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    Clinical Trial Results:
    Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU)

    Summary
    EudraCT number
    2015-000318-24
    Trial protocol
    DK   FI   NO   NL  
    Global end of trial date
    22 Oct 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    02 May 2019
    First version publication date
    02 May 2019
    Other versions
    Summary report(s)
    main results and paper

    Trial information

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    Trial identification
    Sponsor protocol code
    RH-ITA-006
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02467621
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Dept. of Intensive Care 4131, Copenhagen University Hospital Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, DK-2100
    Public contact
    Ass. prof. Morten Hylander Møller, Dept. of Intensive Care 4131, Copenhagen University Hospital Rigshospitalet, 0045 35458685, mortenhylander@gmail.com
    Scientific contact
    Ass. prof. Morten Hylander Møller, Dept. of Intensive Care 4131, Copenhagen University Hospital Rigshospitalet, 0045 35458685, mortenhylander@gmail.com
    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 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess benefits and harms in the use of pantoprazole as stress ulcer prophylaxis in adult critically ill patients.
    Protection of trial subjects
    All trial subjects received the highest standard of care with high degree of monitoring. Also, stress ulcer prophylaxis is an intervention abundantly used across the world.
    Background therapy
    All other treatments than the trial drug were at the discretion of the treating clinicians.
    Evidence for comparator
    Placebo-controlled trial.
    Actual start date of recruitment
    04 Jan 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 172
    Country: Number of subjects enrolled
    Norway: 197
    Country: Number of subjects enrolled
    Denmark: 2125
    Country: Number of subjects enrolled
    Finland: 258
    Country: Number of subjects enrolled
    Switzerland: 472
    Country: Number of subjects enrolled
    United Kingdom: 67
    Worldwide total number of subjects
    3291
    EEA total number of subjects
    2819
    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)
    1389
    From 65 to 84 years
    1742
    85 years and over
    160

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment was performed on schedule.

    Pre-assignment
    Screening details
    Adults (age ≥ 18 years) that were acutely admitted to the ICU and fulfilled one or more of our predefined risk factors for gastrointestinal bleeding were screened We screened 10.000 patients. 3.350 were randomised. 3291 were analysed (specified in published paper).

    Period 1
    Period 1 title
    Intervention period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The following persons were blinded: participants, care providers, investigators, outcomes assessors and trial statistician.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pantoprazole, PR1
    Arm description
    Pantoprazole 40 mg (daily intravenous injection)
    Arm type
    Experimental

    Investigational medicinal product name
    Pantoprazole, PR1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pantoprazole 40 mg milligram(s) administered intravenously once daily until ICU discharge (for a maximum of 90 days). Preceding administration: 10 mL of isotonic sodium chloride 0.9% (normal saline) added to masked study vial containing pantoprazole powder for solution for injection.

    Arm title
    Placebo, PL1
    Arm description
    Placebo (daily intravenous injection)
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo, PL1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo administered intravenously once daily until ICU discharge (for a maximum of 90 days). Preceding administration: 10 mL of isotonic sodium chloride 0.9% (normal saline) added to masked empty study vial.

    Number of subjects in period 1
    Pantoprazole, PR1 Placebo, PL1
    Started
    1644
    1647
    Completed
    1644
    1647

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pantoprazole, PR1
    Reporting group description
    Pantoprazole 40 mg (daily intravenous injection)

    Reporting group title
    Placebo, PL1
    Reporting group description
    Placebo (daily intravenous injection)

    Reporting group values
    Pantoprazole, PR1 Placebo, PL1 Total
    Number of subjects
    1644 1647 3291
    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
    3298 started the trial, however we do not report for the 7 patients (1 in pantoprazole group, 6 in the placebo Group) who withdrew consent to the use of data
    Units: years
        median (inter-quartile range (Q1-Q3))
    67 (56 to 75) 67 (55 to 75) -
    Gender categorical
    Not recorded: 7 patients not allowing for use of data.
    Units: Subjects
        Female
    605 580 1185
        Male
    1039 1067 2106
        Not recorded
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Pantoprazole, PR1
    Reporting group description
    Pantoprazole 40 mg (daily intravenous injection)

    Reporting group title
    Placebo, PL1
    Reporting group description
    Placebo (daily intravenous injection)

    Primary: 90 days all-cause mortality

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    End point title
    90 days all-cause mortality
    End point description
    End point type
    Primary
    End point timeframe
    90 days from randomisation.
    End point values
    Pantoprazole, PR1 Placebo, PL1
    Number of subjects analysed
    1642
    1640
    Units: Numbers
    510
    499
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Analysis adjusted for the stratification variables: trial site and hematological malignancy. 9 patients were lost to 90-day mortality follow-up and were therefore not included in this analysis.
    Comparison groups
    Pantoprazole, PR1 v Placebo, PL1
    Number of subjects included in analysis
    3282
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.76
    Method
    Regression, Logistic
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.91
         upper limit
    1.13
    Notes
    [1] - RR computed from OR

    Secondary: Clinically important events

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    End point title
    Clinically important events
    End point description
    Composite outcome consisting of the following elements: - clinically important gastrointestinal bleeding - new-onset pneumonia - clostridium difficile infection - myocardial ischemia
    End point type
    Secondary
    End point timeframe
    Randomisation until ICU discharge (within a maximum of 90 days from randomisation)
    End point values
    Pantoprazole, PR1 Placebo, PL1
    Number of subjects analysed
    1644
    1647
    Units: Numbers
    360
    372
    Statistical analysis title
    primary analysis
    Statistical analysis description
    Analysis adjusted for stratification variables: trial site and hematological malignancy
    Comparison groups
    Placebo, PL1 v Pantoprazole, PR1
    Number of subjects included in analysis
    3291
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    Method
    Regression, Logistic
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.11
    Notes
    [2] - RR computed from OR P-value not presented for secondary outcomes because of the lack of adjustments for multiple comparisons

