Shorter Weaning From Invasive Ventilation With Levosimendan (WEANLESS)

Radboud University Medical Center

Status and phase: Enrolling; Phase 4

Conditions: Weaning Failure; Mechanical Ventilation

Treatments: Drug: Soluvit; Other: Standard care; Drug: levosimendan

Study type: Interventional

Funder types: Other

Identifiers

NCT07105202

2024-518810-23-00 (EU Trial (CTIS) Number)

Details and patient eligibility

About

Prolonged weaning from mechanical ventilation is a common and serious challenge in the ICU, associated with increased morbidity, mortality, and length of stay. Diaphragm dysfunction plays a key role in weaning failure, and current strategies to support respiratory muscle function are limited. Levosimendan is a calcium sensitizer that enhances cardiac and skeletal muscle contractility, including the diaphragm, without increasing oxygen demand.

The investigators hypothesize that treatment with Levosimendan in difficult-to-wean ICU patients will improve diaphragm function and thereby shorten the duration of mechanical ventilation compared to placebo.

Full description

Objective: To assess the effect of levosimendan on the number of ventilator-free days up until day 28.

Study design: WEANLESS is an investigator-initiated, multicenter, double blind, randomized clinical superiority trial in ventilated adult patients admitted to the ICUs of participating hospitals.

Study population: This study will include 250 patients who are invasively ventilated for more than 48 hours and failed at least one SBT. Patients are enrolled from participating ICUs and randomized within 24 hours after failing their first SBT.

Intervention:

Patients will be randomly assigned in a double-blind manner to receive either levosimendan or placebo. The study medication will be administered as a continuous intravenous infusion over 24 hours, starting at a dose of 0.1 µg/kg/min, with the option to increase to 0.2 µg/kg/min after 4 hours if well tolerated. If weaning is not successful after 7 days, a maximum of four treatment cycles may be given. All patients will continue to receive standard ICU care, including daily assessments of readiness to wean from mechanical ventilation.

In addition to the intervention, health-related quality of life will be assessed using the EQ-5D-5L questionnaire at baseline, 3 months, and 12 months after inclusion. Dyspnea scores will be recorded daily after extubation until ICU discharge.

Main study parameters/endpoints: The primary endpoint of the study is the number of ventilator-free days and alive (VFD) at day 28 from randomization. This is a composite endpoint combining both mortality and the duration of ventilation. Secondary outcomes include ventilator-free days at day 90, dyspnea scores, reintubation rates, ICU readmission, ICU length of stay, hospital length of stay and mortality. Safety outcomes include the occurrence of cardiac arrhythmias, changes in vasopressor requirements and other adverse events related to levosimendan.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The burden for participants is minimal. Levosimendan is a registered drug with a known safety profile and is already used in critical care settings. The placebo is an infusion with Soluvit. All other care follows standard ICU procedures. Data will be collected from the electronic medical record and routine monitoring. No additional invasive procedures are required solely for the main study.

Enrollment: 250 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Invasively ventilated > 48 hours.
• Failed at least one spontaneous breathing trial (SBT).
• Age above 18 years.
• Female patients with age < 60 must have a negative pregnancy test (blood or urine) prior to participation.

Exclusion criteria

• Pre-existing neuromuscular disease (congenital or acquired)
• Endotracheally intubated primarily for neurological reason (e.g., traumatic brain injury, intracranial haemorrhage, epilepsy, intracranial infection), or developed severe intracranial haemorrhage/infarction during ICU stay.
• Contra-indications for levosimendan: severe renal failure (creatinine clearance <30mL/min) unless managed with appropriate continuous kidney replacement therapy (such as CRRT), severe liver failure (Child-Pugh class C), history of torsade des pointes; known significant mechanical obstructions affecting ventricular filling/ outflow or both; prolonged QTc interval (QTc > 470ms); breast feeding; known hypersensitivity to levosimendan.
• Treatment with intermittent haemodialysis.
• Treatment limitation decision in place: do not reintubate
• Previous treatment with levosimendan within 30 days.
• Currently in another interventional trial that might interact with study drug or primary outcome.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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250 participants in 2 patient groups, including a placebo group

Intervention group

Active Comparator group

Description:

Participants randomized to this arm will receive intravenous levosimendan. This group will consist of 125 patients.

Treatment:

Drug: levosimendan

Other: Standard care

Control group

Placebo Comparator group

Description:

Participants randomized to this arm will receive a placebo consisting of Soluvit. This group will consist of 125 participants.

Treatment:

Other: Standard care

Drug: Soluvit