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    Clinical Trial Results:
    A multicenter, randomized, partially blinded, placebo-controlled clinical trial to evaluate the effect on primary dysmenorrheal of vaginal rings with an average daily release of 700 μg nomegestrol acetate (NOMAC) and 300 μg estradiol (E2), or 900 μg nomegestrol acetate (NOMAC) and 300 μg estradiol (E2), or 100 μg etonogestrel (ENG) and 300 μg E2, or 125 μg etonogestrel (ENG) and 300 μg E2

    Summary
    EudraCT number
    		 2012-002449-40
    Trial protocol
    		 DE   NO   NL   BE   SE   PL   DK   ES  
    Global end of trial date
    12 Sep 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2016
    First version publication date
    29 Jul 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-8342B-057
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01670656
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Schering-Plough: SCH 900432 P08257
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    12 Sep 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To identify at least one dose of progestin/estrogen amongst the 4 active doses being tested, administered as a vaginal ring, that shows clinically relevant treatment efficacy in relief of primary dysmenorrhea, as demonstrated by a statistically significantly larger reduction (as compared to baseline) in mean menstrual cramping pain score compared to placebo.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Colombia: 82
    Country: Number of subjects enrolled
    Netherlands: 33
    Country: Number of subjects enrolled
    Norway: 25
    Country: Number of subjects enrolled
    Poland: 167
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Sweden: 12
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Chile: 34
    Country: Number of subjects enrolled
    Mexico: 17
    Country: Number of subjects enrolled
    South Africa: 9
    Country: Number of subjects enrolled
    New Zealand: 12
    Worldwide total number of subjects
    439
    EEA total number of subjects
    277
    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)
    439
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study enrolled adult female participants with a diagnosis of primary dysmenorrhea. Additional inclusion and exclusion criteria applied.

    Pre-assignment
    Screening details
    		 A total of 840 subjects participants were screened to determine their eligibility for entry into the trial. A total of 439 participants were enrolled and 438 participants were treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NOMAC-E2 700/300 mcg
    Arm description
    		 NOMAC-E2 700/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NOMAC-E2
    Investigational medicinal product code
    Other name
    SCH900121, MK-8175A
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    Nomegestrol acetate and estradiol (NOMAC-E2) contraceptive vaginal ring, at either 700 or 900 mcg NOMAC and 300 μg mcg, for two 28 day cycles

    Investigational medicinal product name
    Ibuprofen
    Investigational medicinal product code
    Other name
    Motrin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ibuprofen 400 mg will be dispensed throughout the entire study as needed as rescue medication for treating menstrual cramping pain. The maximum daily ibuprofen dose is 3200 mg (8 tablets).

    Arm title
    		 NOMAC-E2 900/300 mcg
    Arm description
    		 NOMAC-E2 900/300 mcg administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NOMAC-E2
    Investigational medicinal product code
    Other name
    SCH900121, MK-8175A
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    Nomegestrol acetate and estradiol (NOMAC-E2) contraceptive vaginal ring, at either 700 or 900 mcg NOMAC and 300 mcg E2, for two 28 day cycles

    Investigational medicinal product name
    Ibuprofen
    Investigational medicinal product code
    Other name
    Motrin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ibuprofen 400 mg will be dispensed throughout the entire study as needed as rescue medication for treating menstrual cramping pain. The maximum daily ibuprofen dose is 3200 mg (8 tablets).

    Arm title
    		 ENG-E2 100/300 mcg
    Arm description
    		 ENG-E2 100/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ENG-E2
    Investigational medicinal product code
    Other name
    SCH900432, MK-8342B
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    Etonogestrel and estradiol (ENG-E2) contraceptive vaginal ring, at either 100 or 125 mcg ENG and 300 mcg E2, for two 28-day cycles

    Investigational medicinal product name
    Ibuprofen
    Investigational medicinal product code
    Other name
    Motrin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ibuprofen 400 mg will be dispensed throughout the entire study as needed as rescue medication for treating menstrual cramping pain. The maximum daily ibuprofen dose is 3200 mg (8 tablets).

    Arm title
    		 ENG-E2 125/300 mcg
    Arm description
    		 ENG-E2 125/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ENG-E2
    Investigational medicinal product code
    Other name
    SCH900432, MK-8342B
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    Etonogestrel and estradiol (ENG-E2) contraceptive vaginal ring, at either 100 or 125 mcg ENG and 300 mcg, for two 28-day cycles

    Investigational medicinal product name
    Ibuprofen
    Investigational medicinal product code
    Other name
    Motrin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ibuprofen 400 mg will be dispensed throughout the entire study as needed as rescue medication for treating menstrual cramping pain. The maximum daily ibuprofen dose is 3200 mg (8 tablets).

    Arm title
    		 Placebo
    Arm description
    		 Placebo was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    Placebo to match vaginal ring, intravaginally for two 28-day cycles

    Investigational medicinal product name
    Ibuprofen
    Investigational medicinal product code
    Other name
    Motrin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ibuprofen 400 mg will be dispensed throughout the entire study as needed as rescue medication for treating menstrual cramping pain. The maximum daily ibuprofen dose is 3200 mg (8 tablets).

    Number of subjects in period 1
    		NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg Placebo
    Started
    86
    91
    87
    85
    90
    Completed
    83
    84
    79
    79
    79
    Not completed
    3
    7
    8
    6
    11
         Consent withdrawn by subject
    1
    1
    2
    1
    1
         Adverse event, non-fatal
    2
    2
    2
    3
    3
         Pregnancy
    -
    -
    -
    -
    1
         Non-compliance with protocol
    -
    3
    1
    1
    2
         Non-compliance with study drug
    -
    -
    3
    -
    1
         Subject moved
    -
    -
    -
    1
    -
         Lost to follow-up
    -
    -
    -
    -
    3
         Withdrawal by subject
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NOMAC-E2 700/300 mcg
    Reporting group description
    		 NOMAC-E2 700/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    NOMAC-E2 900/300 mcg
    Reporting group description
    		 NOMAC-E2 900/300 mcg administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    ENG-E2 100/300 mcg
    Reporting group description
    		 ENG-E2 100/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    ENG-E2 125/300 mcg
    Reporting group description
    		 ENG-E2 125/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group values
    		 NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg Placebo Total
    Number of subjects
    		 86 91 87 85 90 439
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28.7 ( 7.5 ) 28.7 ( 8.1 ) 29.1 ( 7.7 ) 28.3 ( 7.8 ) 28.4 ( 8.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 86 91 87 85 90 439
        Male
    		 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    NOMAC-E2 700/300 mcg
    Reporting group description
    		 NOMAC-E2 700/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    NOMAC-E2 900/300 mcg
    Reporting group description
    		 NOMAC-E2 900/300 mcg administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    ENG-E2 100/300 mcg
    Reporting group description
    		 ENG-E2 100/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    ENG-E2 125/300 mcg
    Reporting group description
    		 ENG-E2 125/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Primary: Change from Baseline in Mean Menstrual Cramping Pain Score Through Cycle 2

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    End point title
    		 Change from Baseline in Mean Menstrual Cramping Pain Score Through Cycle 2
    End point description
    The Mean Menstrual Cramping Pain score was calculated as the average of the three highest menstrual pain scores on the five point scale of item #3 of the Menstrual Distress Questionnaire in the baseline cycle and treatment Cycle 2, respectively. The daily menstrual cramping pain score was based on five pain categories: none (0); mild (1); moderate (2); strong (3); and severe (4). In case of absence of withdrawal bleeding, or onset of menstruation, the mean of the three highest menstrual cramping pain scores recorded within Days 21-28 was used for analysis. This endpoint was based on the Full Analysis Set (FAS) population, which consisted of all randomized subjects, in whom a vaginal ring was inserted, with at least one baseline or one-post baseline value.
    End point type
    Primary
    End point timeframe
    Baseline and Day 28 to 56 (Cycle 2)
    End point values
    		 NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg Placebo
    Number of subjects analysed
    85
    91
    86
    85
    90
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -1.7 (-2 to -1.5)
    -1.7 (-1.9 to -1.5)
    -1.9 (-2.1 to -1.7)
    -1.7 (-1.9 to -1.5)
    -1.2 (-1.4 to -0.9)
    Statistical analysis title
    		 Chg from BL in Mean Menstrl Cramping Score thru C2
    Comparison groups
    NOMAC-E2 700/300 mcg v Placebo
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 -0.2
    Statistical analysis title
    		 Chg from BL in Mean Menstrl Cramping Score thru C2
    Comparison groups
    NOMAC-E2 900/300 mcg v Placebo
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 -0.2
    Statistical analysis title
    		 Chg from BL in Mean Menstrl Cramping Score thru C2
    Comparison groups
    ENG-E2 100/300 mcg v Placebo
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 -0.4
    Statistical analysis title
    		 Chg from BL in Mean Menstrl Cramping Score thru C2
    Comparison groups
    ENG-E2 125/300 mcg v Placebo
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 -0.2

    Secondary: Change from Baseline in Total Mean Impact Score Through Cycle 2

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    End point title
    		 Change from Baseline in Total Mean Impact Score Through Cycle 2
    End point description
    Total Mean Impact Score, based on responses to questions 6, 8, 9, and 10 in the Dysmenorrhea Daily Diary (DysDD), measures dysmenorrhea's interference with work, physical activities, social/leisure activities, and sleep. Q6: In the past 24 hours, how much did pain or cramps in the pelvic area limit you in your paid work, work around the home, or school work? Q8: In the past 24 hours, how much did pain or cramps in the pelvic area limit you in your physical activities? Q9: In the past 24 hours, how much did pain or cramps in the pelvic area limit you in your social or leisure activities? Q10: In the past 24 hours, how much did pain or cramps in the pelvic area make it difficult for you to sleep? Each question is rated on a 5-point (0-4) scale, 0 being "Not at all" and 5 "Extremely." This endpoint was based on the FAS population, which consisted of all randomized subjects, in whom a vaginal ring was inserted, with at least one baseline or one-post baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 28 to 56 (Cycle 2)
    End point values
    		 NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg Placebo
    Number of subjects analysed
    85
    90
    86
    85
    90
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -4.8 (-5.6 to -4)
    -5 (-5.7 to -4.2)
    -4.7 (-5.5 to -3.9)
    -4.3 (-5.1 to -3.5)
    -3.1 (-3.9 to -2.4)
    Statistical analysis title
    		 Change from BL in Total Mean Impact Score thru C2
    Comparison groups
    NOMAC-E2 700/300 mcg v Placebo
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 -0.4
    Statistical analysis title
    		 Change from BL in Total Mean Impact Score thru C2
    Comparison groups
    NOMAC-E2 900/300 mcg v Placebo
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 -0.6
    Statistical analysis title
    		 Change from BL in Total Mean Impact Score thru C2
    Comparison groups
    ENG-E2 100/300 mcg v Placebo
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 -0.3
    Statistical analysis title
    		 Change from BL in Total Mean Impact Score thru C2
    Comparison groups
    ENG-E2 125/300 mcg v Placebo
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 0.1

    Secondary: Change from Baseline in Number of Ibuprofen Tablets Taken Through Cycle 2

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    End point title
    		 Change from Baseline in Number of Ibuprofen Tablets Taken Through Cycle 2
    End point description
    Participants were provided with ibuprofen 400 mg tablets at the screening visit to be taken throughout the study as needed as rescue medication for treating menstrual cramping pain. The maximum daily ibuprofen dose was 3200 mg (8 tablets). Participants were instructed to take the provided ibuprofen, and no other medications, for the relief of menstrual cramping pain, and to record their ibuprofen usage in their e-Diaries. This endpoint was based on the FAS population, which consisted of all randomized subjects, in whom a vaginal ring was inserted, with at least one baseline or one-post baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 28 to 56 (Cycle 2)
    End point values
    		 NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg Placebo
    Number of subjects analysed
    85
    91
    86
    85
    90
    Units: number of ibuprofen tablets taken
        least squares mean (confidence interval 95%)
    -6.4 (-7.5 to -5.3)
    -6.3 (-7.4 to -5.2)
    -7.1 (-8.2 to -6)
    -6 (-7.1 to -4.9)
    -4.8 (-6 to -3.7)
    Statistical analysis title
    		 Chg from BL in no. of ibuprofen tbs taken thru C2
    Comparison groups
    NOMAC-E2 700/300 mcg v Placebo
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 0.2
    Statistical analysis title
    		 Chg from BL in no. of ibuprofen tbs taken thru C2
    Comparison groups
    NOMAC-E2 900/300 mcg v Placebo
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.036
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 0.2
    Statistical analysis title
    		 Chg from BL in no. of ibuprofen tbs taken thru C2
    Comparison groups
    ENG-E2 100/300 mcg v Placebo
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 -0.5
    Statistical analysis title
    		 Chg from BL in no. of ibuprofen tbs taken thru C2
    Comparison groups
    ENG-E2 125/300 mcg v Placebo
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 0.6

    Secondary: Change from Baseline in Number of Days of Ibuprofen Intake Through Cycle 2

