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

Phase 2

Completed

Conditions: Ovulation Induction
Infertility

Interventions: Drug: Recombinant human luteinizing hormone (r-hLH)
Drug: Recombinant human follicle stimulating hormone (r-hFSH)

Registration Number: NCT01110707

Lead Sponsor: Merck KGaA, Darmstadt, Germany

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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 131

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
r-hFSH alone	Recombinant human luteinizing hormone (r-hLH)	-
r-hFSH + r-hLH	Recombinant human follicle stimulating hormone (r-hFSH)	-
r-hFSH + r-hLH	Recombinant human luteinizing hormone (r-hLH)	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
Endometrial Thickness	r-hCG day (end of stimulation cycle [approximately 28 days])
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.
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.
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.
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.
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