A single-arm, multi-centre trial to evaluate efficacy and safety of imlifidase in highly sensitised children (1-17 years) receiving a kidney transplant with positive crossmatch against a living or deceased donor converted to negative after imlifidase treatment

The primary objective of this study is to evaluate **crossmatch conversion** with imlifidase treatment in highly sensitized pediatric patients receiving a kidney transplant. This is clinically relevant as it addresses the challenge of positive crossmatch, which is a significant barrier to successful transplantation in sensitized patients. By converting a positive crossmatch to negative, the likelihood of a successful transplant increases, potentially improving patient outcomes.

Secondary objectives include:

• Evaluating **renal function** post-transplant, which is crucial for assessing the success and sustainability of the transplant.
• Assessing **human leukocyte antigen (HLA)/donor specific antibody (DSA) levels**, as these are indicators of potential rejection and immune response.
• Evaluating **graft survival** and **patient survival**, which are key measures of long-term transplant success.
• Assessing **delayed graft function (DGF)**, which can impact the immediate success of the transplant.
• Evaluating the **pharmacokinetic (PK) and pharmacodynamic (PD) profiles** of imlifidase, providing insights into the drug's behavior and effects in the body.
• Assessing the **immunogenicity profile** of imlifidase, focusing on anti-drug antibodies (ADAs) that could affect treatment efficacy.
• Evaluating the proportion of biopsy- and serology-confirmed **antibody-mediated reactions (AMRs)** and biopsy-confirmed **cell-mediated rejections (CMRs)**, which are critical for understanding immune responses post-transplant.
• Assessing the **safety and tolerability** of imlifidase treatment, ensuring that the treatment is safe for pediatric use.

The clinical trial involves a total of **2 participants** who are highly sensitized pediatric patients with a positive crossmatch against a living or deceased donor kidney. The study population includes both male and female subjects, aged between **1 to 17 years**, who are diagnosed with **end-stage renal disease (ESRD)** and are awaiting a renal transplant. Participants were selected based on their high sensitization, with panel reactive antibodies (PRA) of 80% or greater, and a positive crossmatch test determined by FCXM and/or CDCXM tests against the donor. The trial population is characterized by their previous unsuccessful desensitization attempts with plasmapheresis, IVIg, or anti-CD20, or an anti-HLA antibody status that is considered too challenging for successful desensitization. The participants are required to be transplantable at the time of informed consent and must demonstrate willingness and ability to comply with the protocol as judged by the investigator. The trial includes a vulnerable population, given the pediatric nature of the participants and their critical health status.

The clinical trial is designed to evaluate the efficacy and safety of **imlifidase** in highly sensitized pediatric patients aged 1 to 17 years who are awaiting a kidney transplant. This is a single-arm, multi-center trial with a primary objective to assess the conversion of a positive crossmatch test to negative within 24 hours following treatment with imlifidase. The trial is categorized as a Phase IV study and is not considered low intervention. The trial is expected to run until July 30, 2030, with recruitment having commenced on March 15, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a positive crossmatch test and a panel reactive antibody level of 80% or higher. Following the screening, eligible participants will receive imlifidase treatment, with subsequent visits scheduled to monitor the primary endpoint of crossmatch conversion and various secondary endpoints. These secondary endpoints include renal function, graft survival, and safety parameters, assessed at multiple time points up to five years post-transplantation. The end-of-study visit will conclude the participant's involvement, which may last up to five years, depending on the timing of their transplantation and subsequent follow-up.

Participant involvement may be terminated early if they are unable to comply with the protocol, experience severe adverse events, or if the investigator deems it necessary for the participant's safety. The trial employs a rigorous methodology to ensure the collection of reliable and valid data, with all procedures conducted in accordance with ethical standards and regulatory requirements. The study's design and procedures are structured to provide comprehensive insights into the potential benefits and risks associated with imlifidase treatment in this specific patient population.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. The primary experimental medication is **Imlifidase**, marketed as Idefirix, which is provided as a powder for concentrate for solution for infusion. It is administered via **intravenous infusion** at a dosage of 0.25 mg/kg, with a maximum total dose of 0.25 mg/kg. The treatment period for Imlifidase is limited to one day. This medication is designated as an orphan drug and is specifically used to evaluate crossmatch conversion in highly sensitized children receiving a kidney transplant.

**Rituximab** is another experimental medication used in the trial. It is available as a concentrate for solution for infusion and is administered intravenously. The dosage is set at 375 mg/m², with a maximum daily and total dose of 375 mg/m². The treatment period for Rituximab is one day. This medication is also designated as an orphan drug.

**Immunoglobulin** is administered as a solution for injection, with an intravenous route of administration. The maximum daily dose is 70 g, and the total dose can reach up to 140 g over a treatment period of two days. This medication is not designated as an orphan drug.

**Anti-human T-lymphocyte immunoglobulin from rabbits** is provided as a solution for infusion and is administered intravenously. The dosage is 1.5 mg/kg per day, with a maximum total dose of 4.5 mg/kg over a treatment period of three days. This medication is not designated as an orphan drug.

**Methylprednisolone** is used in two different dosing regimens. In one regimen, it is administered as a solution for injection/infusion with a maximum daily and total dose of 500 mg over one day. In the second regimen, the maximum daily dose is 250 mg, with a total dose of up to 1000 mg over a four-day treatment period. Both regimens involve intravenous administration, and Methylprednisolone is classified as a corticosteroid.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to assess the efficacy and safety of these treatments in the context of kidney transplantation in highly sensitized pediatric patients.

The efficacy of the clinical trial will be assessed primarily by evaluating the **conversion of a positive crossmatch test to negative** within 24 hours after the start of imlifidase treatment. This primary endpoint will determine the immediate effect of the treatment on crossmatch status, which is critical for the success of kidney transplantation in highly sensitized patients.

Secondary endpoints will provide a comprehensive evaluation of the treatment's long-term efficacy and safety. These include renal function assessments at various time points up to 5 years post-transplantation, measured by estimated glomerular filtration rate (eGFR), serum/plasma creatinine, cystatin C levels, and proteinuria. Additionally, donor-specific antibody (DSA) levels will be monitored from pre-dose imlifidase up to 5 years after transplantation. Other secondary endpoints include graft survival, graft failure-free survival, patient survival, frequency and length of delayed graft function (DGF), and dialysis dependency, all evaluated up to 5 years post-transplantation.

The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of imlifidase will be assessed up to 14 and 9 days after treatment, respectively. Immunogenicity will be evaluated by measuring anti-drug antibodies (ADAs) up to 5 years post-treatment. The trial will also monitor the proportion of patients with biopsy- and serology-confirmed antibody-mediated rejection (AMR) and biopsy-confirmed cellular-mediated rejections (CMRs) up to 5 years after transplantation. Safety parameters, including adverse events (AEs), serious adverse events (SAEs), clinical laboratory tests, vital signs, and electrocardiograms (ECGs), will be tracked up to 5 years post-transplantation. Additionally, the safety will be assessed by the proportion of patients experiencing infusion-related reactions within 48 hours of imlifidase infusion and severe or serious infections within 30 days post-treatment.