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    Clinical Trial Results:
    A phase III, multi-center, open label, uncontrolled trial to investigate the efficacy and safety of MK-8962 (corifollitropin alfa) in combination with human Chorionic Gonadotropin (hCG) in inducing increased testicular volume and spermatogenesis in adult men with hypogonadotropic hypogonadism who remain azoospermic when treated with hCG alone (Phase III; Protocol No. MK-8962-031-00 [also known as SCH 900962, P07937])

    Summary
    EudraCT number
    2012-001258-25
    Trial protocol
    DE   ES   IT   GB   PL   Outside EU/EEA  
    Global end of trial date
    08 Apr 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    28 Aug 2016
    First version publication date
    20 Apr 2016
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    P07937
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01709331
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Merck: MK-8962-031
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000306-PIP01-08
    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
    08 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will assess if corifollitropin alfa (MK-8962), when administered in combination with human chorionic gonadotropin (hCG), will increase testicular volume in men with HH who remain azoospermic after treatment with hCG alone. Hypothesis: The lower limit of the 95% confidence interval for the geometric mean increase in testicular volume from Day 1 to Week 52 is greater than one.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Feb 2014
    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
    Australia: 2
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Spain: 1
    Worldwide total number of subjects
    18
    EEA total number of subjects
    16
    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)
    18
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Twenty-three participants entered the 16-week pretreatment phase with hCG. At the end of the pretreatment phase, 18 participants were enrolled in the 52-week combined treatment phase.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Corifollitropin alfa 150 μg + hCG
    Arm description
    During a 16-week pretreatment phase, participants received twice-weekly subcutaneous (SC) injections of human chorionic gonadotropin (hCG) 1500 or 3000 IU. Eligible participants were then enrolled in the combined treatment phase in which they received a single dose of corifollitropin alfa 150 μg by SC injection once every 2 weeks for 52 weeks. In addition, eligible participants continued to receive twice-weekly hCG injections on the same schedule begun during the pretreatment phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Corifollitropin alfa
    Investigational medicinal product code
    Other name
    MK-8962
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Corifollitropin alfa 150 μg by SC injection, once every 2 weeks for 52 weeks

    Investigational medicinal product name
    human chorionic gonadotropin (hCG)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    hCG 1500 or 3000 international units (IU) by SC injection twice a week; administered alone for 16 weeks (pretreatment phase) and then in combination with corifollitropin alfa for 52 weeks (combined treatment phase)

    Number of subjects in period 1
    Corifollitropin alfa 150 μg + hCG
    Started
    18
    Completed
    17
    Not completed
    1
         Adverse event, non-fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Corifollitropin alfa 150 μg + hCG
    Reporting group description
    During a 16-week pretreatment phase, participants received twice-weekly subcutaneous (SC) injections of human chorionic gonadotropin (hCG) 1500 or 3000 IU. Eligible participants were then enrolled in the combined treatment phase in which they received a single dose of corifollitropin alfa 150 μg by SC injection once every 2 weeks for 52 weeks. In addition, eligible participants continued to receive twice-weekly hCG injections on the same schedule begun during the pretreatment phase.

    Reporting group values
    Corifollitropin alfa 150 μg + hCG Total
    Number of subjects
    18
    Age categorical
    Units: Subjects
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    31.5 ± 8.8 -
    Gender, Male/Female
    Units: Participants
        Female
    0 0
        Male
    18 18
    Subject analysis sets

    Subject analysis set title
    Corifollitropin alfa 150 μg + hCG
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    During a 16-week pretreatment phase, participants received twice-weekly SC injections of hCG 1500 or 3000 IU. Eligible participants were then enrolled in the combined treatment phase in which they received a single dose of corifollitropin alfa 150 μg by SC injection once every 2 weeks for 52 weeks. In addition, eligible participants continued to receive twice-weekly hCG injections on the same schedule begun during the pretreatment phase.

    Subject analysis set title
    Corifollitropin alfa 150 μg + hCG
    Subject analysis set type
    Full analysis
    Subject analysis set description
    During a 16-week pretreatment phase, participants received twice-weekly SC injections of hCG 1500 or 3000 IU. Eligible participants were then enrolled in the combined treatment phase in which they received a single dose of corifollitropin alfa 150 μg by SC injection once every 2 weeks for 52 weeks. In addition, eligible participants continued to receive twice-weekly hCG injections on the same schedule begun during the pretreatment phase.

    Subject analysis sets values
    Corifollitropin alfa 150 μg + hCG Corifollitropin alfa 150 μg + hCG
    Number of subjects
    18
    17
    Age categorical
    Units: Subjects
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    31.5 ± 8.8
    ±
    Gender, Male/Female
    Units: Participants
        Female
    0
        Male
    18

    End points

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    End points reporting groups
    Reporting group title
    Corifollitropin alfa 150 μg + hCG
    Reporting group description
    During a 16-week pretreatment phase, participants received twice-weekly subcutaneous (SC) injections of human chorionic gonadotropin (hCG) 1500 or 3000 IU. Eligible participants were then enrolled in the combined treatment phase in which they received a single dose of corifollitropin alfa 150 μg by SC injection once every 2 weeks for 52 weeks. In addition, eligible participants continued to receive twice-weekly hCG injections on the same schedule begun during the pretreatment phase.

    Subject analysis set title
    Corifollitropin alfa 150 μg + hCG
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    During a 16-week pretreatment phase, participants received twice-weekly SC injections of hCG 1500 or 3000 IU. Eligible participants were then enrolled in the combined treatment phase in which they received a single dose of corifollitropin alfa 150 μg by SC injection once every 2 weeks for 52 weeks. In addition, eligible participants continued to receive twice-weekly hCG injections on the same schedule begun during the pretreatment phase.

    Subject analysis set title
    Corifollitropin alfa 150 μg + hCG
    Subject analysis set type
    Full analysis
    Subject analysis set description
    During a 16-week pretreatment phase, participants received twice-weekly SC injections of hCG 1500 or 3000 IU. Eligible participants were then enrolled in the combined treatment phase in which they received a single dose of corifollitropin alfa 150 μg by SC injection once every 2 weeks for 52 weeks. In addition, eligible participants continued to receive twice-weekly hCG injections on the same schedule begun during the pretreatment phase.

    Primary: Change from Baseline in Log-Transformed Testicular Volume at Week 52

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    End point title
    Change from Baseline in Log-Transformed Testicular Volume at Week 52 [1]
    End point description
    Participants underwent testicular ultrasound in the pretreatment phase at Weeks -16, -8, -1; and during the combined treatment phase at Baseline (predose, Day 1) and at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52. The testicular volume was measured as the sum of volumes of left and right testes. The mean change from Day 1 in log-transformed testicular volume was analyzed using a mixed model with a fixed effect for time point and a random effect for the participant. For each time point, the mean change from Day 1 to that time point and the associated 95% confidence interval (CI) was calculated. The geometric mean fold change in testicular volume and its 95% CI was obtained by exponentiation. This endpoint was based on the Full Analysis Set (FAS) population, which consisted of all participants who received any dose of corifollitropin alfa and who had a baseline and at least one post-baseline measurement of testicular volume.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    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: This was a single-arm study. Therefore no between-group statistical analysis was conducted for the primary end point Fold Change from Baseline in Log-Transformed Testicular Volume at Week 52.
    End point values
    Corifollitropin alfa 150 μg + hCG
    Number of subjects analysed
    18
    Units: Fold change
        geometric mean (confidence interval 95%)
    2.3 (2.03 to 2.62)
    No statistical analyses for this end point

    Primary: Percentage of Participants with Anti-Corifollitropin Alfa Antibodies

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    End point title
    Percentage of Participants with Anti-Corifollitropin Alfa Antibodies [2]
    End point description
    Blood samples were collected for assessment of anti-corifollitropin alfa antibodies in the pretreatment phase at Week -16 and Week -1; during the combined treatment phase at Weeks 4, 16, 28, 50, and 52; and at the post-treatment follow-up visit, which could occur from Week 53 up to Week 57. This endpoint was based on the All-Subjects-as-Treated (ASaT) population, which consisted of all participants who received any dose of corifollitropin alfa.
    End point type
    Primary
    End point timeframe
    Up to Week 57
    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: This was a single-arm study. Therefore no between-group statistical analysis was conducted for the primary end point Percentage of Participants with Anti-Corifollitropin Alfa Antibodies.
    End point values
    Corifollitropin alfa 150 μg + hCG
    Number of subjects analysed
    18
    Units: Percentage of participants
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Induced Spermatogenesis Resulting in a Sperm Count ≥1x10^6/mL at or before Week 52

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    End point title
    Percentage of Participants with Induced Spermatogenesis Resulting in a Sperm Count ≥1x10^6/mL at or before Week 52
    End point description
    Semen samples were produced by masturbation after at least 48 hours of sexual abstinence and collected for evaluation in the pretreatment phase at Week -1, and during the combined treatment phase at Weeks 16, 28, 40, and 52. This endpoint was based on the FAS population, which consisted of all participants who received any dose of corifollitropin alfa and who had a baseline and at least one post-baseline measurement of testicular volume.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Corifollitropin alfa 150 μg + hCG
    Number of subjects analysed
    18
    Units: Percentage of participants
        number (confidence interval 0%)
    77.8 (52.4 to 93.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 57 weeks
    Adverse event reporting additional description
    The Safety Analysis was based on the ASaT population, which consisted of all participants who received any dose of corifollitropin alfa.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Corifollitropin alfa 150 μg + hCG
    Reporting group description
    During a 16-week pretreatment phase, participants received twice-weekly SC injections of hCG 1500 or 3000 IU. Eligible participants were then enrolled in the combined treatment phase in which they received a single dose of corifollitropin alfa 150 μg by SC injection once every 2 weeks for 52 weeks. In addition, eligible participants continued to receive twice-weekly hCG injections on the same schedule begun during the pretreatment phase.

    Serious adverse events
    Corifollitropin alfa 150 μg + hCG
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Corifollitropin alfa 150 μg + hCG
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 18 (61.11%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Blood testosterone increased
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Oestradiol increased
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    4
    Testicular scan abnormal
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Blood testosterone decreased
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Breast tenderness
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Acne
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Alopecia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    5
    Conjunctivitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 May 2013
    The primary reason for the amendment was the addition of text to describe describe the interim analysis (IA) of pharmacokinetic (PK) data after 6 participants completed 6 months of corifollitropin alfa and hCG combined-treatment. The purpose of the IA was to provide data to support preparations for a study in adolescent hypogonadotropic hypogonadism (HH) males (including dose-selection) and development of a PK-model, if necessary, to predict corifollitropin alfa exposure in adolescents. No efficacy or safety analyses were performed in the IA, except that the number of participants with anti-corifollitropin alfa antibodies (Tier-1 Safety Endpoint) was determined.

    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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