Infertility
Conditions
Brief summary
This trial investigates the effects of FE 999049 compared to GONAL-F.
Interventions
Sponsors
Ferring Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
* Informed Consent Documents signed prior to screening evaluations * In good physical and mental health * Pre-menopausal females between the ages of 18 and 40 years * Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or with partners diagnosed with male factor infertility, eligible for in vitro fertilisation (IVF) and/or intracytoplasmic sperm injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor * Infertility for at least one year before randomisation for subjects ≤37 years or for at least 6 months for subjects ≥38 years (not applicable in case of tubal or severe male factor infertility) * The trial cycle will be the subject's first controlled ovarian stimulation cycle for IVF/ICSI * Hysterosalpingography, hysteroscopy, saline infusion sonography, or transvaginal ultrasound documenting a uterus consistent with expected normal function (e.g. no evidence of clinically interfering uterine fibroids defined as submucous or intramural fibroids larger than 3 cm in diameter, no polyps and no congenital structural abnormalities which are associated with a reduced chance of pregnancy) within 1 year prior to randomisation * Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, without evidence of significant abnormality (e.g. no endometrioma greater than 3 cm or enlarged ovaries which would contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) within 1 year prior to randomisation. Both ovaries must be accessible for oocyte retrieval. * Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results obtained within 3 months prior to randomisation) * Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening
Exclusion criteria
* Known endometriosis stage III-IV * One or more follicles ≥10 mm observed on the transvaginal ultrasound prior to randomisation on stimulation day 1 * Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of pregnancy) * Known abnormal karyotype of subject or of her partner/sperm donor, as applicable, depending on source of sperm used for insemination in this trial. * Any known clinically significant systemic disease (e.g. insulin-dependent diabetes) * Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) which can compromise participation in the trial with the exception of controlled thyroid function disease * Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which would contraindicate the use of gonadotropins.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ongoing Pregnancy Rate | 10-11 weeks after blastocyst transfer | Ongoing pregnancy was defined as at least one intrauterine viable fetus 10-11 weeks after blastocyst transfer. |
| Ongoing Implantation Rate | 10-11 weeks after blastocyst transfer | Ongoing implantation rate was defined as the number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved | Day of oocyte retrieval | — |
| Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS | ≤9 days after triggering of final follicular maturation | The proportion of subjects with early OHSS, early OHSS of moderate or severe grade, preventive interventions for early OHSS, early OHSS and/or preventive interventions for early OHSS, and early OHSS of moderate or severe grade and/or preventive interventions for early OHSS are presented. |
| Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | End-of-stimulation (up to 20 stimulation days) | Proportion of subjects with cycle cancellation due to poor ovarian response, excessive ovarian response, and triggering with gonadotropin-releasing hormone (GnRH) agonist are presented. |
| Number of Oocytes Retrieved | Day of oocyte retrieval | — |
| Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Day of oocyte retrieval | — |
| Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection]) | Prior to insemination | Number of oocytes in metaphase II prior to ICSI insemination is presented. |
| Fertilisation Rate | Day 1 after insemination | Fertilisation rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved. |
| Number and Quality of Embryos on Day 3 | On day 3 after oocyte retrieval | 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. |
| Number and Quality of Blastocysts on Day 5 | On day 5 after oocyte retrieval | Number of blastocysts (total and good-quality) on Day 5 are presented. A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher. |
| Vital Pregnancy Rate | 5-6 weeks after blastocyst transfer | Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after blastocyst transfer. |
| Number of Stimulation Days | End-of-stimulation (up to 20 stimulation days) | — |
| Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments | End-of-stimulation (up to 20 stimulation days) | — |
| Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period | End-of-stimulation (up to 20 stimulation days) | Subjects self-assessed injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after each injection. The injection site reactions were assessed as none, mild, moderate and severe. The frequency of injection site reactions (mild, moderate or severe) based on all assessments performed is presented. |
| Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS) | End-of-stimulation and day of blastocyst transfer | The subject self-assessed abdominal discomfort related to controlled ovarian stimulation using a VAS going from 0 mm (no abdominal discomfort) to 100 mm (worst imaginable abdominal discomfort). |
| Changes in Body Weight | End-of-stimulation and day of blastocyst transfer | Change in body weight from baseline to end-of-stimulation and from baseline to day of blastocyst transfer. |
| Changes in Maximum Abdominal Circumference | End-of-stimulation and day of blastocyst transfer | Change in maximum abdominal circumference from baseline to end-of-stimulation and from baseline to day of blastocyst transfer. |
| Proportion of Subjects With Treatment-induced Anti-follicle-stimulating Hormone (FSH) Antibodies | Stimulation day 1, 7-10 days after last FE 999049 or GONAL-F dose and 21-28 days after last FE 999049 or GONAL-F dose | The proportion of subjects with at least one treatment-induced anti-FSH antibody response at any time point. |
| Proportion of Subjects With Late OHSS | >9 days after triggering of final follicular maturation | Late OHSS was defined as OHSS with onset \>9 days after triggering of final follicular maturation.The proportion of subjects with late OHSS, and late OHSS of moderate or severe grade are presented. |
| Technical Malfunctions of the Administration Pen | End-of-stimulation (up to 20 stimulation days) | Confirmed technical malfunction of administration pen. |
| Total Gonadotropin Dose | End-of-stimulation (up to 20 stimulation days) | The total gonadotropin dose was recorded. |
| Implantation Rate | 5-6 weeks after blastocyst transfer | Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred. |
Countries
Belgium, Brazil, Canada, Czechia, Denmark, France, Italy, Poland, Russia, Spain, United Kingdom
Participant flow
Recruitment details
A total of 37 sites randomised subjects into the trial : 3 in Belgium, 3 in Brazil, 3 in Canada, 4 in the Czech Republic, 2 in Denmark, 2 in France, 2 in Italy, 2 in Poland, 4 in Russia, 10 in Spain and 2 in United Kingdom.
Pre-assignment details
A total of 1501 subjects were screened in the trial, of whom 1329 subjects were randomised: 666 subjects to FE 999049 and 663 subjects to GONAL-F. Three subjects were randomisation failures and did not receive investigational medicinal product (IMP); 1 in the FE 999049 group and 2 in the GONAL-F group.
Participants by arm
| Arm | Count |
|---|---|
| FE 999049 FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days. | 665 |
| GONAL-F GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days. | 661 |
| Total | 1,326 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 10 |
| Overall Study | Personal reasons | 1 | 1 |
| Overall Study | Protocol Violation | 25 | 11 |
Baseline characteristics
| Characteristic | FE 999049 | GONAL-F | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 665 Participants | 661 Participants | 1326 Participants |
| Sex: Female, Male Female | 665 Participants | 661 Participants | 1326 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 | — / — | — / — |
| other Total, other adverse events | 168 / 665 | 159 / 661 |
| serious Total, serious adverse events | 16 / 665 | 10 / 661 |
Outcome results
Primary
Ongoing Implantation Rate
Ongoing implantation rate was defined as the number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred.
Time frame: 10-11 weeks after blastocyst transfer
Population: Subjects with blastocyst transfer (a total of 585 and 584 blastocysts were transferred in the FE999049 and GONAL-F groups, respectively).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 | Ongoing Implantation Rate | 35.2 Percentage |
| GONAL-F | Ongoing Implantation Rate | 35.8 Percentage |
Comparison: The pre-specified non-inferiority margin was -8.0% (absolute). Non-inferiority was evaluated based on a two-sided 95% CI derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (\<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.95% CI: [-6.1, 4.8]
Primary
Ongoing Pregnancy Rate
Ongoing pregnancy was defined as at least one intrauterine viable fetus 10-11 weeks after blastocyst transfer.
