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    Clinical Trial Results:
    The effect of intraoperative low dose adrenaline on bleeding in total hip arthroplasty - a randomized placebo-controlled trial

    Summary
    EudraCT number
    		 2012-002889-12
    Trial protocol
    		 DK  
    Global end of trial date
    10 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Feb 2022
    First version publication date
    04 Feb 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RH-4074-OJ2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01708642
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, DK-2100
    Public contact
    Oeivind Jans, Rigshospitalet, Section of surgical Pathophysiology, 4074, 45 35451631, oeivind.jans@rh.regionh.dk
    Scientific contact
    Pär I. Johansson, Rigshospitalet, Section 2034, Capital Blood Bank, 45 35452030, per.johansson@regionh.dk
    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
    15 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The evaluate the effect of intraoperative administration of low-dose adrenaline on intraoperative blood loss.
    Protection of trial subjects
    All patients were admitted to the hospital and were closely monitored during the intervention
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 2012
    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
    Denmark: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    30
    From 65 to 84 years
    60
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients who need hip replacement will be recruited from Gentofte hospital and Vejle Hospital

    Pre-assignment
    Screening details
    		 Patients who were eligable for total hip arthroplasty and above 18 years old were screened for inclusion

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    Acomputer generated randomization list (www.randomization.org) was generated by a researcher outside the author group using permuted blocks (block size 10, allocation ratio 1:1). Subjectswere enrolled in the trial by a dedicated study nurse and assigned a unique randomization number based on sequentially numbered,sealed, opaque envelopes in which allocation was concealed. Just before surgery the envelope was opened by the anaesthesia nurse, who also prepared the study drug (epinephrine

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention arm
    Arm description
    		 Before surgery subjects were randomly allocated to receive an infusion of either epinephrine (Adrenalin “DAK”, Nycomed Denmark ApS) at a weight-adjusted rate of 0.05 μg kg−1 min−1 from placement of spinal anaesthesia to end of surgery (last suture).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adrenaline DAK
    Investigational medicinal product code
    Other name
    epinephrine
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A weight-adjusted rate of 0.05 μg kg−1 min−1 will be given from placement of spinal anaesthesia to end of surgery

    Arm title
    		 Placebo
    Arm description
    		 Before surgery subjects were randomly allocated to receive an infusion of placebo (0.9% saline) from placement of spinal anaesthesia to end of surgery (last suture).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline 0.9%
    Investigational medicinal product code
    Other name
    sodium chloride
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A weight-adjusted rate corresponding the the intervention arm will be given from placement of spinal anaesthesia to end of surgery (last suture).

    Number of subjects in period 1
    		Intervention arm Placebo
    Started
    50
    50
    Completed
    50
    50

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention arm
    Reporting group description
    		 Before surgery subjects were randomly allocated to receive an infusion of either epinephrine (Adrenalin “DAK”, Nycomed Denmark ApS) at a weight-adjusted rate of 0.05 μg kg−1 min−1 from placement of spinal anaesthesia to end of surgery (last suture).

    Reporting group title
    Placebo
    Reporting group description
    		 Before surgery subjects were randomly allocated to receive an infusion of placebo (0.9% saline) from placement of spinal anaesthesia to end of surgery (last suture).

    Reporting group values
    		 Intervention arm Placebo Total
    Number of subjects
    		 50 50 100
    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
        median (standard deviation)
    		 67 ± 10 69 ± 8 -
    Gender categorical
    Units: Subjects
        Female
    		 23 24 47
        Male
    		 27 26 53

    End points

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    End points reporting groups
    Reporting group title
    Intervention arm
    Reporting group description
    		 Before surgery subjects were randomly allocated to receive an infusion of either epinephrine (Adrenalin “DAK”, Nycomed Denmark ApS) at a weight-adjusted rate of 0.05 μg kg−1 min−1 from placement of spinal anaesthesia to end of surgery (last suture).

    Reporting group title
    Placebo
    Reporting group description
    		 Before surgery subjects were randomly allocated to receive an infusion of placebo (0.9% saline) from placement of spinal anaesthesia to end of surgery (last suture).

    Primary: Blood loss

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    End point title
    		 Blood loss
    End point description
    Interaoperative blood loos in ml during the operation
    End point type
    Primary
    End point timeframe
    From start of operation for HIP arthroplasty to end op operation
    End point values
    		 Intervention arm Placebo
    Number of subjects analysed
    50
    50
    Units: ml
    arithmetic mean (standard deviation)
        Blood loss
    343 ± 156
    383 ± 177
    Statistical analysis title
    		 Primary endpoint
    Comparison groups
    Intervention arm v Placebo
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.23
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - Before analyses, all data were evaluated for normal distribution by histograms and Q-Q plots and by the Kolmogrov-Schmirnof test. The primary and secondary outcomes were analysed by modified intention to treat by group comparison using a twosided independent samples t-test for continuous outcomes.

    Secondary: Blood loss at 24 hours

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    End point title
    		 Blood loss at 24 hours
    End point description
    The secondary outcome measure was blood loss at 24 h after surgery
    End point type
    Secondary
    End point timeframe
    From start of operation to 24 hours
    End point values
    		 Intervention arm Placebo
    Number of subjects analysed
    50
    50
    Units: ml
    arithmetic mean (standard deviation)
        Blood loss
    902 ± 368
    1082 ± 481
    Statistical analysis title
    		 Secondaty endpoint - Blood loss 24 h
    Comparison groups
    Intervention arm v Placebo
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Hb concentration 24 hours

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    End point title
    		 Hb concentration 24 hours
    End point description
    Hb measurements were by venous sampling at 24 h after end of surgery (last suture).
    End point type
    Secondary
    End point timeframe
    Changes from start op operation to 24 hours post surgery
    End point values
    		 Intervention arm Placebo
    Number of subjects analysed
    50
    50
    Units: g dl(-1)
    arithmetic mean (standard deviation)
        Haemaglobin
    11.5 ± 1.3
    11.3 ± 1.4
    Statistical analysis title
    		 Hb secondary endpoint
    Comparison groups
    Placebo v Intervention arm
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of operation to post 24 hours.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Intervention group
    Reporting group description
    		 -

    Reporting group title
    Placebo group
    Reporting group description
    		 -

    Serious adverse events
    		 Intervention group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (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: 0%
    Non-serious adverse events
    		 Intervention group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 50 (12.00%)
    5 / 50 (10.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    Haematoma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Bradycardia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Sedation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Dizziness
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Elevated temperature
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Elevated kidney parameters
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26821696
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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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