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    Clinical Trial Results:
    Efficacy and Safety of Prolonged Release (SR) Tramadol Hydrochloride (HCl)/Paracetamol fixed combination and Immediate Release (IR) Tramadol HCl/Paracetamol fixed combination in Patients with Moderate to Severe Acute Low-Back Pain - TreaSuRe

    Summary
    EudraCT number
    		 2015-002875-20
    Trial protocol
    		 SI   CZ   HR   PL  
    Global end of trial date
    18 Dec 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    22 Dec 2021
    First version publication date
    31 May 2020
    Other versions
    		 v1
    Version creation reason
    • Changes to summary attachments
    Some additional results will be posted and summary attachment will be updated.
    Summary report(s)
    		 Treasure_KCT03-2015_main_results_overview

    Trial information

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    Trial identification
    Sponsor protocol code
    KCT03/2015–DORETA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Krka d.d., Novo mesto
    Sponsor organisation address
    Dunajska cesta 65, Ljubljana, Slovenia, 1000
    Public contact
    Tanja Kohek, Krka d.d., Novo mesto Dunajska cesta 65 1000 Ljubljana Slovenia, 00386 41 589769, tanja.kohek@krka.biz
    Scientific contact
    Tanja Kohek, Krka d.d., Novo mesto Dunajska cesta 65 1000 Ljubljana Slovenia, 00386 41 589769, tanja.kohek@krka.biz
    Sponsor organisation name
    Krka ČR s.r.o.
    Sponsor organisation address
    Sokolovská 192/79, Prague, Czech Republic, 180 00
    Public contact
    Martin Sustr, Krka ČR s.r.o. Sokolovská 192/79 180 00 Prague Czech Republic, 00420 602 486846, martin.sustr@krka.biz
    Scientific contact
    Martin Sustr, Krka ČR s.r.o. Sokolovská 192/79 180 00 Prague Czech Republic, 00420 602 486846, martin.sustr@krka.biz
    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 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Main objective of the trial is to evaluate the efficacy, safety and effects on Quality of Life (QOL) of the medicines Doreta IR and Doreta SR produced by Krka, d.d., Novo mesto, Slovenia in patients with moderate to severe acute low-back pain.
    Protection of trial subjects
    Pain assessment was made at the control visits at day 7, 14 and 28 after therapy initiation to obtain data for the primary and secondary efficacy endpoints analysis. Principal methodology was the back pain intensity assessment by means of Visual analogue scale (VAS), Brief pain inventory short form and Quality Of Life (QOL) questionnaire.
    Background therapy
    		 Patients were given naproxen sodium 550 mg (Nalgesin® forte) and are instructed to take two tablet daily in addition to IMP as a rescue therapy, but only if they consider that pain intensity is too high (despite taking Doreta®) over the last 8 hours. Patients were also given pantoprazole 20 mg (Nolpaza®) and are instructed to take one tablet in the morning 1 hour before a meal with some water to prevent peptic ulcers that can occur as a side effect of non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen sodium.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Sep 2016
    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
    Slovenia: 40
    Country: Number of subjects enrolled
    Croatia: 103
    Country: Number of subjects enrolled
    Czech Republic: 100
    Country: Number of subjects enrolled
    Poland: 70
    Worldwide total number of subjects
    313
    EEA total number of subjects
    313
    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)
    248
    From 65 to 84 years
    65
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 316 patients screened from Croatia, Czech Republic, Poland and Slovenia. First patient in on 19.9.2016, last patient concluded on 18.12.2017. At first it was planned that the study will be performed also in Romania (70 patients). Because of the nonresponsiveness of Romanian Agency for Medicines (NAMMDR) the study conduct in Romania was cancelled.

    Pre-assignment
    Screening details
    		 In general, eligible patients for the screening procedure for the enrolment were adult patients aged 18-75 years, of both genders, with previously treated or untreated low back pain of moderate to severe intensity (according to the VAS threshold value), who currently do not participate in another clinical trial.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Instant Release Tramadol/Paracetamol FDC
    Arm description
    		 Patients in Instant Release Tramadol/Paracetamol FDC arm were taking four tablets of IR-TPFC 37,5 mg/325 mg per day, one every 6 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doreta®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet 37,5 mg/325 mg every 6 hours

    Arm title
    		 Sustained Release Tramadol/Paracetamol FDC
    Arm description
    		 Patients in Sustained Release Tramadol/Paracetamol FDC arm were taking two tablets SR-TPFC 75 mg/650 mg per day, one every 12 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doreta® SR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One SR-TPFC tablet 75 mg/650 mg every 12 hours.

    Number of subjects in period 1
    		Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Started
    157
    156
    Completed
    148
    145
    Not completed
    9
    11
         Consent withdrawn by subject
    4
    1
         Adverse event, non-fatal
    2
    5
         Lost to follow-up
    -
    1
         Protocol deviation
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Instant Release Tramadol/Paracetamol FDC
    Reporting group description
    		 Patients in Instant Release Tramadol/Paracetamol FDC arm were taking four tablets of IR-TPFC 37,5 mg/325 mg per day, one every 6 hours.

    Reporting group title
    Sustained Release Tramadol/Paracetamol FDC
    Reporting group description
    		 Patients in Sustained Release Tramadol/Paracetamol FDC arm were taking two tablets SR-TPFC 75 mg/650 mg per day, one every 12 hours.

    Reporting group values
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC Total
    Number of subjects
    		 157 156 313
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.2 ( 13.6 ) 51.5 ( 13.9 ) -
    Gender categorical
    In PP analysis set data about gender are as following: 106 male, 158 female and 1 patient without data about gender.
    Units: Subjects
        Female
    		 94 96 190
        Male
    		 63 60 123
    Subject analysis sets

    Subject analysis set title
    ITT - Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Eligible patients that were enrolled in the study, but had small deviations from the study protocol.

    Subject analysis set title
    PP - Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Eligible patients that were enrolled in the study and completed the study according to the protocol.

    Subject analysis sets values
    		 ITT - Intention to treat PP - Per protocol
    Number of subjects
    313
    265
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    50.9 ( 13.8 )
    NA ( NA )
    Gender categorical
    In PP analysis set data about gender are as following: 106 male, 158 female and 1 patient without data about gender.
    Units: Subjects
        Female
    190
        Male
    123

    End points

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    End points reporting groups
    Reporting group title
    Instant Release Tramadol/Paracetamol FDC
    Reporting group description
    		 Patients in Instant Release Tramadol/Paracetamol FDC arm were taking four tablets of IR-TPFC 37,5 mg/325 mg per day, one every 6 hours.

    Reporting group title
    Sustained Release Tramadol/Paracetamol FDC
    Reporting group description
    		 Patients in Sustained Release Tramadol/Paracetamol FDC arm were taking two tablets SR-TPFC 75 mg/650 mg per day, one every 12 hours.

    Subject analysis set title
    ITT - Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Eligible patients that were enrolled in the study, but had small deviations from the study protocol.

    Subject analysis set title
    PP - Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Eligible patients that were enrolled in the study and completed the study according to the protocol.

    Primary: The proportion of patients with clinically meaningful improvement of low back pain at the regular therapy end visit, i.e. Visit 2, Visit 3 or Visit 4.

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    End point title
    		 The proportion of patients with clinically meaningful improvement of low back pain at the regular therapy end visit, i.e. Visit 2, Visit 3 or Visit 4.
    End point description
    Statistical methods were used to compare bot arms - Immediate Relase and Sustained Release Tramadol/Paracetamol FDC.
    End point type
    Primary
    End point timeframe
    For one patient from 1 to 4 weeks for whole study (19.9.2016 to 18.12.2017). Investigators had an option to conclude the treatment earlier than 4 weeks after the initiation in case patient has reached the target reduction of pain (less tha 30 mm on VAS).
    End point values
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Number of subjects analysed
    157
    156
    Units: mm on VAS scale
    arithmetic mean (standard deviation)
        Pain intensity in mm on VAS at Baseline
    70.3 ( 13.0 )
    72.0 ( 12.8 )
        Pain intensity in mm on VAS on Visit 2
    40.7 ( 22.5 )
    40.1 ( 23.2 )
        Pain intensity in mm on VAS on Visit 3
    35.4 ( 20.5 )
    34.2 ( 20.4 )
        Pain intensity in mm on VAS on Visit 4
    16.3 ( 19.6 )
    14.6 ( 18.2 )
    Statistical analysis title
    		 Non-inferiority test of the primary endpoint
    Statistical analysis description
    We have performed the non-inferiority test associated to the primary endpoint by employing the one-sided asymptotic 95%-confidence interval for the difference pSR-pIR obtained by multiple imputation. The inferiority hypothesis of Group SR-TPFC in relation with Group IR-TPFC is to be rejected if the computed confidence interval for pSR-pIR lies strictly above -0.2.
    Comparison groups
    Instant Release Tramadol/Paracetamol FDC v Sustained Release Tramadol/Paracetamol FDC
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 Wang exact 95%-confidence interval
    Parameter type
    		 difference between p(SR)-p(IR)
    Point estimate
    0.044
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -0.028
         upper limit
    		 -
    Notes
    [1] - We have performed the non-inferiority test by employing the one-sided exact 95%-confidence interval for the difference pSR-pIR due to Wang (The Annals of Statistics, 2010) and as implemented by Shan and Wang.

    Secondary: Pain intensity difference (PID) between pain intensity on baseline and on day 6

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    End point title
    		 Pain intensity difference (PID) between pain intensity on baseline and on day 6
    End point description
    Test of equality of expected differnces was used to compare bot arms - Immediate Relase and Sustained Release Tramadol/Paracetamol FDC.
    End point type
    Secondary
    End point timeframe
    6 days - PID was evaluated on day 6 of the treatment.
    End point values
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Number of subjects analysed
    157
    156
    Units: mm on VAS
    arithmetic mean (standard deviation)
        Pain in mm on VAS at Baseline
    70.3 ( 13.0 )
    72.0 ( 12.8 )
        Pain in mm on VAS on day 6
    43.0 ( 22.1 )
    42.5 ( 20.5 )
        Difference
    -27.3 ( 25.7 )
    -29.5 ( 21.9 )
    Statistical analysis title
    		 PID difference between IR arm and SR arm
    Comparison groups
    Instant Release Tramadol/Paracetamol FDC v Sustained Release Tramadol/Paracetamol FDC
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.13
         upper limit
    		 7.5
    Notes
    [2] - Negative difference between measurement at baseline and beginning of the day 6 means improvement (less pain). PID for IR-TPFC was -27.3 and for SR-TPFC was -29.5. Difference between the groups was 2.2 mm on VAS scale in favor of SR-TPFC (95% CI -3.13, 7.5]. The test of equality of expected differences in Group SR-TPFC and Group IR-TPFC yields a statistically non-significant difference between the two groups.

    Secondary: Cumulative pain intensity (CPI) endpoints

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    End point title
    		 Cumulative pain intensity (CPI) endpoints
    End point description
    End point type
    Secondary
    End point timeframe
    15 days - Cumulative pain intensity (CPI) was assessed on day 2, 3, 6, 8 and 15. There were 5 assessments during the day - Right before the first IMP dose of the day and 2, 6, 8 and 12 hours after the first dose of IMP of the day.
    End point values
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Number of subjects analysed
    157
    156
    Units: mm on VAS
    arithmetic mean (standard deviation)
        CPI day 2
    271.2 ( 86.2 )
    277.6 ( 89.6 )
        CPI day 3
    235.1 ( 87.6 )
    238.3 ( 92.5 )
        CPI day 6
    185.8 ( 106.4 )
    189.5 ( 104.1 )
        CPI day 8
    201.5 ( 96.5 )
    196.3 ( 101.9 )
        CPI day 15
    168.0 ( 103.7 )
    160.5 ( 101.5 )
    Statistical analysis title
    		 Cumulative pain intensity
    Statistical analysis description
    Test of equality for CPI on day 2, 3, 6, 8 and 15 yielded statistically non-significant differences between IR-TPFC group and SR-TPFC group. The largest difference 7.4 mm (95% CI -22.8; 37.6)was on day 15 with higher mean, thus higher pain intensity, in IR-TPFC group.
    Comparison groups
    Instant Release Tramadol/Paracetamol FDC v Sustained Release Tramadol/Paracetamol FDC
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.7
         upper limit
    		 37.63

    Secondary: Cumulative pain intensity (CPI) difference between day 2 and day 3, day 6, day 8 and day 15

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    End point title
    		 Cumulative pain intensity (CPI) difference between day 2 and day 3, day 6, day 8 and day 15
    End point description
    The difference between CPI measured on day 2 with CPI measured on day 3, 6, 8, and 15 yielded statistically significant results for both therapeutic groups. The difference between CPI on day 2 and day 3 was 36.2 mm and 39.4 mm, in IR-TPFC and SR-TPFC group respectively, which yielded a statistically significant reduction of CPI already from day 2 to day 3. The differences between CPI on day 2 and all following measurements on day 6, 8 and 15 were statistically significant. The highest difference, 105.1 mm and 133.1 mm in IR-TPFC and SR-TPFC group respectively, was between measurement on day 2 and day 15.
    End point type
    Secondary
    End point timeframe
    14 days - assessments between day 2 and day 15 of the IMP
    End point values
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Number of subjects analysed
    157
    156
    Units: mm on VAS
    arithmetic mean (standard deviation)
        CPI difference between day 2 and day 3
    -36.2 ( 42.8 )
    -39.4 ( 41.6 )
        CPI difference between day 2 and day 6
    -85.4 ( 80.0 )
    -88.1 ( 77.2 )
        CPI differnece between day 2 and day 8
    -72.1 ( 64.0 )
    -89.1 ( 80.0 )
        CPI difference between day 2 and day 15
    -105.1 ( 94.4 )
    -133.1 ( 88.2 )
    No statistical analyses for this end point

    Secondary: Pain intensity difference (PID) endpoints

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    End point title
    		 Pain intensity difference (PID) endpoints
    End point description
    The baseline and the final values are nominally between 0 and 100 mm; the difference is nominally between -100 and 100 mm. A higher value of pain intensity means more pain; thus, a negative difference here means improvement. The test of equality of expected differences in Group SR-TPFC and Group IR-TPFC yields a statistically non-significant difference between the two groups.
    End point type
    Secondary
    End point timeframe
    Up to 4 weeks - PID 2 at visit 2 (1 week), PID 3 at visit 3 (2 weeks) and PID 4 at visit 4 (4 weeks).
    End point values
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Number of subjects analysed
    157
    156
    Units: mm on VAS
    arithmetic mean (standard deviation)
        PID 2 (1 week)
    -29.7 ( 25.2 )
    -31.9 ( 24.2 )
        PID 3 (2 weeks)
    -33.3 ( 24.9 )
    -37.3 ( 23.2 )
        PID 4 (4 weeks)
    -54.1 ( 25.1 )
    -57.4 ( 22.9 )
    No statistical analyses for this end point

    Secondary: Quality of life (QOL) difference

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    End point title
    		 Quality of life (QOL) difference
    End point description
    Quality of life was assessed by health domains created based on the 36-Item Short Form Survey from the RAND Medical Outcomes Study (MOS). All domains were individually analysed at the Visit 1 (baseline) and Visit 4 (week 4). Each of this measurements were normalized on a scale from 0 (the state of corresponding component is worst) to 100 (the state of the corresponding component is best). The results are thus to be interpreted as: more positive is the difference in each SF-36 domain, the more has analysed aspect of QOL improved. Differences of all domains were positive and were, except for Emotional well-being in SR-TPFC group, all statistically significant. The test of equality of expected differences in Group SR-TPFC and Group IR-TPFC yields a statistically non-significant difference between the two groups.
    End point type
    Secondary
    End point timeframe
    4 weeks - From Visit 1 (baseline) to Visit 4 (week 4)
    End point values
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Number of subjects analysed
    157
    156
    Units: points
    arithmetic mean (standard deviation)
        Physical functioning
    43.0 ( 33.3 )
    41.8 ( 34.5 )
        Role functioning/physical
    8.8 ( 40.3 )
    10.0 ( 45.0 )
        Role functioning/emotional
    11.7 ( 38.6 )
    10.7 ( 42.1 )
        Energy/fatigue
    6.9 ( 21.5 )
    5.3 ( 19.9 )
        Emotional well-being
    3.5 ( 20.4 )
    2.8 ( 20.1 )
        Social functioning
    9.0 ( 25.9 )
    7.3 ( 26.3 )
        Pain
    12.2 ( 27.2 )
    13.6 ( 31.1 )
        General health
    4.6 ( 15.6 )
    4.3 ( 17.8 )
        Health change
    12.6 ( 31.2 )
    14.4 ( 29.6 )
    No statistical analyses for this end point

    Secondary: Pain Interference Score difference (dPIS) on Visit 2

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    End point title
    		 Pain Interference Score difference (dPIS) on Visit 2
    End point description
    The Pain Interference Score (PIS) for each category is scaled from 0 to 10, with results to be interpreted as: the lower the mean PIS, the less pain interferes with the particular activity (negative dPIS therefore means less pain on the following visit). For each of the seven categories dPIS was assessed, which denotes the difference between pain interference score at Visit 2, 3 and 4 and the baseline score at Visit 1 for each of the therapy groups. In both therapeutic groups, IR-TPFC and SR-TPFC, there were statistically significant improvements noted for all Pain Interference Scores (7 categories) at any of the subsequent visits with respect to the baseline values. Regardless of the treatment group significant improvements were noted already at Visit 2 with respect to the baseline values for all 7 categories. The differences between the IR-TPFC and SR-TPFC group in the PIS reduction were consistently non-significant for all 7 categories over all three visits.
    End point type
    Secondary
    End point timeframe
    1 week - From Visit 1 (baseline) to Visit 2 (week 1)
    End point values
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Number of subjects analysed
    157
    156
    Units: points
    arithmetic mean (standard deviation)
        General Activity dPIS
    -1.90 ( 2.20 )
    -1.96 ( 2.20 )
        Mood dPIS
    -1.84 ( 2.47 )
    -1.92 ( 2.29 )
        Walking Ability dPIS
    -1.35 ( 2.37 )
    -1.82 ( 2.33 )
        Normal Work dPIS
    -1.75 ( 2.39 )
    -2.10 ( 2.30 )
        Relation with other people dPIS
    -1.09 ( 2.47 )
    -1.59 ( 2.39 )
        Sleep dPIS
    -2.18 ( 2.40 )
    -2.24 ( 2.58 )
        Enjoyment of Life dPIS
    -1.71 ( 2.61 )
    -2.04 ( 2.71 )
    No statistical analyses for this end point

    Secondary: Pain Interference Score difference (dPIS) on Visit 3

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    End point title
    		 Pain Interference Score difference (dPIS) on Visit 3
    End point description
    The Pain Interference Score (PIS) for each category is scaled from 0 to 10, with results to be interpreted as: the lower the mean PIS, the less pain interferes with the particular activity (negative dPIS therefore means less pain on the following visit). For each of the seven categories dPIS was assessed, which denotes the difference between pain interference score at Visit 2, 3 and 4 and the baseline score at Visit 1 for each of the therapy groups. In both therapeutic groups, IR-TPFC and SR-TPFC, there were statistically significant improvements noted for all Pain Interference Scores (7 categories) at any of the subsequent visits with respect to the baseline values. Regardless of the treatment group significant improvements were noted already at Visit 2 with respect to the baseline values for all 7 categories. The differences between the IR-TPFC and SR-TPFC group in the PIS reduction were consistently non-significant for all 7 categories over all three visits.
    End point type
    Secondary
    End point timeframe
    2 weeks - From Visit 1 (baseline) to Visit 3 (week 2)
    End point values
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Number of subjects analysed
    157
    156
    Units: points
    arithmetic mean (standard deviation)
        General Activity dPIS
    -2.94 ( 2.43 )
    -3.13 ( 2.45 )
        Mood dPIS
    -3.03 ( 2.70 )
    -3.28 ( 2.47 )
        Walking Ability dPIS
    -2.52 ( 2.50 )
    -2.94 ( 2.47 )
        Normal Work dPIS
    -2.79 ( 2.60 )
    -3.40 ( 2.37 )
        Relation with other people dPIS
    -2.21 ( 2.89 )
    -2.64 ( 2.63 )
        Sleep dPIS
    -3.35 ( 2.80 )
    -3.22 ( 2.87 )
        Enjoyment of Life dPIS
    -2.94 ( 2.87 )
    -3.12 ( 2.72 )
    No statistical analyses for this end point

    Secondary: Pain Interference Score difference (dPIS) on Visit 4

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    End point title
    		 Pain Interference Score difference (dPIS) on Visit 4
    End point description
    The Pain Interference Score (PIS) for each category is scaled from 0 to 10, with results to be interpreted as: the lower the mean PIS, the less pain interferes with the particular activity (negative dPIS therefore means less pain on the following visit). For each of the seven categories dPIS was assessed, which denotes the difference between pain interference score at Visit 2, 3 and 4 and the baseline score at Visit 1 for each of the therapy groups. In both therapeutic groups, IR-TPFC and SR-TPFC, there were statistically significant improvements noted for all Pain Interference Scores (7 categories) at any of the subsequent visits with respect to the baseline values. Regardless of the treatment group significant improvements were noted already at Visit 2 with respect to the baseline values for all 7 categories. The differences between the IR-TPFC and SR-TPFC group in the PIS reduction were consistently non-significant for all 7 categories over all three visits.
    End point type
    Secondary
    End point timeframe
    4 weeks - from Visit 1 (baseline) to Visit 4 (week 4)
    End point values
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Number of subjects analysed
    157
    156
    Units: points
    arithmetic mean (standard deviation)
        General Activity dPIS
    -4.87 ( 2.95 )
    -4.95 ( 2.82 )
        Mood dPIS
    -4.87 ( 2.74 )
    -4.63 ( 2.75 )
        Walking Ability dPIS
    -3.96 ( 2.95 )
    -4.43 ( 2.96 )
        Normal Work dPIS
    -4.50 ( 2.92 )
    -4.83 ( 2.66 )
        Relation with other people dPIS
    -3.35 ( 2.93 )
    -3.81 ( 2.72 )
        Sleep dPIS
    -4.69 ( 2.80 )
    -4.60 ( 2.65 )
        Enjoyment of Life dPIS
    -4.34 ( 3.26 )
    -4.42 ( 3.01 )
    No statistical analyses for this end point

    Secondary: Pain Interference Score (PIS) baseline values

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    End point title
    		 Pain Interference Score (PIS) baseline values
    End point description
    The Pain Interference Score (PIS) for each category is scaled from 0 to 10, with results to be interpreted as: the lower the mean PIS, the less pain interferes with the particular activity.
    End point type
    Secondary
    End point timeframe
    Baseline values
    End point values
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Number of subjects analysed
    157
    156
    Units: points
    arithmetic mean (standard deviation)
        General Activity baseline value
    6.95 ( 2.07 )
    6.99 ( 1.95 )
        Mood baseline value
    6.28 ( 2.43 )
    6.24 ( 2.22 )
        Walking Ability baseline value
    5.65 ( 2.43 )
    6.04 ( 2.53 )
        Normal work baseline value
    6.43 ( 2.06 )
    6.62 ( 2.22 )
        Relation with other people baseline value
    4.61 ( 2.59 )
    4.97 ( 2.59 )
        Sleep baseline value
    6.00 ( 2.53 )
    5.88 ( 2.47 )
        Enjoyment of life baseline value
    5.84 ( 2.88 )
    5.96 ( 2.61 )
    No statistical analyses for this end point

    Secondary: Quality of Life (QoL) baseline values

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    End point title
    		 Quality of Life (QoL) baseline values
    End point description
    Quality of life was assessed by health domains created based on the 36-Item Short Form Survey from the RAND Medical Outcomes Study (MOS). All domains were individually analysed at the Visit 1 (baseline).
    End point type
    Secondary
    End point timeframe
    Baseline values
    End point values
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Number of subjects analysed
    157
    156
    Units: points
    arithmetic mean (standard deviation)
        Physical functioning baseline value
    33.5 ( 24.0 )
    32.5 ( 26.3 )
        Role functioning/physical baseline value
    22.6 ( 36.5 )
    24.0 ( 38.7 )
        Role functioning/emotional baseline value
    41.2 ( 42.6 )
    46.4 ( 45.5 )
        Energy/fatigue baseline value
    41.0 ( 20.1 )
    44.4 ( 20.3 )
        Emotional well-being baseline value
    60.0 ( 21.3 )
    59.9 ( 20.7 )
        Social functioning baseline value
    47.0 ( 26.2 )
    51.6 ( 25.4 )
        Pain baseline value
    31.1 ( 23.3 )
    33.9 ( 24.8 )
        General health baseline value
    55.5 ( 21.4 )
    53.4 ( 22.2 )
        Health change baseline value
    36.8 ( 22.8 )
    35.1 ( 20.6 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE reporting timeframe for one patient was up to 4 weeks and was the same for the whole duration of the study (from the day the first patient entered (19.9.2016) to the day the last patient concluded the study (18.12.2017)).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Instant Release Tramadol/Paracetamol FDC
    Reporting group description
    		 -

    Reporting group title
    Sustained Release Tramadol/Paracetamol FDC
    Reporting group description
    		 -

    Serious adverse events
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 156 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Instant Release Tramadol/Paracetamol FDC Sustained Release Tramadol/Paracetamol FDC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 157 (40.76%)
    63 / 156 (40.38%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    24 / 157 (15.29%)
    20 / 156 (12.82%)
         occurrences all number
    27
    25
    Somnolence
         subjects affected / exposed
    10 / 157 (6.37%)
    11 / 156 (7.05%)
         occurrences all number
    16
    19
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    30 / 157 (19.11%)
    28 / 156 (17.95%)
         occurrences all number
    37
    35
    Constipation
         subjects affected / exposed
    21 / 157 (13.38%)
    21 / 156 (13.46%)
         occurrences all number
    26
    35
    Vomiting
         subjects affected / exposed
    10 / 157 (6.37%)
    7 / 156 (4.49%)
         occurrences all number
    10
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Apr 2017
    The purpose of the Protocol ammendment was the addition of 5 new sites in Slovenia.

    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
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