Clinical trial NCT02040584: 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.
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Liver Transplant
Keywords: De Novo Liver Transplant, Tacrolimus Minimisation, Everolimus, Renal Function, Liver transplant, allograft rejection, xenograft rejection, host vs graft disease
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-01-20
Enrollment: 217
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A multicentre, randomized, open-label, controlled, exploratory clinical trial with 12-months (52 weeks) of follow-up".
Primary purpose: TREATMENT

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.

Eligibility criteria: 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) - 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.

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.

Primary outcomes:
measure: Percentages of Participants Showing Clinical Benefit by Renal Function Stratification
timeFrame: week 4, week 52.
Secondary outcomes:
measure: Changes in Creatinine Clearance - Cockcroft-Gault Formula
timeFrame: Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant
measure: Changes in eGFR Based on the MDRD-4 Formula
timeFrame: Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant
measure: eGFR Values(MDRD-4 Formula) According to the MELD Score
timeFrame: Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant
measure: Urine Protein/Creatinine Ratio
timeFrame: Screening visit, week 1,4,18,24, and 52
measure: Percentage of Participants With Incidence of Proteinuria
timeFrame: Screening visit, week 1,4,18,24, and 52
measure: Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR
timeFrame: Throughout the study period, approximately 2 years and 2 months
measure: Time to Rejection
timeFrame: Throughout study period, approximately 2 years and 2 months
measure: Severity of Rejection
timeFrame: Throughout study period, approximately 2 years and 2 months
measure: Percentages of Participants With HCV-positive and HCV Genotype
timeFrame: approximately 2 years and 2 months
measure: Concentration of p-P70S6K
timeFrame: weeks 6,8,12,18,24,36,52 at 0 (Cmin), and 1 (C1h) hrs post-dose.
Other outcomes:
Locations:
city: Cordoba
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Oviedo
country: Spain
facility: Novartis Investigative Site
state: Asturias
city: Valladolid
country: Spain
facility: Novartis Investigative Site
state: Castilla Y Leon
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Cataluña
city: L'Hospitalet de Llobregat
country: Spain
facility: Novartis Investigative Site
state: Cataluña
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: La Coruna
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Santiago de Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: El Palmar
country: Spain
facility: Novartis Investigative Site
state: Murcia
city: Pamplona
country: Spain
facility: Novartis Investigative Site
state: Navarra
city: Barakaldo
country: Spain
facility: Novartis Investigative Site
state: Pais Vasco
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Santa Cruz de Tenerife
country: Spain
facility: Novartis Investigative Site
city: Zaragoza
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: