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    Clinical Trial Results:
    Single centre randomised controlled trial to assess the effect of the addition of twenty-four hours of oral tranexamic acid post-operatively to a single intra-operative intravenous dose of tranexamic acid on calculated blood loss following primary hip and knee arthroplasty.

    Summary
    EudraCT number
    		 2015-002661-36
    Trial protocol
    		 GB  
    Global end of trial date
    08 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Dec 2020
    First version publication date
    19 Dec 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    15039DB-SW
    Additional study identifiers
    ISRCTN number
    		 ISRCTN58790500
    US NCT number
    		 NCT03690037
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Belfast Health and Social Care Trust (BHSCT)
    Sponsor organisation address
    The Royal Hospitals Grosvenor Road, Belfast, United Kingdom, BT12 6BN
    Public contact
    Janet Hill, Primary Joint Unit, Musgrave Park Hospital, +44 028 9504 1753, Janet.Hill@belfasttrust.hscni.net
    Scientific contact
    Professor David Beverland, Primary Joint Unit, Musgrave Park Hospital, +44 07736679869 , david.beverland@belfasttrust.hscni.net
    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
    17 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to determine if the use of oral tranexamic acid post-operatively for up to 24 hours will confer a reduction in calculated blood loss at 48 hours beyond an intra-operative intravenous bolus alone for patients undergoing unilateral primary total hip or knee replacement.
    Protection of trial subjects
    This study investigated the efficacy in using tranexamic acid (TXA) in primary hip and knee arthroplasty and did not subject the patient to any unnecessary risk, pain or discomfort. A risk assessment was carried out by Sponsor prior to trial initiation and a comprehensive exclusion criteria was put in place while patients were also monitored for renal impairment before being prescribed the study drug. An independent Trial Steering Committee (TSC) and Data Monitoring and Ethics Committee (DMEC) were also convened to monitor and guide overall progress while protecting the rights and safety of trial patients.
    Background therapy
    		 All the intervention groups will have primary hip or knee arthroplasty.
    Evidence for comparator
    		 Reducing blood loss after hip and knee arthroplasty helps patients avoid anaemia and allogenic blood transfusion with their incumbent risks. Tranexamic acid (TXA) is effective at reducing blood loss in elective joint arthroplasty, but there is no accepted protocol for the most effective way to administer TXA. It remains unclear as to whether extending a dosing regime of TXA beyond the immediate perioperative period would lead to further reductions in blood loss. Oral TXA would be a cheaper and less labour intensive mode of delivery post-operatively than either intravenous bolus or intravenous infusion regimes. TRAC-24 aims aim to maximise the potential of TXA by continuing administration post-operatively, at the time of greatest loss. The efficacy of TXA will be assessed in a large group of patients, including those at risk of venous or atrierial thrombotic events, undergoing primary hip or knee arthroplasty. This study will allocate patients to one of three groups, two TXA intervention groups (Groups 1 & 2) and one non-treatment group (Control Group 3). Randomisation to Group 3 was stopped after the Interim Analysis following DMEC recommendations. The primary objective of TRAC-24 is to determine if the use of oral tranexamic acid post-operatively for up to 24h hours will confer a reduction in calculated blood loss at 48 hours beyond an intra-operative intravenous bolus alone for patients undergoing unilateral primary total hip or knee replacement. The secondary objective is to determine if the addition of oral TXA post-operatively to an intra-operative intravenous bolus of TXA produces any change in other measurable parameters as compared to those observed either with an intra-operative intravenous bolus alone or no TXA for patients undergoing unilateral primary THA/TKA.
    Actual start date of recruitment
    07 Jul 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Scientific research
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 1086
    Worldwide total number of subjects
    1086
    EEA total number of subjects
    1086
    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)
    402
    From 65 to 84 years
    662
    85 years and over
    22

    Subject disposition

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    Recruitment
    Recruitment details
    		 TRAC-24 is a single site study, opened at Primary Joint Unit, Musgrave Park Hospital Belfast in June 2016. Recruitment started in July 2016 and was completed in July 2019.

    Pre-assignment
    Screening details
    		 Patients were screened for eligibility based on the inclusion/exclusion criteria outlined in trial protocol. Eligibility was confirmed by a medically qualified doctor and the inclusion criteria related to those awaiting primary elective hip or knee replacement within the age group of >18 years of age and ≤100 years.

    Pre-assignment period milestones
    Number of subjects started
    		 1554 [1]
    Number of subjects completed
    		 1086

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Inclusion/Exclusion criteria not met: 468
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1086 patients enrolled as per the worldwide number enrolled. Pre-assignment period (i.e. Screening) - number started 1554 with 1086 completed (i.e. 1086 enrolled at the end of screening)
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Anaesthetists, surgeons, other theatre, recovery and ward staff will not be blinded to the treatment, nor will the study investigators or the patient themselves. Ward staff, recovery staff and patients will be aware of which group each trial patient is in namely; intervention group 1, intervention group 2 or control group 3.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention Group 1
    Arm description
    		 1g IV TXA peri-operatively plus 1g oral TXA every 8hrs for up to 24hrs
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tranexamic acid
    Investigational medicinal product code
    Other name
    TXA
    Pharmaceutical forms
    Tablet, Solution for injection/infusion
    Routes of administration
    Oral use, Intravenous bolus use
    Dosage and administration details
    The IV dose 1g should be administered intra-operatively by slow intravenous injection at 0h within 30 minutes before KTS, and oral 1g doses should be administered within a ±2 hour window at 2h, 10h, 18h and 26h. For patients with raised creatinine levels; 120-249 µmol/L administer TXA IV 0.5g at 0h, TXA oral 0.5g at 2h, 10h, 18h and 26h, 250 – 499 µmol/L administer TXA IV 0.5g at 0h, TXA oral 0.5g at 10h and 26h, and for ≥500 µmol/L administer TXA IV 0.5g at 0h, TXA oral 0.5g at 26h.

    Arm title
    		 Intervention Group 2
    Arm description
    		 Intra-operative IV TXA within 30 mins before KTS or application of tourniquet. Patients with a renal impairment will receive a reduced dose dependent on pre- operative serum creatinine.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tranexamic acid
    Investigational medicinal product code
    Other name
    TXA
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    The IV dose 1g should be administered intra-operatively by slow intravenous injection at 0h within 30 minutes before KTS. For patients with raised creatinine levels ≥120 µmol/L administer TXA IV 0.5g at 0h.

    Arm title
    		 Control Group 3
    Arm description
    		 Standard care_no intervention
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Intervention Group 1 Intervention Group 2 Control Group 3
    Started
    474
    478
    134
    Completed
    473
    478
    134
    Not completed
    1
    0
    0
         Patient ineligible, randomised in error
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention Group 1
    Reporting group description
    		 1g IV TXA peri-operatively plus 1g oral TXA every 8hrs for up to 24hrs

    Reporting group title
    Intervention Group 2
    Reporting group description
    		 Intra-operative IV TXA within 30 mins before KTS or application of tourniquet. Patients with a renal impairment will receive a reduced dose dependent on pre- operative serum creatinine.

    Reporting group title
    Control Group 3
    Reporting group description
    		 Standard care_no intervention

    Reporting group values
    		 Intervention Group 1 Intervention Group 2 Control Group 3 Total
    Number of subjects
    		 474 478 134 1086
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 181 170 51 402
        From 65-84 years
    		 284 297 81 662
        85 years and over
    		 9 11 2 22
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.1 ( 10.4 ) 68.0 ( 10.4 ) 67.4 ( 10.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 255 278 76 609
        Male
    		 218 200 58 476
        Not Recorded
    		 1 0 0 1
    Pre-op Creatinine Level
    Units: Subjects
        Normal (<120 µmol/L)
    		 456 460 128 1044
        High A (120-249 µmol/L)
    		 17 17 5 39
        High B (250-499 µmol/L)
    		 0 1 0 1
        High C (≥500 µmol/L)
    		 0 0 1 1
        Not Recorded
    		 1 0 0 1
    Surgeon
    Units: Subjects
        David Beverland
    		 244 248 72 564
        Seamus O’Hagan
    		 123 122 33 278
        Dennis Molloy
    		 51 50 16 117
        Brian Mockford
    		 55 58 13 126
        Not Recorded
    		 1 0 0 1
    Joint
    Units: Subjects
        Hip
    		 233 235 66 534
        Knee
    		 240 243 68 551
        Not Recorded
    		 1 0 0 1
    History of IHD
    Units: Subjects
        Yes
    		 69 60 13 142
        No
    		 402 418 121 941
        Not Recorded
    		 3 0 0 3
    History of COPD
    Units: Subjects
        Yes
    		 34 32 5 71
        No
    		 437 446 129 1012
        Not Recorded
    		 3 0 0 3
    Is the patient a smoker?
    Units: Subjects
        Yes
    		 49 40 10 99
        No
    		 422 438 124 984
        Not Recorded
    		 3 0 0 3
    History of VTE
    Units: Subjects
        Yes
    		 24 18 9 51
        No
    		 447 460 125 1032
        Not Recorded
    		 3 0 0 3
    History of MI
    Units: Subjects
        Yes
    		 37 28 7 72
        No
    		 434 450 127 1011
        Not Recorded
    		 3 0 0 3
    History of Cardiac Stent
    Units: Subjects
        Yes
    		 29 30 4 63
        No
    		 442 448 130 1020
        Not Recorded
    		 3 0 0 3
    History of TI
    Units: Subjects
        Yes
    		 17 15 6 38
        No
    		 454 463 128 1045
        Not Recorded
    		 3 0 0 3
    History of Stroke
    Units: Subjects
        Yes
    		 5 6 1 12
        No
    		 466 472 133 1071
        Not Recorded
    		 3 0 0 3
    Diabetes
    Units: Subjects
        Yes
    		 51 76 22 149
        No
    		 420 402 112 934
        Not Recorded
    		 3 0 0 3
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 31.4 ( 5.4 ) 31.4 ( 5.9 ) 31.6 ( 5.5 ) -
    Pre-op Haemoglobin
    Units: g/L
        arithmetic mean (standard deviation)
    		 137.1 ( 13.6 ) 135.7 ( 13.1 ) 136.7 ( 12.5 ) -
    Pre-op Haematocrit
    Units: L/L
        arithmetic mean (standard deviation)
    		 0.41 ( 0.04 ) 0.40 ( 0.04 ) 0.40 ( 0.03 ) -
    Pre-op Platelets
    Units: mm³
        arithmetic mean (standard deviation)
    		 255.6 ( 66.0 ) 260.7 ( 65.4 ) 253.9 ( 59.5 ) -
    Pre-op CRP
    Units: mg/l
        arithmetic mean (standard deviation)
    		 4.6 ( 6.6 ) 4.8 ( 8.1 ) 5.5 ( 9.6 ) -
    Pre-op Creatinine Level
    Units: µmol/L
        arithmetic mean (standard deviation)
    		 82.0 ( 19.6 ) 82.2 ( 21.1 ) 85.2 ( 52.9 ) -
    Pre-op OHS
    Units: N/A
        arithmetic mean (standard deviation)
    		 46.6 ( 6.8 ) 46.6 ( 7.3 ) 45.4 ( 6.0 ) -
    Pre-op OKS
    Units: N/A
        arithmetic mean (standard deviation)
    		 44.4 ( 6.8 ) 44.9 ( 6.8 ) 45.3 ( 6.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Intervention Group 1
    Reporting group description
    		 1g IV TXA peri-operatively plus 1g oral TXA every 8hrs for up to 24hrs

    Reporting group title
    Intervention Group 2
    Reporting group description
    		 Intra-operative IV TXA within 30 mins before KTS or application of tourniquet. Patients with a renal impairment will receive a reduced dose dependent on pre- operative serum creatinine.

    Reporting group title
    Control Group 3
    Reporting group description
    		 Standard care_no intervention

    Primary: Primary Outcome

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    End point title
    		 Primary Outcome
    End point description
    Indirect blood loss at 48 hours
    End point type
    Primary
    End point timeframe
    48 Hours
    End point values
    		 Intervention Group 1 Intervention Group 2 Control Group 3
    Number of subjects analysed
    456
    454
    133
    Units: Millilitres
        arithmetic mean (standard deviation)
    790.4 ( 428.8 )
    851.7 ( 423.1 )
    1282.4 ( 592.0 )
    Statistical analysis title
    		 All Patients - 1vs2
    Comparison groups
    Intervention Group 1 v Intervention Group 2
    Number of subjects included in analysis
    910
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -61.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -116.7
         upper limit
    		 -5.8
    Statistical analysis title
    		 All Patients - 1vs2 (Adjusted)
    Statistical analysis description
    adjusted for age, weight, surgeon and recruitment period
    Comparison groups
    Intervention Group 1 v Intervention Group 2
    Number of subjects included in analysis
    910
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -71.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -124.7
         upper limit
    		 -18.5
    Statistical analysis title
    		 All Patients - 1vs2vs3
    Comparison groups
    Intervention Group 1 v Intervention Group 2 v Control Group 3
    Number of subjects included in analysis
    1043
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 All Patients - combined vs 3
    Comparison groups
    Intervention Group 1 v Intervention Group 2 v Control Group 3
    Number of subjects included in analysis
    1043
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    461.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 379.2
         upper limit
    		 534.6
    Notes
    [1] - Comparing the primary outcome for both intervention groups combined against the control group

    Secondary: Secondary: Incidence of post-operative Hb falling below the transfusion trigger (irrespective of transfusion) prior to discharge

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    End point title
    		 Secondary: Incidence of post-operative Hb falling below the transfusion trigger (irrespective of transfusion) prior to discharge
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to discharge
    End point values
    		 Intervention Group 1 Intervention Group 2 Control Group 3
    Number of subjects analysed
    471
    476
    134
    Units: Numbers
    16
    28
    12
    Statistical analysis title
    		 All Patients - 1vs2vs3
    Comparison groups
    Intervention Group 1 v Intervention Group 2 v Control Group 3
    Number of subjects included in analysis
    1081
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025 [2]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [2] - post-hoc comparison of group 1 vs group 2 p=0.07

    Secondary: Secondary: Change in Creatinine level pre-surgery to 48 hours post-surgery

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    End point title
    		 Secondary: Change in Creatinine level pre-surgery to 48 hours post-surgery
    End point description
    End point type
    Secondary
    End point timeframe
    48 hours post-surgery
    End point values
    		 Intervention Group 1 Intervention Group 2 Control Group 3
    Number of subjects analysed
    461
    453
    131
    Units: µmol/l
        arithmetic mean (standard deviation)
    -2.9 ( 10.8 )
    -3.2 ( 12.5 )
    -2.5 ( 12.6 )
    Statistical analysis title
    		 All Patients - 1vs2vs3
    Statistical analysis description
    Change is calculated as 48hr minus pre-op.
    Comparison groups
    Intervention Group 2 v Control Group 3 v Intervention Group 1
    Number of subjects included in analysis
    1045
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.81
    Method
    		 ANOVA
    Confidence interval

    Secondary: Secondary: 90 day mortality

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    End point title
    		 Secondary: 90 day mortality
    End point description
    End point type
    Secondary
    End point timeframe
    90 day
    End point values
    		 Intervention Group 1 Intervention Group 2 Control Group 3
    Number of subjects analysed
    471
    476
    134
    Units: Number
    1
    0
    1
    Statistical analysis title
    		 All Patients - 1vs2vs3
    Comparison groups
    Intervention Group 1 v Intervention Group 2 v Control Group 3
    Number of subjects included in analysis
    1081
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Secondary: 1 year mortality

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    End point title
    		 Secondary: 1 year mortality
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Intervention Group 1 Intervention Group 2 Control Group 3
    Number of subjects analysed
    471
    476
    134
    Units: Number
    5
    3
    3
    Statistical analysis title
    		 All Patients- 1vs2vs3
    Comparison groups
    Intervention Group 1 v Intervention Group 2 v Control Group 3
    Number of subjects included in analysis
    1081
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Secondary: Change in c-reactive protein pre-surgery to 48 hours post-surgery

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    End point title
    		 Secondary: Change in c-reactive protein pre-surgery to 48 hours post-surgery
    End point description
    End point type
    Secondary
    End point timeframe
    48 hours post-surgery
    End point values
    		 Intervention Group 1 Intervention Group 2 Control Group 3
    Number of subjects analysed
    428
    411
    115
    Units: mg/l
        arithmetic mean (standard deviation)
    119.6 ( 80.9 )
    113.0 ( 75.9 )
    111.1 ( 68.4 )
    Statistical analysis title
    		 All Patients - 1vs2vs3
    Comparison groups
    Intervention Group 1 v Intervention Group 2 v Control Group 3
    Number of subjects included in analysis
    954
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 ANOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The AE reporting period for the trial begins upon enrolment into the trial and ends 30 days following the last administration of the study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Intervention Group 1
    Reporting group description
    		 1g IV TXA peri-operatively plus 1g oral TXA every 8hrs for up to 24hrs

    Reporting group title
    Intervention Group 2
    Reporting group description
    		 Intra-operative IV TXA within 30 mins before KTS or application of tourniquet. Patients with a renal impairment will receive a reduced dose dependent on pre- operative serum creatinine.

    Reporting group title
    Control Group 3
    Reporting group description
    		 Standard care_no intervention

    Serious adverse events
    		 Intervention Group 1 Intervention Group 2 Control Group 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 473 (8.03%)
    50 / 478 (10.46%)
    19 / 134 (14.18%)
         number of deaths (all causes)
    5
    3
    3
         number of deaths resulting from adverse events
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic mass and multiple liver metastases
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hematoma
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thromboembolic Event
         subjects affected / exposed
    1 / 473 (0.21%)
    3 / 478 (0.63%)
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Implant Malposition
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    0 / 473 (0.00%)
    3 / 478 (0.63%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 473 (0.42%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Other-General Disorders and Administration Site Conditions
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 473 (0.21%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Other - Psychiatric Disorders
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip dislocation
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Fracture
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound Complication
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Other - Injury, poisoning and procedural complications
         subjects affected / exposed
    1 / 473 (0.21%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Heart Failure
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Other - Cardiac Disorders
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Other-Nervous System Disorders
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 473 (0.42%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    3 / 473 (0.63%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic Perforation
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Constipation
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal Obstruction
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large Bowel Obstruction
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 473 (0.21%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney injury
         subjects affected / exposed
    2 / 473 (0.42%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hematuria
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uriary Retention
         subjects affected / exposed
    1 / 473 (0.21%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bruising
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dislocation
         subjects affected / exposed
    2 / 473 (0.42%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint Effusion
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint Range of Motion Decreased
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Joint Infection
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    0 / 473 (0.00%)
    3 / 478 (0.63%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    3 / 473 (0.63%)
    2 / 478 (0.42%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesemia
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    13 / 473 (2.75%)
    16 / 478 (3.35%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 16
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Other - Metabolism and Nutrition
         subjects affected / exposed
    1 / 473 (0.21%)
    2 / 478 (0.42%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intervention Group 1 Intervention Group 2 Control Group 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    294 / 473 (62.16%)
    311 / 478 (65.06%)
    79 / 134 (58.96%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 473 (0.42%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    2
    0
    0
    Hypervolemia
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Hypotension
         subjects affected / exposed
    3 / 473 (0.63%)
    6 / 478 (1.26%)
    2 / 134 (1.49%)
         occurrences all number
    3
    6
    2
    Thromboembolic event
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    0
    1
    Non Cardiac Chest Pain
         subjects affected / exposed
    3 / 473 (0.63%)
    4 / 478 (0.84%)
    3 / 134 (2.24%)
         occurrences all number
    3
    4
    3
    Oedema Limbs
         subjects affected / exposed
    0 / 473 (0.00%)
    2 / 478 (0.42%)
    0 / 134 (0.00%)
         occurrences all number
    0
    2
    0
    Pain
         subjects affected / exposed
    1 / 473 (0.21%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    1
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Wound infection
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Immune system disorders
    Allergic Reaction
         subjects affected / exposed
    2 / 473 (0.42%)
    2 / 478 (0.42%)
    1 / 134 (0.75%)
         occurrences all number
    2
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 473 (0.21%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    1
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Hiccups
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoxemia
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoxia
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Sleep Apnea
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    8 / 473 (1.69%)
    3 / 478 (0.63%)
    0 / 134 (0.00%)
         occurrences all number
    8
    3
    0
    Delirium
         subjects affected / exposed
    2 / 473 (0.42%)
    5 / 478 (1.05%)
    0 / 134 (0.00%)
         occurrences all number
    2
    5
    0
    Investigations
    Echocardiography
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Ultrasound Liver
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    9 / 473 (1.90%)
    11 / 478 (2.30%)
    2 / 134 (1.49%)
         occurrences all number
    10
    11
    2
    Fracture
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Prosthesis Subluxation
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Subluxation
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Wound Complication
         subjects affected / exposed
    1 / 473 (0.21%)
    1 / 478 (0.21%)
    1 / 134 (0.75%)
         occurrences all number
    1
    1
    1
    Wound Dehiscence
         subjects affected / exposed
    1 / 473 (0.21%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    1
    1
    0
    Cardiac disorders
    Atrial Fibrilation
         subjects affected / exposed
    3 / 473 (0.63%)
    3 / 478 (0.63%)
    3 / 134 (2.24%)
         occurrences all number
    3
    3
    3
    Chest Pain - Cardiac
         subjects affected / exposed
    1 / 473 (0.21%)
    2 / 478 (0.42%)
    1 / 134 (0.75%)
         occurrences all number
    1
    2
    1
    Ectopics
         subjects affected / exposed
    2 / 473 (0.42%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    2
    0
    0
    Hypotension
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Ischemia
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus Bradycardia
         subjects affected / exposed
    8 / 473 (1.69%)
    9 / 478 (1.88%)
    2 / 134 (1.49%)
         occurrences all number
    8
    9
    2
    Sinus Tachycardia
         subjects affected / exposed
    7 / 473 (1.48%)
    8 / 478 (1.67%)
    0 / 134 (0.00%)
         occurrences all number
    7
    8
    0
    Tachycardia
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Ventricular arrhythmia
         subjects affected / exposed
    4 / 473 (0.85%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    4
    0
    0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    19 / 473 (4.02%)
    25 / 478 (5.23%)
    4 / 134 (2.99%)
         occurrences all number
    19
    25
    4
    Dizziness/Vasovagal Reaction
         subjects affected / exposed
    10 / 473 (2.11%)
    19 / 478 (3.97%)
    1 / 134 (0.75%)
         occurrences all number
    10
    19
    1
    Headache
         subjects affected / exposed
    1 / 473 (0.21%)
    3 / 478 (0.63%)
    0 / 134 (0.00%)
         occurrences all number
    1
    3
    0
    Memory impairment
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    0
    1
    Nervous System Disorder
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Other - Non specific Numbness
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 473 (0.21%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    1
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Tremor
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Vasovagal Reaction
         subjects affected / exposed
    57 / 473 (12.05%)
    60 / 478 (12.55%)
    22 / 134 (16.42%)
         occurrences all number
    57
    61
    23
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 473 (0.63%)
    6 / 478 (1.26%)
    9 / 134 (6.72%)
         occurrences all number
    3
    10
    11
    Eye disorders
    Blurred Vision
         subjects affected / exposed
    2 / 473 (0.42%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    2
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Anal Haemorrhage
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    2 / 473 (0.42%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    2
    1
    0
    Diarrhea
         subjects affected / exposed
    4 / 473 (0.85%)
    3 / 478 (0.63%)
    1 / 134 (0.75%)
         occurrences all number
    4
    3
    1
    Dry Mouth
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    3 / 473 (0.63%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    4
    0
    0
    Gastric Haemorrhage
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Gastroesophageal Reflux Disease
         subjects affected / exposed
    0 / 473 (0.00%)
    3 / 478 (0.63%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    Nausea
         subjects affected / exposed
    93 / 473 (19.66%)
    100 / 478 (20.92%)
    22 / 134 (16.42%)
         occurrences all number
    93
    100
    28
    Nausea/Vomiting
         subjects affected / exposed
    52 / 473 (10.99%)
    60 / 478 (12.55%)
    13 / 134 (9.70%)
         occurrences all number
    52
    60
    13
    Vomiting
         subjects affected / exposed
    19 / 473 (4.02%)
    25 / 478 (5.23%)
    6 / 134 (4.48%)
         occurrences all number
    19
    25
    6
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    27 / 473 (5.71%)
    25 / 478 (5.23%)
    1 / 134 (0.75%)
         occurrences all number
    27
    25
    1
    Allergic Reaction
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 478 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    11 / 473 (2.33%)
    12 / 478 (2.51%)
    4 / 134 (2.99%)
         occurrences all number
    11
    12
    4
    Haematuria
         subjects affected / exposed
    1 / 473 (0.21%)
    2 / 478 (0.42%)
    1 / 134 (0.75%)
         occurrences all number
    1
    2
    1
    Poor Urinary output
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary Retention
         subjects affected / exposed
    1 / 473 (0.21%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Bruising
         subjects affected / exposed
    1 / 473 (0.21%)
    2 / 478 (0.42%)
    0 / 134 (0.00%)
         occurrences all number
    1
    2
    0
    Dislocation
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    2
    0
    0
    Hip Pain
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 473 (0.00%)
    2 / 478 (0.42%)
    0 / 134 (0.00%)
         occurrences all number
    0
    2
    0
    Infections and infestations
    Joint Infection
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 478 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    Lower respiratory infections
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Lung Infection
         subjects affected / exposed
    3 / 473 (0.63%)
    4 / 478 (0.84%)
    2 / 134 (1.49%)
         occurrences all number
    3
    4
    2
    Paronychia
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Skin Infection
         subjects affected / exposed
    2 / 473 (0.42%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    2
    1
    0
    Upper Respiratory Infections
         subjects affected / exposed
    1 / 473 (0.21%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 473 (0.00%)
    2 / 478 (0.42%)
    0 / 134 (0.00%)
         occurrences all number
    0
    2
    0
    Wound Infection
         subjects affected / exposed
    1 / 473 (0.21%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    1
    1
    0
    Metabolism and nutrition disorders
    Hyperkalemia
         subjects affected / exposed
    0 / 473 (0.00%)
    1 / 478 (0.21%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalemia
         subjects affected / exposed
    2 / 473 (0.42%)
    1 / 478 (0.21%)
    2 / 134 (1.49%)
         occurrences all number
    2
    1
    2
    Hyponatremia
         subjects affected / exposed
    22 / 473 (4.65%)
    23 / 478 (4.81%)
    10 / 134 (7.46%)
         occurrences all number
    23
    23
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jul 2016
    An amendment to protocol to include clarification of the background and equations for the total indirect blood loss, changes made to the screening procedure for patient recruitment and addition of details for the interim analysis.
    03 Feb 2017
    An amendment to the protocol was submitted as an action following an Urgent Safety Measure (procedures to ensure that all blood results are clinically reviewed, changes to exclusion criteria, details of co-investigators, logistics of obtaining research blood samples and clarification of additional blood tests.
    22 Jun 2017
    This protocol change was to address the DMEC recommendation to terminate the randomisation of pateints to Control Group 3 of the study.
    18 Sep 2018
    An amendment to for cater for the request access to patient records held on electronically retrospectively and in the future.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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