A prospective, post-authorisation long-term follow up trial of patients previously treated with imlifidase prior to kidney transplantation, including a non-comparative concurrent reference cohort

The primary objective of this study is to evaluate long-term **graft failure-free survival** in highly sensitized kidney transplant patients following the administration of **imlifidase**. This is clinically relevant as it aims to assess the effectiveness of imlifidase in improving transplant outcomes in a population with a high risk of graft rejection, thereby potentially enhancing patient prognosis and quality of life.

Secondary objectives include:

• Evaluate graft failure-free survival.
• Evaluate **renal function**.
• Evaluate patient survival.
• Evaluate graft survival.
• Evaluate **Human Leukocyte Antigen (HLA)**/Donor Specific Antibodies (DSA) levels (imlifidase cohort only).
• Evaluate long-term immunogenicity by anti-drug antibodies (ADA) (imlifidase cohort only).
• Evaluate the proportion of patients with biopsy- and serology (DSA)-confirmed Antibody Mediated Rejections (AMRs).
• Evaluate the proportion of patients with biopsy-confirmed Cell-Mediated Rejections (CMRs).
• Evaluate long-term safety of imlifidase (imlifidase cohort only).
• Evaluate long-term clinical outcomes related to maintenance immunosuppression in terms of treatments and comorbidity.
• Evaluate patient-reported data regarding the impact of transplantation on quality of life (QoL).

The clinical trial involves a total of **18 participants** who are highly sensitized patients that have undergone kidney transplantation following the administration of **Idefirix (imlifidase)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their previous involvement in the clinical trial 20-HmedIdeS-19 (PAES) and their willingness and ability to comply with the protocol. The trial does not specify particular lifestyle considerations such as diet or physical activity. The population includes a vulnerable group, indicating that special considerations are taken into account for their participation. The trial aims to evaluate long-term graft failure-free survival in this specific cohort.

The clinical trial is designed as a **prospective, post-authorization long-term follow-up** study, focusing on patients who have previously undergone kidney transplantation after administration of **imlifidase**. The trial includes a non-comparative concurrent reference cohort of less sensitized patients who received a compatible kidney transplant. The primary objective is to evaluate long-term graft failure-free survival in highly sensitized kidney transplant patients who were treated with imlifidase. The study is structured as a **Phase III** trial and is not classified as low intervention.

The trial will commence with a screening visit to ensure participants meet the inclusion criteria, which include having signed informed consent, willingness and ability to comply with the protocol, and previous transplantation in the clinical trial 20-HmedIdeS-19 (PAES). There are no specified exclusion criteria. The trial will monitor participants over a period extending up to five years, with primary endpoints focusing on graft failure-free survival. Secondary endpoints include renal function, patient and graft survival, and various immunological and clinical parameters.

Participants will be required to attend regular follow-up visits throughout the trial duration, where assessments will be conducted to monitor renal function, immunological markers, and overall health status. The end-of-study visit will conclude the trial, summarizing the long-term outcomes of the treatment. The expected length of participant involvement is up to five years, with conditions for early termination including withdrawal of consent or inability to comply with the study protocol.

The trial is expected to end by December 31, 2028, with recruitment having started on May 31, 2023. The study will utilize **intravenous infusion** as the route of administration for the investigational product, Idefirix, which is formulated as a powder for concentrate for solution for infusion. The maximum daily dose is set at 0.25 mg/kg, with the same limit for the total dose. The trial will ensure rigorous monitoring for adverse events and serious adverse events potentially related to imlifidase treatment, particularly in the imlifidase cohort.

The clinical trial involves the administration of **Idefirix**, which contains the active substance **imlifidase**. Idefirix is formulated as a **powder for concentrate for solution for infusion**. The pharmaceutical form is a **solution for infusion**, and it is administered via **intravenous infusion**. The dosage is calculated based on the patient's body weight, with a maximum daily dose of 0.25 mg/kg. The total dose should not exceed 0.25 mg/kg, and the treatment period is limited to a maximum of one day. Imlifidase is a protein derived from **Streptococcus pyogenes**, known for its ability to degrade **immunoglobulin G**. The product is manufactured by Hansa Biopharma AB and is designated as an orphan drug under the European Union's regulations.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of Idefirix to evaluate its efficacy and safety in the context of kidney transplantation. Participant compliance with the dosing schedule is monitored through standard clinical trial procedures, ensuring adherence to the specified infusion protocol. The trial aims to assess long-term graft failure-free survival in highly sensitized kidney transplant patients who have received imlifidase.

Efficacy in this clinical trial will be assessed primarily through the evaluation of **graft failure-free survival** in highly sensitized kidney transplant patients who have been treated with imlifidase. The primary endpoint is the percentage of patients achieving graft failure-free survival up to five years post-transplantation in the imlifidase cohort. Secondary endpoints include graft failure-free survival rates at two and three years, as well as in a non-comparative concurrent reference cohort up to five years. Additional secondary endpoints involve the assessment of renal function through estimated Glomerular Filtration Rate (eGFR) and serum/plasma creatinine levels, patient and graft survival rates, and levels of HLA/DSA and ADA in the imlifidase cohort.

Other efficacy parameters include the proportion of patients with biopsy- and serology-confirmed antibody-mediated rejections (AMRs) and biopsy-confirmed cellular-mediated rejections (CMRs), treatment of graft rejection episodes, and adverse events related to imlifidase treatment. The trial will also monitor ongoing immunosuppressive medication, comorbidities, and changes in patient-reported life participation using the Patient-Reported Outcomes Measurement Information System (PROMIS) Social Health domain. These assessments will be conducted from baseline to five years post-transplantation. The trial is designed to provide a comprehensive evaluation of long-term outcomes following imlifidase administration in kidney transplant patients.