| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the effect of 150, 200, and 250 μg of FE 999302 with 250 μg OVITRELLE and 10,000 IU NOVAREL on oocyte maturity when administered for triggering of final follicular maturation in women undergoing controlled ovarian stimulation |
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| E.2.2 | Secondary objectives of the trial |
1. To compare the effect of 150, 200, and 250 μg of FE 999302 with 250 μg OVITRELLE and 10,000 IU NOVAREL on fertilisation, blastocyst quality, endocrine profile during the luteal phase, and pregnancy, when administered for triggering of final follicular
maturation in women undergoing controlled ovarian stimulation
2. To compare the safety of 150, 200, and 250 μg of FE 999302 with 250 μg OVITRELLE and 10,000 IU NOVAREL when administered for triggering of final follicular maturation in women undergoing controlled ovarian stimulation
3. To investigate the impact of body weight on FE 999302 exposure and assess the population pharmacokinetics of FE 999302 when administered for triggering of final follicular maturation in women undergoing controlled ovarian stimulation
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject informed consent form signed prior to any trial-related activities.
2. Parental informed consent form signed prior to start of stimulation in the trial.
3. In good physical and mental health as judged by the investigator.
4. Pre-menopausal women between the ages of 18 and 42 years. The subjects must be at least 18 years (including the 18th birthday) and no more than 42 years (up to the day before the 43rd birthday) when they sign the informed consent.
5. 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.
6. Infertility for at least 1 year before screening for subjects <35 years or for at least 6 months for subjects ≥35 years (not applicable in case of tubal or severe male factor infertility).
7 No more than two controlled ovarian stimulation cycles initiated, regardless outcome (taking exclusion criteria 3, 4, and 5 into account).
8. Regular menstrual cycles of 24-35 days (both inclusive), presumed to be ovulatory.
9. 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 start of stimulation in the trial.
10. Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, without evidence of significant abnormality (e.g. enlarged ovaries which would contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) within 1 year prior to start of stimulation in the trial. Both ovaries must be accessible for oocyte retrieval.
11. Early follicular phase (cycle day 2-4) serum levels of follicle-stimulating hormone (FSH) between 1 and 15 IU/L (results obtained within 3 months prior to start of stimulation in the trial).
12. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) antibody tests within 1 year prior to start of stimulation in the trial.
13. Follicular development with ≥3 follicles with a diameter ≥17 mm and <20 follicles with a diameter ≥12 mm observed on transvaginal ultrasound at the end of stimulation in the trial cycle.
14. Willing to accept ICSI regardless the cause of infertility.
15. Willing to accept transfer of a single good-quality blastocyst (double blastocyst transfer is allowed if no good-quality blastocyst is available). |
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| E.4 | Principal exclusion criteria |
1. Known polycystic ovary syndrome (PCOS) associated with anovulation or known endometriosis stage III-IV
2. Considered unsuitable for controlled ovarian stimulation with a starting dose of 150 or 225 IU/day highly purified human menopausal gonadotropin (HP-hMG), as judged by the investigator.
3. Poor response in a previous controlled ovarian stimulation cycle using a gonadotropin starting dose of 150 IU/day or higher. Poor response is defined as <4 oocytes retrieved, or cycle cancellation prior to oocyte retrieval due to inadequate follicular development.
4. Excessive ovarian response in a previous controlled ovarian stimulation cycle for IVF/ICSI using a daily FSH/hMG dose of <225 IU, defined as ≥25 oocytes retrieved or cycle cancellation prior to oocyte retrieval due to excessive ovarian response, including risk of ovarian hyperstimulation syndrome (OHSS).
5. Severe OHSS in a previous controlled ovarian stimulation cycle.
6. One or more follicles ≥10 mm (including cysts) observed on the transvaginal ultrasound prior to start of ovarian stimulation on stimulation day 1 (puncture of cysts is allowed prior to start of stimulation).
7. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy and before week 24 of pregnancy, excluding ectopic pregnancy).
8. Known abnormal karyotype of subject or of her partner/sperm donor, as applicable, depending on source of sperm used for insemination in this trial. In case partner sperm will be used and the sperm production is severely impaired (concentration <1 million/mL), normal karyotype, including no Y-chromosome microdeletion, must be documented.
9. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
10. Known inherited or acquired thrombophilia disease.
11. Known active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.
12. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver, or kidney) with the exception of controlled thyroid function disease.
13. Known presence of anti-hCG antibodies (based on the information available in the subject’s medical records; i.e. not based on the anti-hCG antibody analyses conducted in the trial).
14. Known tumours of the ovary, breast, uterus, adrenal gland, pituitary, or hypothalamus which would contraindicate the use of gonadotropins.
15. Known impairment of renal or hepatic function.
16. Any abnormal finding of clinical chemistry and haematology at screening or vital signs at randomisation, which is judged clinically relevant by the investigator and/or requires intervention.
17. Currently breast-feeding.
18. Undiagnosed vaginal bleeding.
19. Known abnormal cervical cytology of clinical significance observed within 3 years prior to start of stimulation in the trial (unless the clinical significance has been resolved).
20. 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.
21. Pregnancy (negative urinary pregnancy tests must be documented at screening and prior to start of stimulation) or contraindication to pregnancy.
22. Known current active pelvic inflammatory disease.
23. Use of fertility modifiers during the last menstrual cycle before start of stimulation in the trial, including dehydroepiandrosterone (DHEA) or cycle programming with oral contraceptives, progestogen or estrogen preparations.
24. Use of hormonal preparations (except for thyroid medication) during the last menstrual cycle before start of stimulation in the trial.
25. Known history of chemotherapy (except for gestational conditions) or radiotherapy.
26. Current or past (1 year prior to start of stimulation in the trial) abuse of alcohol or drugs, and/or current (last month) intake of more than 14 units of alcohol per week.
27. Current or past (90 days prior to start of stimulation in the trial) smoking habit of more than 10 cigarettes per day.
28. Hypersensitivity to any active ingredient or excipients in the medicinal products used in the trial.
29. Previous participation in the trial (i.e. re-screening is not allowed).
30. Use of any non-registered investigational drugs during the last 90 days prior to start of stimulation in the trial. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Number of metaphase II (MII) oocytes |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 36 hours (+/- 2h) after triggering of final follicular maturation |
|
| E.5.2 | Secondary end point(s) |
1. Secondary Efficacy Endpoints
1.1 Number of oocytes retrieved
1.2 Number of fertilised (2 pronuclei) oocytes
1.3 Number and quality of embryos
1.4 Number and quality of blastocysts
1.5 Serum hormone concentrations of progesterone, 17-OH-progesterone, estradiol, follicle-stimulating hormone (FSH), and luteinising hormone (LH)
1.6 Positive βhCG (positive serum βhCG test)
1.7 Clinical pregnancy (at least one gestational sac)
1.8 Vital pregnancy (at least one intrauterine gestational sac with fetal heart beat)
1.9 Ongoing pregnancy (at least one intrauterine viable fetus)
2. Secondary Pharmacokinetics Endpoint
2.1 Serum hCG concentrations
3. Secondary Safety Endpoints
3.1 Ovarian hyperstimulation syndrome (OHSS), overall and by grade and severity
3.2 Injection site reactions (redness, pain, itching, swelling, and bruising) assessed by the
subject following administration of investigational medicinal product (IMP)
3.3 Treatment-induced anti-hCG antibodies, overall as well as with neutralising capacity
3.4 Multi-fetal gestation, biochemical pregnancy, spontaneous abortion, ectopic pregnancy
(with and without medical/surgical intervention), and vanishing twins
4. Exploratory Endpoint
4.1 Biomarkers of oocyte maturation and/or OHSS in follicular fluid and granulosa cells |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.3 on day 3 after oocyte retrieval
1.4 on day 5 after oocyte retrieval
1.5 at end-of-stimulation, the day after triggering, at oocyte retrieval, on day 5 after oocyte retrieval (transfer), on day 7-9 after oocyte retrieval (mid-luteal phase), and 13-15 days after transfer
1.6 13-15 days after transfer
1.7 5-6 weeks after transfer
1.8 5-6 weeks after transfer
1.9 10-11 weeks after transfer
2.1 at end-of-stimulation, the day after triggering, at oocyte retrieval, on day 5 after oocyte retrieval (transfer), and on day 7-9 after oocyte retrieval (mid-luteal phase)
3. Secondary Safety Endpoints ongoing throughout the trial |
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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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| 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 | 5 |
| 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 | 15 |
| 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 | Yes |
| 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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The end of the trial is defined as the date of LPLV, i.e the end-of-trial visit of the last subject
The sponsor shall submit and end-of-trial notification to the regulatory authorities and the concerned ethics committees in the participating countries, when the last data in the pregnancy follow-up period has been collected in all participating countries, i.e when the last 4 week follow-up data on the neonates have been collected.
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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