Infertility, Ovulation Induction
Conditions
Keywords
Reproductive technology, Assisted, Recombinant human follicle stimulating hormone (r-hFSH), Recombinant leutinizing hormone (r-hLH), Ovulation induction, Infertility
Brief summary
This was a prospective, randomized, Phase II, comparative study with a parallel control for evaluating the efficacy and safety of combined treatment of recombinant human follicle stimulating hormone (r-hFSH) and recombinant human luteinizing hormone (r-hLH). The combined treatment was administered at the middle of the follicular phase in subjects undergoing in-vitro fertilisation (IVF) through intracytoplasmic sperm injection (ICSI) and transfer of embryos (ET).
Interventions
Subjects will receive subcutaneous injection of recombinant human follicular stimulating hormone (r-hFSH) 300-450 International Units (IU) administered after pituitary desensitization according to the ovarian response with gonadotrophin-releasing hormone agonist (GnRH-a; at a dose of 0.1 milligram per day \[mg/day\]).
Subjects will receive subcutaneous injection of recombinant human luteinizing hormone (r-hLH) 150 IU/day until the end of ovarian stimulation.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
35 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
All subjects must meet the following inclusion criteria within the 6 months prior to starting the pituitary suppression unless otherwise specified: * Postmenopausal woman aged between 35 and 40 years that wishes to become pregnant * Subjects with basal serum level (beginning of the follicular phase, Day 2-5) of Follicle-Stimulating Hormone (FSH) less than 10 IU/L determined within the 6 months prior as well as Luteinizing hormone (LH) and Estradiol (E2) levels within the normal interval according to standard data for the area where the study was carried out * Subjects with a regular menstrual cycles between 25-35 days * Subjects with infertility that justifies treatment with IVF/ET or ICSI * Subjects undergoing controlled ovarian stimulation (COS) with r-hFSH using a long protocol with GnRH-a * Sperm availability from the subject's current partner unless it is planned to use sperm from a donor * Subjects with both ovaries * Subjects with uterine cavity capable of withstanding the implantation of the embryo and pregnancy * Subjects whose vaginal smear (PAP) was normal within the 3 years prior to starting the stimulation * Subjects with body mass index (BMI) between 18 and 30 at the time of participation in the study * Subjects in whom at least 30 days have elapsed since the last dose of clomiphene citrate or gonadotropins before beginning treatment with GnRH-a * Subjects with a negative pregnancy test result using the beta human chorionic gonadotropin (beta-hCG) test (in urine or blood) before beginning treatment with GnRH-a * Subjects willing to and capable of following the protocol during the entire study * Subjects who have provided informed written consent before carrying out any procedure related with the study (that is not part of the normal medical treatment followed by the subject)
Exclusion criteria
* Subject who were human immunodeficiency virus, hepatitis B and C virus positive * Subjects suffering from any clinically important systematic disease, hypothalmic or pituitary tumour, ovarian, uterine or breast cancer, endocrinopathy and/or medical alterations, biochemical or hematological that as per the investigators judgement, may interfere with the gonadotropin treatment * Subjects who have been subjected to more than 2 assisted reproductive cycles in the past * Subjects who have cancelled 2 cycles in the past * Subjects who have cryopreserved embryos from previous assisted reproductive cycles * Subjects with non explained vaginal haemorrhages * Subjects with polycystic ovary, enlarged ovary or ovarian cysts of unknown aetiology * Subjects with any contraindication for getting pregnant or taking the pregnancy to full term * Subjects with known allergy to the gonadotropin preparations or any of its excipients * Subjects with current drug use or prior personal history of alcohol, drug or psychiatric drug dependency in the past five years * Subjects with prior participation in this study or simultaneous participation in a different clinical study with a medication under investigation * Subjects who were not willing to or incapable of following the study protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Metaphase II (M-II) Oocytes Retrieved | 36 hours post r-hCG administration | Mean number of M-II oocytes were calculated for subjects undergoing ovum pick up for Intra-cytoplasmic Sperm Injection (ICSI). ICSI is an in-vitro fertilization procedure in which a single sperm is injected directly into an egg under a microscope. Metaphase II stage of the oocyte was classified as the time at which the first polar body was observed microscopically. Metaphase II oocytes are a sub-group of the total number of oocytes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Embryos | Day 2-3 post r-hCG administration | Embryos were classified into 5 different grades (1 to 5) based on their capacity of implantation. Grade 1 embryos were those with best capacity of implantation and Grade 5 embryos were those with worst capacity of implantation. Mean number of embryos for each of the 5 grades were reported. |
| Embryo Implantation Rate | 35-42 days post r-hCG administration | Embryo implantation rate was measured as the number of gestational sacs observed divided by the number of embryos transferred multiplied by 100. |
| Clinical Pregnancy Rate | 35-42 days post r-hCG administration | Clinical pregnancy rate defined as the percentage of subjects with a ultrasound confirmation of a gestational sac, with or without fetal heart activity. |
| Number of Fertilized Oocytes (2 Pronuclei [2PN]) | 36 hours post r-hCG administration | Oocytes were fertilized using Intra-cytoplasmic Sperm Injection (ICSI) technique which is an in-vitro fertilization procedure in which a single sperm is injected directly into an egg under a microscope. The appearance of 2PN is the first sign of successful fertilization as observed during in vitro fertilization, and is usually observed after ICSI. The zygote is then termed 2PN. |
| Endometrial Thickness | r-hCG day (end of stimulation cycle [approximately 28 days]) | — |
| Number of Cycles Cancelled Due to Unsatisfactory Response | r-hCG day (end of stimulation cycle [approximately 28 days]) | If the subject was not administered with r-hCG and withdrew prematurely from the trail, it is considered as cycle cancellation |
| Mean Number of Oocytes Retrieved | 36 hours post r-hCG administration | Oocyte retrieval is a technique used in in-vitro fertilization (IVF) in order to remove oocyte from the ovary of the female subject, enabling fertilization outside the body. |
| Mean Number of Follicles Greater Than or Equal to (>=) 14 Millimeter (mm) | r-hCG day (end of stimulation cycle [approximately 28 days]) | Mean number of follicles as per the following categories were presented: \>=14 mm and less than (\<) 16 mm; \>=16 mm and \<18 mm and \>=18 mm. |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| r-hFSH + r-hLH Subjects received subcutaneous injection of recombinant human follicular stimulating hormone (r-hFSH) 300-450 International Units (IU) administered after pituitary desensitization according to the ovarian response with gonadotrophin-releasing hormone agonist (GnRH-a; at a dose of 0.1 milligram per day \[mg/day\]) along with subcutaneous injection of recombinant human luteinizing hormone (r-hLH) 150 IU/day until the end of ovarian stimulation. Administration of both r-hFSH and r-hLH was suspended 36 hours before administering recombinant human chorionic gonadotrophin (r-hCG). | 63 |
| r-hFSH Alone Subjects received subcutaneous injection of a recombinant human follicular stimulating hormone (r-hFSH) 300-450 International Units (IU) administered after pituitary desensitization according to the ovarian response with gonadotrophin-releasing hormone agonist (GnRH-a; at a dose of 0.1 milligram per day \[mg/day\]). | 68 |
| Total | 131 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 3 |
Baseline characteristics
| Characteristic | r-hFSH + r-hLH | r-hFSH Alone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 63 Participants | 68 Participants | 131 Participants |
| Sex: Female, Male Female | 63 Participants | 68 Participants | 131 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 | 2 / 63 | 0 / 68 |
| serious Total, serious adverse events | 0 / 63 | 0 / 68 |
Outcome results
Primary
Mean Number of Metaphase II (M-II) Oocytes Retrieved
Mean number of M-II oocytes were calculated for subjects undergoing ovum pick up for Intra-cytoplasmic Sperm Injection (ICSI). ICSI is an in-vitro fertilization procedure in which a single sperm is injected directly into an egg under a microscope. Metaphase II stage of the oocyte was classified as the time at which the first polar body was observed microscopically. Metaphase II oocytes are a sub-group of the total number of oocytes.
Time frame: 36 hours post r-hCG administration
Population: The Intention-To-Treat (ITT) analysis set included all the randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-hFSH + r-hLH | Mean Number of Metaphase II (M-II) Oocytes Retrieved | 6.7 M-II oocytes | Standard Deviation 4.1 |
| r-hFSH Alone | Mean Number of Metaphase II (M-II) Oocytes Retrieved | 7.0 M-II oocytes | Standard Deviation 4.8 |
Secondary
Clinical Pregnancy Rate
Clinical pregnancy rate defined as the percentage of subjects with a ultrasound confirmation of a gestational sac, with or without fetal heart activity.
Time frame: 35-42 days post r-hCG administration
Population: The ITT analysis set included all the randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| r-hFSH + r-hLH | Clinical Pregnancy Rate | 27.0 Percentage of subjects |
| r-hFSH Alone | Clinical Pregnancy Rate | 14.7 Percentage of subjects |
Secondary
Embryo Implantation Rate
Embryo implantation rate was measured as the number of gestational sacs observed divided by the number of embryos transferred multiplied by 100.
Time frame: 35-42 days post r-hCG administration
Population: The ITT analysis set included all the randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| r-hFSH + r-hLH | Embryo Implantation Rate | 18.1 Percent sacs per embryo |
| r-hFSH Alone | Embryo Implantation Rate | 11.3 Percent sacs per embryo |
Secondary
Endometrial Thickness
Time frame: r-hCG day (end of stimulation cycle [approximately 28 days])
Population: The ITT analysis set included all the randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-hFSH + r-hLH | Endometrial Thickness | 6.0 mm | Standard Deviation 3.2 |
| r-hFSH Alone | Endometrial Thickness | 5.9 mm | Standard Deviation 3.2 |
Secondary
Mean Number of Follicles Greater Than or Equal to (>=) 14 Millimeter (mm)
Mean number of follicles as per the following categories were presented: \>=14 mm and less than (\<) 16 mm; \>=16 mm and \<18 mm and \>=18 mm.
