{"id":"11/14/08","award_type":"Research","award_title":"An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS)","award_amount":1116553.4,"award_amount_disp":"1,116,553.40","app_abstract":"Overwhelming infection, often known as septicaemia, is a major problem for the health community. It is the commonest reason for admission to intensive care in the UK, accounting for approximately 30% of all admissions and rates are increasing. Mortality rates are high; more than 15,000 patients die each year from severe infections and the UK spends at least £700 million per year treating these patients on intensive care units.  Frequently, septicaemia leads to a fall in blood pressure that can lead to damage of other organs such as the kidney and liver. As more organs are damaged mortality rates increase. It is normal practice for intensive care doctors to attempt to restore a patient's blood pressure to a relatively normal level using adrenaline-like drugs called catecholamines which can improve the functioning of the heart. However, it is increasingly being recognised that these drugs have important side effects and may even be associated with harm.    Levosimendan is a new type of drug that improves the function of the heart in a different manner to the adrenaline-like drugs. It has been extensively studied in patients with heart failure and is a licensed drug for this group of patients in many European countries and elsewhere around the world. In patients with septicaemia around half may develop impaired heart function and associated kidney failure, and levosimendan has been shown to improve this. Its use in septicaemia has been studied in both animals and man, and so far the small patient studies have shown promise, but none have been large enough to assess the effect on important patient-centered outcomes. We plan to undertake a randomised, controlled trial in a number of intensive care units to investigate whether levosimendan can produce important benefits for patients with septicaemia by reducing multiple organ failure, which will then hopefully lead to better survival rates.    Research within intensive care can be challenging but the study team has extensive experience of running large-scale trials in intensive care units and includes senior doctors with specific interest in the area of severe infections. Most patients will be unable to consent themselves due to the severity of their acute illness and their treatment with sedative drugs. In these cases consent from a family member / close friend will be sought until they recover sufficiently to give their own consent. If levosimendan is able to reduce or prevent multiple organ failure this will provide patients with better outcomes, improved survival rates and less need for scarce and expensive intensive care treatments.","app_plain_english_summary":"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, 29,025 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 Trust's 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 stu","headline":"Adding levosimendan to standard care for patients with septic shock did not reduce organ dysfunction, and may have increased risk of serious adverse events.","hrcs_health_category":["Infection","Inflammatory and Immune System","Renal and Urogenital"],"rac_code":["6.1 Pharmaceuticals"],"research_type":"Primary Research","programme":"Efficacy and Mechanism Evaluation","funding_stream":"EME Researcher Led","award_status":"Completed","programme_stream":"Researcher Led","contracting_org":"Imperial College London","centre":"NETSCC","contracting_org_title":"Contracting Organisation","start_date":"2013-07-01T23:59:59.000+0000","end_date":"2017-04-30T23:59:59.000+0000","pub_date":"2018-11-14T23:59:59.000+0000","lead_investigator_title":"Chief Investigator","lead_investigator_name":["Professor Anthony Gordon"],"lead_investigator_orcid":["0000-0002-0419-547X"],"co_investigator_name":["Dr Alexina Mason","Dr Andrea Morelli","Dr Kathleen Liu","Dr Robert Orme","Professor Danny McAuley","Professor Deborah Ashby","Professor Gavin Perkins","Professor Mervyn Singer"],"co_investigator_orcid":["0000-0001-7319-4545","","","0000-0003-2847-7778","0000-0002-3283-1947","0000-0003-3146-7466","0000-0003-3027-7548","0000-0002-1042-6350"],"research_call":"EME Researcher Led - 21 March 11","call_id":"11/14","link_type":["Clinical Trials Registry"],"link_title":["ISRCTN Registry"],"link_URL":["http://www.isrctn.com/ISRCTN12776039"],"link_group":["Overview"],"link_date_year":[0],"link_date":["1900-01-01T23:59:59.000+0000"],"award_website":"","funder":"Non-NIHR funding","reg_number_title":["ISRCTN"],"reg_number":["12776039"],"reg_number_url":["http://www.isrctn.com/ISRCTN12776039"],"additional_funder":"Medical Research Council","jl_rep_id":"https://doi.org/10.3310/eme05060","jl_rep_title":"Levosimendan to prevent acute organ dysfunction in sepsis: the LeoPARDS RCT","jl_rep_pub_date":"2018-11-14T23:59:59.000+0000","doc_type":["Protocol","SAP","RSM1"],"doc_group":["Methods","Methods","Results"],"doc_title":["Protocol","Statistical Analysis Plan","Report Supplementary Material 1"],"doc_URL":["https://njl-admin.nihr.ac.uk/document/download/2022097","https://njl-admin.nihr.ac.uk/document/download/2022240","https://njl-admin.nihr.ac.uk/document/download/2022282"],"doc_date":["2015-08-19T23:59:59.000+0000","2017-07-20T23:59:59.000+0000","2018-06-12T23:59:59.000+0000"],"doc_date_year":[2015,2017,2018],"doc_ver":["V13","",""],"output_type":["Journal Article","Journal Article"],"output_title":["An efficacy and mechanism evaluation of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): study protocol for a randomised controlled trial","Levosimendan for the prevention of acute organ dysfunction in sepsis"],"output_authors":["Orme RML, Perkins GD, McAuley DF, Liu KD, Mason AJ, Morelli A, Singer M, Ashby D, Gordon AC","A C Gordon; G D Perkins; M Singer; D F McAuley; R M L'E Orme MB; S Santhakumaran; A J Mason; M Cross; F Al-Beidh; J Best-Lane; D Brealey; C L Nutt; J J McNamee; H Reschreiter; A Breen; K D Liu MD; D Ashby;"],"output_url":["http://www.trialsjournal.com/content/15/1/199","http://www.nejm.org/doi/full/10.1056/NEJMoa1609409t=article"],"output_date":["2014-06-02T23:59:59.000+0000","2016-10-05T23:59:59.000+0000"],"output_date_year":[2014,2016],"output_journal":["Trials","New England Journal of Medicine"],"output_group":["Results","Results"],"highlighting":"","full_contracting_org":"Imperial College London","_version_":1875670576506339328,"full_co_investigator_name":["Dr Alexina Mason","Dr Andrea Morelli","Dr Kathleen Liu","Dr Robert Orme","Professor Danny McAuley","Professor Deborah Ashby","Professor Gavin Perkins","Professor Mervyn Singer"],"start_year":2013,"full_lead_investigator_name":["Professor Anthony Gordon"]}