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    Clinical Trial Results:
    A Randomized, Double-Blind, Multicenter, Placebo- and active Comparator-Controlled Study to evaluate Efficacy and Safety of MR308 in the Treatment of Acute Pain After Third Molar Tooth Extraction (STARDOM1).

    Summary
    EudraCT number
    		 2016-000592-24
    Trial protocol
    		 DE   PL   IT  
    Global end of trial date
    04 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jan 2019
    First version publication date
    18 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MR308-3501
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mundipharma Research Ltd.
    Sponsor organisation address
    194-198 Cambridge Science Park, Cambridge, United Kingdom, CB4 0GW
    Public contact
    Clinical Operations, Mundipharma Research Ltd., +44 1223 424900, info@contact-clinical-trials.com
    Scientific contact
    Clinical Operations, Mundipharma Research Ltd., +44 1223 424900, info@contact-clinical-trials.com
    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
    04 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of MR308 doses in the Treatment of acute moderate to severe pain. Efficacy was assessed by showing superiority of MR308 doses over Placebo and non-inferiority compared with Tramadol, followed by superiority over Tramadol based on the sum of pain intesity differences over 0-4 hours (SPID4).
    Protection of trial subjects
    1) Inclusion criteria: - If a female was of child-bearing potential, she had to use highly effective methods of contraception throughout the study, be not breastfeeding, and have negative pregnancy tests prior to receiving IMP. - The subject was alert and calm, spontaneously payed attention to caregiver, e.g. Richmond Agitation–Sedation Scale (RASS) = 0 (Sessler et al., 2002 & Ely et al., 2003). 2) Exclusion criteria: - Several exclusion criteria excluded subjects who were at risk from the use of IMP (e.g. those with hypersensitivity) or the study methods (please refer to protocol) 3) Dscontinuation: The Investigator(s) or subjects themselves were able to stop study treatment at any time for safety or personal reasons. The participation of an individual subject could be terminated prematurely if subjects were taking the maximum rescue medication dose of 4000 mg Paracetamol per day and still reported uncontrolled pain or if any condition ocurred which, in the opinion of the Investigator, no longer permitted a safe participation in the study. 4) Safety was assessed throughout the study by evaluation of the incidence of adverse events and clinically significant changes on laboratory safety results, vital signs, physical examination, and electrocardiograms (ECGs).
    Background therapy
    		 Paracetamol (Acetaminophen), taken orally, was the rescue pain medication during the Double-blind Period of the study. The rescue medication was supplied to the subject with the IMP at randomisation and could be taken up to four times a day and the maximum daily dose of 4 g in divided doses up to Visit 5. A single dose of rescue medication was defined as 1000 mg (two tablets). At the discretion of the Investigator, the paracetamol dose may have been lowered to 500 mg (1 tablet), if the Investigator or subject felt that the dose was higher than what may be required to provide adequate analgesic effect.
    Evidence for comparator
    		 The new co-crystal MR308 combines two well-known active principles, tramadol and celecoxib. The analgesic effect is expected to occur at lower doses than those of the approved constituents drugs of MR308 (tramadol hydrochloride and celecoxib) for the treatment of acute pain. Therefore it was compared to tramadol, the opiod component in MR308.
    Actual start date of recruitment
    28 Dec 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
    Canada: 11
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Poland: 394
    Country: Number of subjects enrolled
    Spain: 192
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Hungary: 89
    Worldwide total number of subjects
    726
    EEA total number of subjects
    715
    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)
    725
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 31 sites in 6 countries: 3 sites in Canada, 3 sites in Germany, 4 sites in Hungary, 1 site in Italy, 10 sites in Poland and 9 sites in Spain. First patient first visit was 28-Dec-2016, last patient last visit was 04-Jan-2018.

    Pre-assignment
    Screening details
    		 The Screening Period may have taken up to 28 days. Subjects, who did not comply with all screening inclusion and exclusion criteria, withdrew their consent prior to the third molar extractions (Visit 2) and all other subjects who discontinued the study before being randomised were considered Screening Failures.

    Pre-assignment period milestones
    Number of subjects started
    		 887 [1]
    Number of subjects completed
    		 726

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal: 9
    Reason: Number of subjects
    		 Consent withdrawn by subject: 53
    Reason: Number of subjects
    		 Failed procedures: 73
    Reason: Number of subjects
    		 Lost to follow up: 15
    Reason: Number of subjects
    		 Administrative: 11
    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: Age stratification and subjects per-country were only analysed for randomised subjects.
    Period 1
    Period 1 title
    Treatment Period/Double-Blind Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The test IMP MR308 tablets and tramadol capsules were over-encapsulated to have the same appearance. In order to maintain the blind, subjects randomised to MR308 treatment arms were given twice daily additional placebo capsules to match the posology of the active comparator, tramadol, which was given four times daily. Subjects randomised to any treatment arm (including placebo) took their study treatment four times daily.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MR308 100 mg
    Arm description
    		 Subjects received MR308 100 mg (44 mg of tramadol hydrochloride and 56 mg of celecoxib) bid.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tramadol/Celecoxib 100 mg
    Investigational medicinal product code
    MR308 100 mg
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MR308 100 mg (44 mg of tramadol hydrochloride and 56 mg of celecoxib). Subjects received two over-encapsulated tablets with active treatment and two placebo capsules daily. Total daily dose: 200 mg MR308 (88 mg of tramadol hydrochloride and 112 mg of celecoxib).

    Arm title
    		 MR308 150 mg
    Arm description
    		 Subects received MR308 150 mg (66 mg of tramadol hydrochloride and 84 mg of celecoxib) bid.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tramadol/Celecoxib 150 mg
    Investigational medicinal product code
    MR308 150 mg
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MR308 150 mg (66 mg of tramadol hydrochloride and 84 mg of celecoxib). Subjects received two over-encapsulated tablets with active treatment and two placebo capsules daily. Total daily dose: 300 mg MR308 (132 mg of tramadol hydrochloride and 168 mg of celecoxib).

    Arm title
    		 MR308 200 mg
    Arm description
    		 Subjects received MR308 200 mg (88 mg of tramadol hydrochloride and 112 mg of celecoxib) bid.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tramadol/Celecoxib 200 mg
    Investigational medicinal product code
    MR308 200 mg
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MR308 200 mg (88 mg of tramadol hydrochloride and 112 mg of celecoxib). Subjects received two over-encapsulated tablets with active treatment and two placebo capsules daily. Total daily dose: 400 mg MR308 (176 mg of tramadol hydrochloride and 224 mg of celecoxib).

    Arm title
    		 Tramadol
    Arm description
    		 Subjects received Tramadol 100 mg IR qid.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tramadol 100 mg IR
    Investigational medicinal product code
    Tramadol 100 mg
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Tramadol hydrochloride immediate release 100 mg. Subjects received 4 over-encapsulated capsules with active treatment daily. Total daily dose: 400 mg tramadol.

    Arm title
    		 Placebo
    Arm description
    		 Subjects receied placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 4 doses of placebo per day,

    Number of subjects in period 1
    		MR308 100 mg MR308 150 mg MR308 200 mg Tramadol Placebo
    Started
    164
    160
    160
    159
    83
    Completed
    161
    152
    153
    138
    81
    Not completed
    3
    8
    7
    21
    2
         Consent withdrawn by subject
    2
    4
    4
    9
    2
         Administrative
    -
    1
    -
    -
    -
         Adverse event, non-fatal
    1
    3
    3
    12
    -

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    MR308 100 mg
    Reporting group description
    		 Subjects received MR308 100 mg (44 mg of tramadol hydrochloride and 56 mg of celecoxib) bid.

    Reporting group title
    MR308 150 mg
    Reporting group description
    		 Subects received MR308 150 mg (66 mg of tramadol hydrochloride and 84 mg of celecoxib) bid.

    Reporting group title
    MR308 200 mg
    Reporting group description
    		 Subjects received MR308 200 mg (88 mg of tramadol hydrochloride and 112 mg of celecoxib) bid.

