Clinical trial NCT00884221: MENOPUR in Gonadotrophin-releasing Hormone (GnRH) Antagonist Cycles With Single Embryo Transfer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infertility
Lead sponsor: Ferring Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2009-04-20
Enrollment: 749
Sex: FEMALE
Minimum age (years): 21
Maximum age (years): 34
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Ongoing Pregnancy After One Fresh Embryo Replacement Cycle, Intention-to-treat (ITT) Analysis Set
timeFrame: 10-11 weeks after embryo transfer at the blastocyst stage
measure: Ongoing Pregnancy After One Fresh Embryo Replacement Cycle, Per-protocol (PP) Analysis Set
timeFrame: 10-11 weeks after embryo transfer at the blastocyst stage
Secondary outcomes:
measure: Endocrine Profile (Estradiol), Intention-to-treat (ITT) Analysis Set
timeFrame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist
measure: Endocrine Profile (FSH), Intention-to-treat (ITT) Analysis Set
timeFrame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist
measure: Endocrine Profile (Free Androgen Index), Intention-to-treat (ITT) Analysis Set
timeFrame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist
measure: Endocrine Profile (Luteinizing Hormone), Intention-to-treat (ITT) Analysis Set
timeFrame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist
measure: Endocrine Profile (Progesterone), Intention-to-treat (ITT) Analysis Set
timeFrame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist
measure: Endocrine Profile (Prolactin), Intention-to-treat (ITT) Analysis Set
timeFrame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist
measure: Endocrine Profile (Sex Hormone Binding Globulin), Intention-to-treat (ITT) Analysis Set
timeFrame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist
measure: Endocrine Profile (Testosterone), Intention-to-treat (ITT) Analysis Set
timeFrame: On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist
measure: Number of Follicles of >= 12mm, 12-14 mm, 15-16 mm and >= 17 mm in Each Participant, Intention-to-treat (ITT) Analysis Set
timeFrame: Last stimulation day
measure: Number of Oocytes Retrieved in Each Participant, Intention-to-treat (ITT) Analysis Set
timeFrame: 36 h after hCG
measure: Fertilization, Intention-to-treat (ITT) Analysis Set
timeFrame: 1 day after oocyte retrieval (19 h post-insemination)
measure: Blastocyst Quality, Intention-to-treat (ITT) Analysis Set
timeFrame: 5 days after oocyte retrieval (120h post-insemination)
measure: Live Birth for a Single Stimulation Cycle With Single Blastocyst Transfer From Fresh Embryo Replacement Cycle, Intention-to-treat (ITT) Analysis Set
timeFrame: Post-trial information
measure: 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
timeFrame: Post-trial information
Other outcomes:
Locations:
city: Anderlecht
country: Belgium
facility: ERASME Hospital
city: Brussels
country: Belgium
facility: UZ Brussel
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Gent
country: Belgium
facility: UZ Gent
city: Pilsen
country: Czech Republic
facility: IVF Institute
city: Prague
country: Czech Republic
facility: ISCARE IVF a.s.
city: Prague
country: Czech Republic
facility: Pronatal
city: Herlev
country: Denmark
facility: Amtssygehuset Herlev
city: Holbæk
country: Denmark
facility: Sygehus Vestsjælland
city: Hvidovre
country: Denmark
facility: H:S Hvidovre Hospital
city: København
country: Denmark
facility: H:S Rigshospitalet
city: Bialystok
country: Poland
facility: KRIOBANK
city: Warsaw
country: Poland
facility: nOvum
city: Barcelona
country: Spain
facility: IU Dexeus
city: Madrid
country: Spain
facility: GINEFIV, Madrid
city: Madrid
country: Spain
facility: IVI Madrid
city: Sevilla
country: Spain
facility: Ginemed
city: Sevilla
country: Spain
facility: IVI Sevilla
city: Valencia
country: Spain
facility: IVI Valencia
city: Gothenburg
country: Sweden
facility: Fertilitetscentrum AB Gothenburg
city: Malmö
country: Sweden
facility: IVF-kliniken CURA
city: Malmö
country: Sweden
facility: RMC, Malmö
city: Ankara
country: Turkey
facility: Hacettepe University
city: Istanbul
country: Turkey
facility: American Hospital
city: Istanbul
country: Turkey
facility: Memorial Hospital
Study officials:
affiliation: Ferring Pharmaceuticals
name: Clinical Development Support
role: STUDY_DIRECTOR
References:
citation: Devroey P, Pellicer A, Nyboe Andersen A, Arce JC; Menopur in GnRH Antagonist Cycles with Single Embryo Transfer Trial Group. A randomized assessor-blind trial comparing highly purified hMG and recombinant FSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer. Fertil Steril. 2012 Mar;97(3):561-71. doi: 10.1016/j.fertnstert.2011.12.016. Epub 2012 Jan 13.
citation: Arce JC, La Marca A, Mirner Klein B, Nyboe Andersen A, Fleming R. Antimullerian hormone in gonadotropin releasing-hormone antagonist cycles: prediction of ovarian response and cumulative treatment outcome in good-prognosis patients. Fertil Steril. 2013 May;99(6):1644-53. doi: 10.1016/j.fertnstert.2012.12.048. Epub 2013 Feb 5.