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    Clinical Trial Results:
    A randomized, double-blind, controlled with active treatment (tramadol 100 mg) and placebo, parallel groups, Phase II clinical trial to establish the effective dose between 4 strengths of E-58425 for moderate to severe dental pain

    Summary
    EudraCT number
    		 2011-002778-21
    Trial protocol
    		 ES  
    Global end of trial date
    13 Feb 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2016
    First version publication date
    15 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ESTEVE-SACO4-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Laboratorios Dr. Esteve. S.A. (ESTEVE)
    Sponsor organisation address
    Avda. Mare de Déu de Montserrat, 221,, Barcelona, Spain, 08041
    Public contact
    Clinical Investigation Department, Laboratorios del Dr. Esteve, S.A, 34 934466000, svidela@esteve.es
    Scientific contact
    Clinical Investigation Department, Laboratorios del Dr. Esteve, S.A, 34 934466000, svidela@esteve.es
    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
    27 Mar 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Feb 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Feb 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to establish the effective dose between 4 strengths of E 58425 for moderate to severe dental pain based on pain intensity (PI), total pain relief (TOTPAR), use of supplementary analgesic medication, time of onset of pain relief (PAR) and overall assessment.
    Protection of trial subjects
    The study will be conducted in compliance with the protocol, regulatory requirements, good clinical practice (GCP) and the ethical principles of the latest revision of the Declaration of Helsinki as adopted by the World Medical Association.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Feb 2012
    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
    Spain: 334
    Worldwide total number of subjects
    334
    EEA total number of subjects
    334
    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)
    334
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in Spain during 10-Feb-2012 (FSFV) and 13-Feb-2013 (LSLV)

    Pre-assignment
    Screening details
    		 Male and female patients ≥ 18 with Moderate or Severe pain (score of at least 50 mm on VAS) as a result of an oral surgical procedure under local anesthesia and/or sedation. The procedure had to involve the extraction of at least two impacted third molars requiring bone removal.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 E-58425 50 mg
    Arm description
    		 Active experimental arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    E-58425
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg, single dose (all treatments were over-encapsulated for treatment blinding)

    Arm title
    		 E-58425 100 mg
    Arm description
    		 Active experimental arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    E-58425
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg, single dose (all treatments were over-encapsulated for treatment blinding)

    Arm title
    		 E-58425 150 mg
    Arm description
    		 Active experimental arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    E-58425
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg, single dose (all treatments were over-encapsulated for treatment blinding)

    Arm title
    		 E-58425 200 mg
    Arm description
    		 Active experimental arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    E-58425
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg, single dose (all treatments were over-encapsulated for treatment blinding)

    Arm title
    		 Tramadol 100 mg
    Arm description
    		 Active control arm
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tramadol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg, single dose (all treatments were over-encapsulated for treatment blinding)

    Arm title
    		 Placebo
    Arm description
    		 Placebo Control arm
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, single dose (all treatments were over-encapsulated for treatment blinding)

    Number of subjects in period 1
    		E-58425 50 mg E-58425 100 mg E-58425 150 mg E-58425 200 mg Tramadol 100 mg Placebo
    Started
    55
    53
    57
    57
    58
    54
    Completed
    55
    53
    55
    57
    58
    54
    Not completed
    0
    0
    2
    0
    0
    0
         Lost to follow-up
    -
    -
    2
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial (overall period)
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial (overall period) Total
    Number of subjects
    		 334 334
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 24.5 ( 5.63 ) -
    Gender categorical
    Units: Subjects
        Female
    		 192 192
        Male
    		 142 142
    Baseline pain intesity
    Moderate baseline pain: VAS = 50-60 mm Severe baseline pain: VAS = >60 mm (data for Per Protocol Analysis Set)
    Units: Subjects
        Moderate
    		 186 186
        Severe
    		 102 102
        Non per protocol set
    		 46 46

    End points

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    End points reporting groups
    Reporting group title
    E-58425 50 mg
    Reporting group description
    		 Active experimental arm

    Reporting group title
    E-58425 100 mg
    Reporting group description
    		 Active experimental arm

    Reporting group title
    E-58425 150 mg
    Reporting group description
    		 Active experimental arm

    Reporting group title
    E-58425 200 mg
    Reporting group description
    		 Active experimental arm

    Reporting group title
    Tramadol 100 mg
    Reporting group description
    		 Active control arm

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo Control arm

    Subject analysis set title
    Per Protocol Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects who were randomized and who received study medication, for whom no relevant protocol deviations were documented, at least three valid VAS measurements were available eight hours after receiving the study medication and had not taken rescue medication during the first hour post-dose.

    Primary: SPID (0-8 h)

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    End point title
    		 SPID (0-8 h)
    End point description
    The SPID was defined as the sum of PID between time 0 and time t weighted with the time between two consecutive values, i.e., each PIDt value was multiplied with the time interval since the previous evaluation and summed up. The pain intensity difference (PID) was defined as PIDt = PIt-PI0, where PI0 is the pain intensity (VAS) at t=0 hours and PIt is the pain intensity at specific time points. Positive values therefore correspond to an increase in pain, while negative values correspond to a decrease in pain. Pain intensity (PI) was assessed using a 100mm VAS. The first pain intensity VAS score of at least 50mm obtained during the 4 hours post-dental extraction will be considered the study baseline pain, and the study medication will be administered immediately. After receiving the dose of study medication, the pain intensity VAS score was gathered at different time intervals.
    End point type
    Primary
    End point timeframe
    Sum of pain intensity difference from 0-8 hours
    End point values
    		 E-58425 50 mg E-58425 100 mg E-58425 150 mg E-58425 200 mg Tramadol 100 mg Placebo
    Number of subjects analysed
    45
    47
    54
    46
    49
    47
    Units: mm*h
        arithmetic mean (standard deviation)
    -21.05 ( 242.985 )
    -89.53 ( 233.626 )
    -139.04 ( 226.775 )
    -172.82 ( 224.241 )
    22.16 ( 228.242 )
    70.91 ( 212.612 )
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    ANOVA with factors treatment and center without interaction
    Comparison groups
    E-58425 50 mg v E-58425 100 mg v E-58425 150 mg v E-58425 200 mg v Tramadol 100 mg v Placebo
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [1] - Overall p-value for treatment

    Secondary: TOTPAR (0-8 h)

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    End point title
    		 TOTPAR (0-8 h)
    End point description
    TOTPAR was defined as the sum of PAR between time 0 and time t weighted with the time between two consecutive values, i.e., each PARt value was multiplied with the time interval since the previous evaluation. Pain relief (PAR) was assessed by a 5-point ordinal scale at the same time points as the pain intensity (excluding baseline). Patients were asked how much pain relief they had experienced since the intake of study medication.
    End point type
    Secondary
    End point timeframe
    Total pain relief from 0-8 hours
    End point values
    		 E-58425 50 mg E-58425 100 mg E-58425 150 mg E-58425 200 mg Tramadol 100 mg Placebo
    Number of subjects analysed
    45
    47
    54
    46
    49
    47
    Units: Score*Hours
        arithmetic mean (standard deviation)
    15.94 ( 8.458 )
    21.13 ( 10.313 )
    20.63 ( 10.035 )
    22.77 ( 9.991 )
    16.55 ( 9.247 )
    14.72 ( 8.695 )
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    ANOVA with factors treatment and center without interaction
    Comparison groups
    E-58425 50 mg v E-58425 100 mg v E-58425 150 mg v E-58425 200 mg v Tramadol 100 mg v Placebo
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [2] - Overall p-value for treatment

    Secondary: Consumption of rescue medication

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    End point title
    		 Consumption of rescue medication
    End point description
    End point type
    Secondary
    End point timeframe
    Rate of patients of patients that took at least one dose of rescue medication up to 8 hours after study drug administration
    End point values
    		 E-58425 50 mg E-58425 100 mg E-58425 150 mg E-58425 200 mg Tramadol 100 mg Placebo
    Number of subjects analysed
    45
    47
    54
    46
    49
    47
    Units: percent
    number (not applicable)
        Yes
    73.3
    61.7
    50
    39.1
    73.5
    80.9
    Statistical analysis title
    		 Cochran-Mantel-Haenszel
    Statistical analysis description
    Cochran-Mantel-Haenszel test stratified by center
    Comparison groups
    E-58425 50 mg v E-58425 100 mg v E-58425 150 mg v E-58425 200 mg v Tramadol 100 mg v Placebo
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - Overall p-value for treatment

    Secondary: 50% responders rate

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    End point title
    		 50% responders rate
    End point description
    End point type
    Secondary
    End point timeframe
    Rate of patients who had a 50% reduction in pain intesity as compared to baseline up to 8 hours after study drug administration
    End point values
    		 E-58425 50 mg E-58425 100 mg E-58425 150 mg E-58425 200 mg Tramadol 100 mg Placebo
    Number of subjects analysed
    45
    47
    54
    46
    49
    47
    Units: percent
    number (not applicable)
        Yes
    15.6
    31.9
    42.6
    52.2
    18.4
    12.8
    Statistical analysis title
    		 Cochran-Mantel-Haenszel
    Statistical analysis description
    Cochran-Mantel-Haenszel test stratified by center
    Comparison groups
    E-58425 50 mg v E-58425 100 mg v E-58425 150 mg v E-58425 200 mg v Tramadol 100 mg v Placebo
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - Overall p-value for treatment

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first IMP intake to follow-up visit (7 days +/- 2 days) or the last scheduled contact with the patient
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    E-58425 50 mg
    Reporting group description
    		 -

    Reporting group title
    E-58425 100 mg
    Reporting group description
    		 -

    Reporting group title
    E-58425 150 mg
    Reporting group description
    		 -

    Reporting group title
    E-58425 200 mg
    Reporting group description
    		 -

    Reporting group title
    Tramadol 100 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 E-58425 50 mg E-58425 100 mg E-58425 150 mg E-58425 200 mg Tramadol 100 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 53 (0.00%)
    1 / 57 (1.75%)
    1 / 57 (1.75%)
    1 / 58 (1.72%)
    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
    General disorders and administration site conditions
    Inflammation
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 53 (0.00%)
    1 / 57 (1.75%)
    0 / 57 (0.00%)
    0 / 58 (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
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 53 (0.00%)
    0 / 57 (0.00%)
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 53 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    1 / 58 (1.72%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infections and infestations
    Postoperative abscess
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 53 (0.00%)
    0 / 57 (0.00%)
    0 / 57 (0.00%)
    0 / 58 (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
    Infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 53 (0.00%)
    1 / 57 (1.75%)
    0 / 57 (0.00%)
    0 / 58 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 E-58425 50 mg E-58425 100 mg E-58425 150 mg E-58425 200 mg Tramadol 100 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 55 (12.73%)
    6 / 53 (11.32%)
    9 / 57 (15.79%)
    17 / 57 (29.82%)
    17 / 58 (29.31%)
    5 / 54 (9.26%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 53 (1.89%)
    0 / 57 (0.00%)
    4 / 57 (7.02%)
    2 / 58 (3.45%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    0
    4
    2
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 53 (3.77%)
    4 / 57 (7.02%)
    12 / 57 (21.05%)
    11 / 58 (18.97%)
    0 / 54 (0.00%)
         occurrences all number
    0
    2
    4
    12
    12
    0
    Nausea
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 53 (3.77%)
    0 / 57 (0.00%)
    7 / 57 (12.28%)
    6 / 58 (10.34%)
    0 / 54 (0.00%)
         occurrences all number
    1
    2
    0
    7
    6
    0

    More information

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
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