Non-Inferiority Trial of Cilastatin Sodium vs. Sodium Thiosulfate for Nephroprotection in CRS+HIPEC-Cisplatin Patients with Acute Kidney Injury

The primary objective of this clinical trial is to evaluate the **non-inferiority** of cilastatin compared to thiosulfate in reducing acute kidney injury in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) using cisplatin. This is assessed by measuring creatinine levels and using the KDIGO scale during the immediate postoperative period, specifically from days 1 to 7. The clinical relevance of this study lies in its potential to identify an effective nephroprotective agent, which could significantly improve renal outcomes and reduce the incidence of acute kidney injury in this patient population.

Secondary objectives include: - Studying the pharmacokinetics of cisplatin with cilastatin and thiosulfate during the HIPEC procedure. - Analyzing the number of subjects presenting adverse events and serious adverse events during a 30-day follow-up period. - Observing the evolution of acute renal failure (ARF) in patients treated with cilastatin and thiosulfate over a 14-day follow-up. - Evaluating preoperative, intraoperative, and postoperative factors influencing renal damage in CRS+HIPEC-cisplatin. - Investigating the usefulness of urinary H2O2 determination in predicting the occurrence of drug-related renal damage by cisplatin post-HIPEC. - Studying changes in urinary FasL post-HIPEC as an early measure of drug-related renal damage intensity and the specificity of the nephroprotective mechanism expected with cilastatin.

The clinical trial focuses on **acute kidney injury** in patients undergoing CRS+HIPEC-cisplatin treatment during the immediate postoperative period. The study population comprises adult female patients aged 18 to 75 years, with an Eastern Cooperative Oncology Group Performance status of 2. Participants are required to be in a general health status suitable for major surgery, with creatinine, bilirubin, and blood series values close to normal ranges. The trial does not include a vulnerable population. Participants must have disease confined to the abdomen, with specific conditions for metastases and surgical intervention eligibility. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Selection criteria include evaluation by an Anesthesia office and a Multidisciplinary Committee, with a focus on the potential for complete cytoreduction. The trial is designed to assess the non-inferiority of cilastatin versus Thiosulfate in reducing acute kidney damage, measured by creatinine levels and the KDIGO scale, over the first seven days post-surgery.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the nephroprotective effects of **cilastatin** versus **thiosulfate** in patients undergoing debulking surgery with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) using cisplatin. The primary objective is to assess the non-inferiority of cilastatin compared to thiosulfate in reducing **acute kidney injury** during the immediate postoperative period, specifically from days 1 to 7, as measured by creatinine levels and the KDIGO scale. The trial is expected to commence recruitment on February 21, 2025, and is estimated to conclude by October 21, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-75 years), sex (female), and general health status, including creatinine and bilirubin levels. Following successful screening, participants will be randomized to receive either cilastatin or thiosulfate. The trial includes follow-up visits to monitor renal function and adverse events, with a primary endpoint assessment at 7 days post-surgery. If renal damage is detected, follow-up will extend to postoperative day 14. The end-of-study visit will occur at the conclusion of the 14-day follow-up period.

The expected duration of participant involvement is up to 14 days, with conditions for early termination including significant adverse events or withdrawal of consent. The trial will also evaluate secondary endpoints, such as differences in plasma pharmacokinetic variables of cisplatin, the incidence of serious adverse events, and comparisons of urinary biomarkers between patients with and without renal damage. The study aims to provide valuable insights into the comparative effectiveness of cilastatin and thiosulfate in preventing renal complications associated with HIPEC procedures.

The clinical trial involves the administration of **Imipenem/Cilastatin Kabi**, a pharmaceutical product formulated as a **solution for infusion**. This experimental medication contains the active substances **cilastatin sodium** and **imipenem monohydrate**, both of which are of chemical origin. The medication is administered via infusion, with a maximum daily dose of 1.5 grams and a total maximum dose of 1.5 grams over a treatment period of up to 14 days. The product is manufactured by Fresenius Kabi Polska Sp. z o.o. and is authorized for use in the trial under the marketing authorization number 1012620. Participant compliance with the dosing schedule will be monitored throughout the trial.

The comparator treatment in this study is **Sodium Thiosulfate Hope Pharmaceuticals 250 mg/ml solution for Injection**, which is also administered as a **solution for injection**. The active substance in this comparator is **sodium thiosulfate**, a chemical compound. The administration route is infusion, with a maximum daily dose of 9 grams and a total maximum dose of 12 grams over a treatment period of up to 2 days. This product is provided by Hope Pharmaceuticals Limited and holds the marketing authorization number PA22874/002/001. Compliance with the administration and dosing schedule will be closely monitored to ensure adherence to the trial protocol.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints related to renal function and pharmacokinetic variables. The primary endpoint is the percentage of patients experiencing **renal failure** at 7 days, with follow-up extending to postoperative day 14 if renal damage is observed. This will be measured through serum creatinine values and the KDIGO classification. Renal failure is defined as an increase in serum creatinine of 1.5 to 1.9 times the baseline, an increase in serum creatinine by ≥0.3 mg/dL (≥26.5 μmol/L), or a decrease in urine output to less than 0.5 mL/kg/hour for 6 to 12 hours.

Secondary endpoints include differences in plasma pharmacokinetic variables of cisplatin during the HIPEC procedure between patients treated with cilastatin and those treated with thiosulfate. Additionally, the trial will assess the percentage of patients experiencing serious adverse events, adverse events related to the study treatment, and adverse events occurring during the study. Other secondary endpoints involve comparisons of acute renal failure (ARF) in patients treated with cilastatin or thiosulfate over a total follow-up of 14 days, urinary H202 values, preoperative, intraoperative, and postoperative factors, and urinary FasL levels between patients with and without renal damage.