Phase IIb Multicenter Randomized Controlled Trial Evaluating the Efficacy of Sivelestat in Patients With Septic Coagulopathy (SivelSep)

University Hospital, Strasbourg, France

Status and phase: Begins enrollment this month; Phase 2

Conditions: Coagulopathy; Septic Shock

Treatments: Drug: NaCl intravenous infusion; Drug: • Sivelestat intravenous infusion

Study type: Interventional

Funder types: Other

Identifiers

NCT07214103

9415

Details and patient eligibility

About

Sepsis-induced disseminated intravascular coagulation (DIC) is a severe complication occurring in one-third of patients with septic shock, for which no specific treatment currently exists. It results from excessive systemic activation of coagulation and impaired fibrinolysis, leading to the development of disseminated microthromboses. We have recently demonstrated: 1) the contribution of NETs to the hypercoagulability observed in DIC, and 2) the role of neutrophil elastase-bound to NET DNA-in degrading plasminogen, a key factor limiting fibrinolysis and thus preventing the lysis of microthrombi in DIC.

Sivelestat is a neutrophil elastase inhibitor used in Japan for the treatment of acute respiratory distress syndrome (ARDS). It has the potential to inhibit: 1) neutrophil activation and the release of inflammatory mediators, and 2) plasminogen degradation, which drives fibrinolytic failure. A recent meta-analysis including 2,050 patients across 15 studies showed that Sivelestat reduced ARDS patient mortality at day 28-30 (RR = 0.81, 95% CI = 0.66-0.98, p = 0.03), decreased mechanical ventilation duration and ICU length of stay, and improved oxygenation.

We propose to conduct a multicenter, double-blind, placebo-controlled phase IIb trial evaluating the efficacy of Sivelestat in restoring fibrinolysis in patients with septic shock complicated by coagulopathy, defined by a positive SIC score (≥ 4 points).

Enrollment: 120 estimated patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Adults aged 18 to 85 years

• Patient (male or female) admitted to the ICU with:

  • Septic shock defined by Sepsis-3 criteria: acute, life-threatening organ dysfunction related to a suspected or confirmed infection, requiring vasopressor support to maintain a mean arterial pressure ≥ 65 mmHg and a serum lactate level > 2 mmol/L despite adequate fluid resuscitation.
  • Coagulopathy defined by a SIC score ≥ 4 points.

• Randomization within 12 hours after the diagnosis of coagulopathy (positive SIC score).

• Patient affiliated with a national health insurance system.

• Written informed consent: freely given, dated, and signed.

  • By the patient
  • Or by a legal representative if the patient is unable to provide consent.
  • Or through an emergency inclusion procedure if the patient is unable to consent and no family member is available

Exclusion criteria

• History of hypersensitivity reaction to Sivelestat (the only contraindication for Sivelestat)
• Patient weight > 100 kg
• Severe chronic liver disease (Child-Pugh C)
• Contraindication to the use of unfractionated heparin
• Moribund patient at the time of randomization
• Limitation of active therapeutic interventions at the time of study inclusion
• Under legal protection (guardianship, curatorship, or legal safeguard)
• Pregnancy or breastfeeding
• Participation in another interventional drug clinical trial

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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120 participants in 2 patient groups, including a placebo group

Active therapy

Experimental group

Description:

• Sivelestat

Treatment:

Drug: • Sivelestat intravenous infusion

Placebo therapy

Placebo Comparator group

Description:

• NaCl

Treatment:

Drug: NaCl intravenous infusion