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    Clinical Trial Results:
    Characterization of ovulation inhibition of a new vaginal delivery system (EVE 112, Evestra/Germany) containing etonogestrel and ethinylestradiol – an open label, single centre, comparative, parallel-group study in healthy females of childbearing potential

    Summary
    EudraCT number
    		 2016-000115-32
    Trial protocol
    		 DE  
    Global end of trial date
    17 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 May 2020
    First version publication date
    09 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EVE112-CT02-2015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CRO number: 1319ee15ct
    Sponsors
    Sponsor organisation name
    Evestra GmbH
    Sponsor organisation address
    Britzer Strasse 26 , Berlin, Germany, 12439
    Public contact
    Dr. Maika Friedrich, Evestra GmbH, +49 3066509643, mfriedrich@evestra.com
    Scientific contact
    Dr. Maika Friedrich, Evestra GmbH, +49 3066509643, mfriedrich@evestra.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
    11 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary aim of this clinical trial is: •To show the non-inferior efficacy of the Test Product (EVE112) compared to the Reference Product (NuvaRing®) in terms of ovulation inhibition rate based on Hoogland score
    Protection of trial subjects
    Prior to recruitment of subjects, all relevant documents of the clinical study were submitted and proved by the Independent Ethics Committees (IECs) responsible for the participating investigators. Written consent documents embodied the elements of informed consent as described in the Declaration of Helsinki, the ICH Guidelines for Good Clinical Practice (GCP) and were in accordance with all applicable laws and regulations. The informed consent form and subject information sheet described the planned and permitted uses, transfers and disclosures of the subject's personal data and personal health information for purposes of conducting the study. The informed consent form and the subject information sheet further explained the nature of the study, its objectives and potential risks and benefits as well as the date informed consent was given. Before being enrolled in the clinical trial, every subject was informed that participation in this trial was voluntary and that he/she could withdraw from the study at any time without giving a reason and without having to fear any loss in his/her medical care. The subject’s consent was obtained in writing before the start of the study. By signing the informed consent, the subject declared that he/she was participating voluntarily and intended to follow the study protocol instructions and the instructions of the investigator and to answer the questions asked during the course of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Apr 2016
    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
    Germany: 87
    Worldwide total number of subjects
    87
    EEA total number of subjects
    87
    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)
    87
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Assessments of screening examination was performed within 6 weeks prior to start of pre-treatment cycle to evaluate eligibility for the study. A total of 132 healthy female subjects was screened for enrolment and of them 87 subjects were randomised into the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Test - EVE 112
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    EVE 112
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    2 treatment cycles of 28 days each with vaginal application of 1 vaginal ring of Test with a nominal delivery rate of 120 μg/d etonogestrel (ENG) and 15 μg/d ethinylestradiol (EE) applied for 21 days per cycle separated by 7 treatment-free days

    Arm title
    		 Reference - NuvaRing®
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NuvaRing®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal delivery system
    Routes of administration
    Vaginal use
    Dosage and administration details
    2 treatment cycles of 28 days each with vaginal application of 1 vaginal ring of Reference with a nominal delivery rate of 120 μg/d etonogestrel (ENG) and 15 μg/d ethinylestradiol (EE) for 21 days per cycle separated by 7 treatment-free days.

    Number of subjects in period 1
    		Test - EVE 112 Reference - NuvaRing®
    Started
    44
    43
    Completed
    40
    40
    Not completed
    4
    3
         Consent withdrawn by subject
    3
    2
         Pregnancy
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 87 87
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 87 87
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 29 ± 4 -
    Gender categorical
    Units: Subjects
        Female
    		 87 87
    Subject analysis sets

    Subject analysis set title
    SAS
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SAS was defined as all subjects randomised.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all subjects of the SAS, who after randomisation, completed at least one treatment cycle of 28 days, or in whom a Hoogland score >5 was observed in any cycle during randomised treatment.

    Subject analysis set title
    PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS was defined as all subjects randomised • who completely passed the pre-defined treatment regimen and • whose relevant trial variables were available in all treatment cycles, and • who finished the clinical trial without major protocol deviations. PPS was the primary population for the analysis of efficacy endpoints.

