Title: An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS)
Funder: Department of Health (England)

Abstract: Despite advances in sepsis care mortality from severe sepsis and septic shock remains high. According to figures from the ICNARC Case Mix Programme database for 2008/9 29025 patients were admitted to adult intensive care units (ICU) in England Wales and NI with severe sepsis and multiple organ dysfunction with a hospital mortality of ~45%. Mortality rates increase with increasing number of organ failures. Treatment of septic shock requires cardiovascular resuscitation with fluids and catecholamines. However catecholamines particularly in high doses can be harmful. Although developed for use in heart failure there is a growing evidence to suggest that the calcium sensitiser levosimendan may be of benefit in patients with septic shock. It can improve cardiac output and kidney perfusion and potentially allow reduced use of conventional therapy with catecholamines. Furthermore it may have beneficial anti-inflammatory effects. We propose a prospective randomised double-blind placebo-controlled trial to investigate our hypothesis that treatment with a 24 hour infusion of levosimendan in patients with septic shock will lead to a reduction in multi-organ failure and a reduction in the need for catecholamine therapy. The study population will be adult patients who have septic shock (defined according to standard consensus definitions) in intensive care. The intervention will be an infusion of levosimendan titrated up to 0.2 mcg/kg/min for 24 hours commenced within 24 hours of meeting the inclusion criteria versus identical placebo. The primary outcome measure will be mean serial organ failure score (SOFA) in ICU after trial inclusion. The mean SOFA score has been shown to be closely correlated with mortality. We will also examine the effect of levosimendan on the different organ functions (cardiovascular renal hepatic and respiratory). Based upon data from previous septic shock trials and Imperial College NHS Trusts ICU database 250 patients in each arm will provide >90% power to detect a 0.5 difference in mean SOFA score. We will also have adequate power to investigate the mechanism of action of levosimendan on individual organ function. Assuming a 3% study withdrawal 516 patients in total will be required and will be recruited from ~20-25 ICUs across the UK over 30 months. Other outcome measures will include longterm mortality rates ICU free days and rates and duration of renal replacement therapy to help inform a subsequent phase III trial. As well as a thorough assessment of safety we will also undertake a pharmacokinetic study and mechanistic work examining markers of myocardial and renal injury as well as the effects of levosimendan on the inflammatory balance. The trial team include intensive care consultants with extensive experience of running large-scale clinical trials in critically ill patients and specifically septic shock. The Imperial Clinical Trials Unit will run the trial. The Intensive Care Foundation has endorsed this study. This will allow access to an established network of participating investigators and ICUs with a strong track record of recruiting to clinical trials. The results will thus be generalisable throughout the whole NHS.Hypothesis & Aims:Our hypothesis is that levosimendan will improve cardiac output and oxygen delivery and improve peripheral perfusion in patients who have septic shock. This will then reduce the rates and severity of multiple organ failure and thus ultimately improve survival rates. Specifically our primary aim is to conduct a phase II double-blind randomised placebo-controlled trial that will answer these questions:1. Does levosimendan reduce the incidence and severity of acute organ dysfunction in adult patients who have septic shock?2. What is the effect of levosimendan on individual organ function in septic shock?3. What is the safety profile of levosimendan in this group of patients?We will also carry out a detailed pharmacokinetic study in the initial 80 patients recruited to the trial. Our secondary aims include undertaking mechanistic studies to better understand the biological effects of levosimendan in a septic shock population. Given that there is evidence to suggest that conventional catecholamine therapy in these patients is associated with potential harm we also hypothesise that the administration of levosimendan will reduce the need for catecholamine infusions and improve markers of myocardial injury. As well as its haemodynamic effects levosimendan may have important anti-inflammatory properties. Additional questions we will answer:4. Does levosimendan reduce the need for and duration of catecholamine support and thus reduce myocardial injury?5. Does levosimendan alter the pro and anti-inflammatory balance in sepsis?


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION;RENAL AND UROGENITAL