A Trial to Compare the Efficacy and Safety of Ovarian Stimulation With GONAL-f® and Luveris® Starting on Day 1 Versus Day 6 in Women Undergoing Assisted Reproductive Technique

• Total dose of FSH used (in IU) [ Time Frame: After completion of stimulation (day 1 to 6) ] [ Designated as safety issue: No ]
• Mean daily dose of FSH (in IU) [ Time Frame: day 1 to 6 ] [ Designated as safety issue: No ]
• Total number of stimulation treatment days [ Time Frame: After completion of stimulation (day 1 to 6) ] [ Designated as safety issue: No ]
• Implantation rate (foetal sacs per total number of embryos transferred) [ Time Frame: 35-42 days after r-hCG ] [ Designated as safety issue: No ]
• Number of foetal sacs and foetal hearts with activity as seen on an US scan on Day 35-42 post r-hCG (to confirm clinical pregnancy) [ Time Frame: 35-42 days after r-hCG ] [ Designated as safety issue: No ]
• Total and clinical pregnancy rate per subject (per cycle started, and per embryo transfer) [ Time Frame: 35-42 days after r-hCG ] [ Designated as safety issue: No ]
• Cycle cancellation rate prior to r-hCG [ Time Frame: Maximum 85 days ] [ Designated as safety issue: No ]
• Number of biochemical pregnancies (by serum beta-hCG level) [ Time Frame: 35 to 42 days after r-hCG ] [ Designated as safety issue: No ]
• Multiple pregnancy [ Time Frame: 35 to 42 days after r-hCG ] [ Designated as safety issue: No ]
• Occurrence of any adverse events (inc. rate of early and late ovarian hyperstimulation syndrome (OHSS) [ Time Frame: 15 to 20 Days after r-hCG ] [ Designated as safety issue: Yes ]

This is a phase IIIb, interventional, multicentre, multinational, randomised, open-label, comparative trial which primary objective is to generate data on the ovarian stimulation profile obtained when Luveris® is started either on day 1 or day 6 in women in advanced reproductive age (36-42) undergoing Assisted Reproductive Technique (ART).

The subjects who have completed the screening assessments and fulfil all of the eligibility criteria will start down-regulation treatment on day 21-22 of the cycle.

Down-regulation treatment must start within 2 months following the screening visit. The routine long luteal phase protocol for Gonadotrophin-releasing hormone (GnRH) agonist treatment will be followed.

Once down-regulation has been confirmed, a pregnancy test will be performed within one week prior to start of Recombinant human follicle stimulating hormone (r-hFSH) treatment to rule out any pre-existing pregnancy. If the result is negative, the subject will be randomly assigned to one of the two treatment arms of the trial:

• GONAL-f® (Liquid Pen; 300 IU per day) stimulation day 1-5 then add Luveris® (vial/powder, 150 IU per day) from stimulation day 6 and until required recombinant Human chorionic gonadotrophin (r-hCG) level is met. The dose can be adjusted from stimulation day 6 (increased or decreased) based upon the subject's ovarian response and according to the centre's standard practice.
• GONAL-f® (Liquid Pen; 300 IU of per day) stimulation day 1-5 then followed by Luveris® (vial/powder, 150 IU per day) from stimulation day 1 and until required r-hCG level is met. The dose can be adjusted from stimulation day 6 (increased or decreased) based upon the subject's ovarian response and according to the centre's standard practice.

Randomisation across the two treatment arms will be kept balanced in a 1:1 ratio. Subjects will be provided with a subject diary and safety information to record daily dosing information for GONAL-f® and Luveris®. The diary card will also capture information about r-hCG and Crinone® administration and safety.

Follicular development will be monitored according to the centre's standard practice by Ultrasound Scan (US) and/or Oestradiol (E2) levels, until the protocol r-hCG requirement is met (i.e., at least 1 follicle greater or equal to 18 mm and 2 follicles greater or equal to 16 mm). After this, a single injection of 250 mcg of r-hCG (Ovidrel®/Ovitrelle®), will be administered in order to induce final oocyte maturation.

At a time of 34-38 hours after r-hCG administration, oocytes will be recovered vaginally under US monitoring. Oocytes will then be fertilized in vitro and embryos replaced 2-3 days after oocyte recovery. Ovum pick up (OPU), in vitro fertilisation (IVF), Embryo Transfer (ET) and luteal support will be performed as per centre's standard practice. In addition, Crinone 8%® (progesterone gel) will be administered once daily.

A post-treatment safety visit will be performed for all subjects who received r-hCG (pregnant and non-pregnant) on post r-hCG Day 15-20. For subjects who have withdrawn from treatment (i.e. after starting Luveris® or GONAL f® but before r-hCG is given) this visit will take place 20-30 days after their first Luveris® or GONAL-f® treatment injection (excluding pregnancy testing).

• Infertility
• Fertility
• Follicle Stimulating Hormone Deficiency

• Drug: Lutropin alfa
  Luveris® (vial/powder, 150 IU per day) from stimulation day 1 and until required r-hCG level is met.
• Drug: Lutropin alpha
  Luveris® (vial/powder, 150 IU per day) from stimulation day 6 and until required r-hCG level is met.

• Experimental: Luveris® from stimulation day 6
  GONAL-f® (Liquid Pen; 300 IU per day) stimulation day 1-5 then add Luveris® (vial/powder, 150 IU per day) from stimulation day 6 and until required r hCG level is met. The dose can be adjusted from stimulation day 6 (increased or decreased) based upon the subject's ovarian response and according to the centre's standard practice.
  Intervention: Drug: Lutropin alpha
• Experimental: Luveris® from stimulation day 1
  GONAL f® (Liquid Pen; 300 IU of per day) stimulation day 1-5 then followed by Luveris® (vial/powder, 150 IU per day) from stimulation day 1 and until required r hCG level is met. The dose can be adjusted from stimulation day 6 (increased or decreased) based upon the subject's ovarian response and according to the centre's standard practice.
  Intervention: Drug: Lutropin alfa

Inclusion Criteria:

• Be a female subject justifying an In Vitro Fertilization (IVF)/ET treatment
• Be between her 36th and 42nd birthday (both included) at the time of the randomisation visit
• Have early follicular phase (day 2-4) serum level of basal FSH ≤ 12 IU/L measured in the centre's local laboratory during the screening period (i.e. within 2 months prior to down regulation start)
• Have a regular spontaneous ovulatory menstrual cycle between 21 and 35 days in length
• Presence of both ovaries
• Normal uterine cavity, which in the investigator's opinion is compatible with Pregnancy
• Have a negative cervical Papanicolaou (PAP or smear) test within the last 6 months prior to randomisation
• Have at least one wash-out cycle (defined as ≥ 30 days since the last dose of clomiphene citrate or gonadotrophin treatment) since the last ART cycle and/or clomiphene citrate or gonadotrophin treatment prior to starting GnRH agonist therapy
• Be willing and able to comply with the protocol for the duration of the trial
• Have given written informed consent, prior to any trial-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to her future medical care
• Have a male partner with semen analysis within the past 6 months prior to randomisation considered adequate to proceed with regular insemination or ICSI according to the centre's standard practice

Exclusion Criteria:

• Had 2 (or more) previous ART cycles with a poor response to gonadotrophin stimulation defined as 6 (or less) mature follicles and/or 4 (or less) oocytes collected in any previous IVF cycle or previous cycles with a hyper response defined as 25 (or more) oocytes retrieved
• Any medical condition, which in the judgment of the investigator may interfere with the absorption, distribution, metabolism or excretion of the drug. In case of doubt, the subject in question should be discussed with Merck Serono's Medical responsible
• Had previous severe OHSS
• Polycystic ovary syndrome (PCOS; Rotterdam criteria) to reduce the risk of the occurrence of OHSS
• Presence of endometriosis requiring treatment
• Uterine myoma requiring treatment
• Any contraindication to being pregnant and/or carrying a pregnancy to term
• Extra-uterine pregnancy within the last 3 months prior to screening
• History of 3 or more miscarriages (early or late miscarriages) due to any cause
• Tumours of the hypothalamus and pituitary gland
• Ovarian enlargement or cyst of unknown aetiology
• Ovarian, uterine or mammary cancer
• A clinically significant systemic disease
• Known infection with Human Immunodeficiency Virus (HIV), Hepatitis B or C virus in the trial subject or her male partner
• Abnormal gynaecological bleeding of undetermined origin
• Known allergy or hypersensitivity to human gonadotrophin preparations
• Any active substance abuse or history of drug, medication or alcohol abuse in the past 5 years prior to the screening visit
• Entered previously into this trial or simultaneous participation in another clinical trial
• Pregnancy and lactation period
• Participation in another clinical trial within the past 30 days