Evaluation of Immunosuppressive Regimen Reduction in Kidney Transplant Recipients with Septic Shock or Acute Respiratory Failure: A Phase IV Multicenter Study

The primary objective of this study is to evaluate the effectiveness of a strategy of reduction in the level of **immunosuppressive** treatments to improve organ failure at day 5 in kidney transplant recipients admitted to the intensive care unit due to septic shock and/or acute respiratory failure. This is clinically relevant as optimizing immunosuppressive therapy can potentially enhance patient outcomes by reducing organ dysfunction, which is critical in the management of transplant recipients facing severe infections or respiratory complications.

Secondary objectives include evaluating the effects of this strategy on:

• In-ICU mortality and mortality at month 6
• Daily evolution of organ failures from day 1 to 7
• Renal function evolution at the end of ICU stay and at month 6
• Requirement for renal replacement therapy during ICU stay and at month 6
• Occurrence of acute kidney graft rejection, both cellular and/or humoral, until month 6
• Level of anti-Human Leucocyte Antigen antibodies at month 6
• Number of severe infections between ICU discharge and month 6

The clinical trial involves **kidney transplant** recipients, specifically adult patients aged 18 years and older. Both male and female participants are included in the study. The trial population consists of individuals who have undergone kidney transplantation more than three months prior to admission to the intensive care unit (ICU). Participants are admitted to the ICU due to septic shock or acute respiratory failure of presumed infectious origin. All participants are undergoing treatment with at least an immunosuppressive bitherapy, which may include steroids, calcineurin inhibitors, mTOR inhibitors, azathioprine, or mycophenolate mofetil. The study does not involve a vulnerable population. Participants must be affiliated with a social health insurance protection scheme and capable of understanding the research objectives and risks, providing informed consent. Women of childbearing potential are required to have a negative blood pregnancy test on the day of inclusion. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the effectiveness of reducing **immunosuppressive** treatments in kidney transplant recipients admitted to the intensive care unit (ICU) due to septic shock or acute respiratory failure. This is a randomized, open-label, multicentric phase IV study. The trial aims to assess the improvement in organ failure by measuring the reduction in the Sequential Organ Failure Assessment (SOFA) score by at least 4 points at day 5. The trial is expected to commence recruitment on June 1, 2025, and conclude by June 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, kidney transplant status, and current treatment with immunosuppressive bitherapy. The inclusion visit will also involve obtaining informed consent. Follow-up visits will occur during the ICU stay, with daily monitoring of the SOFA score from day 1 to day 7. Additional assessments will include vital status at ICU discharge and at month 6, serum creatinine levels, glomerular filtration rate, dialysis status, and histological evidence of rejection. The end-of-study visit will occur at month 6, where anti-HLA immunization and significant infection episodes will be evaluated.

Participant involvement is expected to last up to 6 months, with conditions for early termination including withdrawal of consent or any adverse events that compromise participant safety. The trial will utilize a variety of **medicinal products**, including Rapamune, Neoral, Advagraf, Myfortic, IMUREL, CORTANCYL, HYDROCORTISONE UPJOHN, CellCept, Certican, and SOLUMEDROL, administered either orally or intravenously, depending on the product. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of several **immunosuppressive** and anti-inflammatory medications, each with specific pharmaceutical forms, dosages, and administration routes. The experimental medication, **Hydrocortisone**, is provided as a 100 mg solution for injection under the brand name HYDROCORTISONE UPJOHN. It is administered intravenously with a maximum daily dose of 200 mg and a total dose limit of 200 mg over a treatment period of one day.

**Sirolimus** is administered as Rapamune 0.5 mg coated tablets. The pharmaceutical form is a coated tablet, and it is taken orally. The maximum daily dose is 40 mg, with a total dose limit of 3.6 g over a treatment period of three months.

**Ciclosporin** is provided as Neoral 100 mg soft capsules, taken orally. The maximum daily dose is 10 mg, with a total dose limit of 1.8 g over a treatment period of six months.

**Tacrolimus** is administered as Advagraf 0.5 mg prolonged-release hard capsules, taken orally. The maximum daily dose is 14 mg, with a total dose limit of 84 g over a treatment period of six months.

**Mycophenolic acid** is provided as Myfortic 180 mg gastro-resistant tablets, taken orally. The maximum daily dose is 1440 mg, with a total dose limit of 260 g over a treatment period of six months.

**Azathioprine** is administered as IMUREL 25 mg film-coated tablets, taken orally. The maximum daily dose is 150 mg, with a total dose limit of 27 g over a treatment period of six months.

**Prednisone** is provided as CORTANCYL 1 mg tablets, taken orally. The maximum daily dose is 20 mg, with a total dose limit of 3.6 g over a treatment period of six months.

**Mycophenolate mofetil** is administered as CellCept 250 mg hard capsules, taken orally. The maximum daily dose is 2 g, with a total dose limit of 360 g over a treatment period of six months.

**Everolimus** is provided as Certican 0.5 mg tablets, taken orally. The maximum daily dose is 2 mg, with a total dose limit of 3.6 g over a treatment period of six months.

**Methylprednisolone hydrogen succinate** is administered as SOLUMEDROL 500 mg powder for solution for injection, given intravenously. The maximum daily dose is 250 mg, with a total dose limit of 750 mg over a treatment period of three days.

All medications are chemically derived and are administered according to the specified dosing schedules. Participant compliance is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to evaluate the effectiveness of reducing immunosuppressive treatments in improving organ failure outcomes in kidney transplantation recipients admitted to the intensive care unit.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the rate of patients showing a reduction in the **SOFA** (Sequential Organ Failure Assessment) score of at least 4 points at day 5. This endpoint is designed to evaluate the effectiveness of the immunosuppressive treatment reduction strategy in improving organ function in kidney transplant recipients admitted to the ICU.

Secondary endpoints include a variety of measures to provide a comprehensive assessment of patient outcomes. These include:

• Vital status at discharge from the ICU and at month 6.
• Daily evolution of the SOFA score from day 1 to day 7.
• Serum creatinine level and glomerular filtration rate (GFR) at discharge from the ICU, assessed by the UV/P method.
• Dialysis status during ICU stay and at month 6, including use, modality, and weaning from renal replacement therapy (RRT).
• Histological evidence and characterization of rejection according to the Banff classification for any biopsy taken between ICU discharge and month 6.
• Evaluation of anti-HLA immunization at month 6, including screening for Donor-Specific Antibodies.
• Collection of significant infection episodes from ICU discharge to month 6, with specific attention to infections requiring hospitalization and viral replication assessments for CMV, EBV, and BK virus.

The efficacy parameters will be measured and collected at specified timepoints, including day 5, ICU discharge, and month 6, using validated methods such as the SOFA score and laboratory tests for creatinine and GFR. The analysis will focus on the changes in these parameters to determine the impact of the treatment strategy on patient outcomes.