Time frame: r-hCG day (end of stimulation cycle [approximately 28 days])
Population: The ITT analysis included all the randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| r-hFSH + r-hLH | Mean Number of Follicles Greater Than or Equal to (>=) 14 Millimeter (mm) | >=14 mm and <16 mm | 2.2 Follicles | Standard Deviation 2 |
| r-hFSH + r-hLH | Mean Number of Follicles Greater Than or Equal to (>=) 14 Millimeter (mm) | >=16 mm and <18 mm | 2.3 Follicles | Standard Deviation 2 |
| r-hFSH + r-hLH | Mean Number of Follicles Greater Than or Equal to (>=) 14 Millimeter (mm) | >=18 mm | 4.0 Follicles | Standard Deviation 3 |
| r-hFSH Alone | Mean Number of Follicles Greater Than or Equal to (>=) 14 Millimeter (mm) | >=14 mm and <16 mm | 2.1 Follicles | Standard Deviation 1.9 |
| r-hFSH Alone | Mean Number of Follicles Greater Than or Equal to (>=) 14 Millimeter (mm) | >=16 mm and <18 mm | 2.7 Follicles | Standard Deviation 2.1 |
| r-hFSH Alone | Mean Number of Follicles Greater Than or Equal to (>=) 14 Millimeter (mm) | >=18 mm | 3.7 Follicles | Standard Deviation 3 |
Secondary
Mean Number of Oocytes Retrieved
Oocyte retrieval is a technique used in in-vitro fertilization (IVF) in order to remove oocyte from the ovary of the female subject, enabling fertilization outside the body.
Time frame: 36 hours post r-hCG administration
Population: The ITT analysis included all the randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-hFSH + r-hLH | Mean Number of Oocytes Retrieved | 8.3 Oocytes | Standard Deviation 4.7 |
| r-hFSH Alone | Mean Number of Oocytes Retrieved | 8.9 Oocytes | Standard Deviation 4.9 |
Secondary
Number of Cycles Cancelled Due to Unsatisfactory Response
If the subject was not administered with r-hCG and withdrew prematurely from the trail, it is considered as cycle cancellation
Time frame: r-hCG day (end of stimulation cycle [approximately 28 days])
Population: The ITT analysis included all the randomized subjects who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| r-hFSH + r-hLH | Number of Cycles Cancelled Due to Unsatisfactory Response | 0 cycles |
| r-hFSH Alone | Number of Cycles Cancelled Due to Unsatisfactory Response | 3 cycles |
Secondary
Number of Fertilized Oocytes (2 Pronuclei [2PN])
Oocytes were fertilized using Intra-cytoplasmic Sperm Injection (ICSI) technique which is an in-vitro fertilization procedure in which a single sperm is injected directly into an egg under a microscope. The appearance of 2PN is the first sign of successful fertilization as observed during in vitro fertilization, and is usually observed after ICSI. The zygote is then termed 2PN.
Time frame: 36 hours post r-hCG administration
Population: The ITT analysis set included all the randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-hFSH + r-hLH | Number of Fertilized Oocytes (2 Pronuclei [2PN]) | 3.1 2PN oocytes | Standard Deviation 2.3 |
| r-hFSH Alone | Number of Fertilized Oocytes (2 Pronuclei [2PN]) | 3.3 2PN oocytes | Standard Deviation 2.6 |
Secondary
Quality of Embryos
Embryos were classified into 5 different grades (1 to 5) based on their capacity of implantation. Grade 1 embryos were those with best capacity of implantation and Grade 5 embryos were those with worst capacity of implantation. Mean number of embryos for each of the 5 grades were reported.
Time frame: Day 2-3 post r-hCG administration
Population: The ITT analysis set included all the randomized subjects who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| r-hFSH + r-hLH | Quality of Embryos | Grade 4 | 0.3 embryos | Standard Deviation 0.5 |
| r-hFSH + r-hLH | Quality of Embryos | Grade 1 | 1.1 embryos | Standard Deviation 1.1 |
| r-hFSH + r-hLH | Quality of Embryos | Grade 3 | 0.5 embryos | Standard Deviation 0.6 |
| r-hFSH + r-hLH | Quality of Embryos | Grade 2 | 1.1 embryos | Standard Deviation 1.5 |
| r-hFSH + r-hLH | Quality of Embryos | Grade 5 | 0.3 embryos | Standard Deviation 1 |
| r-hFSH Alone | Quality of Embryos | Grade 2 | 1.2 embryos | Standard Deviation 1.1 |
| r-hFSH Alone | Quality of Embryos | Grade 5 | 0.2 embryos | Standard Deviation 0.6 |
| r-hFSH Alone | Quality of Embryos | Grade 3 | 0.5 embryos | Standard Deviation 0.9 |
| r-hFSH Alone | Quality of Embryos | Grade 1 | 1.3 embryos | Standard Deviation 1.4 |
| r-hFSH Alone | Quality of Embryos | Grade 4 | 0.2 embryos | Standard Deviation 0.6 |