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    End point title
    		 Change from Baseline in Number of Days of Ibuprofen Intake Through Cycle 2
    End point description
    Participants were provided with ibuprofen 400 mg tablets at the screening visit to be taken throughout the study as needed as rescue medication for treating menstrual cramping pain. The maximum daily ibuprofen dose was 3200 mg (8 tablets). Participants were instructed to take the provided ibuprofen, and no other medications, for the relief of menstrual cramping pain, and to record their ibuprofen usage their e-Diaries. This endpoint was based on the FAS population, which consisted of all randomized subjects, in whom a vaginal ring was inserted, with at least one baseline or one-post baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 28 to 56 (Cycle 2)
    End point values
    		 NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg Placebo
    Number of subjects analysed
    85
    91
    86
    85
    90
    Units: Number of days of ibuprofen intake
        least squares mean (confidence interval 95%)
    -1.3 (-1.5 to -1)
    -1.7 (-2 to -1.4)
    -1.7 (-2 to -1.4)
    -1.4 (-1.7 to -1.1)
    -1.1 (-1.4 to -0.9)
    Statistical analysis title
    		 Chg frm BL in no. of days of ibprfn intake thru C2
    Comparison groups
    NOMAC-E2 700/300 mcg v Placebo
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.477
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0.3
    Statistical analysis title
    		 Chg frm BL in no. of days of ibprfn intake thru C2
    Comparison groups
    NOMAC-E2 900/300 mcg v Placebo
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 -0.1
    Statistical analysis title
    		 Chg frm BL in no. of days of ibprfn intake thru C2
    Comparison groups
    ENG-E2 100/300 mcg v Placebo
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 -0.1
    Statistical analysis title
    		 Chg frm BL in no. of days of ibprfn intake thru C2
    Comparison groups
    ENG-E2 125/300 mcg v Placebo
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.156
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 64 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    NOMAC-E2 700/300 mcg
    Reporting group description
    		 NOMAC-E2 700/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days

    Reporting group title
    NOMAC-E2 900/300 mcg
    Reporting group description
    		 NOMAC-E2 900/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days

    Reporting group title
    ENG-E2 100/300 mcg
    Reporting group description
    		 ENG-E2 100/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days

    Reporting group title
    ENG-E2 125/300 mcg
    Reporting group description
    		 ENG-E2 125/300 mcg was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered for two 28-day treatment periods, each period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Serious adverse events
    		 NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 91 (1.10%)
    0 / 86 (0.00%)
    1 / 85 (1.18%)
    0 / 90 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 91 (1.10%)
    0 / 86 (0.00%)
    0 / 85 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    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
    Psychiatric disorders
    Impulse-control disorder
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 91 (1.10%)
    0 / 86 (0.00%)
    0 / 85 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 91 (0.00%)
    0 / 86 (0.00%)
    1 / 85 (1.18%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    		 NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 86 (13.95%)
    11 / 91 (12.09%)
    14 / 86 (16.28%)
    7 / 85 (8.24%)
    11 / 90 (12.22%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 86 (10.47%)
    9 / 91 (9.89%)
    11 / 86 (12.79%)
    5 / 85 (5.88%)
    7 / 90 (7.78%)
         occurrences all number
    13
    19
    13
    7
    9
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    5 / 86 (5.81%)
    1 / 91 (1.10%)
    1 / 86 (1.16%)
    1 / 85 (1.18%)
    2 / 90 (2.22%)
         occurrences all number
    7
    1
    1
    1
    3
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 91 (1.10%)
    2 / 86 (2.33%)
    1 / 85 (1.18%)
    5 / 90 (5.56%)
         occurrences all number
    1
    1
    2
    1
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2013
    Amendment 1: Changes to the protocol included: Trial Flow Chart - addition of dispensation of ibuprofen; Inclusion Criteria/ Trial Schedule - Clarification of inclusion criterion #8 of history of regular menstrual cycles and inclusion criterion #14 baseline menstrual cycle length; Table 1 Prohibited Medications - formatted table to properly reflect 2 month wash out period, added sex hormones, and corrected bosentan to be reflected as an anti-hypertensive; Subject Exclusion Criteria - Maximum period between screening and randomization changed globally from 80 to 90 days; Non-IMP Medication - added clarifying statements regarding dispensing ibuprofen at Visit 1 and recording of ibuprofen in e-Diary following Visit 2; Dispensing - corrected training/guidance on the use of vaginal ring will completed using a demonstration vaginal ring and not by an unblinded staff member; Events of Clinical Interest - clarified that pregnancies are to be reported on the appropriate pregnancy eCRFs ONLY. They will not be reported on the AE eCRF. Non-serious complications during pregnancy will be reported on AE eCRF; Overdose - ibuprofen overdose definition added to section; Expedited Reporting of Safety Observations by Investigator to Sponsor - removal of references to Global Safety Intake Form and corresponding Table 3; Other Endpoints - MDQ-T Correction of pain score scale from 0-5 to 0-4. Addition of intake of pain relief medications for treatment of pelvic pain as a trigger to enable questionnaire; Efficacy Endpoints - Clarification on definitions of breakthrough bleeding and breakthrough spotting; Statistical Methods for Efficacy Analysis - Daily menstrual cramping pain score item #10 of MDQ-scale corrected globally to item #3; e-Diary Ring Use Questions - Updated to reflect final approved version of ring use questions as they appear in e-Diary in addition to instructions and scenarios for triggering follow up question.

    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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