Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43857   clinical trials with a EudraCT protocol, of which   7284   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Assessment of therapeutical equivalence of a newly developed vaginal tablet containing 10 μg of estradiol in comparison with a marketed reference product (Vagifem®) – a double-blind, double-dummy, multiple dose, parallel-group, placebo- and active-controlled trial with additional characterisation of systemic exposure in postmenopausal female volunteers suffering from vaginal atrophy

    Summary
    EudraCT number
    		 2017-000142-22
    Trial protocol
    		 DE  
    Global end of trial date
    17 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2020
    First version publication date
    11 Oct 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    148-2016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 1335esd16ct: CRO trial number
    Sponsors
    Sponsor organisation name
    Helm AG
    Sponsor organisation address
    Nordkanalstrasse 28, Hamburg, Germany, 20097
    Public contact
    Clinical Development, Helm AG, +49 40 2375 1798, Irina.Maslova@helmag.com
    Scientific contact
    Clinical Development, Helm AG, +49 40 2375 1798, Irina.Maslova@helmag.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
    21 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - Characterisation and comparison of efficacy of Test vs. Reference with regard to pharmacodynamic (PD) surrogate parameters (primary endpoints: change from baseline of vaginal maturation value after 2 weeks of treatment and change from baseline of vaginal pH after 6 weeks of treatment) - Assessment of superiority of Test vs. Placebo with regard to PD primary endpoints - Assessment of therapeutic equivalence of Test vs. Reference with regard to PD primary endpoints - Characterisation of systemic exposure by means of AUC- and Cmax–values of Test and Reference vaginal tablets containing 10 μg estradiol on Day 14 after multiple dose vaginal application (PK group) - Descriptive characterisation of safety and tolerability of the Test and Reference treatments.
    Protection of trial subjects
    Prior to recruitment of patients, all relevant documents of the clinical study were submitted and approved 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 patient information sheet described the planned and permitted uses, transfers and disclosures of the patient's personal data and personal health information for purposes of conducting the study. The informed consent form and the patient 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 patient 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 patient’s consent was obtained in writing before the start of the study. By signing the informed consent, the patient 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
    		 Any pre-existing long-term medication for treatment of existing disorders, which was not considered to interfere with absorption, efficacy, or safety of the IMP or is not listed in the restrictions was permitted.
    Evidence for comparator
    		 Comparators were the following products: a) Marketed reference product Vagifem® 10 µg vaginal tablets (Novo Nordisk, Denmark) b) Placebo for Test (Aenova Holding GmbH, Germany on behalf of Helm AG, Germany) c) Placebo for Reference (Aenova Holding GmbH, Germany on behalf of Helm AG, Germany)
    Actual start date of recruitment
    28 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Moldova, Republic of: 242
    Country: Number of subjects enrolled
    Bulgaria: 188
    Country: Number of subjects enrolled
    Germany: 44
    Worldwide total number of subjects
    474
    EEA total number of subjects
    232
    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)
    369
    From 65 to 84 years
    103
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 In total, 474 female subjects were enrolled in the study. The pharmacokinetic group included 27 subjects in total from Germany. The pharmacodynamic group included 17 subjects from Germany, 188 subjects from Bulgaria and 242 subjects from Moldova.

    Pre-assignment
    Screening details
    		 In total 1736 subjctes were screened for the study. From 56 subjects screened for the pharmacokinetic group, 27 subjects were randomised into this study group. From 1680 subjects screened for the pharmacodynamic group, 447 subjects were randomised into this study group.

    Period 1
    Period 1 title
    Pharmacodynamic Group
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    In order to avoid bias the study was realised with a double-blinded approach in the Pharmacodynamic group for assessment of efficacy, i.e. subjects and investigators as well as the laboratory have not been aware of the treatment administered. Test and Reference vaginal tablets were visually similar but the difficulty for blinding arose from the different application devices. To overcome this drawback the study has been planned with a double-dummy approach for the Pharmacodynamic group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Estradiol 10 µg - Test
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Estradiol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal tablet
    Routes of administration
    Vaginal use
    Dosage and administration details
    Intravaginal application of 1 tablet of Estradiol and 1 tablet of Placebo per day for 14 days (initial treatment period) followed by intravaginal application of 1 tablet of Estradiol and 1 tablet of Placebo-Reference twice a week for 4 weeks (maintenance treatment period).

    Arm title
    		 Vagifem 10 µg - Reference
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vagifem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal tablet
    Routes of administration
    Vaginal use
    Dosage and administration details
    Intravaginal application of 1 tablet of Vagifem and 1 tablet of Placebo per day for 14 days (initial treatment period) followed by intravaginal application of 1 tablet of Vagifem and 1 tablet of Placebo-Test twice a week for 4 weeks (maintenance treatment period).

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal tablet
    Routes of administration
    Vaginal use
    Dosage and administration details
    Intravaginal application of 1 tablet of Placebo-Reference and 1 tablet of Placebo-Test per day for 14 days (initial treatment period) followed by intravaginal application of 1 tablet of Placebo-Reference and 1 tablet of Placebo-Test twice a week for 4 weeks (maintenance treatment period).

    Number of subjects in period 1 [1]
    		Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Started
    203
    179
    60
    Completed
    196
    163
    56
    Not completed
    7
    16
    4
         Adverse event, serious fatal
    -
    1
    -
         Consent withdrawn by subject
    3
    7
    4
         Adverse event, non-fatal
    2
    3
    -
         Protocol deviation
    2
    5
    -
    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: The study consisted of two independent parts, a pharmacokinetic (PK)- and a pharmacodynamic (PD)- part. Due to presentation purposes, PD-group was definded as period 1 (baseline period). Different subjects were enrolled in PK- and PD-group. Thus, number of subjects in the baseline period 1 (PD-group) is not the same as the worldwide number enrolled in the trial (PD- + PK-group).
    Period 2
    Period 2 title
    Pharmacokinetic Group
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    For the PK group, no blinding was necessary, since within this group the focus of the clinical trial was set on the characterisation of the systemic estradiol exposure as a surrogate safety parameter. Thus, for this group the trial was open for both, subjects and investigators but blinded with respect to the bioanalytical laboratory.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Estradiol 10 µg - Test
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Estradiol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal tablet
    Routes of administration
    Vaginal use
    Dosage and administration details
    Intravaginal application of 1 tablet per day for 14 days.

    Arm title
    		 Vagifem 10 µg - Reference
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vagifem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal tablet
    Routes of administration
    Vaginal use
    Dosage and administration details
    Intravaginal application of 1 tablet per day for 14 days.

    Number of subjects in period 2 [2]
    		Estradiol 10 µg - Test Vagifem 10 µg - Reference
    Started
    13
    14
    Completed
    13
    14
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The study consisted of two independent parts, a pharmacokinetic (PK)- and a pharmacodynamic (PD)- part. Different subjects were enrolled in PK- and PD-group. Due to presentation purposes, PD-group was definded as period 1 and PK-group was defined as period 2. Period 1 and period 2 were independent study parts and not subsequent study periods. Thus, numbers of subject starting the single periods are different.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Pharmacodynamic Group
    Reporting group description
    		 -

    Reporting group values
    		 Pharmacodynamic Group Total
    Number of subjects
    		 442 442
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 350 350
        From 65-84 years
    		 90 90
        85 years and over
    		 2 2
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 59.0 (45 to 96) -
    Gender categorical
    Units: Subjects
        Female
    		 442 442
        Male
    		 0 0
    Subject analysis sets

    Subject analysis set title
    PPS_PK
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS was defined as all subjects that: • were randomised • were included in the pharmacokinetic part of the clinical trial • finished the pharmacokinetic part of the clinical trial with no major protocol deviations as defined in the trial protocol and the Statistical Analysis Plan, in particular: o randomized treatment not administered or wrong treatment administered o missing PK samples which result in insufficient profiling

    Subject analysis set title
    FAS_PK
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all subjects randomised into the trial as subject of the pharmacokinetic arm.

    Subject analysis set title
    SAS_PK
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SAS was defined as all subjects that: • were randomised into the trial as subject of the pharmacokinetic arm • received the investigational drug at least once.

    Subject analysis set title
    PPS_PD
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects that were randomized and finished the trial as defined in the protocol without major protocol deviations in particular regarding compliance with the treatment and, thus, being a complete case. The conventions for missed IMP applications apply: - Initial treatment period: At least 80 % of the total IMP-dose had to be applied during the initial phase. Missing IMP applications on single days (but not on subsequent study days) were not considered relevant, because the exposure to IMP was sufficient. - Maintenance period: IMP application had to be performed on at least 7 out of 8 days and was not allowed to exceed a maximum of 9 application days to be compliant to the protocol. - Duration of the maintenance phase was compliant to the protocol if visit 4 was held within 4 days after the last IMP application and within 28±4 days after visit 3. - A complete case was defined as a subject for whom a result for maturation value was available on at least visits 01, 02 and 04.

    Subject analysis set title
    mFAS_PD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The modified Full Analysis Sets were defined to include all subjects that: • were randomised • received the investigational drug at least once. • fulfilled all major entry criteria • provided at least one data value necessary post-baseline for the primary endpoints All subjects for whom the mFAS definition was applicable and who were included in either evaluation of the first stage, evaluation of the second stage or the combined PD analysis, i.e. combining subjects from first stage (interim) analysis and second stage analysis.

    Subject analysis set title
    SAS_PD
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SASPD was defined as all subjects that: • were randomised • received the investigational drug at least once.

    Subject analysis sets values
    		 PPS_PK FAS_PK SAS_PK PPS_PD mFAS_PD SAS_PD
    Number of subjects
    27
    27
    27
    394
    432
    442
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    15
    15
    15
    315
    342
    350
        From 65-84 years
    12
    12
    12
    77
    88
    90
        85 years and over
    0
    0
    0
    2
    2
    2
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    61.9 (49 to 78)
    61.9 (49 to 78)
    61.9 (49 to 78)
    59.0 (45 to 96)
    59.1 (45 to 96)
    59.0 (45 to 96)
    Gender categorical
    Units: Subjects
        Female
    27
    27
    27
    394
    432
    442
        Male
    0
    0
    0
    0
    0
    0

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Estradiol 10 µg - Test
    Reporting group description
    		 -

    Reporting group title
    Vagifem 10 µg - Reference
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    Estradiol 10 µg - Test
    Reporting group description
    		 -

    Reporting group title
    Vagifem 10 µg - Reference
    Reporting group description
    		 -

    Subject analysis set title
    PPS_PK
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS was defined as all subjects that: • were randomised • were included in the pharmacokinetic part of the clinical trial • finished the pharmacokinetic part of the clinical trial with no major protocol deviations as defined in the trial protocol and the Statistical Analysis Plan, in particular: o randomized treatment not administered or wrong treatment administered o missing PK samples which result in insufficient profiling

    Subject analysis set title
    FAS_PK
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all subjects randomised into the trial as subject of the pharmacokinetic arm.

    Subject analysis set title
    SAS_PK
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SAS was defined as all subjects that: • were randomised into the trial as subject of the pharmacokinetic arm • received the investigational drug at least once.

    Subject analysis set title
    PPS_PD
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects that were randomized and finished the trial as defined in the protocol without major protocol deviations in particular regarding compliance with the treatment and, thus, being a complete case. The conventions for missed IMP applications apply: - Initial treatment period: At least 80 % of the total IMP-dose had to be applied during the initial phase. Missing IMP applications on single days (but not on subsequent study days) were not considered relevant, because the exposure to IMP was sufficient. - Maintenance period: IMP application had to be performed on at least 7 out of 8 days and was not allowed to exceed a maximum of 9 application days to be compliant to the protocol. - Duration of the maintenance phase was compliant to the protocol if visit 4 was held within 4 days after the last IMP application and within 28±4 days after visit 3. - A complete case was defined as a subject for whom a result for maturation value was available on at least visits 01, 02 and 04.

    Subject analysis set title
    mFAS_PD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The modified Full Analysis Sets were defined to include all subjects that: • were randomised • received the investigational drug at least once. • fulfilled all major entry criteria • provided at least one data value necessary post-baseline for the primary endpoints All subjects for whom the mFAS definition was applicable and who were included in either evaluation of the first stage, evaluation of the second stage or the combined PD analysis, i.e. combining subjects from first stage (interim) analysis and second stage analysis.

    Subject analysis set title
    SAS_PD
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SASPD was defined as all subjects that: • were randomised • received the investigational drug at least once.

    Primary: AUC0-TAU

    		 Close Top of page
    End point title
    		 AUC0-TAU [1]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline: 1 h, 0.5 h and immediately (within 5 minutes) prior to first IMP application Post-dose: within 5 minutes prior to the 14th IMP application and 2 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 16 h and 24 h after the 14th IMP application.
    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 formal statistial hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference
    Number of subjects analysed
    13
    14
    Units: h*pg/ml
        geometric mean (geometric coefficient of variation)
    77.89 ± 62.63
    101.50 ± 32.16
    No statistical analyses for this end point

    Primary: Cmax

    		 Close Top of page
    End point title
    		 Cmax [2]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline samples: 1 h, 0.5 h and immediately (within 5 minutes) prior to first IMP application Post-dose: within 5 minutes prior to the 14th IMP application and 2 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 16 h and 24 h after the 14th IMP application
    Notes
    [2] - 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 formal statistial hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference
    Number of subjects analysed
    13
    14
    Units: pg/ml
        geometric mean (geometric coefficient of variation)
    6.79 ± 68.30
    7.84 ± 37.16
    No statistical analyses for this end point

    Primary: Vaginal pH value

    		 Close Top of page
    End point title
    		 Vaginal pH value
    End point description
    Statistical analysis (change from study day 1 to study day 43) is reported for the mFAS_PD. Superiority (Test-Placebo) is reported for the mFAS_PD stage 1. Numbers of subjects included in the analysis of endpoint values (vaginal pH value): Period 1 Estradiol 10 µg - Test: 195 Period 1 Vagifem 10 µg - Reference: 167 Period 1 Placebo: 56
    End point type
    Primary
    End point timeframe
    From study day 1 to study day 43.
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    200
    174
    58
    Units: unit(s)
        arithmetic mean (standard deviation)
    -1.44 ± 0.97
    -1.48 ± 0.93
    -0.52 ± 0.73
    Statistical analysis title
    		 Superiority Test - Placebo
    Comparison groups
    Estradiol 10 µg - Test v Placebo
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 ≤ 0.025
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.938406
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -1.19929
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.131961
    Notes
    [3] - Superiority with regard to Placebo had been demonstrated in the interim analysis of the trial and therefore the Placebo arm was omitted after the first stage of the trial. Therfore the number of subjects calculated automatically for this statistical anaylsis is not correct. The numbers of subjects in this analysis are the following: Period 1 Estradiol 10 µg - Test: 104 Period 1 Placebo: 45
    Statistical analysis title
    		 Non-inferiority Theta0= ±0.4
    Statistical analysis description
    Numbers of subjects included in the statistical analysis (non-inferitority, vaginal pH value): 362.
    Comparison groups
    Estradiol 10 µg - Test v Vagifem 10 µg - Reference
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.008673
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13082
         upper limit
    		 0.14816
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.070929
    Notes
    [4] - For the euqivalence tests (non-inferiority), the two one-sided tests procedure will be applied with one-sided tests performed at global level 0.05.

    Primary: Vaginal maturation value

    		 Close Top of page
    End point title
    		 Vaginal maturation value
    End point description
    Statistical analysis (change from study day 1 to study day 15) is reported for the mFAS_PD. Superiority (Test - Placebo) is reported for the mFAS_PD stage 1. Numbers of subjects included in the analysis of endpoint values (vaginal maturation value): Period 1 Estradiol 10 µg - Test: 195 Period 1 Vagifem 10 µg - Reference: 169 Period 1 Placebo: 57
    End point type
    Primary
    End point timeframe
    From study day 1 to study day 15.
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    200
    174
    58
    Units: percent
        arithmetic mean (standard deviation)
    21.57 ± 20.28
    24.06 ± 20.39
    2.07 ± 14.15
    Statistical analysis title
    		 Superiority Test - Placebo
    Comparison groups
    Estradiol 10 µg - Test v Placebo
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 ≤ 0.025
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    18.599367
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 13.18557
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.738069
    Notes
    [5] - Superiority with regard to Placebo had been demonstrated in the interim analysis of the trial and therefore the Placebo arm was omitted after the first stage of the trial. Therfore the number of subjects calculated automatically for this statistical anaylsis is not correct. The numbers of subjects in this analysis are the following: Period 1 Estradiol 10 µg - Test: 104 Period 1 Placebo: 45
    Statistical analysis title
    		 Non-inferiority (Theta0= ±6.5)
    Statistical analysis description
    Numbers of subjects included in the statistical analysis (non-inferitority, vaginal pH value): 369.
    Comparison groups
    Estradiol 10 µg - Test v Vagifem 10 µg - Reference
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.862664
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.98559
         upper limit
    		 1.26026
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.588064
    Notes
    [6] - For the equivalence tests (non-inferiority), the two one-sided tests procedure will be applied with one-sided tests performed at global level 0.05.

    Secondary: Investigator assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - dry vaginal mucosa

    		 Close Top of page
    End point title
    		 Investigator assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - dry vaginal mucosa
    End point description
    End point type
    Secondary
    End point timeframe
    study day 1 (visit 2)
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    200
    174
    58
    Units: units
        arithmetic mean (standard deviation)
    2.1 ± 0.8
    2.1 ± 0.7
    2.1 ± 0.7
    No statistical analyses for this end point

    Secondary: Investigator assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - flattening of folds

    		 Close Top of page
    End point title
    		 Investigator assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - flattening of folds
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 1 (visit 2).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    200
    174
    58
    Units: units
        arithmetic mean (standard deviation)
    2.0 ± 0.8
    2.0 ± 0.8
    2.1 ± 0.7
    No statistical analyses for this end point

    Secondary: Investigator assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - pallor of the mucosa

    		 Close Top of page
    End point title
    		 Investigator assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - pallor of the mucosa
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 1 (visit 2).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    200
    174
    58
    Units: units
        arithmetic mean (standard deviation)
    1.9 ± 0.8
    1.8 ± 0.8
    1.8 ± 0.7
    No statistical analyses for this end point

    Secondary: Investigator assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - fragility of the mucosa

    		 Close Top of page
    End point title
    		 Investigator assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - fragility of the mucosa
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 1 (visit 2).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    200
    174
    58
    Units: units
        arithmetic mean (standard deviation)
    1.8 ± 0.9
    1.7 ± 0.9
    1.7 ± 0.9
    No statistical analyses for this end point

    Secondary: Investigator assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - presence of petechiae

    		 Close Top of page
    End point title
    		 Investigator assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - presence of petechiae
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 1 (visit 2).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    200
    174
    58
    Units: units
        arithmetic mean (standard deviation)
    1.3 ± 1.0
    1.2 ± 1.0
    1.2 ± 1.0
    No statistical analyses for this end point

    Secondary: Investigator assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - dry vaginal mucosa

    		 Close Top of page
    End point title
    		 Investigator assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - dry vaginal mucosa
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 43 (visit 4)
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    195
    167
    56
    Units: units
        arithmetic mean (standard deviation)
    0.6 ± 0.8
    0.6 ± 0.8
    1.0 ± 0.8
    No statistical analyses for this end point

    Secondary: Investigator assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - flattening of folds

    		 Close Top of page
    End point title
    		 Investigator assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - flattening of folds
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 43 (visit 4).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    195
    167
    56
    Units: units
        arithmetic mean (standard deviation)
    0.7 ± 0.8
    0.7 ± 0.7
    1.0 ± 0.9
    No statistical analyses for this end point

    Secondary: Investigator assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - pallor of the mucosa

    		 Close Top of page
    End point title
    		 Investigator assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - pallor of the mucosa
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 43 (visit 4).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    195
    167
    58
    Units: units
        arithmetic mean (standard deviation)
    0.6 ± 0.7
    0.5 ± 0.7
    0.9 ± 0.8
    No statistical analyses for this end point

    Secondary: Investigator assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - fragility of the mucosa

    		 Close Top of page
    End point title
    		 Investigator assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - fragility of the mucosa
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 43 (visit 4).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    195
    167
    56
    Units: units
        arithmetic mean (standard deviation)
    0.4 ± 0.7
    0.3 ± 0.5
    0.7 ± 0.8
    No statistical analyses for this end point

    Secondary: Investigator assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - presence of petechiae

    		 Close Top of page
    End point title
    		 Investigator assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - presence of petechiae
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 43 (visit 4).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    195
    167
    56
    Units: unit(s)
        arithmetic mean (standard deviation)
    0.2 ± 0.5
    0.2 ± 0.5
    0.5 ± 0.8
    No statistical analyses for this end point

    Secondary: Subject assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - vaginal dryness