Time frame: 10-11 weeks after blastocyst transfer
Population: Modified intention-to-treat (mITT) analysis set (all randomised and exposed subjects). This is equivalent to full analysis set (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 | Ongoing Pregnancy Rate | 30.7 Percentage of subjects |
| GONAL-F | Ongoing Pregnancy Rate | 31.6 Percentage of subjects |
Comparison: The pre-specified non-inferiority margin was -8.0% (absolute). Non-inferiority was evaluated based on a two-sided 95% confidence interval (CI) derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (\<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.95% CI: [-5.9, 4.1]
Secondary
Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS)
The subject self-assessed abdominal discomfort related to controlled ovarian stimulation using a VAS going from 0 mm (no abdominal discomfort) to 100 mm (worst imaginable abdominal discomfort).
Time frame: End-of-stimulation and day of blastocyst transfer
Population: Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 | Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS) | End of stimulation visit | 16.1 Millimeter | Standard Deviation 18.14 |
| FE 999049 | Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS) | Transfer visit | 17.2 Millimeter | Standard Deviation 20.02 |
| GONAL-F | Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS) | End of stimulation visit | 15.9 Millimeter | Standard Deviation 17.36 |
| GONAL-F | Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS) | Transfer visit | 16.1 Millimeter | Standard Deviation 19.37 |
Secondary
Changes in Body Weight
Change in body weight from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.
Time frame: End-of-stimulation and day of blastocyst transfer
Population: Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 | Changes in Body Weight | Transfer visit | 0.0 Kg | Standard Deviation 1.03 |
| FE 999049 | Changes in Body Weight | End of stimulation visit | 0.3 Kg | Standard Deviation 1.11 |
| GONAL-F | Changes in Body Weight | Transfer visit | 0.0 Kg | Standard Deviation 0.98 |
| GONAL-F | Changes in Body Weight | End of stimulation visit | 0.2 Kg | Standard Deviation 0.78 |
Secondary
Changes in Maximum Abdominal Circumference
Change in maximum abdominal circumference from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.
Time frame: End-of-stimulation and day of blastocyst transfer
Population: Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 | Changes in Maximum Abdominal Circumference | Transfer visit | 0.6 Centimeter | Standard Deviation 4.79 |
| FE 999049 | Changes in Maximum Abdominal Circumference | End of stimulation visit | 0.3 Centimeter | Standard Deviation 4.41 |
| GONAL-F | Changes in Maximum Abdominal Circumference | Transfer visit | -0.1 Centimeter | Standard Deviation 5.23 |
| GONAL-F | Changes in Maximum Abdominal Circumference | End of stimulation visit | 0.1 Centimeter | Standard Deviation 5.03 |
Secondary
Fertilisation Rate
Fertilisation rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.
Time frame: Day 1 after insemination
Population: Subjects with oocytes retrieved.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 | Fertilisation Rate | 56 Percentage of oocytes | Standard Deviation 24.5 |
| GONAL-F | Fertilisation Rate | 57 Percentage of oocytes | Standard Deviation 23.8 |
Comparison: Treatment comparison: Fertilisation ratep-value: 0.53van Elteren
Secondary
Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period
Subjects self-assessed injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after each injection. The injection site reactions were assessed as none, mild, moderate and severe. The frequency of injection site reactions (mild, moderate or severe) based on all assessments performed is presented.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 | Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period | 3.4 Percentage of events |
| GONAL-F | Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period | 3.5 Percentage of events |
Secondary
Implantation Rate
Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred.
Time frame: 5-6 weeks after blastocyst transfer
Population: Subjects with blastocyst transfer (a total of 585 and 584 blastocysts were transferred in the FE999049 and GONAL-F groups, respectively).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 | Implantation Rate | 39.8 Percentage |
| GONAL-F | Implantation Rate | 41.3 Percentage |
Comparison: Treatment groups were compared using a two-sided 95% CI derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (\<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.95% CI: [-7, 4.2]
Secondary
Number and Quality of Blastocysts on Day 5
Number of blastocysts (total and good-quality) on Day 5 are presented. A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher.
Time frame: On day 5 after oocyte retrieval
Population: Subjects with oocytes retrieved.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 | Number and Quality of Blastocysts on Day 5 | Number of blastocysts | 3.3 Number of blastocytss | Standard Deviation 2.8 |
| FE 999049 | Number and Quality of Blastocysts on Day 5 | Number of good-quality blastocysts | 2.0 Number of blastocytss | Standard Deviation 2.2 |
| GONAL-F | Number and Quality of Blastocysts on Day 5 | Number of blastocysts | 3.5 Number of blastocytss | Standard Deviation 3.2 |
| GONAL-F | Number and Quality of Blastocysts on Day 5 | Number of good-quality blastocysts | 2.1 Number of blastocytss | Standard Deviation 2.4 |
Comparison: Treatment comparison: Number of blastocystsp-value: =0.344van Elteren
Comparison: Treatment comparison: Good-quality blastocystsp-value: =0.58van Elteren
Secondary
Number and Quality of Embryos on Day 3
Number of embryos (total and good-quality) on Day 3 are presented. A good-quality embryo was defined as an embryo with ≥6 blastomeres and fragmentation ≤20% on Day 3.
Time frame: On day 3 after oocyte retrieval
Population: Subjects with oocytes retrieved.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE 999049 | Number and Quality of Embryos on Day 3 | Number of good-quality embryos | 4.2 Number of embryos | Standard Deviation 3.3 |
| FE 999049 | Number and Quality of Embryos on Day 3 | Number of embryos | 5.4 Number of embryos | Standard Deviation 3.7 |
| GONAL-F | Number and Quality of Embryos on Day 3 | Number of good-quality embryos | 4.5 Number of embryos | Standard Deviation 3.7 |
| GONAL-F | Number and Quality of Embryos on Day 3 | Number of embryos | 5.7 Number of embryos | Standard Deviation 4.3 |
Comparison: Treatment comparison: Good quality embryosp-value: =0.414van Elteren
Comparison: Treatment comparison: Number of embryosp-value: =0.59van Elteren
Secondary
Number of Oocytes Retrieved
Time frame: Day of oocyte retrieval
Population: Subjects who underwent triggering of final follicular maturation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 | Number of Oocytes Retrieved | 10.0 Oocytes retrieved | Standard Deviation 5.6 |
| GONAL-F | Number of Oocytes Retrieved | 10.4 Oocytes retrieved | Standard Deviation 6.5 |
Comparison: Treatment comparison: Number of oocytes retrievedp-value: =0.692van Elteren
Secondary
Number of Stimulation Days
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: mITT analysis set (all randomised and exposed subjects). This is equivalent to the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 | Number of Stimulation Days | 8.9 Days | Standard Deviation 1.9 |
| GONAL-F | Number of Stimulation Days | 8.6 Days | Standard Deviation 1.7 |
Comparison: Treatment comparison: Number of stimulation daysp-value: =0.062van Elteren
Secondary
Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection])
Number of oocytes in metaphase II prior to ICSI insemination is presented.
