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    Clinical Trial Results:
    Multicenter, Double-Blind, Randomized, Parallel, Placebo-Controlled Trial Assessing the Analgesic Efficacy of a Single, Oral Dose of an Extended Release Naproxen Sodium Tablet in Postsurgical Dental Pain

    Summary
    EudraCT number
    		 2014-005269-66
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    29 Aug 2008

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Sep 2016
    First version publication date
    15 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    Bayer sponsor contact information to be updated

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY117031/13130
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00720057
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, D-51368, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Sep 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the analgesic efficacy of a single, oral dose of a naproxen sodium extended-release (ER) tablet, compared to placebo in postsurgical dental pain.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects and/or their legally authorized representative. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jun 2008
    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
    United States: 312
    Worldwide total number of subjects
    312
    EEA total number of subjects
    0
    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)
    65
    Adults (18-64 years)
    247
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Three sites in the United States enrolled subjects in the trial between 27 June 2008 (date of first enrollment) and 02 September 2008 (date of last contact).

    Pre-assignment
    Screening details
    		 The screening period occurred up to 28 days prior to the day of dental surgery. A total of 447 subjects were screened, of which 135 were excluded (72 did not meet inclusion criteria, 19 refused to participate, 44 other reasons); 312 subjects were randomized and included in the intent-to-treat (ITT) population for efficacy and safety analysis.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Naproxen Sodium ER (BAYH6689)
    Arm description
    		 Single dose (1 tablet) ER Naproxen sodium 660 milligram (mg) with a full glass of water (240 milliliter [mL]) within 1-4 hours post dental surgery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Naproxen Sodium Extended Release Tablet
    Investigational medicinal product code
    BAYH6689
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose (1 tablet) ER Naproxen sodium 660 mg with a full glass of water (240 mL) within 1-4 hours post dental surgery.

    Arm title
    		 Placebo
    Arm description
    		 Single dose (1 tablet) of placebo with a full glass of water (240 mL) within 1-4 hours post dental surgery.
    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
    Single dose (1 tablet) of placebo with a full glass of water (240 mL) within 1-4 hours post dental surgery.

    Number of subjects in period 1
    		Naproxen Sodium ER (BAYH6689) Placebo
    Started
    153
    159
    Completed
    152
    156
    Not completed
    1
    3
         Consent withdrawn by subject
    -
    1
         Protocol violation
    1
    -
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Naproxen Sodium ER (BAYH6689)
    Reporting group description
    		 Single dose (1 tablet) ER Naproxen sodium 660 milligram (mg) with a full glass of water (240 milliliter [mL]) within 1-4 hours post dental surgery.

    Reporting group title
    Placebo
    Reporting group description
    		 Single dose (1 tablet) of placebo with a full glass of water (240 mL) within 1-4 hours post dental surgery.

    Reporting group values
    		 Naproxen Sodium ER (BAYH6689) Placebo Total
    Number of subjects
    		 153 159 312
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 20.8 ± 4.03 20.4 ± 4.31 -
    Gender categorical
    Units: Subjects
        Female
    		 89 106 195
        Male
    		 64 53 117
    Baseline Pain Intensity by Categorical Scale
    Categorical scale: No Pain (0), Mild Pain (1), Moderate Pain (2), Severe Pain (3).
    Units: Subjects
        Moderate
    		 99 103 202
        Severe
    		 54 56 110
    Baseline Pain Intensity by Visual Analog Scale
    Visual Analog Scale 0-100 millimeter (mm): 0=no pain and 100=worse possible pain.
    Units: scores on a scale
        arithmetic mean (standard deviation)
    		 72.3 ± 13.13 72.6 ± 11.91 -

    End points

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    End points reporting groups
    Reporting group title
    Naproxen Sodium ER (BAYH6689)
    Reporting group description
    		 Single dose (1 tablet) ER Naproxen sodium 660 milligram (mg) with a full glass of water (240 milliliter [mL]) within 1-4 hours post dental surgery.

    Reporting group title
    Placebo
    Reporting group description
    		 Single dose (1 tablet) of placebo with a full glass of water (240 mL) within 1-4 hours post dental surgery.

    Subject analysis set title
    Intent-to-Treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Randomized population was defined as all subjects who signed informed consent form, completed the screening period, and were randomized. The ITT population was defined as all subjects who were randomized and received at least one dose of the study treatment. Efficacy analyses were based on the ITT population (n=312).

