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    Clinical Trial Results:
    A randomized, double-blind, placebo and active-controlled, parallel-group study to evaluate the analgesic efficacy and safety of dexketoprofen trometamol and tramadol hydrochloride oral fixed combination on moderate to severe acute pain after elective unilateral total hip arthroplasty.

    Summary
    EudraCT number
    		 2012-004548-31
    Trial protocol
    		 CZ   ES   HU   LV   LT   PL  
    Global end of trial date
    05 Feb 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Mar 2017
    First version publication date
    25 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DEX-TRA-05
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01902134
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Menarini Ricerche, S.p.A.
    Sponsor organisation address
    via sette santi, 1, Florence, Italy, 50131
    Public contact
    Clinical Research Corporate Director, Menarini Ricerche S.p.A., +39 05556809933, ACapriati@menarini-ricerche.it
    Scientific contact
    Clinical Research Corporate Director, Menarini Ricerche S.p.A., +39 05556809933, ACapriati@menarini-ricerche.it
    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
    24 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the analgesic efficacy of oral dexketoprofen trometamol (DKP.TRIS) and tramadol hydrochloride (TRAM.HCl) fixed combination on moderate to severe pain after elective hip arthroplasty.
    Protection of trial subjects
    If any event(s) related to the conduct of the study or the development of the IMP affects the safety of the study participants, the Sponsor and the Investigator will take appropriate urgent safety measures to protect the patients against any immediate hazard. The CAs and IRB/ECs will be informed forthwith about these new events and the measures taken. For patients participating in the study, Menarini Ricerche S.p.A. has stipulated an insurance policy in accordance with local regulatory requirements. Details on the insurance company, the insurance number and conditions will be made available to patients in the ICF and/or provided as a separate document, in accordance with national requirements. According to the results from phase I and phase II studies, the tested fixed-combination is expected to provide adequate pain relief for the participating patients without raising any safety concerns. In addition, patients will be hospitalized for the entire study treatment duration and monitoring of AEs will be conducted during this period. Upon discharge, they will be instructed to contact the site immediately in case of any medical emergency.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Serbia: 62
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Ukraine: 56
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Czech Republic: 36
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 204
    Country: Number of subjects enrolled
    Latvia: 153
    Country: Number of subjects enrolled
    Lithuania: 84
    Worldwide total number of subjects
    641
    EEA total number of subjects
    516
    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)
    367
    From 65 to 84 years
    274
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was screened on 30th April 2013 and; the first patient randomized on 7th May 2013. The last patient completed the study on 5th February 2014. The study was conducted at 44 study centers in 10 countries (Czech Republic, Germany, Hungary, Latvia, Lithuania, Poland, Serbia, Spain, Taiwan, and Ukraine).

    Pre-assignment
    Screening details
    		 A total of 746 patients were screened and 641 of them were randomized (screening failure rate: 14.1%). The enrollment was competitive.

    Period 1
    Period 1 title
    Screening
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Screening
    Arm description
    		 Screening period, for study eligibility assessment (within 4 weeks prior to randomization). 746 patients were screened and 105 of them were screening failure.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Screening
    Started
    641
    Completed
    641
    Period 2
    Period 2 title
    Treatment and assessment period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Eligible patients were randomized in a 3:3:3:1:1:1 ratio to 1 of the 6 possible treatment arms, as per treatment code assigned by IVRS/IWRS in accordance with the randomisation list. DKP/TRAM and DKP were provided as film-coated tablet with matching appearance and weight. TRAM as two capsules of a marketed drug Contramal® 50mg. Placebos matching with both pharmaceutical forms were available to secure double-blind conditions by using a double-dummy technique.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DKP/TRAM followed by DKP/TRAM
    Arm description
    		 Single-dose phase: Patients received DKP.TRIS 25mg + TRAM.HCl 75mg. Single-dose treatment had to be administered on day 1. Multiple-dose phase: Patients received DKP.TRIS 25mg + TRAM.HCl 75mg. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations (every 8 hours). Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DKP/TRAM
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    DKP.TRIS 25mg + TRAM.HCl 75mg Treatment had to be orally administered, together with approximately 150 mg of still/tap water.

    Arm title
    		 DKP followed by DKP
    Arm description
    		 Single-dose phase: Patients received DKP.TRIS 25mg. Single dose treatment had to be administered on day 1. Multiple-dose phase: Patients received DKP.TRIS 25mg. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations (every 8 hours). Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    DKP
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    DKP.TRIS 25mg Treatment had to be orally administered, together with approximately 150 ml of still/tap water.

    Arm title
    		 TRAM followed by TRAM
    Arm description
    		 Single-dose phase: Patients received TRAM.HCl 100mg. Single-dose treatment had to be administered on day 1. Multiple-dose phase: Patients received TRAM.HCl 100mg. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations (every 8 hours). Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    TRAM
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    TRAM.HCl 100mg Treatment had to be orally administered, together with approximately 150ml of still/tap water.

    Arm title
    		 Placebo followed by DKP/TRAM
    Arm description
    		 Single-dose phase: Patients received Placebo (as one tablet matching DKP.TRIS 25mg + TRAM.HCl 75mg and matching DKP.TRIS 25mg and as two capsules matching TRAM.HCl 50mg). Multiple-dose phase: Placebo assigned patients were allocated to receive DKP.TRIS 25mg + TRAM.HCl 75mg, every 8 hours. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations. Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.
    Arm type
    		 Placebo + experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment had to be orally administered, together with approximately 150 ml of still/tap water.

    Investigational medicinal product name
    DKP/TRAM
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    DKP.TRIS 25mg + TRAM.HCl 75mg Treatment had to be orally administered, together with approximately 150ml of still/tap water.

    Arm title
    		 Placebo followed by DKP
    Arm description
    		 Single-dose phase: Patients received Placebo (as one tablet matching DKP.TRIS 25mg + TRAM.HCl 75mg and matching DKP.TRIS 25mg and as two capsules matching TRAM.HCl 50mg). Multiple-dose phase: Placebo assigned patients were allocated to receive DKP.TRIS 25mg, every 8 hours. Multiple-dose treatment had to be orally administered (starting 8 hours after single dose phase) up to the morning of day 5, for a total of 12 drug administrations. Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.
    Arm type
    		 Placebo + Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment had to be orally administered, together with approximately 150 ml of still/tap water.

    Investigational medicinal product name
    DKP
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment had to be orally administered, together with approximately 150 ml of still/tap water.

    Arm title
    		 Placebo followed by TRAM
    Arm description
    		 Single-dose phase: Patients received Placebo (as one tablet matching DKP.TRIS 25mg + TRAM.HCl 75mg and matching DKP.TRIS 25mg and as two capsules matching TRAM.HCl). Multiple-dose phase: Placebo assigned patients were allocated to receive two capsules of TRAM.HCl 50mg, every 8 hours. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations. Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.
    Arm type
    		 Placebo + Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment had to be orally administered, together with approximately 150 ml of still/tap water.

    Investigational medicinal product name
    TRAM
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment had to be orally administered, together with approximately 150 ml of still/tap water.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The individual study participation included a screening period (period 1) for study eligibility assessment, a treatment and assessment period (period 2), where during the single-dose phase, PI-VAS at rest and PI-VAS on movement were recorded as beaseline, i.e. immediately prior to the time of the first study drug administration (t0). Finally a end of study visit (period 3) for final follow-up.
    Number of subjects in period 2
    		DKP/TRAM followed by DKP/TRAM DKP followed by DKP TRAM followed by TRAM Placebo followed by DKP/TRAM Placebo followed by DKP Placebo followed by TRAM
    Started
    159
    161
    160
    54
    53
    54
    Completed
    151
    150
    145
    52
    46
    45
    Not completed
    8
    11
    15
    2
    7
    9
         Consent withdrawn by subject
    4
    8
    9
    1
    5
    4
         Physician decision
    -
    1
    -
    -
    -
    -
         Adverse event, non-fatal
    3
    1
    2
    1
    1
    3
         NA
    -
    1
    2
    -
    1
    -
         non compliance with study drug
    1
    -
    -
    -
    -
    -
         lack of efficacy
    -
    -
    2
    -
    -
    1
         Protocol deviation
    -
    -
    -
    -
    -
    1
    Period 3
    Period 3 title
    End of study visit
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Treatment blinding was kept for the entire study duration up to the closure of database performed after the last patient last visit.

