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    Clinical Trial Results:
    A multicenter, randomized, partially-blinded, Phase IIb dose-finding study on ovarian function, vaginal bleeding pattern, and pharmacokinetics associated with the use of combined vaginal rings releasing 17β-estradiol plus three different doses of either nomegestrol acetate or etonogestrel in healthy women aged 18-35 years

    Summary
    EudraCT number
    		 2012-002459-41
    Trial protocol
    		 NO   DE   SE   NL   HU   ES   DK   PL  
    Global end of trial date
    15 Oct 2013

    Results information
    Results version number
    		 v1
    This version publication date
    13 Apr 2016
    First version publication date
    01 Aug 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-8175A-012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01709318
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Schering-Plough: SCH900121/SCH900432 P06109
    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
    15 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to identify at least one NGR that demonstrates inhibition of ovulation (which was considered confirmed if in the subset of participants ovulation was observed in less than 15% of the participants at any time during the 3 treatment cycles of the study) and cycle control that was non-inferior to NuvaRing®, as judged by the incidence of breakthrough bleeding and/or spotting (BTB-S) during Cycle 3.
    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
    		 Contraception
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Dec 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
    Netherlands: 163
    Country: Number of subjects enrolled
    Norway: 21
    Country: Number of subjects enrolled
    Poland: 112
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Denmark: 26
    Country: Number of subjects enrolled
    Germany: 298
    Country: Number of subjects enrolled
    Hungary: 40
    Worldwide total number of subjects
    666
    EEA total number of subjects
    666
    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)
    666
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study enrolled healthy female participants aged 18 to 35 years, with cycles between 24 to 35 days in length. Additional inclusion and exclusion criteria applied.

    Pre-assignment
    Screening details
    		 Of the 757 subjects who were screened for inclusion in the trial, 666 subjects were randomized, and 660 subjects 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
    		 Subject, Investigator
    Blinding implementation details
    Note: All NOMAC-E2 and ENG-E2 treatment groups were double-blinded. The NuvaRing treatment group was open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NOMAC-E2 500/300 mcg
    Arm description
    		 Participants received NOMAC-E2 500/300 mcg for three treatment periods, each 28-day treatment 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
    nomegestrol acetate and estradiol, MK-8175A
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    Nomegestrol acetate and estradiol (NOMAC-E2), with daily release of 500, 700, or 900 mcg NOMAC, and daily release of 300 mcg E2

    Arm title
    		 NOMAC-E2 700/300 mcg
    Arm description
    		 Participants received NOMAC-E2 700/300 mcg for three treatment periods, each 28-day treatment 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
    nomegestrol acetate and estradiol, MK-8175A
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    Nomegestrol acetate and estradiol (NOMAC-E2), with daily release of 500, 700, or 900 mcg NOMAC, and daily release of 300 mcg E2

    Arm title
    		 NOMAC-E2 900/300 mcg
    Arm description
    		 Participants received NOMAC-E2 900/300 mcg for three treatment periods, each 28-day treatment 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
    nomegestrol acetate and estradiol, MK-8175A
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    Nomegestrol acetate and estradiol (NOMAC-E2), with daily release of 500, 700, or 900 mcg NOMAC, and daily release of 300 mcg E2

    Arm title
    		 ENG-E2 75/300 mcg
    Arm description
    		 Participants received ENG-E2 75/300 mcg for three treatment periods, each 28-day treatment 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
    etonogestrel and estradiol, MK-8342B
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    Etonogestrel and estradiol (ENG-E2) contraceptive vaginal ring, with daily release of 75, 100, or 125 mcg ENG, and daily release of 300 mcg E2.

    Arm title
    		 ENG-E2 100/300 mcg
    Arm description
    		 Participants received ENG-E2 100/300 mcg for three treatment periods, each 28-day treatment 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
    etonogestrel and estradiol, MK-8342B
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    Etonogestrel and estradiol (ENG-E2) contraceptive vaginal ring, with daily release of 75, 100 or 125 mcg ENG, and daily release of 300 mcg E2.

    Arm title
    		 ENG-E2 125/300 mcg
    Arm description
    		 Participants received ENG-E2 125/300 mcg for three 28-day treatment periods, each treatment 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
    etonogestrel and estradiol, MK-8342B
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    Etonogestrel and estradiol (ENG-E2) contraceptive vaginal ring, with daily release of 75, 100 or 125 mcg ENG, and daily release of 300 mcg E2.

    Arm title
    		 NuvaRing® (ENG-EE 120/15 mcg)
    Arm description
    		 Participants received NuvaRing® for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NuvaRing® (ENG-EE 120/15)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    NuvaRing® (etonogestrel and ethinyl estradiol [ENG-EE]), with daily release of 120 mcg ENG, and daily release of 15 mcg EE

    Number of subjects in period 1 [1]
    		NOMAC-E2 500/300 mcg NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 75/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg NuvaRing® (ENG-EE 120/15 mcg)
    Started
    79
    85
    78
    77
    77
    86
    178
    Completed
    72
    78
    72
    71
    74
    82
    170
    Not completed
    7
    7
    6
    6
    3
    4
    8
         Physician decision
    -
    -
    -
    -
    -
    -
    1
         Adverse event, non-fatal
    3
    4
    2
    2
    -
    1
    2
         Technical problems
    1
    -
    -
    -
    -
    -
    -
         Site discontinued
    -
    1
    -
    -
    -
    -
    -
         Protocol violation
    -
    -
    -
    -
    2
    -
    -
         Non-compliance with study drug
    -
    2
    1
    1
    -
    -
    2
         Lost to follow-up
    2
    -
    -
    -
    1
    1
    1
         Withdrawal by subject
    1
    -
    3
    3
    -
    2
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 666 were enrolled in the study, but 6 participants who were randomized were not treated. The baseline period is based on all participants who were randomized and treated: a total of 660 participants.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NOMAC-E2 500/300 mcg
    Reporting group description
    		 Participants received NOMAC-E2 500/300 mcg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    NOMAC-E2 700/300 mcg
    Reporting group description
    		 Participants received NOMAC-E2 700/300 mcg for three treatment periods, each 28-day treatment 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
    		 Participants received NOMAC-E2 900/300 mcg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    ENG-E2 75/300 mcg
    Reporting group description
    		 Participants received ENG-E2 75/300 mcg for three treatment periods, each 28-day treatment 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
    		 Participants received ENG-E2 100/300 mcg for three treatment periods, each 28-day treatment 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
    		 Participants received ENG-E2 125/300 mcg for three 28-day treatment periods, each treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    NuvaRing® (ENG-EE 120/15 mcg)
    Reporting group description
    		 Participants received NuvaRing® for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group values
    		 NOMAC-E2 500/300 mcg NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 75/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg NuvaRing® (ENG-EE 120/15 mcg) Total
    Number of subjects
    		 79 85 78 77 77 86 178 660
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 26.7 ± 5 26.7 ± 4.9 26.1 ± 4.5 25.5 ± 4.9 26.1 ± 4.5 27.1 ± 4.6 25.9 ± 4.8 -
    Gender categorical
    Units: Subjects
        Female
    		 79 85 78 77 77 86 178 660
        Male
    		 0 0 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    NOMAC-E2 500/300 mcg
    Reporting group description
    		 Participants received NOMAC-E2 500/300 mcg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    NOMAC-E2 700/300 mcg
    Reporting group description
    		 Participants received NOMAC-E2 700/300 mcg for three treatment periods, each 28-day treatment 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
    		 Participants received NOMAC-E2 900/300 mcg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    ENG-E2 75/300 mcg
    Reporting group description
    		 Participants received ENG-E2 75/300 mcg for three treatment periods, each 28-day treatment 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
    		 Participants received ENG-E2 100/300 mcg for three treatment periods, each 28-day treatment 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
    		 Participants received ENG-E2 125/300 mcg for three 28-day treatment periods, each treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    NuvaRing® (ENG-EE 120/15 mcg)
    Reporting group description
    		 Participants received NuvaRing® for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Primary: Number of Participants with Progesterone Concentrations >16 nmol/L, by Cycle

