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    Clinical Trial Results:
    Denosumab and male infertility: a randomized double-blinded intervention study

    Summary
    EudraCT number
    		 2016-003546-84
    Trial protocol
    		 DK  
    Global end of trial date
    20 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2022
    First version publication date
    29 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    01112016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dept. of growth and reproduction
    Sponsor organisation address
    Blegdamsvej 9, copenhagen, Denmark, 2100
    Public contact
    Secretariat, Dpt.of Growth and Reproduction, 0045 35455085, vaekst-repro@rh.dk
    Scientific contact
    Secretariat, Dpt.of Growth and Reproduction, 0045 35455085, vaekst-repro@rh.dk
    Sponsor organisation name
    Dept. of growth and reproduction
    Sponsor organisation address
    Blegdamsvej 9, copenhagen, Denmark, 2100
    Public contact
    Dept of growth and reproduction, Rigshospitalet, group of skeletal, mineral and gonadal endocrinology, +45 30221014, li.juel.mortensen@regionh.dk
    Scientific contact
    Dept of growth and reproduction, Rigshospitalet, group of skeletal, mineral and gonadal endocrinology, +45 30221014, li.juel.mortensen@regionh.dk
    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
    09 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this intervention is to investigate whether Denosumab can improve semen quality of infertile men
    Protection of trial subjects
    extra bloodsample on day 14 to ensure calcium homeostasis unaffected
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 2016
    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
    Denmark: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    100
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 recruited through our andrological clinic at dept of growth and reproduction, RH, Denmark

    Pre-assignment
    Screening details
    		 reffered for evaluation of low semen quality

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Denosumab
    Arm description
    		 60 mg denosumab s.c. once
    Arm type
    		 Experimental

    Investigational medicinal product name
    denosumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    60 mg once

    Arm title
    		 placebo
    Arm description
    		 saline
    Arm type
    		 Placebo

    Investigational medicinal product name
    NaCl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 ml NaCl once

    Number of subjects in period 1
    		Denosumab placebo
    Started
    50
    50
    Completed
    46
    47
    Not completed
    4
    3
         Lost to follow-up
    4
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 100 100
    Age categorical
    mean age at baseline
    Units: Subjects
        Adults (18-64 years)
    		 100 100
    Age continuous
    mean age for all included at baseline
    Units: years
        arithmetic mean (standard deviation)
    		 34.09 ( 6.24 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 100 100

    End points

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    End points reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    		 60 mg denosumab s.c. once

    Reporting group title
    placebo
    Reporting group description
    		 saline

    Primary: semen quality

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    End point title
    		 semen quality
    End point description
    increase in semen concentration 80 days after injection
    End point type
    Primary
    End point timeframe
    80 days
    End point values
    		 Denosumab placebo
    Number of subjects analysed
    45
    44
    Units: mio/mL
        number (not applicable)
    45
    44
    Statistical analysis title
    		 kruskal wallis
    Comparison groups
    Denosumab v placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.749
    Method
    		 Kruskal-wallis
    Parameter type
    		 Median difference (net)
    Point estimate
    11.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.9
         upper limit
    		 16
    Variability estimate
    Standard deviation
    Dispersion value
    15.6

    Primary: live birth rate

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    End point title
    		 live birth rate
    End point description
    End point type
    Primary
    End point timeframe
    160 days + 9 months
    End point values
    		 Denosumab placebo
    Number of subjects analysed
    36
    39
    Units: pregnancies
        number (not applicable)
    36
    39
    Statistical analysis title
    		 kruskal wallis
    Comparison groups
    Denosumab v placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.835
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 100
    Variability estimate
    Standard deviation
    Dispersion value
    0.48
    Notes
    [1] - only 36 in treatment group and 39 in placebo group tried to conceive during study period

    Secondary: inhibin B

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    End point title
    		 inhibin B
    End point description
    End point type
    Secondary
    End point timeframe
    80 days
    End point values
    		 Denosumab placebo
    Number of subjects analysed
    47
    46
    Units: nmol/L
        number (not applicable)
    47
    46
    Statistical analysis title
    		 kruskal wallis
    Comparison groups
    Denosumab v placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.348
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    129.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 89
         upper limit
    		 172
    Variability estimate
    Standard deviation
    Dispersion value
    53

    Secondary: change in reproductive hormones

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    End point title
    		 change in reproductive hormones
    End point description
    End point type
    Secondary
    End point timeframe
    80 days
    End point values
    		 Denosumab placebo
    Number of subjects analysed
    47
    46
    Units: pmol/L
        number (not applicable)
    47
    46
    Statistical analysis title
    		 kruskal wallis
    Statistical analysis description
    testosterone day 80
    Comparison groups
    Denosumab v placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.836
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    18.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13
         upper limit
    		 23
    Variability estimate
    Standard deviation
    Dispersion value
    6.9

    Secondary: DNA fragmentation

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    End point title
    		 DNA fragmentation
    End point description
    End point type
    Secondary
    End point timeframe
    80 days
    End point values
    		 Denosumab placebo
    Number of subjects analysed
    40
    40
    Units: percentage
        number (not applicable)
    40
    40
    Statistical analysis title
    		 kruskal wallis
    Comparison groups
    Denosumab v placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Kruskal-wallis
    Confidence interval
    Statistical analysis title
    		 kruskal wallis
    Comparison groups
    placebo v Denosumab
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.299
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15
         upper limit
    		 30
    Variability estimate
    Standard deviation
    Dispersion value
    13.27

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    anytime during study period of 160 days (interview at day 14, 80 and 160).
    Adverse event reporting additional description
    by personal interview at planned visits
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    		 -

    Reporting group title
    placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Denosumab placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Skin and subcutaneous tissue disorders
    Malignant melanoma
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         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
    		 Denosumab placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 50 (34.00%)
    24 / 50 (48.00%)
    Musculoskeletal and connective tissue disorders
    Joint swelling
    Additional description: unspecifik musculoskeletal pain
         subjects affected / exposed
    17 / 50 (34.00%)
    24 / 50 (48.00%)
         occurrences all number
    17
    24

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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

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