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    Clinical Trial Results:
    Hydrocortisone for Prevention of Septic Shock Placebo-controlled, randomised, double-blind study to investigate the efficacy and safety of low dose hydrocortisone to prevent the development of septic shock in patients with severe sepsis

    Summary
    EudraCT number
    		 2007-004401-10
    Trial protocol
    		 DE  
    Global end of trial date
    29 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Mar 2022
    First version publication date
    08 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HYPRESS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00670254
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 clinical trials: NCT 00670254
    Sponsors
    Sponsor organisation name
    Charité
    Sponsor organisation address
    Augustenburger Platz 1, Berlin, Germany, 13353
    Public contact
    Didier Keh, Charité Universitaetsmedizin Berlin, 0049 30450651048, didier.keh@charite.de
    Scientific contact
    Didier Keh, Charité Universitaetsmedizin Berlin, 0049 30450651048, didier.keh@charite.de
    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
    29 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Prevention of the development of septic shock in patients with severe sepsis
    Protection of trial subjects
    AEs requiring therapy must be treated with recognized standards of medical care to protect the health and well being of the subject. Appropriate resuscitation equipment and medicines must be available to ensure the best possible treatment of an emergency situation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jan 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 380
    Worldwide total number of subjects
    380
    EEA total number of subjects
    380
    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)
    0
    From 65 to 84 years
    380
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patientswere screened in intermediate care units or intensive care units (ICUs) of university andcommunity hospitals for eligibility, and written informed consent was obtained from patients, patient-authorized representatives, or legal representatives. The main exclusion criterion was septic shock.

    Pre-assignment
    Screening details
    		 From January 13, 2009, to August 27, 2013, 9953 patients with severe sepsis or septic shock were screened at 34 study sites for eligibility. A total of 380 patients were randomized to receive hydrocortisone (n = 190)or placebo (n = 190).

    Pre-assignment period milestones
    Number of subjects started
    		 380
    Number of subjects completed
    		 353

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 27
    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Hydrocortisone
    Arm description
    		 Each vial with the study medication contains a lyophylisate of 100 mg hydrocortisone or placebo which has to be diluted with 2 ml of distilled water under sterile conditions. The vials have to be controlled for complete solution of the lyophylisate.
    Arm type
    		 Experimental

    Investigational medicinal product name
    HYDROCORTISONE HYDROGEN SUCCINATE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For bolus application, the lyophylisate of one vial is diluted with 2 ml of distilled water. One ml of this dilution (= 50 mg hydrocortisone or placebo) is diluted to 10 ml with normal saline and administered intravenously. The bolus is immediately followed by Continuous infusion of the study drug: Days 1-5: Dilute 2 x 2 ml of study drug (2 vials = 200 mg hydrocortisone ) in a 50 ml syringe with normal saline. Infusion rate: 200 mg/24 hours. Days 6-7: Dilute 1 x 2 ml of study drug (1 vial = 100 mg hydrocortisone) in a 50 ml syringe with normal saline. Infusion rate: 100 mg/24 hours. Days 8-9: Dilute 1 x 1 ml of study drug (1/2 vial = 50 mg hydrocortisone) in a 50 ml syringe with normal saline. Infusion rate: 50 mg/24 hours. Days 10-11: Dilute 1 x 1/2 ml of study drug (1/4 vial = 25 mg hydrocortisone) in a 50 ml syringe with normal saline. Infusion rate: 25 mg/24 hours.

    Arm title
    		 Placebo
    Arm description
    		 Each vial with the study medication contains a lyophylisate of 100 mg hydrocortisone or placebo which has to be diluted with 2 ml of distilled water under sterile conditions. The vials have to be controlled for complete solution of the lyophylisate.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • Days 1-5: Dilute 2 x 2 ml of study drug (2 vials = 200 mg placebo) in a 50 ml syringe with normal saline. Infusion rate: 200 mg/24 hours.• Days 6-7: Dilute 1 x 2 ml of study drug (1 vial = 100 mg placebo) in a 50 ml syringe with normal saline. Infusion rate: 100 mg/24 hours• Days 8-9: Dilute 1 x 1 ml of study drug (1/2 vial = 50 mgplacebo) in a 50 ml syringe with normal saline. Infusion rate: 50 mg/24 hours.• Days 10-11: Dilute 1 x 1/2 ml of study drug (1/4 vial = 25 mg placebo) in a 50 ml syringe with normal saline. Infusion rate: 25 mg/24 hours.

    Number of subjects in period 1 [1]
    		Hydrocortisone Placebo
    Started
    177
    176
    Completed
    170
    170
    Not completed
    7
    6
         Consent withdrawn by subject
    6
    4
         Lost to follow-up
    1
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 380 patients were screened for enrollment and 353 patients were definitely enrolled in the ITT population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Hydrocortisone
    Reporting group description
    		 Each vial with the study medication contains a lyophylisate of 100 mg hydrocortisone or placebo which has to be diluted with 2 ml of distilled water under sterile conditions. The vials have to be controlled for complete solution of the lyophylisate.

    Reporting group title
    Placebo
    Reporting group description
    		 Each vial with the study medication contains a lyophylisate of 100 mg hydrocortisone or placebo which has to be diluted with 2 ml of distilled water under sterile conditions. The vials have to be controlled for complete solution of the lyophylisate.

    Reporting group values
    		 Hydrocortisone Placebo Total
    Number of subjects
    		 177 176 353
    Age categorical
    Units: Subjects
        Adults >= 18
    		 177 176 353
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.5 ± 14.2 64.6 ± 14.6 -
    Gender categorical
    Units: Subjects
        Female
    		 59 65 124
        Male
    		 118 111 229
    Type of admission, No./total No.
    Units: Subjects
        Surgery, elective
    		 27 42 69
        Surgery, emergency
    		 44 32 76
        Nonsurgery, elective
    		 5 4 9
        Nonsurgery, emergency
    		 100 98 198
        N/A
    		 1 0 1
    Organ dysfunction: Central nervous system
    Units: Subjects
        Central nervous system
    		 41 47 88
        N/A
    		 136 129 265
    Organ dysfunction Coagulation
    Units: Subjects
        Coagulation
    		 35 26 61
        N/A
    		 142 150 292
    Organ dysfunction Pulmonary
    Units: Subjects
        Pulmonary
    		 117 119 236
        N/A
    		 60 57 117
    Organ dysfunction, No./total No. Renal
    Units: Subjects
        Renal
    		 70 73 143
        N/A
    		 107 103 210
    Sequential Organ Failure Assessment
    SOFA
    Units: Score
        arithmetic mean (standard deviation)
    		 6.4 ± 2.6 6.2 ± 2.4 -
    Acute Physiology and Chronic Health Evaluation II
    APACHE II
    Units: Score
        arithmetic mean (standard deviation)
    		 19.5 ± 6.9 18.5 ± 6.0 -
    Simplified Acute Physiology Score II
    SAPS II score
    Units: Score
        arithmetic mean (standard deviation)
    		 56.1 ± 13.3 52.2 ± 9.9 -
    Simplified Acute Physiology Score 3
    SAPS 3 score
    Units: Score
        arithmetic mean (standard deviation)
    		 58.5 ± 11.9 58.4 ± 11.0 -
    Medication within 72 h before randomization
    Intravenous glucocorticoids, No./total No. (%) Placebo :6/176 (3.4) Hydrocortisone: 3/177 (1.7)
    Units: mg
        median (full range (min-max))
    		 200 (200 to 400) 600 (392 to 1000) -

    End points

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    End points reporting groups
    Reporting group title
    Hydrocortisone
    Reporting group description
    		 Each vial with the study medication contains a lyophylisate of 100 mg hydrocortisone or placebo which has to be diluted with 2 ml of distilled water under sterile conditions. The vials have to be controlled for complete solution of the lyophylisate.

    Reporting group title
    Placebo
    Reporting group description
    		 Each vial with the study medication contains a lyophylisate of 100 mg hydrocortisone or placebo which has to be diluted with 2 ml of distilled water under sterile conditions. The vials have to be controlled for complete solution of the lyophylisate.

