Clinical trial NCT01210144
Conditions: In Vitro Fertilization
Keywords: Infertility Gonal-f gene expression Assisted Reproductive Technologies Follitropin alfa endometrium
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2008-08-01; Completion date: 2010-08-01
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase IV, pilot, open-label, national, multi-centric study planned to determine the gene expression profiles and histologic changes of the endometrial tissue before and after stimulation with Gonal-f®. Physicians are interested in identifying predictive genetic markers in assisted reproductive technologies (ART) in addition to the clinical predictive factors already known. Among those predictive factors, the state of the endometrium is considered as an important implantation determining factor for which pharmacogenomic research is of great interest.

The direct benefits of this study will be to know whether the endometrial gene expression profile is modified in response to stimulation treatment and have an impact or not on the endometrial tissue receptivity. The potential benefits of this study could be to assess the therapy optimization based on individual treatment response and gene expression profile compared to group treatment response in infertile women and prediction of response to therapy based on gene expression profiling before and after Gonal-f® stimulation in infertile women.

Detailed description:
This is a pilot open-label, national, multi-centre, Phase IV trial. This trial will be conducted with outpatients. Once subject has met all eligibility criteria, she will be treated with Gonal-f® prefilled pen and will receive on a randomization basis the GnRH agonist or antagonist. The follicle stimulating hormone (FSH) stimulation will start on day 2 of the menstrual cycle with a pre-defined fixed dose of 150 IU per day until follicles are recruited and developed. Dose adjustment will be allowed strictly in case of risk of ovarian hyperstimulation syndrome (OHSS). Ovulation triggering will be performed using a single injection of 250 mcg Ovitrelle®.

Ultrasound scans (US) will be performed concomitantly with hormonal assessment at each visit. Ovulation will be triggered as soon as there are at least 3 follicles \> 16 mm, and with E2 \> 1 mcg/L if agonist used. Oocyte retrieval, in vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI) and blastocyst transfer will be performed as per centre's standard practice. Vaginal progesterone will be administered in the luteal phase for all subjects (600 milligram per day \[mg/d\]).

Hormonal assessment and endometrial biopsy will be performed on:

* Day Luteinizing Hormone+7 ("LH+7") of the previous spontaneous cycle
* Day of Oocyte Retrieval (OR) of the stimulated cycle
* Day "OR+5 or 6" (biopsy performed only in subjects that did not have blastocyst(s) transfer).

Gene expression profiling will be carried out on ribonucleic acid (RNA) from endometrial tissue. As the main objective of this trial is to determine the gene expression profiles of endometrial tissue before and after controlled ovarian stimulation with Gonal-f®, a minimum of 2 endometrial samples per subject will be collected, 1 at day LH+7 of spontaneous cycle and 1 after the stimulation, on the day of OR.

The subjects will be followed up until 15 days after the last injection of Investigational Medicinal Products (IMPs) for the safety assessment. For subjects who will have blastocyst implantation, the pregnancy outcomes will be recorded until 12 weeks of gestation if a pregnancy is ongoing up to that period.

OBJECTIVES

Primary objective:

* To determine the gene expression profile and histological changes of endometrial tissue before (at day LH + 7 of spontaneous cycle) and after stimulation with Gonal-f® (Day of OR: 36 +/- 2 hours post r-hCG administration) in Assisted Reproductive Technology (ART) \[IVF/ICSI\]

Secondary objectives:

* To correlate the gene expression profile of the endometrial tissue at Day LH + 7 of the spontaneous cycle with the blastocyst implantation rate in subjects undergoing ART with Gonal-f®
* To correlate the gene expression profile and histological changes in endometrial tissue before and after stimulation by Gonal-f® with the "down regulation" protocol used (agonist or antagonist) and fertilization mode, IVF/ICSI
* To correlate the gene expression profile and histological changes in endometrial tissue before and after stimulation by Gonal-f® according to the hormonal status of subjects
* To characterize the gene expression profile and histology of endometrial tissue after stimulation with Gonal-f in subjects without blastocyst during the theoretical window of implantation (OR + 5 or 6 days)
* To characterize the gene expression profile and histology of endometrial tissue of good and poor responders to stimulation with Gonal-f® on the Day of OR (response being based on the following criteria):

  1. Quantity of mature oocytes retrieved:

     * Poor responders: 5 mature oocytes or less
     * Good responders: more than 8 mature oocytes
  2. Quantity of Gonal-f® used

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Gonal -f® [r-hFSH] intervention 2: Ovitrelle® [r-hCG alfa] intervention 3: Gonadotropin-releasing hormone (GnRH) Agonist intervention 4: Gonadotropin-releasing hormone (GnRH) Antagonist
Intervention descriptions: intervention 1: On Day 2 of the menstrual cycle, a pre-defined fixed dose of 150 International Units (IU) per day of recombinant human follicle stimulating hormone (r-hFSH) will be administered until follicles are recruited and developed. intervention 2: Ovulation triggering will be performed using a single injection of 250 microgram (mcg) recombinant human chorionic gonadotropin (r-hCG) alfa as soon as follicles satisfy the criteria for follicular development, that is at least 3 follicles greater than (\>) 16 millimeter (mm), and with estradiol (E2) \> 1 microgram per liter (mcg/L) if gonadotropin releasing hormone (GnRH) agonist will be used. intervention 3: To prevent premature ovulation in participants undergoing a controlled ovarian stimulation (COS), 0.1 milligram (mg) GnRH agonist daily will be given after endometrial biopsy, 7 days after the peak day of luteinizing hormone (Day LH + 7) as per summary of product characteristics (SmPC), in long agonist protocol. intervention 4: To prevent premature ovulation in participants undergoing a COS, 0.25 mg GnRH antagonist daily will be given from Day 6 of Gonal-f® stimulation treatment as per SmPC, in multi-dose antagonist protocol.

Protocol documents: