Lutropin Alfa in Women at Risk of Poor Response

Phase 2

Completed

Conditions: Ovarian Stimulation

Interventions: Drug: r-FSH
Drug: Analogous GnRH antagonist
Drug: r-hLH
Drug: r-hCG
Drug: Progesterone

Registration Number: NCT01112358

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: Evaluate the effectiveness of adding lutropin alfa (recombinant human luteinizing hormone \[r-hLH\]) in the middle of the follicular phase compared to no addition, in infertile women at risk of poor response stimulated with follitropin alfa (recombinant Follicle-Stimulating Hormone \[r-FSH\]) under Gonadotropin Releasing Hormone (GnRH) antagonist in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), in the number and quality of oocytes, follicular development, fertilization oocyte, embryo quality, and pregnancy rate.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 58

Inclusion Criteria

Participants who were at risk of poor response by at least one of the following criteria: a) <3 follicles in last cycle, or less than or equal to (</=) 2 metaphase II oocytes, or estradiol (E2) <600 pg/mL; b) Cancellation of previous cycle; c) Early follicular serum Follicle-Stimulating Hormone (FSH) >8.5 milli IU/L
Participants with normal baseline luteinizing hormone and E2 levels
Regular menstrual cycles of 25-35 days
Presence of both ovaries and uterus able to withstand pregnancy

Exclusion Criteria

Participants who had any clinically significant disease including known human immunodeficiency virus (HIV), hepatitis-B virus (HBV)/hepatitis-C virus (HCV) positivity
Participants with more than 3 previous assisted reproductive techniques (ART) cycles
Participants with polycystic ovaries or cyst of unknown etiology; unexplained gynecological bleeding
Participants who had any contraindication to being pregnant
Active substance abuse
Participants who had simultaneously participated in another clinical drug trial

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
r-FSH	r-hCG	Follitropin alfa (r-FSH) will be administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose will then be adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants will also receive analogous GnRH antagonist and natural progesterone, as per standard center practice. To complete follicular maturation and trigger ovulation, a single dose of 250 mg of r-hCG will be administered subcutaneously at 12 hours after the last injection of follitropin alfa and analogous GnRH antagonist.
r-FSH	r-FSH	Follitropin alfa (r-FSH) will be administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose will then be adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants will also receive analogous GnRH antagonist and natural progesterone, as per standard center practice. To complete follicular maturation and trigger ovulation, a single dose of 250 mg of r-hCG will be administered subcutaneously at 12 hours after the last injection of follitropin alfa and analogous GnRH antagonist.
r-FSH	Analogous GnRH antagonist	Follitropin alfa (r-FSH) will be administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose will then be adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants will also receive analogous GnRH antagonist and natural progesterone, as per standard center practice. To complete follicular maturation and trigger ovulation, a single dose of 250 mg of r-hCG will be administered subcutaneously at 12 hours after the last injection of follitropin alfa and analogous GnRH antagonist.
r-FSH + r-hLH	r-FSH	Lutropin alfa (r-hLH) will be administered at a daily dose of 150 International Units (IU) from the presence of at least one follicle greater than (\>) 14 millimeter (mm) to complete ovarian stimulation. Follitropin alfa (r-FSH) will be administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose will then be adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants will also receive analogous GnRH antagonist and natural progesterone, as per standard center practice. To complete follicular maturation and trigger ovulation, a single dose of 250 milligrams (mg) of recombinant Human Chorionic Gonadotropin (r-hCG) will be administered subcutaneously at 12 hours after the last injection of lutropin alfa and/or follitropin alfa and analogous GnRH antagonist.
r-FSH + r-hLH	r-hCG	Lutropin alfa (r-hLH) will be administered at a daily dose of 150 International Units (IU) from the presence of at least one follicle greater than (\>) 14 millimeter (mm) to complete ovarian stimulation. Follitropin alfa (r-FSH) will be administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose will then be adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants will also receive analogous GnRH antagonist and natural progesterone, as per standard center practice. To complete follicular maturation and trigger ovulation, a single dose of 250 milligrams (mg) of recombinant Human Chorionic Gonadotropin (r-hCG) will be administered subcutaneously at 12 hours after the last injection of lutropin alfa and/or follitropin alfa and analogous GnRH antagonist.
r-FSH + r-hLH	Analogous GnRH antagonist	Lutropin alfa (r-hLH) will be administered at a daily dose of 150 International Units (IU) from the presence of at least one follicle greater than (\>) 14 millimeter (mm) to complete ovarian stimulation. Follitropin alfa (r-FSH) will be administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose will then be adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants will also receive analogous GnRH antagonist and natural progesterone, as per standard center practice. To complete follicular maturation and trigger ovulation, a single dose of 250 milligrams (mg) of recombinant Human Chorionic Gonadotropin (r-hCG) will be administered subcutaneously at 12 hours after the last injection of lutropin alfa and/or follitropin alfa and analogous GnRH antagonist.
r-FSH + r-hLH	r-hLH	Lutropin alfa (r-hLH) will be administered at a daily dose of 150 International Units (IU) from the presence of at least one follicle greater than (\>) 14 millimeter (mm) to complete ovarian stimulation. Follitropin alfa (r-FSH) will be administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose will then be adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants will also receive analogous GnRH antagonist and natural progesterone, as per standard center practice. To complete follicular maturation and trigger ovulation, a single dose of 250 milligrams (mg) of recombinant Human Chorionic Gonadotropin (r-hCG) will be administered subcutaneously at 12 hours after the last injection of lutropin alfa and/or follitropin alfa and analogous GnRH antagonist.
r-FSH + r-hLH	Progesterone	Lutropin alfa (r-hLH) will be administered at a daily dose of 150 International Units (IU) from the presence of at least one follicle greater than (\>) 14 millimeter (mm) to complete ovarian stimulation. Follitropin alfa (r-FSH) will be administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose will then be adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants will also receive analogous GnRH antagonist and natural progesterone, as per standard center practice. To complete follicular maturation and trigger ovulation, a single dose of 250 milligrams (mg) of recombinant Human Chorionic Gonadotropin (r-hCG) will be administered subcutaneously at 12 hours after the last injection of lutropin alfa and/or follitropin alfa and analogous GnRH antagonist.
r-FSH	Progesterone	Follitropin alfa (r-FSH) will be administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose will then be adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants will also receive analogous GnRH antagonist and natural progesterone, as per standard center practice. To complete follicular maturation and trigger ovulation, a single dose of 250 mg of r-hCG will be administered subcutaneously at 12 hours after the last injection of follitropin alfa and analogous GnRH antagonist.

Primary Outcome Measures

Name	Time	Method
Number of Oocytes Retrieved	At the end of stimulation (Day 2 up to Day 8)
Oocytes Recovery Rate	At the end of stimulation (Day 2 up to Day 8)	Oocytes recovery rate (oocytes per \>14 mm follicle) is defined as number of oocytes retrieved divided by number of follicles \>14 mm in diameter.
Number of Follicles Greater Than (>) 14 Millimeter (mm) in Diameter	At the end of stimulation (Day 2 up to Day 8)

Secondary Outcome Measures

Name	Time	Method
Number of Embryos by Quality	Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)	Embryo quality was graded according to morphological classification of Veeck. Grade 1: even blastomeres with no fragmentation; Grade 2: even blastomeres with slight fragmentation (less than 20%); Grade 3: uneven size blastomeres with no fragmentation; Grade 4: even or uneven size blastomeres with moderate fragmentation (20-25%); and Grade 5: unrecognizable blastomeres with severe fragmentation (\>50%).
Fertilization Rate	Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)	The fertilization rate (2 pronuclei \[PN\] fertilized oocytes per inseminated oocyte) was defined as number of 2 PN fertilized oocytes divided by number of inseminated oocytes.
Number of Embryos Transferred by In Vitro Fertilization (IVF)	Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Number of Participants With Positive Pregnancy Test	Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)	The beta Human Chorionic Gonadotropin (beta-hCG) test was used as pregnancy test.
Duration of Ovarian Stimulation	Randomization to Day 8	Duration of ovarian stimulation was defined as the time from start of study treatment to time of r-hCG administration.
Oocyte Nuclear Maturity Rate	At the end of stimulation (Day 2 up to Day 8)	Oocyte nuclear maturity rate (metaphase II oocytes per retrieved oocyte) is defined as number of metaphase II oocytes divided by total number of oocytes retrieved.
Number of Participants in Whom At Least 1 Stimulation Cycle Was Cancelled	Randomization to Day 8
Plasma Level of Estradiol	At the time of r-hCG administration (any days between Day 2 to Day 8)
Endometrial Thickness	At the time of r-hCG administration (any days between Day 2 to Day 8)
rFSH Cumulative Dose	Randomization to Day 8
Number of Participants With Clinical Pregnancy	Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)	A clinical pregnancy is a pregnancy that is confirmed by both pregnancy test (beta-hCG test) and sonographic confirmation of a gestational sac or heartbeat (fetal sac).
Implementation Rate	Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)	Implementation rate (clinical pregnancy/embryo transferred) was defined as the number of clinical pregnancies divided by number of embryos transferred.
Plasma Levels of LH	At the time of r-hCG administration (any days between Day 2 to Day 8)