Ovarian Stimulation
Conditions
Keywords
Lutropin alfa, Fertilization in vitro, Intracytoplasmic sperm injection, Reproductive techniques, assisted
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.
Interventions
DRUGr-FSH
r-FSH will be administered as specified in the arm description.
DRUGr-hLH
r-hLH will be administered as specified in the arm description.
DRUGAnalogous GnRH antagonist
Analogous GnRH antagonist will be administered as specified in the arm description.
DRUGr-hCG
r-hCG will be administered as specified in the arm description.
DRUGProgesterone
Progesterone will be administered as specified in the arm description.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
No minimum to 38 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Oocytes Retrieved | At the end of stimulation (Day 2 up to Day 8) | — |
| Number of Follicles Greater Than (>) 14 Millimeter (mm) in Diameter | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 Level of Estradiol | At the time of r-hCG administration (any days between Day 2 to Day 8) | — |
| 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. |
| 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. |
| rFSH Cumulative Dose | Randomization to Day 8 | — |
| Plasma Levels of LH | At the time of r-hCG administration (any days between Day 2 to Day 8) | — |
| Number of Participants in Whom At Least 1 Stimulation Cycle Was Cancelled | Randomization to Day 8 | — |
| Endometrial Thickness | At the time of r-hCG administration (any days between Day 2 to Day 8) | — |
| 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 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%). |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| r-FSH + r-hLH Lutropin alfa (recombinant human luteinizing hormone \[r-hLH\]) was 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 (recombinant Follicle-Stimulating Hormone \[r-FSH\]) was administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose was then adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants also received analogous Gonadotropin Releasing Hormone (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) was administered subcutaneously at 12 hours after the last injection of lutropin alfa and/or follitropin alfa and analogous GnRH antagonist (on Days 2 to 8). | 25 |
| r-FSH Follitropin alfa (r-FSH) was administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose was then adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants also received 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 was administered subcutaneously at 12 hours after the last injection of follitropin alfa and analogous GnRH antagonist (on Days 2 to 8). | 33 |
| Total | 58 |
Baseline characteristics
| Characteristic | r-FSH + r-hLH | r-FSH | Total |
|---|---|---|---|
| Age, Continuous | 34.9 Years STANDARD_DEVIATION 2.2 | 34.4 Years STANDARD_DEVIATION 2 | 34.65 Years STANDARD_DEVIATION 2.1 |
| Sex: Female, Male Female | 25 Participants | 33 Participants | 58 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 25 | 0 / 33 |
| serious Total, serious adverse events | 0 / 25 | 0 / 33 |
Outcome results
Primary
Number of Follicles Greater Than (>) 14 Millimeter (mm) in Diameter
Time frame: At the end of stimulation (Day 2 up to Day 8)
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-FSH + r-hLH | Number of Follicles Greater Than (>) 14 Millimeter (mm) in Diameter | 7.2 Follicles | Standard Deviation 1.1 |
| r-FSH | Number of Follicles Greater Than (>) 14 Millimeter (mm) in Diameter | 7.0 Follicles | Standard Deviation 0.8 |
Primary
Number of Oocytes Retrieved
Time frame: At the end of stimulation (Day 2 up to Day 8)
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-FSH + r-hLH | Number of Oocytes Retrieved | 4.0 Oocytes | Standard Deviation 5.3 |
| r-FSH | Number of Oocytes Retrieved | 3.5 Oocytes | Standard Deviation 3.1 |
Primary
Oocytes Recovery Rate
Oocytes recovery rate (oocytes per \>14 mm follicle) is defined as number of oocytes retrieved divided by number of follicles \>14 mm in diameter.
Time frame: At the end of stimulation (Day 2 up to Day 8)
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-FSH + r-hLH | Oocytes Recovery Rate | 0.56 oocytes per >14 mm follicle | Standard Deviation 0.42 |
| r-FSH | Oocytes Recovery Rate | 0.50 oocytes per >14 mm follicle | Standard Deviation 0.41 |
Secondary
Duration of Ovarian Stimulation
Duration of ovarian stimulation was defined as the time from start of study treatment to time of r-hCG administration.
Time frame: Randomization to Day 8
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-FSH + r-hLH | Duration of Ovarian Stimulation | 4.8 days | Standard Deviation 1.7 |
| r-FSH | Duration of Ovarian Stimulation | 4.8 days | Standard Deviation 1.7 |
Secondary
Endometrial Thickness
Time frame: At the time of r-hCG administration (any days between Day 2 to Day 8)
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-FSH + r-hLH | Endometrial Thickness | 12.3 millimeters (mm) | Standard Deviation 1.8 |
| r-FSH | Endometrial Thickness | 11.2 millimeters (mm) | Standard Deviation 2.1 |
Secondary
Fertilization Rate
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.
Time frame: Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-FSH + r-hLH | Fertilization Rate | 0.70 2PN fertilized oocyte/inseminated oocyte | Standard Deviation 0.35 |
| r-FSH | Fertilization Rate | 0.64 2PN fertilized oocyte/inseminated oocyte | Standard Deviation 0.33 |
Secondary
Implementation Rate
Implementation rate (clinical pregnancy/embryo transferred) was defined as the number of clinical pregnancies divided by number of embryos transferred.
Time frame: Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| r-FSH + r-hLH | Implementation Rate | 0.15 Clinical pregnancy/embryo transferred |
| r-FSH | Implementation Rate | 0.14 Clinical pregnancy/embryo transferred |
Secondary
Number of Embryos by Quality
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%).
Time frame: Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| r-FSH + r-hLH | Number of Embryos by Quality | Grade 3 | 1.8 Embroys | Standard Deviation 2 |
| r-FSH + r-hLH | Number of Embryos by Quality | Grade 2 | 1.4 Embroys | Standard Deviation 1.8 |
| r-FSH + r-hLH | Number of Embryos by Quality | Grade 4 | 0.1 Embroys | Standard Deviation 0.2 |
| r-FSH + r-hLH | Number of Embryos by Quality | Grade 5 | 0.1 Embroys | Standard Deviation 0.2 |
| r-FSH + r-hLH | Number of Embryos by Quality | Grade 1 | 0.6 Embroys | Standard Deviation 0.7 |
| r-FSH | Number of Embryos by Quality | Grade 5 | 0.0 Embroys | Standard Deviation 0.2 |
| r-FSH | Number of Embryos by Quality | Grade 1 | 0.8 Embroys | Standard Deviation 1 |
| r-FSH | Number of Embryos by Quality | Grade 2 | 0.7 Embroys | Standard Deviation 0.76 |
| r-FSH | Number of Embryos by Quality | Grade 3 | 0.6 Embroys | Standard Deviation 0.8 |
| r-FSH | Number of Embryos by Quality | Grade 4 | 0.2 Embroys | Standard Deviation 0.3 |
Secondary
Number of Embryos Transferred by In Vitro Fertilization (IVF)
Time frame: Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-FSH + r-hLH | Number of Embryos Transferred by In Vitro Fertilization (IVF) | 2.0 Embroys | Standard Deviation 1 |
| r-FSH | Number of Embryos Transferred by In Vitro Fertilization (IVF) | 1.6 Embroys | Standard Deviation 0.8 |
Secondary
Number of Participants in Whom At Least 1 Stimulation Cycle Was Cancelled
Time frame: Randomization to Day 8
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| r-FSH + r-hLH | Number of Participants in Whom At Least 1 Stimulation Cycle Was Cancelled | 8 Participants |
| r-FSH | Number of Participants in Whom At Least 1 Stimulation Cycle Was Cancelled | 8 Participants |
Secondary
Number of Participants With Clinical Pregnancy
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).
Time frame: Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| r-FSH + r-hLH | Number of Participants With Clinical Pregnancy | 3 Participants |
| r-FSH | Number of Participants With Clinical Pregnancy | 5 Participants |
Secondary
Number of Participants With Positive Pregnancy Test
The beta Human Chorionic Gonadotropin (beta-hCG) test was used as pregnancy test.
Time frame: Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| r-FSH + r-hLH | Number of Participants With Positive Pregnancy Test | 3 Participants |
| r-FSH | Number of Participants With Positive Pregnancy Test | 5 Participants |
Secondary
Oocyte Nuclear Maturity Rate
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.
Time frame: At the end of stimulation (Day 2 up to Day 8)
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-FSH + r-hLH | Oocyte Nuclear Maturity Rate | 0.73 metaphase II oocytes/retrieved oocyte | Standard Deviation 0.75 |
| r-FSH | Oocyte Nuclear Maturity Rate | 0.61 metaphase II oocytes/retrieved oocyte | Standard Deviation 0.26 |
Secondary
Plasma Level of Estradiol
Time frame: At the time of r-hCG administration (any days between Day 2 to Day 8)
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-FSH + r-hLH | Plasma Level of Estradiol | 1218 Picograms per milliliters (pg/mL) | Standard Deviation 699 |
| r-FSH | Plasma Level of Estradiol | 1029 Picograms per milliliters (pg/mL) | Standard Deviation 336 |
Secondary
Plasma Levels of LH
Time frame: At the time of r-hCG administration (any days between Day 2 to Day 8)
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-FSH + r-hLH | Plasma Levels of LH | 2.8 IU per liter (IU/L) | Standard Deviation 1 |
| r-FSH | Plasma Levels of LH | 2.1 IU per liter (IU/L) | Standard Deviation 2.1 |
Secondary
rFSH Cumulative Dose
Time frame: Randomization to Day 8
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-FSH + r-hLH | rFSH Cumulative Dose | 4338 IU | Standard Deviation 1241 |
| r-FSH | rFSH Cumulative Dose | 4298 IU | Standard Deviation 1137 |