    Primary: Summed Pain Intensity Difference (SPID)

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    End point title
    		 Summed Pain Intensity Difference (SPID)
    End point description
    Categorical pain intensity scale - no pain (0), mild pain (1), moderate pain (2), or severe pain (3) was used for all pain intensity assessments postdose. Time-weighted SPID was calculated by multiplying the Pain Intensity Difference (PID) score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values over 0-24 and 16-24 hours, respectively.
    End point type
    Primary
    End point timeframe
    0 to 24 hours post dose
    End point values
    		 Naproxen Sodium ER (BAYH6689) Placebo
    Number of subjects analysed
    153 [1]
    159 [2]
    Units: units on a scale
    arithmetic mean (standard deviation)
        SPID 0-24
    25.9 ± 25.87
    -3.1 ± 18.4
        SPID 16-24
    8.8 ± 9.3
    -1 ± 6.89
    Notes
    [1] - ITT population.
    [2] - ITT population.
    Statistical analysis title
    		 Summed Pain Intensity Difference (SPID)
    Statistical analysis description
    The treatment differences between the two groups were tested each at the 5% two-sided significant level using a hierarchical testing procedure to control the overall type 1 error. SPID16-24 was eligible for testing only after a statistically significant difference between the two arms with respect to SPID0-24 was observed. The SPIDs were analyzed via Analysis of Co-variance (ANCOVA) model with treatment and trial site as fixed effects and baseline pain intensity score as the covariate.
    Comparison groups
    Naproxen Sodium ER (BAYH6689) v Placebo
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - Placebo-controlled

    Secondary: Total Pain Relief (TOTPAR)

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    End point title
    		 Total Pain Relief (TOTPAR)
    End point description
    Pain relief categorical rating scale - no relief (0), a little relief (1), some relief (2), a lot of relief (3), or complete relief (4) was used for all pain relief assessments postdose. TOTPAR was calculated by multiplying the pain relief score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values.
    End point type
    Secondary
    End point timeframe
    0-24 hours post dose
    End point values
    		 Naproxen Sodium ER (BAYH6689) Placebo
    Number of subjects analysed
    153 [4]
    159 [5]
    Units: units on a scale
    arithmetic mean (standard deviation)
        TOTPAR 0 - 6 hours
    12.7 ± 7.81
    3.1 ± 5.07
        TOTPAR 0 - 12 hours
    25.5 ± 17.06
    5.5 ± 10.7
        TOTPAR 0 - 16 hours
    34.1 ± 23.49
    7.2 ± 14.83
        TOTPAR 0 - 24 hours
    51.3 ± 36.41
    10.9 ± 23.95
        TOTPAR 16 - 24 hours
    17.2 ± 13.37
    3.7 ± 9.4
    Notes
    [4] - ITT population.
    [5] - ITT population.
    Statistical analysis title
    		 Total Pain Relief (TOTPAR)
    Comparison groups
    Naproxen Sodium ER (BAYH6689) v Placebo
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [6] - Placebo-controlled

    Secondary: Summed Pain Intensity Difference at Specific Time Intervals

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    End point title
    		 Summed Pain Intensity Difference at Specific Time Intervals
    End point description
    Categorical pain intensity scale - no pain (0), mild pain (1), moderate pain (2), or severe pain (3) was used for all pain intensity assessments postdose. Time-weighted SPID was calculated by multiplying the PID score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values for 0-6, 0-12, 0-16 hour intervals, respectively.
    End point type
    Secondary
    End point timeframe
    0-16 hours post dose
    End point values
    		 Naproxen Sodium ER (BAYH6689) Placebo
    Number of subjects analysed
    153 [7]
    159 [8]
    Units: units on a scale
    arithmetic mean (standard deviation)
        SPID 0 - 6
    6.2 ± 5.7
    -0.4 ± 4.2
        SPID 0 - 12
    12.7 ± 12.3
    -1.4 ± 8.54
        SPID 0 - 16
    17.1 ± 16.85
    -2 ± 11.68
    Notes
    [7] - ITT population.
    [8] - ITT population.
    Statistical analysis title
    		 SPID at Specific Time Intervals
    Comparison groups
    Naproxen Sodium ER (BAYH6689) v Placebo
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [9] - Placebo-controlled

    Secondary: Time to First Use of Rescue Medication

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    End point title
    		 Time to First Use of Rescue Medication
    End point description
    Time to first use of rescue medication was estimated using the Kaplan-Meier method and analyzed by a log rank test stratified by trial site and baseline pain intensity (PI). The endpoint was time to first use of rescue medication. The criteria were if adequate pain relief was not achieved, then subjects were permitted to take rescue medication.
    End point type
    Secondary
    End point timeframe
    Post dose to first use of rescue medication
    End point values
    		 Naproxen Sodium ER (BAYH6689) Placebo
    Number of subjects analysed
    153 [10]
    159 [11]
    Units: hours
        median (full range (min-max))
    22.27 (1.07 to 22.27)
    1.9 (1.03 to 10.12)
    Notes
    [10] - ITT population.
    [11] - ITT population.
    Statistical analysis title
    		 Time to First Use of Rescue Medication
    Statistical analysis description
    The statistics were from the Kaplan-Meier method. The median for naproxen treatment arm was not estimable from Kaplan-Meier method, therefore it was presented as the maximum value from the full range.
    Comparison groups
    Naproxen Sodium ER (BAYH6689) v Placebo
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 < 0.001
    Method
    		 Logrank
    Confidence interval
    Notes
    [12] - Placebo-controlled

