E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stimulation of multifollicular development in women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian transfer and zygote intrafallopian transfer. |
Estimulación del desarrollo multifolicular en mujeres sometidas a superovulación para técnicas de reproducción asistida como fertilización in vitro, transferencia intra-falopiana gamética y transferencia intra-falopiana de cigotos. |
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E.1.1.1 | Medical condition in easily understood language |
To make the woman's body produce a number of eggs at the same, which can be removed by doctors for infertility treatments. |
Hacer que el cuerpo de la mujer produzca un número de óvulos al mismo tiempo, que puedan ser extraídos por los doctores para tratamientos de infertilidad. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Reproductive physiologi cal processes [G08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10021928 |
E.1.2 | Term | Infertility female |
E.1.2 | System Organ Class | 10038604 - Reproductive system and breast 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 |
To demonstrate equivalence between the numbers of oocytes retrieved after treatment with Actavis rhFSH or GONAL-f in ovulatory subjects participating in an ART program. |
Demostrar la equivalencia entre el número de ovocitos recuperados después del tratamiento con Actavis rhFSH o GONAL-f en mujeres que ovulan, participantes en un programa de TRA. |
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E.2.2 | Secondary objectives of the trial |
? To evaluate pregnancy rate after treatment with Actavis rhFSH and GONAL-f. ? To evaluate dose requirements and duration of Actavis rhFSH and GONAL-f treatment. ? To evaluate the pharmacodynamic properties of Actavis rhFSH and GONAL-f. ? To evaluate the number of good quality oocytes and embryos after treatment with Actavis rhFSH and GONAL-f. ? To evaluate the immunogenicity, in terms of anti-FSH antibodies, after treatment with Actavis rhFSH and GONAL-f. ? To evaluate the general safety of Actavis rhFSH and GONAL-f. |
? Evaluar la tasa de embarazo tras el tratamiento con Actavis rhFSH y GONAL-f. ? Evaluar los requisitos de las dosis y la duración del tratamiento con Actavis rhFSH y GONAL-f. ? Evaluar las propiedades farmacodinámicas de Actavis rhFSH y GONAL-f. ? Evaluar el número de ovocitos y embriones de buena calidad después del tratamiento con Actavis rhFSH y GONAL-f. ? Evaluar la inmunogenicidad, expresada en anticuerpos anti-FSH, después del tratamiento con Actavis rhFSH y GONAL-f. ? Evaluar la seguridad general de Actavis rhFSH y GONAL-f. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
IN01. Is in good health and 18 to 35 years of age (inclusive) with child-bearing potential at the time of screening; IN02. Has a body mass index (BMI) of 18 ? 32 (inclusive); IN03. Has a physical examination, including vital signs, that is within normal limits or clinically acceptable to the Investigator; IN04. Has serum FSH level less than 2x the upper range of normal for the study population on the third day of menstrual cycle at Screening; IN05. Has a current diagnosis of infertility with one of the following categories: tubal factor, ovulation disorder, mild endometriosis (American Society for Reproductive Medicine [ASRM] stage 1-2), male factor, other causes, unexplained cause, multiple factors (female only), and multiple factors (male and female); IN06. Has both ovaries (by ultrasonography at Screening) and normal uterine cavity; IN07. Has a male partner with semen analysis that is at least adequate for ICSI within 6 months before the first test or reference article injection. (Donor sperm is allowed); IN08. Has LH, prolactin (PRL), thyroid stimulating hormone (TSH) results within the reference range for the clinical laboratory or considered not clinically significant by the Investigator at Screening; IN09. Has current general health status that is congruent with the site?s conventional requirements for ART eligibility; IN10. Is willing and able to comply with the requirements of the protocol; IN11. Is willing and able to provide written informed consent and authorisation to disclose after being fully informed of the risks of participating in the study. |
1 En buen estado de salud, entre 18 y 35 años (inclusive). 2 IMC entre 18 y 32 (inclusive).; 3 Examen físico normal a criterio del investigador . 4 Reserva ovárica adecuada: FSH menos del doble del rango superior normal el día 3 del ciclo menstrual del screening y la hormona antimuleriana (AMH) entre 1,0 y 4,5 ng/mL. 5 Presenta un diagnóstico de infertilidad 6 Tiene los dos ovarios y una cavidad uterina normal 7 La pareja masculina presenta un análisis de semen adecuado para ICSI en los 6 meses anteriores a la primera inyección del producto en investigación o el de referencia 8 En el screening LH, prolactina y TSH están en un rango normal o sus desviaciones no se consideran clínicamente significativas por parte del Investigador 9 Estado general de salud normal y compatible con los requisitos para TRA. 10 Dispuesta a cumplir los requisitos del protocolo. 11 Dispuesta a firmar el consentimiento informado, después de ser informada de los riesgos de participar en el estudio |
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E.4 | Principal exclusion criteria |
EX01. Has participated in another study protocol or in a clinical trial with experimental medication within 30 days of Screening; EX02. Has participated in previous ART cycle before this study; EX03. Has taken clomiphene, tamoxifen, injectable GnRH agonists or antagonists, estrogen, androgens, anti-androgens, synthetic progestins, or aromatase inhibitors within 30 days of Screening; EX11. Has 12 or more follicles in either ovary, size 2 - 9 mm in diameter (calculated as the mean of the longitudinal and anteroposterior diameters) and/or an ovarian volume > 10 mL in either ovary (calculated using the formula 0.5 x length x width x thickness), as determined by transvaginal ultrasound examination at Screening Visit 3 or on Treatment Day 1 before the first test or reference article injection; EX12. Has symptoms or signs of pelvic or vaginal infection or abnormal gynecological bleeding; EX13. Has current diagnosis of or signs and symptoms that indicate adrenal dysfunction; EX14. Has a history of recurrent spontaneous abortion (3 or more); EX15. Has a history of extrauterine pregnancy in the past 6 months before Screening; EX16. Has a history of allergy or hypersensitivity to any protein based drugs, including FSH and hCG products and GnRH antagonists, or any excipient in the formulation of the test or reference articles; EX17. Is a smoker with an average > 5 cigarettes (or equivalent tobacco use of other types) a day; EX18. Is unable or unwilling to tolerate injections; EX19. Is judged by the Investigator to be unsuitable for enrollment for any other reason. |
EX01. Ha participado en otro protocolo o ensayo clínicos con una medicación experimental en los 30 días anteriores al screening; EX02. Ha participado en un ciclo de TRA antes de este estudio EX03. Ha tomando clomifeno, tamoxifeno, agonistas o antagonistas inyectables de GnRH, estrógenos, andrógenos, progestinas sintéticas anti-andrógenos o inhibidores de la aromatasa en los 30 días anteriores al screening; EX04. Está embarazada o en periodo de lactancia EX05. Ha empleado anticonceptivos hormonales en los 3 meses anteriores a la primera dosis de los productos de referencia EX06. Presenta unos resultados clínicos que puedan indicar Hepatitis B, C, SIDA. EX07. Tiene quistes ováricos > 30 mm de diámetro o endometrioma, (determinado por ecografía transvaginal) en la visita 3 de screening y en el día 1 de tratamiento antes de la inyección de los productos de referencia EX08. Presenta una historia o actualmente se le he diagnosticado el SHEO (Síndrome de Hiperestimulación ovárica). EX09. Presenta una historia o actualmente se le ha diagnosticado el síndrome de ovario poliquístico, primario o fallo ovárico prematuro, síndrome ovárico resistente u ooforitis autoinmune. EX10. Presenta 12 o más folículos/quistes en cualquier ovario, de tamaño entre 2 y 9 mm de diámetro y /o un volumen ovárico > 10 mL (determinado por ecografía transvaginal) en la visita 3 de sreening o en el día 1 de tratamiento, antes de la primera inyección de los productos de referencia. EX11. Presenta síntomas o signos de infección pélvica o vaginal o sangrado ginecológico anormal EX12. Se la ha diagnosticado o presenta signos o síntomas que pueden indicar disfunción adrenal EX13. Tiene historial de abortos espontáneos recurrentes (3 o más). EX14. Ha tenido un embarazo extrauterino en los 6 meses anteriores al screening; EX15. Presenta historia de alergia o hipersensibilidad frente a fármacos basados en proteínas, incluyendo productos de FSH y hCG, o a cualquier excipiente de la formulación de los productos de referencia. EX16. Fuma de media > 5 cigarrillos al día (o su equivalente en tabaco de otros tipos) EX17. Es incapaz o no tiene voluntad de tolerar las inyecciones EX18. A juicio del investigador no es adecuada para ser incluida, por cualquier otro motivo. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Number of oocytes retrieved in the first ART cycle |
Número de ovocitos recuperados en el primer ciclo de TRA. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluated at the end of the first ART cycle. The overall treatment duration in any ART cycle will not exceed 19 days with average expected to be around 10 days. |
Se evaluará al final del primer ciclo de TRA. La duración del tratamiento general en cualquier ciclo de TRA no excederá los 19 días con una media esperada en torno a 10 días. |
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E.5.2 | Secondary end point(s) |
1. Ongoing pregnancy rate, defined as percentage of subjects with presence of at least one fetus with heart activity, at 10 weeks after embryo transfer; 2. Mean total dose of Actavis rhFSH or GONAL-f required during the ART cycle; 3. Mean number of days of Actavis rhFSH or GONAL-f stimulation during the ART cycle; 4. Percentage of subjects who require an increase or decrease of the dose of Actavis rhFSH or GONAL-f during treatment; 5. Mean number of follicles/cysts with sizes ? 11 mm, ? 15 mm, or ? 17 mm on Treatment Day 6 (before FSH dose adjustment) and the day of hCG administration; 6. Serum concentrations of inhibin-B, E2, LH, FSH, and progesterone on Treatment Day 1 (before Actavis rhFSH or GONAL-f injection) and the day of hCG administration 7. Mean number of fertilised oocytes at 24 hours after the initiation of the IVF for subjects who are not choosing ICSI procedure; 8. Mean number of metaphase II oocytes after oocyte retrieval for subjects with ICSI procedure (metaphase II oocytes are defined as having extruded the first polar body and are in the resting phase of meiosis II); 9. Mean number of Grade 1 and Grade 2 embryos on Day 3 of embryo culture. |
1. Tasa de embarazo en curso, que se define como el porcentaje de mujeres con presencia de al menos un feto con actividad del corazón, a las 10 semanas tras la transferencia de embriones; 2. Dosis total media de Actavis rhFSH o GONAL-f requerida durante el ciclo de TRA; 3. Media del número de días de estimulación con Actavis rhFSH o GONAL-f durante el ciclo de TRA; 4. Porcentaje de mujeres que requieren un aumento o disminución de la dosis de Actavis rhFSH o GONAL-f durante el tratamiento; 5. Número medio de folículos/quistes con tamaño ? 11 mm, ? 15 mm, o ? 17 mm el Día 6 de tratamiento (antes del ajuste de la dosis de FSH) y el día de la administración de hGC; 6. Concentraciones séricas de inhibina-B, E2, HL, FSH, y progesterona el Día 1 de tratamiento (antes de la inyección de FSH) y el día de la administración de hCG; 7. Número medio de ovocitos fertilizados a las 24 horas después de la instauración de la FIV para las mujeres que no eligen el procedimiento IICE; 8. Número medio de ovocitos en metafase II después de la recuperación de ovocitos para las mujeres con procedimiento IICE (los ovocitos en metafase II se definen por tener extruido el primer cuerpo polar y por encontrarse en la fase de reposo de la meiosis II); 9. Número medio de embriones de Grado 1 y Grado 2 el día 3 del cultivo de embriones. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Ongoing pregnancy rate (1) will be evaluated at 10 weeks after embryo transfer. Other secondary endpoints (2, 3, 4, 8) are evaluated at the end of the first ART cycle (as for the primary endpoint). Endpoint (5) on Treatment Day 6 (before FSH dose adjustment) and the day of hCG administration, and (6) on Treatment Day 1 (before FSH injection) and the day of hCG administration. Mean number of fertilised oocytes (7) assessed at 24 hours after the initiation of the IVF for subjects who are not choosing ICSI procedure. Mean number of Grade 1 and Grade 2 embryos (9) assessed on Day 3 of embryo culture |
La tasa de embarazo en curso (1) se evaluará a las 10 semanas tras la transferencia de embriones. Otros criterios de valoración (2, 3, 4, 8) se evaluarán al final del primer ciclo de TRA (en cuanto a la variable principal). El criterio 5 el día 6 de tratamiento (antes de la inyección de FSH) y el día de la administración de hCG, y el 6 el día 1 de tratamiento y el día de la administración de hCG. El número medio de ovocitos fertilizados (7) se valoran 24 horas después del inicio de la FIV para las mujeres que no eligen el procedimiento ICSI. El número medio de embriones de Grado 1 y Grado 2 se valorará el día 3 del cultivo de embriones. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |