Phase IIb Randomized, Placebo‑Controlled Multicenter Trial of Intravenous Sivelestat for Restoring Fibrinolysis in Septic Coagulopathy

Primary objective: To evaluate the efficacy of Sivelestat compared with placebo in restoring fibrinolysis in patients with Septic Coagulopathy (CIS score ≥ 4) during septic shock.

Secondary objectives:

• To obtain initial efficacy data for Sivelestat in septic shock with coagulopathy versus placebo.
• To assess the safety and tolerability of Sivelestat (0.2 mg/kg/h) over the study period compared with placebo.

The trial enrolled adult patients aged 18 to 85 years of both sexes who were admitted to intensive care units with septic shock meeting Sepsis‑3 criteria and with coagulopathy defined by a SIC score of ≥ 4 points; randomisation occurred within 12 hours of coagulopathy diagnosis. Participants were required to be covered by a national health‑insurance system, to provide written informed consent (or consent via a legal representative or emergency procedure), and, for women of childbearing potential, to have a negative pregnancy test. No specific dietary, physical‑activity, or other lifestyle restrictions were stipulated in the eligibility framework. The sponsor did not provide the total number of participants enrolled in the study.

In this Phase IIb multicenter trial, adult patients (18–85 years) with septic coagulopathy meeting Sepsis‑3 criteria and a SIC score ≥ 4 are randomized within 12 hours of diagnosis to receive either intravenous Sivelestat (0.2 mg/kg/h) or an intravenous placebo of sodium chloride (50 ml). The study employs a randomized controlled design with allocation concealed and treatment administered in a double‑blind manner. Screening occurs at the inclusion visit, during which eligibility, informed consent, and baseline laboratory values are obtained; randomisation follows immediately. Study treatment is continued for up to 7 days with plasma plasminogen measured at 24 hours (primary endpoint) and additional coagulation and fibrinolysis biomarkers collected on Days 1, 2, 3, 4, and 7. Clinical assessments, including SOFA score and organ‑failure indices, are performed through Day 28, and resource‑use and mortality outcomes are recorded through Day 90, which constitutes the end‑of‑study visit. Participant involvement therefore spans approximately 90 days from enrolment. The overall recruitment period is planned from May 2026 to January 2028.

The investigational product, designated ELASPOL, is supplied as a powder for solution for injection containing the active ingredient Sivelestat. It is administered intravenously as a continuous infusion at a rate of 0.2 mg/kg/h, calculated on the participant’s body weight. The infusion is initiated after reconstitution of the powder and is maintained for the prescribed treatment period, with the infusion rate adjusted only as required for safety monitoring.

The comparator treatment is a placebo consisting of an intravenous solution (pharmaceutical form PHF00169MIG) that includes potassium chloride, sodium hydrogen carbonate, and sodium chloride. The placebo is delivered intravenously in a volume of 50 ml per administration, following the same schedule and infusion parameters as the active drug to preserve blinding.

Dosing schedules for both arms are aligned to ensure comparable exposure times. Administration is performed by trained clinical staff using calibrated infusion devices. Compliance is monitored through electronic infusion pump records, periodic verification of infusion set integrity, and documentation of any interruptions or deviations in the study case report forms.

The primary efficacy endpoint is the change in plasma plasminogen concentration after 24 hours of treatment, measured from blood samples collected at baseline and at the 24‑hour time point and analyzed by a central laboratory using validated immunoassays.

Secondary efficacy assessments include serial measurement of coagulation and fibrinolysis biomarkers—complete blood count (CBC), prothrombin time (PT), antithrombin, D‑dimers, plasminogen, plasmin, tissue‑type plasminogen activator (tPA), plasminogen activator inhibitor‑1 (PAI‑1), and plasmin‑α2‑antiplasmin complex (PAP)—obtained on Day 1 (baseline), Day 2, Day 3, Day 4, and Day 7. In addition, normalization of the SIC score to a value < 4 is evaluated on Day 7. All laboratory parameters are processed with standardized assays, and scores are calculated by trained investigators according to the established scoring algorithm.

Exploratory clinical efficacy endpoints are recorded to characterize the broader impact of treatment. The Sepsis Support Index and its penalized variant are calculated up to Day 28. The SOFA score is assessed on Days 1, 2, 3, 4, and 7. Renal outcomes are captured using KDIGO criteria and the requirement for renal replacement therapy on Day 7, while thrombotic and hemorrhagic complications are documented at the same time point. Resource‑use outcomes—days free from mechanical ventilation, vasopressor support, ICU stay (all assessed at Day 28), days free from hospitalization (Day 90), and all‑cause mortality at Days 7, 28, and 90—are collected from patient records. Data are entered into an electronic data capture system and analyzed using predefined statistical methods appropriate for each endpoint.