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

• Sponsor: Ferring Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00884221
• Collaborator: (none)
• Enrollment: 749
• Locations: 25
• Arms: 2
• Duration (Months): 18
• Patients Per Site: 30
• Patients Per Site Per Month: 1.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Infertility	Drug: Highly purified menotrophin; Drug: Recombinant FSH	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 749 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: Jul 1, 2009
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Highly Purified Menotrophin	Drug: Highly purified menotrophin; 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.; Other Names: HP-hMG MENOPUR
Active Comparator: Recombinant FSH	Drug: Recombinant FSH; 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.; Other Names: Follitrophin-beta PUREGON FOLLISTIM

Outcome Measures

Primary Outcome Measures

1. Ongoing Pregnancy After One Fresh Embryo Replacement Cycle, Intention-to-treat (ITT) Analysis Set [10-11 weeks after embryo transfer at the blastocyst stage]

   Transvaginal ultrasound showing at least one intrauterine viable fetus 10-11 weeks after embryo transfer at the blastocyst stage

2. Ongoing Pregnancy After One Fresh Embryo Replacement Cycle, Per-protocol (PP) Analysis Set [10-11 weeks after embryo transfer at the blastocyst stage]

   Transvaginal ultrasound showing at least one intrauterine viable fetus 10-11 weeks after embryo transfer at the blastocyst stage

Secondary Outcome Measures

1. Endocrine Profile (Estradiol), Intention-to-treat (ITT) Analysis Set [On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist]

   Blood samples for analysis of circulating concentrations of endocrine parameters were drawn

2. Endocrine Profile (FSH), Intention-to-treat (ITT) Analysis Set [On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist]

   Blood samples for analysis of circulating concentrations of endocrine parameters were drawn

3. Endocrine Profile (Free Androgen Index), Intention-to-treat (ITT) Analysis Set [On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist]

   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

4. Endocrine Profile (Luteinizing Hormone), Intention-to-treat (ITT) Analysis Set [On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist]

   Blood samples for analysis of circulating concentrations of endocrine parameters were drawn

5. Endocrine Profile (Progesterone), Intention-to-treat (ITT) Analysis Set [On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist]

   Blood samples for analysis of circulating concentrations of endocrine parameters were drawn

6. Endocrine Profile (Prolactin), Intention-to-treat (ITT) Analysis Set [On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist]

   Blood samples for analysis of circulating concentrations of endocrine parameters were drawn

7. Endocrine Profile (Sex Hormone Binding Globulin), Intention-to-treat (ITT) Analysis Set [On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist]

   Blood samples for analysis of circulating concentrations of endocrine parameters were drawn

8. Endocrine Profile (Testosterone), Intention-to-treat (ITT) Analysis Set [On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist]

   Blood samples for analysis of circulating concentrations of endocrine parameters were drawn

9. Number of Follicles of >= 12mm, 12-14 mm, 15-16 mm and >= 17 mm in Each Participant, Intention-to-treat (ITT) Analysis Set [Last stimulation day]

   During the controlled ovarian stimulation, transvaginal ultrasound was performed to count the number of follicles and measure the size of the follicles.

10. Number of Oocytes Retrieved in Each Participant, Intention-to-treat (ITT) Analysis Set [36 h after hCG]

    Oocyte retrieval took place 36h (± 2h) after hCG administration. At oocyte retrieval, the number of oocytes retrieved was recorded.

11. Fertilization, Intention-to-treat (ITT) Analysis Set [1 day after oocyte retrieval (19 h post-insemination)]

    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

12. Blastocyst Quality, Intention-to-treat (ITT) Analysis Set [5 days after oocyte retrieval (120h post-insemination)]

    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.

13. 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]

14. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 34 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ERASME Hospital	Anderlecht		Belgium
2	UZ Brussel	Brussels		Belgium
3	UZ Antwerpen	Edegem		Belgium
4	UZ Gent	Gent		Belgium
5	IVF Institute	Pilsen		Czech Republic
6	ISCARE IVF a.s.	Prague		Czech Republic
7	Pronatal	Prague		Czech Republic
8	Amtssygehuset Herlev	Herlev		Denmark
9	Sygehus Vestsjælland	Holbæk		Denmark
10	H:S Hvidovre Hospital	Hvidovre		Denmark
11	H:S Rigshospitalet	København		Denmark
12	KRIOBANK	Bialystok		Poland
13	nOvum	Warsaw		Poland
14	IU Dexeus	Barcelona		Spain
15	GINEFIV, Madrid	Madrid		Spain
16	IVI Madrid	Madrid		Spain
17	Ginemed	Sevilla		Spain
18	IVI Sevilla	Sevilla		Spain
19	IVI Valencia	Valencia		Spain
20	Fertilitetscentrum AB Gothenburg	Gothenburg		Sweden
21	IVF-kliniken CURA	Malmö		Sweden
22	RMC, Malmö	Malmö		Sweden
23	Hacettepe University	Ankara		Turkey
24	American Hospital	Istanbul		Turkey
25	Memorial Hospital	Istanbul		Turkey

Sponsors and Collaborators

• Ferring Pharmaceuticals

Investigators

• Study Director: Clinical Development Support, Ferring Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ferring Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00884221
• Other Study ID Numbers: FE999906 CS08; EudraCT Number: 2008-006775-67
• First Posted: Apr 20, 2009
• Last Update Posted: Apr 20, 2012
• Last Verified: Apr 1, 2012

• Additional relevant MeSH terms: Infertility; Menotropins

Study Results

Participant Flow

Recruitment Details	The participants were recruited among the patients attending the clinics included in the trial.
Pre-assignment Detail	810 participants were screened and 754 were randomised. 749 participants were exposed to highly purified menotrophin or recombinant FSH

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. Hereafter, the subjects 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 subjects could be treated with gonadotrophin for a maximum of 20 days. Coasting was prohibited.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. Hereafter, the subjects 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 subjects could be treated with gonadotrophin for a maximum of 20 days. Coasting was prohibited.
Period Title: Overall Study
STARTED	374	375
COMPLETED	340	343
NOT COMPLETED	34	32

Baseline Characteristics

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH	Total
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.	Total of all reporting groups
Overall Participants	374	375	749
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	374 100%	375 100%	749 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30.8 (2.75)	30.4 (2.62)	30.6 (2.69)
Sex: Female, Male (Count of Participants)
Female	374 100%	375 100%	749 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Belgium	20 5.3%	20 5.3%	40 5.3%
Czech Republic	30 8%	27 7.2%	57 7.6%
Denmark	33 8.8%	33 8.8%	66 8.8%
Poland	72 19.3%	71 18.9%	143 19.1%
Spain	179 47.9%	178 47.5%	357 47.7%
Sweden	14 3.7%	19 5.1%	33 4.4%
Turkey	26 7%	27 7.2%	53 7.1%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.
Measure Participants	374	375
Mean (Standard Deviation) [Percentage of participants]	29 (2.3) 7.8%	27 (2.3) 7.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	The non-inferiority hypothesis to be tested for the primary endpoint was: H0: π MENOPUR - π recombinant FSH ≤ -10.0% against the alternative H1: π MENOPUR - π recombinant FSH > -10.0%, where π MENOPUR and π recombinant FSH denote the ongoing pregnancy rate after treatment with MENOPUR and recombinant FSH, respectively, in a single fresh treatment cycle following a GnRH antagonist protocol.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The null hypothesis (H0) was tested against the alternative by constructing a two-sided 95% confidence interval for the difference in ongoing pregnancy rates. If the lower-limit of the 95% confidence interval was greater than the non-inferiority limit (-10.0%), the null hypothesis was rejected and it would be claimed that highly purified menotrophin was non-inferior to recombinant FSH with respect to ongoing pregnancy rate in a single fresh treatment cycle following a GnRH antagonist protocol.
Statistical Test of Hypothesis	p-Value	0.499
	Comments	Since there was only one primary endpoint, no adjustment for multiplicity was needed for the primary analysis.
	Method	Sign test
	Comments	A two-sided 95% confidence interval for the difference in ongoing pregnancy rates was made. The CI was based on a normal approximation.
Method of Estimation	Estimation Parameter	Difference in pregnancy rates, ITT
	Estimated Value	2.2
	Confidence Interval	(2-Sided) 95%; -4.2 to 8.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference tested: highly purified menotrophin-recombinant FSH, ITT analysis set

2. Secondary Outcome

Title	Endocrine Profile (Estradiol), Intention-to-treat (ITT) Analysis Set
Description	Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
Time Frame	On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.
Measure Participants	374	375
Mean (Standard Deviation) [pmol/L]	8797 (6030)	7022 (4945)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Estradiol
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Linear
	Comments	Tests for treatment differences were based on log-transformed values and adjusted for baseline values

3. Secondary Outcome

Title	Endocrine Profile (FSH), Intention-to-treat (ITT) Analysis Set
Description	Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
Time Frame	On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.
Measure Participants	374	375
Mean (Standard Deviation) [IU/L]	15.7 (4.1)	12.6 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	FSH
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Linear
	Comments	Tests for treatment differences were based on log-transformed values and adjusted for baseline values

4. Secondary Outcome

Title	Endocrine Profile (Free Androgen Index), Intention-to-treat (ITT) Analysis Set
Description	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
Time Frame	On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.
Measure Participants	374	375
Mean (Standard Deviation) [Percentage of participants]	2.8 (2.0) 0.7%	2.5 (2.2) 0.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Free Androgen Index
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Linear
	Comments	Tests for treatment differences were based on log-transformed values and adjusted for baseline values

5. Secondary Outcome

Title	Endocrine Profile (Luteinizing Hormone), Intention-to-treat (ITT) Analysis Set
Description	Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
Time Frame	On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.
Measure Participants	374	375
Mean (Standard Deviation) [IU/L]	2.8 (2.8)	2.1 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Luteinizing hormone
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Linear
	Comments	Tests for treatment differences were based on log-transformed values and adjusted for baseline values

6. Secondary Outcome

Title	Endocrine Profile (Progesterone), Intention-to-treat (ITT) Analysis Set
Description	Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
Time Frame	On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.
Measure Participants	374	375
Mean (Standard Deviation) [nmol/L]	3.1 (3.4)	3.1 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Progesterone
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.630
	Comments
	Method	Regression, Linear
	Comments	Tests for treatment differences were based on log-transformed values and adjusted for baseline values

7. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The per-protocol (PP) analysis set was defined as all randomized and exposed participants except those excluded as a result of major protocol deviations, such as significant non-compliance or other serious unforeseen deviations deemed to invalidate the data and affect the conclusions of the trial.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.
Measure Participants	343	333
Mean (Standard Deviation) [Percentage of participants]	30 (2.5) 8%	27 (2.4) 7.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	The non-inferiority hypothesis to be tested for the primary endpoint was: H0: π MENOPUR - π recombinant FSH ≤ -10.0% against the alternative H1: π MENOPUR - π recombinant FSH > -10.0%, where π MENOPUR and π recombinant FSH denote the ongoing pregnancy rate after treatment with MENOPUR and recombinant FSH, respectively, in a single fresh treatment cycle following a GnRH antagonist protocol.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The null hypothesis (H0) was tested against the alternative by constructing a two-sided 95% confidence interval for the difference in ongoing pregnancy rates. If the lower-limit of the 95% confidence interval was greater than the non-inferiority limit (-10.0%), the null hypothesis was rejected and it would be claimed that highly purified menotrophin was non-inferior to recombinant FSH with respect to ongoing pregnancy rate in a single fresh treatment cycle following a GnRH antagonist protocol.
Statistical Test of Hypothesis	p-Value	0.387
	Comments	Since there was only one primary endpoint, no adjustment for multiplicity was needed for the primary analysis.
	Method	Sign test
	Comments	A two-sided 95% confidence interval for the difference in ongoing pregnancy rates was made. The CI was based on a normal approximation.
Method of Estimation	Estimation Parameter	Difference in pregnancy rates, PP
	Estimated Value	3.0
	Confidence Interval	(2-Sided) 95%; -3.8 to 9.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference tested: highly purified menotrophin - recombinant FSH, PP

8. Secondary Outcome

Title	Endocrine Profile (Prolactin), Intention-to-treat (ITT) Analysis Set
Description	Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
Time Frame	On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.
Measure Participants	374	375
Mean (Standard Deviation) [pmol/L]	1544 (770)	1410 (689)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Prolactin
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.047
	Comments
	Method	Regression, Linear
	Comments	Tests for treatment differences were based on log-transformed values and adjusted for baseline values

9. Secondary Outcome

Title	Endocrine Profile (Sex Hormone Binding Globulin), Intention-to-treat (ITT) Analysis Set
Description	Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
Time Frame	On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.
Measure Participants	374	375
Mean (Standard Deviation) [nmol/L]	111 (51)	107 (48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Sex hormone binding globulin
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Regression, Linear
	Comments	Tests for treatment differences were based on log-transformed values and adjusted for baseline values

10. Secondary Outcome

Title	Endocrine Profile (Testosterone), Intention-to-treat (ITT) Analysis Set
Description	Blood samples for analysis of circulating concentrations of endocrine parameters were drawn
Time Frame	On the last day of stimulation, blood was drawn at least 8 hours after the previous injection of gonadotrophin and GnRH antagonist

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.
Measure Participants	374	375
Mean (Standard Deviation) [nmol/L]	2.5 (1.2)	2.1 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Testosterone
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Linear
	Comments	Tests for treatment differences were based on log-transformed values and adjusted for baseline values

11. Secondary Outcome

Title	Number of Follicles of >= 12mm, 12-14 mm, 15-16 mm and >= 17 mm in Each Participant, Intention-to-treat (ITT) Analysis Set
Description	During the controlled ovarian stimulation, transvaginal ultrasound was performed to count the number of follicles and measure the size of the follicles.
Time Frame	Last stimulation day

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.
Measure Participants	374	375
>= 12 mm	10.9 (4.7)	11.8 (4.9)
12-14 mm	3.3 (2.6)	3.8 (2.9)
15-16 mm	2.7 (2.2)	2.7 (2.3)
>=17 mm	4.9 (2.2)	5.2 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Comparison between treatment groups of the average number of follicles >= 12 mm on the last stimulation day
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Comparison between treatment groups of the average number of follicles 12-14 mm on the last stimulation day
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Comparison between treatment groups of the average number of follicles 15-16 mm on the last stimulation day
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.728
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Comparison between treatment groups of the average number of follicles >=17 mm on the last stimulation day
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.285
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

12. Secondary Outcome

Title	Number of Oocytes Retrieved in Each Participant, Intention-to-treat (ITT) Analysis Set
Description	Oocyte retrieval took place 36h (± 2h) after hCG administration. At oocyte retrieval, the number of oocytes retrieved was recorded.
Time Frame	36 h after hCG

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.
Measure Participants	374	375
Mean (Standard Deviation) [Oocytes per participant]	9.1 (5.2)	10.7 (5.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Treatments were compared using the Wilcoxon test for the average number of oocytes retrieved.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Only participants who underwent the oocyte retrieval procedure were included in the analysis

13. Secondary Outcome

Title	Fertilization, Intention-to-treat (ITT) Analysis Set
Description	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
Time Frame	1 day after oocyte retrieval (19 h post-insemination)

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.
Measure Participants	374	375
Mean (Standard Deviation) [Percentage of metaphase II oocytes]	75 (23)	76 (22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.969
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Only participants who had oocytes retrieved were included in the analysis.

14. Secondary Outcome

Title	Blastocyst Quality, Intention-to-treat (ITT) Analysis Set
Description	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.
Time Frame	5 days after oocyte retrieval (120h post-insemination)

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.
Measure Participants	374	375
Blastocyst 1 / 2 pn	7 (17)	7 (16)
Blastocyst 2 / 2pn	7 (15)	5 (11)
Blastocyst 3 / 2pn	10 (16)	10 (15)
Blastocyst 4 / 2pn	18 (22)	20 (26)
Blastocyst 5 / 2pn	7 (16)	6 (13)
Blastocyst 6 / 2pn	0 (0)	0 (0)
Blastocyst 4AA/ 2pn	5 (13)	5 (14)
Blastocyst 5AA / 2pn	2 (7)	2 (7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Comparison between treatments groups of percentage of blastocysts with expansion and hatching status 1 / 2pn
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.406
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Comparison between treatments groups of percentage of blastocysts with expansion and hatching status 2 / 2pn
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.232
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Comparison between treatments groups of percentage of blastocysts with expansion and hatching status 3 / 2pn
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.412
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Comparison between treatments groups of percentage of blastocysts with expansion and hatching status 4 / 2pn
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.438
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Comparison between treatments groups of percentage of blastocysts with expansion and hatching status 5 / 2pn
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.390
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Comparison between treatments groups of percentage of blastocysts with expansion and hatching status, inner cell mass grading and trophectoderm grading 4AA / 2pn
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.958
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments	Comparison between treatments groups of percentage of blastocysts with expansion and hatching status, inner cell mass grading and trophectoderm grading 5AA / 2pn
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.954
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

15. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.
Measure Participants	374	375
Mean (Standard Deviation) [Percentage of participants]	28 (2.3) 7.5%	26 (2.3) 6.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.398
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	A two-sided 95% confidence interval for the difference in live birth rates was made. The CI was based on a normal approximation.
Method of Estimation	Estimation Parameter	Comparison of distributions
	Estimated Value	0.398
	Confidence Interval	(2-Sided) 95%; -3.6 to 9.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value is difference between highly purified menotrophin and recombinant FSH, ITT analysis set

16. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) analysis set was defined as all randomized and exposed participants. Participants were analyzed according to actual treatment.

Arm/Group Title	Highly Purified Menotrophin	Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the 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 subjects could be treated with gonadotrophin for a maximum of 20 days.
Measure Participants	374	375
Mean (Standard Deviation) [Percentage of participants]	40 (2.5) 10.7%	38 (2.5) 10.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Highly Purified Menotrophin, Recombinant FSH
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.686
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	A two-sided 95% confidence interval for the difference in cumulative live birth rates was made. The CI was based on a normal approximation.
Method of Estimation	Estimation Parameter	Comparison of distributions
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 95%; -5.6 to 9.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value is difference between highly purified menotrophin and recombinant FSH, ITT analysis set

Adverse Events

Time Frame	Adverse events were recorded from signed informed consent until the end-of-trial visit.
Adverse Event Reporting Description	Adverse events were evaluated at each visit.
Arm/Group Title	Highly Purified Menotrophin		Recombinant FSH
Arm/Group Description	The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.		The gonadotrophin starting dose was 150 IU daily for the first 5 days. From stimulation day 6 and onwards, the dosing could be adjusted according to individual participant 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.
All Cause Mortality
	Highly Purified Menotrophin		Recombinant FSH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Highly Purified Menotrophin		Recombinant FSH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/374 (1.3%)		7/375 (1.9%)
Gastrointestinal disorders
Abdominal pain	1/374 (0.3%)	1	0/375 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion missed	0/374 (0%)	0	2/375 (0.5%)	2
Abortion spontaneous	0/374 (0%)	0	1/375 (0.3%)	1
Abortion threatened	0/374 (0%)	0	1/375 (0.3%)	1
Ectopic pregnancy	0/374 (0%)	0	1/375 (0.3%)	1
Reproductive system and breast disorders
Ovarian hyperstimulation syndrome	3/374 (0.8%)	3	2/375 (0.5%)	2
Ovarian cyst	1/374 (0.3%)	1	0/375 (0%)	0
Other (Not Including Serious) Adverse Events
	Highly Purified Menotrophin		Recombinant FSH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/374 (17.6%)		47/375 (12.5%)
Gastrointestinal disorders
Nausea	18/374 (4.8%)	19	15/375 (4%)	16
Nervous system disorders
Headache	25/374 (6.7%)	30	19/375 (5.1%)	23
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	27/374 (7.2%)	27	19/375 (5.1%)	19
Reproductive system and breast disorders
Pelvic pain	18/374 (4.8%)	23	16/375 (4.3%)	20
Vaginal haemorrhage	21/374 (5.6%)	25	10/375 (2.7%)	13

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the principle investigator (PI) is that the sponsor can review the draft manuscript prior to publication and can request delay of publication where any contents are deemed patentable by the sponsor or confidential to the sponsor. Comments will be given within four weeks from receipt of the draft manuscript.