    Reporting group title
    Tramadol
    Reporting group description
    		 Subjects received Tramadol 100 mg IR qid.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects receied placebo.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population is defined as all randomised subjects. The ITT population was analysed according to the treatment arm in which the subject was randomised.

    Primary: SPID4

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    End point title
    		 SPID4
    End point description
    The primary efficacy endpoint was the SPID4. SPID4 is derived as the weighted Sum of Pain Intensity Differences (baseline pain – current pain), measured at different time points via the Pain Intensity - Visual Analogue Scale (PI-VAS, range of scores: 0-100 mm). Time between two consecutive measurements was used for weighting. Larger values indicate larger pain relief. LOCF imputation was employed.
    End point type
    Primary
    End point timeframe
    Sum of pain intensity difference between baseline (pre-dose) and 4 hour post-dose.
    End point values
    		 MR308 100 mg MR308 150 mg MR308 200 mg Tramadol Placebo
    Number of subjects analysed
    163
    160
    160
    158
    83
    Units: PI-VAS score
        arithmetic mean (standard deviation)
    60.61 ( 98.177 )
    64.15 ( 94.870 )
    66.17 ( 99.569 )
    23.45 ( 81.731 )
    -9.12 ( 69.388 )
    Statistical analysis title
    		 Superiority of MR308 100 mg over placebo
    Statistical analysis description
    The comparison of all MR308 doses with placebo and tramadol based on SPID4 was performed using an analysis of covariance model with treatment and QPI (moderate, severe) as fixed effects, centre as a random effect and pre-dose (0h) PI-VAS as covariate. Covariance parameters were estimated via the restricted maximum likelihood method. An unstructured covariance matrix was assumed (common across all treatment arms) and the Kenward and Roger’s method for fixed effects degrees of freedom was used.
    Comparison groups
    Placebo v MR308 100 mg
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001 [2]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - Test for superiority of the MR308 dose over placebo regarding SPID4
    [2] - Raw P-value from one-sided test of superiority for testing the Null Hypothesis that the differences of means is >=0mm*h
    Statistical analysis title
    		 Non-inferiority of MR308 100 mg versus tramadol
    Statistical analysis description
    The comparison of all MR308 doses with placebo and tramadol based on SPID4 was performed using an analysis of covariance model with treatment and QPI (moderate, severe) as fixed effects, centre as a random effect and pre-dose (0h) PI-VAS as covariate. Covariance parameters were estimated via the restricted maximum likelihood method. An unstructured covariance matrix was assumed (common across all treatment arms) and the Kenward and Roger’s method for fixed effects degrees of freedom was used.
    Comparison groups
    MR308 100 mg v Tramadol
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.001 [4]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - Test for non-inferiority versus tramadol (NI-margin of 40mm*h) regarding SPID4
    [4] - Raw P-value from one-sided test of non-inferiority for testing the Null Hypothesis that the differences of means is >=40mm*h
    Statistical analysis title
    		 Superiority of MR308 100 mg over tramadol
    Statistical analysis description
    The comparison of all MR308 doses with placebo and tramadol based on SPID4 was performed using an analysis of covariance model with treatment and QPI (moderate, severe) as fixed effects, centre as a random effect and pre-dose (0h) PI-VAS as covariate. Covariance parameters were estimated via the restricted maximum likelihood method. An unstructured covariance matrix was assumed (common across all treatment arms) and the Kenward and Roger’s method for fixed effects degrees of freedom was used.
    Comparison groups
    MR308 100 mg v Tramadol
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.001 [6]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [5] - Test for : Superiority over tramadol regarding SPID4
    [6] - Raw P-value from one-sided test of superiority for testing the Null Hypothesis that the differences of means is >=0mm*h
    Statistical analysis title
    		 Superiority of MR308 150 mg over placebo
    Statistical analysis description
    The comparison of all MR308 doses with placebo and tramadol based on SPID4 was performed using an analysis of covariance model with treatment and QPI (moderate, severe) as fixed effects, centre as a random effect and pre-dose (0h) PI-VAS as covariate. Covariance parameters were estimated via the restricted maximum likelihood method. An unstructured covariance matrix was assumed (common across all treatment arms) and the Kenward and Roger’s method for fixed effects degrees of freedom was used.
    Comparison groups
    MR308 150 mg v MR308 200 mg v Placebo
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.001 [8]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [7] - Test for superiority of the MR308 dose over placebo regarding SPID4
    [8] - Raw P-value from one-sided test of superiority for testing the Null Hypothesis that the differences of means is >=0mm*h
    Statistical analysis title
    		 Superiority of MR308 200 mg over placebo
    Statistical analysis description
    The comparison of all MR308 doses with placebo and tramadol based on SPID4 was performed using an analysis of covariance model with treatment and QPI (moderate, severe) as fixed effects, centre as a random effect and pre-dose (0h) PI-VAS as covariate. Covariance parameters were estimated via the restricted maximum likelihood method. An unstructured covariance matrix was assumed (common across all treatment arms) and the Kenward and Roger’s method for fixed effects degrees of freedom was used.
    Comparison groups
    MR308 200 mg v Placebo
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.001 [10]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [9] - Test for superiority of the MR308 dose over placebo regarding SPID4
    [10] - Raw P-value from one-sided test of superiority for testing the Null Hypothesis that the differences of means is >=0mm*h
    Statistical analysis title
    		 Non-inferiority of MR308 150 mg versus tra
    Statistical analysis description
    The comparison of all MR308 doses with placebo and tramadol based on SPID4 was performed using an analysis of covariance model with treatment and QPI (moderate, severe) as fixed effects, centre as a random effect and pre-dose (0h) PI-VAS as covariate. Covariance parameters were estimated via the restricted maximum likelihood method. An unstructured covariance matrix was assumed (common across all treatment arms) and the Kenward and Roger’s method for fixed effects degrees of freedom was used.
    Comparison groups
    Tramadol v MR308 150 mg
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    P-value
    		 < 0.001 [12]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [11] - Test for non-inferiority versus tramadol (NI-margin of 40mm*h) regarding SPID4
    [12] - Raw P-value from one-sided test of non-inferiority for testing the Null Hypothesis that the differences of means is >=40mm*h
    Statistical analysis title
    		 Non-inferiority of MR308 200 mg versus tra
    Statistical analysis description
    The comparison of all MR308 doses with placebo and tramadol based on SPID4 was performed using an analysis of covariance model with treatment and QPI (moderate, severe) as fixed effects, centre as a random effect and pre-dose (0h) PI-VAS as covariate. Covariance parameters were estimated via the restricted maximum likelihood method. An unstructured covariance matrix was assumed (common across all treatment arms) and the Kenward and Roger’s method for fixed effects degrees of freedom was used.
    Comparison groups
    Tramadol v MR308 200 mg
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    P-value
    		 = 0.001 [14]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [13] - Test for non-inferiority versus tramadol (NI-margin of 40mm*h) regarding SPID4
    [14] - Raw P-value from one-sided test of non-inferiority for testing the Null Hypothesis that the differences of means is >=40mm*h
    Statistical analysis title
    		 Superiority of MR308 150 mg over tramadol
    Statistical analysis description
    The comparison of all MR308 doses with placebo and tramadol based on SPID4 was performed using an analysis of covariance model with treatment and QPI (moderate, severe) as fixed effects, centre as a random effect and pre-dose (0h) PI-VAS as covariate. Covariance parameters were estimated via the restricted maximum likelihood method. An unstructured covariance matrix was assumed (common across all treatment arms) and the Kenward and Roger’s method for fixed effects degrees of freedom was used.
    Comparison groups
    Tramadol v MR308 150 mg
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 < 0.001 [16]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [15] - Test for : Superiority over tramadol regarding SPID4
    [16] - Raw P-value from one-sided test of superiority for testing the Null Hypothesis that the differences of means is >=0mm*h
    Statistical analysis title
    		 Superiority of MR308 200 mg over tramadol
    Statistical analysis description
    The comparison of all MR308 doses with placebo and tramadol based on SPID4 was performed using an analysis of covariance model with treatment and QPI (moderate, severe) as fixed effects, centre as a random effect and pre-dose (0h) PI-VAS as covariate. Covariance parameters were estimated via the restricted maximum likelihood method. An unstructured covariance matrix was assumed (common across all treatment arms) and the Kenward and Roger’s method for fixed effects degrees of freedom was used.
    Comparison groups
    Tramadol v MR308 200 mg
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.001 [18]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [17] - Test for : Superiority over tramadol regarding SPID4
    [18] - Raw P-value from one-sided test of superiority for testing the Null Hypothesis that the differences of means is >=0mm*h

    Secondary: 50% responder at 4 hours

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    End point title
    		 50% responder at 4 hours
    End point description
    50% responder at 4 hours, defined as subjects with a reduction in pain intensity (PI-VAS) from 0 hours at 4 hours of at least 50%.
    End point type
    Secondary
    End point timeframe
    Baseline to 4 hours after the first dose.
    End point values
    		 MR308 100 mg MR308 150 mg MR308 200 mg Tramadol Placebo
    Number of subjects analysed
    163
    160
    160
    158
    83
    Units: Number of subjects
    54
    54
    65
    32
    6
    Statistical analysis title
    		 50% Responder MR308 100 mg vs placebo at 4 h
    Statistical analysis description
    The probability of being a 50% responder at 4h was analysed using respective logistic regression models with treatment and QPI group (moderate, severe) as fixed effects, centre (pooling) applied as necessary as random effect und pre-dose (0h) PI-VAS as covariate.
    Comparison groups
    MR308 100 mg v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.83
         upper limit
    		 17.296
    Statistical analysis title
    		 50% Responder MR308 150 mg vs placebo at 4h
    Statistical analysis description
    The probability of being a 50% responder at 4h was analysed using respective logistic regression models with treatment and QPI group (moderate, severe) as fixed effects, centre (pooling) applied as necessary as random effect und pre-dose (0h) PI-VAS as covariate.
    Comparison groups
    Placebo v MR308 150 mg
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    7.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.879
         upper limit
    		 17.57
    Statistical analysis title
    		 50% Responder MR308 200 mg vs placebo at 4h
    Statistical analysis description
    The probability of being a 50% responder at 4h was analysed using respective logistic regression models with treatment and QPI group (moderate, severe) as fixed effects, centre (pooling) applied as necessary as random effect und pre-dose (0h) PI-VAS as covariate.
    Comparison groups
    Placebo v MR308 200 mg
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    10.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.125
         upper limit
    		 25.061
    Statistical analysis title
    		 50% Responder MR308 100 mg vs tramadol at 4h
    Statistical analysis description
    The probability of being a 50% responder at 4h was analysed using respective logistic regression models with treatment and QPI group (moderate, severe) as fixed effects, centre (pooling) applied as necessary as random effect und pre-dose (0h) PI-VAS as covariate.
    Comparison groups
    MR308 100 mg v Tramadol
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.143
         upper limit
    		 3.217
    Statistical analysis title
    		 50% Responder MR308 150 mg vs tramadol at 4 h
    Statistical analysis description
    The probability of being a 50% responder at 4h was analysed using respective logistic regression models with treatment and QPI group (moderate, severe) as fixed effects, centre (pooling) applied as necessary as random effect und pre-dose (0h) PI-VAS as covariate.
    Comparison groups
    Tramadol v MR308 150 mg
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.16
         upper limit
    		 3.274
    Statistical analysis title
    		 50% Responder MR308 200 mg vs tramadol at 4h
    Statistical analysis description
    The probability of being a 50% responder at 4h was analysed using respective logistic regression models with treatment and QPI group (moderate, severe) as fixed effects, centre (pooling) applied as necessary as random effect und pre-dose (0h) PI-VAS as covariate.
    Comparison groups
    Tramadol v MR308 200 mg
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.673
         upper limit
    		 4.642

    Secondary: Rescue medication during the first 4 hours

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    End point title
    		 Rescue medication during the first 4 hours
    End point description
    Use of at least one dose of rescue medication during the first 4 hours
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose) to 4 hours post first I;P dose.
    End point values
    		 MR308 100 mg MR308 150 mg MR308 200 mg Tramadol Placebo
    Number of subjects analysed
    163
    160
    160
    158
    83
    Units: Number of subjects who used rescue medic
    67
    71
    63
    89
    66
    Statistical analysis title
    		 Use of RM in first 4h - 100 mg vs placebo
    Statistical analysis description
    The probability of using at least one dose of rescue medication during the first 4h were each analysed using respective logistic regression models with treatment and QPI group (moderate, severe) as fixed effects, centre (pooling) applied as necessary as random effect und pre-dose (0h) PI-VAS as covariate.
    Comparison groups
    MR308 100 mg v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.091
         upper limit
    		 0.32
    Statistical analysis title
    		 Use of RM in first 4h - 150 mg vs placebo
    Statistical analysis description
    The probability of using at least one dose of rescue medication during the first 4h were each analysed using respective logistic regression models with treatment and QPI group (moderate, severe) as fixed effects, centre (pooling) applied as necessary as random effect und pre-dose (0h) PI-VAS as covariate.
    Comparison groups
    Placebo v MR308 150 mg
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.104
         upper limit
    		 0.367
    Statistical analysis title
    		 Use of RM in first 4h - 200 mg vs placebo
    Statistical analysis description
    The probability of using at least one dose of rescue medication during the first 4h were each analysed using respective logistic regression models with treatment and QPI group (moderate, severe) as fixed effects, centre (pooling) applied as necessary as random effect und pre-dose (0h) PI-VAS as covariate.
    Comparison groups
    Placebo v MR308 200 mg
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.081
         upper limit
    		 0.286
    Statistical analysis title
    		 Use of RM in first 4h - 100 mg vs tramadol
    Statistical analysis description
    The probability of using at least one dose of rescue medication during the first 4h were each analysed using respective logistic regression models with treatment and QPI group (moderate, severe) as fixed effects, centre (pooling) applied as necessary as random effect und pre-dose (0h) PI-VAS as covariate.
    Comparison groups
    MR308 100 mg v Tramadol
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.359
         upper limit
    		 0.887
    Statistical analysis title
    		 Use of RM in first 4h - 150 mg vs tramadol
    Statistical analysis description
    The probability of using at least one dose of rescue medication during the first 4h were each analysed using respective logistic regression models with treatment and QPI group (moderate, severe) as fixed effects, centre (pooling) applied as necessary as random effect und pre-dose (0h) PI-VAS as covariate.
    Comparison groups
    Tramadol v MR308 150 mg
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.059
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.411
         upper limit
    		 1.017
    Statistical analysis title
    		 Use of RM in first 4h - 200 mg vs tramadol
    Statistical analysis description
    The probability of using at least one dose of rescue medication during the first 4h were each analysed using respective logistic regression models with treatment and QPI group (moderate, severe) as fixed effects, centre (pooling) applied as necessary as random effect und pre-dose (0h) PI-VAS as covariate.
    Comparison groups
    Tramadol v MR308 200 mg
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.319
         upper limit
    		 0.793

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from the time the informed consent was signed until the follow-up visit, which took place at least 7 days after the subject’s last dose of IMP.
    Adverse event reporting additional description
    AEs were recorded by non-elicited reporting at each study visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    MR308 100 mg
    Reporting group description
    		 Subjects received MR308 100 mg (44 mg of tramadol hydrochloride and 56 mg of celecoxib) bid.

    Reporting group title
    MR308 150 mg
    Reporting group description
    		 Subects received MR308 150 mg (66 mg of tramadol hydrochloride and 84 mg of celecoxib) bid.

    Reporting group title
    MR308 200 mg
    Reporting group description
    		 Subjects received MR308 200 mg (88 mg of tramadol hydrochloride and 112 mg of celecoxib) bid.

    Reporting group title
    Tramadol
    Reporting group description
    		 Subjects received Tramadol 100 mg IR qid.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects receied placebo.

    Serious adverse events
    		 MR308 100 mg MR308 150 mg MR308 200 mg Tramadol Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 159 (0.00%)
    0 / 160 (0.00%)
    1 / 160 (0.63%)
    0 / 83 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 159 (0.00%)
    0 / 160 (0.00%)
    1 / 160 (0.63%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MR308 100 mg MR308 150 mg MR308 200 mg Tramadol Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    120 / 164 (73.17%)
    119 / 159 (74.84%)
    132 / 160 (82.50%)
    137 / 160 (85.63%)
    49 / 83 (59.04%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    46 / 164 (28.05%)
    48 / 159 (30.19%)
    61 / 160 (38.13%)
    90 / 160 (56.25%)
    12 / 83 (14.46%)
         occurrences all number
    54
    59
    75
    116
    12
    Disturbance in attention
         subjects affected / exposed
    27 / 164 (16.46%)
    25 / 159 (15.72%)
    39 / 160 (24.38%)
    51 / 160 (31.88%)
    16 / 83 (19.28%)
         occurrences all number
    31
    26
    51
    73
    16
    Confusional state
         subjects affected / exposed
    11 / 164 (6.71%)
    9 / 159 (5.66%)
    17 / 160 (10.63%)
    30 / 160 (18.75%)
    8 / 83 (9.64%)
         occurrences all number
    14
    11
    20
    41
    9
    Headache
         subjects affected / exposed
    7 / 164 (4.27%)
    3 / 159 (1.89%)
    2 / 160 (1.25%)
    9 / 160 (5.63%)
    1 / 83 (1.20%)
         occurrences all number
    8
    4
    2
    10
    1
    General disorders and administration site conditions
    Somnolence
         subjects affected / exposed
    75 / 164 (45.73%)
    83 / 159 (52.20%)
    105 / 160 (65.63%)
    101 / 160 (63.13%)
    31 / 83 (37.35%)
         occurrences all number
    89
    100
    147
    147
    38
    Fatigue
         subjects affected / exposed
    54 / 164 (32.93%)
    54 / 159 (33.96%)
    66 / 160 (41.25%)
    72 / 160 (45.00%)
    26 / 83 (31.33%)
         occurrences all number
    64
    67
    92
    108
    29
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    48 / 164 (29.27%)
    47 / 159 (29.56%)
    50 / 160 (31.25%)
    90 / 160 (56.25%)
    15 / 83 (18.07%)
         occurrences all number
    55
    63
    67
    109
    16
    Vomiting
         subjects affected / exposed
    40 / 164 (24.39%)
    32 / 159 (20.13%)
    36 / 160 (22.50%)
    88 / 160 (55.00%)
    9 / 83 (10.84%)
         occurrences all number
    47
    37
    45
    105
    11
    Constipation
         subjects affected / exposed
    11 / 164 (6.71%)
    12 / 159 (7.55%)
    17 / 160 (10.63%)
    28 / 160 (17.50%)
    4 / 83 (4.82%)
         occurrences all number
    11
    12
    17
    31
    5
    Retching
         subjects affected / exposed
    2 / 164 (1.22%)
    4 / 159 (2.52%)
    4 / 160 (2.50%)
    13 / 160 (8.13%)
    2 / 83 (2.41%)
         occurrences all number
    2
    4
    4
    13
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    4 / 164 (2.44%)
    18 / 159 (11.32%)
    26 / 160 (16.25%)
    44 / 160 (27.50%)
    3 / 83 (3.61%)
         occurrences all number
    4
    19
    28
    53
    3
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 164 (0.61%)
    5 / 159 (3.14%)
    13 / 160 (8.13%)
    34 / 160 (21.25%)
    2 / 83 (2.41%)
         occurrences all number
    1
    9
    16
    40
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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