    Subject analysis sets values
    		 SAS FAS PPS
    Number of subjects
    87
    81
    78
    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)
    0
    0
    0
        Adults (18-64 years)
    87
    81
    78
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    29 ± 4
    29 ± 4
    29 ± 4
    Gender categorical
    Units: Subjects
        Female
    87
    81
    78

    End points

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    End points reporting groups
    Reporting group title
    Test - EVE 112
    Reporting group description
    		 -

    Reporting group title
    Reference - NuvaRing®
    Reporting group description
    		 -

    Subject analysis set title
    SAS
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SAS was defined as all subjects randomised.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all subjects of the SAS, who after randomisation, completed at least one treatment cycle of 28 days, or in whom a Hoogland score >5 was observed in any cycle during randomised treatment.

    Subject analysis set title
    PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS was defined as all subjects randomised • who completely passed the pre-defined treatment regimen and • whose relevant trial variables were available in all treatment cycles, and • who finished the clinical trial without major protocol deviations. PPS was the primary population for the analysis of efficacy endpoints.

    Primary: Ovulation inhibition rate - Hoogland and Skouby score

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    End point title
    		 Ovulation inhibition rate - Hoogland and Skouby score
    End point description
    End point type
    Primary
    End point timeframe
    The ovulation inhibition rate (defined as the proportion of subjects with a Hoogland and Skouby score ≤ 5) in treatment cycle 2 was calculated.
    End point values
    		 Test - EVE 112 Reference - NuvaRing®
    Number of subjects analysed
    39
    39
    Units: percent
        number (not applicable)
    100
    100
    Statistical analysis title
    		 Ovulation inhibition rate
    Statistical analysis description
    The ovulation inhibition rate (defined as the proportion of subjects with a Hoogland score less than or equal to 5) in treatment cycle 2 was calculated in both treatment arms.
    Comparison groups
    Test - EVE 112 v Reference - NuvaRing®
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.025
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0897
         upper limit
    		 0.0897
    Notes
    [1] - The estimated difference between test and reference proportions and the two-sided 95% Wilson score confidence interval of the difference was calculated. If the confidence interval of the difference between proportions is entirely above -10 % (the non-inferiority margin) then Test was considered non-inferior to Reference.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The observation phase for AEs began with start of the treatment and ended with the discharge of the subject from the clinical trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Test - EVE 112
    Reporting group description
    		 -

    Reporting group title
    Reference - NuvaRing®
    Reporting group description
    		 -

    Serious adverse events
    		 Test - EVE 112 Reference - NuvaRing®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 43 (2.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Cerebral vasoconstriction
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Peritonsillar abscess
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Test - EVE 112 Reference - NuvaRing®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 44 (93.18%)
    41 / 43 (95.35%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 44 (45.45%)
    17 / 43 (39.53%)
         occurrences all number
    32
    30
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 44 (11.36%)
    6 / 43 (13.95%)
         occurrences all number
    7
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    11 / 44 (25.00%)
    4 / 43 (9.30%)
         occurrences all number
    16
    4
    Abdominal pain lower
         subjects affected / exposed
    13 / 44 (29.55%)
    2 / 43 (4.65%)
         occurrences all number
    14
    2
    Vomiting
         subjects affected / exposed
    6 / 44 (13.64%)
    1 / 43 (2.33%)
         occurrences all number
    7
    1
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    25 / 44 (56.82%)
    20 / 43 (46.51%)
         occurrences all number
    39
    31
    Dysmenorrhoea
         subjects affected / exposed
    6 / 44 (13.64%)
    3 / 43 (6.98%)
         occurrences all number
    6
    3
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    6 / 44 (13.64%)
    6 / 43 (13.95%)
         occurrences all number
    8
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    17 / 44 (38.64%)
    22 / 43 (51.16%)
         occurrences all number
    19
    25

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2016
    Amendment 01 of the final Clinical trial protocol became necessary due to changes requested by the Ethics Committee. An additional withdrawal criterion (“Venous and/or arterial thromboembolism after inclusion”) considering the known side effects of the Reference product was added in the protocol.
    01 Apr 2016
    The substantial Amendment 02 of final clinical trial protocol became necessary due to planned changes in the conduct of the trial. Following the Sponsor’s decision, the study objectives were changed in such that the nature of the evaluation was changed from a descriptive level to a confirmative assessment. This change led to an increase of the sample size needed to achieve the study objectives, adaptation of the statistical evaluation description, amendment of the definition of FAS. Furthermore, in order to improve retrospective control of treatment compliance, retrospective determination of the active ingredients ethinylestradiol (EE) and/or etonogestrel (ENG) in serum samples already available for progesterone determination in subjects for whom an ovulation has been observed by TVUS, was added. In addition, according to the SmPC of the reference product, definition of day of first insertion of IMP was adapted.

    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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