Infertility
Conditions
Brief summary
The purpose of this trial is to demonstrate non-inferiority of MENOPUR® versus recombinant Follicle Stimulating Hormone (rFSH) (Gonal-f®) with respect to ongoing pregnancy rate in women undergoing controlled ovarian stimulation (COS) following GnRH treatment.
Interventions
DRUGmenotropin
DRUGrecombinant FSH
Sponsors
Ferring Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
21 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
* Females aged 21 to 35 years with regular ovulatory menstrual cycles of 21 to 45 days, with a Body Mass Index (BMI) between 18 and 30 kg/m2 who desire pregnancy. * Subjects must be high responders, defined as subjects who have a serum anti-Müllerian hormone (AMH) ≥5 ng/mL at screening. * Documented history of infertility (e.g., unable to conceive for at least 12 months or for at least 6 months if receiving donor sperm) with a Day 2 or Day 3 serum FSH level between 1 and 12 IU/L (inclusive), the results of which should be obtained within 6 months prior to randomization.
Exclusion criteria
* Known stage III-IV endometriosis (American Society for Reproductive Medicine, 2012). * History of recurrent miscarriage not followed by a live birth (recurrent is defined as two (2) or more consecutive miscarriages). * Previous in vitro fertilization (IVF) or assisted reproductive technology (ART) failure due to a poor response to gonadotropins. Poor response is defined as development of ≤2 mature follicles or history of 2 previous failed cycle cancellations prior to oocytes retrieval due to poor response.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ongoing Pregnancy Rate | 8-9 weeks after blastocyst transfer in the fresh cycle | Defined as the percentage of participants with the presence of at least 1 intrauterine pregnancy with a detectable fetal heartbeat at 10-11 weeks of gestation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Positive β-human Chorionic Gonadotropin (hCG) Rate | First test approximately 10-14 days after blastocyst transfer in the fresh cycle, with a second test approximately 2 days later if first test was positive | Defined as the percentage of participants with 2 positive β-hCG tests within 2 days in serum. |
| Clinical Pregnancy Rate | 4-5 weeks after blastocyst transfer in the fresh cycle | Defined as percentage of participants with transvaginal ultrasound (TVUS) showing at least 1 intrauterine gestational sac with fetal heart beat at 6-7 weeks of gestation. |
| Early Pregnancy Loss | At 10-11 weeks of gestation in the fresh cycle | Defined as participants with 2 positive β-hCG tests but no ongoing pregnancy at 10-11 weeks of gestation in the fresh cycle. Percentage of participants with early pregnancy loss is presented. |
| Number of Oocytes Retrieved | At oocyte retrieval visit (approximately 36 hours after hCG administration) | — |
| Number of Metaphase II Oocytes | At oocyte retrieval visit (approximately 36 hours after hCG administration) | — |
| Fertilization Rate | On day 1 post-insemination | Defined as 100 times the ratio of number of fertilized 2 pronuclei oocytes to the number of oocytes retrieved, for each participant. |
| Quality of Embryos | 3 days after oocyte retrieval | Assessed by blastomere uniformity, cell size, the degree of fragmentation, and visual signs of multinucleation. |
| Quality of Blastocysts | 5 days after oocyte retrieval | Assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring was based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cell). |
| Follicular Development as Assessed by TVUS | On stimulation Day 6 and last day of stimulation (a maximum of 20 stimulation days) | Defined as average follicle size and average size of 3 largest follicles. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 31 infertility centers in the US between 31 Aug 2014 to 02 Feb 2017.
Participants by arm
| Arm | Count |
|---|---|
| Menotropin Menotropins for injection, provided as a vial with powder (75 IU FSH activity and 75 IU LH activity) and a vial with diluent. | 310 |
| Recombinant FSH Follitropin alpha for injection, human FSH preparation of recombinant DNA origin, provided as pen and cartridges filled with either 300 or 450 IU of FSH activity. | 309 |
| Total | 619 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 5 |
| Overall Study | Lost to Follow-up | 3 | 2 |
| Overall Study | Other reason | 19 | 6 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 4 |
Baseline characteristics
| Characteristic | Menotropin | Total | Recombinant FSH |
|---|---|---|---|
| Age, Continuous | 30.0 years STANDARD_DEVIATION 3.08 | 30.2 years STANDARD_DEVIATION 3.05 | 30.4 years STANDARD_DEVIATION 3.02 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 18 Participants | 51 Participants | 33 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants | 43 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 270 Participants | 514 Participants | 244 Participants |
| Region of Enrollment United States | 310 Participants | 619 Participants | 309 Participants |
| Sex: Female, Male Female | 310 Participants | 619 Participants | 309 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 / 310 | 0 / 309 |
| other Total, other adverse events | 179 / 310 | 218 / 309 |
| serious Total, serious adverse events | 8 / 310 | 11 / 309 |
Outcome results
Primary
Ongoing Pregnancy Rate
Defined as the percentage of participants with the presence of at least 1 intrauterine pregnancy with a detectable fetal heartbeat at 10-11 weeks of gestation.
Time frame: 8-9 weeks after blastocyst transfer in the fresh cycle
Population: The modified intent-to-treat (mITT) analysis set comprised all randomized participants who received at least 1 dose of investigational medicinal product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Menotropin | Ongoing Pregnancy Rate | 35.5 percentage of participants |
| Recombinant FSH | Ongoing Pregnancy Rate | 30.7 percentage of participants |
Comparison: Null hypothesis was defined as the difference between ongoing pregnancy rate of participants randomized and treated with menotropin and recombinant FSH, as ≤-12%.95% CI: [-2.7, 12.1]
Secondary
Clinical Pregnancy Rate
Defined as percentage of participants with transvaginal ultrasound (TVUS) showing at least 1 intrauterine gestational sac with fetal heart beat at 6-7 weeks of gestation.
Time frame: 4-5 weeks after blastocyst transfer in the fresh cycle
Population: The mITT analysis set comprised all randomized participants who received at least 1 dose of investigational medicinal product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Menotropin | Clinical Pregnancy Rate | 37.1 percentage of participants |
| Recombinant FSH | Clinical Pregnancy Rate | 33.3 percentage of participants |
95% CI: [-3.8, 11.3]
Secondary
Early Pregnancy Loss
Defined as participants with 2 positive β-hCG tests but no ongoing pregnancy at 10-11 weeks of gestation in the fresh cycle. Percentage of participants with early pregnancy loss is presented.
Time frame: At 10-11 weeks of gestation in the fresh cycle
Population: The mITT analysis set comprised all randomized participants who received at least 1 dose of investigational medicinal product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Menotropin | Early Pregnancy Loss | 14.3 percentage of participants |
| Recombinant FSH | Early Pregnancy Loss | 23.8 percentage of participants |
95% CI: [-19.2, 0.2]
Secondary
Fertilization Rate
Defined as 100 times the ratio of number of fertilized 2 pronuclei oocytes to the number of oocytes retrieved, for each participant.
Time frame: On day 1 post-insemination
Population: The mITT analysis set comprised all randomized participants who received at least 1 dose of investigational medicinal product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Menotropin | Fertilization Rate | 55.09 percentage of each participant | Standard Deviation 21.731 |
| Recombinant FSH | Fertilization Rate | 59.07 percentage of each participant | Standard Deviation 18.731 |
Secondary
Follicular Development as Assessed by TVUS
Defined as average follicle size and average size of 3 largest follicles.
Time frame: On stimulation Day 6 and last day of stimulation (a maximum of 20 stimulation days)
Population: The mITT analysis set comprised all randomized participants who received at least 1 dose of investigational medicinal product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Menotropin | Follicular Development as Assessed by TVUS | Average follicle size | 5.95 mm | Standard Deviation 1.682 |
| Menotropin | Follicular Development as Assessed by TVUS | Average size of 3 largest follicles | 9.69 mm | Standard Deviation 3.562 |
| Recombinant FSH | Follicular Development as Assessed by TVUS | Average size of 3 largest follicles | 12.17 mm | Standard Deviation 2.59 |
| Recombinant FSH | Follicular Development as Assessed by TVUS | Average follicle size | 7.45 mm | Standard Deviation 2.044 |
| Menotropin, Last Stimulation Day | Follicular Development as Assessed by TVUS | Average follicle size | 12.20 mm | Standard Deviation 3.328 |
| Menotropin, Last Stimulation Day | Follicular Development as Assessed by TVUS | Average size of 3 largest follicles | 21.36 mm | Standard Deviation 2.524 |
| Recombinant FSH, Last Stimulation Day | Follicular Development as Assessed by TVUS | Average follicle size | 13.28 mm | Standard Deviation 2.808 |
| Recombinant FSH, Last Stimulation Day | Follicular Development as Assessed by TVUS | Average size of 3 largest follicles | 21.09 mm | Standard Deviation 2.685 |
Secondary
Follicular Development as Assessed by TVUS
Defined as percentage of participants with follicles having a diameter of ≤9 mm, 10-11 mm, 12-14 mm, 15-16 mm, and ≥17 mm.
Time frame: On stimulation Day 6 and last day of stimulation (a maximum of 20 stimulation days)
Population: The mITT analysis set comprised all randomized participants who received at least 1 dose of investigational medicinal product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Menotropin | Follicular Development as Assessed by TVUS | Follicle size 15-16 mm | 12.6 percentage of participants |
| Menotropin | Follicular Development as Assessed by TVUS | Follicle size 10-11 mm | 73.8 percentage of participants |
| Menotropin | Follicular Development as Assessed by TVUS | Follicle size ≥17 mm | 5.2 percentage of participants |
| Menotropin | Follicular Development as Assessed by TVUS | Follicle size 12-14 mm | 50.2 percentage of participants |
| Menotropin | Follicular Development as Assessed by TVUS | Follicle size ≤9 mm | 99.0 percentage of participants |
| Recombinant FSH | Follicular Development as Assessed by TVUS | Follicle size 12-14 mm | 76.1 percentage of participants |
| Recombinant FSH | Follicular Development as Assessed by TVUS | Follicle size 15-16 mm | 24.9 percentage of participants |
| Recombinant FSH | Follicular Development as Assessed by TVUS | Follicle size ≥17 mm | 9.7 percentage of participants |
| Recombinant FSH | Follicular Development as Assessed by TVUS | Follicle size 10-11 mm | 93.2 percentage of participants |
| Recombinant FSH | Follicular Development as Assessed by TVUS | Follicle size ≤9 mm | 96.4 percentage of participants |
| Menotropin, Last Stimulation Day | Follicular Development as Assessed by TVUS | Follicle size 12-14 mm | 93.5 percentage of participants |
| Menotropin, Last Stimulation Day | Follicular Development as Assessed by TVUS | Follicle size ≤9 mm | 78.4 percentage of participants |
| Menotropin, Last Stimulation Day | Follicular Development as Assessed by TVUS | Follicle size 10-11 mm | 82.7 percentage of participants |
| Menotropin, Last Stimulation Day | Follicular Development as Assessed by TVUS | Follicle size 15-16 mm | 84.9 percentage of participants |
| Menotropin, Last Stimulation Day | Follicular Development as Assessed by TVUS | Follicle size ≥17 mm | 100 percentage of participants |
| Recombinant FSH, Last Stimulation Day | Follicular Development as Assessed by TVUS | Follicle size 15-16 mm | 96.3 percentage of participants |
| Recombinant FSH, Last Stimulation Day | Follicular Development as Assessed by TVUS | Follicle size 10-11 mm | 75.7 percentage of participants |
| Recombinant FSH, Last Stimulation Day | Follicular Development as Assessed by TVUS | Follicle size ≤9 mm | 69.9 percentage of participants |
| Recombinant FSH, Last Stimulation Day | Follicular Development as Assessed by TVUS | Follicle size 12-14 mm | 96.6 percentage of participants |
| Recombinant FSH, Last Stimulation Day | Follicular Development as Assessed by TVUS | Follicle size ≥17 mm | 100 percentage of participants |
Secondary
Number of Metaphase II Oocytes
Time frame: At oocyte retrieval visit (approximately 36 hours after hCG administration)
Population: The mITT analysis set comprised all randomized participants who received at least 1 dose of investigational medicinal product. The number of participants analyzed represent the participants with oocytes retrieved.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Menotropin | Number of Metaphase II Oocytes | 10.1 metaphase II oocytes | Standard Deviation 7.18 |
| Recombinant FSH | Number of Metaphase II Oocytes | 15.9 metaphase II oocytes | Standard Deviation 9.01 |
Secondary
Number of Oocytes Retrieved
Time frame: At oocyte retrieval visit (approximately 36 hours after hCG administration)
Population: The mITT analysis set comprised all randomized participants who received at least 1 dose of investigational medicinal product. The number of participants analyzed represent the participants with oocytes retrieved.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Menotropin | Number of Oocytes Retrieved | 15.1 oocytes | Standard Deviation 10.12 |
| Recombinant FSH | Number of Oocytes Retrieved | 22.2 oocytes | Standard Deviation 11.54 |
Secondary
Positive β-human Chorionic Gonadotropin (hCG) Rate
Defined as the percentage of participants with 2 positive β-hCG tests within 2 days in serum.
Time frame: First test approximately 10-14 days after blastocyst transfer in the fresh cycle, with a second test approximately 2 days later if first test was positive
Population: The mITT analysis set comprised all randomized participants who received at least 1 dose of investigational medicinal product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Menotropin | Positive β-human Chorionic Gonadotropin (hCG) Rate | 40.6 percentage of participants |
| Recombinant FSH | Positive β-human Chorionic Gonadotropin (hCG) Rate | 39.5 percentage of participants |
95% CI: [-6.6, 8.9]
Secondary
Quality of Blastocysts
Assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring was based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cell).
Time frame: 5 days after oocyte retrieval
Population: The mITT analysis set comprised all randomized participants who received at least 1 dose of investigational medicinal product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Menotropin | Quality of Blastocysts | Excellent quality | 28.3 percentage of embryos |
| Menotropin | Quality of Blastocysts | Good quality | 26.5 percentage of embryos |
| Menotropin | Quality of Blastocysts | Neither | 45.1 percentage of embryos |
| Menotropin | Quality of Blastocysts | Missing | 0.1 percentage of embryos |
| Recombinant FSH | Quality of Blastocysts | Missing | 1.0 percentage of embryos |
| Recombinant FSH | Quality of Blastocysts | Excellent quality | 30.7 percentage of embryos |
| Recombinant FSH | Quality of Blastocysts | Neither | 45.8 percentage of embryos |
| Recombinant FSH | Quality of Blastocysts | Good quality | 22.5 percentage of embryos |
Secondary
Quality of Embryos
Assessed by blastomere uniformity, cell size, the degree of fragmentation, and visual signs of multinucleation.
Time frame: 3 days after oocyte retrieval
Population: The mITT analysis set comprised all randomized participants who received at least 1 dose of investigational medicinal product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Menotropin | Quality of Embryos | Blastomere uniformity-Equally sized blastomeres | 63.1 percentage of embryos |
| Menotropin | Quality of Embryos | Cell size classification-Stage specific | 75.5 percentage of embryos |
| Menotropin | Quality of Embryos | Degree of fragmentation-≤10% | 81.1 percentage of embryos |
| Menotropin | Quality of Embryos | Multinucleation present | 0.7 percentage of embryos |
| Recombinant FSH | Quality of Embryos | Multinucleation present | 1.1 percentage of embryos |
| Recombinant FSH | Quality of Embryos | Blastomere uniformity-Equally sized blastomeres | 59.0 percentage of embryos |
| Recombinant FSH | Quality of Embryos | Degree of fragmentation-≤10% | 81.0 percentage of embryos |
| Recombinant FSH | Quality of Embryos | Cell size classification-Stage specific | 70.8 percentage of embryos |
Secondary
Quality of Embryos
Assessed by cleavage stage.
Time frame: 3 days after oocyte retrieval
Population: The mITT analysis set comprised all randomized participants who received at least 1 dose of investigational medicinal product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Menotropin | Quality of Embryos | 7.5 blastomeres | Standard Deviation 2.28 |
| Recombinant FSH | Quality of Embryos | 7.4 blastomeres | Standard Deviation 2.32 |