Infertility
Conditions
Brief summary
To demonstrate non-inferiority of FE 999049 compared to FOLLISTIM with respect to number of oocytes retrieved in Japanese IVF/ICSI patients undergoing controlled ovarian stimulation.
Interventions
Single daily subcutaneous administration through pre-filled injection pen
DRUGFollitropin beta
Single daily subcutaneous injection in the abdomen
Sponsors
Ferring Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
20 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
* Informed Consent Documents signed prior to any trial-related procedures. * In good physical and mental health. * Japanese females between the ages of 20 and 40 years. * Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II (defined by the revised American Society for Reproductive Medicine (ASRM) classification) or with partners diagnosed with male factor infertility, eligible for in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) treatment using ejaculated sperm from male partner. * Infertility for at least 1 year before randomization (not applicable in case of tubal or severe male factor infertility). * The trial cycle will be the participant'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 screening. This also includes women who have been diagnosed with any of the above medical conditions but have had them surgically corrected within 1 year prior to screening. * Transvaginal ultrasound documenting presence and adequate visualization 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 fallopian tubes and surrounding tissue without evidence of significant abnormality (e.g. no hydrosalpinx) within 1 year prior to screening. Both ovaries must be accessible for oocyte retrieval. * 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 screening). * Body mass index (BMI) between 17.5 and 32.0 kg/m\^2 (both inclusive) at screening.
Exclusion criteria
* Known endometriosis stage III-IV (defined by the revised ASRM classification). * One or more follicles \>10 mm (including cysts) observed on the transvaginal ultrasound prior to start of stimulation on stimulation day 1 (puncture of cysts prior randomization is allowed). * 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 participant or of her partner. In case the sperm production is severely impaired (concentration \<1 million/mL), normal karyotype, including no Y chromosome microdeletion, must be documented. * Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Oocytes Retrieved | 36h (± 2h) after triggering of final follicular maturation (On day of oocyte retrieval) | The number of oocytes retrieved was recorded at the oocyte retrieval visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate | 13-15 days after transfer (up to approximately 1.5 months after start of stimulation) | Defined as positive serum beta-hCG test 13-15 days after transfer. |
| Vital Pregnancy Rate | 5-6 weeks after transfer (up to approximately 3 months after start of stimulation) | Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer. |
| Implantation Rate | 5-6 weeks after transfer (up to approximately 3 months after start of stimulation) | Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by the number of blastocysts transferred. |
| Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response | End-of-stimulation (up to 20 stimulation days) | — |
| Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk | End-of-stimulation (up to 20 stimulation days) | — |
| Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | On the day of oocyte retrieval (up to 22 days after start of stimulation) | Defined as proportion of participants grouped according to the number of oocytes retrieved. The proportion of participants with \<4 oocytes (low response), 4-7 oocytes (moderate response), 8-14 oocytes (targeted response), 15-19 oocytes (hyperresponse) and ≥20 oocytes (severe hyperresponse) are presented. |
| Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population | On the day of oocyte retrieval (up to 22 days after start of stimulation) | — |
| Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) | ≤9 days after triggering of final follicular maturation | — |
| Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS | Up to 9 days after triggering of final follicular maturation | Defined as proportion of participants 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. |
| Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade) | >9 days after triggering of final follicular maturation | Defined as proportions of participants with late OHSS (including OHSS of moderate/severe grade). Late OHSS was defined as OHSS with onset \>9 days after triggering of final follicular maturation. The proportion of participants with late OHSS, and late OHSS of moderate or severe grade are presented. All OHSS cases were graded as mild, moderate, or severe. |
| Number of Follicles on Stimulation Day 6 | At Day 6 of stimulation | Defined as the number of follicles observed in both ovaries at the last transvaginal ultrasound (TVUS) in the stimulation phase (on stimulation Day 6). |
| Number of Follicles at End-of-stimulation | End-of-stimulation (up to 20 stimulation days) | Defined as the number of follicles observed in both ovaries at the last TVUS in the stimulation phase (end-of-stimulation). |
| Size of Follicles on Stimulation Day 6 | At Day 6 of stimulation | Defined as size characteristics of follicles on stimulation Day 6. Average size of 3 largest follicles has been presented in this endpoint. |
