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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. (REDUCE)

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ClinicalTrials.gov Identifier: NCT02040584
Recruitment Status : Completed
First Posted : January 20, 2014
Last Update Posted : February 8, 2017
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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 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.

Condition or disease Intervention/treatment Phase
Liver Transplant Drug: Minimisation of TAC Drug: TAC + MMF + corticosteroids Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 194 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : December 2013
Actual Primary Completion Date : February 2016
Actual Study Completion Date : February 2016


Arm Intervention/treatment
Experimental: Minimisation of TAC
Treatment with rTAC+EVR+corticosteroids
Drug: 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: TAC + MMF + corticosteroids
Treatment with TAC + MMF + corticosteroids
Drug: 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 Outcome Measures :
  1. Difference in the percentage of patients showing clinical benefit [ Time Frame: week 4, week 52. ]
    The primary efficacy endpoint will be the difference in the percentage of patients showing clinical benefit, 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.


Secondary Outcome Measures :
  1. 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 ]
    Kidney function will be assessed over time by changes in eGFR (according to the Cockcroft-Gault, MDRD-4 and MDRD-6 formulas) from transplant (Screening Visit), and including weeks 1, 4, 12, 24, 36 and 52 post-transplant in both treatment groups.

  2. Urine protein/creatinine ratio and proteinuria (g/day) [ Time Frame: Screening visit, week 1,4,6,8,12,18,24,36,52 ]
    The urine protein/creatinine ratio will be assessed throughout follow-up in both treatment groups. The incidence of proteinuria (≥0.5-0.9 g/day, ≥1.0-2.9 g/day and ≥3.0 g/day) will be assessed throughout follow-up in both treatment groups (number and percentage of new cases and accumulated percentage of patients per visit)

  3. Acute rejection [ Time Frame: As needed ]
    Acute rejection will be assessed for (1) incidence, (2) time to rejection, and (3) severity, in both treatment groups.

  4. BPAR, loss of the graft and death [ Time Frame: As needed ]
    The incidence of BPAR, loss of the graft and death will be assessed in both treatment groups (number and percentage of new cases and accumulated percentage of patients per visit).

  5. Treated BPAR [ Time Frame: As needed ]
    Treated BPAR will be assessed for (1) incidence, (2) time to rejection, (3) severity and (4) reason for transplant in both treatment groups.

  6. • HCV-positive patients: HCV-RNA viral load, HCV genotype [ Time Frame: Screening visit, week 4, 12, 24, 52 ]
    The viral load of HCV-RNA and HCV genotype (describing the genotypes present) will be assessed in HCV-positive patients

  7. Biomarkers of immunosuppression [ Time Frame: week 1,4,5,6,8,12,18,24,36,52 ]
    A panel of specific biomarkers of immunosuppression will be assessed in a subgroup of patients from each treatment group. For that purpose, the effector/regulatory immune response will first be analysed by using the IFN-/IL-12p70 ratio. Secondly, an analysis will be made of the ratios between levels of various biomarkers of suppression (p70-S6 kinase, IL-12p70, IL-6, IL-10, IFN-, TGF- and IP-10) and the clinical response of the patient (acute rejection or otherwise) by using a t-test and, finally, algorithms will be defined to predict exposure to the drug (rTAC-EVR vs. TAC-MMF) and the clinical response of the patient (acute rejection or otherwise) by using a logistical regression model that fixes the group as a covariable.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02040584


Locations
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Spain
Novartis Investigative Site
Cordoba, Andalucia, Spain, 14004
Novartis Investigative Site
Malaga, Andalucia, Spain, 29010
Novartis Investigative Site
Sevilla, Andalucia, Spain, 41013
Novartis Investigative Site
Oviedo, Asturias, Spain, 33011
Novartis Investigative Site
Valladolid, Castilla y Leon, Spain, 47012
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site
Barcelona, Cataluña, Spain, 08036
Novartis Investigative Site
L'Hospitalet de Llobregat, Cataluña, Spain, 08907
Novartis Investigative Site
Valencia, Comunidad Valenciana, Spain, 46026
Novartis Investigative Site
La Coruna, Galicia, Spain, 15006
Novartis Investigative Site
Santiago de Compostela, Galicia, Spain, 15706
Novartis Investigative Site
Majadahonda, Madrid, Spain, 28222
Novartis Investigative Site
El Palmar, Murcia, Spain, 30120
Novartis Investigative Site
Pamplona, Navarra, Spain, 31008
Novartis Investigative Site
Barakaldo, Pais Vasco, Spain, 48903
Novartis Investigative Site
Madrid, Spain, 28007
Novartis Investigative Site
Madrid, Spain, 28034
Novartis Investigative Site
Madrid, Spain, 28041
Novartis Investigative Site
Santa Cruz de Tenerife, Spain, 38009
Novartis Investigative Site
Zaragoza, Spain, 50009
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02040584     History of Changes
Other Study ID Numbers: CRAD001HES01
First Posted: January 20, 2014    Key Record Dates
Last Update Posted: February 8, 2017
Last Verified: February 2017

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
De Novo Liver Transplant Recipients, Tacrolimus Minimisation, Everolimus, Renal Function

Additional relevant MeSH terms:
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Tacrolimus
Everolimus
Sirolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents