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    Clinical Trial Results:
    PANSAID – PAracetamol and NSAID in combination: A randomised, blinded, parallel 4-group clinical trial

    Summary
    EudraCT number
    2015-002239-16
    Trial protocol
    DK  
    Global end of trial date
    01 Jan 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Jan 2021
    First version publication date
    07 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SM2-KHT-2015
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02571361
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Departement of Anaesthesiology, Næstved Hospital
    Sponsor organisation address
    Ringstedgade 61, Næstved, Denmark, 4700
    Public contact
    Department of Anaesthesiology Daniel Hägi-Pedersen, Næstved Hospital, +45 21517167, dhag@regionsjaelland.dk
    Scientific contact
    Department of Anaesthesiology Daniel Hägi-Pedersen, Næstved Hospital, +45 21517167, dhag@regionsjaelland.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
    01 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this trial is to investigate the analgesic effects and safety of paracetamol and ibuprofen and their combination in different dosages after THA
    Protection of trial subjects
    Subjects received a Patient Controlled Analgesia Pump with morphine, where they could steer their own pain treatment. Thus reducing patients discomfort in trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Dec 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Scientific research
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 556
    Worldwide total number of subjects
    556
    EEA total number of subjects
    556
    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)
    208
    From 65 to 84 years
    335
    85 years and over
    13

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    All patients planned for total hip arthroplasty

    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, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Blinding of trial medication, thus tablets were sealed in opaque hard capsules.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment A
    Arm description
    Paracetamol 1g + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.
    Arm type
    Active comparator

    Investigational medicinal product name
    Pinex
    Investigational medicinal product code
    Other name
    paracetamol
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Paracetamol 1g orally starting1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Investigational medicinal product name
    Ibumetin
    Investigational medicinal product code
    Other name
    Ibumetin
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Arm title
    Treatment B
    Arm description
    Paracetamol 1g + placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.
    Arm type
    Active comparator

    Investigational medicinal product name
    Pinex
    Investigational medicinal product code
    Other name
    paracetamol
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Paracetamol 1g orally starting1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Arm title
    Treatment C
    Arm description
    Placebo + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.
    Arm type
    Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    2 capsules placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Investigational medicinal product name
    Ibumetin
    Investigational medicinal product code
    Other name
    Ibumetin
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Arm title
    Treatment D
    Arm description
    Paracetamol 0,5 g + ibuprofen 200 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.
    Arm type
    Active comparator

    Investigational medicinal product name
    Pinex
    Investigational medicinal product code
    Other name
    paracetamol
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Paracetamol 0,5 g orally starting1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Investigational medicinal product name
    Ibumetin
    Investigational medicinal product code
    Other name
    Ibumetin
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibuprofen 200 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Number of subjects in period 1
    Treatment A Treatment B Treatment C Treatment D
    Started
    136
    142
    139
    139
    Completed
    136
    142
    139
    139

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    Paracetamol 1g + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Reporting group title
    Treatment B
    Reporting group description
    Paracetamol 1g + placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Reporting group title
    Treatment C
    Reporting group description
    Placebo + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Reporting group title
    Treatment D
    Reporting group description
    Paracetamol 0,5 g + ibuprofen 200 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Reporting group values
    Treatment A Treatment B Treatment C Treatment D Total
    Number of subjects
    136 142 139 139 556
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    67 ± 10 67 ± 10 67 ± 11 66 ± 10 -
    Gender categorical
    Units: Subjects
        Female
    68 66 67 76 277
        Male
    68 76 72 63 279
    ASA-score
    American Society of Anaesthesiologists Physical Status Classification System
    Units: Subjects
        ASA 1
    34 44 44 43 165
        ASA 2
    87 84 80 84 335
        ASA 3
    15 14 15 12 56
    Anesthesia
    Type of Anesthesia
    Units: Subjects
        Spinal with sedation
    65 70 66 69 270
        Spinal
    39 42 43 27 151
        General
    29 20 24 38 111
        Conversion of spinal to general
    3 10 6 5 24
    Prior use of paracetamol
    Use of paracetamol prior to the operation.
    Units: Subjects
        No use
    53 52 51 51 207
        As needed
    29 24 24 22 99
        Daily use
    54 66 64 66 250
    Prior use of NSAID
    Use of NSAID prior to the operation.
    Units: Subjects
        No use
    72 77 74 72 295
        As needed
    21 18 16 21 76
        Daily use
    43 47 49 46 185
    Prior use of codeine
    Use of codeine prior to the operation
    Units: Subjects
        No use
    134 141 136 137 548
        As needed
    1 0 1 1 3
        Daily use
    1 1 2 1 5
    Prior use of tramadol
    Use of tramadol prior to the operation.
    Units: Subjects
        No use
    121 127 125 122 495
        As needed
    5 6 6 8 25
        Daily use
    10 9 8 9 36
    Type of surgery
    Units: Subjects
        No cement
    122 129 127 122 500
        Cement
    2 3 2 4 11
        Hybrid
    12 10 10 13 45
    Height
    Units: cm
        arithmetic mean (standard deviation)
    172 ± 9 172 ± 8 172 ± 9 171 ± 9 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    83 ± 16 82 ± 15 80 ± 15 81 ± 16 -
    BMI
    Body Mass Index
    Units: kg/squaremeter
        arithmetic mean (standard deviation)
    27.7 ± 4.3 27.4 ± 4.1 26.8 ± 3.9 27.6 ± 4.7 -
    Bupivacaine, SA
    Bupivacaine dose for spinal anesthesia (SA)
    Units: mg
        arithmetic mean (standard deviation)
    12 ± 2 12 ± 2 12 ± 2 12 ± 2 -
    Sufentanil used if general anesthesia
    Sufentanil dose prior to end of surgery
    Units: micorgram
        arithmetic mean (standard deviation)
    24 ± 7 20 ± 9 21 ± 8 21 ± 8 -
    Duration of surgery
    Units: minute
        arithmetic mean (standard deviation)
    54 ± 19 51 ± 14 53 ± 18 53 ± 15 -

    End points

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    End points reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    Paracetamol 1g + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Reporting group title
    Treatment B
    Reporting group description
    Paracetamol 1g + placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Reporting group title
    Treatment C
    Reporting group description
    Placebo + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Reporting group title
    Treatment D
    Reporting group description
    Paracetamol 0,5 g + ibuprofen 200 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Primary: Morphine consumption the first 24 hours postoperatively

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    End point title
    Morphine consumption the first 24 hours postoperatively
    End point description
    Total need for morphine administered as BOTH patient controlled analgesia (PCA) for the first 24 hours postoperatively AND supplemental morphine administered at the post-anaesthesia unit the first hour postoperatively. Bolus 2.0 mg; lockout: 10 min
    End point type
    Primary
    End point timeframe
    0-24 hours postoperatively
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    136
    141
    137
    137
    Units: miligram
        median (confidence interval 99.6%)
    20 (0 to 148)
    36 (0 to 166)
    26 (2 to 139)
    28 (2 to 145)
    Statistical analysis title
    Comparison of 24.hour morphine consumption, A vs B
    Statistical analysis description
    Pair-wise comparison of the groups.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    Van Elteren
    Parameter type
    Median difference (final values)
    Point estimate
    -16
    Confidence interval
         level
    99.6%
         sides
    2-sided
         lower limit
    -24
         upper limit
    -6.5
    Notes
    [1] - P-value for this anlysis is corrected for co-primary outcome and 6 possible comparisons. P=0.0042.
    Statistical analysis title
    Comparison of 24.hour morphine consumption, A vs C
    Statistical analysis description
    Pair-wise comparison of the groups.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002 [2]
    Method
    Van Elteren
    Parameter type
    Median difference (final values)
    Point estimate
    -6
    Confidence interval
         level
    99.6%
         sides
    2-sided
         lower limit
    -16
         upper limit
    -2
    Notes
    [2] - P-value for this anlysis is corrected for co-primary outcome and 6 possible comparisons. P=0.0042.
    Statistical analysis title
    Comparison of 24.hour morphine consumption, A vs D
    Statistical analysis description
    Pair-wise comparison of the groups.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005 [3]
    Method
    Van Elteren
    Parameter type
    Median difference (final values)
    Point estimate
    -8
    Confidence interval
         level
    99.6%
         sides
    2-sided
         lower limit
    -16
         upper limit
    2
    Notes
    [3] - P-value for this anlysis is corrected for co-primary outcome and 6 possible comparisons. P=0.0042.
    Statistical analysis title
    Comparison of 24.hour morphine consumption,B vs C
    Statistical analysis description
    Pair-wise comparison of the groups.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0044 [4]
    Method
    Van Elteren
    Parameter type
    Median difference (final values)
    Point estimate
    10
    Confidence interval
         level
    99.6%
         sides
    2-sided
         lower limit
    -2
         upper limit
    16
    Notes
    [4] - P-value for this anlysis is corrected for co-primary outcome and 6 possible comparisons. P=0.0042.
    Statistical analysis title
    Comparison of 24.hour morphine consumption,B vs D
    Statistical analysis description
    Pair-wise comparison of the groups.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [5]
    Method
    Van Elteren
    Parameter type
    Median difference (final values)
    Point estimate
    8
    Confidence interval
         level
    99.6%
         sides
    2-sided
         lower limit
    -1
         upper limit
    14
    Notes
    [5] - P-value for this anlysis is corrected for co-primary outcome and 6 possible comparisons. P=0.0042.
    Statistical analysis title
    Comparison of 24.hour morphine consumption, C vs D
    Statistical analysis description
    Pair-wise comparison of the groups.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.81 [6]
    Method
    Van Elteren
    Parameter type
    Median difference (final values)
    Point estimate
    -2
    Confidence interval
         level
    99.6%
         sides
    2-sided
         lower limit
    -7
         upper limit
    10
    Notes
    [6] - P-value for this anlysis is corrected for co-primary outcome and 6 possible comparisons. P=0.0042.

    Primary: Proportion of patients with 1 or more modified SAEs from the surgery to 90 days postoperatively

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    End point title
    Proportion of patients with 1 or more modified SAEs from the surgery to 90 days postoperatively
    End point description
    End point type
    Primary
    End point timeframe
    Surgery to 90 days postoperatively.
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    136
    142
    139
    139
    Units: Number of SAE
    20
    15
    20
    18
    Statistical analysis title
    Comparsion of porpotions of SAE
    Statistical analysis description
    To investigate harm of ibuprofen, patients in the 3 groups randomized to receive ibuprofen (Treatment A + C + D) were compared with patients in the paracetamol-alone group (Treatment B) for the modified SAE outcome.
    Comparison groups
    Treatment A v Treatment B v Treatment C v Treatment D
    Number of subjects included in analysis
    556
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.18 [7]
    Method
    Generalized estimating equations
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.44
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    2.64
    Notes
    [7] - P-value is corrected for co-primary outcome. P=0.025.
    Statistical analysis title
    Proportions of modified SAEs
    Statistical analysis description
    Proportion of patients with 1 or more modified SAEs from the surgery to 90 days postoperatively. To investigate harm of ibuprofen, patients in the 3 groups randomized to receive ibuprofen were compared with patients in the paracetamol-alone group for the modified SAE outcome. A + C + D vs B
    Comparison groups
    Treatment A v Treatment B v Treatment C v Treatment D
    Number of subjects included in analysis
    556
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.18 [8]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.44
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    2.64
    Notes
    [8] - Level of significance corrected, due to co-primary outcome to p= 0.025

    Secondary: Pain scores, with mobilization at 6 h

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    End point title
    Pain scores, with mobilization at 6 h
    End point description
    End point type
    Secondary
    End point timeframe
    6 hours postoperatively.
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    136
    141
    137
    137
    Units: mm
        arithmetic mean (confidence interval 99.2%)
    45 (39 to 51)
    52 (47 to 58)
    50 (44 to 55)
    53 (48 to 58)
    Statistical analysis title
    Comparison pain scores 6 h, mob, A vs B
    Statistical analysis description
    Comparison of the pain scores 6 hours postoperatively, with mobilization.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.03 [9]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -7
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -15
         upper limit
    1
    Notes
    [9] - The statistically significance level i corrected for multiple comparisons til p=0.0084
    Statistical analysis title
    Comparison pain scores 6 h, mob, A vs D
    Statistical analysis description
    Comparison of the pain scores 6 hours postoperatively, with mobilization.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01 [10]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -8
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -15
         upper limit
    0
    Notes
    [10] - The statistically significance level i corrected for multiple comparisons til p=0.0084
    Statistical analysis title
    Comparison pain scores 6 h, mob, B vs C
    Statistical analysis description
    Comparison of the pain scores 6 hours postoperatively, with mobilization.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.34 [11]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    3
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -5
         upper limit
    11
    Notes
    [11] - The statistically significance level i corrected for multiple comparisons til p=0.0084
    Statistical analysis title
    Comparison pain scores 6 h, mob, B vs D
    Statistical analysis description
    Comparison of the pain scores 6 hours postoperatively, with mobilization.
    Comparison groups
    Treatment D v Treatment B
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.86 [12]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -8
         upper limit
    7
    Notes
    [12] - The statistically significance level i corrected for multiple comparisons til p=0.0084
    Statistical analysis title
    Comparison pain scores 6 h, mob, C vs D
    Statistical analysis description
    Comparison of the pain scores 6 hours postoperatively, with mobilization.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.23 [13]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -3
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -11
         upper limit
    4
    Notes
    [13] - The statistically significance level i corrected for multiple comparisons til p=0.0084
    Statistical analysis title
    Comparison pain scores 6 h, mob, A vs C
    Statistical analysis description
    Comparison of the pain scores 6 hours postoperatively, with mobilization.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.17 [14]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -4
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -12
         upper limit
    4
    Notes
    [14] - The statistically significance level i corrected for multiple comparisons til p=0.0084

    Secondary: Pain scores, at rest 6 hours

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    End point title
    Pain scores, at rest 6 hours
    End point description
    End point type
    Secondary
    End point timeframe
    6 hours postoperatively
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    136
    141
    137
    137
    Units: mm
        arithmetic mean (confidence interval 99.2%)
    32 (27 to 37)
    39 (34 to 44)
    37 (32 to 42)
    36 (31 to 41)
    Statistical analysis title
    Comparison of pain scores, at rest 6 hours, A vs B
    Statistical analysis description
    Comparison of pain scores, 6 hours postoperatively at rest.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005 [15]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -8
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -15
         upper limit
    0
    Notes
    [15] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, at rest 6 hours, A vs C
    Statistical analysis description
    Comparison of pain scores, 6 hours postoperatively at rest.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.05 [16]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -5
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -12
         upper limit
    2
    Notes
    [16] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, at rest 6 hours, A vs D
    Statistical analysis description
    Comparison of pain scores, 6 hours postoperatively at rest.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.08 [17]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -5
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -11
         upper limit
    2
    Notes
    [17] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, at rest 6 hours, B vs C
    Statistical analysis description
    Comparison of pain scores, 6 hours postoperatively at rest.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.38 [18]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    2
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -5
         upper limit
    10
    Notes
    [18] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, at rest 6 hours, B vs D
    Statistical analysis description
    Comparison of pain scores, 6 hours postoperatively at rest.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.25 [19]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    3
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -4
         upper limit
    10
    Notes
    [19] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, at rest 6 hours, C vs D
    Statistical analysis description
    Comparison of pain scores, 6 hours postoperatively at rest.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.81 [20]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -6
         upper limit
    8
    Notes
    [20] - Statistical significance level corrected for multiple comparison to p=0.0084.

