Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)

Study Overview
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Brief Summary
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The purpose of the study is to investigate whether corifollitropin alfa (MK-8962), administered alone for 12 weeks and then in combination with human chorionic gonadotropin (hCG) for 52 weeks, increases the testicular volume in adolescent males aged 14 to <18. In addition, the study will evaluate participants for safety, tolerability and for the development of corifollitropin alfa antibodies. No formal hypothesis will be tested for this estimation study

Official Title
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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)

Conditions
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Hypogonadotropic Hypogonadism

Intervention / Treatment
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* Drug: Corifollitropin alfa
* Drug: hCG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have legal representative who understands the study procedures, alternative treatments available and risks involved with the study, and voluntarily agrees to the individual's participation by giving written informed consent, and the individual has an age-appropriate understanding of the same to give informed written assent if applicable. Diagnosed with hypogonadotropic hypogonadism (either isolated or associated with panhypopituitarism), either congenital or acquired with onset prior to puberty. Have bilateral pre-gonadarche testes as defined by testicular volume <4.0 mL for each testicle, as determined by ultrasound and assessed by the investigator (if qualified) or local radiologist with appropriate training and expertise in reading testicular ultrasound. Note: participants with a volume of <4.0 mL in one testicle and a volume of 4-8 mL in the other testicle are considered to be pre-gonadarche and may participate, if there is no history or evidence of a primary testicular disorder (see Exclusion Criteria 1 and 2). Have circulating levels of total testosterone (Total T) less than the lower limit of normal (LLN) of 8.3 nmol/L as specified by the central lab for a young healthy adult male. Have follicle stimulating hormone (FSH) ≤2 IU/L and luteinizing hormone (LH) ≤2 IU/L. Have inhibin-B levels ≤35 pg/mL. (Note: if individual has inhibin-B levels >35 pg/mL, but meets all of the other inclusion/exclusion criteria, either a GnRH agonist (GnRHa) stimulation test or GnRH IV infusion test may be performed. In good general physical and mental health, in the opinion of the investigator/sponsor, as assessed by physical examination and routine clinical laboratory tests. Have a parent/guardian able and willing to support the individual's participation by supporting adherence to study drug dosing and visit schedules. Exclusion Criteria: Have a history of bilateral cryptorchidism (maldescended testes) or unilateral cryptorchidism treated after the age of 2 years. Have a history or presence of clinically significant testicular problems (e.g., epididymitis, orchitis, testicular torsion, varicocele Grade III, testicular atrophy, occlusive azoospermia, etc.) that would impair participants response to treatment or has had known damage or injury to the vas deferens. Had any previous treatment with GnRH, gonadotropins (e.g., hCG, FSH) or androgens (e.g., testosterone, etc.). Note: Use of GnRH and gonadotropins for diagnostic testing purposes only is allowed. Participants with use of hCG and androgen therapy prior to the age of 2 years old can be included in the trial. Participants with transient use of androgens (i.e., for less than 2 weeks) that was stopped at least 6 months prior to signing informed consent can also be included in the trial. Has an untreated or inadequately treated pituitary or hypothalamic tumor. Have uncontrolled endocrinopathies, including thyroid, adrenal, and pituitary disorders not on stable replacement therapies. Has a history of active pituitary hypersecretion as evidenced by hyperprolactinemia or Cushing's disease, acromegaly, or any other active pituitary hypersecretion syndrome. (Note: Individuals who have been treated and are clinically stable, with no evidence of hypersecretion for at least 12 months prior to screening, may participate. Has had hypophysectomy within 12 months to the start of screening. Has history of oncologic chemotherapy treatment. Has had brain radiotherapy within 12 months of start of treatment for a primary tumor, or any history of brain radiotherapy for metastatic disease. Has diabetes mellitus. Has history of Human Immunodeficiency Virus (HIV). Has renal insufficiency, as determined by investigator, based on serum creatinine, blood urea nitrogen, and estimated glomerular filtration rate. Has clinically significant liver disease, including active viral hepatitis or cirrhosis. Individuals with a prior history of liver disease which is now inactive or successfully treated may be enrolled if all liver function values performed within the past year have been normal and within the normal range at Visit 1. Has had a recent history of recreational or illicit drug use, including marijuana; or routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week, or engages in binge drinking. Has an allergy/sensitivity to gonadotropins or its/their excipients. Has used an investigational drug and/or participated in any other clinical trial within the past 8 weeks (prior to Visit 2), or will participate in any other clinical trials (excluding surveys) during the course of this trial.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Corifollitropin alfa (CFA)+human Chorionic Gonadotropin (hCG)<br>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. | Drug: Corifollitropin alfa<br>* 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).<br>* Other names: Elonva;Drug: hCG<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Log-Transformed Testicular Volume (TV) to Week 64 | 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. | Baseline and Week 64 | 
| Number of Participants Who Experienced an Adverse Event (AE) | An adverse event was 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. | Up to approximately 71 Weeks | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An adverse event was 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. | Up to approximately 64 Weeks | 
| Percentage of Participants With Anti-Corifollitropin Alfa (CFA) Antibodies | 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 were reported. | Up to approximately 71 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Serum Inhibin B Concentration to Week 64 | 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. | Baseline and Week 64 | 
| Growth Velocity at Week 36 | 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. | Week 36 | 
| Growth Velocity at Week 64 | 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. | Week 64 | 
| Change From Baseline in Tanner Stage (TS) of Pubertal Development for Pubic Hair to Week 12, Week 36, and Week 64 | 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. | Baseline, Week 12, Week 36, and Week 64 | 
| Change From Baseline in TS of Pubertal Development for Genital Growth to Week 12, Week 36, and Week 64 | Male participants were assessed clinically for pubertal development using TS for genital growth (range: Tanner I-V). TS describes sexual maturity stages (no better or 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. | Baseline, Week 12, Week 36, and Week 64 | 
| Mean Serum Concentration of CFA | Blood samples were collected at pre-specified time points (Day 1 (predose, 6-24 hours postdose after 1st dose), Day 3 (32-52 hours postdose after 1st dose), Day 5 (72-120 hours postdose after 1st dose), Day 8 (144-192 hours postdose after 1st dose), Day 11 (216-244 hours postdose after 1st dose), Day 29 (predose prior to 2nd dose; no hCG), Day 85 (predose, prior to 4th dose; no hCG), Day 169 (predose prior to 7th dose; with hCG co-administration), Day 253 (predose prior to 10th dose with hCG co-administration), Day 337 (predose prior to 13th dose; with hCG co-administration), Days 449 and 456 (postdose)) to report the mean serum concentration of CFA. | 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 | 
| Change From Baseline in Testicular Echogenicity to Week 12, Week 36, and Week 64 | 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. | Baseline, Week 12, Week 36, and Week 64 | 
| Change From Baseline in Luteinizing Hormone (LH) to Week 12, Week 36, and Week 64 | 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. | Baseline, Week 12, Week 36, and Week 64 | 
| Change From Baseline in Calculated Free Testosterone (T) to Week 12, Week 36, and Week 64 | 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 were insufficient to provide the trend change from baseline in T level to Week 12, 36, and 64. | Baseline, Week 12, Week 36, and Week 64 | 
| Change From Baseline in Total Testosterone (Total T) to Week 12, Week 36, and Week 64 | 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. | Baseline, Week 12, Week 36, and Week 64 | 
| Change From Baseline in Estradiol (E2) to Week 12, Week 36, and Week 64 | 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. | Baseline, Week 12, Week 36, and Week 64 | 
| Change From Baseline in Sex Hormone-Binding Globulin (SHBG) to Week 12, Week 36, and Week 64 | 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. | Baseline, Week 12, Week 36, and Week 64 | 
| Change From Baseline in Anti-Müllerian Hormone (AMH) to Week 12, Week 36, and Week 64 | 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. | Baseline, Week 12, Week 36, and Week 64 |