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    End point title
    		 Number of Participants with Progesterone Concentrations >16 nmol/L, by Cycle [1]
    End point description
    Inhibition of ovulation was considered confirmed if, in a subset of participants, ovulation was observed in less than 15% of the participants at any time during the 3 treatment cycles of the study. Ovulation was defined as the presence of two or more consecutive progesterone concentrations >16 nmol/L within 5 days, and supported by ultrasound evidence of ovulation. Ultrasound evidence of ovulation was defined as either follicular rupture or the preceding presence of a follicular-like structure >15 mm in size. This endpoint was based on the Per-Protocol (PP) Population, which was defined as all participants in whom vaginal rings were inserted and who did not have any major protocol violation (a protocol violation that interfered with the assessment[s] of efficacy).
    End point type
    Primary
    End point timeframe
    Day 1 of Treatment Cycle 1 through Day 28 of Treatment Cycle 3 (Study Days 1-84)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No pairwise comparison was performed on the primary endpoint Number of Participants With Progesterone Concentrations >16 nmol/L, by Cycle.
    End point values
    		 NOMAC-E2 500/300 mcg NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 75/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects analysed
    65
    73
    57
    60
    63
    65
    126
    Units: Participants
        Cycle 1 (n=18,19,19,20,19,19,21)
    0
    0
    0
    0
    0
    0
    0
        Cycle 2 (n=17,16,16,20,19,17,19)
    0
    0
    0
    0
    0
    0
    0
        Cycle 3 (n=17,15,14,17,19,17,19)
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants With Breakthrough Bleeding and/or Spotting (BTB-S) During Cycle 3

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    End point title
    		 Percentage of Participants With Breakthrough Bleeding and/or Spotting (BTB-S) During Cycle 3
    End point description
    Breakthrough Bleeding and/or Spotting (BTB-S) was classified as follows: Bleeding = any bloody vaginal discharge that required one or more sanitary pads or tampons per day; Spotting = any bloody vaginal discharge that required no sanitary pads or tampons per day.
    End point type
    Primary
    End point timeframe
    Day 1 Cycle 3 through Day 28 Cycle 3 (Study Days 57-84)
    End point values
    		 NOMAC-E2 500/300 mcg NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 75/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects analysed
    48
    45
    40
    44
    49
    47
    97
    Units: percentage of participants
        number (not applicable)
    14.6
    13.3
    17.5
    13.6
    16.3
    6.4
    6.2
    Statistical analysis title
    		 Pct of participants with BTB-S during Cycle 3
    Comparison groups
    NOMAC-E2 500/300 mcg v NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    8.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 26.5
    Notes
    [2] - Non-inferiority criterion was met if the upper bound of the 95% CI of the difference is <=10%.
    Statistical analysis title
    		 Pct of participants with BTB-S during Cycle 3
    Comparison groups
    NOMAC-E2 700/300 mcg v NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.7
         upper limit
    		 24.8
    Notes
    [3] - Non-inferiority criterion was met if the upper bound of the 95% CI of the difference is <=10%.
    Statistical analysis title
    		 Pct of participants with BTB-S during Cycle 3
    Comparison groups
    NOMAC-E2 900/300 mcg v NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    12.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 33.1
    Notes
    [4] - Non-inferiority criterion was met if the upper bound of the 95% CI of the difference is <=10%.
    Statistical analysis title
    		 Pct of participants with BTB-S during Cycle 3
    Comparison groups
    ENG-E2 75/300 mcg v NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    6.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.7
         upper limit
    		 25.4
    Notes
    [5] - Non-inferiority criterion was met if the upper bound of the 95% CI of the difference is <=10%.
    Statistical analysis title
    		 Pct of participants with BTB-S during Cycle 3
    Comparison groups
    ENG-E2 100/300 mcg v NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    9.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 27.4
    Notes
    [6] - Non-inferiority criterion was met if the upper bound of the 95% CI of the difference is <=10%.
    Statistical analysis title
    		 Pct of participants with BTB-S during Cycle 3
    Comparison groups
    ENG-E2 125/300 mcg v NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.7
         upper limit
    		 15.9
    Notes
    [7] - Non-inferiority criterion was met if the upper bound of the 95% CI of the difference is <=10%.

    Secondary: Percentage of Participants With Absence of Withdrawal Bleeding and/or Spotting During Cycle 2

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    End point title
    		 Percentage of Participants With Absence of Withdrawal Bleeding and/or Spotting During Cycle 2
    End point description
    Withdrawal Bleeding and/or Spotting is considered any bleeding or spotting episode that starts during or continues into the expected bleeding period. Absence of Withdrawal Bleeding is no withdrawal bleeding and/or spotting episodes during an expected bleeding period. This endpoint was based on the PP Population, which was defined as all participants in whom vaginal rings were inserted and who did not have any major protocol violation (a protocol violation that interfered with the assessment[s] of efficacy).
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 2 through Day 28 Cycle 2 (Study Days 29-56)
    End point values
    		 NOMAC-E2 500/300 mcg NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 75/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects analysed
    55
    53
    45
    51
    54
    52
    111
    Units: percentage of participants
        number (not applicable)
    5.5
    1.9
    4.4
    7.8
    3.7
    1.9
    1.8
    Statistical analysis title
    		 Pct of prtcpnts with absence of WB-S during C2
    Comparison groups
    NOMAC-E2 500/300 mcg v NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 16.4
    Notes
    [8] - Non-inferiority criterion was met if the upper bound of the 95% CI of the difference is <=10%.
    Statistical analysis title
    		 Pct of prtcpnts with absence of WB-S during C2
    Comparison groups
    NOMAC-E2 700/300 mcg v NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 11
    Notes
    [9] - Non-inferiority criterion was met if the upper bound of the 95% CI of the difference is <=10%.
    Statistical analysis title
    		 Pct of prtcpnts with absence of WB-S during C2
    Comparison groups
    NOMAC-E2 900/300 mcg v NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 17.5
    Notes
    [10] - Non-inferiority criterion was met if the upper bound of the 95% CI of the difference is <=10%.
    Statistical analysis title
    		 Pct of prtcpnts with absence of WB-S during C2
    Comparison groups
    ENG-E2 75/300 mcg v NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    4.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 18.9
    Notes
    [11] - Non-inferiority criterion was met if the upper bound of the 95% CI of the difference is <=10%.
    Statistical analysis title
    		 Pct of prtcpnts with absence of WB-S during C2
    Comparison groups
    ENG-E2 100/300 mcg v NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 13.4
    Notes
    [12] - Non-inferiority criterion was met if the upper bound of the 95% CI of the difference is <=10%.
    Statistical analysis title
    		 Pct of prtcpnts with absence of WB-S during C2
    Comparison groups
    ENG-E2 125/300 mcg v NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 11
    Notes
    [13] - Non-inferiority criterion was met if the upper bound of the 95% CI of the difference is <=10%.

    Secondary: Intensity of Withdrawal Bleeding During Cycle 2

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    End point title
    		 Intensity of Withdrawal Bleeding During Cycle 2
    End point description
    Intensity of Withdrawal Bleeding During Cycle 2 was defined as the ratio of the number of withdrawal bleeding days divided by the number of withdrawal bleeding and/or spotting days. This endpoint was based on the PP Population, which was defined as all participants in whom vaginal rings were inserted and who did not have any major protocol violation (a protocol violation that interfered with the assessment[s] of efficacy).
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 2 through Day 28 Cycle 2 (Study Days 29-57)
    End point values
    		 NOMAC-E2 500/300 mcg NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 75/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects analysed
    52
    52
    43
    47
    52
    51
    109
    Units: ratio
        arithmetic mean (standard deviation)
    0.9 ± 0.2
    0.9 ± 0.2
    0.9 ± 0.2
    0.9 ± 0.2
    0.9 ± 0.2
    0.9 ± 0.1
    1 ± 0.1
    No statistical analyses for this end point

    Secondary: Intensity of Breakthrough Bleeding and/or Spotting During Cycle 3

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    End point title
    		 Intensity of Breakthrough Bleeding and/or Spotting During Cycle 3
    End point description
    Intensity of Breakthrough Bleeding and/or Spotting (BTB-S) During Cycle 3 was defined as the ratio of the number of breakthrough bleeding days divided by the number of breakthrough bleeding and/or spotting days. This endpoint was based on the PP Population, which was defined as all participants in whom vaginal rings were inserted and who did not have any major protocol violation (a protocol violation that interfered with the assessment[s] of efficacy).
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 3 through Day 28 Cycle 3 (Study Days 57-84)
    End point values
    		 NOMAC-E2 500/300 mcg NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 75/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects analysed
    7
    6
    7
    6
    8
    3
    6
    Units: ratio
        arithmetic mean (standard deviation)
    0.4 ± 0.4
    0.8 ± 0.4
    0.7 ± 0.5
    0.7 ± 0.2
    0.7 ± 0.4
    0.3 ± 0.6
    0.7 ± 0.5
    No statistical analyses for this end point

    Secondary: Number of Participants With Venous or Arterial Thrombotic/Thrombolic Events

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    End point title
    		 Number of Participants With Venous or Arterial Thrombotic/Thrombolic Events
    End point description
    This endpoint was based on the PP Population, which was defined as all participants in whom vaginal rings were inserted and who did not have any major protocol violation (a protocol violation that interfered with the assessment[s] of efficacy).
    End point type
    Secondary
    End point timeframe
    From Cycle 1 Day 1 up to 8 days after Day 28 of Cycle 3 (Study Days 1 through 92)
    End point values
    		 NOMAC-E2 500/300 mcg NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 75/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg NuvaRing® (ENG-EE 120/15 mcg)
    Number of subjects analysed
    79
    85
    78
    77
    77
    86
    178
    Units: Participants
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 92 days
    Adverse event reporting additional description
    The All Subjects as Treated (ASaT) population consists of all randomized subjects in whom a vaginal ring was inserted, regardless if they were randomized or not.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    NOMAC-E2 500/300 mcg
    Reporting group description
    		 Participants received NOMAC-E2 500/300 for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    NOMAC-E2 700/300 mcg
    Reporting group description
    		 Participants received NOMAC-E2 700/300 mcg for three treatment periods, each 28-day treatment 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
    		 Participants received NOMAC-E2 900/300 mcg for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    ENG-E2 75/300 mcg
    Reporting group description
    		 Participants received ENG-E2 75/300 mcg for three treatment periods, each 28-day treatment 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
    		 Participants received ENG-E2 100/300 mcg for three treatment periods, each 28-day treatment 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
    		 Participants received ENG-E2 125/300 for three 28-day treatment periods, each treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Reporting group title
    NuvaRing® (ENG-EE 120/15 mcg)
    Reporting group description
    		 Participants received NuvaRing® for three treatment periods, each 28-day treatment period (cycle) consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.

    Serious adverse events
    		 NOMAC-E2 500/300 mcg NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 75/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg NuvaRing® (ENG-EE 120/15 mcg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 85 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 77 (0.00%)
    0 / 86 (0.00%)
    0 / 178 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 NOMAC-E2 500/300 mcg NOMAC-E2 700/300 mcg NOMAC-E2 900/300 mcg ENG-E2 75/300 mcg ENG-E2 100/300 mcg ENG-E2 125/300 mcg NuvaRing® (ENG-EE 120/15 mcg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 79 (29.11%)
    20 / 85 (23.53%)
    26 / 78 (33.33%)
    24 / 77 (31.17%)
    22 / 77 (28.57%)
    25 / 86 (29.07%)
    46 / 178 (25.84%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 85 (0.00%)
    4 / 78 (5.13%)
    0 / 77 (0.00%)
    0 / 77 (0.00%)
    0 / 86 (0.00%)
    0 / 178 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    12 / 79 (15.19%)
    11 / 85 (12.94%)
    14 / 78 (17.95%)
    13 / 77 (16.88%)
    15 / 77 (19.48%)
    13 / 86 (15.12%)
    24 / 178 (13.48%)
         occurrences all number
    24
    21
    43
    35
    29
    35
    47
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 85 (0.00%)
    1 / 78 (1.28%)
    6 / 77 (7.79%)
    1 / 77 (1.30%)
    3 / 86 (3.49%)
    2 / 178 (1.12%)
         occurrences all number
    2
    0
    2
    9
    1
    3
    3
    Nausea
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 85 (1.18%)
    2 / 78 (2.56%)
    4 / 77 (5.19%)
    1 / 77 (1.30%)
    1 / 86 (1.16%)
    7 / 178 (3.93%)
         occurrences all number
    7
    1
    2
    4
    1
    1
    8
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 85 (2.35%)
    5 / 78 (6.41%)
    2 / 77 (2.60%)
    3 / 77 (3.90%)
    6 / 86 (6.98%)
    7 / 178 (3.93%)
         occurrences all number
    5
    2
    5
    2
    3
    8
    11
    Vaginal discharge
         subjects affected / exposed
    1 / 79 (1.27%)
    6 / 85 (7.06%)
    4 / 78 (5.13%)
    4 / 77 (5.19%)
    5 / 77 (6.49%)
    4 / 86 (4.65%)
    3 / 178 (1.69%)
         occurrences all number
    1
    9
    5
    4
    9
    6
    4
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 85 (1.18%)
    2 / 78 (2.56%)
    4 / 77 (5.19%)
    1 / 77 (1.30%)
    2 / 86 (2.33%)
    4 / 178 (2.25%)
         occurrences all number
    5
    2
    2
    5
    1
    2
    4
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 79 (2.53%)
    3 / 85 (3.53%)
    6 / 78 (7.69%)
    3 / 77 (3.90%)
    2 / 77 (2.60%)
    6 / 86 (6.98%)
    6 / 178 (3.37%)
         occurrences all number
    2
    4
    8
    3
    2
    10
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 85 (0.00%)
    1 / 78 (1.28%)
    1 / 77 (1.30%)
    2 / 77 (2.60%)
    2 / 86 (2.33%)
    4 / 178 (2.25%)
         occurrences all number
    4
    0
    1
    2
    3
    3
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 79 (11.39%)
    5 / 85 (5.88%)
    11 / 78 (14.10%)
    11 / 77 (14.29%)
    7 / 77 (9.09%)
    8 / 86 (9.30%)
    16 / 178 (8.99%)
         occurrences all number
    12
    5
    13
    14
    7
    9
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2013
    Amendment 2: Changes to the protocol included: Trial Flow Chart - screening phase changed from 60 to 80 days - randomization may occur up to 80 days after Visit 1; Table 1 - PD samples (FSH, LH, and P) and the PK should be collected in addition to the ultrasound should the subject need to return every third day until disappearance of the largest follicle that was ≥15 mm on Day 8. SHBG does not need to be repeated; Subject Inclusion Criteria - Clarification of inclusion 5: The intra-individual variation of +/- 3 days is allowed, but individual cycles should be within the 24-35 days in length - Clarification of inclusion 6: If the subject or her partner is surgically sterilized, then condoms are not required; Subjected Exclusion Criteria - Clarification of Table 2 Excluded Medications: table updated to reflect bosentan as an anti-hypertensive and not as an anti-epileptic - typographical error for carbamazepine and herbal remedies wash-out corrected - table layout streamlined to demonstrate that all medicines listed fall under the category of medicines associated with liver enzyme induction thus affecting the bioavailability of steroids.

    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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