    Arms
    Arm title
    		 End of study visit
    Arm description
    		 Treatment blinidng was kept for the entire study duration un to the closure of database performed after the last patient last visit.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		End of study visit
    Started
    589
    Completed
    589

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DKP/TRAM followed by DKP/TRAM
    Reporting group description
    		 Single-dose phase: Patients received DKP.TRIS 25mg + TRAM.HCl 75mg. Single-dose treatment had to be administered on day 1. Multiple-dose phase: Patients received DKP.TRIS 25mg + TRAM.HCl 75mg. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations (every 8 hours). Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    DKP followed by DKP
    Reporting group description
    		 Single-dose phase: Patients received DKP.TRIS 25mg. Single dose treatment had to be administered on day 1. Multiple-dose phase: Patients received DKP.TRIS 25mg. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations (every 8 hours). Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    TRAM followed by TRAM
    Reporting group description
    		 Single-dose phase: Patients received TRAM.HCl 100mg. Single-dose treatment had to be administered on day 1. Multiple-dose phase: Patients received TRAM.HCl 100mg. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations (every 8 hours). Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    Placebo followed by DKP/TRAM
    Reporting group description
    		 Single-dose phase: Patients received Placebo (as one tablet matching DKP.TRIS 25mg + TRAM.HCl 75mg and matching DKP.TRIS 25mg and as two capsules matching TRAM.HCl 50mg). Multiple-dose phase: Placebo assigned patients were allocated to receive DKP.TRIS 25mg + TRAM.HCl 75mg, every 8 hours. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations. Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    Placebo followed by DKP
    Reporting group description
    		 Single-dose phase: Patients received Placebo (as one tablet matching DKP.TRIS 25mg + TRAM.HCl 75mg and matching DKP.TRIS 25mg and as two capsules matching TRAM.HCl 50mg). Multiple-dose phase: Placebo assigned patients were allocated to receive DKP.TRIS 25mg, every 8 hours. Multiple-dose treatment had to be orally administered (starting 8 hours after single dose phase) up to the morning of day 5, for a total of 12 drug administrations. Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    Placebo followed by TRAM
    Reporting group description
    		 Single-dose phase: Patients received Placebo (as one tablet matching DKP.TRIS 25mg + TRAM.HCl 75mg and matching DKP.TRIS 25mg and as two capsules matching TRAM.HCl). Multiple-dose phase: Placebo assigned patients were allocated to receive two capsules of TRAM.HCl 50mg, every 8 hours. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations. Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group values
    		 DKP/TRAM followed by DKP/TRAM DKP followed by DKP TRAM followed by TRAM Placebo followed by DKP/TRAM Placebo followed by DKP Placebo followed by TRAM Total
    Number of subjects
    		 159 161 160 54 53 54 641
    Age categorical
    Units: Subjects
        From 18 to 80 years
    		 159 161 160 54 53 54 641
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 61.3 ( 10.43 ) 63.3 ( 9.01 ) 61.3 ( 9.68 ) 63.9 ( 9 ) 61 ( 11.1 ) 59.8 ( 11.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 86 86 80 37 33 24 346
        Male
    		 73 75 80 17 20 30 295
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 0 2 3 0 0 2 7
        White
    		 159 159 157 54 53 52 634
    Region of Enrollment
    Units: Subjects
        Serbia
    		 15 18 14 5 5 5 62
        Taiwan
    		 0 2 3 0 0 2 7
        Czech Republic
    		 9 10 8 2 4 3 36
        Hungary
    		 49 57 54 17 16 11 204
        Spain
    		 1 0 1 0 0 0 2
        Poland
    		 10 8 8 2 2 3 33
        Ukraine
    		 15 13 13 6 6 3 56
        Lithuania
    		 22 19 21 6 5 11 84
        Germany
    		 1 1 2 0 0 0 4
        Latvia
    		 37 33 36 16 15 16 153
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 83.3 ( 15.37 ) 81.4 ( 15.63 ) 83.5 ( 17.25 ) 82.4 ( 15.91 ) 81.7 ( 13.77 ) 82.1 ( 15.27 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 168.8 ( 8.99 ) 167.9 ( 9.14 ) 169.1 ( 9.2 ) 166.1 ( 8.47 ) 168 ( 9.49 ) 169.9 ( 7.94 ) -

