Infertility
Conditions
Keywords
Healthy, pre-menopausal women, age 18-42 with a history of infertility and requiring IVF
Brief summary
To compare the efficacy and safety of highly purified menotropin (Menopur®) with that of follitropin beta (FOLLISTIM®) in patients who are undergoing gonadotropin-releasing hormone (GnRH) antagonist in vitro fertilization (IVF) cycles
Detailed description
This multicenter, randomized, open-label exploratory study will be performed in approximately 200 healthy females undergoing in vitro fertilization (IVF). Each study center will follow its study center standard practice for in vitro fertilization (IVF) within the study parameters as noted in this protocol. The study centers will use marketed products purchased from Schraft's Pharmacy for all phases of the study (down-regulation, stimulation, ovulation induction, and luteal support). Subjects will be randomly assigned prior to the start of stimulation to highly purified menotropin (Menopur®) or follitropin beta (Follistim Pen®) for stimulation and progesterone vaginal insert (Endometrin®) or progesterone in oil for luteal support. Subjects will return to the study center for regular scheduled clinic visits as required per in vitro fertilization (IVF) protocol at the site and at specified time periods during the cycle for estradiol (E2), progesterone (P4) and human chorionic gonadotropin (hCG) tests, and first serum pregnancy test. All subjects will be required to complete a final study visit at completion of luteal support or negative serum pregnancy test following embryo transfer.
Interventions
DRUGMenotropin
225 IU (up to 450 IU) by subcutaneous injection once per day for up to about 15 days until human chorionic gonadotropin (hCG) criteria are met.
DRUGProgestrone vaginal insert
100 mg progesterone vaginal insert 2 or 3 times daily (BID or TID) (start on the day after oocyte retrieval) until 10 weeks gestation or confirmation of negative pregnancy test.
DRUGfollitropin beta
225 IU (up to 450 IU) by subcutaneous injection once per day for up to about 15 days until human chorionic gonadotropin (hCG) criteria are met.
50 mg by intramuscular injection once per day, starting on the day after oocyte retrieval until 10 weeks gestation or confirmation of negative pregnancy test.
DRUGGanirelix
Ganirelix acetate 250 µg as a daily subcutaneous injection starting on day 6 and continuing until hCG criteria were met.
Sponsors
Ferring Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 42 Years
Healthy volunteers
No
Inclusion criteria
1. Pre-menopausal females between the ages of 18 and 42 years 2. Body mass index (BMI) of 18-34 3. Early follicular phase (day 2-4) Follicle stimulating hormone (FSH) \<15 IU/L and Estradiol (E2) within normal limits 4. Documented history of infertility (e.g., unable to conceive for at least one year, or for 6 months for women \>38 years of age, or bilateral tubal occlusion or absence, or male factor but excluding severe male factor requiring invasive or surgical sperm retrieval. Donor sperm may be used.) 5. Transvaginal ultrasound at screening consistent with findings adequate for assisted reproductive technology (ART) with respect to uterus and adnexa 6. Signed informed consent
Exclusion criteria
1. Gestational or surrogate carrier, donor oocyte 2. Presence of any clinically relevant systemic disease (e.g., insulin-dependent diabetes mellitus, uterine cancer) 3. Surgical or medical condition which, in the judgment of the Investigator or Sponsor, may interfere with absorption, distribution, metabolism, or excretion of the drugs to be used 4. 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 in vitro fertilization (IVF) cycles. 5. History of recurrent pregnancy loss (\>2). 6. Presence of abnormal uterine bleeding of undetermined origin 7. Current or recent substance abuse, including alcohol or smoking \>10 cigarettes per day 8. Refusal or inability to comply with the requirements of the Protocol for any reason, including scheduled clinic visits and laboratory tests 9. Participation in any experimental drug study within 30 days prior to Screening 10. Severe male factor requiring invasive or surgical sperm retrieval (e.g., microsurgical epididymal sperm aspiration \[MESA\], testicular sperm extraction \[TESE\])
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Ongoing Pregnancy at Week 8 | Week 8 (Week 6 of gestation) | The ongoing pregnancy was defined as a positive fetal heart movement (motion) at approximately six weeks of gestation and confirmed in a follow-up pregnancy ultrasound. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Oocytes Retrieved at Day 18 | Approximately Day 18 | The mean number of oocytes retrieved within 34-36 hours of human chorionic gonadotropin (hCG) administration. |
| Proportion of Oocytes Fertilized of the Total Number of Oocytes Retrieved | Approximately Day 19 | The proportion of the number of oocytes inseminated (fertilized) of the total number of oocytes retrieved. |
| Number of Embryos Transferred at Three Stages of Development | Approximately Day 24 | The number of embryos, morula and blastocytes transferred to the study participant on either day 3 or day 5 following fertilization. |
| Number of Embryos Frozen at Day 24 | Approximately Day 24 | The number of embryos that were not transferred but instead were frozen for future use. |
| Number of Follicles Observed at Day 15 | Day 15 | The mean number of follicles observed in both ovaries at the last transvaginal ultrasound in the stimulation phase. |
| Participants With Biochemical Pregnancy at Day 38 | approximately day 38 (Day 14 post embryo transfer) | Biochemical pregnancy is a positive β-hCG pregnancy test 12-14 days post embryo transfer. |
| Participants With Clinical Pregnancy at Week 7 | approximately week 7 | Clinical pregnancy is the confirmation of the presence of intrauterine gestational sacs on pregnancy ultrasound examination. |
| Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Day 1 - week 12 | Number of participants with adverse events (AEs) that started after first treatment. Severity used a three point scale: mild=awareness of signs/symptoms, but no disruption of usual activity moderate=event sufficient to affect usual activity (disturbing) severe=event causes inability to work or perform usual activities (unacceptable) Relatedness to study treatment used a four point scale: unrelated, unlikely, possible, probable. Seriousness refers to death, hospitalization, a life-threatening experience, persistent or significant disability/incapacity, or congenital anomaly. |
| Number of Live Births | Approximately 10 months | — |
| Participants With Cycle Cancellation Following One In Vitro Fertilization (IVF) Treatment Cycle | Day 1 to Day 24 | A count of participants whose discontinuation was clearly documented on the study completion/termination form as 1) due to cycle cancelled or 2) cycle cancellation for risk of ovarian hyperstimulation syndrome (OHSS). |
Countries
United States
Participant flow
Recruitment details
One hundred ninety one (191) participants were screened from 6 study centers in the US; 173 of these participants were eligible for randomization. Six subjects did not receive their respected treatment and two subjects withdrew consent, 165 subjects were included in the statistical analyses
Participants by arm
| Arm | Count |
|---|---|
| Menopur/Endometrin Highly purified menotropin (Menopur®) 225 IU by subcutaneous injection once per day from day 1-6 of menstrual cycle. May be adjusted up to 450 IU daily for more days until human chorionic gonadotropin (hCG) criteria are met.
Progesterone vaginal insert (Endometrin®) 100 mg inserted vaginally 2 or 3 times daily (BID or TID) starts on the day following oocyte retrieval and continues for a total duration of 10 weeks or until a negative pregnancy test is obtained. | 42 |
| Menopur/Progesterone in Oil Highly purified menotropin 225 IU by subcutaneous injection once per day from day 1-6 of menstrual cycle. May be adjusted up to 450 IU daily for more days until human chorionic gonadotropin (hCG) criteria are met.
Progesterone in oil injections 50 mg by intramuscular injection (IM) once per day start on the day following oocyte retrieval and continue for a total duration of 10 weeks or until a negative pregnancy test is obtained. | 42 |
| Follistim/Endometrin Follitropin beta (Follistim®) 225 IU (up to 450 IU) by subcutaneous injection once per day from day 1-6 of menstrual cycle. May be adjusted up to 450 IU daily for more days until human chorionic gonadotropin (hCG) criteria are met.
Progesterone vaginal insert (Endometrin®) 100 mg inserted vaginally 2 or 3 times daily (BID or TID) starts on the day following oocyte retrieval and continues for a total duration of 10 weeks or until a negative pregnancy test is obtained. | 42 |
| Follistim/Progesterone in Oil Follitropin beta (Follistim®) 225 IU (up to 450 IU) by subcutaneous injection once per day from day 1-6 of menstrual cycle. May be adjusted up to 450 IU daily for more days until human chorionic gonadotropin (hCG) criteria are met.
Progesterone in oil injections 50 mg by intramuscular injection (IM) once per day start on the day following oocyte retrieval and continue for a total duration of 10 weeks or until a negative pregnancy test is obtained. | 39 |
| Total | 165 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Cycle cancelled | 0 | 1 | 1 | 1 |
| Overall Study | Inadequate number of oocytes retrieved | 0 | 0 | 0 | 1 |
| Overall Study | No positive serum pregnancy | 17 | 20 | 14 | 10 |
| Overall Study | Other | 2 | 3 | 6 | 3 |
| Overall Study | Pregnancy loss/miscarriage | 0 | 2 | 0 | 3 |
| Overall Study | Pregnancy not confirmed by ultrasound | 1 | 0 | 1 | 0 |
| Overall Study | Risk of ovarian hyperstimulation syndrom | 0 | 0 | 0 | 1 |
| Overall Study | Stimulation failure | 4 | 0 | 3 | 3 |
Baseline characteristics
| Characteristic | Menopur/Progesterone in Oil | Menopur/Endometrin | Total | Follistim/Progesterone in Oil | Follistim/Endometrin |
|---|---|---|---|---|---|
| Age Continuous | 33.2 years STANDARD_DEVIATION 4.8 | 33.5 years STANDARD_DEVIATION 4.1 | 33.9 years STANDARD_DEVIATION 7.4 | 33.9 years STANDARD_DEVIATION 4.3 | 34.0 years STANDARD_DEVIATION 4.3 |
| Body Mass Index (BMI) | 23.8 kg/m^2 STANDARD_DEVIATION 3 | 24.6 kg/m^2 STANDARD_DEVIATION 4.1 | 24.6 kg/m^2 STANDARD_DEVIATION 3.8 | 25.6 kg/m^2 STANDARD_DEVIATION 4.5 | 25.0 kg/m^2 STANDARD_DEVIATION 3.3 |
| Follicle-stimulating hormone level | 7.1 mIU/mL STANDARD_DEVIATION 2.2 | 7.4 mIU/mL STANDARD_DEVIATION 2.3 | 7.3 mIU/mL STANDARD_DEVIATION 2.3 | 6.9 mIU/mL STANDARD_DEVIATION 2.9 | 6.9 mIU/mL STANDARD_DEVIATION 2 |
| Race/Ethnicity, Customized African American | 1 Participants | 5 Participants | 10 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 4 Participants | 14 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Caucasian | 35 Participants | 32 Participants | 130 Participants | 32 Participants | 31 Participants |
| Race/Ethnicity, Customized Hispanic | 4 Participants | 1 Participants | 9 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Female | 42 Participants | 42 Participants | 165 Participants | 39 Participants | 42 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 42 | 18 / 42 | 18 / 42 | 21 / 39 |
| serious Total, serious adverse events | 0 / 42 | 1 / 42 | 1 / 42 | 0 / 39 |
Outcome results
Primary
Percentage of Participants With Ongoing Pregnancy at Week 8
The ongoing pregnancy was defined as a positive fetal heart movement (motion) at approximately six weeks of gestation and confirmed in a follow-up pregnancy ultrasound.
Time frame: Week 8 (Week 6 of gestation)
Population: Intent to treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Menopur | Percentage of Participants With Ongoing Pregnancy at Week 8 | 45.2 percentage of participants |
| Follistim | Percentage of Participants With Ongoing Pregnancy at Week 8 | 45.2 percentage of participants |
| Follistim/Endometrin | Percentage of Participants With Ongoing Pregnancy at Week 8 | 42.9 percentage of participants |
| Follistim/Progesterone in Oil | Percentage of Participants With Ongoing Pregnancy at Week 8 | 48.7 percentage of participants |
Secondary
Number of Embryos Frozen at Day 24
The number of embryos that were not transferred but instead were frozen for future use.
Time frame: Approximately Day 24
Population: Intend-to-treat (ITT) population -- all randomized participants who received at least one dose of study medication and had oocytes fertilized
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Menopur | Number of Embryos Frozen at Day 24 | 1.9 embryos | Standard Deviation 2.9 |
| Follistim | Number of Embryos Frozen at Day 24 | 1.6 embryos | Standard Deviation 2.5 |
Secondary
Number of Embryos Transferred at Three Stages of Development
The number of embryos, morula and blastocytes transferred to the study participant on either day 3 or day 5 following fertilization.
Time frame: Approximately Day 24
Population: Intend-to-treat (ITT) population -- all randomized participants who received at least one dose of study medication and had embryos transferred.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Menopur | Number of Embryos Transferred at Three Stages of Development | Number of Embryos transferred | 2.1 embryos | Standard Deviation 0.7 |
| Menopur | Number of Embryos Transferred at Three Stages of Development | Number of Morula transferred | 0.0 embryos | Standard Deviation 0.1 |
| Menopur | Number of Embryos Transferred at Three Stages of Development | Number of Blastocytes transferred | 0.9 embryos | Standard Deviation 1 |
| Follistim | Number of Embryos Transferred at Three Stages of Development | Number of Embryos transferred | 2.4 embryos | Standard Deviation 0.7 |
| Follistim | Number of Embryos Transferred at Three Stages of Development | Number of Morula transferred | 0.1 embryos | Standard Deviation 0.4 |
| Follistim | Number of Embryos Transferred at Three Stages of Development | Number of Blastocytes transferred | 0.9 embryos | Standard Deviation 1 |
Secondary
Number of Follicles Observed at Day 15
The mean number of follicles observed in both ovaries at the last transvaginal ultrasound in the stimulation phase.
Time frame: Day 15
Population: Intend-to-treat (ITT) population -- all randomized participants who received at least one dose of study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Menopur | Number of Follicles Observed at Day 15 | 15.6 follicles | Standard Deviation 8.6 |
| Follistim | Number of Follicles Observed at Day 15 | 16.2 follicles | Standard Deviation 8.4 |
Secondary
Number of Live Births
Time frame: Approximately 10 months
Population: Database was locked prior to all participants giving birth.
Secondary
Number of Oocytes Retrieved at Day 18
The mean number of oocytes retrieved within 34-36 hours of human chorionic gonadotropin (hCG) administration.
Time frame: Approximately Day 18
Population: Intend-to-treat (ITT) population -- all randomized participants who received at least one dose of study medication and had oocytes retrieved.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Menopur | Number of Oocytes Retrieved at Day 18 | 11.5 oocytes | Standard Deviation 6.3 |
| Follistim | Number of Oocytes Retrieved at Day 18 | 13.8 oocytes | Standard Deviation 7.9 |
Secondary
Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS)
Number of participants with adverse events (AEs) that started after first treatment. Severity used a three point scale: mild=awareness of signs/symptoms, but no disruption of usual activity moderate=event sufficient to affect usual activity (disturbing) severe=event causes inability to work or perform usual activities (unacceptable) Relatedness to study treatment used a four point scale: unrelated, unlikely, possible, probable. Seriousness refers to death, hospitalization, a life-threatening experience, persistent or significant disability/incapacity, or congenital anomaly.
Time frame: Day 1 - week 12
Population: Safety population all randomized and treated participants. The safety population is identical intent-to- treat (ITT) population in this study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Menopur | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | With at least one adverse event | 20 participants |
| Menopur | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Mild or moderate adverse event | 20 participants |
| Menopur | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Severe adverse event | 1 participants |
| Menopur | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Serious adverse event | 0 participants |
| Menopur | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Unrelated or unlikely adverse event | 15 participants |
| Menopur | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Possibly or probably related adverse event | 10 participants |
| Follistim | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Possibly or probably related adverse event | 8 participants |
| Follistim | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Serious adverse event | 1 participants |
| Follistim | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | With at least one adverse event | 18 participants |
| Follistim | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Severe adverse event | 0 participants |
| Follistim | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Mild or moderate adverse event | 18 participants |
| Follistim | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Unrelated or unlikely adverse event | 13 participants |
| Follistim/Endometrin | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Mild or moderate adverse event | 18 participants |
| Follistim/Endometrin | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Severe adverse event | 2 participants |
| Follistim/Endometrin | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Serious adverse event | 1 participants |
| Follistim/Endometrin | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Possibly or probably related adverse event | 7 participants |
| Follistim/Endometrin | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Unrelated or unlikely adverse event | 17 participants |
| Follistim/Endometrin | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | With at least one adverse event | 18 participants |
| Follistim/Progesterone in Oil | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Unrelated or unlikely adverse event | 14 participants |
| Follistim/Progesterone in Oil | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Possibly or probably related adverse event | 15 participants |
| Follistim/Progesterone in Oil | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Mild or moderate adverse event | 21 participants |
| Follistim/Progesterone in Oil | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Serious adverse event | 0 participants |
| Follistim/Progesterone in Oil | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | With at least one adverse event | 21 participants |
| Follistim/Progesterone in Oil | Participants With Adverse Events (AEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Severe adverse event | 0 participants |
Secondary
Participants With Biochemical Pregnancy at Day 38
Biochemical pregnancy is a positive β-hCG pregnancy test 12-14 days post embryo transfer.
Time frame: approximately day 38 (Day 14 post embryo transfer)
Population: Intent-to-treat (ITT) population -- all randomized participants who received at least one dose of study medication and had an embryo transfer
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Menopur | Participants With Biochemical Pregnancy at Day 38 | 21 participants |
| Follistim | Participants With Biochemical Pregnancy at Day 38 | 20 participants |
| Follistim/Endometrin | Participants With Biochemical Pregnancy at Day 38 | 22 participants |
| Follistim/Progesterone in Oil | Participants With Biochemical Pregnancy at Day 38 | 23 participants |
Secondary
Participants With Clinical Pregnancy at Week 7
Clinical pregnancy is the confirmation of the presence of intrauterine gestational sacs on pregnancy ultrasound examination.
Time frame: approximately week 7
Population: Intent-to-treat (ITT) population -- all randomized participants who received at least one dose of study medication and had an embryo transfer
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Menopur | Participants With Clinical Pregnancy at Week 7 | 19 participants |
| Follistim | Participants With Clinical Pregnancy at Week 7 | 19 participants |
| Follistim/Endometrin | Participants With Clinical Pregnancy at Week 7 | 18 participants |
| Follistim/Progesterone in Oil | Participants With Clinical Pregnancy at Week 7 | 20 participants |
Secondary
Participants With Cycle Cancellation Following One In Vitro Fertilization (IVF) Treatment Cycle
A count of participants whose discontinuation was clearly documented on the study completion/termination form as 1) due to cycle cancelled or 2) cycle cancellation for risk of ovarian hyperstimulation syndrome (OHSS).
Time frame: Day 1 to Day 24
Population: Intend-to-treat (ITT) population -- all randomized participants who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Menopur | Participants With Cycle Cancellation Following One In Vitro Fertilization (IVF) Treatment Cycle | 0 participants |
| Follistim | Participants With Cycle Cancellation Following One In Vitro Fertilization (IVF) Treatment Cycle | 1 participants |
| Follistim/Endometrin | Participants With Cycle Cancellation Following One In Vitro Fertilization (IVF) Treatment Cycle | 1 participants |
| Follistim/Progesterone in Oil | Participants With Cycle Cancellation Following One In Vitro Fertilization (IVF) Treatment Cycle | 2 participants |
Secondary
Proportion of Oocytes Fertilized of the Total Number of Oocytes Retrieved
The proportion of the number of oocytes inseminated (fertilized) of the total number of oocytes retrieved.
Time frame: Approximately Day 19
Population: Intend-to-treat (ITT) population -- all randomized participants who received at least one dose of study medication and had oocytes retrieved.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Menopur | Proportion of Oocytes Fertilized of the Total Number of Oocytes Retrieved | 0.3 proportion of oocytes retrieved | Standard Deviation 0.4 |
| Follistim | Proportion of Oocytes Fertilized of the Total Number of Oocytes Retrieved | 0.3 proportion of oocytes retrieved | Standard Deviation 0.4 |