A Trial to Investigate the Efficacy and Safety of FE 999302 as add-on Treatment to Follitropin Delta (REKOVELLE) in Women Undergoing Controlled Ovarian Stimulation.

Study Overview
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Brief Summary
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The purpose of this phase 2 dose-ranging trial is to investigate the effects of FE 999302 on parameters influencing pregnancy rates in women undergoing Controlled Ovarian Stimulation (COS) with follitropin delta in a long gonadotropin releasing hormone (GnRH) agonist protocol. Furthermore, the study intends: To investigate the safety of FE 999302 in women undergoing COS with follitropin delta in a long GnRH agonist protocol. To investigate the potential immunogenicity of FE 999302 in subjects undergoing COS with follitropin delta in a long GnRH agonist protocol. To estimate the impact of body weight on FE 999302 exposure in subjects undergoing COS with follitropin delta in a long GnRH agonist protocol.

Official Title
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A Randomised, Double-blind, Placebo-controlled, Parallel-group, Dose-range Trial to Investigate the Efficacy and Safety of FE 999302 as add-on Treatment to Follitropin Delta (REKOVELLE) in Women Undergoing Controlled Ovarian Stimulation in a Long GnRH Agonist Protocol

Conditions
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Controlled Ovarian Stimulation

Intervention / Treatment
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* Drug: FE 999302 (1 μg) and follitropin delta
* Drug: FE 999302 (2 μg) and follitropin delta
* Drug: FE 999302 (4 μg) and follitropin delta
* Drug: FE 999302 (8 μg) and follitropin delta
* Drug: FE 999302 (12 μg) and follitropin delta
* Other: Placebo and follitropin delta


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 as judged by the investigator. Anti-Müllerian hormone (AMH) levels at screening of 5.0-35.0 pmol/L (as measured by Elecsys® AMH Plus Immunoassay [Roche Diagnostics] at central laboratory). Pre-menopausal women between the ages of 30 and 42 years. The subjects must be at least 30 years (including the 30th birthday) and no more than 42 years (up to the day before the 43rd birthday) when they sign the informed consent. 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 and/or intracytoplasmic sperm injection using fresh or frozen ejaculated sperm from male partner or sperm donor. Infertility for at least 1 year before screening for subjects less than 35 years or for at least 6 months for subjects greater than equal to (≥)35 years (not applicable in case of tubal or severe male factor infertility). Exclusion Criteria: Known polycystic ovary syndrome (PCOS) associated with anovulation or known endometriosis stage III-IV (defined by the revised American Society for Reproductive Medicine [ASRM] classification, 1996). One or more follicles ≥10 mm (including cysts) observed on the transvaginal ultrasound after down-regulation prior to randomisation on stimulation day 1 (puncture of cysts is allowed prior to randomisation). Pregnancy (negative pregnancy tests must be documented at screening and prior to start of down-regulation) or contraindication to pregnancy.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 42 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FE 999302 (1 μg) and follitropin delta<br> | Drug: FE 999302 (1 μg) and follitropin delta<br>* Daily dose of 1 μg of FE 999302, a recombinant human chorionic gonadotropin (rhCG) solution for subcutaneous injection; individualized follitropin delta dose.<br>* Other names: Choriogonadotropin beta;|
| Experimental: FE 999302 (2 μg) and follitropin delta<br> | Drug: FE 999302 (2 μg) and follitropin delta<br>* Daily dose of 2 μg of FE 999302, a rhCG solution for subcutaneous injection; individualized follitropin delta dose.<br>* Other names: Choriogonadotropin beta;|
| Experimental: FE 999302 (4 μg) and follitropin delta<br> | Drug: FE 999302 (4 μg) and follitropin delta<br>* Daily dose of 4 μg of FE 999302, a rhCG solution for subcutaneous injection; individualized follitropin delta dose.<br>* Other names: Choriogonadotropin beta;|
| Experimental: FE 999302 (8 μg) and follitropin delta<br> | Drug: FE 999302 (8 μg) and follitropin delta<br>* Daily dose of 8 μg of FE 999302, a rhCG solution for subcutaneous injection; individualized follitropin delta dose.<br>* Other names: Choriogonadotropin beta;|
| Experimental: FE 999302 (12 μg) and follitropin delta<br> | Drug: FE 999302 (12 μg) and follitropin delta<br>* Daily dose of 12 μg of FE 999302, a rhCG solution for subcutaneous injection; individualized follitropin delta dose.<br>* Other names: Choriogonadotropin beta;|
| Placebo Comparator: Placebo and follitropin delta<br> | Other: Placebo and follitropin delta<br>* Daily dose of placebo; individualized follitropin delta dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of good-quality blastocysts on Day 5 after oocyte retrieval | Quality of blastocysts was assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring was based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cell). | On Day 5 after oocyte retrieval | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with at least one good-quality blastocyst on Day 5 after oocyte retrieval | Quality of blastocysts was assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring was based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cell). | On Day 5 after oocyte retrieval | 
| Number of subjects with at least two good-quality blastocysts on Day 5 after oocyte retrieval | Quality of blastocysts was assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring was based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cell). | On Day 5 after oocyte retrieval | 
| Number and quality of embryos on Day 3 after oocyte retrieval | Embryo quality was assessed by cleavage stage and embryo morphology parameters. The total number of embryos and the number of embryos per quality category were reported. | On Day 3 after oocyte retrieval | 
| Number and quality of blastocysts on Day 5 after oocyte retrieval | Blastocyst quality was assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring was based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cells). The total number of blastocysts and the number of blastocysts per quality category will be reported. | On Day 5 after oocyte retrieval | 
| Changes in serum hormone levels | Blood samples for analysis of hormone concentrations were drawn at stimulation Day 1, stimulation Day 6, stimulation Day 8, last day of stimulation, and at oocyte retrieval. | Stimulation Day 1 (baseline), stimulation Day 6, stimulation Day 8, end-of-stimulation (up to 20 stimulation days), and oocyte retrieval | 
| Number and size of follicles on stimulation Day 6 | Number and size of follicles assessed using transvaginal ultrasound. The total number of follicles and the number of follicles per size category were reported. | On stimulation Day 6 | 
| Number and size of follicles at end-of-stimulation | Number and size of follicles assessed using transvaginal ultrasound. The total number of follicles and the number of follicles per size category were reported. | At end-of-stimulation (up to 20 stimulation days) | 
| Positive beta human chorionic gonadotropin (βhCG) rate | Proportion of patients with positive blood βhCG confirmed by a blood test. | 13-15 days after blastocyst transfer | 
| Clinical pregnancy rate | Clinical pregnancy was defined as at least one gestational sac, either intrauterine or ectopic. | 5-6 weeks after blastocyst transfer | 
| Vital pregnancy rate | Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat, as assessed by transvaginal ultrasound. | 5-6 weeks after blastocyst transfer | 
| Ongoing pregnancy rate | Ongoing pregnancy was defined as at least one intrauterine viable fetus, assessed using transvaginal or abdominal ultrasound. | 10-11 weeks after blastocyst transfer | 
| Number of oocytes retrieved |  | On the day of oocyte retrieval | 
| Number of metaphase II oocytes |  | On the day of oocyte retrieval | 
| Number of fertilised 2 pronuclei (2PN) oocytes |  | On day 1 after insemination | 
| Total gonadotropin dose | The daily dose of FE 999302 or placebo, and follitropin delta were recorded. | At end-of-stimulation (up to 20 stimulation days) | 
| Total number of stimulation days | The start and end dates of administration of FE 999302 or placebo, and follitropin delta were recorded. | At end-of-stimulation (up to 20 stimulation days) | 
| Incidence of cycle cancellation | Cycle cancellation due to poor ovarian response or excessive ovarian response. | At end-of-stimulation (up to 20 stimulation days) | 
| Serum concentrations of FE 999302 |  | On stimulation Day 1 (prior to first dose of FE 999302 or placebo), stimulation Day 6, stimulation Day 8, end-of-stimulation (up to 20 stimulation days) | 
| Incidence of ovarian hyperstimulation syndrome (OHSS) (early or late, any grade) | Early OHSS was defined as OHSS with onset less than equal to 9 days after triggering of final follicular maturation. Late OHSS was defined as OHSS with onset greater than 9 days after triggering of final follicular maturation. All OHSS cases were graded as mild, moderate or severe. | From stimulation Day 1 to end-of-trial (estimated maximum of 4 months from start of stimulation) | 
| Incidence and intensity of adverse events (AEs) |  | From screening to end-of-trial (estimated maximum of 4 months from start of stimulation) | 
| Changes in circulating levels of clinical chemistry and haematology parameters |  | At screening, on stimulation Day 1, end-of-stimulation (up to 20 stimulation days), end-of-trial (estimated maximum of 4 months from start of stimulation) | 
| Incidence and intensity of injection site reactions after FE 999302 administration (redness, pain, itching, swelling and bruising) assessed by the subject during the stimulation period |  | Immediately after injection of FE 999302 or placebo, 30 minutes after injection, and 24 hours after injection | 
| Incidence of treatment-induced anti-FE 999302 antibodies, overall as well as with neutralising capacity | The proportion of subjects with treatment-induced anti-FE999302 antibodies as well as the proportion of subjects with treatment-induced anti-FE999302 antibodies with neutralizing capacity were reported. | On stimulation Day 1, end-of-stimulation (up to 20 stimulation days), 19-28 days after the last FE999302 or placebo dose | 
| Incidence of multi-fetal gestation |  | 5 to 6 weeks after transfer | 
| Incidence of biochemical pregnancy | Biochemical pregnancy was defined as positive βhCG test but no gestational sac was observed on transvaginal ultrasound conducted later, or menstruation is was reported. | Up to 5 to 6 weeks after transfer | 
| Incidence of spontaneous abortion (with and without medical/surgical intervention) | Spontaneous abortion was defined as positive βhCG test but all intrauterine gestational sacs without fetal heart beat as documented by ultrasound, or there were no viable fetuses observed by ultrasound. | Up to 10 to 11 weeks after transfer | 
| Incidence of ectopic pregnancy (with and without medical/surgical intervention) | Ectopic pregnancy was defined as extrauterine gestational sac with or without fetal heart beat as documented by ultrasound or surgery. | Up to 5 to 6 weeks after transfer | 
| Incidence of vanishing twins | Vanishing twin was defined as spontaneous disappearance of an intrauterine gestational sac with or without heart beat in a pregnancy where one viable fetus remained as documented by ultrasound. | Up to 10 to 11 weeks after transfer | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Chorionic Gonadotropin (hCG), Recombinant Human Chorionic Gonadotropin (rhCG), Controlled Ovarian Stimulation (COS), Assisted Reproductive Technologies (ART)