A phase IV prospective, multicentre, randomized, open-label trial to assess the efficacy and safety of GONAL f® at a dose based on subject baseline characteristics determined according to the CONSORT calculator compared with a standard dose of GONAL f® 150 IU per day for ovarian stimulation in women undergoing assisted reproductive technology (ART)

There have been a number of publications in which doctors have identified
numerous variables, which are associated with the ovarian response in a
stimulation cycle. To further address these associations, the Sponsor (Merck
Serono International S.A.) has carried out an analysis of over 2000 ART
treatment cycles available from studies carried out over a number of years. The
combination of information from the publications and the analysis has revealed
that the following 4 variables were highly associated with a patient*s ovarian
response: Age, Body Mass Index, Number of small follicles, Serum Follicle
Stimulating Hormone (FSH) level. These factors are then entered into a
calculator, which provides a GONAL f® starting dose.

The purpose of this trial is to compare the ovarian response in assisted
reproductive technology (ART) subjects administered a GONAL-f® dose determined
according to a calculator system versus a given standard GONAL-f® dose of 150
International Unit (IU) per day. The aim of this calculator, which is based on
individual subject characteristics, is to help reduce an inappropriate response
of the ovaries, thus resulting in improved stimulation treatment efficiency and
safety

Patients who agree to take part in this trial, will be treated for one single
stimulation cycle with GONAL f® Prefilled Pen. They will be asked to visit the
centre approximately 9 times and your participation will last for a total
duration of up to 20 weeks. All investments are standard practice for IVF
treatments. The additional tests on behave of this study are added as follow.
Once down-regulation has been confirmed, a pregnancy test will be performed
within 7 days prior to GONAL f® treatment start 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 via the electronic case report form
(eCRF. .Follicular development will be monitored according to the centre*s
standard practice by US and/or E2 levels, until the protocol r hCG requirement
is met (i.e., at least 1 follicle ³ 18 mm and 2 follicles ³ 16 mm) at which
time the subject will receive a single injection of 250 mcg of r hCG (Ovidrel®/
Ovitrelle®), 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 2-5
days after oocyte recovery. Ovum Pick Up (OPU), in vitro fertilisation (IVF),
ET and luteal support will be performed as per centre*s standard practice. A
post-treatment safety visit will be performed for all subjects who received r
hCG (pregnant and non-pregnant) on post-hCG Day 15-20. For subjects who have
withdrawn from treatment (i.e. after starting GONAL f® but before hCG is given)
this visit (excluding pregnancy testing) will take place 20-30 days after their
first GONAL-f® treatment injection. At the end of the study cycle, between days
15 and 20 after the Ovidrel®/Ovitrelle® injection, you will have to visit the
hospital/clinic for a serum pregnancy test (approximately 1.5 ml of blood will
be taken).This is not routine and is in addition for this study. The subject
will be given a diary card to keep a record of your injection dates and doses.
You will report in the diary card any adverse event (i.e. any sign or symptom)
you might experience and all medications, including self-prescribed medications
that you are taking. This card is not routine and is added for this study. The
subject can participate optional with the PGX study( pahrmacogenetica), for
this one blood sample of 6 ml will be taken at screening visit.

The investigational medicinal product is GONAL f® Prefilled Pen and will be
self administered subcutaneously (s.c.) by the subject. The GONAL f® Prefilled
Pen will be provided in dose presentations of 450 IU and 900 IU. The Prefilled
Pen allows the accurate delivery of a precise dose of GONAL f® in 37.5 IU
incrementsPending on the randomisation the patient will recieve: 1-to the
CONSORT calculator arm (with doses of GONAL f® starting at minimum of 112.5 IU
per day and a maximum of 450 IU per day). The allocated dose must be kept fixed
throughout the stimulation cycle unless if, in the investigator*s judgement,
the subject is at risk of OHSS, in which case the allocated dose may be
decreased according to the centre*s standard practice. or-2- to the GONAL f®
standard treatment arm (150 IU of GONAL f® per day) up to day 5 of stimulation
(S5) after which the dose can be adjusted (increased or decreased) based upon
the subject*s ovarian response and according to the centre*s standard practice.

Blood sampling is a standard procedure. It is safe and unlikely to cause you
any problems although on occasion it can cause slight local discomfort. There
is a slight risk of local pain, bruising, swelling or phlebitis (inflammation
of the vein). Some patients may also experience light-headedness, dizziness and
rarely fainting, and so you may choose to lay down for your blood draw. Very
rarely, a local infection may develop. Transvaginal ultrasonography. This
procedure is standard in all IVF treatments. This procedure is usually
painless.Like all medicines, GONAL-f® can cause side effects. During clinical
development, the most commonly reported adverse events in association with
GONAL f® were ovarian cysts, headaches and mild to severe injection site
reactions (pain, redness, bruising, swelling, irritation at the injection
site). A condition called ovarian hyperstimulation syndrome (OHSS) associated
with various signs/symptoms such as abdominal pain, vomiting and diarrhea may
also occur following treatment with GONAL-f®. Severe OHSS and its complications
appear uncommon. Very rare cases of mild systemic allergic reactions to
GONAL-f®, causing redness of the skin, rash, facial swelling have been
reported. These reactions can sometimes be serious and manifest by one or more
of the following signs/symptoms: hives, diffuse redness of the skin and edema,
facial swelling and difficulty in breathing. Ectopic pregnancy (embryo
implanted outside the womb) may occur especially in women with history of prior
tubal disease. Like all medicines, Ovidrel®/Ovitrelle® can cause side effects.
The majority of the side effects seen to date have been mild to moderate. The
most frequent side effects reported have been tiredness, pain, local reaction
at the site of injection and headache. Other less common side effects include:
very rare systemic allergic reactions (redness of the skin, rash, facial
swelling), usually mild but which may be serious and OHSS and its
complications. Severe OHSS and its complications appear uncommon. Sometimes
treatments for stimulation therapy with hFSH containing preparations for
stimulation of ovulation induction lead to the growth of many follicles, which
may be associated with the risk of enlargement of the ovaries. This is called
Ovarian Hyperstimulation Syndrome (OHSS). In severe cases, this syndrome is
associated with pelvic pain, nausea, vomiting, weight gain, abdominal
distension, difficulty breathing and accumulation of fluid in the abdomen or
lungs. Extremely rare complications associated with OHSS include bleeding into
the abdomen (haemoperitoneum) due to rupture of an ovarian cyst, and a risk of
the formation of blood clots (thrombosis) which potentially could be dislodged
from the involved vein or artery and cause damage to vital organs such as the
lungs, heart or brain. In a clinical trial like this one, every risk or side
effect cannot be predicted. Each person's reaction to a test, drug or procedure
may be different. There is maybe a side effect or be at risk for symptoms,
illnesses and/or complications that could not be predicted by the study doctor
or by the Sponsor of the trial.