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    Clinical Trial Results:
    A phase II international multicentre randomised open label study of oral steroid sulphatase inhibitor BN83495 versus megestrol acetate (MA) in women with advanced or recurrent endometrial cancer.

    Summary
    EudraCT number
    2009-010613-68
    Trial protocol
    BE   GB   FR   ES   CZ   HU   PL   LT   LV  
    Global end of trial date
    10 Jul 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    12 Mar 2016
    First version publication date
    01 Aug 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Review and correction.

    Trial information

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    Trial identification
    Sponsor protocol code
    X-55-58064-004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00910091
    WHO universal trial number (UTN)
    U2009-0106-1368
    Sponsors
    Sponsor organisation name
    Ipsen Pharma
    Sponsor organisation address
    Z.I. de Courtaboeuf 5, Avenue du Canada, Les Ulis, France, 91940
    Public contact
    VP Clinical Sciences, Ipsen Pharma, clinical.trials@ipsen.com
    Scientific contact
    VP Clinical Sciences, Ipsen Pharma, clinical.trials@ipsen.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
    10 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jul 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the antitumour efficacy of BN83495 measured by percentage of women with advanced or recurrent endometrial cancer who have neither progressed nor died after 6 months of treatment. Response and progression have been evaluated by the investigator (local review) in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumours (RECIST) committee version 1.0.
    Protection of trial subjects
    This clinical study was designed and implemented and reported in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC and with the ethical principles laid down in the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    Megestrol Acetate (MA)
    Actual start date of recruitment
    12 Nov 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Ukraine: 4
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    Moldova, Republic of: 1
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Russian Federation: 14
    Worldwide total number of subjects
    73
    EEA total number of subjects
    54
    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)
    28
    From 65 to 84 years
    43
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 40 patients were to be recruited in each treatment group. However, due to the early recruitment termination, only 36 patients were enrolled in the irosustat arm and 37 patients in the MA arm

    Period 1
    Period 1 title
    Randomised
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A: BN83495 40 mg
    Arm description
    BN83495 (Irosustat) 40 mg tablet by mouth once daily
    Arm type
    Experimental

    Investigational medicinal product name
    BN83495
    Investigational medicinal product code
    Other name
    Irosustat
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg tablet by mouth once daily

    Arm title
    Arm B: Megestrol Acetate 160 mg
    Arm description
    Megestrol Acetate (MA) 160 mg tablet by mouth once daily
    Arm type
    Active comparator

    Investigational medicinal product name
    Megestrol Acetate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    160 mg tablet by mouth once daily

    Number of subjects in period 1
    Arm A: BN83495 40 mg Arm B: Megestrol Acetate 160 mg
    Started
    36
    37
    Completed
    36
    35
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    2
    Period 2
    Period 2 title
    Treatment and Survival
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A: BN83495 40 mg
    Arm description
    BN83495 (Irosustat) 40 mg tablet by mouth once daily
    Arm type
    Experimental

    Investigational medicinal product name
    Arm A: BN83495 40 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BN83495 (Irosustat) 40 mg tablet by mouth once daily

    Arm title
    Arm B: MA 160 mg
    Arm description
    Megestrol Acetate (MA) 160 mg tablet by mouth once daily
    Arm type
    Active comparator

    Investigational medicinal product name
    Arm B: MA 160 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MA 160 mg tablet by mouth once daily

    Number of subjects in period 2
    Arm A: BN83495 40 mg Arm B: MA 160 mg
    Started
    36
    35
    Completed
    32
    31
    Not completed
    4
    4
         Adverse event, non-fatal
    1
    -
         Consent withdrawn by subject
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: BN83495 40 mg
    Reporting group description
    BN83495 (Irosustat) 40 mg tablet by mouth once daily

    Reporting group title
    Arm B: Megestrol Acetate 160 mg
    Reporting group description
    Megestrol Acetate (MA) 160 mg tablet by mouth once daily

    Reporting group values
    Arm A: BN83495 40 mg Arm B: Megestrol Acetate 160 mg Total
    Number of subjects
    36 37 73
    Age categorical
    Units: Subjects
        <=18 years
    12 16 28
        Between 18 and 65 years
    13 15 28
        >=65 years
    11 6 17
    Age continuous
    Age continuous for Total population: Arithmetic mean (Standard Deviation) = 67.7 (± 10.0) years
    Units: years
        arithmetic mean (standard deviation)
    68.1 ± 11.4 67.4 ± 8.6 -
    Gender categorical
    Units: Subjects
        Female
    36 37 73
    BMI
    Units: Subjects
        <18.5
    1 0 1
        18.5 - 25
    10 10 20
        >25 - 30
    10 8 18
        >30
    12 17 29
        MISSING
    3 2 5
    Race
    Units: Subjects
        BLACK / AFRICAN AMERICAN
    0 1 1
        CAUCASIAN / WHITE
    36 36 72
    Eastern Cooperative Oncology Group(ECOG) Performance Status Score
    ECOG score ranges from 0 to 5, where 0: Asymptomatic, 1: Symptomatic but completely ambulatory, 2: Symptomatic (<50% in bed during the day - ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours), 3: Symptomatic (>50% in bed, but not bedbound - capable of only limited self-care, confined to bed or chair 50% or more of waking hours), 4: Bedbound (Completely disabled- cannot carry on any self-care) and 5: Death.
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.8 ± 0.6 0.7 ± 0.7 -

    End points

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    End points reporting groups
    Reporting group title
    Arm A: BN83495 40 mg
    Reporting group description
    BN83495 (Irosustat) 40 mg tablet by mouth once daily

    Reporting group title
    Arm B: Megestrol Acetate 160 mg
    Reporting group description
    Megestrol Acetate (MA) 160 mg tablet by mouth once daily
    Reporting group title
    Arm A: BN83495 40 mg
    Reporting group description
    BN83495 (Irosustat) 40 mg tablet by mouth once daily

    Reporting group title
    Arm B: MA 160 mg
    Reporting group description
    Megestrol Acetate (MA) 160 mg tablet by mouth once daily

    Primary: Percentage of Women With Advanced or Recurrent Endometrial Cancer Who Have Neither Progressed Nor Died at 6 months

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    End point title
    Percentage of Women With Advanced or Recurrent Endometrial Cancer Who Have Neither Progressed Nor Died at 6 months [1]
    End point description
    Subject continuation in the study and Response Evaluation Criteria in Solid Tumours (RECIST) assessment has been based on investigator assessment and not on central review. The 6 month timepoint is defined as the treatment start date +183 days (26 weeks). Intent-to-treat (ITT) population includes all randomized subjects who received at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Up to 6 months
    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: Statistical analyses is not performed
    End point values
    Arm A: BN83495 40 mg Arm B: Megestrol Acetate 160 mg
    Number of subjects analysed
    36
    37
    Units: Percentage of subjects
        number (confidence interval 90%)
    36.1 (24.3 to 49.8)
    54.1 (40.8 to 66.8)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Event (AE)

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    End point title
    Percentage of Participants With Adverse Event (AE)
    End point description
    Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe, Grade 4: Life threatening/disabling and Grade 5: Death Assessment of AEs include type, incidence and severity graded by NCI-CTCAE version 3.0 Safety Population: All randomised subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Up to Day 28 follow-up
    End point values
    Arm A: BN83495 40 mg Arm B: Megestrol Acetate 160 mg
    Number of subjects analysed
    36
    35
    Units: Percentage of subjects
    number (not applicable)
        Any AEs
    88.9
    82.9
        Any TEAEs
    88.9
    82.9
        Intensity of TEAEs - Grade 5
    2.8
    2.9
        Intensity of TEAEs - Grade 4
    5.6
    0
        Intensity of TEAEs - Grade 3
    22.2
    25.7
        Intensity of TEAEs - Grade 2
    63.9
    45.7
        Intensity of TEAEs - Grade 1
    80.6
    74.3
        Intensity of TEAEs - Missing
    5.6
    0
        Causality of TEAEs - Related
    55.6
    37.1
        Causality of TEAEs - Not related
    77.8
    77.1
        TEAEs Leading to Withdrawal
    8.3
    2.9
        TEAEs Leading to Death
    2.8
    2.9
        SAEs
    25
    17.1
    No statistical analyses for this end point

    Secondary: Tolerability of BN83495 Based on Length of Exposure

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    End point title
    Tolerability of BN83495 Based on Length of Exposure
    End point description
    Safety Population Length of exposure includes interruptions.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    Arm A: BN83495 40 mg Arm B: Megestrol Acetate 160 mg
    Number of subjects analysed
    36
    35
    Units: Week
        arithmetic mean (standard deviation)
    34.94 ± 38.85
    55.2 ± 49.48
    No statistical analyses for this end point

    Secondary: Tolerability of BN83495 Based on Cumulative Dose Administered

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    End point title
    Tolerability of BN83495 Based on Cumulative Dose Administered
    End point description
    Cumulative dose (CD) is the actual total dose administered. Safety Population Missing number of subjects = 2
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    Arm A: BN83495 40 mg Arm B: Megestrol Acetate 160 mg
    Number of subjects analysed
    36
    33
    Units: mg
        arithmetic mean (standard deviation)
    9452.22 ± 10799.16
    60703.03 ± 51726.14
    No statistical analyses for this end point

    Secondary: Tolerability of BN83495 Based on Dose Interruptions and Reason for Interruptions

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    End point title
    Tolerability of BN83495 Based on Dose Interruptions and Reason for Interruptions
    End point description
    Safety Population Percentage of participants who had dose interruptions and reason for interruptions as AE, study treatment forgotten, and other reasons.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    Arm A: BN83495 40 mg Arm B: Megestrol Acetate 160 mg
    Number of subjects analysed
    36
    35
    Units: Percentage of Participants
    number (not applicable)
        Dose Interruptions
    27.8
    34.5
        Reason for Interruptions (AE)
    16.7
    8.6
        Reason for Interruptions (Treatment forgotten)
    0
    8.6
        Reason for Interruptions (Other)
    13.9
    20
    No statistical analyses for this end point

    Secondary: Percentage of Participants >65 Years of Age With No Change or Deterioration, Improvement of <10%, or Improvement of ≥10% on the EuroQoL Score

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    End point title
    Percentage of Participants >65 Years of Age With No Change or Deterioration, Improvement of <10%, or Improvement of ≥10% on the EuroQoL Score
    End point description
    ITT population EuroQoL (Quality of Life)-5 Dimensions (EQ-5D) is a participant answered questionnaire scoring 5 dimensions: Mobility, self-care, usual activities, pain/discomfort and anxiety/depression. EQ-5D score ranges from 1 to 3 (1 = no problems, 2 = some problems, 3 = Severe problems). The respondent is asked to indicate their health state by choosing the most appropriate statement in each of the 5 dimensions. Three subjects withdrawn the consent from MA 160 mg group and did not have EuroQoL score up to week 32.
    End point type
    Secondary
    End point timeframe
    Up to week 32
    End point values
    Arm A: BN83495 40 mg Arm B: Megestrol Acetate 160 mg
    Number of subjects analysed
    24
    18
    Units: Percentage of Participants
    number (not applicable)
        No Change or Deterioration at week 2
    54.2
    50
        No Change or Deterioration at week 4
    54.2
    61.1
        No Change or Deterioration at week 8
    25
    50
        No Change or Deterioration at week 16
    25
    50
        No Change or Deterioration at week 24
    16.7
    33.3
        No Change or Deterioration at week 32
    16.7
    22.2
        Improvement of <10% at week 2
    0
    5.6
        Improvement of <10% at week 4
    4.2
    5.6
        Improvement of <10% at week 8
    4.2
    5.6
        Improvement of <10% at week 16
    0
    0
        Improvement of <10% at week 24
    0
    5.6
        Improvement of <10% at week 32
    8.3
    5.6
        Improvement of ≥10% at week 2
    20.8
    5.6
        Improvement of ≥10% at week 4
    16.7
    16.7
        Improvement of ≥10% at week 8
    16.7
    16.7
        Improvement of ≥10% at week 16
    12.5
    5.6
        Improvement of ≥10% at week 24
    12.5
    5.6
        Improvement of ≥10% at week 32
    0
    5.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Clinical Benefit [Including Completed Response (CR), Partial Response (PR), and Stable Disease (SD)] ≥12 Weeks

