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 |
A new recombinant FSH (follicle-stimulating hormone) compound intended to induce development of multiple egg sacs in women undergoing ovarian stimulation as part of infertility treatment |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10021926 |
E.1.2 | Term | Infertility |
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 evaluate the immunogenicity of FE 999049 and GONAL-F based on the presence of anti-FSH antibodies and their neutralising capacity in women undergoing repeated controlled ovarian stimulation cycles |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of FE 999049 and GONAL-F in repeated controlled ovarian stimulation cycles on ovarian response, including follicular development and endocrine profile, as well as on embryo development, treatment efficiency and pregnancy rates in the fresh cycles
To evaluate the safety profile of FE 999049 and GONAL-F, including adverse events, routine safety laboratory parameters and local tolerability, in repeated controlled ovarian stimulation cycles
To evaluate FE 999049 with GONAL-F with respect to cost-effectiveness
To evaluate FE 999049 in an expanded dose range
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects who participated in ESTHER-1 - trial 000004 (COS cycle 1) and failed to achieve an ongoing pregnancy may be included in this trial. Subjects failing to achieve an ongoing pregnancy in COS cycle 2 may be offered to start COS cycle 3 after ensuring that they are still compliant with the eligibility criteria. Continuation to COS cycle 3 is only an option until the required number of subjects have been included (approximately 200).
[COS controlled ovarian stimulation] |
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E.4 | Principal exclusion criteria |
Any clinically relevant changes to any of the eligibility criteria in the previous cycle(s) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects with treatment-induced anti-FSH antibodies after up to two repeated controlled ovarian stimulation cycles |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stimulation day 1, 7-10 days after last FE 999049 or GONAL-F dose and 21-28 days after last FE 999049 or GONAL-F dose |
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E.5.2 | Secondary end point(s) |
1. Proportion of subjects with treatment-induced anti-FSH antibodies with neutralising capacity after up to two repeated controlled ovarian stimulation cycles
2. Proportion of subjects with treatment-induced anti-FSH antibodies, overall as well as with neutralising capacity, after one and after two repeated controlled ovarian stimulation cycles
3. Number and size of follicles on stimulation day 6 and end-of stimulation for each controlled ovarian stimulation cycle
4. Proportion of subjects with extreme ovarian responses, defined as <4, ≥15 or ≥20 oocytes retrieved, for each controlled ovarian stimulation cycle
5. Proportion of subjects with early OHSS (including OHSS of moderate/severe grade) and/or preventive interventions for early OHSS for each controlled ovarian stimulation cycle
6. Proportion of subjects with cycle cancellation due to poor ovarian response or excessive ovarian response for each controlled ovarian stimulation cycle
7. Percentage 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 for each controlled ovarian stimulation cycle
8. Circulating concentrations of FSH, LH, estradiol, progesterone, inhibin A and inhibin B on stimulation day 6 and end-of-stimulation for each controlled ovarian stimulation cycle
9. Total gonadotropin dose and number of stimulation days for each controlled ovarian stimulation cycle
10. Positive βhCG rate (positive serum βhCG test 13-15 days after transfer) for each controlled ovarian stimulation cycle
11. Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer) for each controlled ovarian stimulation cycle
12. Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer) for each controlled ovarian stimulation cycle
13. Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred) for each controlled ovarian stimulation cycle
14. Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer) for each controlled ovarian stimulation cycle
15. Ongoing implantation rate (number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred) for each controlled ovarian stimulation cycle
16. Frequency and intensity of adverse events for each controlled ovarian stimulation cycle
17. Changes in circulating levels of clinical chemistry and haematology parameters and proportion of subjects with markedly abnormal changes for each controlled ovarian stimulation cycle
18. Frequency and intensity of injection site reactions (redness, pain, itching, swelling and bruising) assessed by the subject during the stimulation period for each controlled ovarian stimulation cycle |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. As in Primary End Point
2. As in Primary End Point
3. Stimulation day 6, end-of-stimulation
4. Oocyte retrieval
5. 9 days after triggering
6. End-of-stimulation
7. Prior to insemination, and on culture day 1,3 and 5
8. Stimulation day 6, end-of-stimulation
9. End-of-stimulation
10. 13-15 days after transfer
11. 5-6 weeks after transfer
12. 5-6 weeks after transfer
13. 5-6 weeks after transfer
14. 10-11 weeks after transfer
15. 10-11 weeks after transfer
16. From signing Informed consent until end-of-trial
17. Stimulation day 1, end-of-stimulation, end-of-trial
18. End-of-stimulation |
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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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 |
European Union |
Brazil |
Canada |
Mexico |
Russian Federation |
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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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LVLS in the post-trial follow-up phase of the study |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |