Evaluation of Standard Immunosuppression with Tacrolimus and Mycophenolate Mofetil Versus Low-Dose Tacrolimus and Everolimus in Elderly De Novo Renal Transplant Recipients

The primary objective of the OPTIMIZE study is to evaluate the **successful transplantation** in elderly patients undergoing de novo **kidney transplant**. This is defined for the individual strata and analyzed for the entire study population. In Stratum A, the primary endpoint is successful transplantation at two years post-transplantation, characterized by the absence of graft or patient loss and an estimated glomerular filtration rate (eGFR) above 30 ml/min/1.73m². In Stratum B, the primary endpoint is defined similarly, with an eGFR threshold of above 45 ml/min/1.73m². The clinical relevance of this study lies in optimizing immunosuppressive regimens to improve transplant outcomes in this specific patient population.

Secondary objectives include the analysis of successful transplantation outcomes separately per stratum, providing further insights into the stratified efficacy of the treatment regimens.

The clinical trial involves participants who have undergone a **kidney transplant**. The study population includes both male and female subjects aged 65 years and older. Participants are required to have been randomized within 24 hours following the completion of transplant surgery. The trial includes recipients of either a primary or secondary renal transplant, provided the first graft was not lost due to immunological reasons. The donors for these transplants are either deceased individuals aged 65 years or older, or living donors of any age. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, open-label, multicenter study to evaluate the efficacy of different immunosuppressive regimens in patients undergoing **kidney transplant**. The trial aims to compare standard immunosuppression with tacrolimus and mycophenolate mofetil against a low exposure tacrolimus regimen combined with everolimus. The study is structured to include two strata based on the age of the deceased donor, with specific endpoints defined for each stratum. The primary endpoint is the successful transplantation at two years, characterized by the absence of graft or patient loss and maintaining an estimated glomerular filtration rate (eGFR) above specified thresholds.

The trial is expected to run from July 22, 2019, to March 28, 2025, with participant involvement lasting up to 24 months post-transplantation. The study includes several key visits: an initial **screening** visit to confirm eligibility, randomization within 24 hours post-surgery, and follow-up visits at 12 and 24 months to assess primary and secondary endpoints. The end-of-study visit will occur at the 24-month mark, where final assessments will be conducted. Participants may be withdrawn from the study if they experience significant adverse events, serious adverse reactions, or if they fail to adhere to the study protocol.

Inclusion criteria require participants to be 65 years or older, having received a primary or secondary renal transplant from a deceased donor, with informed consent obtained prior to any study-related procedures. The study will monitor various outcomes, including the incidence of death, graft loss, eGFR changes, treated biopsy-proven rejection, and adverse events. Additionally, the trial will evaluate the presence of frailty, immunosenescence markers, health-related quality of life, and the development of donor-specific anti-HLA antibodies over the study period.

The clinical trial involves the administration of several **experimental medications**. **Prednisolone 5mg Soluble Tablets** are utilized in the study, with the active substance being **prednisolone**. These tablets are administered orally, with a maximum daily dose of 999 mg and a total treatment period of up to 1200 days. The pharmaceutical form is soluble tablets, and the product is manufactured by Morningside Healthcare Ltd.

**Certican 0.75 mg tablets**, containing the active substance **everolimus**, are also part of the trial. These tablets are administered orally, with a maximum daily dose of 999 mg and a treatment period of up to 1200 days. The tablets are produced by Novartis Slovakia S.R.O.

Another medication used is **Mycofenolaat mofetil Sandoz 250 mg, capsules, hard**, with the active substance **mycophenolate mofetil**. These capsules are administered orally, with a maximum daily dose of 999 mg and a treatment period of up to 1200 days. The manufacturer is Sandoz B.V.

**Envarsus 0.75 mg prolonged-release tablets** are included in the study, containing the active substance **tacrolimus**. These tablets are administered orally, with a maximum daily dose of 999 mg and a treatment period of up to 1200 days. The tablets are produced by Chiesi Farmaceutici S.P.A.

**Simulect 20 mg powder and solvent for solution for injection or infusion** is used, with the active substance **basiliximab**. This medication is administered via infusion, with a maximum daily dose of 20 mg and a total dose of 40 mg over a treatment period of 2 days. The product is manufactured by Novartis Europharm Limited.

Lastly, **Ciclosporine Teva 25 mg, zachte capsules** are part of the trial, containing the active substance **ciclosporin**. These soft capsules are administered orally, with a maximum daily dose of 999 mg and a treatment period of up to 1200 days. The manufacturer is Teva B.V.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.

Efficacy in the clinical trial will be assessed using a range of primary endpoints focused on the success of renal transplantation. The primary endpoint is defined as "successful transplantation" at two years post-transplantation, characterized by the absence of graft or patient loss and an estimated glomerular filtration rate (eGFR) above 30 ml/min/1.73m² for Stratum A, and above 45 ml/min/1.73m² for Stratum B. Additional primary endpoints include the incidence of individual endpoints such as death, graft loss, and eGFR below the specified thresholds at 12 and 24 months, as well as the incidence of treated biopsy-proven acute rejection (tBPAR).

Secondary efficacy parameters include the evolution of renal function over time, measured by eGFR and creatinine clearance, and the incidence of adverse events, serious adverse events, and adverse reactions. The presence of frailty and markers for **immunosenescence** at 12 and 24 months, as well as changes from baseline, will also be evaluated. Health-related quality of life (HRQoL) will be assessed at baseline, 12, and 24 months, with changes from baseline being recorded. The development of donor-specific anti-HLA antibodies (DSA) and differences in illness perception, BAASIS, and symptoms (DSI + MTSOSD-59) at specified timepoints will be analyzed. The iBOX predicted outcome will be evaluated at 3, 5, and 7 years.

Data collection will occur at multiple timepoints, including baseline, 12 months, and 24 months, with specific assessments scheduled for each endpoint. The analysis will employ validated scales and laboratory tests to ensure accuracy and reliability in measuring the efficacy parameters. The trial will utilize a comprehensive approach to evaluate the efficacy of the treatment regimen in elderly patients undergoing renal transplantation.