Use of Tacrolimus and MTOR Inhibitors With Anticipatory Therapy vs. Tacrolimus and Mycophenolic Acid With Universal Prophylaxis in Renal Recipients at High Risk of Posttransplant Cytomegalovirus.

HYPOTHESIS The use of immunosuppressive maintenance therapy including mTOR inhibitors versus the use of mycophenolic acid in kidney transplant patients with an increased risk of post-transplant CMV disease (R+CMV receiving induction with thymoglobulin) will allow optimisation of the preventive treatment of these patients, presenting a similar incidence of post-transplant CMV disease in both groups and better maintenance of CMV-specific cellular immunity post-transplant.

OBJECTIVES General Objective: To improve the preventive treatment of CMV disease in renal transplant patients at increased risk.

Main Objectives: (1) To compare the incidence of CMV disease at 6 months post-renal transplant in Ig G CMV-positive recipients receiving induction treatment with thymoglobulin and maintenance treatment with tacrolimus and mTOR inhibitors (group 1) with CMV prevention strategy of anticipatory therapy or tacrolimus and mycophenolic acid (group 2) with CMV prevention strategy with universal prophylaxis. (2) Monitor CMV-specific cellular immune response before transplantation and at 15, 30 and 90 days post-transplantation in each of the two treatment groups using Quantiferon-CMV.

Secondary Objectives: (3) To compare between the two groups the incidence of CMV infection, delayed initial graft function, acute rejection diagnosed by renal biopsy, renal function and patient and graft survival in the first 6 months post-transplant. (4) To compare between the two groups the presence of surgical (lymphocele requiring intervention) or haematological (neutropenia) complications in the first 6 months post-transplantation.

STUDY DESIGN Phase IV, exploratory, randomised, open-label, single-centre, exploratory clinical trial to evaluate the effectiveness of CMV prevention strategies comparing early therapy vs. universal prophylaxis in Ig G CMV-positive kidney transplant recipients treated with thymoglobulin receiving tacrolimus and mTOR inhibitors (group 1) vs. tacrolimus and mycophenolic acid (group 2).

Patients who meet the inclusion criteria and who sign the informed consent form the day before transplant surgery (pre-transplant day) will have a blood sample taken for CMV-specific cellular immunity analysis using quantiferon CMV and will be randomised into two groups on the day of renal transplant surgery (day 0).

a) Group 1: Will receive, as a CMV prevention strategy, early therapy, and as maintenance immunosuppressive treatment steroids, tacrolimus and mTOR inhibitors. b) Group 2: Will receive, as a CMV prevention strategy, universal prophylaxis, and as maintenance immunosuppressive therapy steroids, tacrolimus and mycophenolic acid. A randomisation list will be generated using SAS 9.4. software, in order to achieve a balanced randomisation in the treatment groups. The ratio will be 1:1 for each group and stratified by sex.

Definition of the groups: Group 1: Will receive early therapy, as a prevention strategy, which consists of starting antiviral treatment with valganciclovir (900 mg/12 hours, adjusted to renal function, according to the technical data sheet) when CMV viral replication is detected in blood above 1,000 copies/ml and treatment will be suspended when the viral load is negative in two consecutive controls.

Group 2: will receive universal prophylaxis with valganciclovir (900 mg/24 hours, adjusted to renal function, according to technical data sheet) during the first 3 months post-transplant, as a CMV prevention strategy.

All patients will receive immunosuppressive induction treatment with thymoglobulin (at least 1 dose and a maximum of 5 doses) and immunosuppressive maintenance treatment with tacrolimus + mTOR inhibitors (patients in group 1) or tacrolimus + mycophenolic acid (patients in group 2) following the guidelines of the technical file and the centre's usual protocols.

Follow-up visits will be performed at 15, 30, 90, 120, 120, 150 and 180 days post-transplant where clinical, analytical, virological (CMV viral loads by PCR in whole blood) and immunological (analysis of CMV-specific cellular immunity by CMV quantiferon) data of the patients will be evaluated. Data on the presence or absence of CMV infection or disease at each visit, concomitant medication changes and adverse events will also be collected.

• To compare between the two groups the incidence of CMV infection, delayed initial graft function, acute rejection diagnosed by renal biopsy, renal function and patient and graft survival [Time frame: 6 months]
• To compare the presence of surgical (lymphocele requiring intervention) or haematological (neutropenia) complications [Time frame: 6 months]