    Secondary: Pain scores with mobilization at 24 hours

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    End point title
    Pain scores with mobilization at 24 hours
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours postoperatively
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    136
    141
    137
    137
    Units: mm
        arithmetic mean (confidence interval 99.2%)
    37 (32 to 43)
    49 (43 to 54)
    45 (39 to 51)
    46 (40 to 51)
    Statistical analysis title
    Comparison of pain scores, with mob 24 h, A vs B
    Statistical analysis description
    Comparison of pain scores with mobilization 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [21]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -11
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -19
         upper limit
    -3
    Notes
    [21] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, with mob 24 h, A vs C
    Statistical analysis description
    Comparison of pain scores with mobilization 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.009 [22]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -8
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -15
         upper limit
    0
    Notes
    [22] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, with mob 24 h, A vs D
    Statistical analysis description
    Comparison of pain scores with mobilization 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005 [23]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -8
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -16
         upper limit
    0
    Notes
    [23] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, with mob 24 h, B vs C
    Statistical analysis description
    Comparison of pain scores with mobilization 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.24 [24]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    4
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -4
         upper limit
    12
    Notes
    [24] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, with mob 24 h, B vs D
    Statistical analysis description
    Comparison of pain scores with mobilization 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.32 [25]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    3
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -5
         upper limit
    11
    Notes
    [25] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, with mob 24 h, C vs D
    Statistical analysis description
    Comparison of pain scores with mobilization 24 hours postoperatively.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.86 [26]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -8
         upper limit
    7
    Notes
    [26] - Statistical significance level corrected for multiple comparison to p=0.0084.

    Secondary: Pain scores at rest at 24 hours

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    End point title
    Pain scores at rest at 24 hours
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours postoperatively.
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    136
    141
    137
    137
    Units: mm
        arithmetic mean (confidence interval 99.2%)
    13 (10 to 17)
    24 (19 to 29)
    21 (16 to 26)
    19 (15 to 23)
    Statistical analysis title
    Comparison of pain scores, at rest 24 h, A vs B
    Statistical analysis description
    Comparison of pain scores at rest 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [27]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -11
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -17
         upper limit
    -5
    Notes
    [27] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, at rest 24 h, A vs C
    Statistical analysis description
    Comparison of pain scores at rest 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [28]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -8
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -13
         upper limit
    -2
    Notes
    [28] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, at rest 24 h, A vs D
    Statistical analysis description
    Comparison of pain scores at rest 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004 [29]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    -6
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -11
         upper limit
    0
    Notes
    [29] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, at rest 24 h, B vs C
    Statistical analysis description
    Comparison of pain scores at rest 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.21 [30]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    3
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -4
         upper limit
    10
    Notes
    [30] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, at rest 24 h, B vs D
    Statistical analysis description
    Comparison of pain scores at rest 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.04 [31]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    5
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -2
         upper limit
    11
    Notes
    [31] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of pain scores, at rest 24 h, C vs D
    Statistical analysis description
    Comparison of pain scores at rest 24 hours postoperatively.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.46 [32]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Mean difference (final values)
    Point estimate
    2
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    -4
         upper limit
    8
    Notes
    [32] - Statistical significance level corrected for multiple comparison to p=0.0084.

    Secondary: Adverse events in the first 24 h

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    End point title
    Adverse events in the first 24 h
    End point description
    End point type
    Secondary
    End point timeframe
    The first 24 hours postoperatively.
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    136
    141
    137
    137
    Units: Adverse events
    20
    23
    22
    21
    Statistical analysis title
    Comparison of AE in the first 24 hours, A vs B
    Statistical analysis description
    Mean difference (RR) of adverse events in the first 24 hours.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.73 [33]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.91
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    1.91
    Notes
    [33] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of AE in the first 24 hours, A vs C
    Statistical analysis description
    Mean difference (RR) of adverse events in the first 24 hours.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8 [34]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.93
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.98
    Notes
    [34] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of AE in the first 24 hours, A vs D
    Statistical analysis description
    Mean difference (RR) of adverse events in the first 24 hours.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.94 [35]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.02
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    2.22
    Notes
    [35] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of AE in the first 24 hours, B vs C
    Statistical analysis description
    Mean difference (RR) of adverse events in the first 24 hours.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.93 [36]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.02
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    2.11
    Notes
    [36] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of AE in the first 24 hours, B vs D
    Statistical analysis description
    Mean difference (RR) of adverse events in the first 24 hours.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.67 [37]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.13
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    2.37
    Notes
    [37] - Statistical significance level corrected for multiple comparison to p=0.0084.
    Statistical analysis title
    Comparison of AE in the first 24 hours, C vs D
    Statistical analysis description
    Mean difference (RR) of adverse events in the first 24 hours.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.74 [38]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.1
    Confidence interval
         level
    99.2%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    2.34
    Notes
    [38] - Statistical significance level corrected for multiple comparison to p=0.0084.

