Study to Evaluate if the Addition of r-hLH (Luveris®) to FSH From Day 8 of Ovarian Stimulation is Able to Decrease Total FSH Dose and to Improve Cycle Outcome in Infertile Women Undergoing ART, Who Required High FSH Dose in a Previous Cycle (Luveris in ART)

• Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose [ Time Frame: Baseline (S8) until hCG day ] [ Designated as safety issue: No ]
• Mean Number of Ovarian Stimulation Days [ Time Frame: Baseline (S8) until hCG day ] [ Designated as safety issue: No ]
• Change From Baseline in Oestradiol (E2) Levels at Human Choriogonadotropin (hCG) Day [ Time Frame: Baseline (S8) and hCG day ] [ Designated as safety issue: No ]
• Mean Total Number of Retrieved Oocytes [ Time Frame: 34-36 hours post-hCG (OPU) ] [ Designated as safety issue: No ]
  Mean number of oocytes retrieved on the day of ovum pick up (OPU) was counted. Oocyte retrieval is a technique used in in-vitro fertilization in order to remove oocytes from the ovary of the female, enabling fertilization outside the body.
• Mean Number of Mature Oocytes (Metaphase II) [ Time Frame: 34-36 hours post-hCG (OPU) ] [ Designated as safety issue: No ]
  Mean number of metaphase II oocytes was counted for participants undergoing ovum pick up for IntraCytoplasmic Sperm Injection (ICSI). ICSI is a procedure in which a single spermatozoon is injected into the oocyte cytoplasm. 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.
• Fertilization Rate [ Time Frame: 12-18 day post-hCG and/or Week 7 ] [ Designated as safety issue: No ]
  Fertilization rate was measured as the ratio between number of fertilized oocytes and number of inseminated oocytes (maximum 3).
• Number of Obtained Embryos [ Time Frame: Day 3 post-hCG (Embryo transfer [ET]) ] [ Designated as safety issue: No ]
  Total number of obtained embryos with maximum 3 inseminated oocytes was calculated.
• Number of Transferred Embryos [ Time Frame: Day 3 post-hCG (ET) ] [ Designated as safety issue: No ]
  Embryo transfer is the procedure in which one or more embryos are placed in the uterus or Fallopian tube.
• Percentage of Participants With Pregnancy [ Time Frame: 12-18 day post-hCG and/or Week 7 ] [ Designated as safety issue: No ]
• Percentage of Participants With Clinical Pregnancy [ Time Frame: 12-18 day post-hCG and/or Week 7 ] [ Designated as safety issue: No ]
  Clinical pregnancy is defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes ectopic pregnancy.
• Percentage of Participants With Implantation [ Time Frame: 12-18 day post-hCG and/or Week 7 ] [ Designated as safety issue: No ]
  Implantation is the attachment and subsequent penetration by the zona-free blastocyst (usually in the endometrium) that starts five to seven days after fertilization.
• Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS) [ Time Frame: Baseline (S8) until 12-18 day post-hCG and/or Week 7 ] [ Designated as safety issue: Yes ]
  OHSS is an exaggerated systemic response to ovarian stimulation characterized by a wide spectrum of clinical and laboratory manifestations. It is classified as mild, moderate or severe according to the degree of abdominal distention, ovarian enlargement and respiratory, haemodynamic and metabolic complications.
• Number of Cycles Cancelled Due to Risk of OHSS [ Time Frame: Baseline (S8) until 12-18 day post-hCG and/or Week 7 ] [ Designated as safety issue: Yes ]
  OHSS is an exaggerated systemic response to ovarian stimulation characterized by a wide spectrum of clinical and laboratory manifestations. It is classified as mild, moderate or severe according to the degree of abdominal distention, ovarian enlargement and respiratory, haemodynamic and metabolic complications.

The present study was designed to investigate, in hyporesponder subjects, that required in a previous assisted reproductive technologies (ART) cycle follicle stimulating hormone (FSH) >3500 International Unit (IU), the possibility to decrease through recombinant human luteinizing hormone (r-hLH) supplementation, the FSH amount per oocytes retrieved and in the mean time to improve the overall cycle outcome.

Recombinant human follicle stimulating hormone (r-hFSH), which totally lacks LH activity, is widely used to induce multiple follicle development in women under pituitary desensitization, in order to submit them to treatment with assisted reproduction techniques (ART). Clinical experience from hypogonadotropic-hypogonadic women suggests that while FSH alone is sufficient to induce follicle development, LH plays a significant part in final follicle maturation, estrogen synthesis and optimal endometrium growth.