    End points

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    End points reporting groups
    Reporting group title
    Screening
    Reporting group description
    		 Screening period, for study eligibility assessment (within 4 weeks prior to randomization). 746 patients were screened and 105 of them were screening failure.
    Reporting group title
    DKP/TRAM followed by DKP/TRAM
    Reporting group description
    		 Single-dose phase: Patients received DKP.TRIS 25mg + TRAM.HCl 75mg. Single-dose treatment had to be administered on day 1. Multiple-dose phase: Patients received DKP.TRIS 25mg + TRAM.HCl 75mg. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations (every 8 hours). Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    DKP followed by DKP
    Reporting group description
    		 Single-dose phase: Patients received DKP.TRIS 25mg. Single dose treatment had to be administered on day 1. Multiple-dose phase: Patients received DKP.TRIS 25mg. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations (every 8 hours). Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    TRAM followed by TRAM
    Reporting group description
    		 Single-dose phase: Patients received TRAM.HCl 100mg. Single-dose treatment had to be administered on day 1. Multiple-dose phase: Patients received TRAM.HCl 100mg. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations (every 8 hours). Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    Placebo followed by DKP/TRAM
    Reporting group description
    		 Single-dose phase: Patients received Placebo (as one tablet matching DKP.TRIS 25mg + TRAM.HCl 75mg and matching DKP.TRIS 25mg and as two capsules matching TRAM.HCl 50mg). Multiple-dose phase: Placebo assigned patients were allocated to receive DKP.TRIS 25mg + TRAM.HCl 75mg, every 8 hours. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations. Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    Placebo followed by DKP
    Reporting group description
    		 Single-dose phase: Patients received Placebo (as one tablet matching DKP.TRIS 25mg + TRAM.HCl 75mg and matching DKP.TRIS 25mg and as two capsules matching TRAM.HCl 50mg). Multiple-dose phase: Placebo assigned patients were allocated to receive DKP.TRIS 25mg, every 8 hours. Multiple-dose treatment had to be orally administered (starting 8 hours after single dose phase) up to the morning of day 5, for a total of 12 drug administrations. Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    Placebo followed by TRAM
    Reporting group description
    		 Single-dose phase: Patients received Placebo (as one tablet matching DKP.TRIS 25mg + TRAM.HCl 75mg and matching DKP.TRIS 25mg and as two capsules matching TRAM.HCl). Multiple-dose phase: Placebo assigned patients were allocated to receive two capsules of TRAM.HCl 50mg, every 8 hours. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations. Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.
    Reporting group title
    End of study visit
    Reporting group description
    		 Treatment blinidng was kept for the entire study duration un to the closure of database performed after the last patient last visit.

    Subject analysis set title
    DKP/TRAM
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Drug: Dexketoprofen/Tramadol single oral dose (first 8 hours); Arm type: experimental

    Subject analysis set title
    DEXKETOPROFEN
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Drug: Dexketoprofen single oral dose (first 8 hours); Arm type: active comparator;

    Subject analysis set title
    TRAMADOL
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Drug: Tramadol single oral dose (first 8 hours) Arm type: active comparator

    Subject analysis set title
    PLACEBO
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Drug: Placebo single oral dose (first 8 hours); Arm type: Placebo comparator

    Subject analysis set title
    DKP/TRAM
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Drug: Dexketoprofen/ Tramadol multiple doses; Arm type: experimental; Dexketoprofen/Tramadol multiple oral doses t.i.d. for 5 days (a total of 12 doses). This subject analysis set include patients who took DKP/TRAM at single dose phase plus 1/3 of patients who took Placebo at single dose phase.

    Subject analysis set title
    DEXKETOPROFEN
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Drug: Dexketoprofen multiple doses; Arm type: active comparator; Dexketoprofen multiple oral doses t.i.d. for 5 days ( a total of 12 doses). This subject analysis set include patients who took dexketoprofen at single dose phase plus 1/3 of patients who took Placebo at single dose phase.

    Subject analysis set title
    TRAMADOL
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Drug: Tramadol multiple doses; Arm type: active comparator; Tramadol multiple oral doses t.i.d. for 5 days (a total of 12 doses). This subject analysis set include patients who took tramadol at single dose phase plus 1/3 of patients who took Placebo at single dose phase.

