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    Clinical Trial Results:
    The Clinical Carbetocin Myocardium Trial

    Summary
    EudraCT number
    		 2014-000507-27
    Trial protocol
    		 NO  
    Global end of trial date
    19 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jul 2023
    First version publication date
    14 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CarbetocinHeart2014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03899961
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Oslo University Hospital
    Sponsor organisation address
    Box 4950 Nydalen, Oslo, Norway, 0424
    Public contact
    Department of Anesthesiology, Oslo University Hospital, 47 23073700, lrossela@ous-hf.no
    Scientific contact
    Department of Anesthesiology, Oslo University Hospital, 47 23073700, lrossela@ous-hf.no
    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
    08 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Feb 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Cardiac biomarkers may increase after injection of oxytocin. Carbetocin, a new synthetic oxytocin receptor agonist, may have similar effects. This study compares the two drugs in clinical use for treatment and prophylaxis of atonic uterine bleeding. The primary endpoint was group difference in troponin I.
    Protection of trial subjects
    Both interventions are standard clinical practice in Norway and there is no reason to expect any additional risk of pain or discomfort.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Apr 2019
    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
    Norway: 240
    Worldwide total number of subjects
    240
    EEA total number of subjects
    240
    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)
    240
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Potentially eligible participants were screened by the principal investigator for inclusion at their last midwife consultation before their scheduled delivery. Oral and written information was given to each woman at least 24 h before her delivery and written informed consent was obtained before randomization.

    Pre-assignment
    Screening details
    		 Inclusion: - Healthy singleton pregnancy - Gestational age > 36 weeks - Age >=18 and <=50 - Understanding Norwegian Exclusion: - Pregnancy induced hypertension - Invasive placenta - Bleeding disorder - Prolonged QT time or other serious cardiac disease - Liver failure - Renal failure - Epilepsy - Drug intolerance

    Period 1
    Period 1 title
    Baseline
    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
    To maintain treatment masking, both study drugs were diluted to 5 mL using normal saline by a trained member of staff otherwise uninvolved with the trial and labelled with the trial identification and randomization number according with ICH GCP and local regulations.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Carbetocin
    Arm description
    		 Carbetocin 100µg iv
    Arm type
    		 Experimental

    Investigational medicinal product name
    carbetocin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    carbetocin 100 µg

    Arm title
    		 Oxytocin
    Arm description
    		 Oxytocin 2.5 U
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oxytocin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxytocin 2.5 U

    Number of subjects in period 1
    		Carbetocin Oxytocin
    Started
    119
    121
    Exclusion prior to intervention
    16 [1]
    9 [2]
    Completed
    103
    112
    Not completed
    16
    9
         Consent withdrawn by subject
    1
    1
         Delivery prior to intervention
    7
    2
         Required general anesthesia
    2
    1
         Capacity reason
    6
    5
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Some patients were lost after inclusion but prior to set time for planned delivery
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Some patients were lost after inclusion but prior to set time for planned delivery
    Period 2
    Period 2 title
    Treatment 0-30 min
    Is this the baseline period?
    		 Yes [3]
    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
    		 Carbetocin
    Arm description
    		 Carbetocin 100µg iv
    Arm type
    		 Experimental

    Investigational medicinal product name
    carbetocin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    carbetocin 100 µg

    Arm title
    		 Oxytocin
    Arm description
    		 Oxytocin 2.5 U
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oxytocin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxytocin 2.5 U

    Notes
    [3] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Some patients were lost after inclusion but prior to set time for planned delivery
    Number of subjects in period 2 [4]
    		Carbetocin Oxytocin
    Started
    103
    112
    Completed
    103
    112
    Notes
    [4] - 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: Some patients were lost after inclusion but prior to set time for planned delivery
    Period 3
    Period 3 title
    Follow-up 6-10 h
    Is this the baseline period?
    		 No
    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
    		 Carbetocin
    Arm description
    		 Carbetocin 100µg iv
    Arm type
    		 Experimental

    Investigational medicinal product name
    carbetocin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    carbetocin 100 µg

    Arm title
    		 Oxytocin
    Arm description
    		 Oxytocin 2.5 U
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oxytocin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxytocin 2.5 U

    Number of subjects in period 3
    		Carbetocin Oxytocin
    Started
    103
    112
    Completed
    103
    112
    Period 4
    Period 4 title
    Followup 48 hours
    Is this the baseline period?
    		 No
    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
    		 Carbetocin
    Arm description
    		 Carbetocin 100µg iv
    Arm type
    		 Experimental

    Investigational medicinal product name
    carbetocin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    carbetocin 100 µg

    Arm title
    		 Oxytocin
    Arm description
    		 Oxytocin 2.5 U
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oxytocin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxytocin 2.5 U

    Number of subjects in period 4
    		Carbetocin Oxytocin
    Started
    103
    112
    Completed
    103
    112

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Carbetocin
    Reporting group description
    		 Carbetocin 100µg iv

    Reporting group title
    Oxytocin
    Reporting group description
    		 Oxytocin 2.5 U

    Reporting group values
    		 Carbetocin Oxytocin Total
    Number of subjects
    		 103 112 215
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 103 112 215
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 35.0 (24.1 to 47.5) 34.5 (23.4 to 50.9) -
    Gender categorical
    Units: Subjects
        Female
    		 103 112 215
        Male
    		 0 0 0
    Parity
    Units: counts
        median (full range (min-max))
    		 1 (0 to 4) 1 (0 to 5) -
    Gestational age
    Units: weeks
        arithmetic mean (standard deviation)
    		 38.7 ( 0.9 ) 38.6 ( 0.8 ) -
    Mean arterial pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 100 ( 12 ) 100 ( 13 ) -
    BMI
    body mass index
    Units: kg/m*m
        median (full range (min-max))
    		 28.7 (20.4 to 51.6) 27.3 (22.0 to 45.0) -
    Heart rate
    Units: beats/min
        arithmetic mean (standard deviation)
    		 88 ( 15 ) 90 ( 15 ) -
    Troponin value at baseline
    Units: ng/L
        median (full range (min-max))
    		 1.0 (1.0 to 19.2) 1.0 (1.0 to 48.7) -
    Subject analysis sets

    Subject analysis set title
    Modified ITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients included in the study having received the study drug

    Subject analysis sets values
    		 Modified ITT
    Number of subjects
    215
    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)
    215
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    34.8 (23.4 to 50.9)
    Gender categorical
    Units: Subjects
        Female
    215
        Male
    0
    Parity
    Units: counts
        median (full range (min-max))
    1 (0 to 5)
    Gestational age
    Units: weeks
        arithmetic mean (standard deviation)
    38.6 ( 0.9 )
    Mean arterial pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    100 ( 13 )
    BMI
    body mass index
    Units: kg/m*m
        median (full range (min-max))
    28 (20.4 to 51.6)
    Heart rate
    Units: beats/min
        arithmetic mean (standard deviation)
    89 ( 15 )
    Troponin value at baseline
    Units: ng/L
        median (full range (min-max))
    1.0 (1.0 to 48.7)

    End points

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    End points reporting groups
    Reporting group title
    Carbetocin
    Reporting group description
    		 Carbetocin 100µg iv

    Reporting group title
    Oxytocin
    Reporting group description
    		 Oxytocin 2.5 U
    Reporting group title
    Carbetocin
    Reporting group description
    		 Carbetocin 100µg iv

    Reporting group title
    Oxytocin
    Reporting group description
    		 Oxytocin 2.5 U
    Reporting group title
    Carbetocin
    Reporting group description
    		 Carbetocin 100µg iv

    Reporting group title
    Oxytocin
    Reporting group description
    		 Oxytocin 2.5 U
    Reporting group title
    Carbetocin
    Reporting group description
    		 Carbetocin 100µg iv

    Reporting group title
    Oxytocin
    Reporting group description
    		 Oxytocin 2.5 U

    Subject analysis set title
    Modified ITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients included in the study having received the study drug

    Primary: Troponin I

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    End point title
    		 Troponin I
    End point description
    End point type
    Primary
    End point timeframe
    at 6-10 hours
    End point values
    		 Carbetocin Oxytocin
    Number of subjects analysed
    99
    109
    Units: ng/l
        median (full range (min-max))
    1.2 (1.0 to 19.5)
    1.2 (1.0 to 47.0)
    Statistical analysis title
    		 median regression model
    Statistical analysis description
    median regression model for the change from baseline. model was adjusted for treatment. bootstrap was used for confidence intervals.
    Comparison groups
    Carbetocin v Oxytocin
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 median regression
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.09
         upper limit
    		 1.09

    Secondary: Uterine tone at 5 minutes

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    End point title
    		 Uterine tone at 5 minutes
    End point description
    End point type
    Secondary
    End point timeframe
    5 minutes
    End point values
    		 Carbetocin Oxytocin
    Number of subjects analysed
    103
    112
    Units: 11 point scale 0-10
        median (full range (min-max))
    8 (4 to 10)
    7 (4 to 10)
    Statistical analysis title
    		 Mann Whitney test
    Comparison groups
    Carbetocin v Oxytocin
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Blood loss

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    End point title
    		 Blood loss
    End point description
    End point type
    Secondary
    End point timeframe
    10 hours
    End point values
    		 Carbetocin Oxytocin
    Number of subjects analysed
    103
    112
    Units: ml
        arithmetic mean (standard deviation)
    361 ( 435 )
    386 ( 369 )
    Statistical analysis title
    		 t test
    Comparison groups
    Carbetocin v Oxytocin
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Time to end of surgery

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    End point title
    		 Time to end of surgery
    End point description
    End point type
    Secondary
    End point timeframe
    10 hours
    End point values
    		 Carbetocin Oxytocin
    Number of subjects analysed
    103
    112
    Units: minute
        median (full range (min-max))
    30 (14 to 58)
    31 (14 to 91)
    Statistical analysis title
    		 Mann Whitney test
    Comparison groups
    Carbetocin v Oxytocin
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Need for rescue treatment

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    End point title
    		 Need for rescue treatment
    End point description
    End point type
    Secondary
    End point timeframe
    0-30 minutes
    End point values
    		 Carbetocin Oxytocin
    Number of subjects analysed
    103
    112
    Units: Number of patients
    23
    50
    Statistical analysis title
    		 Fisher mid p test
    Comparison groups
    Carbetocin v Oxytocin
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    48 hours
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Carbetocin
    Reporting group description
    		 Carbetocin 100µg iv

    Reporting group title
    Oxytocin
    Reporting group description
    		 Oxytocin 2.5 U

    Serious adverse events
    		 Carbetocin Oxytocin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 112 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Carbetocin Oxytocin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 103 (53.40%)
    50 / 112 (44.64%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    8 / 103 (7.77%)
    11 / 112 (9.82%)
         occurrences all number
    8
    11
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    4 / 103 (3.88%)
    12 / 112 (10.71%)
         occurrences all number
    4
    12
    Palpitations
         subjects affected / exposed
    3 / 103 (2.91%)
    7 / 112 (6.25%)
         occurrences all number
    3
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 103 (7.77%)
    6 / 112 (5.36%)
         occurrences all number
    8
    6
    General disorders and administration site conditions
    Feeling hot
    Additional description: feeling of warmth
         subjects affected / exposed
    27 / 103 (26.21%)
    23 / 112 (20.54%)
         occurrences all number
    27
    23
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    14 / 103 (13.59%)
    1 / 112 (0.89%)
         occurrences all number
    14
    1
    Nausea
         subjects affected / exposed
    10 / 103 (9.71%)
    8 / 112 (7.14%)
         occurrences all number
    10
    8
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    9 / 103 (8.74%)
    6 / 112 (5.36%)
         occurrences all number
    9
    6

    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.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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