MENOPUR® Versus FOLLISTIM®

• Number of Follicles Observed at Day 15 [ Time Frame: Day 15 ] [ Designated as safety issue: No ]
  The mean number of follicles observed in both ovaries at the last transvaginal ultrasound in the stimulation phase.
• Number of Oocytes Retrieved at Day 18 [ Time Frame: Approximately Day 18 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Approximately Day 19 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Approximately Day 24 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Approximately Day 24 ] [ Designated as safety issue: No ]
  The number of embryos that were not transferred but instead were frozen for future use.
• Participants With Cycle Cancellation Following One In Vitro Fertilization (IVF) Treatment Cycle [ Time Frame: Day 1 to Day 24 ] [ Designated as safety issue: No ]
  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).
• Participants With Biochemical Pregnancy at Day 38 [ Time Frame: approximately day 38 (Day 14 post embryo transfer) ] [ Designated as safety issue: No ]
  Biochemical pregnancy is a positive β-hCG pregnancy test 12-14 days post embryo transfer.
• Participants With Clinical Pregnancy at Week 7 [ Time Frame: approximately week 7 ] [ Designated as safety issue: No ]
  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) [ Time Frame: Day 1 - week 12 ] [ Designated as safety issue: Yes ]

  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 [ Time Frame: Approximately 10 months ] [ Designated as safety issue: No ]

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

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.

• Drug: Menotropin
  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.
  Other Names:

  • highly purified menotropins
  • Menopur®
  • hMG
• Drug: Progestrone 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.
  Other Names:

  • progesterone
  • Endometrin®
• Drug: follitropin 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.
  Other Names:

  • follitropin beta
  • Follistim Pen®
  • Follistim®
• Drug: Progesterone in oil
  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.
• Drug: Ganirelix
  Ganirelix acetate 250 µg as a daily subcutaneous injection starting on day 6 and continuing until hCG criteria were met.
  Other Names:

  • ganirelix acetate
  • GnRH antagonist

• Experimental: Menopur/Endometrin

  Highly purified menotropin (Menopur®) 225 IU 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.

  Progestrone vaginal insert (Endometrin®) starts on the day following oocyte retrieval and continues for a total duration of 10 weeks or until a negative pregnancy test is obtained.

  Interventions:

  • Drug: Menotropin
  • Drug: Progestrone vaginal insert
  • Drug: Ganirelix
• Experimental: Menopur/Progesterone in Oil

  Highly purified menotropin (Menopur®) 225 IU 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 start on the day following oocyte retrieval and continue for a total duration of 10 weeks or until a negative pregnancy test is obtained.

  Interventions:

  • Drug: Menotropin
  • Drug: Progesterone in oil
  • Drug: Ganirelix
• Active Comparator: Follistim/Endometrin

  Follitropin beta (Follistim®) 225 IU 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.

  Progestrone vaginal insert (Endometrin®) starts on the day following oocyte retrieval and continues for a total duration of 10 weeks or until a negative pregnancy test is obtained.

  Interventions:

  • Drug: Progestrone vaginal insert
  • Drug: follitropin beta
  • Drug: Ganirelix
• Active Comparator: Follistim/Progesterone in Oil

  Follitropin beta (Follistim®) 225 IU 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 start on the day following oocyte retrieval and continue for a total duration of 10 weeks or until a negative pregnancy test is obtained.

  Interventions:

  • Drug: follitropin beta
  • Drug: Progesterone in oil
  • Drug: Ganirelix

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])