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    Clinical Trial Results:
    A Phase III, Multi-Center, Open Label, Single-Group Trial to Investigate the Efficacy and Safety of MK-8962 (Corifollitropin Alfa) in Combination With Human Chorionic Gonadotropin (hCG) for Initiation or Restoration of Puberty as Assessed by Increased Testicular Volume in Adolescent Males 14 to <18 Years Old With Hypogonadotropic Hypogonadism (MK-8962-043)

    Summary
    EudraCT number
    		 2015-001878-18
    Trial protocol
    		 IT   DK   Outside EU/EEA  
    Global end of trial date
    05 May 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    30 Apr 2021
    First version publication date
    24 Oct 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    8962-043
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03019575
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Protocol Number: MK-8962-043
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a single group study to investigate the efficacy and safety of corifollitropin alfa (CFA, MK-8962) in combination with human chorionic gonadotropin (hCG) for initiation or restoration of puberty assessed by increased testicular volume (TV) in adolescent males with hypogonadotropic hypogonadism (HH). The objectives of the study were: 1) To estimate the change from baseline in TV (measured as the sum of volumes of left and right testes by ultrasound) after 64 weeks of treatment with CFA (in combination with hCG for the last 52 weeks). 2) To evaluate the safety and tolerability of CFA over 64 weeks of treatment, including evaluation of development of antibodies to CFA.
    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
    02 Feb 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
    Brazil: 4
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Russian Federation: 11
    Worldwide total number of subjects
    17
    EEA total number of subjects
    1
    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)
    17
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Male participants with Hypogonadotropic Hypogonadism (HH) aged 14 to <18 years were enrolled in the study. A total of 17 participants were allocated to the study treatment arm. Of 17 participants, 16 participants completed the study treatment.

    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 (CFA)+human Chorionic Gonadotropin (hCG)
    Arm description
    		 Participants received 100 μg (if body weight was ≤60 kg) or 150 μg (if body weight was >60 kg) of CFA as a subcutaneous (SC) injection once every 2 weeks for 64 Weeks (Day 1, Week 0 through Week 64) and 500-5000 IU of hCG reconstituted with 1 ml of 0.9% sodium chloride solution, as a SC injection twice a week for 52 weeks (last day of Week 12 through Week 64). The total treatment duration was 64 Weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Corifollitropin Alfa (CFA)
    Investigational medicinal product code
    Other name
    MK-8962, Elonva
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CFA administered 100 μg (if body weight ≤60 kg) or 150 μg (if body weight >60 kg) by SC injection, once every 2 weeks for 64 weeks (Day 1, Week 0 through Week 64).

    Investigational medicinal product name
    human Chorionic Gonadotropin (hCG)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    hCG 500-5000 IU reconstituted with 1 ml of 0.9% sodium chloride solution, as a SC injection twice a week for 52 weeks (last day of Week 12 through Week 64).

    Number of subjects in period 1
    		Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Started
    17
    Completed
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Reporting group description
    		 Participants received 100 μg (if body weight was ≤60 kg) or 150 μg (if body weight was >60 kg) of CFA as a subcutaneous (SC) injection once every 2 weeks for 64 Weeks (Day 1, Week 0 through Week 64) and 500-5000 IU of hCG reconstituted with 1 ml of 0.9% sodium chloride solution, as a SC injection twice a week for 52 weeks (last day of Week 12 through Week 64). The total treatment duration was 64 Weeks.

    Reporting group values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG) Total
    Number of subjects
    		 17 17
    Age Categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.5 ( 0.9 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 17 17
    Race
    Units: Subjects
        Multiple (Black Or African American, White)
    		 1 1
        White
    		 16 16
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 4
        Not Hispanic or Latino
    		 13 13
    Testicular Volume (TV)
    Units: mL
        arithmetic mean (standard deviation)
    		 2.2 ( 1.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Reporting group description
    		 Participants received 100 μg (if body weight was ≤60 kg) or 150 μg (if body weight was >60 kg) of CFA as a subcutaneous (SC) injection once every 2 weeks for 64 Weeks (Day 1, Week 0 through Week 64) and 500-5000 IU of hCG reconstituted with 1 ml of 0.9% sodium chloride solution, as a SC injection twice a week for 52 weeks (last day of Week 12 through Week 64). The total treatment duration was 64 Weeks.

    Primary: Change from Baseline in Log-Transformed Testicular Volume (TV) to Week 64

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    End point title
    		 Change from Baseline in Log-Transformed Testicular Volume (TV) to Week 64 [1]
    End point description
    Participants underwent testicular ultrasound of left and right testes at pre-specified time points to measure TV. TV was measured as the sum of volumes of left and right testes. The linear mixed model with a fixed effect for baseline and Week 64 and a random effect for participant was used to calculate the mean change in log-transformed TV and associated 95% confidence intervals (CIs) from baseline to Week 64. The geometric mean ratio and its 95% CIs for TV were obtained by exponentiation. The ratio > 1 indicated an increase in TV from baseline. All participants with at least 1 dose of study treatment who had a baseline and at least 1 post baseline TV value, had luteinizing hormone (LH) level ≤3 IU/L anytime in study, had at least 12 weeks of Corifollitropin Alfa (CFA) and 24 weeks of CFA plus human chorionic gonadotropin (hCG) treatment, have last TV value within 4 weeks from last dose of CFA were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline and Week 64
    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 between-group analysis were performed for this endpoint. A single-sided analysis will be presented on ClinicalTrials.gov NCT03019575.
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    13
    Units: Fold change
        geometric mean (confidence interval 95%)
    9.43 (7.44 to 11.97)
    No statistical analyses for this end point

    Primary: Number of Participants who Experienced an Adverse Event (AE)

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    End point title
    		 Number of Participants who Experienced an Adverse Event (AE) [2]
    End point description
    An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE was reported. All participants who received at least 1 dose of study treatment were analyzed.
    End point type
    Primary
    End point timeframe
    Up to approximately 71 Weeks
    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 between-group analysis were performed for this endpoint.
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    17
    Units: Participants
    16
    No statistical analyses for this end point

    Primary: Number of Participants who Discontinued Study Treatment Due to an AE

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    End point title
    		 Number of Participants who Discontinued Study Treatment Due to an AE [3]
    End point description
    An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE was reported. All participants who received at least 1 dose of study treatment were analyzed.
    End point type
    Primary
    End point timeframe
    Up to approximately 64 Weeks
    Notes
    [3] - 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 between-group analysis were performed for this endpoint.
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    17
    Units: Participants
    1
    No statistical analyses for this end point

    Primary: Percentage of Participants with Anti-Corifollitropin Alfa (CFA) Antibodies

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    End point title
    		 Percentage of Participants with Anti-Corifollitropin Alfa (CFA) Antibodies [4]
    End point description
    Blood samples were collected at pre-specified time points to assess anti-CFA antibodies. The percentage of participants with anti-CFA antibodies after administration of CFA was reported. All participants who received at least 1 dose of study treatment were analyzed.
    End point type
    Primary
    End point timeframe
    Up to approximately 71 Weeks
    Notes
    [4] - 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 between-group analysis were performed for this endpoint.
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    17 [5]
    Units: Percentage of Participants
    0
    Notes
    [5] - No participants tested positive for anti-CFA antibodies during the study.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Serum Inhibin B Concentration to Week 64

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    End point title
    		 Change from Baseline in Serum Inhibin B Concentration to Week 64
    End point description
    Serum Inhibin B concentration is a surrogate marker for spermatogenesis in males. Blood samples were collected at baseline and Week 64 post dose to report the mean change from baseline in serum inhibin concentration to Week 64. A mean change from baseline in serum inhibin B concentration to Week 64 was reported. A positive value indicated a higher serum inhibin concentration level. All participants with at least 1 dose of study treatment who had a baseline and at least 1 post baseline TV value, had LH level ≤3 IU/L anytime in study, had at least 12 weeks of CFA and 24 weeks of CFA plus hCG treatment, have last TV value within 4 weeks from last dose of CFA and had a baseline and at least 1 post baseline inhibin value were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 64
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    13
    Units: ng/L
    arithmetic mean (standard deviation)
        Baseline
    31.92 ( 35.30 )
        Baseline to Week 64
    91.46 ( 59.25 )
    No statistical analyses for this end point

    Secondary: Growth Velocity at Week 36

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    End point title
    		 Growth Velocity at Week 36
    End point description
    Growth velocity is the rate of change in height measurement and is a marker for pubertal progress. Height was measured using a wall-mounted calibrated stadiometer. A mixed model was used to assess the overall growth velocity slope over the 36-week treatment period using the slopes estimated from an overall mixed random intercept and random slope model of height (cm) and time (yr) and age as covariates. All participants who had at least 1 dose of study treatment, had a baseline and at least 1 post baseline TV value, had LH level ≤3 IU/L anytime in study, had at least 12 weeks of CFA and 24 weeks of CFA plus hCG treatment, had last TV value within 4 weeks from last dose of CFA and had a baseline and post baseline height records at Week 36 were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 36
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    13
    Units: cm/year
        least squares mean (standard error)
    8.3 ( 1.1 )
    No statistical analyses for this end point

    Secondary: Growth Velocity at Week 64

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    End point title
    		 Growth Velocity at Week 64
    End point description
    Growth velocity is the rate of change in height measurement and is a marker for pubertal progress. Height was measured using a wall-mounted calibrated stadiometer. A mixed model was used to assess the overall growth velocity slope over the 64-week treatment period using the slopes estimated from an overall mixed random intercept and random slope model of height (cm) and time (year) and age as covariates. All participants who had at least 1 dose of study treatment, had a baseline and at least 1 post baseline TV value, had LH level ≤3 IU/L anytime in study, had at least 12 weeks of CFA and 24 weeks of CFA plus hCG treatment, had last TV value within 4 weeks from last dose of CFA and had a baseline and post baseline height records at Week 64 were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 64
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    12
    Units: cm/year
        least squares mean (standard error)
    7.6 ( 1.0 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Tanner Stage (TS) of Pubertal Development for Pubic Hair to Week 12, Week 36, and Week 64

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    End point title
    		 Change from Baseline in Tanner Stage (TS) of Pubertal Development for Pubic Hair to Week 12, Week 36, and Week 64
    End point description
    Male participants were assessed clinically for pubertal development using the TS for pubic hair (range: Tanner I-V). TS describes sexual maturity stages (no better or worse outcome) as: Tanner I: prepubertal state, Tanner II: small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum, Tanner III: hair becomes more coarse and curly, and begins to extend laterally, Tanner IV: adult-like hair quality, extending across pubis but sparing medial thighs and Tanner V: hair extends to medial surface of the thigh. The number of participants in each Tanner stage at baseline and categorical change from baseline in Tanner stages to Weeks 12, 36 and 64 were reported. All participants with at least 1 dose of study treatment who had a baseline and at least 1 post baseline TV value, had LH level ≤3 IU/L anytime in study, had at least 12 weeks of CFA and 24 weeks of CFA plus hCG treatment, have last TV value within 4 weeks from last dose of CFA were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36, and Week 64
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    13
    Units: Participants
        Baseline (BL) Tanner I
    6
        BL Tanner II
    6
        BL Tanner III
    1
        BL Tanner IV
    0
        BL Tanner V
    0
        BL Tanner I to Week 12 Tanner I
    5
        BL Tanner I to Week 12 Tanner II
    1
        BL Tanner II to Week 12 Tanner II
    5
        BL Tanner II to Week 12 Tanner III
    1
        BL Tanner III to Week 12 Tanner III
    1
        BL Tanner I to Week 36 Tanner II
    2
        BL Tanner I to Week 36 Tanner III
    4
        BL Tanner II to Week 36 Tanner II
    2
        BL Tanner II to Week 36 Tanner III
    4
        BL Tanner III to Week 36 Tanner IV
    1
        BL Tanner I to Week 64 Tanner III
    3
        BL Tanner I to Week 64 Tanner IV
    1
        BL Tanner I to Week 64 Tanner V
    2
        BL Tanner II to Week 64 Tanner III
    1
        BL Tanner II to Week 64 Tanner IV
    3
        BL Tanner II to Week 64 Tanner V
    1
        BL Tanner II to Week 64 Unknown
    1
        BL Tanner III to Week 64 Tanner IV
    1
    No statistical analyses for this end point

