A phase III, randomized, controlled, single-blind, multicentre, parallel arm trial to assess the efficacy and safety of Pergoveris® (follitropin alfa and lutropin alfa) and GONAL-f® (follitropin alfa) for multifollicular development as part of an assisted reproductive technology treatment cycle in poor ovarian responders, as defined by the European Society of Human Reproduction and Embryology criteria

Follicle-stimulating hormone (FSH) is used for the stimulation of
multifollicular development in patients undergoing superovulation for assisted
reproductive technologies (ARTs), such as in vitro fertilization (IVF),
intracytoplasmic sperm injection (ICSI), gamete intra-fallopian transfer, and
zygote intra-fallopian transfer. As noted in the GONAL-f® Summary of Product
Characteristics (SmPC), the standard treatment for multifollicular development
in ART involves the administration of 150-225 international units (IU) of
recombinant human follicle stimulating hormone (follitropin alfa) (r-hFSH)
daily for the first days of treatment. Treatment is continued until adequate
follicular development has been achieved, with the dose being adjusted
according to a patient's response, to usually not higher than 450 IU daily. In
the general non-selected population, adequate follicular development is
achieved, on average, by the tenth day of treatment (range: 5 to 20 days). A
single injection of 250 µg recombinant human chorionic gonadotrophin (r-hCG) or
5,000 IU up to 10,000 IU urinary-human chorionic gonadotrophin (hCG) is
administered 24 to 48 hours after the last GONAL-f® injection to induce final
follicular maturation. Down-regulation with a GnRH agonist or antagonist is
commonly used to suppress the endogenous LH surge and to control tonic levels
of LH.

The primary objective of the trial is to demonstrate superiority of Pergoveris®
versus GONAL-f® in poor
ovarian response (POR) patients defined according to modified criteria set
forth by the European Society of Human Reproduction and Embryology (ESHRE).

This is a phase III, randomized, controlled, single-blind, multicenter,
parallel-arm trial to assess the safety and efficacy of Pergoveris® and
GONAL-f® for multifollicular development as part of an assisted reproductive
technology (ART) treatment cycle in poor ovarian responders, as defined by the
ESHRE criteria.

Following signature of informed consent, the screening period (Visit 1) will be
performed within 6 weeks prior to the start of the trial cycle. Once subject
eligibility is confirmed, the subject will be enrolled in the trial. Pituitary
down-regulation (Visit 2) with a gonadotrophinreleasing hormone (GnRH) agonist
(triptorelin acetate) will be self-administered daily in subjects with
spontaneous menses after ovulation and in anovulatory or oligo-ovulatory
subjects with induced menses. In the case of the former, the GnRH agonist
should start on cycle day 20-21 after confirmed ovulation. In the case of
induced menses, the GnRH agonist will be started on cycle day 3-4 of induced
menses.
Confirmation of down-regulation (Visit 3) will be assessed after at least 14
days of triptorelin acetate treatment (Visit 3a) with a serum E2 level of <= 50
pg/mL. If down-regulation is not confirmed, treatment with triptorelin acetate
is authorized for an additional 7 days (maximum of 21 days of total triptorelin
acetate treatment during this portion of the treatment protocol), and if the E2
is <= 50 pg/mL, down-regulation is confirmed (Visit 3b). If E2 is > 50 pg/mL,
the subject will be excluded from further treatment and the trial. Ovarian
stimulation (Visit 4) will begin within 4 days after down-regulation has been
achieved and will continue for up to 21 days (Visits 5 - 10). Patient response
to ovarian stimulation will be monitored according to the center*s standard
criteria. Triptorelin acetate administration will be continued in subjects with
confirmation of down-regulation until r-hCG administration. A single injection
of 250 µg recombinant human chorionic gonadotrophin (r-hCG) will be
administered to trigger final follicular maturation (Visit 11). Oocyte
retrieval (Visit 12) will be performed vaginally under ultrasound (US)
monitoring approximately 34-38 hours after receiving r-hCG. Oocyte and embryo
quality assessments will be performed according to the criteria provided by the
sponsor. In vitro fertilization or intracytoplasmic sperm injection (ICSI) and
embryo transfer (ET) will be performed according to each subject*s specific
requirements and the center*s standard practice. Embryo transfer (Visit 13)
will be scheduled between 2 to 3 days following oocyte retrieval unless
country-specific regulations dictate other requirements, which will then be
recorded in the patient case report form. The number of embryos transferred
will be dictated by local regulations. No more than 3 embryos will be
transferred.
Luteal phase support will begin 24-48 hours after oocyte retrieval and will
continue in subjects with clinical pregnancy for at least 7 weeks unless
miscarriage occurs. Follow-up of all subjects will occur day 15 to 20 following
r-hCG administration for a serum pregnancy test (biochemical pregnancy) (Visit
14).
Pregnancy outcome will be determined for all subjects with a positive serum
pregnancy test. All subjects with a positive pregnancy test and who do not
experience an early miscarriage will undergo vaginal US examination between 35
and 42 days post r-hCG administration to assess the number of fetal sacs with
or without fetal heart activity (clinical pregnancy determination, Visit 15).
Ten weeks after ET, ongoing pregnancy (at least 1 viable fetus with positive
heart activity, Visit 16) will be assessed via vaginal US examination in all
subjects who do not experience a miscarriage after confirmation of a clinical
pregnancy. The outcome of ongoing pregnancy will be determined approximately 6
months later (live birth determination, follow-up Visit 17). This pregnancy
outcome/delivery data will be collected and recorded after the completion of
the trial. A separate, all-inclusive addendum report of the pregnancy outcome
delivery data will be a supplemental report to the Pergoveris® in POR ART Trial
Report. Adverse events and ovarian hyper stimulation syndrome (OHSS)-related
symptoms will be assessed throughout the trial to monitor safety. Safety will
also be evaluated through physical examination, vital signs, urinalysis, and
hematology and clinical chemistry assessments. Local tolerability, as assessed
through injection site reactions included in the label, will be documented.

The investigational medicinal product is Pergoveris®.
Pergoveris® will be self-administered daily subcutaneously (SC) by the subject.
The reference therapy is GONAL-f®. GONAL-f® will be self-administered daily SC
by the
subject.

The majority of ART patients benefit from FSH-only ovarian stimulation.
However, some patients exhibit POR to FSH, which manifests as reduced
follicular response, resulting in a reduced number of retrieved oocytes and a
decreased likelihood of obtaining multiple embryos for transfer. Poor ovarian
responders may undergo multiple unsuccessful ART treatment cycles due to
inadequate follicular response, repeated cycle cancellation, or lack of
pregnancy.

The trial concept reflects current clinical practice, which has been verified
during the feasibility assessment phase for this trial. Furthermore, reports in
the literature have documented the existence of a group of patients in whom
treatment with exogenous r-hFSH alone at starting doses of 225 IU and higher
and with appropriate dose increases according to the patient*s response result
in development and retrieval of few oocytes, resulting in low number of embryos
available for transfer. Such patients can be characterized by having a previous
cycle with limited pre-ovulatory follicles or oocytes; and/or having an
abnormal Ovarian reserve test; and/or being of advanced maternal age or
according to the ESHRE criteria for POR. The conventional approach of
increasing FSH dose to improve follicular response appears to be ineffective in
these patients. Supplementation with LH (or LH activity-containing
formulations, such as human menopausal gonadotropins) has been widely used and
reported in the literature as beneficial due to the pharmacological action of
LH.