| Size of Follicles at End-of-Stimulation | End-of-stimulation (up to 20 stimulation days) | Defined as size characteristics of follicles at end-of-stimulation. Average size of 3 largest follicles has been presented in this endpoint. |
| Fertilization Rate | Day 1 after oocyte retrieval (up to approximately 22 days after start of stimulation) | The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved. |
| Number and Quality of Embryos | Day 3 after oocyte retrieval (up to approximately 24 days after start of stimulation) | 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. |
| Total Gonadotropin Dose of FE 999049 | End-of-stimulation (up to 20 stimulation days) | — |
| Number and Quality of Blastocysts | Day 5 after oocyte retrieval (up to approximately 26 days after start of stimulation) | Number of embryos (total and good-quality) on Day 5 are presented. The quality evaluation of blastocysts consisted of assessment of three parameters, as per the Gardner & Schoolcraft system: blastocyst expansion and hatching status (graded: 1-6), inner cell mass (graded: A-D) and trophectoderm (graded: A-D). A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher. |
| Clinical Pregnancy Rate | 5-6 weeks after transfer (up to approximately 3 months after start of stimulation) | Clinical pregnancy was defined as at least one gestational sac 5-6 weeks after transfer. |
| Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation | End-of-stimulation (up to 20 stimulation days) | The median and IQR of FSH and LH levels at end-of-stimulation are presented. |
| Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6 | At Day 6 of stimulation | The median and IQR of estradiol levels on stimulation Day 6 are presented. |
| Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation | End-of-stimulation (up to 20 stimulation days) | The median and IQR of estradiol levels at end-of-stimulation are presented. |
| Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6 | At Day 6 of stimulation | The median and IQR of progesterone levels on stimulation Day 6 are presented. |
| Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation | End-of-stimulation (up to 20 stimulation days) | The median and IQR of progesterone levels at end-of-stimulation are presented. |
| Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6 | At Day 6 of stimulation | The median and IQR of Inhibin A levels on stimulation Day 6 are presented. |
| Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation | End-of-stimulation (up to 20 stimulation days) | The median and IQR of Inhibin A levels at end-of-stimulation are presented. |
| Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6 | At Day 6 of stimulation | The median and IQR of inhibin B levels on stimulation Day 6 are presented. |
| Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation | End-of-stimulation (up to 20 stimulation days) | The median and IQR of inhibin B levels at end-of-stimulation are presented. |
| Number of Stimulation Days | End-of-stimulation (up to 20 stimulation days) | — |
| Total Gonadotropin Dose of FOLLISTIM | End-of-stimulation (up to 20 stimulation days) | — |
| Number of Participants With Adverse Events (AEs) Stratified by Intensity | From signed informed consent up to 5-6 weeks after transfer | The frequency of participants with total AEs and AEs by categories of intensity (mild, moderate, severe) are presented. An AE was any untoward medical occurrence in a participants participating in clinical trial. The intensity of AE was classified using the following 3-point scale: mild = awareness of signs or symptoms, but no disruption of usual activity); moderate = event sufficient to affect usual activity (disturbing); or severe = inability to work or perform usual activities (unacceptable). |
| Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation | End-of-stimulation (up to 20 stimulation days) | Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid. |
| Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation | End-of-stimulation (up to 20 stimulation days) | Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets. |
| Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial | Up to 5-6 weeks after transfer | Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid. |
| Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial | Up to 5-6 weeks after transfer | Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets. |
| Frequency and Intensity of Injection Site Reactions | End-of-stimulation (up to 20 stimulation days) | The presence of of injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after the injection are presented. The injection site reactions were assessed as none, mild, moderate and severe. The number of injection site reactions (mild, moderate or severe) based on all assessments performed is presented. |
| Technical Malfunctions of the Administration Pens | End-of-stimulation (up to 20 stimulation days) | — |
| Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6 | At Day 6 of stimulation | The median and inter-quartile range (IQR) of FSH and LH levels on stimulation Day 6 are presented. |
Countries
Japan
Participant flow
Recruitment details
A total of 17 investigational sites in Japan randomized participants to the trial between 29 July 2017 to 08 July 2019.
Pre-assignment details
A total of 373 participants were screened. Of these, 25 were screening failures and 348 participants were randomized: 170 participants were exposed to FE 999049 & 177 participants were exposed to FOLLISTIM. One participant was randomized to FOLLISTIM but not exposed to investigational medicinal product (IMP) was considered a randomization failure.
Participants by arm
| Arm | Count |
|---|---|
| FE 999049 (Follitropin Delta) FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days. | 170 |
| FOLLISTIM (Follitropin Beta) FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days. | 177 |
| Total | 347 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 18 |
| Overall Study | Other | 9 | 16 |
| Overall Study | Randomization failure | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | FE 999049 (Follitropin Delta) | FOLLISTIM (Follitropin Beta) | Total |
|---|---|---|---|
| Age, Continuous | 34.2 years STANDARD_DEVIATION 3.5 | 34.0 years STANDARD_DEVIATION 3.4 | 34.1 years STANDARD_DEVIATION 3.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 170 Participants | 177 Participants | 347 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 170 Participants | 177 Participants | 347 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 170 participants | 177 participants | 347 participants |
| Sex: Female, Male Female | 170 Participants | 177 Participants | 347 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 / 170 | 0 / 177 |
| other Total, other adverse events | 73 / 170 | 92 / 177 |
| serious Total, serious adverse events | 0 / 170 | 2 / 177 |
Outcome results
Primary
Number of Oocytes Retrieved
The number of oocytes retrieved was recorded at the oocyte retrieval visit.
Time frame: 36h (± 2h) after triggering of final follicular maturation (On day of oocyte retrieval)
Population: The full analysis set (FAS) comprised all randomized and exposed participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Number of Oocytes Retrieved | 9.3 Oocytes retrieved | Standard Deviation 5.4 |
| FOLLISTIM (Follitropin Beta) | Number of Oocytes Retrieved | 10.5 Oocytes retrieved | Standard Deviation 6.1 |
Comparison: Mean number of oocytes retrieved.95% CI: [-2.3, -0.1]
Secondary
Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation
The median and IQR of estradiol levels at end-of-stimulation are presented.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation | 6517.0 pmol/L |
| FOLLISTIM (Follitropin Beta) | Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation | 7438.8 pmol/L |
Comparison: Circulating levels of estradiol at end-of-stimulation.p-value: 0.00395% CI: [0.76, 0.95]ANCOVA
Secondary
Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6
The median and IQR of estradiol levels on stimulation Day 6 are presented.
Time frame: At Day 6 of stimulation
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6 | 2277.1 pmol/L |
| FOLLISTIM (Follitropin Beta) | Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6 | 2680.0 pmol/L |
Comparison: Circulating levels of estradiol on stimulation Day 6.p-value: 0.00295% CI: [0.71, 0.93]ANCOVA
Secondary
Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation
The median and IQR of progesterone levels at end-of-stimulation are presented.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation | 2.5 nmol/L |
| FOLLISTIM (Follitropin Beta) | Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation | 3.1 nmol/L |
Comparison: Circulating levels of progesterone levels at end-of-stimulation.p-value: <0.00195% CI: [0.68, 0.88]ANCOVA
Secondary
Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6
The median and IQR of progesterone levels on stimulation Day 6 are presented.
Time frame: At Day 6 of stimulation
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6 | 1.7 nmol/L |
| FOLLISTIM (Follitropin Beta) | Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6 | 1.7 nmol/L |
Comparison: Circulating levels of progesterone on stimulation Day 6.p-value: 0.81495% CI: [0.89, 1.16]ANCOVA
Secondary
Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation
The median and IQR of FSH and LH levels at end-of-stimulation are presented.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation | FSH | 14.3 IU/L |
| FE 999049 (Follitropin Delta) | Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation | LH | 1.6 IU/L |
| FOLLISTIM (Follitropin Beta) | Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation | FSH | 16.4 IU/L |
| FOLLISTIM (Follitropin Beta) | Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation | LH | 1.4 IU/L |
Comparison: Circulating levels of FSH at end-of-stimulation.p-value: <0.00195% CI: [0.84, 0.94]ANCOVA
Comparison: Circulating levels of LH at end-of-stimulation.p-value: 0.05795% CI: [1, 1.39]ANCOVA
Secondary
Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6
The median and inter-quartile range (IQR) of FSH and LH levels on stimulation Day 6 are presented.
Time frame: At Day 6 of stimulation
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6 | FSH | 15.4 IU/L |
| FE 999049 (Follitropin Delta) | Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6 | LH | 2.6 IU/L |
| FOLLISTIM (Follitropin Beta) | Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6 | FSH | 14.7 IU/L |
| FOLLISTIM (Follitropin Beta) | Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6 | LH | 2.8 IU/L |
Comparison: Circulating levels of FSH on stimulation Day 6.p-value: 0.22895% CI: [0.98, 1.09]ANCOVA
Comparison: Circulating levels of LH on stimulation Day 6.p-value: 0.77795% CI: [0.81, 1.17]ANCOVA
Secondary
Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation
The median and IQR of Inhibin A levels at end-of-stimulation are presented.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation | 323.8 ng/L |
| FOLLISTIM (Follitropin Beta) | Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation | 390.3 ng/L |
Comparison: Circulating levels of Inhibin A at end-of-stimulation.p-value: <0.00195% CI: [0.72, 0.88]ANCOVA
Secondary
Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6
The median and IQR of Inhibin A levels on stimulation Day 6 are presented.
Time frame: At Day 6 of stimulation
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6 | 113.1 ng/L |
| FOLLISTIM (Follitropin Beta) | Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6 | 129.8 ng/L |
Comparison: Circulating levels of Inhibin A on stimulation Day 6.p-value: <0.00195% CI: [0.73, 0.92]ANCOVA
Secondary
Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation
The median and IQR of inhibin B levels at end-of-stimulation are presented.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation | 686.0 ng/L |
| FOLLISTIM (Follitropin Beta) | Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation | 734.5 ng/L |
Comparison: Circulating levels of Inhibin B at end-of-stimulation.p-value: 0.02795% CI: [0.79, 0.99]ANCOVA
Secondary
Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6
The median and IQR of inhibin B levels on stimulation Day 6 are presented.
Time frame: At Day 6 of stimulation
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6 | 570.5 ng/L |
| FOLLISTIM (Follitropin Beta) | Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6 | 686.0 ng/L |
Comparison: Circulating levels of Inhibin B on stimulation Day 6.p-value: <0.00195% CI: [0.75, 0.93]ANCOVA
Secondary
Clinical Pregnancy Rate
Clinical pregnancy was defined as at least one gestational sac 5-6 weeks after transfer.
Time frame: 5-6 weeks after transfer (up to approximately 3 months after start of stimulation)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Clinical Pregnancy Rate | 25.3 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Clinical Pregnancy Rate | 23.7 percentage of participants |
Comparison: Percentage of participants with at least one gestational sac 5-6 weeks after transfer.95% CI: [-7.5, 10.6]
Secondary
Fertilization Rate
The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.
Time frame: Day 1 after oocyte retrieval (up to approximately 22 days after start of stimulation)
Population: The FAS comprised all randomized and exposed participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Fertilization Rate | 54.5 percentage of fertilized oocytes | Standard Deviation 26.1 |
| FOLLISTIM (Follitropin Beta) | Fertilization Rate | 57.1 percentage of fertilized oocytes | Standard Deviation 23.4 |
Comparison: The fertilization rate (number of oocytes with 2 pronuclei divided by the number of oocytes retrieved) was analyzed.p-value: 0.395van Elteren test
Secondary
Frequency and Intensity of Injection Site Reactions
The presence of of injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after the injection are presented. The injection site reactions were assessed as none, mild, moderate and severe. The number of injection site reactions (mild, moderate or severe) based on all assessments performed is presented.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The safety analysis set comprised of all randomized and exposed participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Any mild injection site reaction | 271 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Moderate itching | 1 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Mild redness | 140 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Severe itching | 0 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Severe swelling | 0 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Mild pain | 19 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Moderate redness | 2 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Moderate pain | 1 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Any moderate injection site reaction | 7 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Severe pain | 0 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Mild bruising | 102 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Mild swelling | 6 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Severe redness | 0 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Moderate swelling | 0 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Moderate bruising | 3 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Any severe injection site reaction | 1 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Severe bruising | 1 events |
| FE 999049 (Follitropin Delta) | Frequency and Intensity of Injection Site Reactions | Mild itching | 4 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Severe bruising | 0 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Severe swelling | 0 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Any mild injection site reaction | 719 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Any moderate injection site reaction | 19 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Any severe injection site reaction | 0 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Mild redness | 174 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Moderate redness | 0 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Mild bruising | 119 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Severe redness | 0 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Mild itching | 5 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Moderate itching | 0 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Severe itching | 0 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Mild pain | 411 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Moderate pain | 16 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Severe pain | 0 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Mild swelling | 10 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Moderate bruising | 3 events |
| FOLLISTIM (Follitropin Beta) | Frequency and Intensity of Injection Site Reactions | Moderate swelling | 0 events |
Secondary
Implantation Rate
Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by the number of blastocysts transferred.
Time frame: 5-6 weeks after transfer (up to approximately 3 months after start of stimulation)
Population: The FAS comprised of all randomized and exposed participants with blastocyst transfer.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Implantation Rate | 31.9 % of sacs/blastocysts transferred |
| FOLLISTIM (Follitropin Beta) | Implantation Rate | 29.8 % of sacs/blastocysts transferred |
Comparison: Percentage of implanted embryos 5-6 weeks after transfer.95% CI: [-8.9, 12.8]
Secondary
Number and Quality of Blastocysts
Number of embryos (total and good-quality) on Day 5 are presented. The quality evaluation of blastocysts consisted of assessment of three parameters, as per the Gardner & Schoolcraft system: blastocyst expansion and hatching status (graded: 1-6), inner cell mass (graded: A-D) and trophectoderm (graded: A-D). A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher.
Time frame: Day 5 after oocyte retrieval (up to approximately 26 days after start of stimulation)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 (Follitropin Delta) | Number and Quality of Blastocysts | Number of blastocysts | 3.1 Blastocysts | Standard Deviation 2.7 |
| FE 999049 (Follitropin Delta) | Number and Quality of Blastocysts | Number of good-quality blastocysts | 2.3 Blastocysts | Standard Deviation 2.3 |
| FOLLISTIM (Follitropin Beta) | Number and Quality of Blastocysts | Number of blastocysts | 4.2 Blastocysts | Standard Deviation 3.4 |
| FOLLISTIM (Follitropin Beta) | Number and Quality of Blastocysts | Number of good-quality blastocysts | 3.0 Blastocysts | Standard Deviation 2.6 |
Comparison: The number of blastocysts on Day 5 was analyzed.p-value: <0.001van Elteren test
Comparison: The number of good-quality blastocysts on Day 5 was analyzed.p-value: <0.001van Elteren test
Secondary
Number and Quality of Embryos
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.
Time frame: Day 3 after oocyte retrieval (up to approximately 24 days after start of stimulation)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 (Follitropin Delta) | Number and Quality of Embryos | Number of embryo | 5.8 Embryo | Standard Deviation 4.2 |
| FE 999049 (Follitropin Delta) | Number and Quality of Embryos | Number of good-quality embryo | 3.9 Embryo | Standard Deviation 3.3 |
| FOLLISTIM (Follitropin Beta) | Number and Quality of Embryos | Number of embryo | 7.0 Embryo | Standard Deviation 4.3 |
| FOLLISTIM (Follitropin Beta) | Number and Quality of Embryos | Number of good-quality embryo | 4.6 Embryo | Standard Deviation 3.3 |
Comparison: The number of embryos on Day 3 was analyzed.p-value: 0.001van Elteren test
Comparison: The number of good-quality embryos on Day 3 was analyzed.p-value: 0.004van Elteren test
Secondary
Number of Follicles at End-of-stimulation
Defined as the number of follicles observed in both ovaries at the last TVUS in the stimulation phase (end-of-stimulation).
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The FAS comprised of all randomized or exposed participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Number of Follicles at End-of-stimulation | 14.9 Follicles | Standard Deviation 8 |
| FOLLISTIM (Follitropin Beta) | Number of Follicles at End-of-stimulation | 16.3 Follicles | Standard Deviation 8.8 |
Comparison: The number of follicles at end-of-stimulation was analyzed.p-value: 0.036van Elteren test
Secondary
Number of Follicles on Stimulation Day 6
Defined as the number of follicles observed in both ovaries at the last transvaginal ultrasound (TVUS) in the stimulation phase (on stimulation Day 6).