    Primary: SPID8 (Sum of Pain Intensity Differences Over 8 Hours)

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    End point title
    		 SPID8 (Sum of Pain Intensity Differences Over 8 Hours)
    End point description
    Sum of Pain Intensity Differences calculated as the weighted sum of the PI-VAS differences over 8 hours period. PI-VAS corresponds to the pain intensity measured by a 0-100 visual analogue scale (0= no pain to 100=worst pain imaginable) which was measured at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h and 8h after the first dose. A higher value in SPID indicates greater pain relief. The analysis was performed combining all randomization arms including placebo into one group, which resulted in the following 4 analysis groups: DKP/TRAM, DEXKETOPROFEN, TRAMADOL and Placebo.
    End point type
    Primary
    End point timeframe
    over 8 hours after the first dose
    End point values
    		 DKP/TRAM DEXKETOPROFEN TRAMADOL PLACEBO
    Number of subjects analysed
    159
    161
    160
    161
    Units: units on a scale
        arithmetic mean (standard deviation)
    246.9 ( 156.5 )
    208.8 ( 154.69 )
    204.6 ( 145.79 )
    151.1 ( 158.51 )
    Statistical analysis title
    		 SPID8 at rest (DKP.TRIS + TRAM.HCl vs. DKP.TRIS)
    Statistical analysis description
    The null hypothesis of equality between DKP.TRIS + TRAM.HCl and DKP.TRIS and between DKP.TRIS + TRAM.HCl and TRAM.HCl was tested as co-primary efficacy endpoints using an analysis of covariance and a 2-sided overall significance of 5%. The two variables included as covariates in the ANCOVA model were treatment (as the main effect) and PI-level during screening.
    Comparison groups
    DKP/TRAM v DEXKETOPROFEN
    Number of subjects included in analysis
    320
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 standard error
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [1] - For all statistical analysis performed on data collected during the single-dose phase, the following treatment comparisons were presented: DKP.TRIS + TRAM.HCl vs. DKP.TRIS DKP.TRIS + TRAM.HCl vs. TRAM.HCl TRAM.HCl vs. Placebo DKP.TRIS vs. Placebo
    Statistical analysis title
    		 SPID8 at rest (DKP.TRIS + TRAM.HCl vs. TRAM.HCl)
    Statistical analysis description
    The null hypothesis of equality between DKP.TRIS + TRAM.HCl and DKP.TRIS and between DKP.TRIS + TRAM.HCl and TRAM.HCl was tested as co-primary efficacy endpoints using an analysis of covariance and a 2-sided overall significance of 5%. The two variables included as covariates in the ANCOVA model were treatment (as the main effect) and PI-level during screening.
    Comparison groups
    DKP/TRAM v TRAMADOL
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 standard error
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [2] - For all statistical analysis performed on data collected during the single-dose phase, the following treatment comparisons were presented: DKP.TRIS + TRAM.HCl vs. DKP.TRIS DKP.TRIS + TRAM.HCl vs. TRAM.HCl TRAM.HCl vs. Placebo DKP.TRIS vs. Placebo
    Statistical analysis title
    		 SPID8 at rest (TRAM.HCl vs. Placebo)
    Statistical analysis description
    The null hypothesis of equality between DKP.TRIS + TRAM.HCl and DKP.TRIS and between DKP.TRIS + TRAM.HCl and TRAM.HCl was tested as co-primary efficacy endpoints using an analysis of covariance and a 2-sided overall significance of 5%. The two variables included as covariates in the ANCOVA model were treatment (as the main effect) and PI-level during screening.
    Comparison groups
    PLACEBO v TRAMADOL
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 standard error
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [3] - For all statistical analysis performed on data collected during the single-dose phase, the following treatment comparisons were presented: DKP.TRIS + TRAM.HCl vs. DKP.TRIS DKP.TRIS + TRAM.HCl vs. TRAM.HCl TRAM.HCl vs. Placebo DKP.TRIS vs. Placebo
    Statistical analysis title
    		 SPID8 at rest (DKP.TRIS + Placebo)
    Statistical analysis description
    The null hypothesis of equality between DKP.TRIS + TRAM.HCl and DKP.TRIS and between DKP.TRIS + TRAM.HCl and TRAM.HCl was tested as co-primary efficacy endpoints using an analysis of covariance and a 2-sided overall significance of 5%. The two variables included as covariates in the ANCOVA model were treatment (as the main effect) and PI-level during screening.
    Comparison groups
    DEXKETOPROFEN v PLACEBO
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 standard error
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [4] - For all statistical analysis performed on data collected during the single-dose phase, the following treatment comparisons were presented: DKP.TRIS + TRAM.HCl vs. DKP.TRIS DKP.TRIS + TRAM.HCl vs. TRAM.HCl TRAM.HCl vs. Placebo DKP.TRIS vs. Placebo

    Secondary: SPID48 (Sum of Pain Intensity Differences Over 48 Hours of the Multiple-dose Phase)

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    End point title
    		 SPID48 (Sum of Pain Intensity Differences Over 48 Hours of the Multiple-dose Phase)
    End point description
    Sum of Pain Intensity Differences calculated as the weighted sum of the PI-VAS differences over 48 hours of the multiple-dose phase. PI-VAS corresponds to the pain intensity measured by a 0-100 visual analogue scale (0=no pain to 100 worst pain imaginable) which was measured every two hours over the first 48 hours of the multiple-dose phase. A higher value in SPID indicates greater pain relief. The analysis was performed combining all randomization arms including the same active treatment, which resulted in the following 3 analysis groups: DKP/TRAM, DEXKETOPROFEN and TRAMADOL.
    End point type
    Secondary
    End point timeframe
    over 48 hours of the multiple-dose phase
    End point values
    		 DKP/TRAM DEXKETOPROFEN TRAMADOL
    Number of subjects analysed
    213
    214
    214
    Units: units on a scale
        arithmetic mean (standard deviation)
    1943.7 ( 1000.51 )
    1677.5 ( 1070.91 )
    1765.6 ( 963.49 )
    No statistical analyses for this end point

    Secondary: Percentage of Responders According to PI-VAS (Pain Intensity - Visual Analogue Scale)

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    End point title
    		 Percentage of Responders According to PI-VAS (Pain Intensity - Visual Analogue Scale)
    End point description
    Percentage of responders; response defined as achievement a mean pain intensity, PI-VAS ˂ 40 mm (PI-VAS corresponds to the pain intensity measured by a 0-100 visual analogue scale, 0=no pain to 100=worst pain imaginable), over 48 hours of the multiple-dose phase. The analysis was performed combining all randomization arms including the same active treatment, which resulted in the following 3 analysis groups: DKP/TRAM, DEXKETOPROFEN and TRAMADOL.
    End point type
    Secondary
    End point timeframe
    over 48 hours of the multiple-dose phase
    End point values
    		 DKP/TRAM DEXKETOPROFEN TRAMADOL
    Number of subjects analysed
    213
    214
    214
    Units: percentage of participants
        number (not applicable)
    90.1
    76.6
    82.2
    No statistical analyses for this end point

    Secondary: Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief)

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    End point title
    		 Percentage of Responders According to 50% Max TOTPAR (Total Pain Relief)
    End point description
    Percentage of responders over 8 hours after first dose, according to the 50% maximum total pain relief rule: maximum TOTPAR calculated as the theoretical maximum weighted sum of PAR-VRS (Pain Relief - Verbal Rating Scale: pain relief 0=none, 4=complete) scores. The analysis was performed combining all randomization arms including placebo into one group, which resulted in the following 4 analysis groups: DKP/TRAM, DEXKETOPROFEN, TRAMADOL and Placebo.
    End point type
    Secondary
    End point timeframe
    over 8 hours after the first dose
    End point values
    		 DKP/TRAM DEXKETOPROFEN TRAMADOL PLACEBO
    Number of subjects analysed
    159
    161
    160
    161
    Units: percentage of participants
        number (not applicable)
    57.9
    56.5
    51.9
    37.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Study duration for patients was up to 6 weeks.
    Adverse event reporting additional description
    Analyzed for the Safety population (all randomized patients who received at least one dose of the study treatment). Includes adverse events emerging after at least one dose of active study treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    DKP/TRAM Followed by DKP/TRAM
    Reporting group description
    		 Single-dose phase: Patients received DKP.TRIS 25mg + TRAM.HCl 75mg. Single-dose treatment had to be administered on day 1. Multiple-dose phase: Patients received DKP.TRIS 25mg + TRAM.HCl 75mg. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations (every 8 hours). Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    DKP Followed by DKP
    Reporting group description
    		 Single-dose phase: Patients received DKP.TRIS 25mg. Single dose treatment had to be administered on day 1. Multiple-dose phase: Patients received DKP.TRIS 25mg. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations (every 8 hours). Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy deisgn) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    TRAM Followed by TRAM
    Reporting group description
    		 Single-dose phase: Patients received TRAM.HCl 100mg. Single-dose treatment had to be administered on day 1. Multiple-dose phase: Patients received TRAM.HCl 100mg. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations (every 8 hours). Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    Placebo Followed by DKP/TRAM
    Reporting group description
    		 Single-dose phase: Patients received Placebo (as one tablet matching DKP.TRIS 25mg + TRAM.HCl 75mg and matching DKP.TRIS 25mg and as two capsules matching TRAM.HCl 50mg). Multiple-dose phase: Placebo assigned patients were allocated to receive DKP.TRIS 25mg + TRAM.HCl 75mg, every 8 hours. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations. Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    Placebo Followed by DKP
    Reporting group description
    		 Single-dose phase: Patients received Placebo (as one tablet matching DKP.TRIS 25mg + TRAM.HCl 75mg and matching DKP.TRIS 25mg and as two capsules matching TRAM.HCl 50mg). Multiple-dose phase: Placebo assigned patients were allocated to receive DKP.TRIS 25mg, every 8 hours. Multiple-dose treatment had to be orally administered (starting 8 hours after single dose phase) up to the morning of day 5, for a total of 12 drug administrations. Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Reporting group title
    Placebo Followed by TRAM
    Reporting group description
    		 Single-dose phase: Patients received Placebo (as one tablet matching DKP.TRIS 25mg + TRAM.HCl 75mg and matching DKP.TRIS 25mg and as two capsules matching TRAM.HCl). Multiple-dose phase: Placebo assigned patients were allocated to receive two capsules of TRAM.HCl 50mg, every 8 hours. Multiple-dose treatment had to be orally administered (starting 8 hours after the single dose phase) up to the morning of day 5, for a total of 12 drug administrations. Each dose treatment consisting of 1 film-coated tablet and 2 capsules (according to double dummy design) had to be orally administered, together with approximately 150 ml of still/tap water.

    Serious adverse events
    		 DKP/TRAM Followed by DKP/TRAM DKP Followed by DKP TRAM Followed by TRAM Placebo Followed by DKP/TRAM Placebo Followed by DKP Placebo Followed by TRAM
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 159 (1.26%)
    3 / 161 (1.86%)
    1 / 160 (0.63%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Periprosthetic fracture
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 161 (0.62%)
    0 / 160 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac Disorder
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 161 (0.00%)
    0 / 160 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bone operation
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 161 (0.62%)
    1 / 160 (0.63%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heart valve replacement
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 161 (0.00%)
    0 / 160 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular graft
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 161 (0.00%)
    0 / 160 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device dislocation
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 161 (0.00%)
    1 / 160 (0.63%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 161 (0.00%)
    0 / 160 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 161 (0.00%)
    0 / 160 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 161 (0.62%)
    0 / 160 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Laryngeal oedema
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 161 (0.00%)
    0 / 160 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 161 (0.62%)
    0 / 160 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 161 (0.00%)
    0 / 160 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Soft tissue infection
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 161 (0.00%)
    0 / 160 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DKP/TRAM Followed by DKP/TRAM DKP Followed by DKP TRAM Followed by TRAM Placebo Followed by DKP/TRAM Placebo Followed by DKP Placebo Followed by TRAM
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 159 (9.43%)
    18 / 161 (11.18%)
    24 / 160 (15.00%)
    9 / 54 (16.67%)
    2 / 53 (3.77%)
    5 / 54 (9.26%)
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    7 / 159 (4.40%)
    6 / 161 (3.73%)
    5 / 160 (3.13%)
    3 / 54 (5.56%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    7
    6
    5
    3
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 159 (1.89%)
    1 / 161 (0.62%)
    1 / 160 (0.63%)
    3 / 54 (5.56%)
    0 / 53 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    3
    1
    1
    3
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 159 (1.89%)
    9 / 161 (5.59%)
    11 / 160 (6.88%)
    3 / 54 (5.56%)
    2 / 53 (3.77%)
    4 / 54 (7.41%)
         occurrences all number
    3
    10
    12
    3
    3
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 159 (1.26%)
    4 / 161 (2.48%)
    9 / 160 (5.63%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    2
    4
    9
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Oct 2013
    The content of this Amendment Nº 1 refers to changes to the study protocol version 1.0 of 07 December 2012. This amendment does not alter the scientific or medical basis of the protocol. An integrated version of study protocol, inclusive of the current Amendment N° 1 was issued in order to have a single updated study protocol document available for the investigator and identified as the study protocol version 2.0 of 15 October 2013.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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