Recombinant Follicle Stimulating Hormone (FSH) (Gonal-f®): Use in Ovulation Induction
Condition: Ovulation Induction
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Recombinant FSH (follitropin alpha)
Intervention type(s): Drug
Intervention description(s): 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.
Other intervention name(s): Gonal-f®; Follitropin alpha
Intervention MeSH terms: Follicle Stimulating Hormone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Infertility; Ovulation induction; Gonal-f; Follitropin alpha; Polycystic ovarian syndrome; Anovulatory infertility