MENOPUR in Gonadotrophin-releasing Hormone (GnRH) Antagonist Cycles With Single Embryo Transfer (MEGASET)

• Ongoing Pregnancy After One Fresh Embryo Replacement Cycle, Intention-to-treat (ITT) Analysis Set [ Time Frame: 10-11 weeks after embryo transfer at the blastocyst stage ] [ Designated as safety issue: No ]
  Transvaginal ultrasound showing at least one intrauterine viable fetus 10-11 weeks after embryo transfer at the blastocyst stage
  
  
• Ongoing Pregnancy After One Fresh Embryo Replacement Cycle, Per-protocol (PP) Analysis Set [ Time Frame: 10-11 weeks after embryo transfer at the blastocyst stage ] [ Designated as safety issue: No ]
  Transvaginal ultrasound showing at least one intrauterine viable fetus 10-11 weeks after embryo transfer at the blastocyst stage
  
  

• Endocrine Profile (Estradiol), Intention-to-treat (ITT) Analysis Set [ Time Frame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist ] [ Designated as safety issue: No ]
  Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
  
  
• Endocrine Profile (FSH), Intention-to-treat (ITT) Analysis Set [ Time Frame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist ] [ Designated as safety issue: No ]
  Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
  
  
• Endocrine Profile (Free Androgen Index), Intention-to-treat (ITT) Analysis Set [ Time Frame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist ] [ Designated as safety issue: No ]
  Blood samples for analysis of circulating concentrations of endocrine parameters were drawn. Free androgen index = (testosterone (nmol/L)/ sex hormone binding globulin (nmol/L))*100
  
  
• Endocrine Profile (Luteinizing Hormone), Intention-to-treat (ITT) Analysis Set [ Time Frame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist ] [ Designated as safety issue: No ]
  Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
  
  
• Endocrine Profile (Progesterone), Intention-to-treat (ITT) Analysis Set [ Time Frame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist ] [ Designated as safety issue: No ]
  Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
  
  
• Endocrine Profile (Prolactin), Intention-to-treat (ITT) Analysis Set [ Time Frame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist ] [ Designated as safety issue: No ]
  Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
  
  
• Endocrine Profile (Sex Hormone Binding Globulin), Intention-to-treat (ITT) Analysis Set [ Time Frame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist ] [ Designated as safety issue: No ]
  Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
  
  
• Endocrine Profile (Testosterone), Intention-to-treat (ITT) Analysis Set [ Time Frame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist ] [ Designated as safety issue: No ]
  Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
  
  
• Number of Follicles of >= 12mm, 12-14 mm, 15-16 mm and >= 17 mm in Each Participant, Intention-to-treat (ITT) Analysis Set [ Time Frame: Last stimulation day ] [ Designated as safety issue: No ]
  During the controlled ovarian stimulation, transvaginal ultrasound was performed to count the number of follicles and measure the size of the follicles.
  
  
• Number of Oocytes Retrieved in Each Participant, Intention-to-treat (ITT) Analysis Set [ Time Frame: 36 h after hCG ] [ Designated as safety issue: No ]
  Oocyte retrieval took place 36h (± 2h) after hCG administration. At oocyte retrieval, the number of oocytes retrieved was recorded.
  
  
• Fertilization, Intention-to-treat (ITT) Analysis Set [ Time Frame: 1 day after oocyte retrieval (19 h post-insemination) ] [ Designated as safety issue: No ]
  Fertilized oocytes with 2 pronuclei were regarded as correctly fertilized. Fertilization was estimated as (Number of oocytes with 2 pronuclei / number of metaphase II oocytes)*100
  
  
• Blastocyst Quality, Intention-to-treat (ITT) Analysis Set [ Time Frame: 5 days after oocyte retrieval (120h post-insemination) ] [ Designated as safety issue: No ]

  Blastocyst quality on day 5 was based on the blastocyst expansion and hatching status, inner cell mass grading and trophectoderm grading.

  Excellent-quality blastocysts were defined as those with blastocyst expansion and hatching status 4, 5 or 6, inner cell mass grading A, and trophectoderm grading A or B. Good-quality blastocysts were defined as those with blastocyst expansion and hatching status 3, 4, 5 or 6, inner cell mass grading A or B, and trophectoderm grading A or B.

  
  
• Live Birth for a Single Stimulation Cycle With Single Blastocyst Transfer From Fresh Embryo Replacement Cycle, Intention-to-treat (ITT) Analysis Set [ Time Frame: Post-trial information ] [ Designated as safety issue: No ]
  
• Cumulative Live Birth for a Single Stimulation Cycle With Single Blastocyst Transfer From Fresh and 1 Year Frozen Embryo Replacement Cycles, Intention-to-treat (ITT) Analysis Set [ Time Frame: Post-trial information ] [ Designated as safety issue: No ]
  

This was a randomized, open-label, assessor-blind, parallel groups, multicentre trial comparing the efficacy of highly purified menotrophin (MENOPUR; Ferring) and recombinant FSH (PUREGON/FOLLISTIM; MSD/Merck) in women undergoing controlled ovarian stimulation following a GnRH antagonist protocol.

The use of oral contraceptives for programming of the trial cycle was prohibited. On day 2-3 of the menstrual cycle, participants were randomized in a 1:1 fashion to treatment with either highly purified menotrophin (MENOPUR) or recombinant FSH, and stimulation was initiated.

The gonadotrophin starting dose was 150 international units (IU) daily for the first 5 days. Hereafter, the participants were seen on stimulation day 6 and subsequently at least every 2 days when a transvaginal ultrasound was made to monitor response to stimulation. From stimulation day 6 and onwards, dosing could be adjusted according to individual patient response with the purpose of achieving 8-10 oocytes at the time of oocyte retrieval. The dose adjustment could be by 75 IU per adjustment and could not be done more frequently than every 4 days. The maximum allowed gonadotrophin dose was 375 IU daily and participants could be treated with gonadotrophin for a maximum of 20 days. Coasting was prohibited.

The GnRH antagonist (ORGALUTRAN/GANIRELIX ACETATE INJECTION; MSD/Merck) was initiated on stimulation day 6 at a daily dose of 0.25 mg and continued throughout the gonadotrophin treatment period. A single injection of recombinant human chorionic gonadotrophin (hCG) 250 µg (OVITRELLE/OVIDREL; Merck Serono/EMD Serono) was administered to induce final follicular maturation as soon as 3 follicles of ≥ 17 mm were observed; i.e., the day of reaching the hCG criterion or the next day. Oocyte retrieval took place 36h (± 2h) after hCG administration. Oocytes were inseminated using partner sperm by intracytoplasmic sperm injection (ICSI) 4h (± 1h) after retrieval. Oocyte, embryo and blastocyst quality was assessed daily from oocyte retrieval till 5 days after. On day 5 after oocyte retrieval, a single blastocyst of the best quality available was transferred and all remaining blastocysts were frozen. Vaginal progesterone capsules (UTROGESTAN; Seid) 600 mg/day were provided for luteal phase support from the day after oocyte retrieval till the day of the beta human chorionic gonadotrophin (βhCG) test (13-15 days after embryo transfer); prolonged luteal phase support beyond this time point was not allowed. Clinical pregnancy was confirmed by transvaginal ultrasound 5-6 weeks after embryo transfer and ongoing pregnancy was confirmed by transvaginal ultrasound 10-11 weeks after embryo transfer. Post-trial follow-up included pregnancy outcome (e.g. live birth) and neonatal health from the fresh trial cycle. Additional post-trial activities included follow-up of frozen embryo replacement cycles initiated within 1 year after the participant's randomization date.