Evaluation of Belatacept Versus Calcineurin Inhibitors on Endothelial Function in Kidney Transplant Recipients

The primary objective of this study is to demonstrate that the replacement of **anticalcineurins** with **Belatacept** in kidney transplant patients results in an improvement at 6 months in the endothelium-dependent dilation of peripheral conductance arteries in response to post-ischemic hyperemia. This is clinically relevant as it may enhance vascular function and potentially improve long-term outcomes in kidney transplant recipients.

Secondary objectives include:

• Demonstrating that the replacement of anticalcineurins with Belatacept allows an improvement at 6 months in endothelium-dependent dilation of peripheral conductance arteries during a sustained increase in blood flow.
• Demonstrating a reduction at 6 months in the rigidity of the aorta and its main branches.
• Demonstrating a reduction in peripheral and central blood pressure at 6 months.
• Demonstrating an increase at 6 months in the endothelial release of NO and EETs at the level of the peripheral conductance arteries during the sustained increase in blood flow.

The clinical trial involves participants who have undergone a **kidney transplant**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants are generally in stable health, as indicated by the requirement for stable renal function in the anticalcinurin group. The trial does not include a vulnerable population. The selection criteria for the trial population include patients who have been treated with anticalcineurins for more than a year or those who have undergone a graft biopsy due to impaired renal function, leading to the introduction of Belatacept. All participants must have had their kidney transplant more than a year prior to the study and must have received clear information about the trial, understood the information letter, and signed the consent form. Women participants are required to use contraception and have a negative pregnancy test or have experienced 12 months of amenorrhea. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the effects of **Belatacept** compared to anticalcineurins in patients who have undergone a **kidney transplant**. This study is structured as a randomized, double-blind, controlled trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias. The trial is expected to span a duration of approximately three years, with an estimated end date of August 1, 2027. Participants will be involved in the study for a period of six months, during which they will undergo a series of study visits to monitor their progress and gather data on the primary and secondary endpoints.

The sequence of study visits includes an initial inclusion (screening) visit, where eligibility criteria are assessed, followed by multiple follow-up visits. The primary endpoint is assessed by comparing the variation over six months in the amplitude of endothelium-dependent dilation during the post-ischemic hyperemia maneuver, measured by vascular ultrasound. Secondary endpoints include variations in distensibility, Young's elastic modulus, carotid-femoral pulse wave velocity, and blood concentrations of nitrites and epoxyeicosatrienoic acids. These measurements are taken at specific follow-up visits, designated as V2 and V3, to ensure consistent data collection.

Participants are expected to adhere to the study protocol for the entire six-month period unless specific conditions necessitate early termination. Such conditions may include adverse reactions to the investigational products, significant deviations from the protocol, or withdrawal of consent by the participant. The end-of-study visit will conclude the participant's involvement, where final assessments are conducted, and data is collected for analysis. The trial is categorized as low intervention, with investigational drugs used in accordance with their Summary of Product Characteristics (SmPC), ensuring safety and compliance with regulatory standards.

The clinical trial involves the administration of several treatments, including **Ciclosporin**, which is provided in the form of a soft capsule. The active substance, **Ciclosporin**, is of chemical origin. The medication is administered orally with a maximum daily dose of 12 mg/kg and a total maximum dose of 2562 mg/kg over a treatment period of up to 7 days. Participant compliance with the dosing schedule is monitored throughout the trial.

Another treatment used in the trial is **Tacrolimus**, available as a prolonged-release hard capsule. This chemical-origin medication is also administered orally. The maximum daily dose is 0.3 mg/kg, with a total maximum dose of 64 mg/kg, and the treatment period is limited to 7 days. The administration schedule is designed to ensure consistent therapeutic levels, and adherence is closely monitored.

The experimental medication **Belatacept** is provided as a powder for concentrate for solution for infusion, known commercially as NULOJIX 250 mg. The active substance, **Belatacept**, is a protein of other origin. It is administered via intravenous injection or infusion, with a maximum daily dose of 6 mg/kg and a total maximum dose of 54 mg/kg over a 7-day period. The infusion schedule is carefully managed to maintain optimal drug levels, and participant compliance is assessed regularly.

Additionally, **Glyceryl Trinitrate** is used as an auxiliary treatment in the form of a sublingual spray, marketed as NATISPRAY 0.30 mg/dose. This chemical-origin medication is administered sublingually, with a maximum daily dose of 0.3 mg and a total maximum dose of 0.6 mg over a 2-day period. The administration is intended for rapid onset of action, and adherence to the dosing regimen is monitored to ensure efficacy and safety.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints related to the improvement of endothelial function in kidney transplant patients. The primary endpoint focuses on comparing the variation over 6 months in the amplitude of **endothelium-dependent dilation** during the post-ischemic hyperemia maneuver. This will be measured using vascular ultrasound with automated software analysis in real-time between the Belatacept group and the anticalcineurin group. Measurements will be taken at specific visits, V2 and V3.

Secondary endpoints include several parameters: the variation over 6 months in the amplitude of endothelium-dependent dilation during distal skin heating, measured by echotracking; the variation in distensibility and Young's elastic modulus, indicators of carotid stiffness, measured 2 cm below the bifurcation by echotracking; and the variation in carotid-femoral pulse wave velocity (PWV), an indicator of aortic stiffness, measured by applanation tonometry. Additionally, the trial will compare the variation in humeral and carotid blood pressure measurements and the carotid augmentation index, an indicator of cardio-circulatory coupling, also measured by applanation tonometry. The augmentation index is calculated as the difference between the peak systolic and the inflection in protosystole, expressed as a percentage of the central pulse pressure. Furthermore, the trial will assess the variation over 6 months in blood concentrations of nitrites and epoxyeicosatrienoic acids (EETs), indicators of the availability of nitric oxide (NO), between temperatures of 44°C and 34°C. These secondary endpoints will also be evaluated at visits V2 and V3.