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. Phase 4 Clinical Trial. TIMTOR STUDY.
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. Phase 4 Clinical Trial. TIMTOR STUDY.
The overall objective of this project is to optimise preventive treatment of CMV infection/disease in renal transplant recipients at increased risk of CMV post-transplantation. The specific objectives are: (1) To compare the incidence of CMV infection/disease at 6 months post-transplant in Ig G CMV positive (R+CMV) recipients receiving induction treatment with thymoglobulin and one of the two maintenance immunosuppressive treatment regimens used in routine clinical practice : tacrolimus and MTOR inhibitors (group 1) or tacrolimus and mycophenolic acid (group 2); (2) To monitor CMV-specific cellular immunity before transplantation, at 15, 30 and 90 days post-transplantation. For this purpose, an exploratory phase 4 clinical trial has been designed in which will select 30 R+CMV patients receiving renal transplantation with induction treatment with thymoglobulin. After signing informed consent, patients will be randomised to receive one of the two immunosuppression regimens indicated above. The patients in group 1 will receive early therapy as a CMV prevention strategy and patients in group 2 will receive universal prophylaxis for 3 months. Follow-up visits to will be conducted according to the usual protocol and clinical and virological variables will be collected. In addition, blood samples will be collected for the assessment of CMV-specific cellular immunity before and after transplantation. The primary endpoint is the presence of CMV infection/disease post-renal transplantation at 6 months. Secondary variables include renal function, acute rejection, patient and graft survival and the occurrence of surgical or haematological complications.
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.
Inclusion Criteria:
Exclusion Criteria:
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