LeoPARDS - An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis.

Conditions

Septic shock. MedDRA version: 16.0 Level: LLT Classification code 10028237 Term: Multiple organ failure System Organ Class: 100000004867 MedDRA version: 16.0 Level: PT Classification code 10040070 Term: Septic shock System Organ Class: 10021881 - Infections and infestations

R. Orme, Gavin D. Perkins, Daniel F. McAuley, Kathleen D. Liu, Alexina J. Mason et al. (9 authors)

Trials2014-06-0238 citations

10.1186/1745-6215-15-199

Interventions

Trade Name: Simdax Product Name: Levosimendan Pharmaceutical Form: Injection INN or Proposed INN: Levosimendan CAS Number: CAS-141505-3

Eligibility

Sex/Gender

All

Inclusion criteria

Inclusion criteria: The target population is adult patients (=18 years) who require vasopressor support for the management of sepsis despite fluid resuscitation. Inclusion criteria will use the internationally-established consensus definitions of sepsis. In brief: Fulfil 2/4 of the criteria of the systemic inflammatory response syndrome (SIRS) due to known or suspected infection within the previous 24 hours. The SIRS criteria are: (1) fever (>38 C) or hypothermia ( 90 beats per minute), (3) tachypnoea (respiratory rate > 20 breaths per minute or PaCO2 12,000 cells/mm3, 10% immature [band] forms). Hypotension, despite adequate intravenous fluid resuscitation, requiring treatment with a vasopressor infusion (e.g. noradrenaline / adrenaline / vasopressin analogue) for at least four hours and still having an ongoing vasopressor requirement at the time of randomisation. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 240 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 276

Exclusion criteria

Exclusion criteria: The exclusion criteria are as follows: 1. More than 24 hours since meeting all the inclusion criteria 2. End-stage renal failure at presentation (previously dialysis-dependent). 3. Severe hepatic impairment (Child-Pugh class C). 4. A history of Torsades de Pointes. 5. Significant mechanical obstructions affecting ventricular filling or outflow or both. 6. Treatment limitation decision in place (e.g. DNAR or not for ventilation/ dialysis). 7. Known or estimated weight >135kg. 8. Known to be pregnant. 9. Previous treatment with levosimendan within 30 days. 10. Known hypersensitivity to levosimendan or any of the excipients 111.Known to have received another investigational medicinal product within 30 days or currently in another interventional trial that might interact with the study drug.

Design outcomes

Secondary

Measure	Time frame
Secondary end point(s): CARDIOVASCULAR - Central venous oxygen saturations and cardiac output RENAL - Stage of Acute Kidney Injury RESPIRATORY - Time to extubation OTHER CLINICAL OUTCOMES 28-day, hospital and three & six-month survival ICU and hospital length of stay, and ICU-free days Duration of renal replacement therapy Days free from catecholamine therapy Blood and urinary biomarkers PHARMACOKINETICS ; Timepoint(s) of evaluation of this end point: CARDIOVASCULAR - Over the first 96 hours RENAL - at Day 14	—

Measure

Time frame

Secondary end point(s): CARDIOVASCULAR - Central venous oxygen saturations and cardiac output RENAL - Stage of Acute Kidney Injury RESPIRATORY - Time to extubation OTHER CLINICAL OUTCOMES 28-day, hospital and three & six-month survival ICU and hospital length of stay, and ICU-free days Duration of renal replacement therapy Days free from catecholamine therapy Blood and urinary biomarkers PHARMACOKINETICS ; Timepoint(s) of evaluation of this end point: CARDIOVASCULAR - Over the first 96 hours RENAL - at Day 14

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Primary

Measure	Time frame
Timepoint(s) of evaluation of this end point: End of ICU stay.; Main Objective: The main objectives of this trial are: 1. To ascertain if levosimendan reduces the incidence and severity of organ failure as compared to placebo in adult patients who have septic shock. 2. To identify the effect of levosimendan on the function of individual organs function in septic shock. 3. To establish the safety profile and the metabolism of levosimendan by the body in this group of patients. ; Secondary Objective: The secondary objectives of this trial are: 1. To identify whether levosimendan reduces the need for and duration of blood pressure support with conventional adrenaline-like drugs called catecholamines and whether levosimendan reduces the damage to the heart that is associated with septic shock and the use of these drugs. 2. To establish whether levosimendan affects the degree of inflammation that is seen in septic shock by measuring the levels of chemicals that are released in response to overwhelming infection. 3. To collect longer-term (3 and 6 month) outcome data to help inform the appropriate outcome measure for a subsequent larger trial if the efficacy of levosimendan is confirmed in this study. ;Primary end point(s): The primary outcome will compare mean Sequential Organ Failure Assessment (SOFA) score after randomisation between treatment groups. This is a well validated scoring system assessing the severity of organ failures. The mean SOFA is predictive of mortality regardless of ICU length of stay and therefore no imputation for death is required. All SOFA scores while alive in ICU (excluding neurological component) will be used for all patients to calculate the mean SOFA score for each patient.	—

Measure

Time frame

Timepoint(s) of evaluation of this end point: End of ICU stay.; Main Objective: The main objectives of this trial are: 1. To ascertain if levosimendan reduces the incidence and severity of organ failure as compared to placebo in adult patients who have septic shock. 2. To identify the effect of levosimendan on the function of individual organs function in septic shock. 3. To establish the safety profile and the metabolism of levosimendan by the body in this group of patients. ; Secondary Objective: The secondary objectives of this trial are: 1. To identify whether levosimendan reduces the need for and duration of blood pressure support with conventional adrenaline-like drugs called catecholamines and whether levosimendan reduces the damage to the heart that is associated with septic shock and the use of these drugs. 2. To establish whether levosimendan affects the degree of inflammation that is seen in septic shock by measuring the levels of chemicals that are released in response to overwhelming infection. 3. To collect longer-term (3 and 6 month) outcome data to help inform the appropriate outcome measure for a subsequent larger trial if the efficacy of levosimendan is confirmed in this study. ;Primary end point(s): The primary outcome will compare mean Sequential Organ Failure Assessment (SOFA) score after randomisation between treatment groups. This is a well validated scoring system assessing the severity of organ failures. The mean SOFA is predictive of mortality regardless of ICU length of stay and therefore no imputation for death is required. All SOFA scores while alive in ICU (excluding neurological component) will be used for all patients to calculate the mean SOFA score for each patient.

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Countries

United Kingdom

Contacts

Public ContactAnthony Gordon

Imperial College London

anthony.gordon@imperial.ac.uk020 3313 0657

Outcome results

None listed