    Secondary: Clinically important gastrointestinal bleeding

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    End point title
    Clinically important gastrointestinal bleeding
    End point description
    Defined as overt gastrointestinal bleeding and at least one of the following four features within 24 hours of gastrointestinal bleeding, in the absence of other causes, in the ICU: - a spontaneous decrease in systolic blood pressure, mean arterial pressure, or diastolic blood pressure of 20 mm Hg or more - initiation of treatment with a vasopressor or a 20% increase in vasopressor dose - a decrease in hemoglobin of at least 2 g per deciliter [1.24 mmol per liter] - transfusion of two or more units of packed red cells
    End point type
    Secondary
    End point timeframe
    Randomisation until ICU discharge (within a maximum of 90 days from randomisation)
    End point values
    Pantoprazole, PR1 Placebo, PL1
    Number of subjects analysed
    1644
    1647
    Units: Numbers
    41
    69
    Statistical analysis title
    primary analysis
    Statistical analysis description
    Analysis adjusted for stratification variables: trial site and hematological malignancy
    Comparison groups
    Pantoprazole, PR1 v Placebo, PL1
    Number of subjects included in analysis
    3291
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    Method
    Regression, Logistic
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    0.86
    Notes
    [3] - RR computed from OR P-value not presented for secondary outcomes because of the lack of adjustments for multiple comparisons

    Secondary: Infectious adverse events

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    End point title
    Infectious adverse events
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation until ICU discharge (within a maximum of 90 days from randomisation)
    End point values
    Pantoprazole, PR1 Placebo, PL1
    Number of subjects analysed
    1644
    1647
    Units: Numbers
    276
    279
    Statistical analysis title
    primary analysis
    Statistical analysis description
    Analysis adjusted for the stratification variables: trial site and hematological malignancy
    Comparison groups
    Placebo, PL1 v Pantoprazole, PR1
    Number of subjects included in analysis
    3291
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    Method
    Regression, Logistic
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    1.16
    Notes
    [4] - RR computed from OR P-value not presented for secondary outcomes because of the lack of adjustments for multiple comparisons

    Secondary: Serious adverse reactions

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    End point title
    Serious adverse reactions
    End point description
    Severe adverse reactions were defined as: - anaphylactic reactions* - agranulocytosis* - pancytopenia* - acute hepatic failure* - the Stevens–Johnson syndrome* - toxic epidermal necrolysis* - interstitial nephritis* - angioedema* * related to the intervention (as judged by the treating clinicians and investigators)
    End point type
    Secondary
    End point timeframe
    Randomisation until ICU discharge (within a maximum of 90 days from randomisation)
    End point values
    Pantoprazole, PR1 Placebo, PL1
    Number of subjects analysed
    1644
    1647
    Units: Numbers
    0
    0
    No statistical analyses for this end point

    Secondary: Days alive without the use of life support

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    End point title
    Days alive without the use of life support
    End point description
    The percentage of days alive without the use of life support was calculated as the number of days without the use of invasive or noninvasive mechanical ventilation, infusion of vasopressor or inotropic agents, or any form of renal-replacement therapy, divided by the number of days alive within the 90-day follow-up period
    End point type
    Secondary
    End point timeframe
    90 days from randomisation
    End point values
    Pantoprazole, PR1 Placebo, PL1
    Number of subjects analysed
    1644
    1647
    Units: Percentage of days
        median (inter-quartile range (Q1-Q3))
    92 (60 to 97)
    92 (65 to 97)
    Statistical analysis title
    primary analysis
    Statistical analysis description
    Analysis adjusted for trial site
    Comparison groups
    Pantoprazole, PR1 v Placebo, PL1
    Number of subjects included in analysis
    3291
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.34 [6]
    Method
    The van Elteren test
    Confidence interval
    Notes
    [5] - P-value presented as no parameter estimates can be presented for this test. Please note: the p-value should be interpreted with caution due to lack of adjustments for multiple comparisons
    [6] - Please note: the p-value should be interpreted with caution due to lack of adjustments for multiple comparisons

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    During ICU stay (from randomisation until a maximum of 90 days from randomisation)
    Adverse event reporting additional description
    Serious adverse events were predefined outcome measures in the trial - please see the 'end points'-section of this report. Full description available in the published paper.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    1
    Frequency threshold for reporting non-serious adverse events: 0%
    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: SAEs were not recorded as one entity, because the majority of ICU patients will experience several SAEs during their critical illness. The most important SAEs were captured in specific trial outcome measures (incl. in this report - 'end points'-section) . Patient charts contain daily registrations of clinical data, which can be obtained on request from medical authorities.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2017
    Cancellation of the second interim analysis (of 2.500/3.350 included patients). Due to a high patient inclusion rate in the last part of the SUP-ICU trial, the trial Steering Committee, in full agreement with the the Data Monitoring and Safety Committee (DMSC), decided to cancel the second interim analysis (of 2500/3350 included patients) as the results (incl. 90-day follow-up of 2500 patients) would be available only after the inclusion of the last trial patient. A statement paper from the DMSC following the first interim analysis (1675/3350 included patients) supports this decision. The decision was approved by relevant Danish authorities.

    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/30354950
    http://www.ncbi.nlm.nih.gov/pubmed/27093939
    http://www.ncbi.nlm.nih.gov/pubmed/28608496
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