Time frame: Prior to insemination
Population: Subjects with all oocytes inseminated using ICSI.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 | Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection]) | 7.4 Number of oocytes | Standard Deviation 4.3 |
| GONAL-F | Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection]) | 7.7 Number of oocytes | Standard Deviation 5.2 |
Comparison: Treatment comparison: Number of metaphase II oocytesp-value: =0.909van Elteren
Secondary
Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
Time frame: Day of oocyte retrieval
Population: Subjects who underwent triggering of final follicular maturation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Moderate response (4-7 oocytes) | 30.1 Percentage of subjects |
| FE 999049 | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Hyperresponse (15-19 oocytes) | 12.1 Percentage of subjects |
| FE 999049 | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Targeted response (8-14 oocytes) | 43.3 Percentage of subjects |
| FE 999049 | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Severe hyperresponse (≥ 20 oocytes) | 6.5 Percentage of subjects |
| FE 999049 | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Low response (<4 oocytes) | 8.0 Percentage of subjects |
| GONAL-F | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Severe hyperresponse (≥ 20 oocytes) | 8.7 Percentage of subjects |
| GONAL-F | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Low response (<4 oocytes) | 9.6 Percentage of subjects |
| GONAL-F | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Moderate response (4-7 oocytes) | 30.3 Percentage of subjects |
| GONAL-F | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Targeted response (8-14 oocytes) | 38.4 Percentage of subjects |
| GONAL-F | Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved | Hyperresponse (15-19 oocytes) | 12.9 Percentage of subjects |
Comparison: The relation between ovarian response potential (AMH at screening) and probability of achieving the targeted response was modelled using logistic regression models.p-value: =0.019Likelihood ratio test
Secondary
Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response
Proportion of subjects with cycle cancellation due to poor ovarian response, excessive ovarian response, and triggering with gonadotropin-releasing hormone (GnRH) agonist are presented.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: mITT analysis set (all randomised and exposed subjects). This is equivalent to the FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 | Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Cycle cancelled due to excessive ovarian response | 0 Percentage of subjects |
| FE 999049 | Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Triggering with GnRH agonist | 1.5 Percentage of subjects |
| FE 999049 | Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Cycle cancelled due to poor ovarian response | 3.8 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Cycle cancelled due to poor ovarian response | 2.7 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Cycle cancelled due to excessive ovarian response | 0 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response | Triggering with GnRH agonist | 3.5 Percentage of subjects |
Comparison: Treatment comparison: Cycle cancelled due to poor responsep-value: =0.30295% CI: [0.74, 2.57]Likelihood ratio test
Comparison: Treatment comparison:Triggering with GnRH agonistp-value: 0.01995% CI: [0.2, 0.9]Likelihood ratio test
Secondary
Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS
The proportion of subjects with early OHSS, early OHSS of moderate or severe grade, preventive interventions for early OHSS, early OHSS and/or preventive interventions for early OHSS, and early OHSS of moderate or severe grade and/or preventive interventions for early OHSS are presented.
Time frame: ≤9 days after triggering of final follicular maturation
Population: mITT analysis set (all randomised and exposed subjects). This is equivalent to the FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 | Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS | Early OHSS (any grade) | 2.6 Percentage of subjects |
| FE 999049 | Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS | Early OHSS (any grade) / preventive interventions | 4.7 Percentage of subjects |
| FE 999049 | Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS | Any preventive intervention | 2.3 Percentage of subjects |
| FE 999049 | Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS | Early OHSS (moderate/severe) | 1.4 Percentage of subjects |
| FE 999049 | Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS | Early OHSS (mod/severe) / preventive interventions | 3.6 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS | Early OHSS (mod/severe) / preventive interventions | 5.1 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS | Early OHSS (any grade) / preventive interventions | 6.2 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS | Early OHSS (moderate/severe) | 1.4 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS | Any preventive intervention | 4.5 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS | Early OHSS (any grade) | 3.0 Percentage of subjects |
Comparison: Treatment comparison: Early OHSS (any grade)p-value: =0.291Likelihood ratio test
Comparison: Treatment comparison: Early OHSS (moderate/severe)p-value: =0.644Likelihood ratio test
Comparison: Treatment comparison: Preventive interventionsp-value: =0.005Likelihood ratio test
Comparison: Treatment comparison: Early OHSS (any grade) and/or preventive interventionsp-value: =0.046Likelihood ratio test
Comparison: Treatment comparison: Early OHSS (moderate/severe) and/or preventive interventionsp-value: =0.019Likelihood ratio test
Secondary
Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved
Time frame: Day of oocyte retrieval
Population: Subjects who underwent triggering of final follicular maturation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 | Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved | <4 or >=15 oocytes retrieved | 26.6 Percentage of subjects |
| FE 999049 | Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved | <4 or >=20 oocytes retrieved | 14.5 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved | <4 or >=15 oocytes retrieved | 31.3 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved | <4 or >=20 oocytes retrieved | 18.4 Percentage of subjects |
Comparison: Treatment comparison: \<4 or \>=15 oocytes retrievedp-value: =0.001Likelihood ratio test
Comparison: Treatment comparison: \<4 or \>=20 oocytes retrievedp-value: =0.002Likelihood ratio test
Secondary
Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: mITT analysis set (all randomised and exposed subjects). This is equivalent to the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 | Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments | 33.2 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments | 36.8 Percentage of subjects |
Comparison: Treatment comparison: Investigator-requested gonadotropin dose adjustmentsp-value: =0.178Chi-squared
Secondary
Proportion of Subjects With Late OHSS
Late OHSS was defined as OHSS with onset \>9 days after triggering of final follicular maturation.The proportion of subjects with late OHSS, and late OHSS of moderate or severe grade are presented.