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    End point title
    Percentage of Participants With Clinical Benefit [Including Completed Response (CR), Partial Response (PR), and Stable Disease (SD)] ≥12 Weeks
    End point description
    CR: Disappearance of all known disease & no new sites / disease related symptoms confirmed at least 12 weeks after initial documentation. Disappearance of all non-target lesions. Normalization of tumor marker level confirmed at least 12 wks after initial documentation. PR: Minimum 30% decrease in sum of the longest diameters of target lesions, taking as a reference the baseline sum of the longest diameters confirmed at least 12 wks after initial documentation. PR is also recorded when all measurable disease has completely disappeared, but a non-measurable component (i.e., ascites) is still present but not progressing. As well as persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above normal limits. RECIST defines SD for target lesions as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, no occurrence of progression disease for non-target lesions and no new lesion
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    Arm A: BN83495 40 mg Arm B: Megestrol Acetate 160 mg
    Number of subjects analysed
    36
    37
    Units: Percentage of Participants
        number (not applicable)
    36.1
    51.4
    Statistical analysis title
    Arm A: BN83495 40 mg, Arm B: MA 160 mg
    Comparison groups
    Arm A: BN83495 40 mg v Arm B: Megestrol Acetate 160 mg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1895
    Method
    Chi-squared
    Confidence interval

    Secondary: Percentage of Participants With Overall Response (OR) Including CR and PR

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    End point title
    Percentage of Participants With Overall Response (OR) Including CR and PR
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    Arm A: BN83495 40 mg Arm B: Megestrol Acetate 160 mg
    Number of subjects analysed
    36
    37
    Units: Percentage of subjects
        number (not applicable)
    8.3
    29.7
    Statistical analysis title
    Arm A: BN83495 40 mg, Arm B: MA 160 mg
    Comparison groups
    Arm A: BN83495 40 mg v Arm B: Megestrol Acetate 160 mg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0203
    Method
    Chi-squared
    Confidence interval

    Secondary: Percentage of Participants With First Documentation of Objective Tumour Progression From Randomisation

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    End point title
    Percentage of Participants With First Documentation of Objective Tumour Progression From Randomisation
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    Arm A: BN83495 40 mg Arm B: Megestrol Acetate 160 mg
    Number of subjects analysed
    36
    37
    Units: Percentage of subjects
        number (not applicable)
    83.3
    64.9
    No statistical analyses for this end point

    Secondary: Duration of Response (DR) in Responders

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    End point title
    Duration of Response (DR) in Responders [2]
    End point description
    ITT population. DR is defined as period from the time that measurement criteria are first met for CR or PR until first date of documented Progressive Disease (PD) or death. DR was assessed in participants with a best overall response of CR or PR. Arm A: BN83495 40 mg: Median (90% Confidence Interval) = Not Calculable (23.14, Not Calculable) Arm B: Megestrol Acetate 160 mg: Median (90% Confidence Interval) = 105.14 (47.71, Not Calculable)
    End point type
    Secondary
    End point timeframe
    At 2 years
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arm A values are not entered due to system limitation. The details are updated in the Description field.
    End point values
    Arm B: Megestrol Acetate 160 mg
    Number of subjects analysed
    37
    Units: Weeks
        number (not applicable)
    105.14
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS) [3]
    End point description
    ITT population. OS is defined as the time from the date of enrollment to the date of death due to any cause. Arm B: Megestrol Acetate 160 mg: Subjects analysed is 37, median (90% Confidence Interval) = not calculable (56.14, not calculable)
    End point type
    Secondary
    End point timeframe
    At 2 years
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arm B values are not entered due to system limitation. The details are updated in the Description field.
    End point values
    Arm A: BN83495 40 mg
    Number of subjects analysed
    36
    Units: weeks
        median (confidence interval 90%)
    63.43 (37.57 to 100.29)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS): Time From Randomisation Until Objective Tumour Progression or Death From Any Cause

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    End point title
    Progression Free Survival (PFS): Time From Randomisation Until Objective Tumour Progression or Death From Any Cause
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    Arm A: BN83495 40 mg Arm B: Megestrol Acetate 160 mg
    Number of subjects analysed
    36
    37
    Units: Weeks
        median (confidence interval 90%)
    16.14 (9 to 31.43)
    40.14 (16.29 to 64)
    Statistical analysis title
    Arm A: BN83495 40 mg
    Comparison groups
    Arm A: BN83495 40 mg v Arm B: Megestrol Acetate 160 mg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0484
    Method
    Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to day 28 follow-up
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Arm B: MA 160 mg
    Reporting group description
    -

    Reporting group title
    Arm A: BN83495 40 mg
    Reporting group description
    -

    Serious adverse events
    Arm B: MA 160 mg Arm A: BN83495 40 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 35 (17.14%)
    9 / 36 (25.00%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung Neoplasm Malignant
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour Haemorrhage
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic Pain
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure Acute
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower Respiratory Tract Infection
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Arm B: MA 160 mg Arm A: BN83495 40 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 35 (82.86%)
    32 / 36 (88.89%)
    Vascular disorders
    Hot Flush
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Hypertension
         subjects affected / exposed
    4 / 35 (11.43%)
    2 / 36 (5.56%)
         occurrences all number
    4
    2
    Immune system disorders
    Contrast Media Allergy
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 35 (5.71%)
    6 / 36 (16.67%)
         occurrences all number
    2
    6
    Fatigue
         subjects affected / exposed
    4 / 35 (11.43%)
    6 / 36 (16.67%)
         occurrences all number
    4
    6
    Oedema Peripheral
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Spinal Pain
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Reproductive system and breast disorders
    Pelvic Pain
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Vaginal Haemorrhage
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Blood Creatinine Increased
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Blood Urea Increased
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Dyspnoea
         subjects affected / exposed
    5 / 35 (14.29%)
    3 / 36 (8.33%)
         occurrences all number
    5
    3
    Pulmonary Embolism
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    4 / 36 (11.11%)
         occurrences all number
    2
    4
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Headache
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Lethargy
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Constipation
         subjects affected / exposed
    4 / 35 (11.43%)
    5 / 36 (13.89%)
         occurrences all number
    4
    5
    Diarrhoea
         subjects affected / exposed
    6 / 35 (17.14%)
    5 / 36 (13.89%)
         occurrences all number
    6
    5
    Dry Mouth
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Dyspepsia
         subjects affected / exposed
    3 / 35 (8.57%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    Nausea
         subjects affected / exposed
    3 / 35 (8.57%)
    7 / 36 (19.44%)
         occurrences all number
    3
    7
    Vomiting
         subjects affected / exposed
    4 / 35 (11.43%)
    6 / 36 (16.67%)
         occurrences all number
    4
    6
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Urinary Incontinence
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Urinary Retention
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    5 / 35 (14.29%)
    14 / 36 (38.89%)
         occurrences all number
    5
    14
    Rash
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Skin Fissures
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Urticaria
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Back Pain
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Muscle Spasms
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Osteoarthritis
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Dehydration
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Hypokalaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Infections and infestations
    Cystitis
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Lower Respiratory Tract Infection
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Urinary Tract Infection
         subjects affected / exposed
    6 / 35 (17.14%)
    1 / 36 (2.78%)
         occurrences all number
    6
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jul 2009
    The protocol was amended to clarify the conditions under which previous chemotherapy is acceptable in order to reflect recent changes in the standard Good Clinical Practice (GCP) and the use of chemotherapy in adjuvant setting. This amendment was to facilitate recruitment of patients into the study as most women with advanced or recurrent endometrial cancer had previously received chemotherapy in the adjuvant setting. The amendment also added an evaluation of AR status as an exploratory objective and made provisions for the assessment of skin dryness. Other non-substantial typographical, consistency errors and points of detail were corrected.
    17 Mar 2010
    The protocol was amended following discussions with external experts and the primary analysis of the study was modified from a comparison between the two treatment groups with 80% power to a comparison of the PFS rate at 6 months with a predefined threshold rate (one stage Fleming’s design) and 90% power, thus reducing the risk of a false negative result and allowing for a clearer decision rule at the completion of the study.
    04 Nov 2010
    The protocol was amended to modify and clarify some inclusion and exclusion criteria as the previous protocol was deemed too stringent by the Investigators. Concomitant medications that should be avoided were updated, to include drugs metabolised by CYP1A2, which may be inhibited by irosustat metabolite.
    16 Jan 2012
    The protocol was amended for administrative reasons; to notify the change of the Sponsor’s Medically Responsible Person and the job title mentioned on the signature page.
    30 Aug 2012
    The protocol was amended to simplify the following protocol planned assessments: the quality of life, oncogeriatric assessments, pharmacodynamics, pharmacokinetics, safety and exploratory analyses due to the discontinuation of the development of irosustat as monotherapy. This was considered to have no safety impact on the patients. The study design was also amended to clarify the anticipated end of study and clarification on the review of tumour response data was done.

    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.
    On 06 June 2011, the Sponsor (Ipsen) decided to discontinue the development of irosustat as monotherapy. This decision was based on the futility analysis from this current study and on the Phase I clinical study results obtained in locally advanced.
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