PERgoveriS In Stratified Treatment for Assisted Reproductive Technique (PERSIST)

• ClinicalTrials.gov Identifier: NCT01297465
• Recruitment Status: Completed
• First Posted: February 16, 2011
• Results First Posted: February 24, 2014
• Last Update Posted: February 24, 2014
• Sponsor: Merck KGaA, Darmstadt, Germany
• Collaborators: Merck Serono S.A., Geneva; Merck A/S, Denmark; Merck OY, Finland; Merck Serono S.A.S, France; Merck Serono GmbH, Germany; Merck A.E., Greece; Merck B.V., Netherlands; Merck SP. Z.O.O., Poland; Merck Serono S.P.A., Italy; Merck Services U.K. Ltd, UK; LLC Merck, Russia; Merck spol. s r.o., Slovakia; Merck Pharma, K.S., Slovakia
• Information provided by (Responsible Party): Merck KGaA, Darmstadt, Germany

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Assisted Reproductive Techniques; Reproductive Technology, Assisted
• Interventions: Drug: Gonal-f®; Drug: Pergoveris®; Drug: Recombinant human chorionic gonadotropin (r-hCG)
• Enrollment: 202

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Period Title: Overall Study
Started	99	103
Completed	91	93
Not Completed	8	10
Reason Not Completed
Lack of Ovarian Response	1	1
Ovarian hyperstimulation syndrome risk	0	1
No Oocytes Retrieved	1	1
Poor oocyte quality	0	1
No Fertilization	6	4
All Embryos Discarded	0	1
Intention to Freeze all Embryos	0	1

Baseline Characteristics

Arm/Group Title		Gonal-f® Plus Pergoveris®	Pergoveris®	Total
Arm/Group Description		Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.	Total of all reporting groups
Overall Number of Baseline Participants		99	103	202
Baseline Analysis Population Description		Safety Population included all the randomized participants who had received at least 1 dose of Pergoveris® or Gonal-f®.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	99 participants	103 participants	202 participants
		37.6 (1.16)	37.4 (1.14)	37.5 (1.15)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	99 participants	103 participants	202 participants
	Female	99 100.0%	103 100.0%	202 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%
Race; Measure Type: Number; Unit of measure: Participants	Number Analyzed	99 participants	103 participants	202 participants
Black		4	3	7
Asian		4	6	10
Other		2	2	4
White		89	92	181
Height; Mean (Standard Deviation); Unit of measure: Centimeter
	Number Analyzed	99 participants	103 participants	202 participants
		166.1 (6.49)	166.3 (6.47)	166.2 (6.46)
Weight; Mean (Standard Deviation); Unit of measure: Kilogram
	Number Analyzed	99 participants	103 participants	202 participants
		64.81 (10.364)	65.82 (8.923)	65.33 (9.645)

Outcome Measures

1. Primary Outcome

Title	Total Number of Oocytes Retrieved
Description	The total number of oocytes retrieved per reporting group on the day of ovum pick-up (OPU) (34-38 hours post r-hCG day) was calculated. Oocyte retrieval is a technique used in in-vitro fertilization (IVF) in order to remove oocytes from the ovary of the female participant, enabling fertilization outside the body.
Time Frame	OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 11 days}])

Outcome Measure Data

Analysis Population Description

Modified intention-to-treat (Mod-ITT) population included all the randomized participants who had received at least one dose of GONAL-f® or Pergoveris®, and completed the primary efficacy assessment.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	98	101
Mean (Standard Deviation); Unit of Measure: oocytes
	10.9 (6.5)	9.7 (6.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gonal-f® Plus Pergoveris®, Pergoveris®
	Comments	The null hypothesis was that the difference between the mean number of oocytes is less than (-3) or greater than (+3) between the two treatment arm. The alternate hypothesis was that the difference is between (-3) and (+3). The study had 80% power to show that the group randomized to Pergoveris® has an absolute difference of no more than 3 oocytes retrieved in comparison to the group randomized to GONAL-f®/Pergoveris®
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANOVA
	Comments	ANOVA model adjusted for treatment and country
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.28
	Confidence Interval	(2-Sided) 95%; -3.15 to 0.59
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.947
	Estimation Comments	The primary efficacy variable was to be analyzed using an analysis of variance (ANOVA) model, adjusted for treatment and country.

2. Secondary Outcome

Title	Total Dose and Mean Daily Dose of Follicle Stimulating Hormone (FSH)
Description	[Not Specified]
Time Frame	Day 1 up to r-hCG day (end of stimulation cycle [approximately 11 days])

Outcome Measure Data

Analysis Population Description

Safety Population included all the randomized participants who had received at least 1 dose of Pergoveris® or Gonal-f®.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	99	103
Mean (Standard Deviation); Unit of Measure: IU
Total Dose	3292 (851)	3321 (850)
Mean Daily Dose	307 (43)	311 (41)

3. Secondary Outcome

Title	Total Number of Stimulation Treatment Days
Description	[Not Specified]
Time Frame	Day 1 up to r-hCG day (end of stimulation cycle [approximately 11 days])

Outcome Measure Data

Analysis Population Description

Safety Population included all the randomized participants who had received at least 1 dose of Pergoveris® or Gonal-f®.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	99	103
Mean (Standard Deviation); Unit of Measure: days
	10.6 (1.6)	10.6 (1.7)

4. Secondary Outcome

Title	Implantation Rate
Description	Implantation rate per reporting group was measured as the number of fetal sacs observed, divided by the number of embryos transferred multiplied by 100.
Time Frame	Days 35-42 post r-hCG day (end of stimulation cycle [approximately 11 days])

Outcome Measure Data

Analysis Population Description

Mod-ITT population included all the randomized participants who had received at least one dose of GONAL-f® or Pergoveris®, and completed the primary efficacy assessment.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	90	93
Mean (Standard Deviation); Unit of Measure: percent sacs per embryo
	13.3 (29.1)	24.7 (36.1)

5. Secondary Outcome

Title	Number of Fetal Sacs With Activity
Description	Number of fetal sacs with activity was evaluated by ultrasound scan
Time Frame	Days 35-42 post r-hCG day [end of stimulation cycle {approximately 11 days}])

Outcome Measure Data

Analysis Population Description

Mod-ITT population included all the randomized participants who had received at least one dose of GONAL-f® or Pergoveris®, and completed the primary efficacy assessment."N" (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	18	35
Mean (Standard Deviation); Unit of Measure: fetal sacs
	1.4 (0.5)	1.2 (0.4)

6. Secondary Outcome

Title	Number of Fetal Hearts With Activity
Description	Number of fetal hearts with activity was evaluated by ultrasound scan
Time Frame	Days 35-42 post r-hCG day [end of stimulation cycle {approximately 11 days}])

Outcome Measure Data

Analysis Population Description

Mod-ITT population included all the randomized participants who had received at least one dose of GONAL-f® or Pergoveris®, and completed the primary efficacy assessment."N" (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	17	32
Mean (Standard Deviation); Unit of Measure: fetal hearts
	1.4 (0.5)	1.3 (0.5)

7. Secondary Outcome

Title	Clinical Pregnancy Rate
Description	Clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes ectopic pregnancy. Clinical pregnancy rate was reported as total clinical pregnancy rate, clinical pregnancy rate per cycle started and per embryo transfer [ET]).
Time Frame	Days 35-42 post r-hCG day (end of stimulation cycle [approximately 11 days])

Outcome Measure Data

Analysis Population Description

Mod-ITT population included all the randomized participants who had received at least one dose of GONAL-f® or Pergoveris®, and had completed the primary efficacy assessment. "N" signifies those participants who had their ET in study treatment cycle. "n" signifies those participants who were evaluated for this measure in specified categories.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	97	101
Measure Type: Number; Unit of Measure: percentage of participants
Total clinical pregnancy rate (n=97, 101)	17.5	31.7
Clinical pregnancy rate per cycle (n=97, 101)	17.5	31.7
Clinical pregnancy rate per ET (n=90, 93)	18.9	34.4

8. Secondary Outcome

Title	Number of Participants With Cancelled Cycles Due to Excessive or Insufficient Ovarian Response to Treatment
Description	An excessive ovarian response: greater than or equal to 25 oocytes which could put the participant at risk of OHSS; An insufficient ovarian response: defined as 3 or less follicles of greater than or equal to 12 millimeter developing following at least 7 days of treatment.
Time Frame	S1 until Day 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])

Outcome Measure Data

Analysis Population Description

Safety Population included all the randomized participants who had received at least 1 dose of Pergoveris® or Gonal-f®.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	99	103
Measure Type: Number; Unit of Measure: participants
Insufficient ovarian response	1	1
Excessive ovarian response	0	1

9. Secondary Outcome

Title	Biochemical Pregnancies Rate
Description	Biochemical pregnancy was defined as the pregnancy diagnosed only by the detection of human chorionic gonadotropin (hCG) in serum or urine and that does not develop into a clinical pregnancy. Participants with beta- hCG concentration greater than 10 international units per liter (IU/L) were considered as biochemical pregnant.
Time Frame	Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])

Outcome Measure Data

Analysis Population Description

Mod-ITT population included all the randomized participants who had received at least one dose of GONAL-f® or Pergoveris®, and completed the primary efficacy assessment. . "N" (number of participants analyzed) signifies those participants who had their embryo transfer in study treatment cycle.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	97	101
Measure Type: Number; Unit of Measure: participants
	23	41

10. Secondary Outcome

Title	Number of Participants With Multiple Pregnancies
Description	Multiple pregnancy was defined as the existence of more than one fetal sac with fetal heart activity.
Time Frame	Days 35-42 post r-hCG day (end of stimulation cycle [approximately 11 days])

Outcome Measure Data

Analysis Population Description

Mod-ITT population included all the randomized participants who had received at least one dose of GONAL-f® or Pergoveris®, and completed the primary efficacy assessment. "N" (number of participants analyzed) signifies those participants who had their embryo transfer in study treatment cycle.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	97	101
Measure Type: Number; Unit of Measure: participants
	6	8

11. Secondary Outcome

Title	Number of Participants With Early and Late Ovarian Hyper Stimulation Syndrome (OHSS)
Description	Ovarian Hyper Stimulation Syndrome (OHSS) is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting. Early OHSS was defined as the onset of OHSS occurring within 9 days after oocyte retrieval and late OHSS was defined as the onset of OHSS occurring on or after day 10 from oocyte retrieval.
Time Frame	Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])

Outcome Measure Data

Analysis Population Description

Safety Population included all the randomized participants who had received at least 1 dose of Pergoveris® or Gonal-f®.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	99	103
Measure Type: Number; Unit of Measure: participants
Early Ovarian hyperstimulation syndrome	4	1
Late Ovarian hyperstimulation syndrome	0	1

12. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events
Description	An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered.
Time Frame	Day 1 up to days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])

Outcome Measure Data

Analysis Population Description

Safety Population included all the randomized participants who had received at least 1 dose of Pergoveris® or Gonal-f®.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	99	103
Measure Type: Number; Unit of Measure: participants
	26	23

13. Secondary Outcome

Title	Systolic and Diastolic Arterial Blood Pressure Assessments
Description	[Not Specified]
Time Frame	Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])

Outcome Measure Data

Analysis Population Description

Safety Population included all the randomized participants who had received at least 1 dose of Pergoveris® or Gonal-f®. ."N" (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	93	99
Mean (Standard Deviation); Unit of Measure: millimeter of mercury ( mm Hg)
Systolic Blood Pressure	118.9 (12.8)	121.2 (14.8)
Diastolic Blood Pressure	74.8 (9.8)	76.8 (9.5)

14. Secondary Outcome

Title	Heart Rate Assessments
Description	[Not Specified]
Time Frame	Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])

Outcome Measure Data

Analysis Population Description

Safety Population included all the randomized participants who had received at least 1 dose of Pergoveris® or Gonal-f®. ."N" (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description:	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Overall Number of Participants Analyzed	93	99
Mean (Standard Deviation); Unit of Measure: beats per minute (bpm)
	75.7 (10.5)	76.5 (10)

Adverse Events

Time Frame	Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Gonal-f® Plus Pergoveris®	Pergoveris®
Arm/Group Description	Gonal-f® (follitropin alfa) 300 International Unit (IU) was administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5) followed by subsequent daily administration of Pergoveris® (follitropin alfa and lutropin alfa) 300 IU subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) (Ovidrel®/Ovitrelle®) administration day (at least 1 follicles greater than or equal to (>=) 18 millimeter [mm]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.	Pergoveris® (follitropin alfa and lutropin alfa) 300 IU was administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). On r-hCG (Ovidrel®/Ovitrelle®) day, 250 microgram of r-hCG was administered once subcutaneously. The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
All-Cause Mortality
	Gonal-f® Plus Pergoveris®	Pergoveris®
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Gonal-f® Plus Pergoveris®	Pergoveris®
	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/99 (2.02%)	0/103 (0.00%)
Reproductive system and breast disorders
Ovarian hyperstimulation syndrome * 1	2/99 (2.02%)	0/103 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 15.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Gonal-f® Plus Pergoveris®	Pergoveris®
	Affected / at Risk (%)	Affected / at Risk (%)
Total	31/99 (31.31%)	32/103 (31.07%)
Cardiac disorders
Extrasystoles * 1	1/99 (1.01%)	0/103 (0.00%)
Ear and labyrinth disorders
Vertigo * 1	0/99 (0.00%)	1/103 (0.97%)
Eye disorders
Myopia * 1	1/99 (1.01%)	0/103 (0.00%)
Gastrointestinal disorders
Abdominal pain * 1	6/99 (6.06%)	4/103 (3.88%)
Abdominal distension * 1	2/99 (2.02%)	2/103 (1.94%)
Abdominal pain lower * 1	2/99 (2.02%)	2/103 (1.94%)
Nausea * 1	1/99 (1.01%)	3/103 (2.91%)
Flatulence * 1	1/99 (1.01%)	2/103 (1.94%)
Diarrhoea * 1	1/99 (1.01%)	1/103 (0.97%)
Abdominal discomfort * 1	1/99 (1.01%)	0/103 (0.00%)
Abdominal pain upper * 1	1/99 (1.01%)	0/103 (0.00%)
Constipation * 1	0/99 (0.00%)	1/103 (0.97%)
Dental caries * 1	1/99 (1.01%)	0/103 (0.00%)
Dyspepsia * 1	1/99 (1.01%)	0/103 (0.00%)
Lip pruritus * 1	1/99 (1.01%)	0/103 (0.00%)
General disorders
Fatigue * 1	0/99 (0.00%)	2/103 (1.94%)
Injection site induration * 1	0/99 (0.00%)	1/103 (0.97%)
Infections and infestations
Nasopharyngitis * 1	2/99 (2.02%)	6/103 (5.83%)
Oral herpes * 1	1/99 (1.01%)	1/103 (0.97%)
Escherichia vaginitis * 1	1/99 (1.01%)	0/103 (0.00%)
Eye infection viral * 1	0/99 (0.00%)	1/103 (0.97%)
Vaginitis bacterial * 1	1/99 (1.01%)	0/103 (0.00%)
Injury, poisoning and procedural complications
Procedural pain * 1	1/99 (1.01%)	1/103 (0.97%)
Investigations
Waist circumference increased * 1	2/99 (2.02%)	0/103 (0.00%)
Oestradiol increased * 1	0/99 (0.00%)	1/103 (0.97%)
Weight increased * 1	0/99 (0.00%)	1/103 (0.97%)
Musculoskeletal and connective tissue disorders
Back pain * 1	1/99 (1.01%)	1/103 (0.97%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Fibroadenoma of breast * 1	0/99 (0.00%)	1/103 (0.97%)
Nervous system disorders
Headache * 1	14/99 (14.14%)	13/103 (12.62%)
Somnolence * 1	1/99 (1.01%)	2/103 (1.94%)
Migraine * 1	1/99 (1.01%)	0/103 (0.00%)
Syncope * 1	0/99 (0.00%)	1/103 (0.97%)
Pregnancy, puerperium and perinatal conditions
Abortion missed * 1	1/99 (1.01%)	0/103 (0.00%)
Abortion spontaneous * 1	0/99 (0.00%)	1/103 (0.97%)
Renal and urinary disorders
Renal colic * 1	1/99 (1.01%)	0/103 (0.00%)
Reproductive system and breast disorders
Ovarian hyperstimulation syndrome * 1	3/99 (3.03%)	4/103 (3.88%)
Vaginal haemorrhage * 1	3/99 (3.03%)	3/103 (2.91%)
Dysmenorrhoea * 1	3/99 (3.03%)	2/103 (1.94%)
Adnexa uteri pain * 1	2/99 (2.02%)	2/103 (1.94%)
Breast pain * 1	1/99 (1.01%)	1/103 (0.97%)
Vulvovaginal burning sensation * 1	2/99 (2.02%)	0/103 (0.00%)
Vulvovaginal pruritus * 1	2/99 (2.02%)	0/103 (0.00%)
Breast tenderness * 1	1/99 (1.01%)	0/103 (0.00%)
Menopausal symptoms * 1	1/99 (1.01%)	0/103 (0.00%)
Pelvic pain * 1	0/99 (0.00%)	1/103 (0.97%)
Vulvovaginal pain * 1	0/99 (0.00%)	1/103 (0.97%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain * 1	2/99 (2.02%)	1/103 (0.97%)
Skin and subcutaneous tissue disorders
Pruritus * 1	1/99 (1.01%)	1/103 (0.97%)
Dermatitis allergic * 1	0/99 (0.00%)	1/103 (0.97%)
Dermatitis contact * 1	1/99 (1.01%)	0/103 (0.00%)
Dry skin * 1	1/99 (1.01%)	0/103 (0.00%)
Eczema * 1	0/99 (0.00%)	1/103 (0.97%)
Erythema * 1	1/99 (1.01%)	0/103 (0.00%)
Rash * 1	1/99 (1.01%)	0/103 (0.00%)
Xeroderma * 1	0/99 (0.00%)	1/103 (0.97%)
Vascular disorders
Hypertension * 1	3/99 (3.03%)	0/103 (0.00%)
Hot flush * 1	0/99 (0.00%)	1/103 (0.97%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 15.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Merck KGaA Communication Center
• Organization: Merck Serono, a division of Merck KGaA
• Phone: +49-6151-72-5200
• EMail: service@merckgroup.com

Publications of Results:

H Behre, C Howles, S Longobardi. Luteinizing hormone supplementation from Day 1 versus 6 of ovarian stimulation in women aged 36-40 years: results from an open-label, randomized, multicentre, multinational trial. Human Reproduction. 2013;28(suppl 1)

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT01297465
• Other Study ID Numbers: EMR 200061-504; 2010-023534-23 ( EudraCT Number )
• First Submitted: February 15, 2011
• First Posted: February 16, 2011
• Results First Submitted: October 23, 2013
• Results First Posted: February 24, 2014
• Last Update Posted: February 24, 2014