Time frame: >9 days after triggering of final follicular maturation
Population: Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FE 999049 | Proportion of Subjects With Late OHSS | Late OHSS (any grade) | 0.9 Percentage of subjects |
| FE 999049 | Proportion of Subjects With Late OHSS | Late OHSS (moderate/severe) | 0.8 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Late OHSS | Late OHSS (any grade) | 1.8 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Late OHSS | Late OHSS (moderate/severe) | 1.5 Percentage of subjects |
Comparison: Treatment comparison: Late OHSS (any grade)p-value: 0.32Likelihood ratio test
Comparison: Treatment comparison: Late OHSS (moderate/severe)p-value: 0.39Likelihood ratio test
Secondary
Proportion of Subjects With Treatment-induced Anti-follicle-stimulating Hormone (FSH) Antibodies
The proportion of subjects with at least one treatment-induced anti-FSH antibody response at any time point.
Time frame: Stimulation day 1, 7-10 days after last FE 999049 or GONAL-F dose and 21-28 days after last FE 999049 or GONAL-F dose
Population: Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 | Proportion of Subjects With Treatment-induced Anti-follicle-stimulating Hormone (FSH) Antibodies | 1.05 Percentage of subjects |
| GONAL-F | Proportion of Subjects With Treatment-induced Anti-follicle-stimulating Hormone (FSH) Antibodies | 0.76 Percentage of subjects |
Secondary
Technical Malfunctions of the Administration Pen
Confirmed technical malfunction of administration pen.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 | Technical Malfunctions of the Administration Pen | 0.15 Percentage of subjects |
| GONAL-F | Technical Malfunctions of the Administration Pen | 0.00 Percentage of subjects |
Secondary
Total Gonadotropin Dose
The total gonadotropin dose was recorded.
Time frame: End-of-stimulation (up to 20 stimulation days)
Population: mITT analysis set (all randomised and exposed subjects). This is equivalent to the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FE 999049 | Total Gonadotropin Dose | 90 µg of dose | Standard Deviation 25.3 |
| GONAL-F | Total Gonadotropin Dose | 103.7 µg of dose | Standard Deviation 33.6 |
Comparison: Treatment comparison: Total gonadotropin dosep-value: <0.001van Elteren
Secondary
Vital Pregnancy Rate
Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after blastocyst transfer.
Time frame: 5-6 weeks after blastocyst transfer
Population: mITT analysis set (all randomised and exposed subjects). This is equivalent to the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE 999049 | Vital Pregnancy Rate | 31.7 Percentage of subjects |
| GONAL-F | Vital Pregnancy Rate | 33.4 Percentage of subjects |
Comparison: Treatment groups were compared using a two-sided 95% CI derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (\<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.95% CI: [-6.7, 3.4]