Time frame: At Day 6 of stimulation
Population: The FAS comprised of all randomized or exposed participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Number of Follicles on Stimulation Day 6 | 12.8 Follicles | Standard Deviation 7.2 |
| FOLLISTIM (Follitropin Beta) | Number of Follicles on Stimulation Day 6 | 13.3 Follicles | Standard Deviation 7.1 |
Comparison: The number of follicles on stimulation Day 6 was analyzed.p-value: 0.198van Elteren test
Secondary
Number of Participants With Adverse Events (AEs) Stratified by Intensity
The frequency of participants with total AEs and AEs by categories of intensity (mild, moderate, severe) are presented. An AE was any untoward medical occurrence in a participants participating in clinical trial. The intensity of AE was classified using the following 3-point scale: mild = awareness of signs or symptoms, but no disruption of usual activity); moderate = event sufficient to affect usual activity (disturbing); or severe = inability to work or perform usual activities (unacceptable).
Time frame: From signed informed consent up to 5-6 weeks after transfer
Population: The safety analysis set comprised of all randomized and exposed participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Number of Participants With Adverse Events (AEs) Stratified by Intensity | Any AE | 73 Participants |
| FE 999049 (Follitropin Delta) | Number of Participants With Adverse Events (AEs) Stratified by Intensity | Mild AE | 69 Participants |
| FE 999049 (Follitropin Delta) | Number of Participants With Adverse Events (AEs) Stratified by Intensity | Moderate AE | 8 Participants |
| FE 999049 (Follitropin Delta) | Number of Participants With Adverse Events (AEs) Stratified by Intensity | Severe AE | 0 Participants |
| FOLLISTIM (Follitropin Beta) | Number of Participants With Adverse Events (AEs) Stratified by Intensity | Severe AE | 1 Participants |
| FOLLISTIM (Follitropin Beta) | Number of Participants With Adverse Events (AEs) Stratified by Intensity | Any AE | 92 Participants |
| FOLLISTIM (Follitropin Beta) | Number of Participants With Adverse Events (AEs) Stratified by Intensity | Moderate AE | 12 Participants |
| FOLLISTIM (Follitropin Beta) | Number of Participants With Adverse Events (AEs) Stratified by Intensity | Mild AE | 86 Participants |
Secondary
Number of Stimulation Days
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The safety analysis set comprised of all randomized and exposed participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Number of Stimulation Days | 8.9 Days | Standard Deviation 1.9 |
| FOLLISTIM (Follitropin Beta) | Number of Stimulation Days | 8.8 Days | Standard Deviation 1.7 |
Comparison: The number of stimulation days at end-of-stimulation.p-value: 0.694van Elteren test
Secondary
Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate
Defined as positive serum beta-hCG test 13-15 days after transfer.
Time frame: 13-15 days after transfer (up to approximately 1.5 months after start of stimulation)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate | 29.4 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate | 29.4 percentage of participants |
Comparison: Percentage of participants with positive beta-hCG.95% CI: [-9.5, 9.6]
Secondary
Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation
Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The safety analysis set comprised of all randomized and exposed participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation | ALT (IU/L): Normal to markedly high (>3xULN) | 0 participants |
| FE 999049 (Follitropin Delta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation | AST (IU/L): Normal to markedly high (>3xULN) | 0 participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation | ALT (IU/L): Normal to markedly high (>3xULN) | 1 participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation | AST (IU/L): Normal to markedly high (>3xULN) | 1 participants |
Secondary
Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial
Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.
Time frame: Up to 5-6 weeks after transfer
Population: The safety analysis set comprised of all randomized and exposed participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial | 0 participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial | 0 participants |
Secondary
Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation
Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The safety analysis set comprised of all randomized and exposed participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation | 0 participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation | 0 participants |
Secondary
Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial
Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
Time frame: Up to 5-6 weeks after transfer
Population: The safety analysis set comprised of all randomized and exposed participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial | Leukocytes (10^9/L) Normal to markedly high (>=16) | 0 participants |
| FE 999049 (Follitropin Delta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial | Hemoglobin (g/L) Normal to markedly low | 0 participants |
| FE 999049 (Follitropin Delta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial | Hematocrit (ratio) Normal to markedly low (>=0.56) | 0 participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial | Leukocytes (10^9/L) Normal to markedly high (>=16) | 1 participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial | Hemoglobin (g/L) Normal to markedly low | 1 participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial | Hematocrit (ratio) Normal to markedly low (>=0.56) | 1 participants |
Secondary
Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
Defined as proportion of participants grouped according to the number of oocytes retrieved. The proportion of participants with \<4 oocytes (low response), 4-7 oocytes (moderate response), 8-14 oocytes (targeted response), 15-19 oocytes (hyperresponse) and ≥20 oocytes (severe hyperresponse) are presented.
Time frame: On the day of oocyte retrieval (up to 22 days after start of stimulation)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Moderate response (4-7 oocytes) | 36.1 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Hyperresponse (15-19 oocytes) | 10.1 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Targeted response (8-14 oocytes) | 40.8 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Severe hyperresponse (≥ 20 oocytes) | 4.7 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Low response (<4 oocytes) | 8.3 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Severe hyperresponse (≥ 20 oocytes) | 11.0 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Low response (<4 oocytes) | 5.2 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Moderate response (4-7 oocytes) | 26.6 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Targeted response (8-14 oocytes) | 42.8 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Hyperresponse (15-19 oocytes) | 14.5 percentage of participants |
Comparison: Proportion of participants with \<4 oocytes retrieved (low response).p-value: 0.254Regression, Logistic
Comparison: Proportion of participants with 4-7 oocytes retrieved (moderate response).p-value: 0.041Regression, Logistic
Comparison: Proportion of participants with 8-14 oocytes retrieved (targeted response).p-value: 0.705Regression, Logistic
Comparison: Proportion of participants with 15-19 oocytes retrieved (hyperresponse).p-value: 0.183Regression, Logistic
Comparison: Proportion of participants with \>= (more than equal to) 20 oocytes retrieved (severe hyperresponse).p-value: 0.03Regression, Logistic
Secondary
Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk | 7.6 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk | 11.3 percentage of participants |
Comparison: Proportion of participants with blastocyst transfer cancellation.p-value: 0.244Regression, Logistic
Secondary
Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response | Cycle cancelled due to poor ovarian response | 1.2 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response | Cycle cancelled due to excessive ovarian response | 0 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response | Cycle cancelled due to poor ovarian response | 0.6 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response | Cycle cancelled due to excessive ovarian response | 1.1 percentage of participants |
Secondary
Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population
Time frame: On the day of oocyte retrieval (up to 22 days after start of stimulation)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population | AMH < 15 pmol/L (<4 oocytes retrieved) | 11.6 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population | AMH >= 15 pmol/L (>=15 oocytes retrieved) | 22.0 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population | AMH >= 15 pmol/L (>=20 oocytes retrieved) | 8.0 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population | AMH >= 15 pmol/L (>=15 oocytes retrieved) | 42.0 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population | AMH < 15 pmol/L (<4 oocytes retrieved) | 12.3 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population | AMH >= 15 pmol/L (>=20 oocytes retrieved) | 19.0 percentage of participants |
Comparison: Proportion of participants with extreme ovarian responses: AMH \< 15 pmol/L (\<4 oocytes retrieved)p-value: 0.893Chi-squared
Comparison: Proportion of participants with extreme ovarian responses: AMH \>= 15 pmol/L (\>=15 oocytes retrieved)p-value: 0.002Chi-squared
Comparison: Proportion of participants with extreme ovarian responses: AMH \>= 15 pmol/L (\>=20 oocytes retrieved)p-value: 0.021Chi-squared
Secondary
Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS)
Time frame: ≤9 days after triggering of final follicular maturation
Population: The FAS comprised of all participants randomized or exposed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) | Cycle cancellation | 0 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) | Triggering with GnRH agonist | 1.2 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) | Administration of dopamine agonist | 0.6 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) | Cycle cancellation | 1.1 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) | Triggering with GnRH agonist | 1.1 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) | Administration of dopamine agonist | 1.7 percentage of participants |
Secondary
Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS
Defined as proportion of participants 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.
