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.

Study Overview
=================
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.

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.

Conditions
-----------------
Liver Transplant

Intervention / Treatment
-----------------
* Drug: Minimisation of TAC
* Drug: TAC + MMF + corticosteroids


Participation Criteria
=================
Eligibility Criteria
-----------------
Screening Visit - Inclusion Criteria Recipients age 18 or over receiving a first liver transplant from a cadaver donor. 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. 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. Screening Visit - Exclusion Criteria 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. Randomisation Visit - Inclusion Criteria 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. Glomerular filtrate ≥30 mL/min/1.73 m2 (calculated using the MDRD-4 equation). Randomisation Visit - Exclusion Criteria 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. Patients with severe hypercholesterolaemia (≥350 mg/dL; ≥9 mmol/L) or severe hypertriglyceridaemia (≥750 mg/dL; ≥8.5 mmol/L). Patients with a platelet count ≤50,000/mm3. Patients with an absolute neutrophil count ≤1,000/mm3 or WBC count ≤2,000/mm3. Patients who cannot take oral medication. Patients with clinically significant systemic infection who require active use of intravenous antibiotics. Patients who are in intensive care units and require vital support measures such as mechanical ventilation, dialysis, or vasoactive drugs. Patients who have required renal replacement therapy in the 7 days prior to randomisation. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A multicentre, randomized, open-label, controlled, exploratory clinical trial with 12-months (52 weeks) of follow-up.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Minimisation of TAC<br>Treatment with rTAC+EVR+corticosteroids | Drug: Minimisation of TAC<br>* •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<br>|
| Active Comparator: TAC + MMF + corticosteroids<br>Treatment with TAC + MMF + corticosteroids | Drug: TAC + MMF + corticosteroids<br>* •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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Creatinine Clearance - Cockcroft-Gault Formula | Kidney function was assessed over time by creatine clearance based on the Cockcroft-Gault formula. Estimated creatinine clearance (mL/min) = [(140 - age) x (weight) x (0.85 if female)] / (72 x serum creatinine). Units: age (years); weight (kg); serum creatinine (mg/dL). The values of the eGFR according to the creatinine clearance (Cockcroft-Gault formula) for the ITT population were ml/min/1.73 m^2. | Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant | 
| Changes in eGFR Based on the MDRD-4 Formula | Kidney function was assessed over time by changes in eGFR according to the MDRD-4 formula. The MDRD-4 formula (Levey et al., 2000) was used based on serum concentration of creatinine (conventional units): eGFR (mL/min/1.73 m2) = 186 x (serum creatinine)-1.154 x (age)-0.203 x (0.742 if female) x (1.210 if of African descent). Units: serum creatinine (mg/dL); age (years). | Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant | 
| eGFR Values(MDRD-4 Formula) According to the MELD Score | Model for End Stage Liver Disease (MELD) score: ≤14, 15-19, 20-24, 25-29, ≥30. The higher the number indicates the urgency for transplant. | Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant | 
| Urine Protein/Creatinine Ratio | The urine protein/creatinine ratio was assessed throughout follow-up in both treatment groups. | Screening visit, week 1,4,18,24, and 52 | 
| Percentage of Participants With Incidence of Proteinuria | The incidence of proteinuria (≥0.5-0.9 g/day, ≥1.0-2.9 g/day and ≥3.0 g/day) was assessed throughout follow-up in both treatment groups. Proteinuria was defined as protein/creatinine ratio ≥ 0.5. | Screening visit, week 1,4,18,24, and 52 | 
| Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR | Liver biopsy had to be performed in all cases where acute rejection was suspected. Results of the biopsy were interpreted by the local pathologist (who did not known the treatment given to the patient) according to the Banff classification (1997). Biopsy-proven acute rejection (BPAR) defined as clinical suspicion of acute rejection confirmed in biopsy. Treated BPAR was deemed to be an episode of acute rejection in which the interpretation of the local pathologist showed that it reached any grade of acute rejection under the Banff classification, and for which anti-rejection therapy was administered. Loss of the liver allograft was deemed to have occurred the day that the patient was again included on the waiting list for liver transplant, the day he or she received another allograft or upon the death of the patient. All suspected hepatic allograft rejections were considered acute rejection | Throughout the study period, approximately 2 years and 2 months | 
| Time to Rejection | Time to acute rejection was calculated from the date of transplantation. Acute rejection date was taken from biopsy date, as the date of rejection was not collected. Time to treated BPAR was calculated from the date of transplantation. | Throughout study period, approximately 2 years and 2 months | 
| Severity of Rejection | Severity of acute rejection and treated BPAR was graded according to Banff criteria. Grade of acute rejection according to Banff criteria: mild, moderate, severe. | Throughout study period, approximately 2 years and 2 months | 
| Percentages of Participants With HCV-positive and HCV Genotype | The viral load of HCV-RNA and HCV genotype was assessed in HCV-positive patients. The term genotype was used to describe strains of HCV that vary but were related to the virus. Worldwide, there were 11 primary groups of HCV genotypes designated by the numbers from 1-11, with the most common in our setting being subtypes 1a, 1b, 2 and 3, which were identified in the local laboratory according to their usual testing methods. | approximately 2 years and 2 months | 
| Concentration of p-P70S6K | the biomarker of personal response to everolimus, monitoring of the activity of the target, kinase P70 S6, in its phosphorylated form at Thr389. EVR=everolimus Cmin=minimum concentration | weeks 6,8,12,18,24,36,52 at 0 (Cmin), and 1 (C1h) hrs post-dose. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
De Novo Liver Transplant, Tacrolimus Minimisation, Everolimus, Renal Function, Liver transplant, allograft rejection, xenograft rejection, host vs graft disease