Infertility, Female
Conditions
Brief summary
To compare the efficacy and safety of FE 999049 (follitropin delta) and its personalized dosing algorithm in controlled ovarian stimulation for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) using a long gonadotropin-releasing hormone (GnRH) agonist protocol versus a short GnRH antagonist protocol.
Interventions
DRUGFE 999049 + GnRH agonist (GONAPEPTYL)
Pre-filled injection pen
DRUGFE 999049 + GnRH antagonist (CETROTIDE)
Powder and solvent for solution for injection
Sponsors
Ferring Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
* Infertile women aged 18-40 undergoing their first IVF/ICSI cycle that are in good physical and mental health and that have been diagnosed with problems in the fallopian tubes, mild endometriosis or have partners with decreased sperm quality. * The participants must have a regular menstrual cycle, a normal uterus and 2 normal ovaries. * The allowed body mass index is 17.5-32 Kg/m\^2.
Exclusion criteria
* Women with very high ovarian reserve, strong preference for either treatment, severe endometriosis, history of repeated miscarriage, couples with known problems in the chromosomes, history or high risk of producing blood cloths, women known to have chronic diseases, women recently participating in trials with non-registered drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Oocytes Retrieved | On day of oocyte retrieval (up to 22 days after start of stimulation) | The number of oocytes retrieved was recorded at the oocyte retrieval visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Positive Beta Human Chorionic Gonadotropin (βhCG) Rate | 13-15 days after transfer (up to approximately 1.5 months after start of stimulation) | Defined as positive serum βhCG test |
| Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | At end-of-stimulation (up to 20 days) | For each participant, the reason for cycle cancellation was recorded |
| Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | At end of transfer (up to 4 weeks) | For each participant, the reason for blastocyst transfer cancellation was recorded. |
| Number of Follicles | On stimulation day 6 and at end-of-stimulation (up to 20 days) | The total number of follicles and the number of follicles per size category will be reported |
| Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | On day of oocyte retrieval (up to 22 days after start of stimulation) | Grouped according to number of oocytes |
| Number of Metaphase II Oocytes | On day of oocyte retrieval (up to 22 days after start of stimulation) | Only applicable for those inseminated using ICSI |
| Fertilization Rate | On day 1 after oocyte retrieval (up to 23 days after start of stimulation) | Measured by the number of pronuclei. Fertilized oocytes with 2 pronuclei were regarded as correctly fertilized |
| Number of Embryos | On day 3 after oocyte retrieval (up to 25 days after start of stimulation) | The number of embryos (total and good-quality) was reported. Embryo quality is determined by combined assessment of cleavage stage (number of blastomeres/compaction status) and embryo morphology parameters |
| Number of Blastocysts | On day 5 after oocyte retrieval (up to 27 days after start of stimulation) | The number of blastocysts (total and good-quality) was reported. Blastocyst quality is assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring is 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) |
| Circulating Concentrations of Follicle-stimulating Hormone (FSH) | On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation) | Blood samples for analysis of circulating concentrations of FSH were drawn. |
| Circulating Concentrations of Luteinizing Hormone (LH) | On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation) | Blood samples for analysis of circulating concentrations of LH were drawn |
| Circulating Concentrations of Estradiol | On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation) | Blood samples for analysis of circulating concentrations of estradiol were drawn |
| Number of Stimulation Days | Up to 20 days | Calculated by start dates and end dates |
| Circulating Concentrations of Inhibin B | On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation) | Blood samples for analysis of circulating concentrations of Inhibin B were drawn |
| Total Gonadotropin Dose | Up to 20 days | Calculated by start dates, end dates and daily dose of investigational medicinal product |
| Implantation Rate | 5-6 weeks after transfer (up to approximately 2.5 months after start of stimulation) | Defined as the number of gestational sacs after transfer divided by number of blastocysts transferred |
| Clinical Pregnancy Rate | 5-6 weeks after transfer (up to approximately 2.5 months after start of stimulation) | Defined as at least one gestational sac |
| Vital Pregnancy Rate | 5-6 weeks after transfer (up to approximately 2.5 months after start of stimulation) | Defined as at least one intrauterine gestational sac with fetal heart beat |
| Ongoing Pregnancy Rate | 10-11 weeks after transfer (up to approximately 4 months after start of stimulation) | At least one intrauterine viable fetus |
| Ongoing Implantation Rate | 10-11 weeks after transfer (up to approximately 4 months after start of stimulation) | Defined as number of intrauterine viable fetuses divided by the number of blastocysts transferred |
| Proportion of Subjects With Early OHSS (Including OHSS of Moderate/Severe Grade) | Up to 9 days after triggering of final follicular maturation | Classification of grade was according to Golan's classification system, and all OHSS cases were graded as mild, moderate or severe. |
| Proportion of Subjects With Late OHSS (Including OHSS of Moderate/Severe Grade) | >9 days after triggering of final follicular maturation | Classification of grade was according to Golan's classification system, and all OHSS cases were graded as mild, moderate or severe. |
| Frequency of Adverse Events | From time of signing informed consent until the end-of-trial (approximately 7 months) | Any untoward medical occurrence |
| Intensity of Adverse Events | From time of signing informed consent until the end-of-trial (approximately 7 months) | Categorized as mild, moderate or severe |
| Technical Malfunctions of the Pre-filled Injection Pen | Up to 20 days | Incidences of technical malfunctions of the pre-filled injection pen were recorded |
| Circulating Concentrations of Progesterone | On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation) | Blood samples for analysis of circulating concentrations of progesterone were drawn |
Countries
Austria, Denmark, Israel, Italy, Netherlands, Norway, Switzerland
Participant flow
Recruitment details
The trial was opened for recruitment in April 2019, and participants were assessed at 16 investigational sites in 7 countries between May 2019 and Feb 2022.
Pre-assignment details
In total, 532 participants were screened of which 437 were randomized. Of the 437 participants, 435 participants were included in the Full Analysis Set (FAS): 220 participants to long GnRH agonist and 215 participants to GnRH antagonist. 406 participants were exposed to the investigational medicinal product (IMP): 202 participants to long GnRH agonist and 204 participants to GnRH antagonist. Two participants discontinued before the start of stimulation with FE999049 due to COVID-19 pandemic.
Participants by arm
| Arm | Count |
|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) FE 999049 + GnRH agonist (GONAPEPTYL): Pre-filled injection pen | 220 |
| FE 999049 + GnRH Antagonist (CETROTIDE) FE 999049 + GnRH antagonist (CETROTIDE): Powder and solvent for solution for injection | 215 |
| Total | 435 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 9 |
| Overall Study | COVID-19 | 3 | 1 |
| Overall Study | Participant was discontinued by investigator | 12 | 7 |
| Overall Study | Withdrawal by Subject | 7 | 3 |
Baseline characteristics
| Characteristic | FE 999049 + GnRH Agonist (GONAPEPTYL) | FE 999049 + GnRH Antagonist (CETROTIDE) | Total |
|---|---|---|---|
| Age, Continuous | 32.3 years STANDARD_DEVIATION 4.4 | 32.4 years STANDARD_DEVIATION 4.2 | 32.3 years STANDARD_DEVIATION 4.3 |
| Age, Customized 35-37 years | 47 Participants | 48 Participants | 95 Participants |
| Age, Customized <35 years | 143 Participants | 141 Participants | 284 Participants |
| Age, Customized 38-40 years | 30 Participants | 26 Participants | 56 Participants |
| Body Mass Index (BMI) | 24.36 kg/m^2 STANDARD_DEVIATION 3.5 | 24.39 kg/m^2 STANDARD_DEVIATION 3.55 | 24.37 kg/m^2 STANDARD_DEVIATION 3.52 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 10 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 211 Participants | 205 Participants | 416 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 8 Participants | 17 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 208 Participants | 202 Participants | 410 Participants |
| Region of Enrollment Austria | 29 participants | 31 participants | 60 participants |
| Region of Enrollment Denmark | 15 participants | 16 participants | 31 participants |
| Region of Enrollment Israel | 13 participants | 12 participants | 25 participants |
| Region of Enrollment Italy | 9 participants | 12 participants | 21 participants |
| Region of Enrollment Netherlands | 31 participants | 26 participants | 57 participants |
| Region of Enrollment Norway | 117 participants | 114 participants | 231 participants |
| Region of Enrollment Switzerland | 6 participants | 4 participants | 10 participants |
| Sex: Female, Male Female | 220 Participants | 215 Participants | 435 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 202 | 0 / 204 |
| other Total, other adverse events | 68 / 202 | 69 / 204 |
| serious Total, serious adverse events | 4 / 202 | 6 / 204 |
Outcome results
Primary
Number of Oocytes Retrieved
The number of oocytes retrieved was recorded at the oocyte retrieval visit.
Time frame: On day of oocyte retrieval (up to 22 days after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Oocytes Retrieved | 11.1 Oocytes | Standard Deviation 5.9 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Oocytes Retrieved | 9.6 Oocytes | Standard Deviation 5.5 |
p-value: 0.018595% CI: [0.22, 2.4]Negative binomial regression
Secondary
Circulating Concentrations of Estradiol
Blood samples for analysis of circulating concentrations of estradiol were drawn
Time frame: On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Estradiol | Stimulation Day 6 | 1190.1 pmol/L | Standard Deviation 1101.2 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Estradiol | End-of-stimulation | 7542.7 pmol/L | Standard Deviation 4106.8 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Estradiol | Oocyte retrieval | 3485.1 pmol/L | Standard Deviation 2129 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Estradiol | Stimulation Day 6 | 2675.8 pmol/L | Standard Deviation 1544.3 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Estradiol | End-of-stimulation | 6487.7 pmol/L | Standard Deviation 3960.2 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Estradiol | Oocyte retrieval | 3163.5 pmol/L | Standard Deviation 1865 |
Secondary
Circulating Concentrations of Follicle-stimulating Hormone (FSH)
Blood samples for analysis of circulating concentrations of FSH were drawn.
Time frame: On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Follicle-stimulating Hormone (FSH) | Stimulation Day 6 | 15.5 IU/L | Standard Deviation 4.3 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Follicle-stimulating Hormone (FSH) | End-of-stimulation | 16.2 IU/L | Standard Deviation 4.4 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Follicle-stimulating Hormone (FSH) | Oocyte retrieval | 9.4 IU/L | Standard Deviation 2.8 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Follicle-stimulating Hormone (FSH) | Stimulation Day 6 | 16.7 IU/L | Standard Deviation 4.5 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Follicle-stimulating Hormone (FSH) | End-of-stimulation | 15.8 IU/L | Standard Deviation 4 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Follicle-stimulating Hormone (FSH) | Oocyte retrieval | 9.8 IU/L | Standard Deviation 2.9 |
Secondary
Circulating Concentrations of Inhibin B
Blood samples for analysis of circulating concentrations of Inhibin B were drawn
Time frame: On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Inhibin B | Stimulation Day 6 | 690.4 pg/mL | Standard Deviation 419.1 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Inhibin B | End-of-stimulation | 1032.6 pg/mL | Standard Deviation 605.2 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Inhibin B | Oocyte retrieval | 416.6 pg/mL | Standard Deviation 253.9 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Inhibin B | Stimulation Day 6 | 808.2 pg/mL | Standard Deviation 428.5 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Inhibin B | End-of-stimulation | 938.1 pg/mL | Standard Deviation 570 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Inhibin B | Oocyte retrieval | 389.0 pg/mL | Standard Deviation 226.6 |
Secondary
Circulating Concentrations of Luteinizing Hormone (LH)
Blood samples for analysis of circulating concentrations of LH were drawn
Time frame: On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Luteinizing Hormone (LH) | End-of-stimulation | 1.8 IU/L | Standard Deviation 0.9 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Luteinizing Hormone (LH) | Oocyte retrieval | 0.2 IU/L | Standard Deviation 0.2 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Luteinizing Hormone (LH) | Stimulation Day 6 | 1.5 IU/L | Standard Deviation 0.9 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Luteinizing Hormone (LH) | End-of-stimulation | 1.8 IU/L | Standard Deviation 1.5 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Luteinizing Hormone (LH) | Oocyte retrieval | 2.0 IU/L | Standard Deviation 2.1 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Luteinizing Hormone (LH) | Stimulation Day 6 | 5.6 IU/L | Standard Deviation 6 |
Secondary
Circulating Concentrations of Progesterone
Blood samples for analysis of circulating concentrations of progesterone were drawn
Time frame: On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Progesterone | End-of-stimulation | 3.1 nmol/L | Standard Deviation 1.4 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Progesterone | Oocyte retrieval | 25.9 nmol/L | Standard Deviation 12.9 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Circulating Concentrations of Progesterone | Stimulation Day 6 | 1.8 nmol/L | Standard Deviation 1 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Progesterone | Stimulation Day 6 | 2.6 nmol/L | Standard Deviation 1.5 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Progesterone | End-of-stimulation | 3.5 nmol/L | Standard Deviation 2 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Circulating Concentrations of Progesterone | Oocyte retrieval | 26.0 nmol/L | Standard Deviation 13.2 |
Secondary
Clinical Pregnancy Rate
Defined as at least one gestational sac
Time frame: 5-6 weeks after transfer (up to approximately 2.5 months after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Clinical Pregnancy Rate | Positive | 81 Participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Clinical Pregnancy Rate | Negtaive | 121 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Clinical Pregnancy Rate | Positive | 68 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Clinical Pregnancy Rate | Negtaive | 136 Participants |
p-value: 0.113495% CI: [-1.82, 17.14]Regression, Logistic
Secondary
Fertilization Rate
Measured by the number of pronuclei. Fertilized oocytes with 2 pronuclei were regarded as correctly fertilized
Time frame: On day 1 after oocyte retrieval (up to 23 days after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Fertilization Rate | 53.8 percentage of fertilized oocytes | Standard Deviation 24.1 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Fertilization Rate | 54.4 percentage of fertilized oocytes | Standard Deviation 26.8 |
Secondary
Frequency of Adverse Events
Any untoward medical occurrence
Time frame: From time of signing informed consent until the end-of-trial (approximately 7 months)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Frequency of Adverse Events | 112 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Frequency of Adverse Events | 109 Participants |
Secondary
Implantation Rate
Defined as the number of gestational sacs after transfer divided by number of blastocysts transferred
Time frame: 5-6 weeks after transfer (up to approximately 2.5 months after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Implantation Rate | 82 Embryos |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Implantation Rate | 68 Embryos |
Secondary
Intensity of Adverse Events
Categorized as mild, moderate or severe
Time frame: From time of signing informed consent until the end-of-trial (approximately 7 months)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Intensity of Adverse Events | Severe adverse events | 4.0 Percentage of participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Intensity of Adverse Events | Mild adverse events | 42.6 Percentage of participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Intensity of Adverse Events | Moderate adverse events | 18.8 Percentage of participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Intensity of Adverse Events | Severe adverse events | 3.4 Percentage of participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Intensity of Adverse Events | Mild adverse events | 41.7 Percentage of participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Intensity of Adverse Events | Moderate adverse events | 16.7 Percentage of participants |
Secondary
Number of Blastocysts
The number of blastocysts (total and good-quality) was reported. Blastocyst quality is assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring is 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)
Time frame: On day 5 after oocyte retrieval (up to 27 days after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Blastocysts | Total Number of blastocysts | 3.8 Blastocysts | Standard Deviation 3.1 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Blastocysts | Number of good-quality blastocysts | 2.3 Blastocysts | Standard Deviation 2.3 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Blastocysts | Number of good-quality blastocysts | 2.1 Blastocysts | Standard Deviation 2.2 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Blastocysts | Total Number of blastocysts | 3.3 Blastocysts | Standard Deviation 2.9 |
Comparison: Total number of blastocystsp-value: 0.202595% CI: [-0.2, 0.94]Negative binomial regression
Comparison: Number of good-quality blastocystsp-value: 0.594695% CI: [-0.31, 0.54]Negative binomial regression
Secondary
Number of Embryos
The number of embryos (total and good-quality) was reported. Embryo quality is determined by combined assessment of cleavage stage (number of blastomeres/compaction status) and embryo morphology parameters
Time frame: On day 3 after oocyte retrieval (up to 25 days after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Embryos | Total number of embryos | 5.7 Embryos | Standard Deviation 3.9 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Embryos | Number of good-quality embryos | 4.0 Embryos | Standard Deviation 3.2 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Embryos | Total number of embryos | 5.0 Embryos | Standard Deviation 3.9 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Embryos | Number of good-quality embryos | 3.9 Embryos | Standard Deviation 3.3 |
Comparison: Number of embryosp-value: 0.189495% CI: [-0.25, 1.27]Negative binomial regression
Comparison: Number of Good-quality embryosp-value: 0.936195% CI: [-0.68, 0.63]Negative binomial regression
Secondary
Number of Follicles
The total number of follicles and the number of follicles per size category will be reported
Time frame: On stimulation day 6 and at end-of-stimulation (up to 20 days)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Follicles | Total number of follicles at Stimulation Day 6 | 15.2 Number of follicles | Standard Deviation 6.3 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Follicles | Follicles >= 10 mm at End-of-stimulation visit | 14.8 Number of follicles | Standard Deviation 6.4 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Follicles | Follicles >= 12 mm at Stimulation Day 6 | 1.6 Number of follicles | Standard Deviation 2.7 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Follicles | Follicles >= 12 mm at End-of-stimulation visit | 12.2 Number of follicles | Standard Deviation 5.3 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Follicles | Follicles >= 10 mm at Stimulation Day 6 | 4.6 Number of follicles | Standard Deviation 4.3 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Follicles | Follicles >= 15 mm at End-of-stimulation visit | 7.9 Number of follicles | Standard Deviation 3.7 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Follicles | Total number of follicles at End-of-stimulation visit | 18.3 Number of follicles | Standard Deviation 7.1 |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Follicles | Follicles >= 17 mm at End-of-stimulation visit | 4.8 Number of follicles | Standard Deviation 2.1 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Follicles | Total number of follicles at End-of-stimulation visit | 17.1 Number of follicles | Standard Deviation 8 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Follicles | Total number of follicles at Stimulation Day 6 | 14.9 Number of follicles | Standard Deviation 6.3 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Follicles | Follicles >= 10 mm at Stimulation Day 6 | 7.1 Number of follicles | Standard Deviation 3.6 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Follicles | Follicles >= 12 mm at Stimulation Day 6 | 3.8 Number of follicles | Standard Deviation 2.9 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Follicles | Follicles >= 17 mm at End-of-stimulation visit | 4.6 Number of follicles | Standard Deviation 2 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Follicles | Follicles >= 10 mm at End-of-stimulation visit | 13.3 Number of follicles | Standard Deviation 6.1 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Follicles | Follicles >= 12 mm at End-of-stimulation visit | 10.9 Number of follicles | Standard Deviation 5.1 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Follicles | Follicles >= 15 mm at End-of-stimulation visit | 7.2 Number of follicles | Standard Deviation 3.3 |
Comparison: \>=10 mm at end of stimulationp-value: 0.028195% CI: [0.12, 2.15]Negative binomial regression
Comparison: \>=12 mm at end of stimulationp-value: 0.025895% CI: [0.12, 1.86]Negative binomial regression
Comparison: \>=15 mm at end of stimulationp-value: 0.067295% CI: [-0.04, 1.2]Negative binomial regression
Comparison: \>=17 mm at end of stimulationp-value: 0.33995% CI: [-0.22, 0.63]Negative binomial regression
Secondary
Number of Metaphase II Oocytes
Only applicable for those inseminated using ICSI
Time frame: On day of oocyte retrieval (up to 22 days after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Metaphase II Oocytes | 9.2 MII oocytes | Standard Deviation 4.8 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Metaphase II Oocytes | 7.9 MII oocytes | Standard Deviation 4.7 |
p-value: 0.096295% CI: [-0.2, 2.41]Negative binomial regression
Secondary
Number of Stimulation Days
Calculated by start dates and end dates
Time frame: Up to 20 days
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Number of Stimulation Days | 10.4 Days | Standard Deviation 1.9 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Number of Stimulation Days | 8.8 Days | Standard Deviation 1.8 |
p-value: <0.000195% CI: [1.19, 1.92]ANOVA
Secondary
Ongoing Implantation Rate
Defined as number of intrauterine viable fetuses divided by the number of blastocysts transferred
Time frame: 10-11 weeks after transfer (up to approximately 4 months after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Ongoing Implantation Rate | 74 Embryos |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Ongoing Implantation Rate | 60 Embryos |
Secondary
Ongoing Pregnancy Rate
At least one intrauterine viable fetus
Time frame: 10-11 weeks after transfer (up to approximately 4 months after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Ongoing Pregnancy Rate | Positive | 73 Participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Ongoing Pregnancy Rate | Negative | 129 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Ongoing Pregnancy Rate | Positive | 60 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Ongoing Pregnancy Rate | Negative | 144 Participants |
p-value: 0.100295% CI: [-1.49, 16.97]Regression, Logistic
Secondary
Positive Beta Human Chorionic Gonadotropin (βhCG) Rate
Defined as positive serum βhCG test
Time frame: 13-15 days after transfer (up to approximately 1.5 months after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Positive Beta Human Chorionic Gonadotropin (βhCG) Rate | Positive βhCG test | 91 Participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Positive Beta Human Chorionic Gonadotropin (βhCG) Rate | Negative βhCG test | 111 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Positive Beta Human Chorionic Gonadotropin (βhCG) Rate | Positive βhCG test | 79 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Positive Beta Human Chorionic Gonadotropin (βhCG) Rate | Negative βhCG test | 125 Participants |
p-value: 0.157995% CI: [-2.71, 16.7]Regression, Logistic
Secondary
Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
Grouped according to number of oocytes
Time frame: On day of oocyte retrieval (up to 22 days after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | 4-7 Oocytes Retrieved | 47 Participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | 15-19 Oocytes Retrieved | 42 Participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | 8-14 Oocytes Retrieved | 84 Participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | >=20 Oocytes Retrieved | 16 Participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | <4 Oocytes Retrieved | 13 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | >=20 Oocytes Retrieved | 11 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | <4 Oocytes Retrieved | 26 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | 4-7 Oocytes Retrieved | 56 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | 8-14 Oocytes Retrieved | 82 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | 15-19 Oocytes Retrieved | 29 Participants |
Secondary
Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS)
For each participant, the reason for blastocyst transfer cancellation was recorded.
Time frame: At end of transfer (up to 4 weeks)
Population: Participants analyzed for this endpoint represent participants with blastocyst transfer cancellation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | Reason for transfer cancellation: Adverse Event | 5 participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | Reason for transfer cancellation: Risk of OHSS | 1 participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | Transfer cancellation | 27 participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | Reason for transfer cancellation: No blastocyst | 13 participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | Reason for transfer cancellation: COVID-19 | 3 participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | Reason for transfer cancellation: Other reason | 5 participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | Reason for transfer cancellation: COVID-19 | 1 participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | Reason for transfer cancellation: Adverse Event | 8 participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | Reason for transfer cancellation: No blastocyst | 18 participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | Reason for transfer cancellation: Other reason | 2 participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | Transfer cancellation | 30 participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS) | Reason for transfer cancellation: Risk of OHSS | 1 participants |
Secondary
Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response
For each participant, the reason for cycle cancellation was recorded
Time frame: At end-of-stimulation (up to 20 days)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Excessive response | 2 participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Poor response | 1 participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Other reason | 1 participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Excessive response | 3 participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Poor response | 3 participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Other reason | 1 participants |
Secondary
Proportion of Subjects With Early OHSS (Including OHSS of Moderate/Severe Grade)
Classification of grade was according to Golan's classification system, and all OHSS cases were graded as mild, moderate or severe.
Time frame: Up to 9 days after triggering of final follicular maturation
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With Early OHSS (Including OHSS of Moderate/Severe Grade) | 8 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With Early OHSS (Including OHSS of Moderate/Severe Grade) | 5 Participants |
Secondary
Proportion of Subjects With Late OHSS (Including OHSS of Moderate/Severe Grade)
Classification of grade was according to Golan's classification system, and all OHSS cases were graded as mild, moderate or severe.
Time frame: >9 days after triggering of final follicular maturation
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Proportion of Subjects With Late OHSS (Including OHSS of Moderate/Severe Grade) | 4 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Proportion of Subjects With Late OHSS (Including OHSS of Moderate/Severe Grade) | 6 Participants |
Secondary
Technical Malfunctions of the Pre-filled Injection Pen
Incidences of technical malfunctions of the pre-filled injection pen were recorded
Time frame: Up to 20 days
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Technical Malfunctions of the Pre-filled Injection Pen | 2 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Technical Malfunctions of the Pre-filled Injection Pen | 0 Participants |
Secondary
Total Gonadotropin Dose
Calculated by start dates, end dates and daily dose of investigational medicinal product
Time frame: Up to 20 days
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Total Gonadotropin Dose | 112.2 ug | Standard Deviation 28.9 |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Total Gonadotropin Dose | 96.5 ug | Standard Deviation 26 |
p-value: <0.000195% CI: [12.13, 21.74]ANOVA
Secondary
Vital Pregnancy Rate
Defined as at least one intrauterine gestational sac with fetal heart beat
Time frame: 5-6 weeks after transfer (up to approximately 2.5 months after start of stimulation)
Population: Participants analyzed for this endpoint represent participants who were evaluable for this outcome measure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Vital Pregnancy Rate | Negative | 125 Participants |
| FE 999049 + GnRH Agonist (GONAPEPTYL) | Vital Pregnancy Rate | Positive | 77 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Vital Pregnancy Rate | Negative | 142 Participants |
| FE 999049 + GnRH Antagonist (CETROTIDE) | Vital Pregnancy Rate | Positive | 62 Participants |
p-value: 0.064295% CI: [-0.52, 18.14]Regression, Logistic