Clinical Trial Results:
An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS)
Summary
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EudraCT number |
2012-005159-18 |
Trial protocol |
GB |
Global end of trial date |
21 Jun 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Mar 2018
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First version publication date |
10 Mar 2018
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CRO2047
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Additional study identifiers
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ISRCTN number |
ISRCTN12776039 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Imperial College London
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Sponsor organisation address |
2nd floor Medical Building, st Mary's Campus, Praed street, London, United Kingdom, W2 1NY
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Public contact |
Anthony Gordon, Imperial College London, +44 020 3313 0657, anthony.gordon@imperial.ac.uk
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Scientific contact |
Anthony Gordon, Imperial College London, +44 020 3313 0657, anthony.gordon@imperial.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 Jun 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Jun 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Jun 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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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
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 515
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Worldwide total number of subjects |
515
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EEA total number of subjects |
515
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
191
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From 65 to 84 years |
299
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85 years and over |
25
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Recruitment
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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
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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
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Period 1 title |
Randomised and included (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
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Other name |
Simdax
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous drip use
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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
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Arm title
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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
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Investigational medicinal product code |
N/A
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Other name |
N/A
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous drip use
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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).
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Baseline characteristics reporting groups
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Reporting group title |
Randomised and included
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Levosimendan
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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
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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. |
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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.
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End point type |
Primary
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End point timeframe |
From randomisation to ICU discharge
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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.
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Comparison groups |
Levosimendan v placebo
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.61
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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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.
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Comparison groups |
Levosimendan v placebo
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.59
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.02 | ||||||||||||
upper limit |
1.2 |
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End point title |
Respiratory SOFA score | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
From randomisation to ICU discharge up to a maximum of 28 days
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Statistical analysis title |
Mean difference (bootstrap CI) | ||||||||||||
Statistical analysis description |
Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
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Comparison groups |
Levosimendan v placebo
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.14
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.06 | ||||||||||||
upper limit |
0.34 |
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End point title |
Coagulation SOFA score | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
From randomisation to ICU discharge up to a maximum of 28 days
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Statistical analysis title |
Mean difference (bootstrap CI) | ||||||||||||
Statistical analysis description |
Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
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Comparison groups |
Levosimendan v placebo
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.18 | ||||||||||||
upper limit |
0.17 |
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End point title |
Hepatic SOFA score | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
From randomisation to ICU discharge up to a maximum of 28 days
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Statistical analysis title |
Mean difference (bootstrap CI) | ||||||||||||
Statistical analysis description |
Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
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Comparison groups |
Levosimendan v placebo
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.06
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.08 | ||||||||||||
upper limit |
0.19 |
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End point title |
Cardiovascular SOFA score | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
From randomisation to ICU discharge up to a maximum of 28 days
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Statistical analysis title |
Mean difference (bootstrap CI) | ||||||||||||
Statistical analysis description |
Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
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Comparison groups |
Levosimendan v placebo
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.25
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.04 | ||||||||||||
upper limit |
0.46 |
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End point title |
Renal SOFA score | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
From randomisation to ICU discharge up to a maximum of 28 days
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Statistical analysis title |
Mean difference (bootstrap CI) | ||||||||||||
Statistical analysis description |
Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
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Comparison groups |
Levosimendan v placebo
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.18
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.07 | ||||||||||||
upper limit |
0.42 |
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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.
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End point type |
Primary
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End point timeframe |
From randomisation to ICU discharge up to a maximum of 28 days
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Statistical analysis title |
Mean difference (bootstrap CI) | ||||||||||||
Statistical analysis description |
Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
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Comparison groups |
Levosimendan v placebo
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.36
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.17 | ||||||||||||
upper limit |
0.9 |
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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.
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End point type |
Primary
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End point timeframe |
From randomisation to ICU discharge up to a maximum of 28 days
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Statistical analysis title |
Mean difference (bootstrap CI) | ||||||||||||
Statistical analysis description |
Absolute difference in means comparing levosimendan and placebo with bootstrapped confidence interval.
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Comparison groups |
Levosimendan v placebo
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.41
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.24 | ||||||||||||
upper limit |
1.06 |
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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
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
End point title |
Mortality at ICU discharge | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation to ICU discharge
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
End point title |
Mortality at hospital discharge | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation until hospital discharge
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
End point title |
need for new renal replacement therapy | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomisation to day 28
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
End point title |
Length of ICU stay | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From ICU admission to ICU discharge
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
End point title |
Length of hospital stay | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From hospital admission to hospital discharge
|
||||||||||||
|
|||||||||||||
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 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
|
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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. |
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|
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Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||
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 | |||||||
|
|||||||
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 |