A Randomised, Phase II, Comparative Study With a Parallel Control for Evaluating the Efficacy and Safety of Combined Treatment of Lutropin Alpha and Recombinant Human Luteinizing Hormone in the Middle of the Controlled Ovarian Stimulation Follicular Phase in Women With Reduced Ovarian Reserve

Study Overview
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Brief Summary
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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).

Official Title
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Lutropin Alpha in the Middle of the Controlled Ovarian Stimulation Follicular Phase in Women With Reduced Ovarian Reserve: Comparative Study, in Phase II, With Parallel Control

Conditions
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Infertility, Ovulation Induction

Intervention / Treatment
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* Drug: Recombinant human follicle stimulating hormone (r-hFSH)
* Drug: Recombinant human luteinizing hormone (r-hLH)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: r-hFSH + r-hLH<br> | Drug: Recombinant human follicle stimulating hormone (r-hFSH)<br>* 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]).<br>* Other names: Follitrophin alpha;Drug: Recombinant human luteinizing hormone (r-hLH)<br>* Subjects will receive subcutaneous injection of recombinant human luteinizing hormone (r-hLH) 150 IU/day until the end of ovarian stimulation.<br>* Other names: Lutrophin alpha;|
| Active Comparator: r-hFSH alone<br> | Drug: Recombinant human luteinizing hormone (r-hLH)<br>* Subjects will receive subcutaneous injection of recombinant human luteinizing hormone (r-hLH) 150 IU/day until the end of ovarian stimulation.<br>* Other names: Lutrophin alpha;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 36 hours post r-hCG administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 36 hours post r-hCG administration | 
| 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. | Day 2-3 post r-hCG administration | 
| 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. | 35-42 days post r-hCG administration | 
| 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. | 35-42 days post r-hCG administration | 
| 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. | r-hCG day (end of stimulation cycle [approximately 28 days]) | 
| Endometrial Thickness |  | r-hCG day (end of stimulation cycle [approximately 28 days]) | 
| 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 | r-hCG day (end of stimulation cycle [approximately 28 days]) | 
| 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. | 36 hours post r-hCG administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Reproductive technology, Assisted, Recombinant human follicle stimulating hormone (r-hFSH), Recombinant leutinizing hormone (r-hLH), Ovulation induction, Infertility