This was a phase III, multicentre, randomized, open-label comparative study to evaluate if the addition of r-hLH (Luveris) in a 2:1 ratio to FSH from day 8 of ovarian stimulation is able to decrease the total FSH dose and to improve cycle outcome in 250 infertile women undergoing ART, who required high FSH dose in a previous cycle (≥ 3500 IU). Subjects who have met all the inclusion criteria, achieved pituitary desensitization and started controlled ovarian hyperstimulation (COH) treatment with FSH, on stimulation day 8 (S8) received an identification number and will be allocated to one of the two following arms:

Arm : FSH + r-hLH (2:1 ratio of FSH:r-hLH), Arm : FSH alone. Treatment with Luveris was commenced on day 8 (S8) and continued until injection of hCG or cancellation of the treatment cycle.

Monitoring of stimulation, FSH dose escalation, criteria for injection of hCG, ovum pick up, embryo transfer and pregnancy confirmation took place according to standard management practice. The in-vitro fertilization (IVF) or intracytosolic sperm injection (ICSI) procedure, including luteal phase support, was performed according to each centres' normal procedures.

The subjects were followed up and the treatment outcome (menstruation or pregnancy) was recorded. The delivery outcome for any pregnant subjects was recorded in the Case Report Form (CRF).

Information on the delivery outcome for each pregnancy was collected. Information on adverse events was collected during the study period.

OBJECTIVES

The primary objective of the study was:

To determine whether the addition of r-hLH (Luveris) from day 8 of ovarian stimulation reduces the FSH dose needed to obtain/retrieve each oocyte.

The secondary objectives of the study were:

• To determine whether the addition of Luveris to FSH at day 8 of ovarian stimulation improves cycle outcome based on secondary endpoints
• To determine the safety of Luveris in this indication

• Drug: Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH)
  One r-hFSH and one r-hLH injection subcutaneously (s.c.) once daily during the treatment phase from Day 8 of stimulation until injection of human chorionic gonadotropin (hCG) or cancellation of the treatment cycle.
  Other Names:

  • r-hLH
  • r-hFSH
• Drug: r-hFSH
  One r-hFSH injection s.c. once daily during the treatment phase from Day 8 of stimulation until injection of hCG or cancellation of the treatment cycle.
  Other Name: r-hFSH

• Experimental: A
  Subjects treated with r-hFSH and r-hLH (2:1 ratio of r-hFSH:r-hLH)
  Intervention: Drug: Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH)
• Active Comparator: B
  Subjects treated with r-hFSH alone
  Intervention: Drug: r-hFSH

Inclusion Criteria:

• Pre-menopausal infertile woman, aged 18 to 40 years inclusive, who wishes to conceive
• Regular, spontaneous menstrual cycle of 25-35 days
• Body mass index (BMI) ≤ 28
• FSH ≤ 10 IU/L (follicular phase, days 2-5)
• Prolactin (PRL) within the normal ranges
• Evidence of both ovaries by ultrasound scan
• Women undergoing IVF-Embryo Transfer (ET) or ICSI, down regulated with Gonadotropin releasing hormone analogues (GnRHa) (daily dose) under controlled ovarian hyperstimulation (COH) with FSH
• Washout > 90 days from last dose of clomiphene or gonadotrophin, before ongoing COH cycle
• Only one previous IVF-ET or ICSI cycle (in the last 9 months preceding the ongoing COH cycle) resulted in a hypo-response properly documented (from 6 to 12 oocytes with a total FSH dose ≥ 4000 IU)
• Negative pregnancy hCG test (urine or blood sample) before the ongoing COH cycles
• Willing and able to comply with the protocol for the duration of the study
• Written informed consent before applying any procedure related to the study protocol, which is not part of routine medical care, with the understanding that consent may be withdrawn by the subject at any time, without prejudice on their future medical care

Exclusion Criteria:

• Oligo/Anovulatory cycles (World Health Organization [WHO] I and II)
• Male partner azoospermia (assessed within the last 12 months)
• Follicular phase (day 2-5) FSH > 10 IU/L even if only once observed in the medical history
• Abnormal cervical cytology (assessed within the last 12 months)
• History of unexplained gynecologic hemorrhage
• Any contraindication to pregnancy
• Known allergy to gonadotrophin
• Any clinically important systemic disease (e.g. insulin-dependent diabetes mellitus, epilepsy, serious migraine, intermittent purpura, hepatic, renal or cardiovascular disease, serious corticoid-dependent asthma) which constitutes a contraindication to gonadotropin use
• Any medical condition which, according to the investigator's judgement, may affect the absorption, distribution, metabolism or excretion of the drug. In case of doubt, inclusion of the subject in question should be discussed with the Medical Responsible of Serono
• Known Human Immunodeficiency Virus (HIV) positivity
• Any substance abuse or history of drugs or alcohol abuse within the past 5 years
• Prior inclusion in the present study or simultaneous inclusion in a clinical study of another drug
• Refusal or inability to comply with the protocol