Evaluation of Tacrolimus and MTOR Inhibitors with Anticipatory Therapy Versus Tacrolimus and Mycophenolic Acid in High-Risk Renal Transplant Recipients

The primary objective of this study is to evaluate the **time from hospital arrival to revascularization** in patients with acute ischemic stroke undergoing mechanical thrombectomy. This assessment is crucial as it may influence the choice of anesthesia, comparing sedation with high-flow nasal cannula (HFNC) versus general anesthesia, which could impact patient outcomes. Additionally, the study aims to monitor the cytomegalovirus (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. This monitoring is significant for understanding the immune response in renal recipients at high risk of post-transplant CMV.

Secondary objectives include:

• Comparing between the two groups the incidence of delayed initial graft function, acute rejection diagnosed by renal biopsy, renal function, and patient and graft survival in the first 6 months post-transplantation.
• Comparing between the two groups the presence of surgical complications, such as lymphocele requiring intervention, or hematological complications, such as neutropenia, in the first 6 months post-transplantation.

The clinical trial involves participants diagnosed with **advanced chronic renal insufficiency**. The study population includes both male and female subjects, aged 18 years and older. The trial does not focus on a vulnerable population. Participants were selected based on specific inclusion criteria, such as having a positive pretransplant Ig G CMV serology and receiving immunosuppressive induction treatment with thymoglobulin. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the efficacy of different immunosuppressive regimens in renal transplant recipients at high risk of post-transplant **cytomegalovirus** (CMV) infection. The trial will compare the use of **tacrolimus** and MTOR inhibitors with anticipatory therapy against tacrolimus and **mycophenolic acid** with universal prophylaxis. The study is a Phase IV trial, aiming to optimize CMV prevention strategies in this patient population. The trial is expected to commence recruitment on June 1, 2025, and conclude by December 31, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), positive pretransplant IgG CMV serology, and receipt of immunosuppressive induction treatment with **thymoglobulin**. Following the screening, participants will be randomized into one of the treatment arms. The primary endpoint, the presence of CMV infection or disease, will be assessed at 6 months post-transplantation. Secondary endpoints include demographic variables, chronic kidney disease-related variables, donor variables, peri-transplant variables, and CMV-related variables.

The trial will involve multiple follow-up visits to monitor the CMV-specific cellular immune response at 15, 30, and 90 days post-transplantation using Quantiferon-CMV. The end-of-study visit will occur at the 6-month mark, where the primary endpoint will be evaluated. The expected length of participant involvement is approximately 6 months, with conditions for early termination including withdrawal of consent, adverse events, or protocol non-compliance.

Participants will receive one of the following investigational products: Myfortic 180 mg gastro-resistant tablets, Rapamune 0.5 mg coated tablets, TIMOGLOBULINA 5 mg/ml solution for infusion, prednisona cinfa 5 mg tablets, Advagraf 1 mg prolonged-release hard capsules, Urbason 40 mg solution for injection, or Valganciclovir Aurovitas 450 mg film-coated tablets. The administration routes include oral and intravenous use, with treatment periods varying from 3 to 176 days depending on the product. The trial is categorized as low intervention, with a focus on optimizing CMV prevention strategies in renal transplant recipients.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Mycophenolic acid**, marketed as Myfortic 180 mg gastro-resistant tablets, is administered orally. The maximum daily dose is 1440 mg, with a total maximum dose of 259200 mg over a treatment period of up to 6 months. This medication is classified as an immunosuppressor and is produced by Novartis Farmacéutica S.A.

**Sirolimus**, available as Rapamune 0.5 mg coated tablets, is also administered orally. The maximum daily dose is 0.5 mg/kg, with a total maximum dose of 45 mg/kg over a 3-month period. This immunosuppressor is manufactured by Pfizer Europe MA EEIG.

**Rabbit anti-human thymocyte immunoglobulin**, known as TIMOGLOBULINA 5 mg/ml, is provided as a solution for infusion. It is administered intravenously with a maximum daily dose of 1 mg/kg and a total maximum dose of 7 mg/kg over a 7-day period. This immunosuppressor is produced by Sanofi B.V.

**Prednisone**, marketed as prednisona cinfa 5 mg tablets, is administered orally. The maximum daily dose is 20 mg, with a total maximum dose of 1480 mg over a treatment period of up to 176 days. This medication is classified as a corticoid and is produced by Laboratorios Cinfa S.A.

**Tacrolimus**, available as Advagraf 1 mg prolonged-release hard capsules, is administered orally. The maximum daily dose is 0.1 mg/kg, with a total maximum dose of 17.3 mg/kg over a treatment period of up to 173 days. This immunosuppressor is manufactured by Astellas Pharma Europe B.V.

**Methylprednisolone sodium succinate**, marketed as Urbason 40 mg solution for injection, is administered via intravenous injection. The maximum daily dose is 100 mg, with a total maximum dose of 1830 mg over a 6-day period. This glucocorticoid is produced by Fidia Farmaceutici S.p.A.

**Valganciclovir**, available as Valganciclovir Aurovitas 450 mg film-coated tablets, is administered orally. The maximum daily dose is 900 mg, with a total maximum dose of 75600 mg over a 12-week period. This antiviral medication is produced by Aurovitas Spain, S.A.U.

The efficacy of the clinical trial will be assessed primarily through the evaluation of the presence of **Cytomegalovirus (CMV)** infection or disease after renal transplantation. This primary endpoint will be measured at 6 months post-transplantation. The study will monitor the 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. This method provides a quantitative measure of the immune response to CMV, which is crucial for assessing the efficacy of the prophylactic strategies being tested.

Secondary endpoints will include a range of recipient and donor variables. Recipient demographic variables such as gender and age, as well as variables related to chronic kidney disease (CKD), including the etiology of CKD, renal replacement therapy (RRT) prior to transplantation, and time on RRT in months, will be collected. Donor variables will encompass demographics (age and sex), cause of death, donor type (living, cadaveric, and cadaveric donor type), and Ig G CMV serology. Additionally, peri-transplant and CMV-related variables will be analyzed to provide a comprehensive assessment of the factors influencing the efficacy of the treatment regimens.