    		 Close Top of page
    End point title
    		 Subject assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - vaginal dryness
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 1 (visit 2).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    200
    174
    58
    Units: units
        arithmetic mean (standard deviation)
    2.0 ± 0.8
    2.1 ± 0.7
    1.9 ± 0.7
    No statistical analyses for this end point

    Secondary: Subject assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - vaginal and/or vulvar irritation/itching

    		 Close Top of page
    End point title
    		 Subject assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - vaginal and/or vulvar irritation/itching
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 1 (visit 2).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    200
    174
    58
    Units: units
        arithmetic mean (standard deviation)
    1.6 ± 1.0
    1.5 ± 1.1
    1.5 ± 1.0
    No statistical analyses for this end point

    Secondary: Subject assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - vaginal soreness

    		 Close Top of page
    End point title
    		 Subject assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - vaginal soreness
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 1 (visit 2).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    200
    174
    58
    Units: units
        arithmetic mean (standard deviation)
    1.4 ± 1.0
    1.3 ± 1.0
    1.3 ± 1.0
    No statistical analyses for this end point

    Secondary: Subject assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - dysuria

    		 Close Top of page
    End point title
    		 Subject assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - dysuria
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 1 (visit 2).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    200
    174
    58
    Units: units
        arithmetic mean (standard deviation)
    1.3 ± 1.1
    1.3 ± 1.0
    1.2 ± 1.0
    No statistical analyses for this end point

    Secondary: Subject assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - dyspareunia and vaginal bleeding associated with sexual activity

    		 Close Top of page
    End point title
    		 Subject assessment of vaginal health - signs of vaginal atrophy study day 1 (visit 2) - dyspareunia and vaginal bleeding associated with sexual activity
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 1 (visit 2).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    200
    174
    58
    Units: units
        arithmetic mean (standard deviation)
    1.4 ± 1.1
    1.3 ± 1.1
    1.2 ± 1.0
    No statistical analyses for this end point

    Secondary: Subject assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - dysuria

    		 Close Top of page
    End point title
    		 Subject assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - dysuria
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 43 (visit 4).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    196
    167
    56
    Units: units
        arithmetic mean (standard deviation)
    0.3 ± 0.5
    0.3 ± 0.6
    0.4 ± 0.7
    No statistical analyses for this end point

    Secondary: Subject assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - vaginal soreness

    		 Close Top of page
    End point title
    		 Subject assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - vaginal soreness
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 43 (visit 4).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    196
    167
    56
    Units: unis
        arithmetic mean (standard deviation)
    0.3 ± 0.6
    0.3 ± 0.6
    0.4 ± 0.6
    No statistical analyses for this end point

    Secondary: Subject assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - vaginal and/or vulvar irritation/itching

    		 Close Top of page
    End point title
    		 Subject assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - vaginal and/or vulvar irritation/itching
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 43 (visit 4).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    196
    167
    56
    Units: units
        arithmetic mean (standard deviation)
    0.3 ± 0.5
    0.3 ± 0.5
    0.4 ± 0.6
    No statistical analyses for this end point

    Secondary: Subject assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - vaginal dryness

    		 Close Top of page
    End point title
    		 Subject assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - vaginal dryness
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 43 (visit 4).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    196
    167
    56
    Units: units
        arithmetic mean (standard deviation)
    0.5 ± 0.7
    0.5 ± 0.8
    0.7 ± 0.8
    No statistical analyses for this end point

    Secondary: Subject assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - dyspareunia and vaginal bleeding associated with sexual activity

    		 Close Top of page
    End point title
    		 Subject assessment of vaginal health - signs of vaginal atrophy study day 43 (visit 4) - dyspareunia and vaginal bleeding associated with sexual activity
    End point description
    End point type
    Secondary
    End point timeframe
    Study day 43 (visit 4).
    End point values
    		 Estradiol 10 µg - Test Vagifem 10 µg - Reference Placebo
    Number of subjects analysed
    196
    167
    56
    Units: units
        arithmetic mean (standard deviation)
    0.3 ± 0.5
    0.3 ± 0.6
    0.5 ± 0.7
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    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
    21.1
    Reporting groups
    Reporting group title
    Pharmacodynamic Group -Test-
    Reporting group description
    		 -

