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    Clinical Trial Results:
    ENOS: Efficacy of Nitric Oxide in Stroke. Estudio ENOS: Eficacia del óxido nítrico en el ictus

    Summary
    EudraCT number
    2004-003870-27
    Trial protocol
    ES   DK   SE   GR  
    Global end of trial date
    22 Oct 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Feb 2019
    First version publication date
    24 Feb 2019
    Other versions
    Summary report(s)
    Effi cacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial

    Trial information

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    Trial identification
    Sponsor protocol code
    RA2363
    Additional study identifiers
    ISRCTN number
    ISRCTN99414122
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Nottingham
    Sponsor organisation address
    R&I, East Atrium Jubilee Conference Centre, Nottingham, United Kingdom, NG8 1DH
    Public contact
    Philip Bath, University of Nottingham, +44 115 823 1765, philip.bath@nottingham.ac.uk
    Scientific contact
    Angela Shone, University of Nottingham, +44 115 84 67906, angela.shone@nottingham.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke
    Protection of trial subjects
    N/A
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Jul 2001
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Sri Lanka: 110
    Country: Number of subjects enrolled
    Sweden: 14
    Country: Number of subjects enrolled
    Turkey: 14
    Country: Number of subjects enrolled
    United Kingdom: 2545
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    China: 103
    Country: Number of subjects enrolled
    Denmark: 17
    Country: Number of subjects enrolled
    Egypt: 148
    Country: Number of subjects enrolled
    Georgia: 195
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    India: 157
    Country: Number of subjects enrolled
    Ireland: 10
    Country: Number of subjects enrolled
    Italy: 33
    Country: Number of subjects enrolled
    Malaysia: 14
    Country: Number of subjects enrolled
    New Zealand: 71
    Country: Number of subjects enrolled
    Norway: 4
    Country: Number of subjects enrolled
    Philippines: 16
    Country: Number of subjects enrolled
    Poland: 123
    Country: Number of subjects enrolled
    Romania: 217
    Country: Number of subjects enrolled
    Singapore: 155
    Worldwide total number of subjects
    4011
    EEA total number of subjects
    2983
    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)
    1244
    From 65 to 84 years
    2299
    85 years and over
    468

    Subject disposition

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    Recruitment
    Recruitment details
    Between 20th July 2001 and 14th October 2013, 4011 patients from 173 sites were enrolled across 23 countries

    Pre-assignment
    Screening details
    Inclusion criteria: Within 48 hours of stroke onset with raised systolic blood pressure of 140 - 220mmHg Patients who were taking antihypertensives were also randomised to either continue or stop their treatment

    Period 1
    Period 1 title
    Randomisation
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind [1]
    Roles blinded
    Carer, Assessor, Subject, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    No

    Arm title
    GTN arm
    Arm description
    Treatment arm
    Arm type
    Experimental

    Investigational medicinal product name
    Glyceryl trinitrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Impregnated pad
    Routes of administration
    Transdermal use
    Dosage and administration details
    5mg patch applied once per day for 7 days

    Arm title
    No GTN
    Arm description
    No active treatment patch given
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Continue antihypertensives
    Arm description
    Continuing prior antihypertensive treatment
    Arm type
    Continuing antihypertensives

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Stop antihypertensives
    Arm description
    Stop prior antihypertensive treatment
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: Participant was blinded
    Number of subjects in period 1
    GTN arm No GTN Continue antihypertensives Stop antihypertensives
    Started
    2000
    2011
    1053
    1044
    Completed
    2000
    2011
    1053
    1044
    Period 2
    Period 2 title
    Day 90
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind [2]
    Roles blinded
    Carer, Assessor, Subject, Monitor, Data analyst
    Blinding implementation details
    Day 90 follow up coordinator blinded to treatment assignments

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    GTN arm
    Arm description
    Treatment arm
    Arm type
    Experimental

    Investigational medicinal product name
    Glyceryl trinitrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Impregnated pad
    Routes of administration
    Transdermal use
    Dosage and administration details
    5mg patch applied once per day for 7 days

    Arm title
    No GTN
    Arm description
    No active treatment patch given
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Continue antihypertensives
    Arm description
    Continuing prior antihypertensive treatment
    Arm type
    Continue antihypertensives

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Stop antihypertensives
    Arm description
    Stop prior antihypertensive treatment
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [2] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: Participant was blinded
    Number of subjects in period 2
    GTN arm No GTN Continue antihypertensives Stop antihypertensives
    Started
    2000
    2011
    1053
    1044
    Completed
    1993
    2002
    1050
    1040
    Not completed
    7
    9
    3
    4
         Lost to follow-up
    7
    9
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GTN arm
    Reporting group description
    Treatment arm

    Reporting group title
    No GTN
    Reporting group description
    No active treatment patch given

    Reporting group title
    Continue antihypertensives
    Reporting group description
    Continuing prior antihypertensive treatment

    Reporting group title
    Stop antihypertensives
    Reporting group description
    Stop prior antihypertensive treatment

    Reporting group values
    GTN arm No GTN Continue antihypertensives Stop antihypertensives Total
    Number of subjects
    2000 2011 1053 1044 4011
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    620 624 232 240 1244
        From 65-84 years
    1147 1152 656 663 2299
        85 years and over
    233 235 165 141 468
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    70 ± 12 70 ± 12 73 ± 11 73 ± 11 -
    Gender categorical
    Units: Subjects
        Female
    853 861 525 504 1714
        Male
    1147 1150 528 540 2297

    End points

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    End points reporting groups
    Reporting group title
    GTN arm
    Reporting group description
    Treatment arm

    Reporting group title
    No GTN
    Reporting group description
    No active treatment patch given

    Reporting group title
    Continue antihypertensives
    Reporting group description
    Continuing prior antihypertensive treatment

    Reporting group title
    Stop antihypertensives
    Reporting group description
    Stop prior antihypertensive treatment
    Reporting group title
    GTN arm
    Reporting group description
    Treatment arm

    Reporting group title
    No GTN
    Reporting group description
    No active treatment patch given

    Reporting group title
    Continue antihypertensives
    Reporting group description
    Continuing prior antihypertensive treatment

    Reporting group title
    Stop antihypertensives
    Reporting group description
    Stop prior antihypertensive treatment

    Primary: Day 90 mRs

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    End point title
    Day 90 mRs
    End point description
    End point type
    Primary
    End point timeframe
    Day 90
    End point values
    GTN arm No GTN Continue antihypertensives Stop antihypertensives
    Number of subjects analysed
    1993
    2002
    1050
    1040
    Units: score
        median (inter-quartile range (Q1-Q3))
    3 (2 to 4)
    3 (2 to 4)
    3 (2 to 5)
    3 (2 to 4)
    Statistical analysis title
    Primary outcome analysis GTN
    Comparison groups
    GTN arm v No GTN
    Number of subjects included in analysis
    3995
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.83
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.91
         upper limit
    1.13
    Statistical analysis title
    Primary analysis - continue/stop
    Comparison groups
    Continue antihypertensives v Stop antihypertensives
    Number of subjects included in analysis
    2090
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.55
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    1.22

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Up to day 90
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    All participants
    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: ENOS had a pre-specified list of adverse events for reporting
    Serious adverse events
    All participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1022 / 4011 (25.48%)
         number of deaths (all causes)
    448
         number of deaths resulting from adverse events
    448
    General disorders and administration site conditions
    Serious adverse events
         subjects affected / exposed
    1022 / 4011 (25.48%)
         occurrences causally related to treatment / all
    24 / 1444
         deaths causally related to treatment / all
    0 / 448
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    All participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 4011 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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.
    N/A

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/25465108
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