    Other pre-specified: Nausea, 6 hours %

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    End point title
    Nausea, 6 hours %
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Surgery to 24 hours postoperatively.
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    135
    139
    130
    134
    Units: mild, moderat, severe nausea
    22
    32
    19
    28
    Statistical analysis title
    Comparison nausea 6 hours, A vs B
    Statistical analysis description
    Comparison of the proportions of nausea 6 hours postoperatively.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.17 [39]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    1.15
    Notes
    [39] - Significance level p= 0.05
    Statistical analysis title
    Comparison nausea 6 hours, A vs C
    Statistical analysis description
    Comparison of the proportions of nausea 6 hours postoperatively.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.82 [40]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.86
    Notes
    [40] - Significance level p= 0.05
    Statistical analysis title
    Comparison nausea 6 hours, A vs D
    Statistical analysis description
    Comparison of the proportions of nausea 6 hours postoperatively.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.33 [41]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    1.29
    Notes
    [41] - Significance level p= 0.05
    Statistical analysis title
    Comparison nausea 6 hours, B vs C
    Statistical analysis description
    Comparison of the proportions of nausea 6 hours postoperatively.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.11 [42]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.91
         upper limit
    2.5
    Notes
    [42] - Significance level p= 0.05
    Statistical analysis title
    Comparison nausea 6 hours, B vs D
    Statistical analysis description
    Comparison of the proportions of nausea 6 hours postoperatively.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.67 [43]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.72
    Notes
    [43] - Significance level p= 0.05
    Statistical analysis title
    Comparison nausea 6 hours, C vs D
    Statistical analysis description
    Comparison of the proportions of nausea 6 hours postoperatively.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.24 [44]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    1.23
    Notes
    [44] - Significance level p= 0.05

    Other pre-specified: Nausea, 24 hours postoperatively

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    End point title
    Nausea, 24 hours postoperatively
    End point description
    End point type
    Other pre-specified
    End point timeframe
    24 hours postoperatively.
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    134
    137
    132
    135
    Units: mild, moderate, severe nausea
    17
    33
    30
    38
    Statistical analysis title
    Comparison nausea 24 hours, A vs B
    Statistical analysis description
    Comparison of proportions of nausea at 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.019 [45]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.31
         upper limit
    0.9
    Notes
    [45] - Level of significance p = 0.05.
    Statistical analysis title
    Comparison nausea 24 hours, A vs C
    Statistical analysis description
    Comparison of proportions of nausea at 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.036 [46]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.32
         upper limit
    0.96
    Notes
    [46] - Level of significance p = 0.05.
    Statistical analysis title
    Comparison nausea 24 hours, A vs D
    Statistical analysis description
    Comparison of proportions of nausea at 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [47]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    0.76
    Notes
    [47] - Level of significance p = 0.05.
    Statistical analysis title
    Comparison nausea 24 hours, B vs C
    Statistical analysis description
    Comparison of proportions of nausea at 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.79 [48]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    1.63
    Notes
    [48] - Level of significance p = 0.05.
    Statistical analysis title
    Comparison nausea 24 hours, B vs D
    Statistical analysis description
    Comparison of proportions of nausea at 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.45 [49]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.28
    Notes
    [49] - Level of significance p = 0.05.
    Statistical analysis title
    Comparison nausea 24 hours, C vs D
    Statistical analysis description
    Comparison of proportions of nausea at 24 hours postoperatively.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.31 [50]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    1.22
    Notes
    [50] - Level of significance p = 0.05.

    Other pre-specified: Sedation 6 hours postoperatively

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    End point title
    Sedation 6 hours postoperatively
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 hours postoperatively
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    135
    138
    130
    132
    Units: mild, moderate, severe sedation
    33
    51
    27
    38
    Statistical analysis title
    Comparison sedation 6 hours, A vs B
    Statistical analysis description
    Comparison of proportions of sedation 6 hours postoperatively.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.028 [51]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    0.96
    Notes
    [51] - Level of significance p = 0.05
    Statistical analysis title
    Comparison sedation 6 hours, A vs C
    Statistical analysis description
    Comparison of proportions of sedation 6 hours postoperatively.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.48 [52]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.75
         upper limit
    1.84
    Notes
    [52] - Level of significance p = 0.05
    Statistical analysis title
    Comparison sedation 6 hours, A vs D
    Statistical analysis description
    Comparison of proportions of sedation 6 hours postoperatively.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.42 [53]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.27
    Notes
    [53] - Level of significance p = 0.05
    Statistical analysis title
    Comparison sedation 6 hours, B vs C
    Statistical analysis description
    Comparison of proportions of sedation 6 hours postoperatively.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005 [54]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.19
         upper limit
    2.66
    Notes
    [54] - Level of significance p = 0.05
    Statistical analysis title
    Comparison sedation 6 hours, B vs D
    Statistical analysis description
    Comparison of proportions of sedation 6 hours postoperatively.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.16 [55]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.91
         upper limit
    1.81
    Notes
    [55] - Level of significance p = 0.05
    Statistical analysis title
    Comparison sedation 6 hours, C vs D
    Statistical analysis description
    Comparison of proportions of sedation 6 hours postoperatively.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14 [56]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    1.11
    Notes
    [56] - Level of significance p = 0.05

    Other pre-specified: Sedation, 24 hours postoperatively

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    End point title
    Sedation, 24 hours postoperatively
    End point description
    End point type
    Other pre-specified
    End point timeframe
    24 hours postoperatively.
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    134
    137
    132
    135
    Units: mild, moderate, severe sedation
    44
    58
    47
    57
    Statistical analysis title
    Comparison sedation 24 hours, A vs B
    Statistical analysis description
    Comaprison of proportions of sedation 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.019 [57]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.31
         upper limit
    0.9
    Notes
    [57] - Level of significance p = 0.05
    Statistical analysis title
    Comparison sedation 24 hours, A vs C
    Statistical analysis description
    Comaprison of proportions of sedation 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.036 [58]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.32
         upper limit
    0.96
    Notes
    [58] - Level of significance p = 0.05
    Statistical analysis title
    Comparison sedation 24 hours, A vs D
    Statistical analysis description
    Comaprison of proportions of sedation 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [59]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    0.76
    Notes
    [59] - Level of significance p = 0.05
    Statistical analysis title
    Comparison sedation 24 hours, B vs C
    Statistical analysis description
    Comaprison of proportions of sedation 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.79 [60]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    1.63
    Notes
    [60] - Level of significance p = 0.05
    Statistical analysis title
    Comparison sedation 24 hours, B vs D
    Statistical analysis description
    Comaprison of proportions of sedation 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.45 [61]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.28
    Notes
    [61] - Level of significance p = 0.05
    Statistical analysis title
    Comparison sedation 24 hours, C vs D
    Statistical analysis description
    Comaprison of proportions of sedation 24 hours postoperatively.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.31 [62]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    1.22
    Notes
    [62] - Level of significance p = 0.05

    Other pre-specified: Dizziness, 6 hours postoperatively

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    End point title
    Dizziness, 6 hours postoperatively
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 hours postoperatively.
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    135
    139
    130
    133
    Units: mild, moderate, severe dizziness
    19
    35
    26
    32
    Statistical analysis title
    Comparison dizziness 6 hours, A vs B
    Statistical analysis description
    Comparison of proportions of dizziness 6 hours postoperatively.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.024 [63]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    0.93
    Notes
    [63] - Level of significance p = 0.05
    Statistical analysis title
    Comparison dizziness 6 hours, A vs C
    Statistical analysis description
    Comparison of proportions of dizziness 6 hours postoperatively.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2 [64]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    1.21
    Notes
    [64] - Level of significance p = 0.05
    Statistical analysis title
    Comparison dizziness 6 hours, A vs D
    Statistical analysis description
    Comparison of proportions of dizziness 6 hours postoperatively.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.041 [65]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.35
         upper limit
    0.98
    Notes
    [65] - Level of significance p = 0.05
    Statistical analysis title
    Comparison dizziness 6 hours, B vs C
    Statistical analysis description
    Comparison of proportions of dizziness 6 hours postoperatively.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.31 [66]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.97
    Notes
    [66] - Level of significance p = 0.05
    Statistical analysis title
    Comparison dizziness 6 hours, B vs D
    Statistical analysis description
    Comparison of proportions of dizziness 6 hours postoperatively.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.83 [67]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    1.59
    Notes
    [67] - Level of significance p = 0.05
    Statistical analysis title
    Comparison dizziness 6 hours, C vs D
    Statistical analysis description
    Comparison of proportions of dizziness 6 hours postoperatively.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.43 [68]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    1.31
    Notes
    [68] - Level of significance p = 0.05

    Other pre-specified: Dizziness, 24 hours postoperatively

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    End point title
    Dizziness, 24 hours postoperatively
    End point description
    End point type
    Other pre-specified
    End point timeframe
    24 hours postoperatively.
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    134
    137
    132
    135
    Units: mild, moderate, severe dizziness
    26
    32
    38
    37
    Statistical analysis title
    Comparison dizziness 24 hours, A vs B
    Statistical analysis description
    Comparison of proportions of dizziness 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.43 [69]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    1.32
    Notes
    [69] - Level of significance p = 0.05.
    Statistical analysis title
    Comparison dizziness 24 hours, A vs C
    Statistical analysis description
    Comparison of proportions of dizziness 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.77 [70]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.04
    Notes
    [70] - Level of significance p = 0.05.
    Statistical analysis title
    Comparison dizziness 24 hours, A vs D
    Statistical analysis description
    Comparison of proportions of dizziness 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.13 [71]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    1.1
    Notes
    [71] - Level of significance p = 0.05.
    Statistical analysis title
    Comparison dizziness 24 hours, B vs C
    Statistical analysis description
    Comparison of proportions of dizziness 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.31 [72]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.22
    Notes
    [72] - Level of significance p = 0.05.
    Statistical analysis title
    Comparison dizziness 24 hours, B vs D
    Statistical analysis description
    Comparison of proportions of dizziness 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.44 [73]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.28
    Notes
    [73] - Level of significance p = 0.05.
    Statistical analysis title
    Copy of Comparison dizziness 24 hours, C vs D
    Statistical analysis description
    Comparison of proportions of dizziness 24 hours postoperatively.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8 [74]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    1.54
    Notes
    [74] - Level of significance p = 0.05.

    Other pre-specified: Vomiting, first 24 hours postoperatively.

