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    Clinical Trial Results:
    A phase I, single center, open-label parallel group trial to compare the pharmacokinetics of NOMAC between healthy female adolescents (aged 14-17 years) and healthy female adults (aged 18-50 years) after single dose administration of NOMAC-E2 tablets

    Summary
    EudraCT number
    		 2008-002142-38
    Trial protocol
    		 GB  
    Global end of trial date
    18 May 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    24 Jun 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    P05873
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Registration: MK-8175A-009
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000250-PIP01-08
    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
    18 May 2009
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 May 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    18 May 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To compare the pharmacokinetics of NOMAC (nomegestrol acetate) between female adolescents (aged 14-17 years) and female adults (aged 18-50 years) after single dose administration of NOMAC- E2 (17beta-estradiol).
    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
    23 Mar 2009
    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 Kingdom: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    15
    Adults (18-64 years)
    15
    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 with a normal menstrual cycle. Other inclusion and exclusion criteria applied.

    Pre-assignment
    Screening details
    		 A total of 52 participants were screened and 30 participants were enrolled in the study.

    Pre-assignment period milestones
    Number of subjects started
    		 30
    Number of subjects completed
    		 30

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NOMAC-E2 Ages 14-17
    Arm description
    		 Healthy female participants, ages 14 to 17 years, with normal menstrual cycles, received a single oral dose of NOMAC-E2, consisting of 2.5 mg NOMAC and 1.5 E2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NOMAC-E2
    Investigational medicinal product code
    Other name
    SCH 900121, MK-8175A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single oral dose of NOMAC-E2, consisting of 2.5 mg NOMAC and 1.5 mg E2.

    Arm title
    		 NOMAC-E2 Ages 18-50
    Arm description
    		 Healthy female participants, ages 18 to 50 years, with normal menstrual cycles, received a single oral dose of NOMAC-E2, consisting of 2.5 mg NOMAC and 1.5 E2.
    Arm type
    		 Control

    Investigational medicinal product name
    NOMAC-E2
    Investigational medicinal product code
    Other name
    SCH 900121, MK-8175A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single oral dose of NOMAC-E2, consisting of 2.5 mg NOMAC and 1.5 mg E2.

    Number of subjects in period 1
    		NOMAC-E2 Ages 14-17 NOMAC-E2 Ages 18-50
    Started
    15
    15
    Completed
    15
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NOMAC-E2 Ages 14-17
    Reporting group description
    		 Healthy female participants, ages 14 to 17 years, with normal menstrual cycles, received a single oral dose of NOMAC-E2, consisting of 2.5 mg NOMAC and 1.5 E2.

    Reporting group title
    NOMAC-E2 Ages 18-50
    Reporting group description
    		 Healthy female participants, ages 18 to 50 years, with normal menstrual cycles, received a single oral dose of NOMAC-E2, consisting of 2.5 mg NOMAC and 1.5 E2.

    Reporting group values
    		 NOMAC-E2 Ages 14-17 NOMAC-E2 Ages 18-50 Total
    Number of subjects
    		 15 15 30
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 15 0 15
        Adults (18-64 years)
    		 0 15 15
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.5 ± 1 33.3 ± 9 -
    Gender categorical
    Units: Subjects
        Female
    		 15 15 30
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    NOMAC-E2 Ages 14-17
    Reporting group description
    		 Healthy female participants, ages 14 to 17 years, with normal menstrual cycles, received a single oral dose of NOMAC-E2, consisting of 2.5 mg NOMAC and 1.5 E2.

    Reporting group title
    NOMAC-E2 Ages 18-50
    Reporting group description
    		 Healthy female participants, ages 18 to 50 years, with normal menstrual cycles, received a single oral dose of NOMAC-E2, consisting of 2.5 mg NOMAC and 1.5 E2.

    Primary: Time to maximum concentration (Tmax) of NOMAC 2.5 mg

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    End point title
    		 Time to maximum concentration (Tmax) of NOMAC 2.5 mg [1]
    End point description
    Blood samples were collected for determination of NOMAC levels predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours after dosing. NOMAC in plasma was determined using validated liquid chromatographic assays with mass spectrometric detection.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours postdose
    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: Justification: No statistical analysis was performed for the primary end point Time to Maximum Concentration (Tmax) of NOMAC 2.5 mg.
    End point values
    		 NOMAC-E2 Ages 14-17 NOMAC-E2 Ages 18-50
    Number of subjects analysed
    15
    15
    Units: hours
        median (full range (min-max))
    2.52 (1 to 6)
    3.03 (2 to 4.07)
    No statistical analyses for this end point

    Primary: Maximum concentration (Cmax) of NOMAC 2.5 mg

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    End point title
    		 Maximum concentration (Cmax) of NOMAC 2.5 mg
    End point description
    Blood samples were collected for determination of NOMAC levels predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours after dosing. NOMAC in plasma was determined using validated liquid chromatographic assays with mass spectrometric detection.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours postdose
    End point values
    		 NOMAC-E2 Ages 14-17 NOMAC-E2 Ages 18-50
    Number of subjects analysed
    15
    15
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    6.92 ± 30.8
    6.56 ± 32.8
    Statistical analysis title
    		 Cmax Geometric Mean Ratio
    Comparison groups
    NOMAC-E2 Ages 14-17 v NOMAC-E2 Ages 18-50
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.33

    Primary: Area under the concentration-time curve from time 0 to last determination (0-tlast) of NOMAC 2.5 mg

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    End point title
    		 Area under the concentration-time curve from time 0 to last determination (0-tlast) of NOMAC 2.5 mg
    End point description
    Blood samples were collected for determination of NOMAC levels predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours after dosing. NOMAC in plasma was determined using validated liquid chromatographic assays with mass spectrometric detection.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours postdose
    End point values
    		 NOMAC-E2 Ages 14-17 NOMAC-E2 Ages 18-50
    Number of subjects analysed
    15
    15
    Units: ng∙h/mL
        geometric mean (geometric coefficient of variation)
    86.9 ± 25.9
    91.5 ± 23.6
    Statistical analysis title
    		 AUC 0-tlast Geometric Mean Ratio
    Comparison groups
    NOMAC-E2 Ages 14-17 v NOMAC-E2 Ages 18-50
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.14

    Primary: Area under the concentration-time curve from time 0 to infinity (AUC0-∞) of NOMAC 2.5 mg

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    End point title
    		 Area under the concentration-time curve from time 0 to infinity (AUC0-∞) of NOMAC 2.5 mg
    End point description
    Blood samples were collected for determination of NOMAC levels predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours after dosing. NOMAC in plasma was determined using validated liquid chromatographic assays with mass spectrometric detection.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours postdose
    End point values
    		 NOMAC-E2 Ages 14-17 NOMAC-E2 Ages 18-50
    Number of subjects analysed
    15
    15
    Units: ng∙h/mL
        geometric mean (geometric coefficient of variation)
    95.6 ± 26.3
    106 ± 35.3
    Statistical analysis title
    		 AUC0-∞ Geometric Mean Ratio
    Comparison groups
    NOMAC-E2 Ages 14-17 v NOMAC-E2 Ages 18-50
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.13

    Primary: Weight-normalized apparent clearance (wn-CL/f) of NOMAC 2.5 mg

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    End point title
    		 Weight-normalized apparent clearance (wn-CL/f) of NOMAC 2.5 mg
    End point description
    Blood samples were collected for determination of NOMAC levels predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours after dosing. NOMAC in plasma was determined using validated liquid chromatographic assays with mass spectrometric detection.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours after dosing
    End point values
    		 NOMAC-E2 Ages 14-17 NOMAC-E2 Ages 18-50
    Number of subjects analysed
    15
    15
    Units: L/h/kg
        geometric mean (geometric coefficient of variation)
    0.441 ± 27.3
    0.36 ± 36
    Statistical analysis title
    		 wn-CL/f Geometric Mean Ratio
    Comparison groups
    NOMAC-E2 Ages 14-17 v NOMAC-E2 Ages 18-50
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.54

    Primary: Weight-normalized apparent volume of distribution (wn-Vd/f) of NOMAC 2.5 mg

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    End point title
    		 Weight-normalized apparent volume of distribution (wn-Vd/f) of NOMAC 2.5 mg
    End point description
    Blood samples were collected for determination of NOMAC levels predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours after dosing. NOMAC in plasma was determined using validated liquid chromatographic assays with mass spectrometric detection.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours postdose
    End point values
    		 NOMAC-E2 Ages 14-17 NOMAC-E2 Ages 18-50
    Number of subjects analysed
    15
    15
    Units: L/kg
        geometric mean (geometric coefficient of variation)
    25 ± 40.9
    25 ± 30.1
    Statistical analysis title
    		 wn-Vd/f Geometric Mean Ratio
    Comparison groups
    NOMAC-E2 Ages 14-17 v NOMAC-E2 Ages 18-50
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.29

    Primary: Apparent terminal half-life (t1/2) of NOMAC 2.5 mg

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    End point title
    		 Apparent terminal half-life (t1/2) of NOMAC 2.5 mg
    End point description
    Blood samples were collected for determination of NOMAC levels predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours after dosing. NOMAC in plasma was determined using validated liquid chromatographic assays with mass spectrometric detection.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 33, 57, 81, 105, and 129 hours postdose
    End point values
    		 NOMAC-E2 Ages 14-17 NOMAC-E2 Ages 18-50
    Number of subjects analysed
    15
    15
    Units: hours
        geometric mean (geometric coefficient of variation)
    39.3 ± 45.4
    48.1 ± 45.9
    Statistical analysis title
    		 t1/2 Geometric Mean Ratio
    Comparison groups
    NOMAC-E2 Ages 14-17 v NOMAC-E2 Ages 18-50
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.13

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening up to 6 days after study drug administration
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    NOMAC-E2 Ages 14-17
    Reporting group description
    		 Healthy female participants, ages 14 to 17 years, with normal menstrual cycles, received a single oral dose of NOMAC-E2, consisting of 2.5 mg NOMAC and 1.5 E2.

    Reporting group title
    NOMAC-E2 Ages 18-50
    Reporting group description
    		 Healthy female participants, ages 18 to 50 years, with normal menstrual cycles, received a single oral dose of NOMAC-E2, consisting of 2.5 mg NOMAC and 1.5 E2.

    Serious adverse events
    		 NOMAC-E2 Ages 14-17 NOMAC-E2 Ages 18-50
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 15 (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: 5%
    Non-serious adverse events
    		 NOMAC-E2 Ages 14-17 NOMAC-E2 Ages 18-50
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 15 (33.33%)
    3 / 15 (20.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    Hemicephalalgia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Vaginal discharge
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Varicella
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         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
    08 Jan 2009
    Amendment 1: As a result of requests from the Institute of Child Health/Great Ormond Street Hospital Research Ethics Committee (30 Guilford Street, London, WC1N 1 EH), serology testing (HIV and hepatitis) was removed from the younger age group and revised for the adult population only.
    17 Feb 2009
    For Amendment 2, there were 2 requests of the Institute of Child Health/Great Ormond Street Hospital Research Ethics Committee (REC), 30 Guilford Street, London, WC1N 1 EH: 1. Serology testing (HIV, hepatitis etc.), which had been removed from the younger age group, also be removed for the adult population. 2. REC noted from evidence given that the average age of menarche is 12.8 years and that contraception could be prescribed from the time when girls had a regular periods for 6 months: this would be around the age of 13.5. Although the REC understood the pressure to prescribe for the younger age group, it was of the view that the case was not clearly made for the drug to be tested in the 12-14 years olds. The REC however felt that they could approve the research for 14+s. The 12 and 13 year old age group should therefore be removed from the protocol.

    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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    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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