    Subject analysis set title
    Placebo Safty population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population is defined by all patients randomised with informed consent who received at least once the study medication. In the safety analyses, patients will be evaluated according to the treatment they actually received, irrespective of the randomisation.

    Subject analysis set title
    Safty population Hydrocortisone
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population is defined by all patients randomised with informed consent who received at least once the study medication. In the safety analyses, patients will be evaluated according to the treatment they actually received, irrespective of the randomisation.

    Primary: Primärer Endpunkt – Septic Schock within 14 days (ITT)

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    End point title
    		 Primärer Endpunkt – Septic Schock within 14 days (ITT)
    End point description
    End point type
    Primary
    End point timeframe
    14 Days
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    170
    170
    Units: Subject
    number (not applicable)
        ITT Population
    36
    39
    Statistical analysis title
    		 Patients with septic shock within 14days
    Statistical analysis description
    The primary end point was assessed by χ² test; heterogeneity between centers with more than 10 recruited patients was assessed by I²
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 17.9
         upper limit
    		 26.9

    Primary: Primärer Endpunkt – Septic Schock within 14 days (PP)

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    End point title
    		 Primärer Endpunkt – Septic Schock within 14 days (PP)
    End point description
    End point type
    Primary
    End point timeframe
    14 Days
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    155
    156
    Units: Subjects
    number (not applicable)
        PP population
    29
    33
    Statistical analysis title
    		 Patients with septic shock within 14days
    Statistical analysis description
    The primary end point was assessed by χ² test; heterogeneity between centers with more than 10 recruited
    Comparison groups
    Placebo v Hydrocortisone
    Number of subjects included in analysis
    311
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 17.9
         upper limit
    		 26.9

    Secondary: Mortality, No./total No. [95% CI] 28 Days

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    End point title
    		 Mortality, No./total No. [95% CI] 28 Days
    End point description
    End point type
    Secondary
    End point timeframe
    28 Day
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    171
    170
    Units: Subjects
    number (not applicable)
        28 Days
    15
    14
    No statistical analyses for this end point

    Secondary: Mortality, No./total No. [95% CI] 90 Days

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    End point title
    		 Mortality, No./total No. [95% CI] 90 Days
    End point description
    End point type
    Secondary
    End point timeframe
    90 Days
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    171
    168
    Units: Subjects
    number (not applicable)
        90 d
    34
    28
    No statistical analyses for this end point

    Secondary: Mortality, No./total No. [95% CI] 180 Days

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    End point title
    		 Mortality, No./total No. [95% CI] 180 Days
    End point description
    End point type
    Secondary
    End point timeframe
    180 Days
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    168
    167
    Units: Subjects
    number (not applicable)
        180 d
    45
    37
    No statistical analyses for this end point

    Secondary: ICU

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    End point title
    		 ICU
    End point description
    End point type
    Secondary
    End point timeframe
    180
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    171
    172
    Units: Subject
        number (not applicable)
    23
    22
    No statistical analyses for this end point

    Secondary: Hospital

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    End point title
    		 Hospital
    End point description
    End point type
    Secondary
    End point timeframe
    180 Days
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    171
    171
    Units: Subject
        number (not applicable)
    23
    22
    No statistical analyses for this end point

    Secondary: length of stay (LOS)

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    End point title
    		 length of stay (LOS)
    End point description
    End point type
    Secondary
    End point timeframe
    180 Days
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    177
    176
    Units: Days
    arithmetic mean (full range (min-max))
        ICU
    8 (6 to 15)
    9 (6 to 17)
        Hospital
    26 (16 to 46)
    25 (16 to 40)
    No statistical analyses for this end point

    Secondary: Mechanical ventilation

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    End point title
    		 Mechanical ventilation
    End point description
    Mechanical ventilation, No./total No.
    End point type
    Secondary
    End point timeframe
    180 Days
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    171
    172
    Units: Subject
        number (not applicable)
    91
    103
    No statistical analyses for this end point

    Secondary: MV-free time

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    End point title
    		 MV-free time
    End point description
    M/V =MV-free timeMV-free time, median (IQR),
    End point type
    Secondary
    End point timeframe
    180 Days
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    177
    176
    Units: Days
        median (inter-quartile range (Q1-Q3))
    4 (2 to 7)
    5 (2 to 7)
    No statistical analyses for this end point

    Secondary: RRT, No./total No. [95%CI]

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    End point title
    		 RRT, No./total No. [95%CI]
    End point description
    RRT, renal replacement therapy;
    End point type
    Secondary
    End point timeframe
    180 Days
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    171
    172
    Units: Subject
        number (not applicable)
    21
    21
    No statistical analyses for this end point

    Secondary: RRT, renal replacement therapy- free time

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    End point title
    		 RRT, renal replacement therapy- free time
    End point description
    End point type
    Secondary
    End point timeframe
    up to 180 days
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    177
    176
    Units: Score
    arithmetic mean (inter-quartile range (Q1-Q3))
        RRT-free time
    6 (4 to 12)
    7 (4 to 14)
    No statistical analyses for this end point

    Secondary: SOFA score until day 14

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    End point title
    		 SOFA score until day 14
    End point description
    SOFA (Sequential Organ Failure Assessment) score
    End point type
    Secondary
    End point timeframe
    Mean total SOFA (organ dysfunction) and mean SOFA sub-scores until ICU discharge but day 14 at maximum
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    177
    176
    Units: Score
    arithmetic mean (inter-quartile range (Q1-Q3))
        Sofa Score
    6 (4 to 12)
    5 (2 to 7)
    No statistical analyses for this end point

    Secondary: Delirium

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    End point title
    		 Delirium
    End point description
    -Delirium was assessed by the Richmond Agitation-Sedation Scale and the Confusion Assessment Method for the ICU in 286 of 353 patients (81.0%). -Twenty-six patients were excluded from analysis owing to low Richmond Agitation-Sedation Scale score or incomplete data. -The results remained significant after exclusion of another 60 patients (28 from the placebo group, 32 from the hydrocortisone group) who were diagnosed by the investigator to have no delirium but had at least 1 incomplete delirium assessment or had only 1 baseline assessment (n = 6 in the hydrocortisone group) (with delirium occurring in 11 of 98 patients [11.2%] in the hydrocortisone group vs 25 of 102 patients [24.5%] in the placebo group; difference, −13.3%; 95% CI, −23.7% to −2.6%; P = .01).
    End point type
    Secondary
    End point timeframe
    180 Days
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    98
    102
    Units: Subjects
    11
    25
    No statistical analyses for this end point

    Secondary: sodium concentration

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    End point title
    		 sodium concentration
    End point description
    Safety endpoints Blood sodium level and frequency of hypernatremia (> 155 mmol/l) within 14 days
    End point type
    Secondary
    End point timeframe
    14 Days
    End point values
    		 Placebo Safty population Safty population Hydrocortisone
    Number of subjects analysed
    189
    186
    Units: mEq/L
    arithmetic mean (standard deviation)
        Maximum sodium concentration
    141 ± 6
    141 ± 5
        Sodium concentration during study medication admin
    140 ± 6
    141 ± 5
    No statistical analyses for this end point

    Secondary: glucose concentration

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    End point title
    		 glucose concentration
    End point description
    Safety endpoints: Blood glucose level and frequency of hyperglycemia (> 150 mg/dl) within 14 days
    End point type
    Secondary
    End point timeframe
    14 Days
    End point values
    		 Placebo Safty population Safty population Hydrocortisone
    Number of subjects analysed
    189
    186
    Units: mg/dL
    median (inter-quartile range (Q1-Q3))
        Maximum glucose concentration
    160 (134 to 196)
    164 (145 to 204)
        Maximum glucose concentration during study medicat
    157 (133 to 198)
    170 (147 to 208)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    180 Days
    Adverse event reporting additional description
    the safety analysis set included 375 patients.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Total Adverse Events in Safety Set
    Reporting group description
    		 There were more episodes of hyperglycemia (blood glucose level >150mg/dL [to convert to millimoles per liter, multiply by 0.0555]) in the hydrocortisone group (169 of 186 patients [90.9%]) than in the placebo group(154of 189patients [81.5%]) (difference, 9.4%; 95%CI, 2.4%to 16.4%; P = .009). The total amount of administered insulin was not significantly different between the hydrocortisone and placebo groups (safety set analysis: mean [SD], 264.6 [312.2] vs 212.2 [246.8] IU, respectively; difference, 52.4 IU; 95% CI, −21.8 to 126.7 IU; P = .17). Two patients developed severe hypertension during hydrocortisone administration, which required antihypertensive therapy. Both patients recovered without sequelae. Secondary infections, weaning failure, muscleweakness,hypernatremia,orother adverse events were not significantly different between treatment groups.

    Serious adverse events
    		 Total Adverse Events in Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    88 / 375 (23.47%)
         number of deaths (all causes)
    5
         number of deaths resulting from adverse events
    Investigations
    Blood creatine increased
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic leak
         subjects affected / exposed
    4 / 375 (1.07%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Post procedural bile leak
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suture related complication
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheal haemorrhage
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheostomy malfunction
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urostomy complication
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Weaning failure
         subjects affected / exposed
    4 / 375 (1.07%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 375 (0.53%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    A cute myocardial infraction
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    A trial fibrillation
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    A trial flutter
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    A trioventricular block complete
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    5 / 375 (1.33%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Laparotomy
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Resuscitation
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 375 (0.53%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Orthostatic intolerance
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroduodenal haemorrhage
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 375 (1.07%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal fistula
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    2 / 375 (0.53%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    2 / 375 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 375 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 375 (1.33%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    Stridor
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    2 / 375 (0.53%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Candida sepsis
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dural abscess
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mediastine
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocarditis
         subjects affected / exposed
    2 / 375 (0.53%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal gangrene
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    4 / 375 (1.07%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 375 (1.07%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Retroperitoneal abscess
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 375 (0.53%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Total Adverse Events in Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    323 / 375 (86.13%)
    Injury, poisoning and procedural complications
    Impaired wound healing
         subjects affected / exposed
    8 / 375 (2.13%)
         occurrences all number
    8
    Cardiac disorders
    Arterial hypertension
         subjects affected / exposed
    6 / 375 (1.60%)
         occurrences all number
    6
    other
         subjects affected / exposed
    32 / 375 (8.53%)
         occurrences all number
    32
    Nervous system disorders
    Stroke, TIA or convulsion
    Additional description: TIA: transient ischemic attack
         subjects affected / exposed
    7 / 375 (1.87%)
         occurrences all number
    7
    Delirium
         subjects affected / exposed
    9 / 375 (2.40%)
         occurrences all number
    9
    other
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences all number
    1
    Gastrointestinal disorders
    Gastrointestinal bleeding
         subjects affected / exposed
    5 / 375 (1.33%)
         occurrences all number
    5
    Ulcer
         subjects affected / exposed
    1 / 375 (0.27%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Weaning failure
         subjects affected / exposed
    32 / 375 (8.53%)
         occurrences all number
    32
    Respiratory failure
         subjects affected / exposed
    10 / 375 (2.67%)
         occurrences all number
    10
    other
         subjects affected / exposed
    15 / 375 (4.00%)
         occurrences all number
    15
    Musculoskeletal and connective tissue disorders
    MRC Scale for Muscle Strength scor available
         subjects affected / exposed
    301 / 375 (80.27%)
         occurrences all number
    301
    Muscle weakness
         subjects affected / exposed
    82 / 375 (21.87%)
         occurrences all number
    82
    Infections and infestations
    Secondary infections
         subjects affected / exposed
    40 / 375 (10.67%)
         occurrences all number
    40

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 May 2008
    investigational medication
    30 Sep 2008
    Amendment for the trial protocol
    02 Apr 2009
    PI- Change
    07 Apr 2009
    PI-Change and subsequent registration of a Trial Centre
    27 Jul 2009
    PI-Change
    20 Nov 2009
    PI-Change
    27 Oct 2010
    PI-Change
    29 Mar 2011
    PI-Change
    30 Aug 2011
    study term extention
    18 Jan 2012
    PI-Change
    03 Mar 2012
    Subsequent registration of a Trial Centre
    19 Mar 2013
    cancellation of a Trial Centre
    14 Apr 2014
    term extension

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    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/27695824
    For support, Contact us.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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