| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of adolescent males 14 to <18 years old with HH |
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| E.1.1.1 | Medical condition in easily understood language |
| hypogonadotropic hypogonadism |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Male diseases of the urinary and reproductive systems [C12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021012 |
| E.1.2 | Term | Hypogonadotrophic hypogonadism |
| E.1.2 | System Organ Class | 100000004860 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1) Objective: To estimate the change from baseline in testicular volume (measured as the sum of volumes of left and right testes by ultrasound) after 64 weeks of treatment with MK-8962 (in combination with hCG for the last 52 weeks).
2) Objective: To evaluate the safety and tolerability of MK-8962 over 64 weeks of treatment, including evaluation of development of antibodies to MK-8962. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the following parameters over 64 weeks of treatment with MK-8962 (in combination with hCG for the last 52 weeks):
1) Objective: the change from baseline in inhibin B concentrations.
2) Objective: growth velocity (height).
3) Objective: the change from baseline in Tanner Stage of pubertal development.
4) Objective: the change from baseline in levels of endocrine parameters (i.e., luteinizing hormone [LH], calculated free testosterone [T], total testosterone [Total T], estradiol [E2], sex hormone-binding globulin [SHBG], and anti-Müllerian hormone [AMH].
5) Objective: testicular sonographic pattern reflecting pubertal development.
6) Objective: the PK of MK-8962 (based on serum MK-8962 concentrations). |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The Sponsor will conduct Future Biomedical Research on specimens collected for future biomedical research during this clinical trial. This research may include genetic analyses (DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects receive the correct dose of the correct drug/vaccine at the correct time. |
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| E.3 | Principal inclusion criteria |
1. Have a legal representative who understands the study procedures, alternative treatments available and risks involved with the study, and voluntarily agrees to the subject’s participation by giving written informed consent, and the subject has an age-appropriate understanding of the same to give informed written assent if applicable (i.e., in accordance with local requirements). Subjects with an illiterate legal representative may be included if, in the opinion of the investigator, the legal representative fully understands the risks of the subject’s participation and provides consent. In addition, the legal representative may also consent to (and in accordance with local requirements, the subject may assent to) have the subject participate in Future Biomedical Research by signing a separate consent.
2. Be male.
3. Be 14 to <18 years of age at the time when consent/assent is signed, with treatment to begin prior to the subject’s 18th birthday.
4. Have been diagnosed with hypogonadotropic hypogonadism (either isolated or associated with panhypopituitarism), either congenital or acquired with onset prior to puberty.
5. 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: subjects 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).
6. Have circulating levels of 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.
7. Have FSH < or = 2 IU/L and LH < or = 2 IU/L.
8. Have inhibin-B levels < or = 35 pg/mL.
9. Be in good general physical and mental health, in the opinion of the investigator/sponsor, as assessed by physical examination and routine clinical laboratory tests.
10. Have a parent/guardian able and willing to support the subject’s participation by supporting adherence to study drug dosing and visit schedules.
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| E.4 | Principal exclusion criteria |
1. Has a history of bilateral cryptorchidism (maldescended testes) or unilateral cryptorchidism treated after the age of 2 years.
2. Has a history or presence of clinically significant testicular problems (e.g., epididymitis, orchitis, testicular torsion, varicocele Grade III, testicular atrophy, occlusive azoospermia, etc.) that in the opinion of the investigator would impair the subjects response to treatment or has had known damage or injury to the vas deferens.
3. Has had any previous treatment with GnRH, gonadotropins (e.g., hCG, FSH) or androgens (e.g., testosterone, etc.).
4. Has an untreated or inadequately treated pituitary or hypothalamic tumor.
5. Has uncontrolled endocrinopathies, including thyroid, adrenal, and pituitary disorders not on stable replacement therapies (i.e., subject has not been on stable doses for at least 3 months).
6. Has a history of active pituitary hypersecretion as evidenced by hyperprolactinemia or Cushing’s disease, or acromegaly, or any other active pituitary hypersecretion syndrome.
7. Has had hypophysectomy within a period of 12 months prior to the start of screening.
8. Has history of oncologic chemotherapy treatment.
9. Has had brain radiotherapy within 12 months of the start of treatment for a primary tumor, or any history of brain radiotherapy for metastatic disease.
10. Has diabetes mellitus.
11. Has a history of Human Immunodeficiency Virus (HIV).
12. Has clinically significant liver disease, including active viral hepatitis or cirrhosis.
Subjects with a prior history of liver disease which is now inactive or successfully treated may be enrolled if all liver function values (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin) performed within the past year have been normal and are within the normal range (per central lab) at V1. Liver function testing may be repeated once prior to allocation of treatment at the discretion of the investigator if results are inconsistent with the subject’s clinical status or recent laboratory results.
13. Has had a recent history (i.e., within 1 year prior to signing the informed consent) of recreational (e.g., for non-medical purposes) 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.
14. Adecuate organ function laboratory values in accordance with the current protocol.
15. Has an allergy/sensitivity to gonadotropins or its/their excipients.
16. Has any clinically significant condition or situation that, in the opinion of the investigator, would interfere with the trial evaluations or optimal participation in the trial.
17. Has used an investigational drug and/or participated in any other clinical trial within the past 8 weeks (prior to V2), or will participate in any other clinical trials (excluding surveys) during the course of this trial.
18. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint for this trial is the change from Baseline (Day 1) to Week 64 in log-transformed testicular volume (measured as the sum of volumes of left and right testes by ultrasound). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Visit 1, 2, 9, 12, 15 or post-treatment follow up visit and discontinuation or post-treatment follow up visit |
|
| E.5.2 | Secondary end point(s) |
1.Change from baseline in serum inhibin B concentrations
2.Growth velocity
3.Tanner Stage of pubertal development
4.Characterization of MK-8962 pharmacokinetics (based on serum MK-8962 concentrations)
5.Characterization of testicular sonographic pattern reflecting pubertal development
6.Changes from baseline in endocrine parameters
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Week 64
2.Week 36 and Week 64
3.Weeks 12, 36 and 64.
4.Through 64 weeks of treatment.
5.Through 64 weeks of treatment
6.Weeks 12, 36 and 64
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Brazil |
| Mexico |
| Russian Federation |
| South Africa |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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