    Reporting group title
    Pharmacokinetic Group -Test-
    Reporting group description
    		 -

    Reporting group title
    Pharmacodynamic Group -Reference-
    Reporting group description
    		 -

    Reporting group title
    Pharmacodynamic Group -Placebo-
    Reporting group description
    		 -

    Reporting group title
    Pharmacokinetic Group -Reference-
    Reporting group description
    		 -

    Serious adverse events
    		 Pharmacodynamic Group -Test- Pharmacokinetic Group -Test- Pharmacodynamic Group -Reference- Pharmacodynamic Group -Placebo- Pharmacokinetic Group -Reference-
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 203 (1.48%)
    0 / 13 (0.00%)
    1 / 179 (0.56%)
    0 / 60 (0.00%)
    0 / 14 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 13 (0.00%)
    0 / 179 (0.00%)
    0 / 60 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 203 (0.00%)
    0 / 13 (0.00%)
    1 / 179 (0.56%)
    0 / 60 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 203 (0.00%)
    0 / 13 (0.00%)
    1 / 179 (0.56%)
    0 / 60 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 13 (0.00%)
    0 / 179 (0.00%)
    0 / 60 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 13 (0.00%)
    0 / 179 (0.00%)
    0 / 60 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.68%
    Non-serious adverse events
    		 Pharmacodynamic Group -Test- Pharmacokinetic Group -Test- Pharmacodynamic Group -Reference- Pharmacodynamic Group -Placebo- Pharmacokinetic Group -Reference-
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 203 (5.42%)
    6 / 13 (46.15%)
    8 / 179 (4.47%)
    3 / 60 (5.00%)
    6 / 14 (42.86%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 203 (1.48%)
    3 / 13 (23.08%)
    2 / 179 (1.12%)
    1 / 60 (1.67%)
    2 / 14 (14.29%)
         occurrences all number
    4
    3
    2
    1
    6
    General disorders and administration site conditions
    Fatigue
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 203 (0.00%)
    0 / 13 (0.00%)
    0 / 179 (0.00%)
    0 / 60 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    4 / 203 (1.97%)
    0 / 13 (0.00%)
    0 / 179 (0.00%)
    0 / 60 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    4
    0
    0
    0
    1
    Vaginal discharge
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 13 (15.38%)
    2 / 179 (1.12%)
    0 / 60 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    2
    2
    0
    3
    Menopausal symptoms
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 13 (7.69%)
    0 / 179 (0.00%)
    0 / 60 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Pelvic pain
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 203 (0.00%)
    3 / 13 (23.08%)
    0 / 179 (0.00%)
    0 / 60 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Breast discomfort
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 13 (7.69%)
    0 / 179 (0.00%)
    0 / 60 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Uterine polyp
         subjects affected / exposed
    0 / 203 (0.00%)
    0 / 13 (0.00%)
    1 / 179 (0.56%)
    0 / 60 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    0
    1
    Ovarian cyst
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 13 (0.00%)
    0 / 179 (0.00%)
    0 / 60 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    0
    0
    1
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 13 (7.69%)
    1 / 179 (0.56%)
    1 / 60 (1.67%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 13 (0.00%)
    1 / 179 (0.56%)
    1 / 60 (1.67%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    4
    3
    Nausea
         subjects affected / exposed
    0 / 203 (0.00%)
    0 / 13 (0.00%)
    1 / 179 (0.56%)
    0 / 60 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    2
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 13 (7.69%)
    0 / 179 (0.00%)
    0 / 60 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jun 2018
    The substantial Amendment 04 (dated 2018-06-12) to the Amendment 03 of the clinical trial protocol became necessary due to the adaptive design of the clinical trial. It determined all necessary details about the continuation of trial procedures following the interim analysis. It was submitted to the Ethics Committees in Bulgaria and Moldova. For Germany Amendment 04 was not submitted to the Ethics Committee as the trial was not re-started in Germany after interim analysis. The substantial amendment 04 was submitted to the Ethics Committees in Bulgaria and Moldova and the members of the committees referred to above, confirmed that the given vote remained unchanged.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    21 Mar 2018
    Temporary hold of the clinical trial for the duration of interim analysis due to adaptive design of the trial with sample size estimation.
    16 Jul 2018

    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.

    European Medicines Agency © 1995-Wed Apr 24 00:36:03 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA