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.
- Conditions
- Liver Transplant
- Interventions
- Drug: TAC + MMF + corticosteroidsDrug: Minimisation of TAC
- Registration Number
- NCT02040584
- Lead Sponsor
- 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 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 217
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description TAC + MMF + corticosteroids TAC + MMF + corticosteroids Treatment with TAC + MMF + corticosteroids Minimisation of TAC Minimisation of TAC Treatment with rTAC+EVR+corticosteroids
- Primary Outcome Measures
Name Time Method Percentages of Participants Showing Clinical Benefit by Renal Function Stratification week 4, week 52. 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.
- Secondary Outcome Measures
Name Time Method Changes in Creatinine Clearance - Cockcroft-Gault Formula Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant 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.Urine Protein/Creatinine Ratio Screening visit, week 1,4,18,24, and 52 The urine protein/creatinine ratio was assessed throughout follow-up in both treatment groups.
Percentage of Participants With Incidence of Proteinuria Screening visit, week 1,4,18,24, and 52 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.
Severity of Rejection Throughout study period, approximately 2 years and 2 months Severity of acute rejection and treated BPAR was graded according to Banff criteria.
Grade of acute rejection according to Banff criteria: mild, moderate, severe.Percentages of Participants With HCV-positive and HCV Genotype approximately 2 years and 2 months 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.Concentration of p-P70S6K weeks 6,8,12,18,24,36,52 at 0 (Cmin), and 1 (C1h) hrs post-dose. 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 concentrationChanges in eGFR Based on the MDRD-4 Formula Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant 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).eGFR Values(MDRD-4 Formula) According to the MELD Score Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant 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.
Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR Throughout the study period, approximately 2 years and 2 months 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 rejectionTime to Rejection Throughout study period, approximately 2 years and 2 months 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.
Trial Locations
- Locations (1)
Novartis Investigative Site
🇪🇸Zaragoza, Spain