    Secondary: Global Assessment of the Investigational Product as a Pain Reliever

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    End point title
    		 Global Assessment of the Investigational Product as a Pain Reliever
    End point description
    Categorical Scale: Poor (0), Fair (1), Good (2), Very Good (3), Excellent (4).
    End point type
    Secondary
    End point timeframe
    At 24 hours postdose or immediately before first use of rescue medication
    End point values
    		 Naproxen Sodium ER (BAYH6689) Placebo
    Number of subjects analysed
    153 [13]
    159 [14]
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.3 ± 1.43
    0.6 ± 1.04
    Notes
    [13] - ITT population.
    [14] - ITT population.
    Statistical analysis title
    		 Global Assessment of the Investigational Product
    Comparison groups
    Naproxen Sodium ER (BAYH6689) v Placebo
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [15] - Placebo-controlled

    Secondary: Time to Onset of Effect

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    End point title
    		 Time to Onset of Effect
    End point description
    Time to onset of effect was defined as the time to meaningful pain relief, provided that the subjects experienced both "perceptible" and "meaningful" pain relief. Perceptible pain relief was defined as when the subject first began to feel any pain-relieving effect from the investigational product. Meaningful pain relief was defined as when the subject felt the degree of pain relief was meaningful to them.
    End point type
    Secondary
    End point timeframe
    From post dose to onset of first perceptible and meaningful pain relief for up to 6 hours
    End point values
    		 Naproxen Sodium ER (BAYH6689) Placebo
    Number of subjects analysed
    153 [16]
    159 [17]
    Units: hours
        median (full range (min-max))
    1.37 (0.07 to 4.98)
    4.13 (0.07 to 4.75)
    Notes
    [16] - ITT population.
    [17] - ITT population.
    Statistical analysis title
    		 Time to Onset of Effect
    Comparison groups
    Naproxen Sodium ER (BAYH6689) v Placebo
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 < 0.001
    Method
    		 Logrank
    Confidence interval
    Notes
    [18] - Placebo-controlled

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded throughout the treatment period through 5 days after investigational product or placebo administration. All serious adverse events were collected through about 30 days after the last dose of investigational product or placebo.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Single dose (1 tablet) of placebo with a full glass of water (240 mL) within 1-4 hours post dental surgery.

    Reporting group title
    Naproxen Sodium ER (BAYH6689)
    Reporting group description
    		 Single dose (1 tablet) ER Naproxen sodium 660 mg with a full glass of water (240 mL) within 1-4 hours post dental surgery.

    Serious adverse events
    		 Placebo Naproxen Sodium ER (BAYH6689)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 153 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo Naproxen Sodium ER (BAYH6689)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 159 (22.64%)
    10 / 153 (6.54%)
    Injury, poisoning and procedural complications
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    FLUSHING
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 153 (0.65%)
         occurrences all number
    0
    1
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    8 / 159 (5.03%)
    1 / 153 (0.65%)
         occurrences all number
    8
    1
    HEADACHE
         subjects affected / exposed
    6 / 159 (3.77%)
    5 / 153 (3.27%)
         occurrences all number
    6
    5
    SYNCOPE
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 153 (0.65%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 153 (0.65%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    TINNITUS
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    CONJUNCTIVITIS
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 153 (0.00%)
         occurrences all number
    2
    0
    EYE SWELLING
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 153 (0.65%)
         occurrences all number
    0
    1
    SCOTOMA
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    DYSPEPSIA
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    NAUSEA
         subjects affected / exposed
    24 / 159 (15.09%)
    3 / 153 (1.96%)
         occurrences all number
    24
    3
    STOMACH DISCOMFORT
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    VOMITING
         subjects affected / exposed
    14 / 159 (8.81%)
    2 / 153 (1.31%)
         occurrences all number
    14
    2
    TOOTH SOCKET HAEMORRHAGE
         subjects affected / exposed
    2 / 159 (1.26%)
    1 / 153 (0.65%)
         occurrences all number
    2
    1
    Respiratory, thoracic and mediastinal disorders
    PHARYNGOLARYNGEAL PAIN
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 153 (0.65%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    HYPERHIDROSIS
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    TOOTH ABSCESS
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    ABSCESS ORAL
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 153 (0.65%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jul 2008
    To ensure consistency and accuracy of time measurements, the amendment instructed trial coordinators, rather than subjects, to start the stopwatches at the time of dosing.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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