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    Clinical Trial Results:
    Does nitrite reduce ischaemia-reperfusion injury in patients with acute ST segment elevation myocaridal infarction?

    Summary
    EudraCT number
    2010-023571-26
    Trial protocol
    GB  
    Global end of trial date
    04 Feb 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Jul 2018
    First version publication date
    20 Jul 2018
    Other versions
    Summary report(s)
    NIAMI results paper

    Trial information

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    Trial identification
    Sponsor protocol code
    3/030/10
    Additional study identifiers
    ISRCTN number
    ISRCTN57596739
    US NCT number
    NCT01388504
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Aberdeen
    Sponsor organisation address
    Foresterhill House Annex, Aberdeen, United Kingdom, AB25 2ZD
    Public contact
    Professor Graeme MacLennan, University of Aberdeen, 01224 438198, g.maclennan@abdn.ac.uk
    Scientific contact
    Professor Graeme MacLennan, University of Aberdeen, 01224 438198, g.maclennan@abdn.ac.uk
    Sponsor organisation name
    NHS Grampian
    Sponsor organisation address
    Foresterhill House Annexe, Aberdeen, United Kingdom, AB25 2ZD
    Public contact
    Professor Graeme MacLennan, University of Aberdeen, 01224 438198, g.maclennan@abdn.ac.uk
    Scientific contact
    Professor Graeme MacLennan, University of Aberdeen, 01224 438198, g.maclennan@abdn.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
    03 Jun 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jun 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In patients who have had a heart attack and are undergoing percutanuous coronary intervention (angioplasty), does a 5 minute intravenous injection of sodium nitrite immediately prior to opening of an infarct related artery reduce the size of the infarct (ie reduce the amount of damage caused to the heart)?
    Protection of trial subjects
    Initial verbal agreement, followed by fully informed consent. Oversight by sponsor, data monitoring committee and trial steering committee who reviewed accruing data.
    Background therapy
    All usual therapy. The protocol stated that unless absolutely indicated for the patient, IV or oral nitrates should not be commenced within five minutes of the percutaneous coronary intervention (PCI).
    Evidence for comparator
    Placebo controlled (normal saline)
    Actual start date of recruitment
    11 Aug 2011
    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
    Australia: 7
    Country: Number of subjects enrolled
    United Kingdom: 273
    Worldwide total number of subjects
    280
    EEA total number of subjects
    273
    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)
    148
    From 65 to 84 years
    119
    85 years and over
    13

    Subject disposition

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    Recruitment
    Recruitment details
    Patients presenting with acute STEMI were assessed for eligibility. A verbal statement was read to eligible patients and they were asked to give verbal agreement or informed consent. Those giving verbal agreement were approached post-intervention for fully informed consent.

    Pre-assignment
    Screening details
    Screening by medically qualified clinician against inclusion/exclusion criteria.

    Period 1
    Period 1 title
    Recruitment
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Sodium nitrite and placebo were identical in appearance, packaging and labelling.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sodium nitrite
    Arm description
    sterile solution containing 70 micromol sodium nitrite dissolved in 5ml water injected intravenously over a period of 2½ - 5 minutes.
    Arm type
    Experimental

    Investigational medicinal product name
    Sodium Nitrite
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    sterile solution containing 70 micromol sodium nitrite dissolved in 5ml water injected intravenously over a period of 2½ - 5 minutes.

    Arm title
    Placeo
    Arm description
    sterile solution containing 0.9%w/v sodium chloride in 5ml water injected intravenously over a period of 2½ - 5 minutes.
    Arm type
    Placebo

    Investigational medicinal product name
    Normal saline (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    sterile solution containing 0.9%w/v sodium chloride in 5ml water injected intravenously over a period of 2½ - 5 minutes.

    Number of subjects in period 1
    Sodium nitrite Placeo
    Started
    146
    134
    Completed
    118
    111
    Not completed
    28
    23
         No fully informed consent
    15
    -
         Patient not eligible
    -
    15
         Not eligible
    13
    -
         No fully informed consent
    -
    8
    Period 2
    Period 2 title
    confirmation of eligibility, consent
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sodium nitrite
    Arm description
    sterile solution containing 70 micromol sodium nitrite dissolved in 5ml water injected intravenously over a period of 2½ - 5 minutes.
    Arm type
    Experimental

    Investigational medicinal product name
    Sodium Nitrite
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    sterile solution containing 70 micromol sodium nitrite dissolved in 5ml water injected intravenously over a period of 2½ - 5 minutes.

    Arm title
    Placeo
    Arm description
    sterile solution containing 0.9%w/v sodium chloride in 5ml water injected intravenously over a period of 2½ - 5 minutes.
    Arm type
    Placebo

    Investigational medicinal product name
    Normal saline (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    sterile solution containing 0.9%w/v sodium chloride in 5ml water injected intravenously over a period of 2½ - 5 minutes.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: trial in emergency setting. Period 1 was recruitment, period 2 confirmation of eligibility and consent, period 3 outcome assessment.
    Number of subjects in period 2 [2]
    Sodium nitrite Placeo
    Started
    118
    111
    Completed
    118
    111
    Notes
    [2] - 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: Trial in emergency setting, not all people enrolled were confirmed as eligible after inclusion. Only those confirmed as eligible are in the baseline period.
    Period 3
    Period 3 title
    Outcome assessment
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Subject, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sodium nitrite
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Sodium Nitrite
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    sterile solution containing 70 micromol sodium nitrite dissolved in 5ml water injected intravenously over a period of 2½ - 5 minutes.

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Normal saline (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    sterile solution containing 0.9%w/v sodium chloride in 5ml water injected intravenously over a period of 2½ - 5 minutes.

    Number of subjects in period 3 [3]
    Sodium nitrite Placebo
    Started
    85
    88
    Completed
    85
    88
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Some patients did not enter the outcome assessment phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sodium nitrite
    Reporting group description
    sterile solution containing 70 micromol sodium nitrite dissolved in 5ml water injected intravenously over a period of 2½ - 5 minutes.

    Reporting group title
    Placeo
    Reporting group description
    sterile solution containing 0.9%w/v sodium chloride in 5ml water injected intravenously over a period of 2½ - 5 minutes.

    Reporting group values
    Sodium nitrite Placeo Total
    Number of subjects
    118 111 229
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63 ± 12 64 ± 13 -
    Gender categorical
    Units: Subjects
        Female
    22 30 52
        Male
    96 81 177
    Previous hypertension
    Units: Subjects
        Yes
    35 35 70
        No
    83 76 159
    Previous hyperlipidaemia
    Units: Subjects
        Yes
    55 52 107
        No
    63 59 122
    Previous diabetes
    Units: Subjects
        yes
    14 19 33
        No
    104 92 196
    Current smoker
    Units: Subjects
        Yes
    53 47 100
        No
    65 64 129
    Infarct site
    Units: Subjects
        Anterior
    46 41 87
        other
    72 70 142
    TIMI grade pre-PCI
    Units: Subjects
        TIMI0
    105 101 206
        TIMI1
    11 9 20
        missing
    2 1 3
    Nitrate use pre/during PCI
    Units: Subjects
        Yes
    99 105 204
        No
    19 6 25
    Morphine use pre/during PCI
    Units: Subjects
        Yes
    70 66 136
        No
    48 45 93
    Prior beta-blocker use
    Units: Subjects
        Yes
    12 6 18
        No
    106 105 211
    Prior calcium channel blocker use
    Units: Subjects
        Yes
    24 29 53
        No
    94 82 176
    Prior statin use
    Units: Subjects
        Yes
    3 1 4
        No
    115 110 225
    Prior heparin use
    Units: Subjects
        Yes
    103 99 202
        No
    15 12 27
    Prior ACE inhibitor use
    Units: Subjects
        Yes
    0 1 1
        No
    118 110 228
    Weight
    Units: kg
        median (inter-quartile range (Q1-Q3))
    82 (75 to 91) 77 (69 to 89) -
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    28 ± 4 27 ± 4 -
    Syptom to balloon time
    Units: minutes
        arithmetic mean (standard deviation)
    208 ± 119 238 ± 135 -
    Symptom to balloon time
    Units: minutes
        median (inter-quartile range (Q1-Q3))
    164 (127 to 256) 203 (133 to 317) -

    End points

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    End points reporting groups
    Reporting group title
    Sodium nitrite
    Reporting group description
    sterile solution containing 70 micromol sodium nitrite dissolved in 5ml water injected intravenously over a period of 2½ - 5 minutes.

    Reporting group title
    Placeo
    Reporting group description
    sterile solution containing 0.9%w/v sodium chloride in 5ml water injected intravenously over a period of 2½ - 5 minutes.
    Reporting group title
    Sodium nitrite
    Reporting group description
    sterile solution containing 70 micromol sodium nitrite dissolved in 5ml water injected intravenously over a period of 2½ - 5 minutes.

    Reporting group title
    Placeo
    Reporting group description
    sterile solution containing 0.9%w/v sodium chloride in 5ml water injected intravenously over a period of 2½ - 5 minutes.
    Reporting group title
    Sodium nitrite
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Subject analysis set title
    Baseline characteristics
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Received intervention/placebo, confirmed as eligible, provided fully informed consent

    Subject analysis set title
    Outcome analysis
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    173 participants who were recruited, confirmed as eligible and gave fully informed consent

    Primary: Infarct size 6-8 days

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    End point title
    Infarct size 6-8 days
    End point description
    End point type
    Primary
    End point timeframe
    6-8 days
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    85
    88
    Units: Percent of LV myocardial mass
        arithmetic mean (standard deviation)
    22.9 ± 13.5
    23.1 ± 13.2
    Statistical analysis title
    Infarct size 6-8 days
    Comparison groups
    Sodium nitrite v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.2
         upper limit
    0.7

    Secondary: Troponin AUC

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    End point title
    Troponin AUC
    End point description
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    81
    87
    Units: AUC
        arithmetic mean (standard deviation)
    3734 ± 3091
    3807 ± 3262
    Statistical analysis title
    Troponin AUC
    Comparison groups
    Placebo v Sodium nitrite
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.81
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -125
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1139
         upper limit
    888

    Secondary: Creatinine kinase

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    End point title
    Creatinine kinase
    End point description
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    81
    87
    Units: AUC
        arithmetic mean (standard deviation)
    67019 ± 42446
    59574 ± 48337
    Statistical analysis title
    Creatinine Kinase AUC
    Comparison groups
    Sodium nitrite v Placebo
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.79
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    5766
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8695
         upper limit
    20288

    Secondary: Infarct size measured using CMR LGE hyperenhancement extent defined using a cut-off of 5-SD greater than the intensite in the remote myocardium

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    End point title
    Infarct size measured using CMR LGE hyperenhancement extent defined using a cut-off of 5-SD greater than the intensite in the remote myocardium
    End point description
    End point type
    Secondary
    End point timeframe
    6-8 days
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    82
    84
    Units: infarct size
        arithmetic mean (standard deviation)
    14.5 ± 10.5
    14.7 ± 11.2
    Statistical analysis title
    Infarct size 6-8 days (5-SD)
    Comparison groups
    Sodium nitrite v Placebo
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.92
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    2.8

    Secondary: final infarct size at 6 months

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    End point title
    final infarct size at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    63
    55
    Units: infarct size
        arithmetic mean (standard deviation)
    13.3 ± 8.7
    15.0 ± 9.7
    Statistical analysis title
    Final infarct size at 6 months
    Comparison groups
    Sodium nitrite v Placebo
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.19
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    5.5

    Secondary: Left Ventricular end diastolic volume 6-8 days

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    End point title
    Left Ventricular end diastolic volume 6-8 days
    End point description
    End point type
    Secondary
    End point timeframe
    6-8 days
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    75
    84
    Units: ml
        arithmetic mean (standard deviation)
    159 ± 41
    162 ± 40
    Statistical analysis title
    Left Ventricular end diastolic volume 6-8 days
    Comparison groups
    Sodium nitrite v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.58
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.3
         upper limit
    9.2

    Secondary: Left Ventricular end diastolic volume at 6 months

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    End point title
    Left Ventricular end diastolic volume at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    64
    54
    Units: ml
        arithmetic mean (standard deviation)
    159 ± 42
    165 ± 37
    Statistical analysis title
    Left Ventricular end diastolic volume at 6 months
    Comparison groups
    Sodium nitrite v Placebo
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.8
         upper limit
    9.8

    Secondary: Left Ventricular end diastolic volume delta

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    End point title
    Left Ventricular end diastolic volume delta
    End point description
    End point type
    Secondary
    End point timeframe
    6-8 days to 6 months
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    63
    51
    Units: ml
        arithmetic mean (standard deviation)
    -1 ± 29
    -3 ± 32
    Statistical analysis title
    Left Ventricular end diastolic volume delta
    Comparison groups
    Sodium nitrite v Placebo
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.82
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.1
         upper limit
    12.6

    Secondary: Left Ventricular end systolic volume

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    End point title
    Left Ventricular end systolic volume
    End point description
    End point type
    Secondary
    End point timeframe
    6-8 days
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    75
    84
    Units: ml
        arithmetic mean (standard deviation)
    85 ± 36
    85 ± 32
    Statistical analysis title
    Left Ventricular end systolic volume 6-8 days
    Comparison groups
    Sodium nitrite v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.93
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.4
         upper limit
    11.3

    Secondary: Left Ventricular end systolic volume 6 months

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    End point title
    Left Ventricular end systolic volume 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    64
    54
    Units: ml
        arithmetic mean (standard deviation)
    75 ± 31
    78 ± 28
    Statistical analysis title
    Left Ventricular end systolic volume 6 months
    Comparison groups
    Sodium nitrite v Placebo
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.63
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.7
         upper limit
    8.3

    Secondary: Left Ventricular end systolic volume delta

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    End point title
    Left Ventricular end systolic volume delta
    End point description
    End point type
    Secondary
    End point timeframe
    6-8 days to 6 months
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    63
    63
    Units: ml
        arithmetic mean (standard deviation)
    9 ± 25
    6 ± 24
    Statistical analysis title
    Left Ventricular end systolic volume delta
    Comparison groups
    Sodium nitrite v Placebo
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.66
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.2
         upper limit
    11.2

    Secondary: Left ventricular ejection fraction

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    End point title
    Left ventricular ejection fraction
    End point description
    End point type
    Secondary
    End point timeframe
    6-8 days
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    75
    84
    Units: ml
        arithmetic mean (standard deviation)
    48 ± 11
    50 ± 18
    Statistical analysis title
    Left ventricular ejection fraction 6-8 days
    Comparison groups
    Sodium nitrite v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.34
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.1
         upper limit
    2.4

    Secondary: Left ventricular ejection fraction 6 months

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    End point title
    Left ventricular ejection fraction 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    64
    54
    Units: ml
        arithmetic mean (standard deviation)
    53 ± 9
    53 ± 9
    Statistical analysis title
    Left ventricular ejection fraction 6 months
    Comparison groups
    Sodium nitrite v Placebo
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.72
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.9
         upper limit
    2.7

    Secondary: Left ventricular ejection fraction delta

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    End point title
    Left ventricular ejection fraction delta
    End point description
    End point type
    Secondary
    End point timeframe
    6-8 days to 6 months
    End point values
    Sodium nitrite Placebo
    Number of subjects analysed
    63
    51
    Units: ml
        arithmetic mean (standard deviation)
    -5 ± 8
    -3 ± 22
    Statistical analysis title
    Left ventricular ejection fraction delta
    Comparison groups
    Placebo v Sodium nitrite
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.57
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.6
         upper limit
    4.2

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    6 months post intervention
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    No dictionary used
    Dictionary version
    0
    Reporting groups
    Reporting group title
    randomised - sodium nitrite
    Reporting group description
    -

