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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Infertility

Intervention / Treatment
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* Drug: Highly purified menotrophin
* Drug: Recombinant FSH


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 34 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Highly Purified Menotrophin<br> | Drug: Highly purified menotrophin<br>* The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, dosing could be adjusted according to individual participant response. 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. NOTE: The gonadotrophins (highly purified menotrophin and the active comparator recombinant FSH) were administered in an identical fashion.<br>* Other names: MENOPUR;|
| Active Comparator: Recombinant FSH<br> | Drug: Recombinant FSH<br>* The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, dosing could be adjusted according to individual participant response. 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. NOTE: The gonadotrophins (highly purified menotrophin and the active comparator recombinant FSH) were administered in an identical fashion.<br>* Other names: FOLLISTIM;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing Pregnancy After One Fresh Embryo Replacement Cycle, Intention-to-treat (ITT) Analysis Set | Transvaginal ultrasound showing at least one intrauterine viable fetus 10-11 weeks after embryo transfer at the blastocyst stage | 10-11 weeks after embryo transfer at the blastocyst stage | 
| Ongoing Pregnancy After One Fresh Embryo Replacement Cycle, Per-protocol (PP) Analysis Set | Transvaginal ultrasound showing at least one intrauterine viable fetus 10-11 weeks after embryo transfer at the blastocyst stage | 10-11 weeks after embryo transfer at the blastocyst stage | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endocrine Profile (Estradiol), Intention-to-treat (ITT) Analysis Set | Blood samples for analysis of circulating concentrations of endocrine parameters were drawn | On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist | 
| Endocrine Profile (FSH), Intention-to-treat (ITT) Analysis Set | Blood samples for analysis of circulating concentrations of endocrine parameters were drawn | On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist | 
| Endocrine Profile (Free Androgen Index), Intention-to-treat (ITT) Analysis Set | 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 | On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist | 
| Endocrine Profile (Luteinizing Hormone), Intention-to-treat (ITT) Analysis Set | Blood samples for analysis of circulating concentrations of endocrine parameters were drawn | On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist | 
| Endocrine Profile (Progesterone), Intention-to-treat (ITT) Analysis Set | Blood samples for analysis of circulating concentrations of endocrine parameters were drawn | On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist | 
| Endocrine Profile (Prolactin), Intention-to-treat (ITT) Analysis Set | Blood samples for analysis of circulating concentrations of endocrine parameters were drawn | On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist | 
| Endocrine Profile (Sex Hormone Binding Globulin), Intention-to-treat (ITT) Analysis Set | Blood samples for analysis of circulating concentrations of endocrine parameters were drawn | On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist | 
| Endocrine Profile (Testosterone), Intention-to-treat (ITT) Analysis Set | Blood samples for analysis of circulating concentrations of endocrine parameters were drawn | On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist | 
| Number of Follicles of >= 12mm, 12-14 mm, 15-16 mm and >= 17 mm in Each Participant, Intention-to-treat (ITT) Analysis Set | During the controlled ovarian stimulation, transvaginal ultrasound was performed to count the number of follicles and measure the size of the follicles. | Last stimulation day | 
| Number of Oocytes Retrieved in Each Participant, Intention-to-treat (ITT) Analysis Set | Oocyte retrieval took place 36h (± 2h) after hCG administration. At oocyte retrieval, the number of oocytes retrieved was recorded. | 36 h after hCG | 
| Fertilization, Intention-to-treat (ITT) Analysis Set | 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 | 1 day after oocyte retrieval (19 h post-insemination) | 
| Blastocyst Quality, Intention-to-treat (ITT) Analysis Set | 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. | 5 days after oocyte retrieval (120h post-insemination) | 
| Live Birth for a Single Stimulation Cycle With Single Blastocyst Transfer From Fresh Embryo Replacement Cycle, Intention-to-treat (ITT) Analysis Set |  | Post-trial information | 
| 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 |  | Post-trial information |