    Secondary: Change from Baseline in TS of Pubertal Development for Genital Growth to Week 12, Week 36, and Week 64

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    End point title
    		 Change from Baseline in TS of Pubertal Development for Genital Growth to Week 12, Week 36, and Week 64
    End point description
    Male participants were assessed clinically for pubertal development using TS for genital growth (range: Tanner I-V). TS describes sexual maturity stages (no better/worse outcome) as: Tanner I: prepubertal (TV <1.5 ml; small penis), Tanner II: TV 1.6-6ml; skin on scrotum thins, reddens and enlarges; penis length unchanged, Tanner III: TV 6-12ml; scrotum enlarges further; penis begins to lengthen Tanner IV: TV 12-20ml; scrotum enlarges further and darkens; penis increases in length and circumference, and Tanner V: TV >20ml; adult scrotum and penis. The number of participants in each Tanner stage at baseline and categorical change from baseline in Tanner stages to Weeks 12, 36 and 64 were reported. All participants with at least 1 dose of study treatment who had a baseline and at least 1 post baseline TV value, had LH level ≤3 IU/L anytime in study, had at least 12 weeks of CFA and 24 weeks of CFA plus hCG treatment, have last TV value within 4 weeks from last dose of CFA were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36, and Week 64
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    13
    Units: Participants
        Baseline (BL) Tanner I
    12
        BL Tanner II
    1
        BL Tanner III
    0
        BL Tanner IV
    0
        BL Tanner V
    0
        BL Tanner I to Week 12 Tanner I
    9
        BL Tanner I to Week 12 Tanner II
    3
        BL Tanner II to Week 12 Tanner II
    1
        BL Tanner I to Week 36 Tanner I
    2
        BL Tanner I to Week 36 Tanner II
    1
        BL Tanner I to Week 36 Tanner III
    8
        BL Tanner I to Week 36 Tanner IV
    1
        BL Tanner II to Week 36 Tanner II
    1
        BL Tanner I to Week 64 Tanner II
    1
        BL Tanner I to Week 64 Tanner III
    4
        BL Tanner I to Week 64 Tanner IV
    4
        BL Tanner I to Week 64 Tanner V
    2
        BL Tanner I to Week 64 Unknown
    1
        BL Tanner II to Week 64 Tanner III
    1
    No statistical analyses for this end point

    Secondary: Mean Serum Concentration of CFA

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    End point title
    		 Mean Serum Concentration of CFA
    End point description
    Blood samples were collected at pre-specified time points to report the mean serum concentration of CFA. All enrolled participants in the study were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1: predose, 6-24 hours postdose; Day 3: 32-52 hours postdose; Day 5: 72-120 hours postdose; Day 8: 144-192 hours postdose; Day 11: 216-244 hours postdose; Days 29, 85, 169, 253, 337: predose; Days 449, 456: postdose
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    17 [6]
    Units: ng/L
    arithmetic mean (standard deviation)
        Predose Day 1 [n =16]
    0.0 ( 0.0 )
        Postdose Day 1 (6-24 hours) [n =16]
    4100 ( 2630 )
        Postdose Day 3 (32-52 hours) [n =17]
    5880 ( 1640 )
        Postdose Day 5 (72-120 hours) [n =17]
    4240 ( 1180 )
        Postdose Day 8 (144-192 hours) [n =16]
    2110 ( 864 )
        Postdose Day 11 (216-264 hours) [n =17]
    1150 ( 655 )
        Predose Day 29 [n = 16]
    480 ( 348 )
        Predose Day 85 [n = 17]
    695 ( 1310 )
        Predose Day 169 [n = 17]
    691 ( 1060 )
        Predose Day 253 [n = 17]
    301 ( 297 )
        Predose Day 337 [n = 16]
    556 ( 1260 )
        Postdose Day 449 [n = 16]
    864 ( 1290 )
        Postdose Day 456 [n = 16]
    0.0 ( 0.0 )
    Notes
    [6] - Day 1 predose and postdose samples for 1 participant were excluded due to biological implausibility.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Testicular Echogenicity to Week 12, Week 36, and Week 64

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    End point title
    		 Change from Baseline in Testicular Echogenicity to Week 12, Week 36, and Week 64
    End point description
    Testicular Echogenicity was determined by evaluating the sonographic patterns obtained on testicular ultrasound of right and left testes at baseline, Week 12, Week 36 and 64. The sonographic patterns were assessed by central imaging unit by an independent radiologist and categorized as Hypoechoic (decreased echogenicity as compared to echogenicity at baseline), Isoechoic (same echogenicity as compared to echogenicity at baseline) and Hyperechoic (increased echogenicity as compared to echogenicity at baseline). The number of participants with a sonographic pattern at Weeks 12, 36 and 64 were reported. All participants with at least 1 dose of study treatment who had a baseline and at least 1 post baseline TV value, had LH level ≤3 IU/L anytime in study, had at least 12 weeks of CFA and 24 weeks of CFA plus hCG treatment, have last TV value within 4 weeks from last dose of CFA were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36, and Week 64
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    13
    Units: Participants
        Left Testes: Baseline (BL) to Week 12: Hypoechoic
    2
        Left Testes: BL to Week 12: Isoechoic
    10
        Left Testes: BL to Week 12: Hyperechoic
    1
        Right Testes: BL to Week 12: Hypoechoic
    1
        Right Testes: BL to Week 12: Isoechoic
    12
        Left Testes: BL to Week 36: Hypoechoic
    2
        Left Testes: BL to Week 36: Isoechoic
    10
        Left Testes: BL to Week 36: Hyperechoic
    1
        Right Testes: BL to Week 36: Hypoechoic
    1
        Right Testes: BL to Week 36: Isoechoic
    9
        Right Testes: BL to Week 36: Hyperechoic
    3
        Left Testes: BL to Week 64: Hypoechoic
    2
        Left Testes: BL to Week 64: Isoechoic
    8
        Left Testes: BL to Week 64: Hyperechoic
    3
        Right Testes: BL to Week 64: Isoechoic
    10
        Right Testes: BL to Week 64: Hyperechoic
    3
    No statistical analyses for this end point

    Secondary: Change from Baseline in Luteinizing Hormone (LH) to Week 12, Week 36, and Week 64

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    End point title
    		 Change from Baseline in Luteinizing Hormone (LH) to Week 12, Week 36, and Week 64
    End point description
    LH is a gonadotropin secreted from the anterior pituitary and is a marker for spontaneous puberty. Blood samples were collected at baseline, Week 12, Week 36 and Week 64 to report the mean change from baseline in LH level to Weeks 12, 36 and 64. All participants with at least 1 dose of study treatment who had a baseline and at least 1 post baseline TV value, had LH level ≤3 IU/L anytime in study, had at least 12 weeks of CFA and 24 weeks of CFA plus hCG treatment, had last TV value within 4 weeks from last dose of CFA and had a baseline and post baseline LH values at Weeks 12, 36 and 64 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36, and Week 64
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    13
    Units: IU/L
    arithmetic mean (standard deviation)
        Baseline [n =13]
    0.25 ( 0.24 )
        Baseline to Week 12 [n = 13]
    -0.08 ( 0.15 )
        Baseline to Week 36 [n =12]
    -0.13 ( 0.25 )
        Baseline to Week 64 [n =13]
    -0.14 ( 0.25 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Calculated Free Testosterone (T) to Week 12, Week 36, and Week 64

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    End point title
    		 Change from Baseline in Calculated Free Testosterone (T) to Week 12, Week 36, and Week 64
    End point description
    Blood samples were collected at baseline, Week 12, Week 36 and Week 64 to report the mean change from baseline in T level to Weeks 12, 36 and 64. The change from baseline in T level to Week 12, 36, and 64 could not be calculated as planned because only 2 participants had baseline T level values which was insufficient to provide the trend change from baseline in T level to Week 12, 36, and 64. All participants with at least 1 dose of study treatment who had a baseline and at least 1 post baseline TV value, had LH level ≤3 IU/L anytime in study, had at least 12 weeks of CFA and 24 weeks of CFA plus hCG treatment, had last TV value within 4 weeks from last dose of CFA and had a baseline and post baseline T value at Week 12, 36 and 64 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36, and Week 64
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    0 [7]
    Units: ng/L
        arithmetic mean (standard deviation)
    ( )
    Notes
    [7] - Insufficient T data at BL to calculate reliable mean change from BL for T.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Total Testosterone (Total T) to Week 12, Week 36, and Week 64

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    End point title
    		 Change from Baseline in Total Testosterone (Total T) to Week 12, Week 36, and Week 64
    End point description
    Total T is a marker for progress of puberty in males. Total T levels increase during puberty as the testes respond to the gonadotropins. Blood samples were collected at baseline, Week 12, Week 36 and Week 64 post dose to report the mean change from baseline in Total T level to Weeks 12, 36 and 64. A negative value indicated a lower Total T level. All participants with at least 1 dose of study treatment who had a baseline and at least 1 post baseline TV value, had LH level ≤3 IU/L anytime in study, had at least 12 weeks of CFA and 24 weeks of CFA plus hCG treatment, had last TV value within 4 weeks from last dose of CFA and had a baseline and post baseline Total T value at Week 12, 36 and 64 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36, and Week 64
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    13
    Units: ug/L
    arithmetic mean (standard deviation)
        Baseline [n =13]
    0.11 ( 0.12 )
        Baseline to Week 12 [n =12]
    -0.01 ( 0.07 )
        Baseline to Week 36 [n =13]
    4.87 ( 3.97 )
        Baseline to Week 64 [n =13]
    5.31 ( 3.31 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Estradiol (E2) to Week 12, Week 36, and Week 64

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    End point title
    		 Change from Baseline in Estradiol (E2) to Week 12, Week 36, and Week 64
    End point description
    E2 levels rise during puberty in males when some of the T secreted is aromatized. Blood samples were collected at baseline, Week 12, Week 36 and Week 64 to report the mean change from baseline in E2 level to Weeks 12, 36 and 64. A positive value indicated a higher E2 level. All participants with at least 1 dose of study treatment who had a baseline and at least 1 post baseline TV value, had LH level ≤3 IU/L anytime in study, had at least 12 weeks of CFA and 24 weeks of CFA plus hCG treatment, had last TV value within 4 weeks from last dose of CFA and had a baseline and post baseline E2 value at Week 12, 36 and 64 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36, and Week 64
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    13
    Units: ng/L
    arithmetic mean (standard deviation)
        Baseline [n = 13]
    9.51 ( 0.00 )
        Baseline to Week 12 [n = 13]
    0.81 ( 2.90 )
        Baseline to Week 36 [n = 13]
    37.57 ( 28.73 )
        Baseline to Week 64 [n = 13]
    45.58 ( 41.09 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Sex Hormone-Binding Globulin (SHBG) to Week 12, Week 36, and Week 64

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    End point title
    		 Change from Baseline in Sex Hormone-Binding Globulin (SHBG) to Week 12, Week 36, and Week 64
    End point description
    SHBG is a blood protein that controls the amount of T body tissues in males. SHBG is regulated by the ratio of T and E2 levels in addition to other factors (thyroid hormone status, dietary factors, certain diseases and medications). Blood samples were collected at baseline, Week 12, Week 36 and Week 64 to report the mean change from baseline in SHBG level to Weeks 12, 36 and 64. A negative value indicated a lower SHBG level. All participants with at least 1 dose of study treatment who had a baseline and at least 1 post baseline TV value, had LH level ≤3 IU/L anytime in study, had at least 12 weeks of CFA and 24 weeks of CFA plus hCG treatment, had last TV value within 4 weeks from last dose of CFA and had a baseline and post baseline SHBG value at Week 12, 36 and 64 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36, and Week 64
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    13
    Units: ug/dL
    arithmetic mean (standard deviation)
        Baseline [n = 13]
    1.53 ( 0.91 )
        Baseline to Week 12 [n = 13]
    0.04 ( 0.45 )
        Baseline to Week 36 [n = 12]
    -0.53 ( 0.73 )
        Baseline to Week 64 [n = 13]
    -0.68 ( 0.76 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Anti-Müllerian Hormone (AMH) to Week 12, Week 36, and Week 64

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    End point title
    		 Change from Baseline in Anti-Müllerian Hormone (AMH) to Week 12, Week 36, and Week 64
    End point description
    AMH is a marker for progress of puberty in males. Blood samples were collected at baseline, Week 12, Week 36 and Week 64 to report the mean change from baseline in AMH level to Weeks 12, 36 and 64. A negative value indicated a lower AMH level. All participants with at least 1 dose of study treatment who had a baseline and at least 1 post baseline TV value, had LH level ≤3 IU/L anytime in study, had at least 12 weeks of CFA and 24 weeks of CFA plus hCG treatment, had last TV value within 4 weeks from last dose of CFA and had a baseline and post baseline AMH value at Week 12, 36 and 64 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 36, and Week 64
    End point values
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Number of subjects analysed
    13
    Units: ug/L
    arithmetic mean (standard deviation)
        Baseline [n =13]
    23.62 ( 11.07 )
        Baseline to Week 12 [n =13]
    17.98 ( 8.39 )
        Baseline to Week 36 [n =12]
    -10.23 ( 15.69 )
        Baseline to Week 64 [n =13]
    -15.83 ( 11.58 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 71 Weeks
    Adverse event reporting additional description
    All participants who received at least one dose of study treatment were analyzed.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Reporting group description
    		 Participants received 100 μg (if body weight was ≤60 kg) or 150 μg (if body weight was >60 kg) of CFA as a subcutaneous (SC) injection once every 2 weeks for 64 Weeks (Day 1, Week 0 through Week 64) and 500-5000 IU of hCG reconstituted with 1 ml of 0.9% sodium chloride solution, as a SC injection twice a week for 52 weeks (last day of Week 12 through Week 64). The total treatment duration was 64 Weeks.

    Serious adverse events
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 17 (5.88%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Craniopharyngioma
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Corifollitropin Alfa (CFA)+human Chorionic Gonadotropin (hCG)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 17 (94.12%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Pruritus genital
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Scrotal disorder
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Spermatocele
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    6
    Varicocele
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Rhinitis allergic
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Investigations
    Blood prolactin increased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood testosterone decreased
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Blood testosterone free increased
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Blood testosterone increased
         subjects affected / exposed
    4 / 17 (23.53%)
         occurrences all number
    4
    Human chorionic gonadotropin increased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Oestradiol increased
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    5
    Testicular scan abnormal
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Ultrasound testes abnormal
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Foot fracture
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Nervous system disorders
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    4 / 17 (23.53%)
         occurrences all number
    4
    Migraine
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Presyncope
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Dental caries
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Gingival oedema
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Acanthosis nigricans
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Acne
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Dermatitis contact
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Tinea infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Tracheitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hyperphagia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Metabolic syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
         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
    02 Dec 2016
    Major changes of Amendment (AM) 1 included testicular ultrasound images to be read locally by the investigator or local radiologist at Visit 1/Screening, additional blood samples for total T and E2 at Study Visits 10, 11, 13 and 14, and allowed participants with previous GnRH, gonadotropins and androgen treatments to participate in the study.
    19 Jun 2018
    Major change of AM3 included addition of vials as a dosage form for hCG and sodium chloride solution.
    26 Jun 2018
    Major change of AM6 allowed for hCG dose titration.

    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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