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    Clinical Trial Results:
    Single center, phase II, open label randomized clinical trial to evaluate the inhibition of ovulation of three prolonged release formulations containing a combination of Dienogest and Ethinyl Estradiol versus a flexible regimen contraceptive containing drospirenone 3mg and Ethinyl Estradiol 20µg in 100 healthy women.

    Summary
    EudraCT number
    		 2016-003830-26
    Trial protocol
    		 DE  
    Global end of trial date
    06 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Oct 2019
    First version publication date
    12 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LPRI-421/201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Exeltis France
    Sponsor organisation address
    7 rue Victor Hugo, Sevres, France, 92310
    Public contact
    Project leader, Chemo Research, +34 917711500, covadonga.paneda@exeltis.com
    Scientific contact
    Project leader, Chemo Research, +34 917711500, covadonga.paneda@exeltis.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
    06 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the inhibition of ovarian activity (Hoogland Score) of LPRI-421 compared with Velmari® Langzyklus in Treatment Cycle 1 and Treatment Cycle 4.
    Protection of trial subjects
    N/A
    Background therapy
    		 N/A
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Mar 2017
    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: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    100
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted between 02 March 2017 and 06 February 2018. A total of 150 subjects were enrolled in the study and screened. One hundred subjects were randomized and received at least 1 dose of IMP, and 84 subjects completed the study. Sixteen subjects discontinued their study participation

    Pre-assignment
    Screening details
    		 Fifty subjects were screening failures: 41 subjects did not meet the inclusion/exclusion criteria 4 were not randomized because the maximum number of subjects in the preferred group had been reached, and 3 withdrew their consent in the screening phase. Two subjects were lost to follow-up in the screening phase

    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
    		 Treatment 1 (T1)
    Arm description
    		 EE/DNG 10 ug/1 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    EE/DNG 10 ug/1 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each tablet contains 10 ug of Ethinyl estradiol and 1 mg of Dienogest. Subjects were asked to take their daily IMP for a period of 87 consecutive days followed by a 4-day pill-free period and then a further 28 consecutive days of active treatment. The first dose was taken on the first or second day of the next menses following the pretreatment cycle, depending on the time of day the menses started. Subjects had to have a negative home pregnancy test before intake of the first dose on the first dosing day. Tablets were taken with a drink, with or without food. Missed tablets were taken as soon as the subject remembered, even if this resulted in 2 tablets being taken on the same day. If vomiting or diarrhea occurred in first 4 hours after taking the tablet, subjects had to take a reserve tablet as soon as the vomiting/diarrhea had stopped.

    Arm title
    		 Treatment 2 (T2)
    Arm description
    		 EE/DNG 10 ug/2 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    EE/DNG 10 ug/2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each tablet contains 10 ug of Ethinyl estradiol and 2 mg of Dienogest. Subjects were asked to take their daily IMP for a period of 87 consecutive days followed by a 4-day pill-free period and then a further 28 consecutive days of active treatment. The first dose was taken on the first or second day of the next menses following the pretreatment cycle, depending on the time of day the menses started. Subjects had to have a negative home pregnancy test before intake of the first dose on the first dosing day. Tablets were taken with a drink, with or without food. Missed tablets were taken as soon as the subject remembered, even if this resulted in 2 tablets being taken on the same day. If vomiting or diarrhea occurred in first 4 hours after taking the tablet, subjects had to take a reserve tablet as soon as the vomiting/diarrhea had stopped.

    Arm title
    		 Treatment 3 (T3)
    Arm description
    		 EE/DNG 20 ug/2 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    EE/DNG 20 ug/2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each tablet contains 20 ug of Ethinyl estradiol and 2 mg of Dienogest. Subjects were asked to take their daily IMP for a period of 87 consecutive days followed by a 4-day pill-free period and then a further 28 consecutive days of active treatment. The first dose was taken on the first or second day of the next menses following the pretreatment cycle, depending on the time of day the menses started. Subjects had to have a negative home pregnancy test before intake of the first dose on the first dosing day. Tablets were taken with a drink, with or without food. Missed tablets were taken as soon as the subject remembered, even if this resulted in 2 tablets being taken on the same day. If vomiting or diarrhea occurred in first 4 hours after taking the tablet, subjects had to take a reserve tablet as soon as the vomiting/diarrhea had stopped.

    Arm title
    		 Velmari
    Arm description
    		 Velmari Langzyklus
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Velmari® Langzyklus 0.02/3 mg tablets (EE 20 μg/drospirenone 3 mg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each tablet contains Ethinylestradiol 20 μg and drospirenone 3 mg. Subjects were asked to take their daily IMP for a period of 87 consecutive days followed by a 4-day pill-free period and then a further 28 consecutive days of active treatment. The first dose was taken on the first or second day of the next menses following the pretreatment cycle, depending on the time of day the menses started. Subjects had to have a negative home pregnancy test before intake of the first dose on the first dosing day. Tablets were taken with a drink, with or without food. Missed tablets were taken as soon as the subject remembered, even if this resulted in 2 tablets being taken on the same day. If vomiting or diarrhea occurred in first 4 hours after taking the tablet, subjects had to take a reserve tablet as soon as the vomiting/diarrhea had stopped.

    Number of subjects in period 1
    		Treatment 1 (T1) Treatment 2 (T2) Treatment 3 (T3) Velmari
    Started
    25
    25
    25
    25
    Completed
    22
    22
    22
    18
    Not completed
    3
    3
    3
    7
         Intake of prohibited medication
    -
    -
    1
    -
         Physician decision
    -
    -
    -
    1
         Adverse event, non-fatal
    2
    2
    -
    3
         Use of emerg. contracep in posttreatment cycles
    -
    -
    1
    -
         Unavailability for visit schedule
    1
    1
    1
    2
         Protocol deviation
    -
    -
    -
    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
    		 100 100
    Age categorical
    Units: Subjects
        Adults (18 - 35)
    		 100 100
    Gender categorical
    Units: Subjects
        Female
    		 100 100
    Subject analysis sets

    Subject analysis set title
    Safety analysis (SA) set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis (SA) set included all subjects who were randomized and received at least 1 dose of the study product. Treatment assignment was based on the treatment actually received.

    Subject analysis set title
    Full Analysis (FA) set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis (FA) set included all subjects of the SA set with at least 1 measurement of the primary efficacy variable

    Subject analysis set title
    Per Protocol (PP) analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol (PP) set included all subjects of the FA set for whom no major protocol deviations were documented

    Subject analysis sets values
    		 Safety analysis (SA) set Full Analysis (FA) set Per Protocol (PP) analysis Set
    Number of subjects
    100
    98
    86
    Age categorical
    Units: Subjects
        Adults (18 - 35)
    100
    98
    86
    Age continuous
    Units:
        
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    100
    98
    86

    End points

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    End points reporting groups
    Reporting group title
    Treatment 1 (T1)
    Reporting group description
    		 EE/DNG 10 ug/1 mg

    Reporting group title
    Treatment 2 (T2)
    Reporting group description
    		 EE/DNG 10 ug/2 mg

    Reporting group title
    Treatment 3 (T3)
    Reporting group description
    		 EE/DNG 20 ug/2 mg

    Reporting group title
    Velmari
    Reporting group description
    		 Velmari Langzyklus

    Subject analysis set title
    Safety analysis (SA) set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis (SA) set included all subjects who were randomized and received at least 1 dose of the study product. Treatment assignment was based on the treatment actually received.

    Subject analysis set title
    Full Analysis (FA) set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis (FA) set included all subjects of the SA set with at least 1 measurement of the primary efficacy variable

    Subject analysis set title
    Per Protocol (PP) analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol (PP) set included all subjects of the FA set for whom no major protocol deviations were documented

    Primary: Hoogland score

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    End point title
    		 Hoogland score [1]
    End point description
    It reflects the ovarian status and will be assessed per cycle based on data from multiple serum analyses of estradiol and progesterone and by multiple ovarian follicle size measurements by TVU at the scheduled visits during the 1st and 4th treatment cycle. The Hoogland score combines follicle size in mm and progesterone/estradiol serum concentrations in nmol/L The maximum Hoogland score observed during the study was used for the efficacy assessment. Three categories were defined based on the Hoogland score: Categories 1 and 2 (scores 1 to 4) were classified as “inhibition of ovulation” for the efficacy assessment.
    End point type
    Primary
    End point timeframe
    Treatment Cycle (TC) 1 and Treatment Cycle (TC) 4
    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: All efficacy parameters were analyzed descriptively per treatment group. No statistical tests were planned
    End point values
    		 Treatment 1 (T1) Treatment 2 (T2) Treatment 3 (T3) Velmari Full Analysis (FA) set Per Protocol (PP) analysis Set
    Number of subjects analysed
    25 [2]
    24 [3]
    25 [4]
    24 [5]
    86
    86
    Units: mm; nmol/L
        scores 1 to 4: inhibition of ovulation
    24
    24
    25
    24
    83
    83
        scores 5 to 6: no inhibition of ovulation
    1
    0
    0
    0
    3
    3
    Notes
    [2] - results for TC 4: inh of ovulation 20 and no inh of ovulation 2
    [3] - For TC 4: inh of ovulation 21 and no inh of ovulation 1
    [4] - For TC 4: inhibition of ovulation 22 and no inhibition of ovulation 0
    [5] - For TC 4: Inhibition of ovulation 20 and No inh of ovulation 0
    No statistical analyses for this end point

    Secondary: Landgren Score

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    End point title
    		 Landgren Score
    End point description
    The Landgren score is based on the serum progesterone measurements at the scheduled visits. The Landgren score was determined in TC 1 and TC 4 if an ovulation was suspected in the TVU examination and if the corresponding Hoogland score was 5 or 6, and additionally in a T1 subject with a Hoogland score of 4 in TC 4 based on the investigator’s decision. Thus, there were 5 Landgren score determinations in total (T1: 4 cases; T2: 1 case). The Landgren score was positive in one T1 subject during TC 4 and negative in all other cases.
    End point type
    Secondary
    End point timeframe
    TC1 and TC4
    End point values
    		 Treatment 1 (T1) Treatment 2 (T2) Treatment 3 (T3) Velmari Full Analysis (FA) set
    Number of subjects analysed
    25 [6]
    24 [7]
    25 [8]
    24 [9]
    98 [10]
    Units: positive/negative
        Positive
    0
    0
    0
    0
    0
        Negative
    1
    0
    0
    0
    1
        Not analyzed
    24
    24
    25
    24
    97
    Notes
    [6] - in TC 4: 1 Positive; 2 Negative; 19 Not analyzed
    [7] - In TC 4: 0 positive; 1 negative; 22 not analyzed
    [8] - In TC 4: 0 positive; 0 negative; 23 not analyzed
    [9] - In TC 4: 0 positive; 0 negative; 22 not analyzed
    [10] - In TC 4: 1 positive; 3 negative; 86 not analyzed
    No statistical analyses for this end point

    Secondary: Insler Score

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    End point title
    		 Insler Score
    End point description
    The cervix condition will be evaluated by means of the Insler Score during the precycle, TC 1 and TC 4 whenever a follicle size ≥13 mm. The Insler Score was developed and used as an instrument for timing fertilization and reflects the cervical condition for a possible ascension of the sperms. High values correspond to an excellent condition for sperm ascension under high estrogen influence during ovulation and low values mean worse condition for sperm ascension. The Insler Score comprises the following criteria: a) cervix status by inspection; b) amount of mucus by inspection; c) spinnability of the mucus by spreading a mucus sample in a sponge forceps; d) ferning by microscopy. The following evaluation will be made based on the Insler scoring criteria: 0 - 3 points = negative 4 - 6 points = slight 7 - 9 points = moderate 10 - 12 points = full
    End point type
    Secondary
    End point timeframe
    TC1 and TC4
    End point values
    		 Treatment 1 (T1) Treatment 2 (T2) Treatment 3 (T3) Velmari Full Analysis (FA) set
    Number of subjects analysed
    25 [11]
    24 [12]
    25 [13]
    24 [14]
    98 [15]
    Units: points
        full
    1
    0
    0
    0
    1
        moderate
    3
    3
    0
    2
    8
        negative/slight
    21
    21
    25
    22
    89
    Notes
    [11] - for TC 4: 1 Full; 7 Moderate; 17 negative/slight
    [12] - for TC 4: 0 Full; 1 Moderate; 23 negative/slight
    [13] - for TC 4: 0 Full; 1 Moderate; 24 negative/slight
    [14] - for TC 4: 0 Full; 1 Moderate; 23 negative/slight
    [15] - for TC 4: 1 Full; 10 Moderate; 87 negative/slight
    No statistical analyses for this end point

    Secondary: Transvaginal ultrasound

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    End point title
    		 Transvaginal ultrasound
    End point description
    The TVU will assess the reproductive organs including the uterus, cervix, endometrium and follicle diameter (left and right ovary). Any abnormalities detected in the bladder will be documented however inspection of the bladder is not routine at every visit. The Douglas pouch will be assessed during screening and at the final examination. The maximum follicle diameter and endometrial thickness will be recorded for both ovaries in the eCRF. Any abnormalities seen must be documented.
    End point type
    Secondary
    End point timeframe
    Uterus condition: at screening and final examination Endometrial Thickness: at each visit Mean diameter of largest follicle: D12 of pretreatment and D27 of posttreatment
    End point values
    		 Treatment 1 (T1) Treatment 2 (T2) Treatment 3 (T3) Velmari Full Analysis (FA) set
    Number of subjects analysed
    25
    24
    25
    24
    98
    Units: N/A
    25
    24
    25
    24
    98
    No statistical analyses for this end point

    Secondary: Serum levels of progesterone (P4), E2, FSH and LH

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    End point title
    		 Serum levels of progesterone (P4), E2, FSH and LH
    End point description
    Serum levels of progesterone were used for (a) determining the Hoogland score; (b) confirming a sonographically suspected ovulation; and (c) determining the Landgren score.
    End point type
    Secondary
    End point timeframe
    Progesterone: T1 (TC3), T2 (TC4), T3 (TC1), Velmari: (TC4) Estradiol: T1 (TC4), T2 (TC4), T3 (TC4), Velmari: (TC1) FSH: T1 (TC1), T2 (TC1), T3 (TC4), Velmari: (TC1) LH: T1 (TC4), T2 (TC4), T3 (TC4), Velmari: (TC1)
    End point values
    		 Treatment 1 (T1) Treatment 2 (T2) Treatment 3 (T3) Velmari Full Analysis (FA) set
    Number of subjects analysed
    25
    24
    25
    24
    98
    Units: nmol/L
    25
    24
    25
    24
    98
    No statistical analyses for this end point

    Secondary: vital signs

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    End point title
    		 vital signs
    End point description
    End point type
    Secondary
    End point timeframe
    Vital signs (including heart rate, systolic and diastolic blood pressure) will be summarized using descriptive statistics at run in/screening phase and at each post-screening time point.
    End point values
    		 Treatment 1 (T1) Treatment 2 (T2) Treatment 3 (T3) Velmari Safety analysis (SA) set
    Number of subjects analysed
    25
    25
    25
    25
    100
    Units: N/A
    25
    25
    25
    25
    100
    No statistical analyses for this end point

    Secondary: Clinical Laboratory Evaluation

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    End point title
    		 Clinical Laboratory Evaluation
    End point description
    End point type
    Secondary
    End point timeframe
    Laboratory parameters (clinical chemistry, haematology, serology (HBsAg, HBV, HCV and HIV) and urinalysis) will be summarized using descriptive statistics at run in/screening phase and at each post-screening time point.
    End point values
    		 Treatment 1 (T1) Treatment 2 (T2) Treatment 3 (T3) Velmari Safety analysis (SA) set
    Number of subjects analysed
    25
    25
    25
    25
    100
    Units: N/A
    25
    25
    25
    25
    100
    No statistical analyses for this end point

    Secondary: Adverse events

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    End point title
    		 Adverse events
    End point description
    All adverse event summaries will be restricted to Treatment Emergent Adverse Events (TEAE), which are defined as those AEs that occurred after dosing and those existing AEs that worsened during the study. If it cannot be determined whether the AE is treatment emergent due to a partial onset date then it will be counted as such
    End point type
    Secondary
    End point timeframe
    AEs should be reported up to 28 days after the last adm of the IMP. Also, any reportable AEs that are unresolved at the subject’s LV in the study will be FU by the Investigator for as long as medically indicated, but without further recording in the eCRF
    End point values
    		 Treatment 1 (T1) Treatment 2 (T2) Treatment 3 (T3) Velmari Safety analysis (SA) set
    Number of subjects analysed
    25
    25
    25
    25
    100
    Units: N/A
    25
    25
    25
    25
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs should be reported up to 28 days after the last administration of the IMP. Also, Any reportable AEs that are unresolved at the subject’s last visit in the study will be followed up by the Investigator for as long as medically indicated.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Safety Set
    Reporting group description
    		 -

    Serious adverse events
    		 Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 100 (1.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    99 / 100 (99.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Vascular disorders
    Hot flush
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    5
    Surgical and medical procedures
    Breast operation
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Endodontic procedure
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Jaw operation
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    10 / 100 (10.00%)
         occurrences all number
    11
    Peripheral swelling
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    3
    Chest discomfort
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    2
    Malaise
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Sensitivity to weather change
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Swelling
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Vessel puncture site haematoma
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Hypersensitivity
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Seasonal allergy
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Breast discomfort
         subjects affected / exposed
    17 / 100 (17.00%)
         occurrences all number
    17
    Ovarian cyst
         subjects affected / exposed
    13 / 100 (13.00%)
         occurrences all number
    20
    Breast enlargement
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    6
    Dysmenorrhoea
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    9
    Vulvovaginal pruritus
         subjects affected / exposed
    4 / 100 (4.00%)
         occurrences all number
    4
    Vaginal haemorrhage
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    3
    Breast pain
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Pelvic pain
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Vaginal discharge
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    3
    Vulvovaginal dryness
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Breast tenderness
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Fibrocystic breast disease
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Menorrhagia
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Vulvovaginal discomfort
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Vulvovaginal pain
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    5
    Oropharyngeal pain
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    5
    Dry throat
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Psychiatric disorders
    Mood altered
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    7
    Affective disorder
         subjects affected / exposed
    4 / 100 (4.00%)
         occurrences all number
    4
    Irritability
         subjects affected / exposed
    4 / 100 (4.00%)
         occurrences all number
    6
    Libido decreased
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    3
    Anxiety
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Depressed mood
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Nightmare
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 100 (4.00%)
         occurrences all number
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    3
    Blood urea decreased
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Nitrite urine present
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Weight increased
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    3
    Blood bilirubin increased
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Platelet count decreased
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Platelet count increased
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Protein total decreased
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Weight decreased
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    5
    Contusion
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Ligament sprain
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Sunburn
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Arthropod sting
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Thermal burn
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Traumatic haematoma
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    49 / 100 (49.00%)
         occurrences all number
    124
    Dizziness
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    3
    Paraesthesia
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Migraine
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    20 / 100 (20.00%)
         occurrences all number
    30
    Nausea
         subjects affected / exposed
    14 / 100 (14.00%)
         occurrences all number
    20
    Diarrhoea
         subjects affected / exposed
    13 / 100 (13.00%)
         occurrences all number
    14
    Vomiting
         subjects affected / exposed
    11 / 100 (11.00%)
         occurrences all number
    13
    Abdominal pain
         subjects affected / exposed
    7 / 100 (7.00%)
         occurrences all number
    8
    Abdominal pain upper
         subjects affected / exposed
    4 / 100 (4.00%)
         occurrences all number
    4
    Flatulence
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Gastritis
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Toothache
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    3
    Abdominal discomfort
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Douglas' pouch mass
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Swollen tongue
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    11 / 100 (11.00%)
         occurrences all number
    12
    Alopecia
         subjects affected / exposed
    4 / 100 (4.00%)
         occurrences all number
    4
    Blister
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Dermatitis allergic
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Night sweats
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Seborrhoea
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Skin odour abnormal
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    13 / 100 (13.00%)
         occurrences all number
    14
    Leukocyturia
         subjects affected / exposed
    12 / 100 (12.00%)
         occurrences all number
    14
    Dysuria
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Ketonuria
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Proteinuria
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Micturition urgency
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 100 (4.00%)
         occurrences all number
    5
    Arthralgia
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    3
    Muscle spasms
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Neck pain
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences all number
    2
    Joint swelling
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    62 / 100 (62.00%)
         occurrences all number
    76
    Vulvovaginal candidiasis
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    6
    Gastrointestinal infection
         subjects affected / exposed
    4 / 100 (4.00%)
         occurrences all number
    4
    Oral herpes
         subjects affected / exposed
    4 / 100 (4.00%)
         occurrences all number
    5
    Sinusitis
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    3
    Vaginal infection
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    4
    Candida infection
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    4
    Conjunctivitis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Cystitis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Eye abscess
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Infected bite
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Otitis externa
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    2
    Paronychia
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Tooth infection
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    4
    Increased appetite
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences all number
    3
    Fluid retention
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2017
    - First visit subject is changed from January 2017 to 02-March-2017 - For PK compliance check blood samples will be taken at every visit during TC1 and TC4 and when the sonographically suspected ovulation is confirmed the EE concentration will be measured in 3 blood samples: day of sonographically suspected ovulation under treatment and in blood samples taken at the 2 previous visits (-3 days and -6 days). - blood volumes in laboratory analysis corrected. - other minor corrections to the protocol requested by the EC or for clarification

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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