    Reporting group title
    randomised - 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: Non-serious adverse events were not recorded in this study.
    Serious adverse events
    randomised - sodium nitrite randomised - placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 146 (14.38%)
    29 / 134 (21.64%)
         number of deaths (all causes)
    1
    4
         number of deaths resulting from adverse events
    1
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign lung neoplasm
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural complication
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Air embolism
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    closure of patent foramen ovale
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 146 (0.68%)
    4 / 134 (2.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    3 / 146 (2.05%)
    4 / 134 (2.99%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 146 (1.37%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Left ventricular thrombus
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 146 (1.37%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paroxysmal arrhythmia
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 146 (0.68%)
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular failure
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 146 (0.68%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Chest pain
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Femoral artery pseuoaneurysm
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 146 (1.37%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    randomised - sodium nitrite randomised - placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 134 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Oct 2010
    1. Change to when the primary outcome measure is assessed - final infarct size measured using MRI at six months (or slightly earlier for patients who may be scheduled for an implantable defibrillator/antiarrhythmic therapy). Oedema imaging (to correct for area at risk) will be added as a covariate to the analysis. The oedema imaging will be carried out during the first MRI scan that participants will have. Originally this was scheduled for 10-14 days after the MI, but we propose to carry this MRI out 6-8 days after the MI. The proposed changes to the timing of assessment of both final infarct size and oedema are based on the latest available evidence. 2. Change in the timing of the secondary endpoints, previously assessed at MRI at 10-14 days, to MRI at 6-8 days. This change fits in with the change in time of the first MRI scan (described in 1 above), and avoids the need to have a third MRI scan at 10-14 days. 3. Revision to inclusion criteria such that women aged <55 years who are not pregnant, sterilised, have had a hysterectomy or are using effective contraception, would be eligible to participate in the study. 4. To clarify that patients with new left bundle branch lock are suitable for inclusion in the study. 5. To add an exclusion criteria (left Main disease which after PCI of their culprit lesion (culprit lesions may be located in the LAD or LCx or RCA) are likely to require CABG within the time course of the study period (6 months)). 6. to reword the section on MRI imaging parameters. While the sequences will be standardised between centres as much as possible, bt the individual scan parameters will be optimised as appropriate according to the individual patient. The parameters that were previously given in the protocol are one example of how the MRI might be carried out. 7. To include three additional expected adverse events: pulmonary oedema, re-occlusion and respiratory arrest (REC only)
    03 May 2011
    Inclusion of two additional exclusion criteria (prior coronary artery bypass grafting and prior thrombolysis for this event). Clarification that the prior revascularisation procedure is only an exclusion criteria if it was carried out in the same territory as the current infarct. Removal of atrial fibrillation at time of randomisation as an exclusion criterion. Restriction, unless absolutely indicated for the patient, the use of IV or oral nitrates within five minutes of PCI. Inclusion of additional outcome measure of LV end systolic volume index. Revision to the list of expected adverse events following administration of Investigational Medicinal Product or following PCI. Addition of information about storage conditions for IMP and placebo. Revision of dosing information such that the dose is given over 2.5 to 5 minutes. Revision of definition of PCI to include thrombus extraction. Confirmation that distilled water will be used for the preparation of IMP and placebo. Clarification of the timing of the injection in relation to the PCI. (REC only)
    18 Aug 2011
    Removal of requirement to gain consent from a relative/legal representative following verbal agreement from a trial particiant who dies before giving informed consent. (REC only)
    22 Feb 2012
    To add an recruitment site outwith the UK. To clarify that part of the NIAMI project will be written up as an educational project. (REC only)
    06 Aug 2012
    Amendment to protocol and PIL to clarify where MRI images will be analysed. Amendment to publication policy. Amendment to protocol in relation to minor temperature deviations of study medication. Addition of sub-study to investigate blood plasma nitrite levels and methaemoglobin. Amendment to sample size. Clarification of inclusion criteria that patients with posterior infarcts with ST depression which meet the inclusion criteria can also be included. (REC and Regulatory Authority)
    31 Oct 2012
    A change in the time-point at which the primary end-point is assessed. For scientific and logistical reasons, we propose to revert to measuring the primary end-point (infarct size) at the first MRI scan (6-8 days after infarct). This has been discussed with the Trial Steering Committee and they have ratified our proposal. Infarct size at 6 months will become a secondary endpoint. All MRI scans will be analysed in Aberdeen. We propose that there will be no transfer of images to Imperial College London. All scans will be assessed by a blinded observer. A second blinded observer will analyse a sample of images. We also propose to amend the patient information leaflet to take account of this change. Proposed sample size. To take account of our proposed change to the time-point at which the primary end-point is assessed, we have revised the section on proposed sample size. To account for loss of outcome measure due to death, those who decline MRI or are unsuitable for MRI due to renal dysfunction and those in whom the MRI scans are technically inadequate, we plan to recruit approximately 200-210 participants. (REC only)

    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.
    Exclusion of participant's post-randomisation (either ineligible, or declined to give fully informed consent to remain in the study) Missing outcome data
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