Recombinant Follicle Stimulating Hormone (FSH) (Gonal-f®): Use in Ovulation Induction

This is an open-label, prospective, randomized, controlled, multicentric, multinational, phase IV study to evaluate the use of Gonal-f in inducing ovulation in female subjects with chronic anovulation. It has been observed that conventional high dose set up regimen of gonadotropin and human chorionic gonadotropin (hCG) is effective in anovulatory subjects in terms of overall pregnancy rates. However, development of multiple follicles leading to multiple pregnancy and/or ovarian hyperstimulation syndrome (OHSS) is the major complications associated with this high dose set up. Chronic low-dose (CLD) protocols of follicle stimulating hormone (FSH), aimed at finding the threshold amount of FSH necessary to promote monofolliculogenesis, have been found to be successful in reducing the rate of OHSS almost to nil and the rate of multiple pregnancies to a minimum. This post-marketing study will investigate tailoring of recombinant follicle stimulating hormone (r-FSH) in a large population (N=310) of subjects from a region (North Africa/Middle East) that has not been included in previous studies of ovulation induction in subjects with chronic anovulation. The study aims to increase current knowledge of the efficacy and safety of Gonal-f, and provide fertility physicians with experience in Gonal-f treatment in anovulatory infertility, thereby contributing to the development of FSH dosing guidelines for ovulation induction by defining the optimal CLD and Low dose (LD) regimens.

Gonal-f is a recombinant form of human FSH (r-hFSH), an endogenous gonadotropin which is being produced in genetically engineered chinese hamster ovary cells and is indicated for induction of ovulation and pregnancy in anovulatory infertile women in whom the cause of infertility is functional and not due to primary ovarian failure. It is also indicated for the development of multiple follicles in ovulatory women participating in an assisted reproductive technology (ART) programme, such as in in vitro fertilization (IVF). The primary cause of infertility in women is an abnormality of ovulation. Most of these anovulatory subjects fall into the World Health Organization (WHO) Group II category, characterized by asynchronous gonadotropin and oestrogen production and normal levels of prolactin (PRL). These subjects present with a variety of menstrual disorders, most commonly polycystic ovarian syndrome (PCOS).

Gonal-f is administered as a course of daily injections, subcutaneously into the anterior abdominal wall. A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 IU, or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate but not excessive response. A single injection of 5,000 IU urinary hCG (u-hCG) (or 250 microgram \[mcg\] r-hCG) should be administered after the last dose of Gonal-f and when the leading follicle has reached 17 mm in diameter. The subject is later recommended to have coitus on the day of, and the day following, hCG administration. The efficacy of Gonal-f in the treatment of WHO Group II anovulatory infertile women has been confirmed by 2 randomized, open-label, multicentric, phase III non-inferiority studies that compared Gonal-f with Metrodin® (urinary FSH) for ovulation induction. The possible serious adverse events (SAEs) associated with Gonal-f include OHSS and its possible complications, multiple pregnancies, pregnancy wastage, ectopic pregnancies and the possible risk of ovarian cancer and reproductive system neoplasms (e.g. endometrial, breast carcinoma).

OBJECTIVES

Primary objective:

* To investigate tailoring of recombinant FSH treatment in subjects with chronic anovulation

Secondary objectives:

* To evaluate commonly used ovulation induction regimens and treatments
* To establish local experience with the Gonal-f pen and investigate ease of use

The study will enroll 310 eligible subjects, randomized in a 1:1 ratio to either Group I or II at the baseline visit prior to the first dose of FSH (pre-stimulation). Each subject will be refrained from the use of gonadotropins or any other ovulation stimulation therapy during the period from screening to the start of stimulation treatment. During the stimulation period, Gonal-f will be administered as a course of once daily (OD) injections, s.c. into the anterior abdominal wall through Gonal-f pen, according to either one of the following 2 step-up, low-dose regimens:

Group I: CLD regimen which recommends a starting dose of 75 IU and a first adjustment on Day 14 of stimulation, if no ovarian response is observed.

Group II: LD regimen which recommends a starting dose of 75 IU and a first adjustment on Day 7 of stimulation, if no ovarian response is observed.

For both groups, when at least 1 follicle reaches 10 to 12 mm in diameter, the Gonal-f administration will be maintained at that dose until the leading follicle reaches 17 mm or more in diameter and no more than 2 follicles have reached 14 mm in diameter. A single injection of hCG (5,000 IU u-hCG or 250 mcg r-hCG) will be administered intramuscularly or subcutaneously after the last Gonal-f injection, to trigger ovulation. Subjects will also be advised to have coitus on the day of, and the day following hCG administration. The total length of the stimulation treatment will not exceed 35 days unless an ultrasound assessment suggests imminent follicular growth and maturation and each subject will undergo one cycle of stimulation treatment only. Subjects will also be followed for a post stimulation period of up to 20 days after the triggering of ovulation by hCG injection, or cancellation of the cycle.

Eligibility Criteria:
Inclusion Criteria:

* Premenopausal female subjects, aged between 18 and 37 years inclusive
* Subjects willing to conceive
* Subjects who are infertile due to chronic anovulation demonstrated by a cycle duration of \> 35 days, or regular cycles with progesterone (P4) levels \< 1 nanomole/milliliter (nmol/mL) during luteal phase (Day 25)
* Subjects who have experienced spontaneous menses, menses induced by clomiphene citrate therapy, or a positive progestin-induced withdrawal within the previous year
* Subjects with FSH and PRL serum values within the normal range in the early follicular phase
* Subjects with total antral follicle count (AFC) \> 10 (of follicle size ≥ 2 mm and \< 11 mm) in both ovaries
* Subjects with at least 1 patent tube, as documented by recent (within 2 years before treatment assignment) hysterosalpingography (HSG)
* Subjects with normal uterine cavity, as documented by recent (within 2 years before treatment assignment) hysteroscopy, HSG or ultrasound scan
* Subjects with body mass index (BMI) \>20 and ≤32 kilogram square per meter (kg/m\^2)
* Subjects with negative cervical Papanicolaou (PAP) test within the 6 months prior to screening
* Male partners of female subjects with sperm compatible with non assisted fertilization
* Subjects who are willing and able to participate in the study and have provided written, informed consent

Exclusion Criteria:

* Subjects with history of hypersensitivity to the active substance follitropin alpha, FSH, or to any of the excipients of Gonal-f
* Subjects with ovarian enlargement or ovarian cyst unrelated to PCOS, and of unknown origin on ultrasound
* Subjects with evidence of diminished ovarian reserve (cycle length \< 26 days; FSH above the upper limit of local serum FSH values, total AFC in both ovaries \< 10)
* Subjects with myomatous uterus, which in the opinion of the investigator could impair pregnancy evolution
* Subjects who have undergone 3 or more previous miscarriages
* Subjects with any previous extrauterine pregnancy
* Pregnant or lactating female subjects
* Subjects with abnormal gynecological bleeding of unknown etiology
* Subjects with previous history of severe OHSS
* Subjects who have undergone operative pelvic surgery which could induce mechanical infertility (e.g tubes blockage) or pelvic inflammatory disease (PID) before treatment assignment excluding curettage and hysteroscopy
* Subjects with tumors of the hypothalamus and pituitary gland
* Subjects with ovarian, uterine or mammary carcinoma
* Subjects treated with clomiphene citrate or gonadotropins within 1 month of the screening evaluation
* Subjects with any medical condition which, in the opinion of the investigator, would prevent an effective response, such as primary ovarian failure, or malformations of the reproductive organs incompatible with pregnancy
* Subjects with any medical condition which, in the opinion of the investigator, may interfere with the absorption, distribution, metabolism or excretion of the drug
* Subjects with any clinically significant systemic disease (e.g. insulin-dependent diabetes) or any contraindication to being pregnant and/or carrying a pregnancy to term; also including subjects with non insulin dependent diabetes mellitus (NIDDM)
* An active substance abuser
* Subjects with known infection with Human Immunodeficiency Virus (HIV), Hepatitis B or C virus in the trial subject or her male partner
* Subjects who have simultaneously participated in another clinical trial