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    Clinical Trial Results:
    Clinical effect of follicular preparation with testosterone in poor ovarian response: a randomized controlled clinical trial (TESTOPRIM)

    Summary
    EudraCT number
    		 2016-004302-33
    Trial protocol
    		 ES  
    Global end of trial date
    11 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Feb 2022
    First version publication date
    16 Feb 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TESTOPRIM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Instituto de Investigación Sanitaria La Fe de Valencia
    Sponsor organisation address
    Avenida Fernando Abril Martorell, Torre 106 A 7planta, 46026 València, , Valencia, Spain,
    Public contact
    UREC, INSTITUTO DE INVESTIGACION SANITARIA LA FE, 0034 961246711, investigacion_clinica@iislafe.es
    Scientific contact
    UREC, INSTITUTO DE INVESTIGACION SANITARIA LA FE, 0034 961246711, investigacion_clinica@iislafe.es
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determining whether a Follicular preparation with transdermal testosterone increases the number of mature oocytes retrieved in patients diagnosed with Poor Ovarian Response and which testosterone administration regimen is more effective for this purpose.
    Protection of trial subjects
    The reference study was conducted in Spain under the legal framework of Royal Decree 1090/2015. It has been performed in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, adopted by the General Assembly of the World Medical Association (1996). In addition, the study has been conducted in accordance with the protocol, good clinical practice (GCP) in accordance with the guidelines of the international conference on harmonization (ICH) and regulatory requirements for participating institutions. An appropriately performed informed consent has been used, in compliance with GCP according to ICH guidelines and approved by the CEIm of the Hospital Universitario y Politécnico La Fe. Prior to inclusion of subjects in the study, a copy of the CEIm-approved informed consent has been reviewed with the prospective participant, signed and dated. The investigator has provided a copy of each subject's signed informed consent form and has retained a copy in the subject's study file.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 63
    Worldwide total number of subjects
    63
    EEA total number of subjects
    63
    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)
    63
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Previous episode of POR defined by 3 or less oocytes retrieved with a conventional stimulation protocol. Advanced maternal age (40 years old or more) or any other factor for POR such as ovarian endometriomas, previous ovarian surgery and previous exposure to known gonadotoxic agents. At least one abnormal ovarian reserve test (AFC < 7 or AMH < 7.9

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 63
    Number of subjects completed
    		 49

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 14
    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1 long Testosterone
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Testim®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Transdermal use
    Dosage and administration details
    The dose calculated to be received by the intervention groups was 12.5 mg a day. This was equivalent to 1.25 g of the gel (10 mg per gram). Patients were instructed by the research nurse to fill an empty 2.5 ml syringe to 1.50 ml which according to the calculations performed by our pharmacy unit was the volume of gel containing 12.5 mg of testosterone. This finding was reproducible with several experiments by the pharmacy unit.

    Arm title
    		 Group 2 Short Testosterone
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Testim®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Transdermal use
    Dosage and administration details
    The dose calculated to be received by the intervention groups was 12.5 mg a day. This was equivalent to 1.25 g of the gel (10 mg per gram). Patients were instructed by the research nurse to fill an empty 2.5 ml syringe to 1.50 ml which according to the calculations performed by our pharmacy unit was the volume of gel containing 12.5 mg of testosterone. This finding was reproducible with several experiments by the pharmacy unit.

    Arm title
    		 Group 3 Control
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		Group 1 long Testosterone Group 2 Short Testosterone Group 3 Control
    Started
    17
    16
    16
    Completed
    17
    16
    16
    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 globally number enrolled are all patients who have been pre-screened, under "pre-screening" all those who were not part of the clinical trial have been removed.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1 long Testosterone
    Reporting group description
    		 -

    Reporting group title
    Group 2 Short Testosterone
    Reporting group description
    		 -

    Reporting group title
    Group 3 Control
    Reporting group description
    		 -

    Reporting group values
    		 Group 1 long Testosterone Group 2 Short Testosterone Group 3 Control Total
    Number of subjects
    		 17 16 16 49
    Age categorical
    Units: Subjects
        >18 years
    		 17 16 16 49
    Gender categorical
    Units: Subjects
        Female
    		 17 16 16 49

    End points

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    End points reporting groups
    Reporting group title
    Group 1 long Testosterone
    Reporting group description
    		 -

    Reporting group title
    Group 2 Short Testosterone
    Reporting group description
    		 -

    Reporting group title
    Group 3 Control
    Reporting group description
    		 -

    Primary: MII oocytes

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    End point title
    		 MII oocytes
    End point description
    End point type
    Primary
    End point timeframe
    72 days
    End point values
    		 Group 1 long Testosterone Group 2 Short Testosterone Group 3 Control
    Number of subjects analysed
    17
    16
    16
    Units: number
    arithmetic mean (standard deviation)
        MII oocytes
    2.16 ( 2.65 )
    2.71 ( 2.95 )
    2.91 ( 2.43 )
    Statistical analysis title
    		 Poisson
    Comparison groups
    Group 1 long Testosterone v Group 2 Short Testosterone v Group 3 Control
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 POISSON
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.719
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 0.719
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Dispersion value
    0.71

    Secondary: Testosterone Hormone

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    End point title
    		 Testosterone Hormone
    End point description
    End point type
    Secondary
    End point timeframe
    the first day of the cycle at the time of inclusion in the study, the day of initiation of controlled ovarian stimulation and the day of ovulation induction will be analyzed.
    End point values
    		 Group 1 long Testosterone Group 2 Short Testosterone Group 3 Control
    Number of subjects analysed
    17
    16
    16
    Units: ng/ml
    arithmetic mean (standard deviation)
        Testosterone start COS
    1.67 ( 1.38 )
    3.03 ( 2.39 )
    0.14 ( 0.11 )
        Testosterone HCG day
    0.34 ( 0.13 )
    0.34 ( 0.29 )
    0.21 ( 0.09 )
    No statistical analyses for this end point

    Secondary: Androstendione Hormone

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    End point title
    		 Androstendione Hormone
    End point description
    End point type
    Secondary
    End point timeframe
    the first day of the cycle at the time of inclusion in the study, the day of initiation of controlled ovarian stimulation and the day of ovulation induction will be analyzed.
    End point values
    		 Group 1 long Testosterone Group 2 Short Testosterone Group 3 Control
    Number of subjects analysed
    17
    16
    16
    Units: ng/ml
    arithmetic mean (standard deviation)
        Androstendione start COS
    1.46 ( 1.05 )
    1.85 ( 0.89 )
    1.27 ( 0.97 )
        Androstendione HCG day
    1.95 ( 0.61 )
    2.04 ( 0.95 )
    1.50 ( 0.39 )
    No statistical analyses for this end point

    Secondary: s-DHEA hormone

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    End point title
    		 s-DHEA hormone
    End point description
    End point type
    Secondary
    End point timeframe
    the first day of the cycle at the time of inclusion in the study, the day of initiation of controlled ovarian stimulation and the day of ovulation induction will be analyzed.
    End point values
    		 Group 1 long Testosterone Group 2 Short Testosterone Group 3 Control
    Number of subjects analysed
    17
    16
    16
    Units: ng/ml
    arithmetic mean (standard deviation)
        s-DHEA start COS (ng/ml)
    1899.87 ( 896.08 )
    2338 ( 2077.57 )
    1490.15 ( 675.01 )
        s-DHEA HCG day (ng/ml)
    1815.86 ( 532.24 )
    1750.75 ( 914.50 )
    1442.45 ( 579.10 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    The investigator will report all SAEs immediately (within 24 hours) after becoming aware of the event. The report has to be communicated to the promoter. The initial report will be immediately followed by detailed written reports and reflected in the CRF.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No adverse side effects were reported on any of the groups, apart from one natural pregnancy during follicular preparation in one patient allocated to Group 1 (long-testosterone). The patient discontinued the use of testosterone as soon as the pregnancy was confirmed and the pregnancy was followed-up with no complications reported.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jul 2017
    Protocol changes
    24 Nov 2017
    Protocol y HIPyCI changes

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34312088
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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
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