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

A Randomized, Open-label, Assessor-blind, Parallel Groups, Multicentre Trial Comparing the Efficacy of MENOPUR Versus Recombinant FSH in Controlled Ovarian Stimulation Following a GnRH Antagonist Protocol and Single Embryo Transfer

The main purpose of this clinical research trial was to compare the ongoing pregnancy rate between two gonadotrophins for controlled ovarian stimulation (MENOPUR and recombinant follicle-stimulating hormone (FSH)), in cycles where a gonadotrophin-releasing hormone (GnRH) antagonist was used for prevention of premature luteinizing hormone (LH) surge and where a single embryo was transferred at the blastocyst stage.

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.

Inclusion criteria:

• Informed Consent Documents signed prior to screening evaluations
• In good physical and mental health
• Pre-menopausal females 21-34 years of age
• Body mass index (BMI)18-25 kg/m2
• Eligible for intracytoplasmic sperm injection (ICSI)
• Unexplained infertility or partner with mild male factor infertility
• Infertility for at least 12 months before randomization
• Regular menstrual cycles of 24-35 days, presumed to be ovulatory
• Hysterosalpingography, hysteroscopy, or transvaginal ultrasound documenting a uterus consistent with expected normal function
• Transvaginal ultrasound documenting expected normal function of the ovaries
• Early follicular phase serum levels of FSH between 1 and 12 IU/L
• Early follicular phase total antral follicle (diameter 2-10 mm) count ≥ 10 for both ovaries combined
• Willing to accept transfer of one blastocyst in the fresh cycle
• Willing to undergo frozen embryo replacement cycles with transfer of one blastocyst per cycle within the first year after randomisation

Exclusion criteria:

• Known polycystic ovarian syndrome or known endometriosis stage I-IV
• Diagnosed as "poor responder" in a previous controlled ovarian stimulation (COS) cycle
• Severe ovarian hyperstimulation syndrome (OHSS)in a previous COS cycle
• History of recurrent miscarriage
• Current or past (12 months prior to randomization) abuse of alcohol or drugs, and/or current (last month) intake of more than 14 units of alcohol per week
• Current or past smoking habit of more than 10 cigarettes per day
• Hypersensitivity to any active ingredient or excipients in the medicinal products used in the trial
• Hypersensitivity to gonadotrophin-releasing hormone (GnRH) or any other GnRH analogue
• Previous participation in the trial
• Use of any non registered investigational drugs during 3 months before randomization