E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult men with hypogonadotropic hypogonadism |
Varones adultos con hipogonadismo hipogonadótropo |
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E.1.1.1 | Medical condition in easily understood language |
Adult men with hypogonadotropic hypogonadism |
Varones adultos con hipogonadismo hipogonadótropo |
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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 | 15.0 |
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.Evaluar la eficacia de MK 8962 150 µg, administrado una vez cada dos semanas durante 52 semanas, en combinación con una dosis dos veces a la semana de hCG, para aumentar el volumen testicular medido como la suma del volumen de ambos testículos por ecografía en varones con hipogonadismo hipogonadótropo que presentan azoospermia persistente después de 16 semanas de tratamiento con hCG en monoterapia.
2.Evaluar si el tratamiento con MK 8962 150 µg durante 52 semanas en combinación con hCG es seguro en varones con HH, a juzgar por la aparición de acontecimientos adversos (graves) y la presencia de anticuerpos anti MK 8962 (criterio de valoración de la seguridad especificado de antemano). |
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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.Evaluar la eficacia de MK 8962 150 µg, administrado una vez cada dos semanas durante 52 semanas, en combinación con una dosis dos veces a la semana de hCG, para inducir la espermatogenia con aparición de un recuento de espermatozoides ? 1 x 106/ml en varones con HH que presentan azoospermia persistente después de 16 semanas de tratamiento con hCG en monoterapia.
2.Definir la farmacocinética (FC) de MK 8962, basándose en su concentración sérica, durante 52 semanas de tratamiento en varones con HH tras la administración subcutánea (SC) de 150 µg de MK 8962. |
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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 |
ICF (Version 00 Genetic and future samples 27/06/2012) |
HIP (Versión 00 Genético y Muestras Futuras del 27/06/2012) |
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E.3 | Principal inclusion criteria |
-Each subject must have been diagnosed with HH, either congenital or acquired. 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 be ?18 to ?50 years of age at the time of signing ICF.
-Each subject must have low circulating levels of Testosterone (T): T ? 6 nmol/L, as assessed after an adequate wash-out period from previous testosterone use (if applicable).
-Each subject must have low circulating levels of gonadotropins: follicle stimulating hormone (FSH) ? 2 IU/L and luteinizing hormone (LH) ? 2 IU/L (after adequate wash-out from previous testosterone use [if applicable]).
- Each subject must have presence of scrotal testes (left and right).
- Each subject must have azoospermia (according to the World Health Organization [WHO] criteria). |
-El sujeto debe tener un diagnóstico de HH, ya sea congénito o adquirido. Nota: No podrán participar sujetos con HH de origen farmacológico (por ejemplo, uso incorrecto de esteroides anabolizantes, uso prolongado de glucocorticoides o analgésicos opiáceos, etc.).
-El sujeto debe tener entre ? 18 y ? 50 años de edad en el momento de firmar el DCI.
-El sujeto debe tener una concentración circulante baja de testosterona (T): T ? 6 nmol/l, evaluada tras un período adecuado de lavado del uso previo de testosterona (si procede).
-El sujeto debe tener concentraciones circulantes bajas de gonadotropinas: folitropina (FSH) ? 2 UI/l y lutropina (LH) ? 2 UI/l (tras el período adecuado de lavado del uso previo de testosterona [si procede]).
-El sujeto debe tener testículos escrotales (derecho e izquierdo).
-El sujeto debe tener azoospermia (según los criterios de la Organización Mundial de la Salud [OMS]). |
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E.4 | Principal exclusion criteria |
-The subject has primary hypogonadism, such as Klinefelter's syndrome.
-The subject 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 a history or presence of testicular pathology of clinical importance (e.g., epididymitis,
orchitis, testicular torsion, varicocele stage III, testicular atrophy, occlusive azoospermia, etc), and/or vasectomy.
- 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.
- The subject 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 trial.
- The subject has had hypophysectomy within a period of 6 months prior to the start of screening.
At Visit 6 / Day 1
Key Inclusion Criteria:
- Each subject must have circulating T levels within the normal range
- Each subject must still have azoospermia (according to WHO criteria). |
-El sujeto presenta hipogonadismo primario, como síndrome de Klinefelter.
-El sujeto tiene antecedentes de criptorquidia uni o bilateral. Nota: En este ensayo podrán participar sujetos con antecedentes de criptorquidia unilateral tratada antes de los 2 años de edad.
-El sujeto tiene antecedentes o presencia de trastornos testiculares de importancia clínica (por ejemplo, epididimitis, orquitis, torsión testicular, varicocele en estadio III, atrofia testicular, azoospermia obstructiva, etc.), o vasectomía.
-El sujeto ha sido tratado con FSH, hCG o gonadoliberina (GnRH) en los tres meses anteriores a la firma del consentimiento informado o durante más de un mes en los seis meses anteriores a la firma del consentimiento informado.
-El sujeto presenta espermatogenia confirmada durante el tratamiento con hCG en monoterapia.
-El sujeto ha tenido un intento infructuoso previo con hCG en combinación con gonadotropina menopáusica humana (hMG)/FSH para lograr la espermatogenia.
-El sujeto ha precisado una dosis de hCG superior a 6000 UI por semana en un intento previo para normalizar la concentración de T.
-El sujeto presenta un tumor hipofisario o hipotalámico no tratado o tratado inadecuadamente que probablemente mostrará progresión durante el ensayo.
-El sujeto se ha sometido a una hipofisectomía en los 6 meses anteriores al inicio de la selección.
En la visita 6/día 1
Criterios de inclusión fundamentales:
-El sujeto debe tener una concentración circulante de T dentro del intervalo normal.
-El sujeto debe seguir presentando azoospermia (según los criterios de la OMS). |
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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). |
El criterio de valoración principal de la eficacia del presente ensayo es la variación con respecto al momento basal entre el día 1 (es decir, el primer día de tratamiento combinado con MK 8962 y hCG) y la semana 52 del volumen testicular transformado logarítmicamente (medido como la suma de los volúmenes de los testículos izquierdo y derecho por ecografía). |
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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 |
Semana -16, semana -8, semana -1, Día 1 y cada 4 semanas hasta la semana 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). |
-Porcentaje de sujetos con espermatogenia inducida (es decir, recuento de espermatozoides ? 1 x 106/ml).
-Determinación de la farmacocinética de MK 8962 en varones con HH basándose en la concentración sérica de MK 8962.
-Concentración, morfología y motilidad de los espermatozoides.
-Concentraciones séricas de hormonas (FSH, LH, hCG, T total, E2, SHBG, inhibina B y 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. |
-Parámetros de espermatozoides: Semana-16, Semana -1, Semana 16, Semana 28, Semana 40 and Semana 52/visita de discontinuación.
-Farmacocinética de MK 8962: Toma de muestras detalladas de PK durante las 2 primeras semanas de tratamiento (6 visitas), Semana 4, Semana 16, Semana 28, Semana 40, semana 52/visita de discontinuación y en la visita de seguimiento de post-tratamiento.
-Concentraciones séricas de hormonas: Semana-16, Semana-8, Semana-1, y cada 4 semanas hasta la semana 52 y en la visita de seguimiento de post-tratamiento |
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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 | No |
E.8.1.2 | Open | No |
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) | 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.8.3 |
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 | 2 |
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 |
Australia |
Finland |
Germany |
Italy |
Poland |
Spain |
United Kingdom |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |