E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypogonadotropic hypogonadism (HH) in males may result from either absent or inadequate gonadotropin-releasing hormone (GnRH) secretion by the hypothalamus or failure of pituitary gonadotropin secretion (luteinizing hormone (LH) & follicle stimulating hormone (FSH)). HH is characterized by androgen deficiency and by inappropriately low serum concentrations of LH and FSH. |
: Ipogonadismo Ipogonadotropo (HH). Questa condizione negli uomini può derivare o da una mancata o inadeguata secrezione da parte dell'ipotalamo dell'ormone di rilascio delle gonadotropine (GnRH), o dalla mancata secrezione di gonadotropine (ormone liutenizzante (LH) e ormone follicolo stimolante (FSH)). L'HH è caratterizzata da una deficienza di ormoni androgeni e da una bassa concentrazione sierica di LH e FSH. |
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E.1.1.1 | Medical condition in easily understood language |
Men with diagnosed hypogonadotropic hypogonadism lack essential hormones, gonadotropins, and as a result of this, the testes are not stimulated to produce testosterone & sperm. |
Uomini con diagnosi di HH non hanno ormoni essenziali e gonadotropine in quantità adeguata e, di conseguenza, i testicoli non sono stimolati a produrre testosterone e sperma. |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021012 |
E.1.2 | Term | Hypogonadotrophic hypogonadism |
E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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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 |
The primary objectives of the trial are: 1) to assess the efficacy of 150 μg MK-8962, given once every two weeks for 52 weeks - in combination with a twice weekly dose of hCG - to increase testicular volume measured as the sum of volumes of left and right testes by ultrasound in men with hypogonadotropic hypogonadism who remain azoospermic after 16 weeks of hCG alone and 2) to evaluate whether treatment with 150 μg MK-8962 for 52 weeks in combination with hCG is safe in HH men, as evaluated by the occurrence of (serious) adverse events and presence of anti-MK-8962 antibodies (pre-specified safety endpoint). |
1. Valutare l'efficacia di 150 µg di MK-8962, somministrato una volta ogni due settimane per 52 settimane - in combinazione con una somministrazione bisettimanale di hCG - nell'aumentare il volume testicolare, valutato come la somma del volume del testicolo sinistro e del testicolo destro valutati con ecografia in soggetti maschi adulti con ipogonadismo ipogonadotropico che rimangano azoospermici dopo 16 settimane di monoterapia con hCG. 2. Valutare se il trattamento con 150 µg di MK-8962 per 52 settimane in combinazione con hCG sia sicuro in uomini affetti da HH, come valutato dall'incidenza di eventi avversi, eventi avversi seri e dalla presenza di anticorpi anti-MK-8962 (endpoint di sicurezza predefinito). |
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E.2.2 | Secondary objectives of the trial |
The key secondary objectives are 1) to assess the efficacy of 150 μg MK- 8962, given once every two weeks for 52 weeks - in combination with a twice weekly dose of hCG - to induce spermatogenesis resulting in a sperm count ≥ 1x106 / mL in HH men who remain azoospermic after 16 weeks of hCG alone, and 2) to characterize the pharmacokinetics of MK- 8962 in HH men after subcutaneous (SC) administration of 150 μg MK- 8962 based on serum MK-8962 concentrations. Other secondary objectives are to evaluate the effect of 150 μg MK-8962 in combination with hCG on endocrinological parameters (FSH, LH, hCG, total testosterone [total T], estradiol [E2], sex hormone-binding globulin [SHBG], inhibin-B, and anti-Müllerian hormone [AMH]) as determined by a central laboratory and on sperm parameters (concentration, morphology, motility) as determined by the local laboratory of each clinic. |
1. Valutare l'efficacia di 150 µg di MK-8962, somministrato una volta ogni due settimane per 52 settimane - in combinazione con una somministrazione bisettimanale di hCG - nell'indurre spermatogenesi, valutata come una conta di spermatozoi ≥ 1x106 / mL in uomini HH in cui persisteva azoospermia dopo 16 settimane di monoterapia con hCG. 2. Caratterizzare la farmacocinetica (PK) di MK-8962 nelle 52 settimane di trattamento in uomini HH dopo somministrazione sottocute (SC) 150 µg MK-8962, sulla base della concentrazione sierica di MK-8962. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Each subject must be a male, diagnosed with hypogonadotropic hypogonadism (either congenital or acquired), and be ≥18 to ≤50 years of age at the time of signing ICF. (Note: Subjects with drug-induced HH [e.g. misuse of anabolic steroids, chronic use of glucocorticoids or narcotic analgesics, etc.] are not allowed to participate). Each subject must have low circulating levels of Testosterone (T): T ≤ 6 nmol/L, and low circulating levels of gonadotropins (FSH ≤ 2 IU/L and LH ≤ 2 IU/L), as assessed after an adequate wash-out period from previous testosterone use (if applicable). Each subject must have presence of scrotal testes (left and right) and must have azoospermia (according to the criteria specified in the 2010 World Health Organization [WHO] Laboratory Manual for the Examination and Processing of Human Semen, 5th Edition). Each subject must have adequate replacement of other pituitary hormones (if applicable). |
Ogni soggetto deve avere ricevuto diagnosi di HH, congenito o acquisito, e deve avere un'eta compresa tra 18 e 50 anni al momento della firma del consenso informato. (Nota: Soggetti con HH iatrogeno (per esempio abuso di steroidi anabolizzanti, uso cronico di glucocorticoidi, narcotici, analgesici ecc) non possono partecipare allo studio). Ogni paziente deve avere bassi livelli di Testosterone circolante (T): T ≤ 6nmol/L, e bassi livelli di gonadotropine circolanti (FSH ≤ 2IU/L e LH ≤ 2 IU/L), misurati dopo un adeguato periodo di astensione da precedente uso di testosterone (se applicabile)). Ogni soggetto deve avere testicoli e scroto (destro e sinistro) e deve avere azoospermia (in accordo ai criteri dell'Organizzazione Mondiale della Sanità (WHO)). Ogni soggetto deve avere ancora azoospermia (in accordo ai criteri del Manuale di Laboratorio WHO per l'esame di liquido seminale, Quinta edizione). |
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E.4 | Principal exclusion criteria |
The subject has primary hypogonadism such as Klinefelter's syndrome, or has a history of unilateral or bilateral cryptorchidism (maldescended testes). (Note: Subjects with a history of unilateral cryptorchidism which was treated before the age of 2 years are allowed in this trial). The subject has testicular pathology of clinical importance (e.g., epididymitis, orchitis, testicular torsion, varicocele stage III, testicular atrophy, occlusive azoospermia, etc). The subject has been treated with FSH, hCG or gonadotropin releasing hormone (GnRH) within a period of three months prior to signing informed consent or for more than one month within a period of six months prior to signing informed consent. The subject has proven spermatogenesis upon hCG treatment alone, or has had a previous unsuccessful attempt with hCG in combination with human menopausal gonadotropin (hMG)/FSH to achieve spermatogenesis. The subject had required a dose of hCG of more than 6000 IU per week in a previous attempt to normalize T levels. The subject has untreated pituitary or hypothalamic tumor, or inadequately treated pituitary or hypothalamic tumor that is likely to progress during the study. The subject has had hypophysectomy within a period of 6 months prior to the start of screening. The subject has a history or presence (known or suspected) of testicular, prostatic or breast cancer, has prostate pathology of clinical importance, or has past or present oncological treatment (chemo/radiotherapy). (Note: Previous local radiation of the brain in case of a pituitary tumor is allowed, but not in case of brain metastases). The subject has diabetes mellitus, untreated hyperprolactinaemia or uncontrolled non-gonadal endocrinopathies (thyroid, adrenal, pituitary disorders). The subject has tested positive for Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C (results obtained within 1 year prior to signing ICF are considered valid). |
Il soggetto è affetto da ipogonadismo primario, come la sindrome di Klinefelter o il soggetto ha anamnesi di criptorchidismo monolaterale o bilaterale (mancata discesa dei testicoli). (Nota: I soggetti con anamnesi di criptorchidismo bilaterale trattato prima del compimento dei 2 anni di vita possono partecipare allo studio). Il soggetto ha anamnesi o evidenza presente di patologia testicolare di rilevanza clinica (come epididimite, orchite, torsione del testicolo, varicocele di III stadio, atrofia del testicolo, azoospermia ostruttiva etc). Il soggetto è stato trattato con FSH, hCG o ormone di rilascio delle gonadotropine (GnRH) nei tre mesi precedenti alla firma del consenso informato, o è stato trattatto per più di un mese nei 6 mesi precedenti alla firma del consenso informato. Il soggetto ha comprovata spermatogenesi dopo il trattamento con monoterapia con hCG o il soggetto ha avuto un tentativo precedente d'induzione di spermatogenesi, senza successo, con hCG in combinazione con gonadotropina della menopausa umana (hMG)/FSH. Il soggetto in un tentativo precedente di normalizzazione dei livelli di Testosterone aveva richiesto una dose di hCG superiore alle 6000 IU. Il soggetto ha tumore dell'ipofisi o dell'ipotalamo non trattato, o con trattamento non adeguato, con possibile progressione in corso di studio. Il soggetto ha avuto ipofisectomia nei sei mesi precedenti all'inizio della fase di screening. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint for the current trial is the change from baseline from Day 1 (i.e., the first day of combined treatment with MK- 8962 and hCG) to Week 52 in log-transformed testicular volume (measured as the sum of volumes of left and right testes by ultrasound). |
Cambiamento del volume testicolare dalla situazione iniziale del giorno 1 (cioè il primo giorno di somministrazione della terapia di combinazione con MK-8962 e hCG) alla settimana 52 (valutato come la somma del volume del testicolo sinistro e del testicolo destro valutati con ecografia). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Wk -16, Wk -8, Wk -1, Day 1 and every 4 weeks thereafter till Wk 52. |
Settimana -16, -8. -1, giorno 1 e ogni 4 settimane fino alla settimana 52. |
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E.5.2 | Secondary end point(s) |
• Induced spermatogenesis (i.e., sperm count ≥ 1x106 / mL). • characterization of MK-8962 pharmacokinetics in HH men based on MK-8962 serum concentration data. • Sperm concentration • Sperm morphology • Sperm motility • Serum hormone levels (FSH, LH, hCG, total testosterone, E2, SHBG, inhibin-B, and AMH). |
La percentuale dei soggetti con spermatogenesi indotta (Conta spermatozoi ≥ 1x106 / mL). • Caratterizzazione della farmacocinetica di MK-8962 in uomini HH in base alla concentrazione di MK-8962 nel siero. -Concentrazione degli spermatozoi -Morfologia degli spermatozoi -Motilita degli spermatozoi -Livelli sierici degli ormoni (FSH, LH, hCG, T totale, E2, SHBG, InibinaB, AMH) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Sperm parameters: Wk -16, Wk -1, Wk 16, Wk 28, Wk 40 and Wk 52/discontinuation visit • PK of MK-8962: detailed PK sampling during the first 2 weeks of treatment (6 visits), Wk 4, Wk 16, Wk 28, Wk 40, Wk 52/ discontinuation visit, and post-treatment follow-up visit. • Serum hormone levels: Wk-16, Wk-8, Wk-1, every 4 weeks thereafter till Wk52, and post-treatment follow-up visit. |
Analisi dello sperma: Settimana -16, -1, 16, 28, 40, 52/Visita di discontinuazione
Analisi di PK di MK-8962: raccolta dettagliata durante le prime 2 settimane di trattamento (prime 6 visite), Settimana 4,16,28,40, 52/Visita di discontinuazione,Visite di FollowUp dopo la fine del periodo di trattamento
Livelli ormonali sierici: Settimana -16, -8. -1, ogni 4 settimane fino alla settimana 52, Visite di FollowUp dopo la fine del periodo di trattamento. |
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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 | Yes |
E.6.11 | Pharmacogenomic | No |
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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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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.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 27 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 27 |
E.8.9.2 | In all countries concerned by the trial days | 0 |