Investigation of Siplizumab, Cyclophosphamide, and Splenectomy for Inducing Allogeneic Tolerance in Deceased Donor Liver Transplant Recipients

The primary objective of this study is to investigate whether a **siplizumab**-based regimen can induce allogeneic tolerance in deceased donor liver transplant recipients. This is clinically relevant as achieving allogeneic tolerance could potentially reduce the need for long-term immunosuppression, thereby minimizing associated risks and improving patient outcomes in liver transplantation.

Secondary objectives include exploring the safety of **siplizumab**. Understanding the safety profile is crucial for assessing the risk-benefit ratio of the treatment regimen and ensuring patient safety during and after the intervention.

The clinical trial focuses on **prophylaxis against liver allograft rejection** following tolerance induction. The study population comprises adult subjects aged 18 to 70 years who are recipients of an ABO-compatible deceased donor liver transplant. Both male and female participants are included, with a requirement for a stable cardio-pulmonary status and eligibility for transplantation as per local regulations. Participants must be EBV sero-positive and SARS-CoV-2 negative. The trial includes individuals with a MELD score of less than 30, evaluated within 60 days of screening. Male participants are required to maintain barrier contraception and agree not to father a child until 12 weeks after the last dose of MMF. The sponsor has not provided information regarding the total number of participants. The trial population selection considers the inclusion of a vulnerable population, ensuring a comprehensive assessment of the siplizumab-based regimen's efficacy in inducing allogeneic tolerance in deceased donor liver transplant recipients.

The clinical trial is designed as a **single-arm**, proof-of-concept study to evaluate the efficacy of a **siplizumab**-based regimen in inducing allogeneic tolerance in recipients of deceased donor liver transplants. The trial will span a total duration of 60 months, with the primary objective being to assess the proportion of patients who are free from immunosuppression at 30 months post-transplant. Secondary endpoints include the composite efficacy failure rate, the proportion of patients remaining off immunosuppression for at least 12 months, and the incidence and severity of acute rejection.

Participants will be adult subjects aged 18-70 who are receiving an ABO-compatible deceased donor liver transplant, with a MELD score of less than 30, stable cardio-pulmonary status, and EBV sero-positive status. The trial will exclude individuals who do not meet these criteria. The study will commence with a screening visit to confirm eligibility, followed by the administration of the investigational product, **siplizumab**, via intravenous infusion. The maximum daily dose is set at 0.6 mg/kg, with a total maximum dose of 1.8 mg/kg over a treatment period of up to 5 days.

Participants will be required to attend regular follow-up visits to monitor their response to the treatment and to assess any adverse events. These visits will include clinical evaluations, laboratory tests, and imaging studies as necessary. The end-of-study visit will occur at the conclusion of the 60-month period, where final assessments will be conducted to evaluate the long-term outcomes of the treatment regimen.

The expected length of participant involvement is up to 60 months, with conditions for early termination including significant adverse events, withdrawal of consent, or failure to adhere to the study protocol. The trial is categorized as a Phase IIA clinical trial, focusing on the prophylaxis against liver allograft rejection following tolerance induction. The study is not classified as low intervention, and it adheres to the regulatory requirements for disclosure and ethical conduct in clinical research.

The clinical trial involves the administration of **siplizumab**, an experimental medication, which is a **solution for injection/infusion**. Siplizumab is an anti-CD2 antibody, classified under the origin of "Protein - Other." The pharmaceutical form of siplizumab is a solution intended for intravenous administration. The dosing regimen for siplizumab involves a maximum daily dose of 0.6 mg/kg and a maximum total dose of 1.8 mg/kg over a treatment period of up to 5 days. The administration of siplizumab is conducted intravenously, ensuring precise delivery of the medication into the bloodstream. The sponsor product code for siplizumab is TCD601, and it is designated as an orphan drug under the number EU/3/17/1931.

In addition to siplizumab, the study protocol includes the use of **cyclophosphamide** and a surgical procedure known as **splenectomy**. Cyclophosphamide is a standard-of-care therapy used in combination with siplizumab to enhance the induction of allogeneic tolerance in liver transplant recipients. The dosing schedule and administration route for cyclophosphamide are determined according to standard medical guidelines and are not specified in the trial data. Splenectomy, a surgical procedure involving the removal of the spleen, is performed as part of the treatment regimen to further support the induction of tolerance. Participant compliance with the treatment regimen is monitored throughout the study to ensure adherence to the dosing schedules and to evaluate the safety and efficacy of the combined treatment approach.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients who are free from immunosuppression at Month 30 post-transplant. Secondary endpoints include the composite efficacy failure rate of treated biopsy-proven acute rejection (tBPAR), graft loss, or death at Month 30, the proportion of patients who remain off immunosuppression for at least 12 months, and the incidence, severity, and treatment of acute rejection. These secondary endpoints will be derived from biopsy, rejection, adverse event (AE), and treatment Case Report Forms (CRFs).

The trial is designed to evaluate the efficacy of a siplizumab-based regimen in inducing allogeneic tolerance in deceased donor liver transplant recipients. The assessment of efficacy will be conducted at specified timepoints, with the primary endpoint evaluated at Month 30 post-transplant. The secondary endpoints will also be assessed at Month 30, with additional evaluations for immunosuppression status over a 12-month period. The data collection will involve validated scales and laboratory tests to ensure accurate and reliable measurement of the endpoints. The trial will utilize **siplizumab**, an anti-CD2 antibody, in combination with cyclophosphamide and splenectomy, to achieve the study's objectives.