Hierarchy (Ancestors)

Immune System Diseases

Intervention Hierarchy (Ancestors)

Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

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

Study Record Dates

• First Submitted: January 7, 2014
• First Posted: January 20, 2014
• Study Start: December 20, 2013
• Primary Completion: February 10, 2016
• Study Completion: February 10, 2016
• Last Updated: June 13, 2019
• Results First Posted: June 13, 2019

Record last verified: 2019-03

Locations

ES (20)