Time frame: Up to 9 days after triggering of final follicular maturation
Population: The FAS comprised of all participants randomized and exposed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS | Early OHSS (any grade) | 10.0 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS | Early OHSS (moderate/severe) | 6.5 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS | Early OHSS (any grade) and/or preventive | 10.6 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS | Early OHSS (moderate/severe) and/or preventive | 7.6 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS | Early OHSS (moderate/severe) and/or preventive | 16.4 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS | Early OHSS (any grade) | 18.6 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS | Early OHSS (any grade) and/or preventive | 20.9 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS | Early OHSS (moderate/severe) | 13.0 percentage of participants |
Comparison: Proportions of participants with early OHSS (any grade).p-value: 0.017Regression, Logistic
Comparison: Proportion of participants with early OHSS (moderate/severe).p-value: 0.035Regression, Logistic
Comparison: Proportion of participants with early OHSS (any grade) and/or preventive interventions.p-value: 0.006Regression, Logistic
Comparison: Proportion of participants with early OHSS (moderate/severe) and/or preventive interventions.p-value: 0.009Regression, Logistic
Secondary
Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade)
Defined as proportions of participants with late OHSS (including OHSS of moderate/severe grade). Late OHSS was defined as OHSS with onset \>9 days after triggering of final follicular maturation. The proportion of participants with late OHSS, and late OHSS of moderate or severe grade are presented. All OHSS cases were graded as mild, moderate, or severe.
Time frame: >9 days after triggering of final follicular maturation
Population: The FAS comprised of all participants randomized or exposed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade) | Late OHSS (any grade) | 1.2 percentage of participants |
| FE 999049 (Follitropin Delta) | Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade) | Late OHSS (moderate/severe) | 0.6 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade) | Late OHSS (any grade) | 1.1 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade) | Late OHSS (moderate/severe) | 1.1 percentage of participants |
Comparison: Proportions of participants with late OHSS (any grade).p-value: 0.968Regression, Logistic
Comparison: Proportions of participants with late OHSS (moderate/severe).p-value: 0.582Regression, Logistic
Secondary
Size of Follicles at End-of-Stimulation
Defined as size characteristics of follicles at end-of-stimulation. Average size of 3 largest follicles has been presented in this endpoint.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The FAS comprised of all randomized and exposed participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Size of Follicles at End-of-Stimulation | 19.2 mm | Standard Deviation 1.5 |
| FOLLISTIM (Follitropin Beta) | Size of Follicles at End-of-Stimulation | 19.4 mm | Standard Deviation 1.6 |
Comparison: The average size of 3 largest follicles was analyzed.p-value: 0.286van Elteren test
Secondary
Size of Follicles on Stimulation Day 6
Defined as size characteristics of follicles on stimulation Day 6. Average size of 3 largest follicles has been presented in this endpoint.
Time frame: At Day 6 of stimulation
Population: The FAS comprised of all randomized and exposed participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Size of Follicles on Stimulation Day 6 | 12.7 mm | Standard Deviation 2.1 |
| FOLLISTIM (Follitropin Beta) | Size of Follicles on Stimulation Day 6 | 12.8 mm | Standard Deviation 2 |
Comparison: The average size of 3 largest follicles was analyzed.p-value: 0.592van Elteren test
Secondary
Technical Malfunctions of the Administration Pens
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The safety analysis set comprised of all randomized and exposed participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Technical Malfunctions of the Administration Pens | 0 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Technical Malfunctions of the Administration Pens | 0 percentage of participants |
Secondary
Total Gonadotropin Dose of FE 999049
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The safety analysis set comprised of all randomized and exposed participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Total Gonadotropin Dose of FE 999049 | 83.5 μg | Standard Deviation 28.9 |
Secondary
Total Gonadotropin Dose of FOLLISTIM
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: The safety analysis set comprised of all randomized and exposed participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 (Follitropin Delta) | Total Gonadotropin Dose of FOLLISTIM | 1499 IU | Standard Deviation 514 |
Secondary
Vital Pregnancy Rate
Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer.
Time frame: 5-6 weeks after transfer (up to approximately 3 months after start of stimulation)
Population: The FAS comprised of all randomized and exposed participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 (Follitropin Delta) | Vital Pregnancy Rate | 23.5 percentage of participants |
| FOLLISTIM (Follitropin Beta) | Vital Pregnancy Rate | 21.5 percentage of participants |
Comparison: Percentage of participants with vital pregnancy.95% CI: [-6.7, 10.8]