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Background Prolonged weaning from invasive mechanical ventilation is a major challenge in critically ill patients failing a spontaneous breathing trial. Levosimendan, a calcium sensitiser, has been shown to improve respiratory muscle function. However, its effect on clinically relevant endpoints in difficult to wean patients has not yet been investigated. We aim to assess whether levosimendan shortens the weaning process in invasively ventilated intensive care unit (ICU) patients who fail a separation attempt. The objective is to assess the effect of levosimendan on the number of ventilator-free days and alive at day 28.Methods The WEANing with LEvoSimendan Study (WEANLESS) is an investigator-initiated, multicentre, double-blind, parallel-group, randomised clinical superiority trial. Adult invasively ventilated patients who failed a separation attempt are randomly assigned to receive either intravenous levosimendan (intervention) or placebo (control). The primary outcome is the number of ventilator-free days and alive at day 28 from randomisation. WEANLESS also evaluates the effects of levosimendan on patient-reported outcomes, measured through daily dyspnoea scores and uses an EQ-5D-5L questionnaire. Additionally, we will evaluate healthcare resource utilisation and intensive care capacity, assessed through reintubation rates, ICU readmissions within 90 days, the need for non-invasive respiratory support and ICU length of stay. WEANLESS includes a pharmacokinetic analysis of levosimendan and its metabolites.Discussion WEANLESS is the first clinical study that is sufficiently powered to determine the effect of intravenous levosimendan in difficult to wean patients on the duration of weaning from invasive ventilation.Ethics and dissemination WEANLESS is registered before the inclusion of the first patient at clinicaltrials.gov; the study protocol has been approved by the relevant ethics committee. Its findings will be disseminated through presentations at scientific conferences and publications in a peer-reviewed journal.Trial registration number NCT07105202.