Clinical trial NCT01081626
Conditions: Ovulation Induction
Keywords: Infertility Ovulation induction Gonal-f Follitropin alpha Polycystic ovarian syndrome Anovulatory infertility
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2009-03-01; Completion date: 2011-03-01
Enrollment: 310 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: Gonal-f will be injected on the second or third day of a spontaneous or progestogen-induced menstrual cycle (Day 0), with a daily dose of 75 International Units (IU) for 7 days. Ovarian response will be assessed on Day 7 of stimulation by ultrasound scan. If no follicle has reached at least 10 to 12 millimeter (mm) diameter, stimulation will be continued with the same dose for further 7 days. On Day 14 of stimulation, if no ovarian response is seen, the dose will be increased by 37.5 IU (total 112.5 IU) and administered for the next 7 days. Subsequent increments of 37.5 IU, at intervals of 7 days up to Day 35 of stimulation would be made, depending on ovarian response. arm 2: Gonal-f will be administered on the second or third day of a spontaneous or progestogen-induced menstrual cycle (Day 0), with a daily dose of 75 IU for 7 days. Ovarian response will be assessed on Day 7 of stimulation by ultrasound scan. If no follicle has reached at least 10 to 12 mm diameter, the dose will be increased by 37.5 IU (total 112.5 IU) and administered for the next 7 days. Subsequent increments of 37.5 IU, at intervals of 7 days up to Day 35 of stimulation will be made, depending on ovarian response.
Interventions: intervention 1: Recombinant FSH (follitropin alpha)
Intervention descriptions: intervention 1: A starting dose of 75 IU and a first adjustment on Day 14 or Day 7 of stimulation in Group I and II respectively, if no ovarian response is observed.

Protocol documents: