E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Infertility in women undergoing assisted reproductive technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycle |
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E.1.1.1 | Medical condition in easily understood language |
Infertility - Inability to conceive children |
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E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10016398 |
E.1.2 | Term | Female infertility |
E.1.2 | System Organ Class | 100000004872 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10016403 |
E.1.2 | Term | Female infertility of tubal origin |
E.1.2 | System Organ Class | 100000004872 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025511 |
E.1.2 | Term | Male infertility, unspecified |
E.1.2 | System Organ Class | 100000004872 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10014787 |
E.1.2 | Term | Endometriosis of uterus |
E.1.2 | System Organ Class | 100000004872 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10014784 |
E.1.2 | Term | Endometriosis of ovary |
E.1.2 | System Organ Class | 100000004872 |
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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 evaluate the effect of individualised FE 999049 treatment on ovarian response in a long GnRH agonist protocol versus a GnRH antagonist protocol |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of individualised FE 999049 treatment on other pharmacodynamic parameters in a long GnRH agonist protocol versus a GnRH antagonist protocol
• To evaluate the effect of individualised FE 999049 treatment on pregnancy rates in a long GnRH agonist protocol versus a GnRH antagonist protocol
• To evaluate the safety of individualised FE 999049 treatment in a long GnRH agonist protocol versus a GnRH antagonist protocol |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Informed Consent Documents signed prior to screening evaluations.
2. In good physical and mental health.
3. The subjects must be at least 18 years (including the 18th birthday) when they sign the informed consent and no more than 40 years (up to the day before the 41st birthday) at the time of randomisation.
4. Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or with partners diagnosed with male factor infertility, eligible for in vitro fertilisation (IVF) and/or intracytoplasmic sperm injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor.
5. Infertility for at least one year before randomisation for subjects < 38 years or for at least 6 months for subjects ≥38 years (not applicable in case of tubal or severe male factor infertility).
6. The trial cycle will be the subject’s first controlled ovarian stimulation cycle for IVF/ICSI.
7. Regular menstrual cycles of 24-35 days (both inclusive), presumed to be ovulatory.
8. Hysterosalpingography, hysteroscopy, saline infusion sonography, or transvaginal ultrasound documenting a uterus consistent with expected normal function (e.g. no evidence of clinically interfering uterine fibroids defined as submucous or intramural fibroids larger than 3 cm in diameter, no polyps and no congenital structural abnormalities which are associated with a reduced chance of pregnancy) within 1 year prior to randomisation.
9. Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, without evidence of significant abnormality (e.g. no endometrioma greater than 2 cm or enlarged ovaries which would contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) within 1 year prior to randomisation. Both ovaries must be accessible for oocyte retrieval.
10. Early follicular phase (cycle day 2-5) serum levels of FSH between 1 and 15 IU/L at screening.
11. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) antibody tests within 1 year prior to randomisation.
12. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening.
13. If < 38 years willing to accept single blastocyst transfer. If ≥38 years willing to accept transfer of a single good-quality blastocyst (double blastocyst transfer may be performed if no good-quality blastocyst is available). |
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E.4 | Principal exclusion criteria |
1. AMH >35 pmol/L at screening.
2. Strong preference of the subject for either treatment protocol.
3. Known endometriosis stage III-IV (defined by the revised American Society for Reproductive Medicine [ASRM] classification, 1996).
4. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of pregnancy).
5. Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, depending on source of sperm used for insemination in this trial.
6. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
7. Known inherited or acquired thrombophilia disease.
8. Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.
9. Known porphyria.
10. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) with the exception of controlled thyroid function disease.
11. Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which would contraindicate the use of gonadotropins.
12. Known moderate or severe impairment of renal or hepatic function.
13. Currently breast-feeding.
14. Undiagnosed vaginal bleeding.
15. Known abnormal cervical cytology of clinical significance observed within 3 years prior to randomisation (unless the clinical significance has been resolved).
16. Findings at the gynaecological examination at screening which preclude gonadotropin stimulation or are associated with a reduced chance of pregnancy, e.g. congenital uterine abnormalities or retained intrauterine device.
17. Pregnancy (negative pregnancy test must be documented at screening) or contraindication to pregnancy.
18. Known current active pelvic inflammatory disease.
19. Use of fertility modifiers during the last menstrual cycle before randomisation, including dehydroepiandrosterone (DHEA), metformin or cycle programming with oral contraceptives, progestogen or estrogen preparations.
20. Use of hormonal preparations (except for thyroid medication) during the last menstrual cycle before randomisation.
21. Known history of chemotherapy (except for gestational conditions) or radiotherapy.
22. Current or past (1 year prior to randomisation) abuse of alcohol or drugs and/or current (last month) intake of more than 14 units of alcohol per week.
23. Current or past (3 months prior to randomisation) smoking habit of more than 10 cigarettes per day.
24. Hypersensitivity to any active ingredient or excipients in the medicinal products used in the trial.
25. Previous participation in the trial
26. Use of any non-registered investigational drugs during the last 3 months prior to randomisation.
See also Withdrawal Criteria in the study protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Number of oocytes retrieved |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation |
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E.5.2 | Secondary end point(s) |
• Proportion of subjects with cycle cancellation due to poor ovarian response or excessive ovarian response
• Proportion of subjects with blastocyst transfer cancellation after oocyte retrieval due to (risk of) ovarian hyperstimulation syndrome (OHSS)
• Number and size of follicles on stimulation day 6 and end-of-stimulation
• Proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved
• Number of metaphase II oocytes (only applicable for those inseminated using ICSI), fertilisation rate as well as number and quality of embryos on day 3 and blastocysts on day 5 after oocyte retrieval
• Circulating concentrations of FSH, luteinising hormone (LH), estradiol, progesterone and inhibin B on stimulation day 6, end-of-stimulation and at oocyte retrieval
• Total gonadotropin dose and number of stimulation days
• Positive βhCG rate (positive serum βhCG test 13-15 days after transfer)
• Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred)
• Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)
• Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer)
• Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer
• Ongoing implantation rate (number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred)
• Proportion of subjects with early OHSS (including OHSS of moderate/severe grade)
• Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)
• Frequency and intensity of adverse events
• Technical malfunctions of the prefilled injection pen |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoint is included in the relevant endpoint |
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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 | No |
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 | 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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
same product in long GnRH agonist arm or GnRH antagonist arm |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 |
Austria |
Denmark |
Israel |
Italy |
Netherlands |
Norway |
Switzerland |
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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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End of trial is Post-trial follow-up period completed Q3 2021 |
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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 | 7 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |