Evidence-based Stimulation Trial With Human rFSH in Europe and Rest of World 1

Study Overview
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Brief Summary
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This trial investigates the effects of FE 999049 compared to GONAL-F.

Official Title
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A Randomised, Controlled, Assessor-blind, Parallel Groups, Multicentre, Multinational Trial Comparing the Efficacy and Safety of FE 999049 With Follitropin Alfa (GONAL-F) in Controlled Ovarian Stimulation in Women Undergoing an Assisted Reproductive Technology Programme

Conditions
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Infertility

Intervention / Treatment
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* Drug: Follitropin Delta (FE 999049)
* Drug: Follitropin Alfa (GONAL-F)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed Consent Documents signed prior to screening evaluations In good physical and mental health Pre-menopausal females between the ages of 18 and 40 years 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 Infertility for at least one year before randomisation for subjects ≤37 years or for at least 6 months for subjects ≥38 years (not applicable in case of tubal or severe male factor infertility) The trial cycle will be the subject's first controlled ovarian stimulation cycle for IVF/ICSI 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 Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, without evidence of significant abnormality (e.g. no endometrioma greater than 3 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. Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results obtained within 3 months prior to randomisation) Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening Exclusion Criteria: Known endometriosis stage III-IV One or more follicles ≥10 mm observed on the transvaginal ultrasound prior to randomisation on stimulation day 1 Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of pregnancy) Known abnormal karyotype of subject or of her partner/sperm donor, as applicable, depending on source of sperm used for insemination in this trial. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes) Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) which can compromise participation in the trial with the exception of controlled thyroid function disease Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which would contraindicate the use of gonadotropins.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>Follitropin Delta (FE 999049) | Drug: Follitropin Delta (FE 999049)<br> <br> |
| Active Comparator: B<br>Follitropin Alfa (GONAL-F) | Drug: Follitropin Alfa (GONAL-F)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing Pregnancy Rate | Ongoing pregnancy was defined as at least one intrauterine viable fetus 10-11 weeks after blastocyst transfer. | 10-11 weeks after blastocyst transfer | 
| Ongoing Implantation Rate | Ongoing implantation rate was defined as the number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred. | 10-11 weeks after blastocyst transfer | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vital Pregnancy Rate | Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after blastocyst transfer. | 5-6 weeks after blastocyst transfer | 
| Implantation Rate | Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred. | 5-6 weeks after blastocyst transfer | 
| Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved |  | Day of oocyte retrieval | 
| Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS | The proportion of subjects with early OHSS, early OHSS of moderate or severe grade, preventive interventions for early OHSS, early OHSS and/or preventive interventions for early OHSS, and early OHSS of moderate or severe grade and/or preventive interventions for early OHSS are presented. | ≤9 days after triggering of final follicular maturation | 
| Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Proportion of subjects with cycle cancellation due to poor ovarian response, excessive ovarian response, and triggering with gonadotropin-releasing hormone (GnRH) agonist are presented. | End-of-stimulation (up to 20 stimulation days) | 
| Number of Oocytes Retrieved |  | Day of oocyte retrieval | 
| Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved |  | Day of oocyte retrieval | 
| Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection]) | Number of oocytes in metaphase II prior to ICSI insemination is presented. | Prior to insemination | 
| Fertilisation Rate | Fertilisation rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved. | Day 1 after insemination | 
| Number and Quality of Embryos on Day 3 | Number of embryos (total and good-quality) on Day 3 are presented. A good-quality embryo was defined as an embryo with ≥6 blastomeres and fragmentation ≤20% on Day 3. | On day 3 after oocyte retrieval | 
| Number and Quality of Blastocysts on Day 5 | Number of blastocysts (total and good-quality) on Day 5 are presented. A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher. | On day 5 after oocyte retrieval | 
| Total Gonadotropin Dose | The total gonadotropin dose was recorded. | End-of-stimulation (up to 20 stimulation days) | 
| Number of Stimulation Days |  | End-of-stimulation (up to 20 stimulation days) | 
| Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments |  | End-of-stimulation (up to 20 stimulation days) | 
| Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period | Subjects self-assessed injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after each injection. The injection site reactions were assessed as none, mild, moderate and severe. The frequency of injection site reactions (mild, moderate or severe) based on all assessments performed is presented. | End-of-stimulation (up to 20 stimulation days) | 
| Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS) | The subject self-assessed abdominal discomfort related to controlled ovarian stimulation using a VAS going from 0 mm (no abdominal discomfort) to 100 mm (worst imaginable abdominal discomfort). | End-of-stimulation and day of blastocyst transfer | 
| Changes in Body Weight | Change in body weight from baseline to end-of-stimulation and from baseline to day of blastocyst transfer. | End-of-stimulation and day of blastocyst transfer | 
| Changes in Maximum Abdominal Circumference | Change in maximum abdominal circumference from baseline to end-of-stimulation and from baseline to day of blastocyst transfer. | End-of-stimulation and day of blastocyst transfer | 
| Proportion of Subjects With Treatment-induced Anti-follicle-stimulating Hormone (FSH) Antibodies | The proportion of subjects with at least one treatment-induced anti-FSH antibody response at any time 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 | 
| Proportion of Subjects With Late OHSS | Late OHSS was defined as OHSS with onset >9 days after triggering of final follicular maturation.The proportion of subjects with late OHSS, and late OHSS of moderate or severe grade are presented. | >9 days after triggering of final follicular maturation | 
| Technical Malfunctions of the Administration Pen | Confirmed technical malfunction of administration pen. | End-of-stimulation (up to 20 stimulation days) |