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    Clinical Trial Results:
    An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS)

    Summary
    EudraCT number
    		 2012-005159-18
    Trial protocol
    		 GB  
    Global end of trial date
    21 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Mar 2018
    First version publication date
    10 Mar 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CRO2047
    Additional study identifiers
    ISRCTN number
    		 ISRCTN12776039
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    2nd floor Medical Building, st Mary's Campus, Praed street, London, United Kingdom, W2 1NY
    Public contact
    Anthony Gordon, Imperial College London, +44 020 3313 0657, anthony.gordon@imperial.ac.uk
    Scientific contact
    Anthony Gordon, Imperial College London, +44 020 3313 0657, anthony.gordon@imperial.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    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.
    Protection of trial subjects
    All patients were treated in an intensive care unit with constant 1:1 nursing care to ensure safety and comfort and minimise any distress.
    Background therapy
    		 Patients were randomised to either treatment group or control group. The study drug was not started until the treating physician was confident that adequate fluid resuscitation has been achieved and the patient had reached their target mean arterial pressure (suggested target 65-70 mmHg ). Adequate fluid resuscitation was achieved using repeated fluid challenges. Examples of appropriate targets include any or all of the following: • Central venous pressure ≥8mmHg (≥12 mmHg in mechanically ventilated patients) • Good peripheral perfusion on clinical examination • Other measures of cardiac output / flow, e.g. Stroke Volume Variability (SVV), Global End-Diastolic Volume Index (GEDVI) Patients received all normal standard care and in addition they received either a 24-hour blinded intravenous infusion of levosimendan or the matched placebo. During the study drug administration and especially during the first 6 hours patients were repeatedly reassessed to ensure adequate fluid resuscitation using any or all of the targets above. Other management of septic shock including use of inotropes ( e.g. dobutamine) was at the treating physician's discretion, based on the international 'Surviving Sepsis' guidelines. All other drugs was prescribed as clinically indicated.
    Evidence for comparator
    		 There is a substantial body of research which provides proof of concept that levosimendan improves cardiac output, regional perfusion and other physiological endpoints, including creatinine clearance and glomerular filtration rate in patients who have septic shock. This trial had an exploratory trial design to identify important clinical outcome benefits and to explore the mechanism of action of levosimendan in septic shock. Given that multiple organ dysfunction is associated with an increased mortality, a reduction in the incidence and severity of organ failure would be associated with meaningful benefits to patients and clinicians alike.
    Actual start date of recruitment
    10 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 515
    Worldwide total number of subjects
    515
    EEA total number of subjects
    515
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    191
    From 65 to 84 years
    299
    85 years and over
    25

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a double-blind randomised placebo controlled parallel group trial. It was conducted in 34 general adult ICUs within the UK. Patients were randomised to receive an intravenous infusion of either levosimendan or placebo for the duration of 24hours in addition to standard care.

    Pre-assignment
    Screening details
    		 Patients who were clinically judged to have septic shock were screened against the inclusion and exclusion criteria and this required a history and clinical examination. A full blood count or an arterial blood gas samples would be needed but this would be collected as part of their routine clinical care.

    Period 1
    Period 1 title
    Randomised and included (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Vials of levosimendan and matching placebo were supplied by Orion Corporation Orion Pharma, Espoo, Finland. Trial specific labelling and packaging, to ensure trial packs were identical, was undertaken by Victoria Pharmaceuticals, Belfast, UK. Patients, clinical and research staff remained blinded to treatment allocation throughout the trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Levosimendan
    Arm description
    		 Patients will be randomised to receive an intravenous infusion of either levosimendan (0.05 to 0.2 µg/kg/min) . The study drug infusion will start at 0.1 µg/kg/min and if tolerated will be increased after 2-4 hours to 0.2 µg/kg/min for the remaining 20-22 hours (maximum 24 hour infusion). If there are subsequent adverse effects the rate of infusion will be reduced back to 0.1 µg/kg/min. If there are adverse effects at an infusion rate of 0.1 µg/kg/min (either initially or later) then the rate of infusion will be reduced to 0.05 µg/kg/min or discontinued.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levosimendan
    Investigational medicinal product code
    Other name
    Simdax
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    The study drug was commenced at a rate of 0.1ug/kg/min and if tolerated was increased after 2-4 hours to 0.2ug/kg/min for a further 20-22 hours. patients received intravenous fluid boluses for ant clinically significant drop in blood pressure and , if ne

    Arm title
    		 placebo
    Arm description
    		 Patients will be randomised to receive an intravenous infusion of placebo (0.05 to 0.2 µg/kg/min) for a duration of 24 hours in addition to standard care.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    N/A
    Other name
    N/A
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Patients will receive all normal standard care and in addition they will receive a 24-hour blinded intravenous infusion of matching placebo. The placebo infusion rate will follow the treatment group regimen; infusion will start at 0.1 µg/kg/min and if tolerated will be increased after 2-4 hours to 0.2 µg/kg/min for a further 20-22 hours (total infusion of 24 hours).

    Number of subjects in period 1
    		Levosimendan placebo
    Started
    258
    257
    Completed
    255
    254
    Not completed
    3
    3
         Adverse event, serious fatal
    2
    2
         Physician decision
    1
    -
         Enrolled while trial on temporary halt
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Randomised and included
    Reporting group description
    		 -

    Reporting group values
    		 Randomised and included Total
    Number of subjects
    		 515 515
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 68 (58 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 226 226
        Male
    		 289 289
    Source of infection
    Units: Subjects
        Lung
    		 201 201
        abdomen
    		 191 191
        urine
    		 29 29
        primary bacteremia
    		 10 10
        neurological
    		 5 5
        Soft tissue or line
    		 26 26
        other
    		 52 52
        Missing
    		 1 1
    Mechanical ventilation
    Units: Subjects
        Receiving mechanical ventilation
    		 417 417
        Not receiving mechanical ventilation
    		 98 98
    Renal replacement therapy (RRT)
    Units: Subjects
        Receiving RRT
    		 89 89
        Not receiving RRT
    		 426 426
    Moderate or severe ARDS
    Units: Subjects
        Yes
    		 131 131
        No
    		 384 384
    Ethnicity
    Units: Subjects
        Asian
    		 21 21
        Black
    		 10 10
        White
    		 480 480
        Other
    		 4 4
    History of recent surgery
    Defined as admission to the intensive care unit from the operating room.
    Units: Subjects
        Yes
    		 189 189
        No
    		 326 326
    Beta-blockers normally taken
    Units: Subjects
        Yes
    		 99 99
        No
    		 416 416
    Positive microbiological culture
    Units: Subjects
        Yes
    		 221 221
        No
    		 294 294
    Heart rhythm
    Units: Subjects
        Sinus rhythm
    		 419 419
        Atrial fibrilation
    		 53 53
        Paced
    		 5 5
        Other irregular rhythm
    		 36 36
        Missing
    		 2 2
    Respiratory Failure at Randomisation
    Patients can have failure in more than one organ. Some patients were missing organ failure data at baseline as follows: respiratory - 2 patients; coagulation- 4 patients; hepatic - 11 patients; neurological - 79 patients; renal - 1 patient.
    Units: Subjects
        Respiratory Failure
    		 200 200
        No Respiratory Failure
    		 315 315
    Renal Failure at Randomisation
    Patients can have failure in more than one organ. Some patients were missing organ failure data at baseline as follows: respiratory - 2 patients; coagulation- 4 patients; hepatic - 11 patients; neurological - 79 patients; renal - 1 patient.
    Units: Subjects
        Renal Failure
    		 151 151
        No Renal Failure
    		 364 364
    Hepatic Failure at Randomisation
    Patients can have failure in more than one organ. Some patients were missing organ failure data at baseline as follows: respiratory - 2 patients; coagulation- 4 patients; hepatic - 11 patients; neurological - 79 patients; renal - 1 patient.
    Units: Subjects
        Hepatic Failure
    		 14 14
        No Hepatic Failure
    		 501 501
    Coagulation failure at randomisation
    Patients can have failure in more than one organ. Some patients were missing organ failure data at baseline as follows: respiratory - 2 patients; coagulation- 4 patients; hepatic - 11 patients; neurological - 79 patients; renal - 1 patient.
    Units: Subjects
        coagulation failure
    		 29 29
        No coagulation Failure
    		 486 486
    Neurological failure at randomisation
    Patients can have failure in more than one organ. Some patients were missing organ failure data at baseline as follows: respiratory - 2 patients; coagulation- 4 patients; hepatic - 11 patients; neurological - 79 patients; renal - 1 patient.
    Units: Subjects
        neurological failure
    		 228 228
        No Neurological Failure
    		 287 287
    Pre-existing conditions:Ischemic Heart disease
    One subject can have multiple conditions
    Units: Subjects
        Ischemic heart disease
    		 77 77
        No Ischemic heart disease
    		 438 438
    Pre-existing conditions congestive heart failure
    One subject can have more than one condition
    Units: Subjects
        congestive heart failure
    		 5 5
        No congestive heart failure
    		 510 510
    Pre-exisiting condition: cardiac failure
    one subject can have more than one condition
    Units: Subjects
        cardiac failure
    		 49 49
        No cardiac Failure
    		 466 466
    Pre-exisiting conditions: Severe COPD
    One subject can have more than one condition
    Units: Subjects
        severe COPD
    		 27 27
        No severe COPD
    		 488 488
    Pre-existing conditions: Chronic renal failure
    One subject can have more than 1 condition
    Units: Subjects
        Chronic renal failure
    		 37 37
        No chronic renal failure
    		 478 478
    Pre-existing conditions: Cirrhosis
    One subject may have more than 1 condition
    Units: Subjects
        Cirrhosis
    		 10 10
        No cirrhosis
    		 505 505
    Pre-exisiting condition: Immunocompromised condition
    one subject can have more than 1 condition
    Units: Subjects
        immunocompromised
    		 47 47
        not Immunocompromised
    		 468 468
    Pre-existing condition: diabetes
    one patient may have more than 1 condition
    Units: Subjects
        Diabetes
    		 110 110
        No diabetes
    		 405 405
    Vasoactive drugs at randomisation: Noradrenaline
    Units: Subjects
        Noradrenaline
    		 508 508
        No Noradrenaline
    		 7 7
    Vasoactive drugs at randomisation: Vasopressin
    Units: Subjects
        Vasopressin
    		 70 70
        No vasopressin
    		 445 445
    Vasoactive drugs at randomisation : Dobutamine
    Units: Subjects
        Dobutamine
    		 40 40
        No dobutamine
    		 475 475
    Vasoactive drugs at randomisation: Adrenaline
    Units: Subjects
        Adrenaline
    		 42 42
        No adrenaline
    		 473 473
    BMI (kg/m2)
    Missing for 9 patients.
    Units: kg/m2
        median (inter-quartile range (Q1-Q3))
    		 27 (23 to 31) -
    APACHE II score
    Acute physiology and chronic health evaluation ( range 0-72, a higher score corresponds to a more severe illness and a higher risk of death)
    Units: number
        median (inter-quartile range (Q1-Q3))
    		 25 (21 to 30) -
    Mean Arterial pressure
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 74 (68 to 79) -
    heart rate
    Units: beats / minute
        median (inter-quartile range (Q1-Q3))
    		 95 (80 to 110) -
    cardiac index
    Units: L/min/m2
        median (inter-quartile range (Q1-Q3))
    		 3 (2.2 to 3.8) -
    Lactate
    Missing for 5 patients.
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 2.3 (1.4 to 3.6) -
    Time from shock to randomisation
    The onset of shock was defined as the initiation of vasopressors
    Units: hours
        median (inter-quartile range (Q1-Q3))
    		 16 (0 to 21) -
    Noradrenaline dose at randomisation
    Restricted to patients receiving noradrenaline at baseline
    Units: micrograms/kg/hour
        median (inter-quartile range (Q1-Q3))
    		 0.28 (0.16 to 0.47) -
    Adrenaline dose at randomisation
    Restricted to patients receiving adrenaline at randomisation
    Units: micrograms/kg/hour
        median (inter-quartile range (Q1-Q3))
    		 0.14 (0.07 to 0.3) -
    Vasopressin dose at randomisation
    Restricted to patients receiving vasopressin at randomisation
    Units: Units/min
        median (inter-quartile range (Q1-Q3))
    		 0.03 (0.02 to 0.04) -
    Dobutamine dose at randomisation
    Restricted to patients receiving dobutamine at randomisation
    Units: milligram(s)/hour
        median (inter-quartile range (Q1-Q3))
    		 5.2 (4.4 to 6.5) -
    APACHE II score
    Scores on the Acute Physiology and Chronic Health Evaluation (APACHE) II range from 0-72, with higher scores indicating more severe illness and a higher risk of death.
    Units: none
        median (inter-quartile range (Q1-Q3))
    		 25 (21 to 30) -
    Total SOFA score at randomisation
    Scores on the Sequential Organ Failure Assessment (SOFA) were calculated on the basis of six organ systems (cardiovascular, respiratory, renal, hepatic, coagulation, neurological) at baseline. Note that the neurological score was not included for scores after randomisation.
    Units: none
        median (inter-quartile range (Q1-Q3))
    		 10 (8 to 12) -
    Central venous pressure
    Missing for 143 patients.
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 11 (8 to 15) -
    Arterial oxygen saturation (SaO2)
    Missing for 6 patients.
    Units: percent
        median (inter-quartile range (Q1-Q3))
    		 97 (95 to 98) -
    Central venous oxygen saturation (ScvO2)
    Missing for 172 patients.
    Units: percent
        median (inter-quartile range (Q1-Q3))
    		 76 (69 to 81) -
    PaO2/FiO2 ratio
    Units: kPa
        median (inter-quartile range (Q1-Q3))
    		 29 (20 to 39) -
    Creatinine
    Missing for 2 patients.
    Units: micromole(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 138 (91 to 213) -
    Bilirubin
    Missing for 11 patients.
    Units: micromole(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 14 (8 to 26) -
    Haemoglobin
    Units: gram(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 108 (94 to 124) -
    Platelets
    Missing for 4 patients.
    Units: x 10-9 per litre
        median (inter-quartile range (Q1-Q3))
    		 215 (140 to 307) -
    Glasgow Coma Scale score
    Scores range from 3 to 15, with lower scores indicating a greater depression of consciousness. Missing for 79 patients.
    Units: none
        median (inter-quartile range (Q1-Q3))
    		 9 (3 to 15) -

    End points

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    End points reporting groups
    Reporting group title
    Levosimendan
    Reporting group description
    		 Patients will be randomised to receive an intravenous infusion of either levosimendan (0.05 to 0.2 µg/kg/min) . The study drug infusion will start at 0.1 µg/kg/min and if tolerated will be increased after 2-4 hours to 0.2 µg/kg/min for the remaining 20-22 hours (maximum 24 hour infusion). If there are subsequent adverse effects the rate of infusion will be reduced back to 0.1 µg/kg/min. If there are adverse effects at an infusion rate of 0.1 µg/kg/min (either initially or later) then the rate of infusion will be reduced to 0.05 µg/kg/min or discontinued.

    Reporting group title
    placebo
    Reporting group description
    		 Patients will be randomised to receive an intravenous infusion of placebo (0.05 to 0.2 µg/kg/min) for a duration of 24 hours in addition to standard care.

    Primary: Mean Daily SOFA score

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    End point title
    		 Mean Daily SOFA score
    End point description
    The mean daily Sequential Organ Failure Assessment (SOFA) score while the patient was in ICU, as measured from randomisation to a maximum of 28 days. The daily score was calculated for each of 5 organ systems (cardiovascular, respiratory, renal, hepatic, and coagulation systems). Component scores range from 0-4 (with higher scores indicating more severe organ dysfunction) giving a maximum total score of 20. For each patient, scores from each day were added together and divided by the number of days to give the mean daily SOFA score.
    End point type
    Primary
    End point timeframe
    From randomisation to ICU discharge
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    257
    Units: no units
        arithmetic mean (standard deviation)
    6.68 ( 3.96 )
    6.06 ( 3.89 )
    Statistical analysis title
    		 Mean difference (bootstrap CI)
    Statistical analysis description
    The absolute mean difference (levosimendan - placebo) with a 95% confidence interval calculated using bootstrap methods.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 1.29
    Statistical analysis title
    		 Adjusted mean difference
    Statistical analysis description
    Mean difference in SOFA score comparing levosimendan and placebo from regression analysis, adjusting for age, baseline APACHE II score and allowing for clustering by ICU.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 1.2

    Primary: Respiratory SOFA score

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    End point title
    		 Respiratory SOFA score
    End point description
    End point type
    Primary
    End point timeframe
    From randomisation to ICU discharge up to a maximum of 28 days
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    257
    Units: none
        arithmetic mean (standard deviation)
    1.7 ( 1.18 )
    1.56 ( 1.15 )
    Statistical analysis title
    		 Mean difference (bootstrap CI)
    Statistical analysis description
    Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.34

    Primary: Coagulation SOFA score

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    End point title
    		 Coagulation SOFA score
    End point description
    End point type
    Primary
    End point timeframe
    From randomisation to ICU discharge up to a maximum of 28 days
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    257
    Units: none
        arithmetic mean (standard deviation)
    0.75 ( 1.05 )
    0.75 ( 1.02 )
    Statistical analysis title
    		 Mean difference (bootstrap CI)
    Statistical analysis description
    Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.17

    Primary: Hepatic SOFA score

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    End point title
    		 Hepatic SOFA score
    End point description
    End point type
    Primary
    End point timeframe
    From randomisation to ICU discharge up to a maximum of 28 days
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    257
    Units: none
        arithmetic mean (standard deviation)
    0.51 ( 0.84 )
    0.45 ( 0.77 )
    Statistical analysis title
    		 Mean difference (bootstrap CI)
    Statistical analysis description
    Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.19

    Primary: Cardiovascular SOFA score

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    End point title
    		 Cardiovascular SOFA score
    End point description
    End point type
    Primary
    End point timeframe
    From randomisation to ICU discharge up to a maximum of 28 days
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    257
    Units: none
        arithmetic mean (standard deviation)
    2.27 ( 1.2 )
    2.02 ( 1.2 )
    Statistical analysis title
    		 Mean difference (bootstrap CI)
    Statistical analysis description
    Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.46

    Primary: Renal SOFA score

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    End point title
    		 Renal SOFA score
    End point description
    End point type
    Primary
    End point timeframe
    From randomisation to ICU discharge up to a maximum of 28 days
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    257
    Units: none
        arithmetic mean (standard deviation)
    1.46 ( 1.49 )
    1.28 ( 1.38 )
    Statistical analysis title
    		 Mean difference (bootstrap CI)
    Statistical analysis description
    Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.42

    Primary: Mean daily SOFA score - excluding cardiovascular

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    End point title
    		 Mean daily SOFA score - excluding cardiovascular
    End point description
    Sensitivity analysis for primary outcome excluding the cardiovascular component.
    End point type
    Primary
    End point timeframe
    From randomisation to ICU discharge up to a maximum of 28 days
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    257
    Units: none
        arithmetic mean (standard deviation)
    4.41 ( 3.13 )
    4.05 ( 3.07 )
    Statistical analysis title
    		 Mean difference (bootstrap CI)
    Statistical analysis description
    Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.9

    Primary: Mean SOFA score - sensitivity analysis

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    End point title
    		 Mean SOFA score - sensitivity analysis
    End point description
    Sensitivity analysis using Bayesian methods to impute the missing data rather than the last observation carried forward approach taken in the main analysis.
    End point type
    Primary
    End point timeframe
    From randomisation to ICU discharge up to a maximum of 28 days
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    257
    Units: none
        arithmetic mean (standard deviation)
    7.19 ( 3.72 )
    6.78 ( 3.74 )
    Statistical analysis title
    		 Mean difference (bootstrap CI)
    Statistical analysis description
    Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 1.06

    Secondary: 28 day mortality

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    End point title
    		 28 day mortality
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to 28 days
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    256 [1]
    Units: Number of patients
        Died
    89
    79
    Attachments
    		 Kaplan Meier plot of survival to 28 days
    Notes
    [1] - One patient declined follow up after ICU discharge but before day 28
    Statistical analysis title
    		 Absolute difference in proportions
    Comparison groups
    placebo v Levosimendan
    Number of subjects included in analysis
    514
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 11.7

    Secondary: Mortality at ICU discharge

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    End point title
    		 Mortality at ICU discharge
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to ICU discharge
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    257
    Units: Number of patients
        Died
    83
    76
    Statistical analysis title
    		 Absolute difference in proportions
    Comparison groups
    placebo v Levosimendan
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.4
         upper limit
    		 10.6

    Secondary: number of catecholamine free days

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    End point title
    		 number of catecholamine free days
    End point description
    Days free of any catecholamine therapy (noradrenaline, adrenaline and dobutamine). There were no patients with 28 days free of catecholamine therapy as this was an inclusion criterion to enter the trial.
    End point type
    Secondary
    End point timeframe
    From randomisation to 28 days.
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    256 [2]
    Units: days
        median (inter-quartile range (Q1-Q3))
    22 (0 to 26)
    23 (0 to 26)
    Notes
    [2] - One patient withdrew consent after ICU discharge but before day 28
    Statistical analysis title
    		 Absolute difference in medians
    Statistical analysis description
    Absolute difference in medians calculated using bootstrapping.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    514
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 1

    Secondary: Number of ventilation free days

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    End point title
    		 Number of ventilation free days
    End point description
    0 for patients that died before extubation; 28 less the number of ventilation days for patients surviving to day 28; days to death less ventilation days for subjects dead at day 28 but after extubation. For subjects discharged from ICU before 28 days whilst ventilated, days between ICU discharge and successful weaning from ventilation were counted as ventilation days.
    End point type
    Secondary
    End point timeframe
    From randomisation to 28 days
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    256 [3]
    253 [4]
    Units: days
        median (inter-quartile range (Q1-Q3))
    16 (0 to 25)
    19 (0 to 25)
    Notes
    [3] - 2 patients had missing data as they were transferred ventilated before 28 days.
    [4] - Four patients excluded due to missing data on weaning from ventilation.
    Statistical analysis title
    		 Absolute difference in medians
    Statistical analysis description
    Absolute difference in medians with bootstrap confidence interval.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    509
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.5
         upper limit
    		 1

    Secondary: Major acute kidney event over 28 days

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    End point title
    		 Major acute kidney event over 28 days
    End point description
    Patients were defined as having MAKE28 if they died, required renal replacement therapy (RRT) before day 28, or had prolonged renal failure defined as AKI stage 2 or 3 at day 28 (or at ICU discharge if discharged before day 28).
    End point type
    Secondary
    End point timeframe
    From randomisation to day 28
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    256 [5]
    Units: number of patients
        MAKE28
    148
    139
    Notes
    [5] - One patient withdrew consent after ICU discharge but before day 28
    Statistical analysis title
    		 Absolute difference in proportions
    Statistical analysis description
    Absolute difference in proportions comparing levosimendan with placebo.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    514
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 11.6

    Secondary: Mortality at hospital discharge

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    End point title
    		 Mortality at hospital discharge
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation until hospital discharge
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    256 [6]
    Units: number of patients
        Died
    97
    84
    Notes
    [6] - One patient withdrew consent after ICU discharge but before day 28
    Statistical analysis title
    		 Absolute difference in proportions
    Statistical analysis description
    Absolute difference in proportions comparing levosimendan with placebo.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    514
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 13

    Secondary: need for new renal replacement therapy

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    End point title
    		 need for new renal replacement therapy
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to day 28
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    257 [7]
    257
    Units: Number of patients
        RRT
    62
    62
    Notes
    [7] - One patient with missing data
    Statistical analysis title
    		 Absolute difference in proportions
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    514
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.4
         upper limit
    		 7.4

    Secondary: Time to extubation

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    End point title
    		 Time to extubation
    End point description
    Time to extubation in days. All patients were censored at 28 days and deaths were treated as still ventilated at the end of follow up. Patients who were not ventilated at baseline or day 1 were excluded.
    End point type
    Secondary
    End point timeframe
    From randomisation to extubation, up to a maximum of 28 days.
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    215 [8]
    218 [9]
    Units: Number of patients
        Number extubated by day 28
    127
    150
    Attachments
    		 Kaplan Meier plot of time to extubation
    Notes
    [8] - Restricted to patients ventilated on baseline or day 1.
    [9] - Restricted to patients ventilated at baseline or day 1.
    Statistical analysis title
    		 Cox regression
    Statistical analysis description
    Cox regression comparing time to extubation in Levosimendan and Placebo.
    Comparison groups
    placebo v Levosimendan
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 0.99

    Secondary: Sustained renal failure

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    End point title
    		 Sustained renal failure
    End point description
    Sustained renal failure at day 28, or at ICU discharge if before 28 days.
    End point type
    Secondary
    End point timeframe
    Day 28, or at ICU discharge if before 28 days.
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    257
    Units: Patients
        Sustained renal failure
    118
    108
    Statistical analysis title
    		 Absolute difference in proportions
    Statistical analysis description
    Absolute difference in proportions comparing Levosimendan and placebo
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.9
         upper limit
    		 12.3

    Secondary: Length of ICU stay

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    End point title
    		 Length of ICU stay
    End point description
    End point type
    Secondary
    End point timeframe
    From ICU admission to ICU discharge
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    257
    Units: days
        median (inter-quartile range (Q1-Q3))
    7.3 (3.2 to 14.8)
    8.3 (3.9 to 13.5)
    Statistical analysis title
    		 Median difference (bootstrap CI)
    Statistical analysis description
    Absolute difference in medians comparing levosimendan and placebo with bootstrapped confidence interval.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 0.8

    Secondary: Length of hospital stay

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    End point title
    		 Length of hospital stay
    End point description
    End point type
    Secondary
    End point timeframe
    From hospital admission to hospital discharge
    End point values
    		 Levosimendan placebo
    Number of subjects analysed
    258
    257
    Units: days
        median (inter-quartile range (Q1-Q3))
    19.6 (10.1 to 40.4)
    22.7 (11.7 to 42.3)
    Statistical analysis title
    		 Median difference (bootstrap CI)
    Statistical analysis description
    Absolute difference in medians comparing levosimendan and placebo with bootstrapped confidence interval.
    Comparison groups
    Levosimendan v placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7
         upper limit
    		 2.2

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Serious Adverse Events should be reported within 24 hours. Fatal or life threatening SAEs should be reported on the day that the local site is aware of the event.
    Adverse event reporting additional description
    clinical outcomes from sepsis are exempt from adverse event reporting unless the investigator deems the event to be related to the administration of the study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Levosimendan
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: As all patients included in the trial were critically ill, by definition, it is very difficult to define what is an adverse event as they will all have abnormal blood results and physiological signs as part of their underlying illness. Therefore the trial focused only on serious adverse events, as the priority safety analysis.
    Serious adverse events
    		 Levosimendan Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 255 (12.55%)
    23 / 253 (9.09%)
         number of deaths (all causes)
    10
    9
         number of deaths resulting from adverse events
    0
    0
    Investigations
    investigations
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    vascular disorder
         subjects affected / exposed
    7 / 255 (2.75%)
    4 / 253 (1.58%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Cardiac disorders
    atrial fibrillation / supraventricular tachycardia
         subjects affected / exposed
    8 / 255 (3.14%)
    1 / 253 (0.40%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 255 (0.00%)
    2 / 253 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ventricular fibrillation / tachycardia
         subjects affected / exposed
    7 / 255 (2.75%)
    3 / 253 (1.19%)
         occurrences causally related to treatment / all
    7 / 7
    1 / 3
         deaths causally related to treatment / all
    2 / 2
    0 / 1
    Myocardial infarction / acute coronary syndrome
         subjects affected / exposed
    3 / 255 (1.18%)
    1 / 253 (0.40%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    2 / 255 (0.78%)
    1 / 253 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    4 / 255 (1.57%)
    7 / 253 (2.77%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
         subjects affected / exposed
    4 / 255 (1.57%)
    5 / 253 (1.98%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Levosimendan Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 253 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Aug 2013
    •Addition of 3 new investigational sites, Nottingham University Hospitals NHS Trust (PI is Dan Harvey), Western Health and Social Care Trust, Northern Ireland (PI is Noel Hemmings) and Northern Health and Social Care Trust, Northern Ireland (PI is Christopher Nutt) •Change in the name of Principal Investigator at 3 participating investigational sites South Tees Hospitals NHS Foundation Trust (PI change from Judith Wright to Jost Mullenheim) York Teaching Hospitals NHS Foundation Trust (PI change from David Yates to John Berridge) Belfast Health and Social Care Trust (PI change from Danny McAuley to James McNamee)
    18 Nov 2013
    Change in the name of Principal Investigator at 3 participating investigational sites: 1.Norfolk and Norwich University Hospitals NHS Foundation Trust (PI change from Simon Fletcher to Jurgens Nortje) 2.Queen Elizabeth Hospital, Kings Lynn, NHS Foundation Trust (PI change from Mark Blunt to Darcy Pearson) 3.James Paget University Hospitals NHS Foundation Trust (PI change from Pieter Bothma to Hazel Stuart)
    28 Jul 2014
    Temporary halt of recruitment. Recruitment was temporarily halted by the Sponsor due to some mould being found on the secondary packaging of some IMP kits.
    18 Aug 2014
    Re-start of Patient Recruitment. The IMP has been recalled, effected kits destroyed and other packs reworked and now released for trial use.
    05 Sep 2014
    Addition of 10 new investigational sites: 1.Royal Sussex County Hospital, Brighton and Sussex University Hospitals NHS Trust; PI: Dr Stephen Drage 2.Frenchay Hospital Bristol, North Bristol NHS Trust; PI: Dr Matt Thomas 3.Countess of Chester Hospital NHS Trust; PI: Dr Nicole Robin 4.Medway Maritime Hospital, Medway NHS Foundation Trust; PI: Dr Nandita Divekar 5.Ipswich Hospital NHS Trust; PI: Dr Richard Howard-Griffin 6.Kettering General Hospital NHS Foundation Trust; PI: Dr Philip Watt 7.Leicester Royal Infirmary, University Hospital of Leicester NHS Trust; PI: Dr Simon Scott 8.Royal Free Hospital, Royal Free London NHS Foundation Trust; PI: Dr Daniel Martin 9.Salford Royal NHS Foundation Trust; PI: Dr Paul Dark 10.Pinderfields Hospital, The Mid Yorkshire Hospital NHS Trust; PI: Dr Alastair Rose
    08 Oct 2014
    Change of 2 Principal Investigators at participating study sites: 1.Countess of Chester Hospital NHS Trust; New PI: Dr Peter Turton (previously: Dr Nicole Robin) 2.Salford Royal NHS Foundation Trust; New PI: Dr Justin Roberts (previously Dr Paul Dark)
    12 Jan 2015
    Change of 1 Principal Investigators at participating study site: 1.University Hospital of North Midlands NHS Trust (formerly University Hospital of North Staffordshire NHS Trust); New PI: Dr Nicholas Coleman (previously: Dr Kumaresh Venkatesan)
    06 May 2015
    The trial protocol was updated to version 1.1 due to the addition of a tertiary exploratory outcome measure in the form of an echocardiographic sub-study. We also performed some minor corrections and clarifications. In line with the above amendment we also added a sentence to the patient information sheet and updated this to v1.4. The additional wording is: “In some hospitals we are also carrying out ultrasound scans of the heart on three occasions in the intensive care unit to examine the effect of levosimendan on heart function. This is a routine examination in these hospitals and will only involve placing an ultrasound probe with some jelly on your chest.” The echocardiographic sub-study was discussed with the Trial Management Group and the Trial Steering Committee with patient and public representation.
    06 May 2015
    Change of 1 Principal Investigator at a participating study site: 1.Countess of Chester Hospital NHS Trust; New PI: Dr Simon Ridler (previously: Dr Peter Turton)

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    28 Jul 2014
    Recruitment was temporarily halted by the Sponsor due to some mould being found on the secondary packaging of some IMP kits. The IMP has been recalled, effected kits destroyed and other packs reworked and now released for trial use. REC approval for restart of the trial was received on 26/08/14 and MHRA approval for restart of the trial was received on 08/09/14. The 1st patient after the halt, was recruited on 15/09/14 and recruitment remained unaffected for the remainder of the trial.
    08 Sep 2014

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27705084
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