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    End point title
    Vomiting, first 24 hours postoperatively.
    End point description
    End point type
    Other pre-specified
    End point timeframe
    First 24 hours postoperatively.
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    136
    141
    137
    137
    Units: number of vomiting
    0
    0
    0
    0
    Statistical analysis title
    Comparison of vomiting, first 24 hours, A vs B
    Statistical analysis description
    Comparison of vomiting, the first 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.47
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0
    Statistical analysis title
    Comparison of vomiting, first 24 hours, A vs C
    Statistical analysis description
    Comparison of vomiting, the first 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.96
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0
    Statistical analysis title
    Comparison of vomiting, first 24 hours, A vs D
    Statistical analysis description
    Comparison of vomiting, the first 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    1
    Statistical analysis title
    Comparison of vomiting, first 24 hours, B vs C
    Statistical analysis description
    Comparison of vomiting, the first 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.36
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0
    Statistical analysis title
    Comparison of vomiting, first 24 hours, B vs D
    Statistical analysis description
    Comparison of vomiting, the first 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.55
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    1
    Statistical analysis title
    Comparison of vomiting, first 24 hours, C vs D
    Statistical analysis description
    Comparison of vomiting, the first 24 hours postoperatively.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.13
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    1

    Other pre-specified: Ondansetron use first 24 hours

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    End point title
    Ondansetron use first 24 hours
    End point description
    End point type
    Other pre-specified
    End point timeframe
    First 24 hours postoperatively.
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    136
    140
    136
    139
    Units: mg
        median (inter-quartile range (Q1-Q3))
    0 (0 to 4)
    0 (0 to 4)
    0 (0 to 4)
    0 (0 to 5)
    Statistical analysis title
    Comparsion of ondansetron use, first 24 h, A vs B
    Statistical analysis description
    Comparison of the use of ondansetron, the first 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.09 [75]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    0
    Notes
    [75] - Level of significance p = 0.05
    Statistical analysis title
    Comparsion of ondansetron use, first 24 h, A vs C
    Statistical analysis description
    Comparison of the use of ondansetron, the first 24 hours postoperatively.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.86 [76]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0
    Notes
    [76] - Level of significance p = 0.05
    Statistical analysis title
    Comparsion of ondansetron use, first 24 h, A vs D
    Statistical analysis description
    Comparison of the use of ondansetron, the first 24 hours postoperatively.
    Comparison groups
    Treatment D v Treatment A
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2 [77]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    1
    Notes
    [77] - Level of significance p = 0.05
    Statistical analysis title
    Comparsion of ondansetron use, first 24 h, B vs C
    Statistical analysis description
    Comparison of the use of ondansetron, the first 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.15 [78]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    2
    Notes
    [78] - Level of significance p = 0.05
    Statistical analysis title
    Comparsion of ondansetron use, first 24 h, B vs D
    Statistical analysis description
    Comparison of the use of ondansetron, the first 24 hours postoperatively.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.73 [79]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    2
    Notes
    [79] - Level of significance p = 0.05
    Statistical analysis title
    Comparsion of ondansetron use, first 24 h, C vs D
    Statistical analysis description
    Comparison of the use of ondansetron, the first 24 hours postoperatively.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.05 [80]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    0
    Notes
    [80] - Level of significance p = 0.05

    Other pre-specified: Blood loss

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    End point title
    Blood loss
    End point description
    Exploratory outcome
    End point type
    Other pre-specified
    End point timeframe
    Peroperative blood loss.
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    132
    137
    136
    134
    Units: ml
        median (inter-quartile range (Q1-Q3))
    300 (200 to 415)
    300 (200 to 470)
    265 (177.5 to 400)
    287.5 (165 to 400)
    Statistical analysis title
    Comparison blood loss, A vs B
    Statistical analysis description
    Comparsion of peroperative blood loss in ml.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9 [81]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Risk ratio (RR)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -60
         upper limit
    52.5
    Notes
    [81] - Level of Significance p = 0.05
    Statistical analysis title
    Comparison blood loss, A vs C
    Statistical analysis description
    Comparsion of peroperative blood loss in ml.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.29 [82]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25
         upper limit
    85
    Notes
    [82] - Level of Significance p = 0.05
    Statistical analysis title
    Comparison blood loss, A vs D
    Statistical analysis description
    Comparsion of peroperative blood loss in ml.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.36 [83]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    12.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -50
         upper limit
    65
    Notes
    [83] - Level of Significance p = 0.05
    Statistical analysis title
    Comparison blood loss, B vs C
    Statistical analysis description
    Comparsion of peroperative blood loss in ml.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.19 [84]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20
         upper limit
    100
    Notes
    [84] - Level of Significance p = 0.05
    Statistical analysis title
    Comparison blood loss, B vs D
    Statistical analysis description
    Comparsion of peroperative blood loss in ml.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.37 [85]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    12.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -50
         upper limit
    50
    Notes
    [85] - Level of Significance p = 0.05
    Statistical analysis title
    Comparison blood loss,v C vs D
    Statistical analysis description
    Comparsion of peroperative blood loss in ml.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.85 [86]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    -22.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -75
         upper limit
    50
    Notes
    [86] - Level of Significance p = 0.05

    Other pre-specified: Days alive and outside hospital, days

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    End point title
    Days alive and outside hospital, days
    End point description
    Exploratory outcome
    End point type
    Other pre-specified
    End point timeframe
    Days alive and outside hospital, days
    End point values
    Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    134
    141
    138
    138
    Units: days
        median (inter-quartile range (Q1-Q3))
    89 (88 to 89)
    88 (88 to 89)
    88 (88 to 89)
    88 (88 to 89)
    Statistical analysis title
    Median differences, days alive and outside, A vs B
    Statistical analysis description
    Median differences of days alive and outside of hospital.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.46 [87]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    1
    Notes
    [87] - Level of significance p = 0.05.
    Statistical analysis title
    Median differences, days alive and outside, A vs C
    Statistical analysis description
    Median differences of days alive and outside of hospital.
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.13 [88]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    1
    Notes
    [88] - Level of significance p = 0.05.
    Statistical analysis title
    Median differences, days alive and outside, A vs D
    Statistical analysis description
    Median differences of days alive and outside of hospital.
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.55 [89]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    1
    Notes
    [89] - Level of significance p = 0.05.
    Statistical analysis title
    Median differences, days alive and outside, B vs C
    Statistical analysis description
    Median differences of days alive and outside of hospital.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.69 [90]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    2
    Notes
    [90] - Level of significance p = 0.05.
    Statistical analysis title
    Median differences, days alive and outside, B vs D
    Statistical analysis description
    Median differences of days alive and outside of hospital.
    Comparison groups
    Treatment B v Treatment D
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.94 [91]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    1
    Notes
    [91] - Level of significance p = 0.05.
    Statistical analysis title
    Median differences, days alive and outside, C vs D
    Statistical analysis description
    Median differences of days alive and outside of hospital.
    Comparison groups
    Treatment D v Treatment C
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.56 [92]
    Method
    Generalized estimating equation (GEE)
    Parameter type
    Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    1
    Notes
    [92] - Level of significance p = 0.05.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From operation to 90 days postoperatively.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    ICH-GCP
    Dictionary version
    Revision 2
    Reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    Paracetamol 1g + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Reporting group title
    Treatment B
    Reporting group description
    Paracetamol 1g + placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Reporting group title
    Treatment C
    Reporting group description
    Placebo + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Reporting group title
    Treatment D
    Reporting group description
    Paracetamol 0,5 g + ibuprofen 200 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative.

    Serious adverse events
    Treatment A Treatment B Treatment C Treatment D
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 136 (18.38%)
    15 / 142 (10.56%)
    20 / 139 (14.39%)
    18 / 139 (12.95%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Deep venous thrombosis (CVT)
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 142 (0.00%)
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Unknown
         subjects affected / exposed
    5 / 136 (3.68%)
    4 / 142 (2.82%)
    3 / 139 (2.16%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Mechanical problems with the prosthesis
         subjects affected / exposed
    5 / 136 (3.68%)
    4 / 142 (2.82%)
    3 / 139 (2.16%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiological
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 142 (0.70%)
    3 / 139 (2.16%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Low hemoglobin
         subjects affected / exposed
    2 / 136 (1.47%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 142 (0.00%)
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Delirium
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture, not anatomical related
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Surgical site infection
         subjects affected / exposed
    5 / 136 (3.68%)
    4 / 142 (2.82%)
    5 / 139 (3.60%)
    4 / 139 (2.88%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection, not anatomical related
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment A Treatment B Treatment C Treatment D
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 136 (14.71%)
    23 / 142 (16.20%)
    22 / 139 (15.83%)
    21 / 139 (15.11%)
    Surgical and medical procedures
    Hot flush when using PCA-morphine
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    2 / 139 (1.44%)
    1 / 139 (0.72%)
         occurrences all number
    0
    0
    2
    1
    Leaking from surgical site
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Transfer to an other hospital
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vasovagal episode during anesthesia
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences all number
    0
    0
    0
    1
    Low blood pressure
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    3 / 139 (2.16%)
    0 / 139 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Blood and lymphatic system disorders
    Low hemoglobin
         subjects affected / exposed
    3 / 136 (2.21%)
    0 / 142 (0.00%)
    2 / 139 (1.44%)
    2 / 139 (1.44%)
         occurrences all number
    3
    0
    2
    2
    Nervous system disorders
    Confusion
         subjects affected / exposed
    2 / 136 (1.47%)
    3 / 142 (2.11%)
    4 / 139 (2.88%)
    1 / 139 (0.72%)
         occurrences all number
    2
    3
    4
    1
    Headache
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sleep disorder
         subjects affected / exposed
    1 / 136 (0.74%)
    2 / 142 (1.41%)
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Vasovagal episode during mobilization
         subjects affected / exposed
    1 / 136 (0.74%)
    3 / 142 (2.11%)
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences all number
    1
    3
    1
    0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    3 / 136 (2.21%)
    4 / 142 (2.82%)
    1 / 139 (0.72%)
    5 / 139 (3.60%)
         occurrences all number
    3
    4
    1
    5
    Incontinence (stool)
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences all number
    0
    1
    0
    1
    Ructus
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences all number
    0
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences all number
    0
    1
    0
    1
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    0 / 139 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Elevated creatinin
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences all number
    0
    0
    1
    1
    Product issues
    Pain when using PCA-morphine
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Itching, PCA
         subjects affected / exposed
    7 / 136 (5.15%)
    5 / 142 (3.52%)
    3 / 139 (2.16%)
    2 / 139 (1.44%)
         occurrences all number
    7
    5
    3
    2
    Musculoskeletal and connective tissue disorders
    Fall
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    0 / 139 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Not mobilized
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences all number
    0
    1
    0
    1
    Shivering
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
    0 / 139 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Syncope during mobilization
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    0 / 139 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Endocrine disorders
    Low potassium
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Fever
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences all number
    0
    1
    1
    0

    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/30747964
    http://www.ncbi.nlm.nih.gov/pubmed/31648374
    http://www.ncbi.nlm.nih.gov/pubmed/32270482
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